Characterizing Disease Severity Through Surgical Recurrence Rates in Idiopathic Subglottic Stenosis

Authors: Andrew Jay Bowen, Andrew Awadallah, Monet McCalla, Ariel Roitman, Hawa Ali, Glen Leverson, Yousuf Khalil, Sydney Ring, Eric Edell, Matthew Koster, Semirra Bayan, Katherine Xie, Ruth Davis, David O. Francis, Dale Ekbom, Seth H. Dailey

Abstract

Objective

There is currently not a marker of disease severity in idiopathic subglottic stenosis (iSGS). Our objective was to characterize iSGS patients' disease severity using endoscopic surgery rates.

Methods

This was a two‐center retrospective analysis of iSGS patients with a minimum of 4 years of follow up following an initial endoscopic procedure (laser wedge excision (LWE) or endoscopic dilation (ED)). Disease severity was classified into Groups A–C, based on whether patients had fewer (Group A), the same number (Group B), or more surgeries (Group C) in years 3–5 compared to years 1 and 2. Disease severity proportions were compared across institutions using chi‐square analysis. Nonparametric testing compared clinical characteristics such as age, BMI, and GERD across severity groups.

Results

There were 104 patients from institution 1 and 53 patients from institution 2 that were all female and predominantly Caucasian. Both institutions had clinically and statistically similar proportions of patients in Group A (64% vs. 62%), Group B (20% vs. 19%), and Group C (16% vs. 19%) disease (p > 0.05). No clinical characteristic (e.g., age, sex, race, BMI, GERD) was associated with disease severity.

Conclusion

Across tertiary care institutions there is a consistent proportion of iSGS patients who either demonstrate nonrecurrent/decelerating (Group A), stable but persistent (Group B), or rapidly recurring disease (Group C). Two‐year surgery rates appear to be an important timepoint for providing expectations to patients on the likelihood of possessing severe disease.

Level of Evidence

4

Introduction

Idiopathic subglottic stenosis (iSGS) remains a condition associated with surgical recurrence (defined as requiring another operative intervention) within the first 5 years following initial surgical intervention [1, 2]. There are observations that some iSGS patients possess a mild disease form, in which surgical recurrence does not occur or occurs many years later [3]. Alternatively, other patients demonstrate highly recurrent disease, in which surgical recurrence recurs quickly and in the face of adjuvants designed to halt scar progression [4].

Disease severity could explain the decrease in the time interval between surgeries that was recently observed in a cohort of iSGS patients following multiple endoscopic laser wedge excision surgeries (LWE) [5]. Disease severity may also explain why the total number of surgeries an iSGS patient has undergone behaves as a confounder in survival analyses of long‐term surgical recurrence [1]. However, to date there are no biological markers of disease severity in iSGS and thus no definitive way of counseling patients on disease prognosis. Additionally, no large‐scale studies have identified patient characteristics that influence disease severity outside of age [6].

Our two institutions regularly treat a large population of iSGS patients, with many patients having their complete treatment course solely at our respective institutions. Our experience with this population demonstrates that many patients possess relatively indolent disease that responds well to endoscopic surgery without recurrence. In contrast, other patients possess rapidly recurring disease that appears to recur quickly after endoscopic surgery, typically within 2 years of initially beginning treatment. We therefore hypothesize that comparing surgical recurrence rates at the start of disease to their rate later in their disease course could provide a way of classifying disease severity in this surgical population. This study aimed to examine 5‐year surgical disease rates across our two institutions, assessing the identification of any clinical characteristics predictive of higher rates of surgical recurrence. We additionally aimed to take these 5‐year surgical disease rates and characterize disease severity by comparing surgical rates during a patient's initial 2 years of treatment to their subsequent 3 years.

Methods

This multi‐institutional study received approval from both the Mayo Clinic Institutional Review Board (IRB) (IRB #17‐008563) and the University of Wisconsin‐Madison (#IRB 2013‐0751). A data use agreement was created allowing for the transfer of data from the Mayo Clinic (“Institution 1”) to the University of Wisconsin‐Madison (“Institution 2”) for analysis (Agreement ID: UNI‐324930). The surgical populations under analysis at both institutions were patients with a previous diagnosis of iSGS with a negative history of tracheal trauma, tracheal infection, prolonged or traumatic intubation, inhalational injury, or autoimmune disease associated with subglottic stenosis. Patients needed at least 4 years of follow up data for study inclusion. Additionally, any patient who underwent an open surgery for iSGS within the first 4 years of treatment was excluded.

