Subglottic stenosis (SGS) management has changed dramatically in the last decade. An improved understanding of SGS’ underlying mechanism is spawning new research into how to control the inflammatory process at the core of the disease.
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August 2020“The goal of treatment has shifted over time to include a more personalized plan of care based on early recognition of at-risk populations and the understanding of the divergent pathophysiology affecting the unique patient subgroups,” said Alexander Gelbard, MD, associate professor of otolaryngology–head and neck surgery and co-director of the Complex Airway Reconstruction Program at The Vanderbilt Bill Wilkerson Center for Otolaryngology and Communication Sciences in Nashville.
Understanding Idiopathic SGS
Over the last 10 years, researchers and clinicians have increasingly appreciated three distinct categories of SGS: SGS from iatrogenic injury, autoimmune stenosis, and idiopathic subglottic stenosis. All three arise from luminal narrowing at the level of the subglottis. Fibrotic remodeling of this region in the airway manifests as fixed extrathoracic restriction of pulmonary ventilation, which patients experience as symptomatic dyspnea. Although most airway stenosis appears similar on anatomic imaging and clinical examination, different mechanisms of injury are associated with differing rates of long-term tracheostomy dependence.
Iatrogenic injury from long-term endotracheal intubation is the most common cause of SGS (70% of cases), followed by autoimmune stenosis associated with collagen vascular disease (15%), such as granulomatosis with polyangiitis, formerly known as Wegener’s granulomatosis. Idiopathic subglottic stenosis (iSGS), however, develops without a known antecedent injury and is the least common variant (15%) (Laryngoscope 2015;125:1137-1143).
Idiopathic SGS is a recurrent fibroinflammatory disease that leads to upper airway obstruction and severe shortness of breath. “Unlike many disorders, iSGS has a pretty homogenously affected patient population,” Dr. Gelbard said. Patients who develop iSGS, he noted, are almost exclusively healthy women (98%), nearly all adults (age 40 to 50), and white. “Traditionally, because of high recurrence rates, more than half of the patients with iSGS required repeat surgical procedures within 12 months of their initial diagnosis,” he added.
Surgical iSGS Management
Surgical iSGS management includes two different types of endoscopic procedures: dilation with or without cuts or laser, and resection with lasers and medical therapies. “Endoscopic iSGS treatment generally includes lysis of scar tissue, judicious excision of scar, balloon dilation, serial dilation, or a combination of these techniques,” noted Michael Johns, MD, director of the University of Southern California Voice Center and clinical professor of otolaryngology–head and neck surgery at the Keck School of Medicine of USC in Los Angeles.
We need to treat SGS more like an inflammatory disease rather than a clogged pipe. —Michael Johns III, MD
Open surgery is associated with more significant risks than endoscopic procedures, including the potential for significant postoperative voice changes. The benefit of open surgery is the potential for durable long-term cure, which enables patients to avoid repeat procedures every one to three years.
In the largest prospective comparative study to date, the investigators of the North American Airway Collaborative examined 1,056 iSGS patients across 40 participating institutions. The aim of the study was to measure days from initial surgical procedure to recurrent surgical procedure and evaluate quality of life issues, including vocal changes and postoperative complications (JAMA Otolaryngol Head Neck Surg. Published online Oct. 31, 2019).
Of the 810 patients who were evaluated, 75% underwent endoscopic dilation, 15% had endoscopic resection with medical therapy (ERMT), and 10% underwent open resection. The findings of the study mirrored clinical experience: Endoscopic dilation, the least invasive technique, was associated with a higher recurrence rate compared with the other procedures. Specifically, 169 of 603 patients who underwent endoscopic dilation (28%) required recurrent surgery during the three-year study compared with only one of 86 patients undergoing open surgery (1.2%) and 15 of 121 patients (12.4%) in the ERMT group.
One interesting result was ERMT’s efficacy, Dr. Gelbard noted. ERMT offered significantly improved disease control compared with endoscopic dilation, with minimal impact on phonatory function, particularly when compared with open resection. Whether ERMT’s reduced disease recurrence rate was associated with surgical technique, postoperative medications, or a combination remains unclear and is an active area of research.
Another surprising finding of the study has been the patient’s perception of their outcome after surgery, Dr. Gelbard noted. Although cricotracheal resection had the highest perioperative risk and the greatest impact on postoperative voice outcomes, the patients who underwent this surgery rated their global quality of life as the highest among the treatment options at 360 days.
“Seeing how well people did with an open resection was interesting,” Dr. Gelbard said. “Prior to the study, there had been a bias among some surgeons that the open resection technique was more invasive and the endoscopic approach more appropriate to preserve voicing. Patients’ experience offers a wrinkle to this bias. It appears that some patients with iSGS … are willing to trade some loss of voice function for a life without worrying about breathing and undergoing recurrent surgeries.”
One of the biggest challenges now is tailoring the treatment options to patient preferences. When meeting with a patient, Dr. Gelbard spends most of the consultation reviewing the risks and benefits of each of the iSGS treatment options available. “I believe providing all the information up front about what their treatment options are, and how those different approaches will impact their life, helps patients feel more in control of their disease, and allows them to select a treatment approach that matches their priorities.”
