Abstract
Objective:
To determine the efficacy of office-based intralesional steroid injections (ILSI) as a management therapy for adult subglottic stenosis (SGS).
Data Sources:
A systematic review was completed using PubMed and Science Direct for office-based management of SGS due to various etiologies.
Review Methods:
The primary end point measured was a change in surgery free interval (SFI) between endoscopic procedures due to office-based serial ILSI. The secondary end point was to determine what percentage of patients did not require further operative intervention for SGS maintenance therapy after changing management to office-based serial ILSI.
Results:
We identified 187 abstracts, 4 of which were included in the analysis. The total number of participants was 55. The mean age was 50.4, and 78.1% were women. The etiologies were as follows: idiopathic (58.2%), postintubation/tracheotomy (29.1%), and autoimmune (12.7%). The SFI was reported in 3 of the 4 studies. The reported mean pre-ILSI SFI was 362.9 days and the post-ILSI SFI was 582.2 days. The secondary outcome was reported in 3 of the 4 studies. Forty-one of the 55 patients (74.5%) did not require further operative intervention during the duration of the study.
Conclusion:
This review explored office-based ILSI as a potential treatment option for patients with SGS. The limited data presented found ILSI significantly lengthened SFI, potentially reducing surgical burden. In addition, ILSI was found to be safe with few reported side effects.
Introduction
Rationale
Subglottic stenosis (SGS) is defined as the narrowing of the airway distal to the vocal folds and is attributed to various causes including trauma, autoimmune disease, or idiopathic etiology.1,2 Traditionally, management of SGS is done in the operating room (OR). These approaches can be divided into 2 areas: open or endoscopic management. Cricotracheal resection is the most common open procedure; however, it is associated with an increased risk of temporary tracheostomy and permanent unilateral vocal fold paralysis. 3 Endoscopic techniques include dilation, scar excision, and vaporization with a carbon dioxide laser. Although these forms of treatment are less invasive, they have higher rates of stenosis reoccurrence. 4 Mitomycin C and corticosteroids have been used as adjuvants to endoscopic procedures.4,5 Although the efficacy of intralesional corticosteroids has not been firmly established for treatment of SGS, and the molecular mechanisms of its actions in the airway mucosa remain obscure, it is postulated to blunt the host inflammatory response through its actions on both adaptive T cell subsets as well as arresting the fibrinogenic cascade through its inhibition of collagen synthesis, glycosaminoglycans deposition, and fibroblast proliferation. 6
Due to the recurrent and chronic nature of SGS, there has been increased interest in office-based procedures to address this disease process. Office-based procedures are completed under local or topical anesthesia, and the patients are awake in order to reduce risks associated with repeated general anesthesia and potential airway compromise. Intralesional steroid injection (ILSI) is an office-based procedure in which corticosteroids are injected into the stenotic scar tissue. Intralesional steroid injection has shown promise in helping to manage SGS and may increase the time between endoscopic treatments, defined as the surgery free interval (SFI). 1 This review is necessary to highlight the potential benefits and harms of this novel treatment for a chronic illness.
Objectives
This systematic review aims to identify the SFI with ILSI and secondarily identify the percentage of patients who no longer needed operative management for their SGS after ILSI.
Research Question
Can office-based ILSI effectively manage SGS by increasing the SFI and be a sufficient treatment modality to replace OR management?
Methods
Protocol
This study was reported as a systematic review based on the statements from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. 7 To define the objectives and methodology of this systematic review, a priori was established. The PICO question (population [P], intervention [I], comparison [C], and outcome [O]) was the following: “In adults with SGS, can office-based ILSI increase the surgery free interval?”
Eligibility Criteria
The systematic review included strict inclusion and exclusion criteria. The population defined is adults aged >18 years with the diagnosis of SGS (Figure 1). Articles were included based on these criteria: (1) intralesional steroid use, (2) all etiologies of SGS, (3) office-based management, and (4) English language. Articles were excluded based on these criteria: (1) surgical management, (2) pediatric population <18 years age, (3) no SFI reported, (4) supraglottic stenosis, (5) animal studies, (6) case studies, and (7) duplicate studies.
