Comparative Treatment Outcomes for Idiopathic Subglottic Stenosis: 5-Year Update.

The North American Airway Collaborative (NoAAC) previously published a 3-year multi-institutional prospective cohort study showing variation in treatment effectiveness between 3 primary surgical techniques for idiopathic subglottic stenosis (iSGS). In this report, we update these findings to include 5 years of data evaluating treatment effectiveness. Patients in the NoAAC cohort were re-enrolled for 2 additional years and followed using the prespecified published protocol. Consistent with prior data, prospective observation of 487 iSGS patients for 5 years showed treatment effectiveness differed by modality. Cricotracheal resection maintained the lowest rate of recurrent operation (5%), followed by endoscopic resection with adjuvant medical therapy (30%) and endoscopic dilation (50%). These data support the initial observations and continue to provide value to providers and patients navigating longitudinal decision-making. Level of evidence: 2-prospective cohort study.

Association of Social Determinants of Health with Time to Diagnosis and Treatment Outcomes in Idiopathic Subglottic Stenosis.

OBJECTIVES: To examine whether social determinants of health (SDH) factors are associated with time to diagnosis, treatment selection, and time to recurrent surgical intervention in idiopathic subglottic stenosis (iSGS) patients. METHODS: Adult patients with diagnosed iSGS were recruited prospectively (2015-2017) via clinical providers as part of the North American Airway Collaborative (NoAAC) and via an online iSGS support community on Facebook. Patient-specific SDH factors included highest educational attainment (self-reported), median household income (matched from home zip code via U.S. Census data), and number of close friends (self-reported) as a measure of social support. Main outcomes of interest were time to disease diagnosis (years from symptom onset), treatment selection (endoscopic dilation [ED] vs cricotracheal resection [CTR] vs endoscopic resection with adjuvant medical therapy [ERMT]), and time to recurrent surgical intervention (number of days from initial surgical procedure) as a surrogate for disease recurrence. RESULTS: The total 810 participants were 98.5% female, 97.2% Caucasian, and had a median age of 50 years (IQR, 43-58). The cohort had a median household income of $62 307 (IQR, $50 345-$79 773), a median of 7 close friends (IQR, 4-10), and 64.7% of patients completed college or graduate school. Education, income, and number of friends were not associated with time to diagnosis via multivariable linear regression modeling. Univariable multinominal logistic regression demonstrated an association between education and income for selecting ED versus ERMT, but no associations were noted for CTR. No associations were noted for time to recurrent surgical procedure via Kaplan Meier modeling and Cox proportional hazards regression. CONCLUSIONS: Patient education, income, and social support were not associated with time to diagnosis or time to disease recurrence. This suggests additional patient, procedure, or disease-specific factors contribute to the observed variations in iSGS surgical outcomes.

Impact of the COVID-19 Pandemic on Patients With Idiopathic Subglottic Stenosis.

OBJECTIVES: To determine the number of patients with idiopathic subglottic stenosis (iSGS) who have contracted coronavirus disease 2019 (COVID-19), the impact of the pandemic on patients' attitudes on seeking help and attending hospitals, as well as the delays in the offer of treatment from the local health care systems. METHODS: A 29-question survey was distributed to an international mailing list of patients with subglottic stenosis to assess the patient experience during the COVID-19 pandemic. RESULTS: A total of 543 patients with iSGS participated. Fewer than 1 in 10 patients with iSGS have experienced COVID-19 symptoms, which were predominantly mild to moderate, with only 2 hospitalizations. Most patients with iSGS (80.0%) have not been advised they are high risk for COVID-19, despite 36.5% of patients with iSGS being obese (body mass index of 30+). Delays to surgeries and in-office procedures have impacted 40.1% of patients currently receiving treatment, with 38.8% of patients increasingly struggling to breathe as a result. Anxiety and stress are increasing among patients, with 3 in 4 (75.2%) reporting they are anxious about travelling by public transport, contracting the virus in hospital and infecting loved ones (69.0% and 71.9%, respectively). Of greater concern is that 23.1% with increasing dyspnea state they are staying away from hospital despite their deteriorating health. CONCLUSIONS: The COVID-19 pandemic has had an impact on the physical and psychological health of patients with iSGS. Surgeons managing cases of laryngotracheal stenosis need to offer appropriate support and communication to these high risk patients. During the pandemic, this should include self-isolation if they are dyspneic or on treatments that may have reduced their immunity. In addition, they should offer safe clinical pathways to airway assessment and treatments, if they become necessary. To minimize unnecessary travel, much of the clinical monitoring can be carried out remotely, using telephone or video-based consultations, in conjunction with local health professionals.

