James J. Daniero

Disease homogeneity and treatment heterogeneity in idiopathic subglottic stenosis

Idiopathic subglottic stenosis (iSGS) is a rare and potentially life‐threatening disease marked by recurrent and progressive airway obstruction frequently requiring repeated surgery to stabilize the airway. Unknown etiology and low disease prevalence have limited the ability to characterize the natural history of iSGS and resulted in variability in surgical management. It is uncertain how this variation relates to clinical outcomes.

Idiopathic subglottic stenosis is associated with activation of the inflammatory IL-17A/IL-23 axis.

Rationale Idiopathic subglottic stenosis (iSGS) is a rare and devastating extrathoracic obstruction involving the lower laryngeal and upper tracheal airway. It arises without known antecedent injury or associated disease process. Persistent mucosal inflammation and a localized fibrotic response are hallmarks of the disease. Despite the initial clinical description of iSGS more than 40 year ago, there have been no substantive investigations into the pathogenesis of this enigmatic and progressive airway obstruction.Idiopathic subglottic stenosis (iSGS) is a rare and devastating extrathoracic obstruction involving the lower laryngeal and upper tracheal airway. It arises without known antecedent injury or associated disease process. Persistent mucosal inflammation and a localized fibrotic response are hallmarks of the disease. Despite the initial clinical description of iSGS more than 40 year ago, there have been no substantive investigations into the pathogenesis of this enigmatic and progressive airway obstruction. In these studies, we present the initial characterization of the molecular pathogenesis underlying the fibrosing phenotype of iSGS.

Molecular analysis of idiopathic subglottic stenosis for Mycobacterium species.

Idiopathic subglottic stenosis (iSGS) is an unexplained obstruction involving the lower laryngeal and upper tracheal airway. Persistent mucosal inflammation is a hallmark of the disease. Epithelial microbiota dysbiosis is found in other chronic inflammatory mucosal diseases; however, the relationship between tracheal microbiota composition and iSGS is unknown.

Voice-Related Patient-Reported Outcome Measures: A Systematic Review of Instrument Development and Validation.

Purpose The purpose of this study was to perform a comprehensive systematic review of the literature on voice-related patient-reported outcome (PRO) measures in adults and to evaluate each instrument for the presence of important measurement properties. Method MEDLINE, the Cumulative Index of Nursing and Allied Health Literature, and the Health and Psychosocial Instrument databases were searched using relevant vocabulary terms and key terms related to PRO measures and voice. Inclusion and exclusion criteria were developed in consultation with an expert panel. Three independent investigators assessed study methodology using criteria developed a priori. Measurement properties were examined and entered into evidence tables. Results A total of 3,744 studies assessing voice-related constructs were identified. This list was narrowed to 32 PRO measures on the basis of predetermined inclusion and exclusion criteria. Questionnaire measurement properties varied widely. Important thematic deficiencies were apparent: (a) lack of patient involvement in the item development process, (b) lack of robust construct validity, and (c) lack of clear interpretability and scaling. Conclusions PRO measures are a principal means of evaluating treatment effectiveness in voice-related conditions. Despite their prominence, available PRO measures have disparate methodological rigor. Care must be taken to understand the psychometric and measurement properties and the applicability of PRO measures before advocating for their use in clinical or research applications.

Novel application of the Sonopet for endoscopic posterior split and cartilage graft laryngoplasty

INTRODUCTION Posterior glottic stenosis (PGS) presents a challenge to the airway surgeon. A variety of techniques, ranging from endoscopic laser arytenoidectomy and partial cordotomy to open laryngotracheoplasty with anterior and posterior costal cartilage grafting, have been described with variable results in addressing this problem in adults. Endoscopic posterior cricoid split and rib graft (EPCS/RG) was first described in 2003 by Inglis et al. in 10 pediatric patients with PGS and subglottic stenosis as an alternative to open procedures. Adult patients present additional challenges to the airway surgeon. Increased incidence of cervical spine disease can make adequate exposure difficult in adult patients, and increased rates of ossification in the adult airway cartilages and mature scar tissue can make endoscopically splitting the cricoid difficult. The authors present a series of adult patients with PGS and tracheotomy dependence who were managed with EPCS/RG, although one patient was unable to complete the operation in a fully endoscopic fashion due to cricoid ossification. Challenges in intraoperative management will be discussed in presenting EPCS/RG as a feasible option for select adult patients. We herein present an algorithm that posits an ultrasonic aspirator as a solution to the problem of splitting an ossified cricoid seen more commonly in this population. MATERIALS AND METHODS

Treatment options in idiopathic subglottic stenosis: protocol for a prospective international multicentre pragmatic trial