Fluxogram of the selection of articles. A review of current literature was completed with 2 electronic databases (PubMed and ScienceDirect).
Information Sources and Search
A systematic review of the literature was completed using the databases of PubMed and ScienceDirect in July 2020. The search included the terms: “subglottic stenosis” AND “steroids”, OR “endoscopic management” AND/OR “office-based” AND “adults”. Articles were excluded if the main subject was not in relation to the domain or if they were not in English. The references of the articles were also screened to include all relevant articles. The years searched were from January 1900 to July 2020.
Study Selection
Identification of publications and screening of titles and abstracts based on the strict inclusion and exclusion criteria was conducted by 1 reviewer (AL). Subsequently, selected articles were assessed in full text and studies corresponding to the eligibility criteria were included in the systematic review. Finally, 2 reviewers extracted the relevant data from the articles (AL and IH). Two of the studies had an overlap of patients (Hoffman et al 8 and Hoffman et al 9 ). Only the patients in the study by Hoffman et al 8 were included in the statistical analysis.
Data Collection Process, Data Items, and Risk of Bias
Data were extracted through a data collection form. The form was organized to include information for the type of study, the etiology of the SGS, age, gender, reported degree of stenosis, specific techniques of the intralesional injections, duration of follow-up, mean number of interventions performed, other outcomes reported, and any complications. The primary end point was the SFI and the effect ILSI had on the SFI. The secondary end point was the number of patients who did not need to return to the OR for the remainder of the study and were able to manage their SGS by completing only office-based ILSI. The analysis and inclusion criteria were established from the beginning in an attempt to limit selection bias. Other potential biases are discussed in the Discussion section.
Results
Study Selection
There were 187 abstracts identified in the search. One hundred forty-two were removed initially after review of the abstract alone based on the exclusion criteria. An additional 41 articles were removed after reviewing the full text. Four articles were used in the final analysis. The results are shown in the PRISMA flow diagram. In order to determine internal validity of each study, a quality assessment tool was used from The National Institutes of Health. Specifically, the “Quality Assessment Tool for Before–After Studies (Pre–Post) with No Control Group” (Table 1).
The National Institutes of Health Quality Assessment Tool for Before–After Studies (Pre–Post) With No Control Group.
Abbreviations: N, no; N/A, not available; Y, yes.
Patient Characteristics
All of the studies were retrospective chart reviews with a total of 55 patients among the 4 studies. The average size was 18.3 patients. The etiologies varied, the most common was idiopathic (58.2%), postintubation/tracheotomy (29.1%), and autoimmune (12.7%). The mean age was 50.4 years (standard deviation [SD] 0.52). The majority of patients were female with 43 total (78.2%) and 12 males (21.8%). All of the idiopathic patients were women except 1 (96.9% female). Degree of stenosis was reported in 3 of the 4 studies. The most frequent Cotton-Meyer Grade for 1 article was grade I (41.7% of patients). 11 The other 2 articles reported percentage stenosis with a range from 15% to 65% stenosis.9,10 The technique for ILSI was reported in all studies. The 2 approaches that were used were transnasal and transcervical. One study used transnasal exclusively, 2 used transcervical exclusively, and 1 study used both.
The steroids used were either triamcinolone or betamethasone. Betamethasone was used in 1 study. The other 3 studies used triamcinolone. The dose of steroids was standardized across each administration. Triamcinolone was at a concentration of 40 mg/mL while betamethasone was at a concentration of 6 mg/mL. The mean number of procedures completed for all studies was 3.6 rounds of steroid injections. The range of means was 2.5 to 4.4 rounds. These were completed with 3 to 7 weeks between each round of injections, with 1 study reporting an average of 7.2 weeks between injections.8-11
Outcomes Measured
The primary end point measured was the SFI which can be divided into pre-ILSI SFI and post-ILSI SFI. Surgery free interval was reported in all studies, however, not all patients had completed at least 2 surgeries and had sufficient follow-up prior to beginning ILSI to be included in the calculation. Of the 55 patients, 35 met the criteria to determine the pre-ILSI (63.6%) and post-ILSI SFI. Of the 35 patients, the mean pre-ILSI SFI was determined to be 362.9 days. The range in means was 288.6 to 497 days. The mean post-ILSI SFI was determined to be 582.2 days. The range in means was 523 to 678 days. The difference between the pre- and post-ILSI SFI is 219.3 days (Tables 2 and 3).