Utilization and Influence of Online Support Communities in Idiopathic Subglottic Stenosis Patients.

OBJECTIVES: To determine the factors that shape utilization of social media-based online support communities (OSCs) and study the influence of these communities on medical decision-making in patients with Idiopathic Subglottic Stenosis (iSGS). STUDY DESIGN: Survey study. METHODS: A survey investigating OSC use was sent to the 1,056 members of the North American Airway Collaborative (NoAAC) iSGS1000 cohort in January 2018. Responses were merged with the existing NoAAC data set containing extensive demographic data, disease-specific history, and responses to validated patient-reported outcome measures. RESULTS: A total of 755 individuals with iSGS and mean age of 51.8 ± 11.6 years were included (99% female, 98% white, 63% college educated) and 58% were OSC users. Younger age, female gender, and college education were each associated with OSC use (P < .05). Users spent 2.5 ± 3.3 hours per week on the platforms. Time spent on OSC was not associated with total number of prior treatments. Higher disease anxiety (FoP-Q, R = 0.26, P < .001), lower social support (MOS, R = -0.12, P = .037), and lower level of shared-decision-making with the treating physician (SDM-Q9, R = -0.16, P = .007) were weakly associated with more hours spent engaging an OSC. OSC use influenced treatment and physician choice in 35% and 26% of users, respectively. Increased time spent on OSC use was associated with increased influence on patient medical decisions regarding treatment, surgery, and physician choice (P < .05). CONCLUSION: OSC engagement is common in patients with iSGS. Disease anxiety, social support, and relationship with the physician may influence OSC utilization. More OSC engagement weakly associated with greater OSC influence on patient medical decision-making. LEVEL OF EVIDENCE: NA. Laryngoscope, 131:1821-1827, 2021.

Idiopathic Subglottic Stenosis during Pregnancy: A Support Group Survey.

OBJECTIVES: (1) To determine how pregnancy affects idiopathic subglottic stenosis (iSGS) symptoms. (2) To determine treatments utilized (including operating room (OR) and in-office procedures) for iSGS before, during, and after pregnancy. METHODS: A 24-question survey was distributed to an international iSGS support group to assess the patient experience among individuals who have been pregnant with diagnosis of iSGS. Descriptive statistics and chi2 analyses were completed. RESULTS: A total of 413 iSGS patients participated; 84.7% (n = 350) of patients were diagnosed prior to menopause. A total of 25.5% patients reported being pregnant when they had airway stenosis; 71.1% of those reported more severe airway symptoms during pregnancy. The proportion of patients that reported requiring ≥1 OR interventions (microlaryngoscopy and bronchoscopy, laser, balloon dilation, or steroid injection) before, during and after pregnancy was the following, respectively: 37.3%, 35.6%, 51.3%. Whereas the proportion of patients that reported requiring ≥1 in-office interventions (awake balloon dilation or steroid injection) before, during and after pregnancy was the following, respectively: 13.6%, 11.8%, 15.8%. Number of pregnancies and age of diagnosis was not related to severity of symptoms or requiring more airway interventions (P > .05). CONCLUSIONS: This survey reveals worsening of symptoms during pregnancy, however, this did not lead to increase in operative or clinic interventions to improve airway symptoms during pregnancy. Future avenues for research include optimizing management of airway symptoms during pregnancy to limit OR-based interventions. LEVEL OF EVIDENCE: Level IV.

Comparative Treatment Outcomes for Patients With Idiopathic Subglottic Stenosis.