Introduction Idiopathic subglottic stenosis (iSGS) is an unexplained progressive obstruction of the upper airway that occurs almost exclusively in adult, Caucasian women. The disease is characterised by mucosal inflammation and localised fibrosis resulting in life-threatening blockage of the upper airway. Because of high recurrence rates, patients with iSGS will frequently require multiple procedures following their initial diagnosis. Both the disease and its therapies profoundly affect patients’ ability to breathe, communicate and swallow. A variety of treatments have been advanced to manage this condition. However, comparative data on effectiveness and side effects of the unique approaches have never been systematically evaluated. This study will create an international, multi-institutional prospective cohort of patients with iSGS. It will compare three surgical approaches to determine how well the most commonly used treatments in iSGS ‘work’ and what quality of life (QOL) trade-offs are associated with each approach. Methods and analysis A prospective pragmatic trial comparing the ‘Standard of Care’ for iSGS at multiple international institutions. Patients with a diagnosis of iSGS without clinical or laboratory evidence of vasculitis or a history of endotracheal intubation 2 years prior to symptom onset will be included in the study. Prospective evaluation of disease recurrence requiring operative intervention, validated patient-reported outcome (PRO) measures as well as patient-generated health data (mobile peak flow recordings and daily steps taken) will be longitudinally tracked for 36 months. The primary endpoint is treatment effectiveness defined as time to recurrent operative procedure. Secondary endpoints relate to treatment side effects and include PRO measures in voice, swallowing, breathing and global QOL as well as patient-generated health data. Ethics and dissemination This protocol was approved by the local IRB Committee of the Vanderbilt University Medical Center in July 2015. The findings of the trial will be disseminated through peer-reviewed journals, national and international conference presentations and directly to patient with iSGS via social media-based support groups. Trial registration number NCT02481817.

Recovery of Vocal Fold Epithelium after Acute Phonotrauma

We investigated the timeline of tissue repair of vocal fold epithelium after acute vibration exposure using an in vivo rabbit model. Sixty-five New Zealand white breeder rabbits were randomized to 120 min of modal- or raised-intensity phonation. After the larynges were harvested at 0, 4, 8, and 24 h, and at 3 and 7 days, the vocal fold tissue was evaluated using electron microscopy and quantitative real-time polymerase chain reaction. There was an immediate decrease in the microprojection depth and height following raised-intensity phonation, paired with upregulation of cyclooxygenase-2. This initial 24-h period was also characterized by the significant downregulation of junction proteins. Interleukin 1β and transforming growth factor β1 were upregulated for 3 and 7 days, respectively, followed by an increase in epithelial cell surface depth at 3 and 7 days. These data appear to demonstrate a shift from inflammatory response to the initiation of a restorative process in the vocal fold epithelium between 24 h and 3 days. Despite the initial damage from raised-intensity phonation, the vocal fold epithelium demonstrates a remarkable capacity for the expeditious recovery of structural changes from transient episodes of acute phonotrauma. While structurally intact, the return of functional barrier integrity may be delayed by repeated episodes of phonotrauma and may also play an important role in the pathophysiology of vocal fold lesions.

Inaugural symposium on advanced surgical techniques in adult airway reconstruction: Proceedings of the North American Airway Collaborative (NoAAC)

T he North American Airway Collaborative (NoAAC) network is an international voluntary consortium founded in 2014 to advance the science and treatment of adult airway disorders. The collaborative is composed of clinicians and study personnel at more than 50 centers of excellence in adult airway disorders, as well as involved patient partners. The NoAAC aims to continuously improve the quality, safety, effectiveness, and cost of medical interventions in adult airway disorders through support of translation science and the establishment of best practices for diagnosis, evaluation, and treatment. In support of these goals, NoAAC hosted the inaugural Symposium on Advanced Surgical Techniques in Adult Airway Reconstruction at The Johns Hopkins Hospital in Baltimore, Maryland, on February 22, 2016. The symposium brought together airway experts with diverse skill sets to share ideas and the nuances of their respective approaches to advance the field of adult airway reconstruction. Participants from the United States and the United Kingdom spanned a broad range of disciplines, including plastic surgery, pediatric otolaryngology, laryngology, head and neck surgery, and rheumatology. The result was an interactive educational forum that disseminated diverse practices across disciplines and geography; a landmark event in the intellectual diaspora of adult airway reconstruction. This article presents this experience to the larger scientific community.