Identifying the Inflammatory Process
Dr. Gelbard first encountered SGS during his residency, which ended in 2013. Over the course of his career, “it became clear that we knew little about the basic biology of airway stenosis. Beyond knowledge gaps in pathophysiology, we lacked a complete understanding of the natural history of the disorder,” he said.
Building on well-phenotyped natural history data obtained from the recent prospective iSGS study, a number of researchers have been investigating iSGS scar tissue, including Alexander Hillel, MD, associate professor of otolaryngology–head and neck surgery at Johns Hopkins Medicine in Baltimore. “When you study the scar tissue, you find a lot of infiltrating immune cells within that scar,” he said. Subsequent work has demonstrated an increased adaptive immune response consisting of antigen-presenting dendritic cells as well as CD4 and CD8 T lymphocytes. It also appears that interleukin (IL)-17A is abundant in the mucosa of iSGS patients and “appears to drive fibroblast proliferation, but we don’t know if there’s a common mechanism in the immune cells and in the fibroblasts. What are the principal cell types that lead to unregulated fibrosis? If we could target the abnormal immune cells as well as the abnormal metabolism of the fibroblast, then we might be able to shut off the dysfunctional system,” Dr. Hillel said.
Powerful new techniques, including single-cell RNA sequencing (scRNA-seq), are proving essential to identifying the individual cell types within the scar tissue. “This technique is so useful because it provides a high-resolution atlas of the cellular constituents of airway scarring, as well as transcriptional data that can be used to understand the cells’ function,” reported Dr. Gelbard. “Additionally, scRNA-seq provides information on the T-cell receptor sequence of the infiltrating immune cells, which can be used to work backward to understand the target of the observed host immune response. Together, this knowledge is beginning to provide insight into what started this disease and offer new routes to treat it.”
Robert J Morrison, MD, assistant professor in the department of otolaryngology–head and neck surgery at Michigan Medicine in Ann Arbor, also studied fibroblast behavior in the scar tissue of patients with iSGS while working with Dr. Gelbard. “Experimental treatment of the scar tissue with IL-17A inhibitors seems to block the fibroblast proliferation and activation seen in the scar tissue,” he said. “There is research interested in looking at these IL-17 inhibition agents, including what’s the best way to deliver them—intravenously, through intralesional injection, or topically,” Dr. Morrison said. “Our hope is that in five to 10 years, iSGS will be a medically treated disease, rather than a surgical one.”
Advances in Therapy
Researchers have uncovered some novel therapies for SGS.
Intralesional Steroid Injections. A drawback of endoscopic SGS treatment has been stenosis recurrence following surgery, necessitating repeated procedures. As knowledge of the underlying proinflammatory/profibrotic mechanisms of the disease has grown, surgeons have begun to use adjuvant treatments to tamp down the wound-healing response and reduce scarring, Dr. Johns noted. These strategies have included the use of systemic antibiotics; topical and intralesional antineoplastic compounds, such as mitomycin C or fluorouracil; and systemic, inhaled, or intralesional corticosteroids, with mixed results.
“Otolaryngologists have borrowed many of these ideas from dermatology. Dermatologists have been injecting the scars of patients susceptible to keloid development with steroids following excision, which can help reduce the inflammatory response and the severity of keloid recurrence,” Dr. Johns said.
There’s something about the skin graft that seems to turn off the fibroblast process. It may be the mechanical pressure of the graft on the fibroblasts, or the extracellular matrix molecules that are within the superficial layer of dermis, that signal the scar to stop progressing in SGS patients. —Alexander Hillel, MD
A recent study by Bertelsen and colleagues evaluated the effectiveness of serial in-office intralesional steroid injections (ISI) after endoscopic dilation (JAMA Otolaryngol Head Neck Surg 2018;144:203-210). A series of 24 patients with varying causes of stenosis were treated with inhaled corticosteroids for one month and oral trimethoprim/sulfamethoxazole for two to four weeks after endoscopic dilation. During the ISI procedure, which included a series of three to six injections spaced three to six weeks apart, 1 to 2 mL of triamcinolone 40 mg/mL was injected into multiple locations in the region of stenosis. After a mean follow-up of 32 months, 17 patients did not require further surgery after ISI.
“Our goal is to extend the interval between surgeries by focusing our treatment on the underlying inflammatory response that’s causing the stenosis re-formation,” Dr. Johns said. “We need to treat SGS more like an inflammatory disease rather than a clogged pipe.”
ISI also has been used to delay surgery in newly diagnosed iSGS patients. “In my practice, ISI has probably been the most transformative advance for my patients,” Dr. Morrison said. “I have a number of patients who have avoided surgery with steroid injections in the office or, at the very least, have significantly reduced the frequency of surgery.”
Split Thickness Skin Grafts. “One problem with current endoscopic SGS treatment is the inability to truly cut the scar out—that requires an open procedure,” Dr. Hillel noted. Two new minimally invasive surgical approaches focus on selective endoscopic removal of affected mucosa, with epithelial reconstitution with dermal or buccal grafts (JAMA Otolaryngol Head Neck Surg 2017;143:609–613;).