Importance: Surgical treatment comparisons in rare diseases are difficult secondary to the geographic distribution of patients. Fortunately, emerging technologies offer promise to reduce these barriers for research. Objective: To prospectively compare the outcomes of the 3 most common surgical approaches for idiopathic subglottic stenosis (iSGS), a rare airway disease. Design, Setting, and Participants: In this international, prospective, 3-year multicenter cohort study, 810 patients with untreated, newly diagnosed, or previously treated iSGS were enrolled after undergoing a surgical procedure (endoscopic dilation [ED], endoscopic resection with adjuvant medical therapy [ERMT], or cricotracheal resection [CTR]). Patients were recruited from clinician practices in the North American Airway Collaborative and an online iSGS community on Facebook. Main Outcomes and Measures: The primary end point was days from initial surgical procedure to recurrent surgical procedure. Secondary end points included quality of life using the Clinical COPD (chronic obstructive pulmonary disease) Questionnaire (CCQ), Voice Handicap Index-10 (VHI-10), Eating Assessment Test-10 (EAT-10), the 12-Item Short-Form Version 2 (SF-12v2), and postoperative complications. Results: Of 810 patients in this cohort, 798 (98.5%) were female and 787 (97.2%) were white, with a median age of 50 years (interquartile range, 43-58 years). Index surgical procedures were ED (n = 603; 74.4%), ERMT (n = 121; 14.9%), and CTR (n = 86; 10.6%). Overall, 185 patients (22.8%) had a recurrent surgical procedure during the 3-year study, but recurrence differed by modality (CTR, 1 patient [1.2%]; ERMT, 15 [12.4%]; and ED, 169 [28.0%]). Weighted, propensity score-matched, Cox proportional hazards regression models showed ED was inferior to ERMT (hazard ratio [HR], 3.16; 95% CI, 1.8-5.5). Among successfully treated patients without recurrence, those treated with CTR had the best CCQ (0.75 points) and SF-12v2 (54 points) scores and worst VHI-10 score (13 points) 360 days after enrollment as well as the greatest perioperative risk. Conclusions and Relevance: In this cohort study of 810 patients with iSGS, endoscopic dilation, the most popular surgical approach for iSGS, was associated with a higher recurrence rate compared with other procedures. Cricotracheal resection offered the most durable results but showed the greatest perioperative risk and the worst long-term voice outcomes. Endoscopic resection with medical therapy was associated with better disease control compared with ED and had minimal association with vocal function. These results may be used to inform individual patient treatment decision-making.

RNA sequencing and pathway analysis identify tumor necrosis factor alpha driven small proline-rich protein dysregulation in chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous inflammatory disorder in which many pathways contribute to end-organ disease. Small proline-rich proteins (SPRR) are polypeptides that have recently been shown to contribute to epithelial biomechanical properties relevant in T-helper type 2 inflammation. There is evidence that genetic polymorphism in SPRR genes may predict the development of asthma in children with atopy and, correlatively, that expression of SPRRs is increased under allergic conditions, which leads to epithelial barrier dysfunction in atopic disease. METHODS: RNAs from uncinate tissue specimens from patients with CRS and control subjects were compared by RNA sequencing by using Ingenuity Pathway Analysis (n = 4 each), and quantitative polymerase chain reaction (PCR) (n = 15). A separate cohort of archived sinus tissue was examined by immunohistochemistry (n = 19). RESULTS: A statistically significant increase of SPRR expression in CRS sinus tissue was identified that was not a result of atopic presence. SPRR1 and SPRR2A expressions were markedly increased in patients with CRS (p < 0.01) on RNA sequencing, with confirmation by using real-time PCR. Immunohistochemistry of archived surgical samples demonstrated staining of SPRR proteins within squamous epithelium of both groups. Pathway analysis indicated tumor necrosis factor (TNF) alpha as a master regulator of the SPRR gene products. CONCLUSION: Expression of SPRR1 and of SPRR2A is increased in mucosal samples from patients with CRS and appeared as a downstream result of TNF alpha modulation, which possibly resulted in epithelial barrier dysfunction.

Mice Lacking Pannexin 1 Release ATP and Respond Normally to All Taste Qualities.

Adenosine triphosphate (ATP) is required for the transmission of all taste qualities from taste cells to afferent nerve fibers. ATP is released from Type II taste cells by a nonvesicular mechanism and activates purinergic receptors containing P2X2 and P2X3 on nerve fibers. Several ATP release channels are expressed in taste cells including CALHM1, Pannexin 1, Connexin 30, and Connexin 43, but whether all are involved in ATP release is not clear. We have used a global Pannexin 1 knock out (Panx1 KO) mouse in a series of in vitro and in vivo experiments. Our results confirm that Panx1 channels are absent in taste buds of the knockout mice and that other known ATP release channels are not upregulated. Using a luciferin/luciferase assay, we show that circumvallate taste buds from Panx1 KO mice normally release ATP upon taste stimulation compared with wild type (WT) mice. Gustatory nerve recordings in response to various tastants applied to the tongue and brief-access behavioral testing with SC45647 also show no difference between Panx1 KO and WT. These results confirm that Panx1 is not required for the taste evoked release of ATP or for neural and behavioral responses to taste stimuli.