Expanding Perspectives in Airway Stenosis

As surgeons, we take pride in our craft and, therefore, are biased toward our preferred techniques. Similarly, our clinical research is often guided by this motivation, steering us to share the outcomes of our favored techniques. This natural bias is evident in the literature. For example, at the time of publication, a PubMed search “Laryngostenosis/surgery[Mesh]” (which includes subglottic stenosis) revealed 1294 articles on surgical approaches to upper airway stenosis. In contrast, the search “Laryngostenosis/ drug therapy[Mesh]” (which includes use of mitomycin and other adjuvant therapies) resulted in only 80 articles. The article by Feinstein et al1 in this issue of JAMA Otolaryngology–Head & Neck Surgery joins several others to reinforce the concept that perhaps it is not the surgical finesse or latest technology used in endoscopic procedures to modify the structural airway anatomy that matters, but rather how we can manipulate the immunologic response and wound healing process afterward.2-4 However, this is in contrast to more technically difficult open airway reconstruction, clearly demonstrating improved outcomes and higher “cure rate” in high-volume centers.2 The airway narrowing of subglottic stenosis can be managed by a variety of techniques, including rigid bronchoscopy, carbon dioxide laser, balloon dilation, cryotherapy, cold excision, microdebrider, open laryngotracheoplasty, and finally open cricotracheal resection. As the authors point out in the discussion of this article,1 recent interest has been generated regarding adjuvant modulation of fibrosis with study of agents such as fluorouracil, tacrolimus, and sirolimus. Based on this and other studies, there does appear to be some beneficial effect of mitomycin treatment.5,6 However, the tissue concentration and kinetics of topical drug delivery remains unknown. Furthermore, there are risks of using mitomycin, even at a standard concentration of 0.4 mg/mL. In patients without an alternate airway, such as a tracheotomy, there is a small but real risk of airway obstruction and death.7 Mitomycin treatment appears to increase surgical intervals by a mean of 5 months in this heterogeneous population, with mean intervals increased from 11 to 16 months. While this is certainly a better outcome demonstrating statistical significance, the clinical significance to the patient may not be as tangible. There is room for study of the optimal adjuvant use of mitomycin maximizing the therapeutic effect based on pharmacokinetics. In contrast to this study, another recent study showed a benefit of intralesional steroid injection in patients with idiopathic subglottic stenosis, suggesting that there may be an etiologyspecific treatment for this specific subset of patients with subglottic stenosis that addresses a unique inflammatory phenotype.8 Although Feinstein et al1 did not find significantly different outcomes by etiology, a recent study by Gelbard et al9 showed varying rates of tracheostomy dependence by etiology, a surrogate marker for severity of stenosis. Specifically, this large study showed significantly more patients in the iatrogenic (66%) and autoimmune (54%) groups remaining tracheostomy dependent compared with the traumatic (33%) or idiopathic (0%) groups. Frequently, patients with airway stenoses become frustrated with the recurrent nature of the disease and live in fear of the inevitable airway narrowing that will be present for the rest of their lives. Therefore, the goal of an airway intervention should be to ensure the longest interval until symptomatic narrowing and reduce the need for further procedures in each individual treated patient. This goal of increased interval between treatments and reduced number of treatments should be the standard for evaluating adjuvant therapies. Open airway procedures meet this criterion,2,10 but contraindications and increased morbidity and mortality compared with endoscopic interventions have limited uniform adoption as the standard of care. Like most studies published on this topic, there are limitations of this study,1 including its uncontrolled and retrospective design with inherent selection bias and a heterogeneous patient population. However, it seems that this study, with one of the largest patient populations, fits into the overarching theme developing in laryngotracheal stenosis research, that is, one that is less technique based and more focused on the details of mucosal repair mechanisms; however, in the case of open surgery this is achieved by complete removal of the diseased mucosa. Nevertheless, to further our understanding of laryngotracheal stenosis, researchers will need to conduct larger and, ideally, randomized, clinical trials with reliable clinical data, valid taxonomy of disease, and attention to clinical reasoning. The challenges of conducting an adequately powered multi-institutional randomized clinical trial comparing surgical interventions are substantial. Currently, a randomized, prospective, double-blind, placebo-controlled clinical trial of the use of mitomycin as an adjunctive treatment for laryngotracheal stenosis is being conducted at the University of California, San Francisco (ClinicalTrials.gov Identifier:NCT01523275). We will need to continue to develop new paradigms in airway surgery outcomes research including meta-analyses of the current data and large multicenter clinical trials providing more precise and accurate data for results reporting. The results from these studies will provide patient care answers and help clarify whether we are even asking the right questions of our surgical data. Fortunately, the North American Airway Collaborative has begun this effort and a clinical trial has been developed including more than 40 major centers to create a massive prospectively collected data set for patients with idiopathic subglottic stenosis (ClinicalTrials.gov Identifier: NCT02481817). This project will hopefully serve as a model for large-scale collaborative research and expand our understanding of upper airway stenosis. Related article Expanding Perspectives in Airway Stenosis Invited Commentary