Guri Sandhu, MBBS, MD, a consultant otolaryngologist at the Imperial College in London, developed the Maddern procedure to endoscopically resect SGS. The procedure involves resecting the mucosa and scar of the subglottis and replacing it with a split thickness skin graft to re-line the affected area. The graft is held in place with a stent that’s removed approximately 14 days after the endoscopic procedure. With this approach, the diseased mucosa is removed while avoiding alteration of the cartilage framework.
At the same time that Dr. Sandhu was developing the Maddern procedure, Robert Lorenz, MD, a surgeon in the Head and Neck Institute at the Cleveland Clinic, was working on his own technique, which he termed the retrograde endoscopically assisted cricoid hypertrophic epithelial resection (REACHER) procedure. In a technique otherwise similar to the Maddern procedure, the surgeon instead approaches the scar tissue from below, retrograde, through a temporary tracheal opening. After consultation with Dr. Sandhu in which the feasibility of the transoral approach was validated, Dr. Lorenz abandoned the REACHER procedure in 2015 and began performing a modified Maddern procedure in 2016.
To date, Dr. Lorenz has performed the procedure on 28 patients [in press], of which the last eight surgeries have been performed using buccal mucosa to re-line the trachea. This has eliminated one of the side effects of using thigh tissue. “Thigh skin includes keratin, which subsequently collects in the airway, causing coughing and irritation,” he said. “The use of the buccal mucosa appears to eliminate this problem, thus avoiding the need to resurface the skin graft in later endoscopic laser procedures.”
Dr. Lorenz has trained residents, fellows, and observers in the procedure over the past five years and has focused his upcoming publication on “shortening the learning curve,” especially with the use of the more challenging buccal graft. The greatest benefit of the Maddern procedure over open surgery is eliminating removal of the anterior cricoid cartilage and attached cricothyroid muscle, which causes a drop in fundamental frequency by 10 Hz and decreases inflection in speech, both of which are especially detrimental in this mostly female cohort of patients.
According to Dr. Hillel, Dr. Sandhu’s advancement was placing the skin graft endoscopically. “There’s something about the skin graft that seems to turn off the fibroblast process,” he said, although it isn’t entirely clear how that occurs. “It may be the mechanical pressure of the graft on the fibroblasts, or the extracellular matrix molecules that are within the superficial layer of dermis, that signal the scar to stop progressing in SGS patients.”
“This technique is considerably less invasive than an open resection but will still lead to a permanent and long-lasting improvement in the patient’s airway,” Dr. Lorenz said.
Dr. Morrison agreed. “I think these procedures are providing a more aggressive treatment for our patients, with less morbidity than an open procedure.”
Drug-Eluting Stents. Some of the advancements in surgical approaches to the treatment of iSGS have also targeted the underlying inflammatory process that creates the scar tissue. Dr. Hillel and colleagues have developed a drug-eluting stent that can be placed at the surgical site after the scar is removed to inhibit fibroblast proliferation and collagen production.
In a study led by Dr. Hillel, two biodegradable, drug-eluting stents containing 1.0% rapamycin, which is FDA approved for use in cardiac stents for coronary artery disease, were compared in situ in a mouse model (Biomater Sci. 2019;23:7:1863-1874;). The researchers found that the PLLA-PCL (70% poly-L-lactide and 30% polycarprolactone blend) stent exhibited greater mechanical strength and showed more reliable rapamycin release than the PDLGA (poly-DL-lactide-co-glycolide) stent. The rapamycin stents decreased collagen 1 and fibroblast cell proliferation in vitro and reduced laminar propria thickness in vivo. The potential benefit of the stent was that it could be used in combination with any endoscopic procedures or split-thickness skin grafts, Dr. Hillel noted. “A drug-eluting stent that’s placed for two weeks following resection of a scar might be an option in idiopathic and other types of SGS,” he said.
Nikki Kean is a freelance medical writer based in New Jersey.
Integrating Crowdsourcing into Research: NoAAC
Investigators have realized that the study of rare disease is inherently limited by the restricted number of patients seen at any individual center. To recruit patients for a large prospective study comparing surgical approaches, Alexander Gelbard, MD, associate professor and co-director of the Complex Airway Reconstruction Program at The Vanderbilt Bill Wilkerson Center for Otolaryngology and Communication Sciences in Nashville and colleagues created a network of airway surgeons (the North American Airway Collaborative: NoAAC) drawn from 30 national and international institutions.
“Patients with iSGS are well educated and have formed online communities to share information about treatments and living with a chronic disease,” Dr. Gelbard said. Through the Living with Idiopathic Subglottic Stenosis Facebook page, developed by Catherine Andersen, a patient from Australia, NoAAC was able to recruit more than 1,000 patients in 16 months for the first prospective study comparing surgical techniques. “One surgeon alone would never have been able to recruit that many patients for a prospective study, so it was a great example of engaging with an online health community to rapidly recruit patients and improve our understanding of a rare disease,” he said.