Surgical Techniques, Variables, Rates

A description of endoscopic dilation (ED) and LWE has been described previously [7, 8]. The ED category included patients who underwent balloon or rigid dilation with or without radial laser incisions. Previous investigations using these cohorts [1, 9] demonstrated that the majority of patients across both institutions are largely surgically naive upon initial presentation. Given that the LWE was until recently almost exclusively performed at Institution 1, the decision was made to only include LWE patients with no prior surgical history before their first LWE. At Institution 2, the vast majority of patients underwent ED as their first operative intervention. As ED is the most commonly performed surgical intervention for iSGS, patients with a prior surgical history before presentation at Institution 2 were included if the surgical technique performed along with the date of surgery was present, allowing for the beginning of treatment to begin with these outside operations.

5 Year Disease Severity Rates

Overall surgical recurrence rate was the number of endoscopic surgical procedures performed over the 5‐year follow‐up period. Given that preliminary analysis demonstrated that the majority of patients at Institution 1 could be evenly distributed into having 1, 2, or 3+ surgeries over their 5‐year rate, patients were stratified into these 3 categories for later analysis. At Institution 2, this same distribution was not present. Moreover, there were several patients who were managed without requiring operative intervention (4 patients). For these reasons, patients were stratified into those with 0 or 1 operation and patients who had 2 or greater procedures over the 5‐year disease course for analysis.

Disease Severity Classification

The 5‐year follow up period was divided into the first 2 years (Interval 1) and last 3 years (Interval 2). Each patient's surgical recurrence rate was calculated for both intervals and was compared. Patients were then classified into “Group A” (considered nonrecurrent or decelerating disease) when Interval 1 was greater than Interval 2; “Group B” (considered stable but persistent disease): when Interval 1 was equivalent to Interval 2; and “Group C” (considered aggressive highly recurrent disease): when Interval 2 was greater than Interval 1. Frequencies of these severities were collected for each institution.

Covariates

Demographic data such as age and BMI were collected. For comorbidities, gastroesophageal reflux disease (GERD), hiatal hernia, and asthma were individually reported. Additionally, the Charlson Comorbidity Index (CCI) score was calculated. Autoimmune conditions not traditionally associated with subglottic stenosis were also recorded. Finally, the following autoimmune antibodies were recorded if they were identified as positive at any point in a patient's disease anti‐nuclear antibody (ANA), non‐specific ANCA (performed at Institution 2), myeloperoxidase antibody (MPO), and any other autoimmune antibody that was ever positive (please see Supporting Information on list of antibodies tested). No patient at either institution was included if they had prior positive Antineutrophil Cytoplasmic (C‐ANCA) antibody.

Statistical Analysis

Intra‐institutional comparisons comparing 5‐year surgery rates with the stratifications listed above followed by stratification by disease severity groups was performed using nonparametric Wilcoxon Rank Sum tests for continuous clinical covariates and Fisher's exact tests for categorical covariates. Next, a Chi‐square analysis was performed to compare disease severity groups between Institution 1 and Institution 2. Finally, the mean number of surgeries across Group A, Group B, and Group C at Interval 1 was compared to the mean number at Interval 2 through Wilcoxon‐signed rank tests. A separate qualitative analysis examining how the proportion of patients who were in Group A or had no surgical recurrence during Interval 2 was influenced by an increasing number of surgeries during Interval 1 was conducted. Statistical significance was defined as a p value less than 0.05. All analysis was performed using SAS Version 9.4 Copyright (c) 2016 by SAS Institute Inc., Cary, NC, USA and R version 4.0.3.

Results

From Institution 1's initial 131 patients, 27 patients were excluded, making for a total of 104 patients for analysis. From Institution 2's initial 65 patients, 12 patients were excluded making for a total of 53 patients. All patients were female and Caucasian at both institutions.

5 Year Surgical Rates and Clinical Characteristics

Over the 5‐year study period, four patients (8%) at Institution 2 required zero surgeries, and one was needed for 54% and 40% of patients at Institutions 1 and 2, respectively (Table 1). At Institution 1, BMI was associated with the number of surgeries required, with the mean BMI being significantly lower in patients that had more than three recurrent surgeries (1 30.7, 2 32.2, 3+ 25.9; p < 0.01). No other characteristics at either site were associated with the number of surgeries needed.

Disease Severity and Clinical Characteristics

Figure 1 graphically represents disease severity at Institution #1 and #2. Using the disease severity classification, patients at each site had a similar distribution of disease severity (p = 0.85; Table 2). Specifically, 64% and 62% were in Group A, 20% and 19% of patients were in Group B, and 16% and 19% of patients were in Group C at Institution #1 and #2, respectively. No patient clinical characteristic was associated with disease severity at either institution (all p > 0.05; Table 2).