Characteristics of the Studies Included.
Abbreviations: ET, endotracheal; F, female; ILSI, intralesional steroid injection; M, male; N/A, not available.
Characteristics of the Studies Included.
Abbreviations: ET, endotracheal; F, female; ILSI, intralesional steroid injection; M, male; N/A, not available; OR, operating room.
The secondary end point measured was the number of patients who were able to adequately manage their SGS through office-based serial ILSI alone without any further OR intervention. Three of the studies reported on these data accounting for all 55 patients. Forty-one patients of 55 patients undergoing ILSI did not need to return to the OR during the length of the study (74.5%). The exact length of the study was reported in 2 of the studies with an average of 26.4 months.9,11 The other 2 studies followed up within 6 months at the end of the series of steroid injections.9,10 However, the retrospective chart review was completed at 363 ± 143 days from the time of the first injection to the time of review in the study by Hoffman et al. 8
Complications Reported
No serious complications were reported, and no patient required a visit to the emergency department. However, 1 patient experienced significant anxiety and was unable to receive any injections. One other patient experienced a self-limited vasovagal reaction but was able to complete the procedure. Hoffman et al reported on patient reported side effects. The most common complaint was of increased airway restriction for <48 hours after treatment. This was reported in 5 of 16 patients (31%) and in 13 total instances (28%). The next most common complaints were of cough, 3 of 46 cases (23%), and nasal pain, 2 of 46 cases (4.3%). 10
In addition to these side effects, 9 patients returned to the OR after initiating ILSI. The most common reasons were due to either failure to improve or worsening stenosis as in the case of 7 of the 9 patients. Three of the 7 were able to return to office-based ILSI.
Surgery Free Interval by Etiology
Bertelsen et al 11 distinguished its results by etiology of the SGS. The different etiologies showed various responses to the ILSI therapy. The mean (SD) SFI was 534 (315) days overall and was 471 (318) for idiopathic SGS, 414 (297) days for postintubation/tracheotomy, and 801 (507) days for autoimmune SGS. Mean SFI was longer for autoimmune compared with postintubation/tracheotomy SGS (mean difference, 389 days) and compared with idiopathic SGS (mean difference, 330 days). Mean SFI was marginally longer for idiopathic compared with postintubation/tracheotomy SGS (mean difference, 57 days).
Discussion
Subglottic stenosis can result in debilitating airway compromise and severely impact quality of life (QOL). Traditionally, this disease process has been managed in the OR with open versus endoscopic procedures aimed at excising scar, dilating the stenosis, and injecting or applying topical medication. 1 In recent years, there has been an interest in office-based management using ILSI. This systematic review has found 4 articles that have used office-based ILSI and met inclusion criteria. The 2 key indicators investigated include the effect ILSI had on SFI, and second, the number of patients who did not require further operative intervention for SGS maintenance therapy after changing management to office-based serial ILSI. The data from the 4 articles do show that the SFI increases with office-based ILSI compared to OR management and that many patients were able to avoid the OR once they begun office-based ILSI. There were, however, several limitations to this study. Therefore, drawing comparisons between these articles was difficult as there is a lack of uniformity in data reported.
The studies included in this review are limited by their retrospective study design and small sample size, which is a direct result of the specific patient population of interest. This restriction, however, allowed for a targeted review of disease and management in these patients. Further research is needed to increase the number of studies, particularly controlled prospective studies, that explore the efficacy of ILSI treatment for SGS. More specifically, the prospective studies needed are those that will follow a predefined protocol, are high-powered, and adjust for confounding variables among patients.
Other potential biases can be identified in this study. First, there is a selection bias in both outcomes measured. Of the total 55 patients, only 35 had enough data to make a comparison in SFI (63.6%). Less than half of the patients were not included in the analysis. Confounding variables can also be identified. First, there was a variety of techniques attempted prior to beginning ILSI. Second, the different etiologies of SGS included in the analysis can make it difficult to compare as the pathogenesis of scarring differs from autoimmune etiologies. These limitations indicate a lack of standardization within clinical practice in regard to reporting ILSI outcomes. It would be extremely beneficial if treatment outcomes could be reported consistently between patients and clinical centers. Future studies should work to develop a concrete metric that can be used to report data pertaining to ILSI.