Table 3 shows the mean number of surgeries across severity groups by institution. For Group A, the mean number of surgeries between intervals decreased by 65%–90%, while in Group C, the number of surgeries increased 160%–210% across intervals. Table 4 shows the number of patients at both institutions by increasing surgical rate at Interval 1 who went on to be classified into Group A or did not recur during Interval 2. For patients with surgical rates of 1, 2, 3 for Interval 1, there was a steady proportion (60%–69%) of patients who were ultimately characterized in Group A (Table 4). However, the proportion of patients who did not recur during Interval 2 decreased with every additional surgery performed during Interval 1 (Table 4).

Discussion

Our multi‐institutional study examined the surgical recurrence rates of treatment naïve iSGS patients over a 5‐year period. Using data from two tertiary care centers, a disease classification system was developed by comparing the rate of surgery in the first 2 years after diagnosis to the next 3 years. The distribution of patients classified into Groups A‐C was remarkably similar across institutions with very different surgical treatment philosophies. Understanding the distribution of iSGS disease severity could provide a window into the pathophysiology underlying this condition and also help clinicians to better counsel patients about their expected disease course.

Need for Biomarkers

There are currently no biological markers available that reliably predict recurrence patterns in iSGS patients following surgery [10, 11]. Presently, disease severity is defined by how quickly a patient requires reoperation, with marked variability in the times to surgical recurrence [3]. Adjuvants to surgery such as medical therapy (i.e., inhaled corticosteroids, proton pump inhibitors, trimethoprim‐sulfamethaxole) and serial intralesional steroid injections (SILSI) have not reliably influenced surgical recurrence time in larger scale studies [1, 12, 13, 14]. Part of the reason for this lack of significance in previous large scale investigations is the inclusion of patients with a prior surgical history which behaves as a confounding variable, with those who present with a prior airway history demonstrating more rapidly recurring disease [1]. This is particularly relevant as an observed shortening of inter‐surgical intervals was previously observed with successive endoscopic procedures in the iSGS population [5]. Despite these observations, our observation is that the vast majority of iSGS patients seemingly respond well to treatment with few surgical procedures [3]. Therefore, it is possible that those who demonstrate progressively shortening intervals between repeat surgeries possess a severe form of iSGS. We were therefore interested in examining whether the proportion of patients with rapidly recurring disease is consistent across institutions.

Classifying Severity of iSGS

We classified iSGS disease into three separate groups (A‐C) variants by comparing the rate of surgical recurrence in the first 2 years of disease to the subsequent 3 years. Using this classification, we found an almost identical proportion of patients fit into this classification across two institutions that employ very different treatment philosophies. All providers at Institution 1 perform LWE followed by medical adjuvant therapy consisting of trimethoprim‐sulfamethoxazole (Bactrim), proton pump inhibitors (most commonly omeprazole), and inhaled corticosteroids (most commonly Flovent) post operatively [8, 15]. Alternatively, at Institution 2, ED was exclusively performed for many years with the more recent addition of SILSI and less strict adherence to medical adjuvant therapy [9]. Given that LWE, ED, medical adjuvant therapy, and SILSI all previously demonstrated influence on surgical recurrence, the fact that the proportions were nearly identical suggests that this classification reflects actual disease severity.

We chose to divide 5‐year follow up at 2 years given that most patients do not require repeat surgery during the first 2 years of treatment [1, 16]. Per this classification, approximately 60% of our iSGS patients fell into Group A reflecting less operations during Interval 2. This group is composed primarily of patients who only required a single endoscopic surgery during the 5‐year study period, making up 84% of slow disease patients at Institution 1 and 51% of Institution 2. This would be consistent with the general consensus amongst the laryngology community that the majority of iSGS patients respond well to endoscopic surgery, whether it be LWE or ED [3]. Moreover, as demonstrated by comparing the number of surgeries from Interval 1 and Interval 2, patients in Group A demonstrate opposing trajectories in their disease course compared to Group C patients, with surgery numbers decreasing by 65%–90% (Table 3) from Interval 1 to Interval 2. Patients in Group C alternatively demonstrate a near doubling of operations at Interval 2 (Table 3).

The experience during the first 2 years after diagnosis appears to portend prognosis for treatment‐naïve iSGS patients. For example, patients who had a single surgery in Interval 1 had the highest likelihood of remaining surgery free for the rest of follow up. Additionally, while the proportion of patients who qualify for Group A (60%–69%) remains consistent with increasing operations during Interval 1, ultimately the proportion of surgery free patients at Interval 2 severely drops with every increasing operation during Interval 1 (Table 4). This knowledge could help both patients and providers decide when to escalate further adjuvants such as SILSI or immunologic agents such as methotrexate or rituximab, which have been used in highly recurrent disease [4].

Lack of Disease Modifying Factors

While our disease classification appears to consistently categorize patients into milder and more aggressive forms of disease, no clinical factor was found to be associated with this classification. Instead, BMI was the only clinical characteristic that was associated with increasing 5‐year surgical rates (p < 0.05) at Institution 1. This finding was unexpected given that higher BMI was previously shown to correlate with worsening recurrences [10]. However, this trend was not observed at Institution 2, leading to less certainty on the significance of this result.

Granulomatosis with Polyangiitis (GPA) is an autoimmune disease also associated with subglottic narrowing that demonstrates fluctuating levels of C‐ANCA over the lifetime of the disease, with positivity associated with disease flares [17]. While the diagnosis for iSGS is partly ruled in with confirmatory negative C‐ANCA results, antibodies such as ANA are prevalent in the iSGS population, although the prognostic significance is unknown [18]. We did not identify a relationship between ANA positivity and 5‐year rates or disease severity groups in this investigation. While this would suggest that there is no relationship between ANA and disease severity or recurrence rates, we were limited in available results to investigate in this cohort, which may have underpowered our ability to identify a relationship.

We separately performed a broad examination for an association between disease severity or 5‐year surgery rates with any positive antibody (excluding C‐ANCA) at any point in a patient's disease course. While no relationship was identified between 5‐year surgery rates and antibody positivity at either institution (both p = 0.05), there was an apparent trend between antibody positivity and greater disease severity both at Institution #2 (Group A: 15% vs. Group B: 30% vs. Group C: 50%; Table 2) and to a lesser degree at Institution #1 (Group A: 18% vs. Group B: 14% vs. Group C: 31%). However, the association at Institution #2 was just outside of statistical significance (p = 0.058) and was not significant at Institution #1 (p = 0.42). Nevertheless, the question of antibody significance as a prognosticator of more severe disease should be readily explored, possibly with antibody titers performed on an annual basis or at least with each successive surgical recurrence.

Limitations

This is a retrospective study using patients who possessed 4–5 years of follow‐up data from either the beginning of their diagnosis or following their first surgical operation. This study did not control for the influence of medical adjuvant therapy or SILSI, which have all demonstrated influence on surgical recurrence times [1, 6, 9]. However, as stated previously, the fact that disease severity proportions were very similar despite not controlling for these variables suggests that the classification system proposed in this investigation is depicting an innate feature of the disease pathophysiology underlying iSGS.

While our study focused on following disease trends with patients who received endoscopic treatment for their iSGS disease, open surgery is an alternative surgical option that demonstrates a near 0% recurrence rate for patients for at least the initial decade following surgery [10, 16]. With a near zero recurrence rate, it appears that this modality, which entirely removes the diseased cricotracheal segment from a patient, is able to overcome more aggressive disease as it is often employed for patients who demonstrate rapidly recurrent disease. Given that this procedure was performed for a minority of patients at both institutions, the decision was made to focus only on patients who were managed with endoscopic surgery during their first 5 years of treatment.

In the absence of biological markers informing iSGS disease severity, this classification system represents an initial step towards demonstrating disease severity in iSGS. Nevertheless, the system has its limitations. For example, the four patients with 0 surgeries during intervals 1 and 2 at Institution two were classified into Group B based on the definitions set for this disease classification. Additionally, patients who may have had four operations during Interval 1 would still be classified into Group A as long as the number of operations during Interval 2 was less than 4. The classification should therefore be carefully applied to iSGS patients in practice as it will likely undergo further refinement in the future with more data and patients. Furthermore, we acknowledge that disease classification failed to demonstrate any major differences in patient characteristics across disease severity groups, including age (Table 2). While this decreases the applicability of the classification system in providing prognostic value on disease severity in iSGS, our findings could also reflect that disease severity in iSGS is ultimately dictated by the disease itself without predisposing factors.

Conclusion

A disease classification system in iSGS that uses intervals contained within a 5‐year surgery rate to categorize patients into three separate groups with worsening disease severity demonstrated near identical proportions across institutions. The 2‐year surgery rate starting from a patient's first treatment appears particularly valuable in showing the proportion of patients who will be classified into Group A, the mildest form of the disease, and those who will remain surgery free. This information is beneficial for patient counseling and should spur further work in classifying disease severity for a condition that currently is unpredictable in response to treatment.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information