In addition, when examining the effectiveness of therapy for the treatment of SGS, it is important to note the general time course of this illness. In 2020, Gelbard et al examined the rate of recurrence for patients receiving endoscopic dilations without adjuvant therapy for treatment of idiopathic SGS. The rate of recurrence was 22.8% of patients with a median (interquartile range) follow-up of 1.3 (0.4-2.2) years. 3 This median time of over 1 year can be attributed in part to the temporary success of endoscopic dilation as well as the recurrent nature of idiopathic SGS. Therefore, SFI may be an unreliable metric when used in isolation. Future studies could include specific objective metrics such as peak expiratory flow and peak inspiratory flow percentage changes or subjective QOL surveys. 12 These metrics would greatly supplement the SFI measurements and provide a better picture on ILSI effectiveness and help differentiate between the natural time course of SGS and therapies attempted.
As previously stated, sufficient follow-up time is essential to assess the strength of office-based ILSI. The average pre-ILSI SFI was 362.9 days, which shows that follow-up for new therapy should be at least greater than 1 year to demonstrate any effectiveness of the intervention. Of the 4 studies, only 2 stated an exact length of follow-up of 32.3 and 20.4 months, both of which exceed the 1-year time frame. However, the study by Hoffman et al 8 reported a limited follow-up of only 6 months from the time of the last injection to transnasal tracheoscopy. Even so, their retrospective chart review was completed at 363 ± 143 days after the first injection in the series. This indicates that this study had an extended follow-up period which will allow for better assessment of the new intervention.
This study is principally hindered by the paucity of current research on the use of office-based ILSI, however, the limited data presented are promising and illustrate a longer SFI with office-based ILSI compared to OR-based management. The mean pre-ILSI SFI was 362.9 days compared to post-ILSI SFI of 582.2 days. The mean difference was 219.3 days. In addition, 41 of 55 patients (74.5%) did not need to return to the OR for management once office-based ILSI had begun. These results show that ILSI may be a viable option for patients with SGS in order to avoid multiple operative interventions. Otolaryngologists should consider this treatment method when determining management options for these patients.
This review also looked at other considerations when determining the efficacy of office-based ILSI. First, ILSI was shown to be safe with few side effects. No serious negative outcomes were reported and only Hoffman et al 9 reported on further safety concerns. The most frequent being transient airway restriction lasting <48 hours and was reported in 28% of cases. The other notable side effect was a self-limited vasovagal reaction; however, the patient was still able to complete the procedure.
Another point for consideration was the number of patients who returned to the OR for management after initiating ILSI. In total, 9 patients returned to the OR. Seven patients were considered either nonresponders or experienced worsening stenosis after the initiation of ILSI. One patient chose to return to the OR due to preference and another could not complete the ILSI due to significant anxiety. Three of the 7 nonresponders did return to office-based ILSI. When considering potential candidates for office-based ILSI, it is noteworthy that most patients were considered to have mild to moderate stenosis. Three studies reported the degree of stenosis. For 2 of the studies, the range of stenosis was from 15% to 65%. Bertelsen et al had 5 patients with Cotton-Meyer Grade IV accounting for 9.1% of all patients. 11
Finally, it is important to note that the injections were completed on a scheduled course with flexibility in the schedule for worsening symptoms. Most were completed with 1 to 3 months between procedures and routine monitoring via laryngoscope.
Conclusion
This systematic review explored office-based ILSI as a potential treatment option for patients suffering from SGS. The studies included in this review are limited by their retrospective nature, small sample size, inadequate power, and limited follow-up; however, they still provide insight on the usage of ILSI for management of SGS. The limited data presented suggest ILSI treatment may increase the treatment interval between operative interventions. Additionally, ILSI was found to be safe with few reported side effects. As an innovative new approach for management of SGS, ILSI should be considered as a potential treatment option for these patients.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the publication of this article: This work was supported by Rosalind Franklin University of Medicine and Science Chicago Medical School.