Postsynaptic P2X3-containing receptors in gustatory nerve fibres mediate responses to all taste qualities in mice.

Taste buds release ATP to activate ionotropic purinoceptors composed of P2X2 and P2X3 subunits, present on the taste nerves. Mice with genetic deletion of P2X2 and P2X3 receptors (double knockout mice) lack responses to all taste stimuli presumably due to the absence of ATP-gated receptors on the afferent nerves. Recent experiments on the double knockout mice showed, however, that their taste buds fail to release ATP, suggesting the possibility of pleiotropic deficits in these global knockouts. To test further the role of postsynaptic P2X receptors in afferent signalling, we used AF-353, a selective antagonist of P2X3-containing receptors to inhibit the receptors acutely during taste nerve recording and behaviour. The specificity of AF-353 for P2X3-containing receptors was tested by recording Ca(2+) transients to exogenously applied ATP in fura-2 loaded isolated geniculate ganglion neurons from wild-type and P2X3 knockout mice. ATP responses were completely inhibited by 10 µm or 100 µm AF-353, but neither concentration blocked responses in P2X3 single knockout mice wherein the ganglion cells express only P2X2-containing receptors. Furthermore, AF-353 had no effect on taste-evoked ATP release from taste buds. In wild-type mice, i.p. injection of AF-353 or simple application of the drug directly to the tongue, inhibited taste nerve responses to all taste qualities in a dose-dependent fashion. A brief access behavioural assay confirmed the electrophysiological results and showed that preference for a synthetic sweetener, SC-45647, was abolished following i.p. injection of AF-353. These data indicate that activation of P2X3-containing receptors is required for transmission of all taste qualities.

Role of the ectonucleotidase NTPDase2 in taste bud function.

Taste buds are unusual in requiring ATP as a transmitter to activate sensory nerve fibers. In response to taste stimuli, taste cells release ATP, activating purinergic receptors containing the P2X2 and P2X3 subunits on taste nerves. In turn, the released ATP is hydrolyzed to ADP by a plasma membrane nucleoside triphosphate previously identified as nucleoside triphosphate diphosphohydrolase-2 (NTPDase2). In this paper we investigate the role of this ectonucleotidase in the function of taste buds by examining gene-targeted Entpd2-null mice globally lacking NTPDase2. RT-PCR confirmed the absence of NTPDase2, and ATPase enzyme histochemistry reveals no reaction product in taste buds of knockout mice, suggesting that NTPDase2 is the dominant form in taste buds. RT-PCR and immunocytochemistry demonstrated that in knockout mice all cell types are present in taste buds, even those cells normally expressing NTPDase2. In addition, the overall number and size of taste buds are normal in Entpd2-null mice. Luciferin/luciferase assays of circumvallate tissue of knockout mice detected elevated levels of extracellular ATP. Electrophysiological recordings from two taste nerves, the chorda tympani and glossopharyngeal, revealed depressed responses to all taste stimuli in Entpd2-null mice. Responses were more depressed in the glossopharyngeal nerve than in the chorda tympani nerve and involved all taste qualities; responses in the chorda tympani were more depressed to sweet and umami stimuli than to other qualities. We suggest that the excessive levels of extracellular ATP in the Entpd2-knockout animals desensitize the P2X receptors associated with nerve fibers, thereby depressing taste responses.

Abdominoplasty with direct resection of deep fat.

BACKGROUND: Suction-assisted lipectomy is an integral component of abdominoplasty for many surgeons. Its potential to affect the vascularity of the abdominal flap is usually offset by limiting the extent of undermining and not suctioning the central flap. The authors address whether these guidelines apply to direct excision of subscarpal fat and whether direct excision provides aesthetically superior abdominoplasty results with fewer complications. METHODS: A 10-year review of consecutive abdominoplasty patients (n = 181) was conducted. Undermining was done to the xyphoid and just beyond the lower rib margins superiorly and at least as far as the anterior axillary line laterally. Fat deep to Scarpa's fascia was removed by tangential excision in all zones of the abdominal flap, including those considered at high risk for vascular compromise if subjected to liposuction after similar undermining. Concurrent liposuction of the abdominal flap was not done. Thirty patients had concurrent flank liposuction. RESULTS: No patients experienced major full-thickness tissue loss. The incidence of limited necrosis at the incision line requiring subsequent scar revision was 0.7 percent in the 151 patients having abdominoplasty and 6.7 percent in the 30 patients having abdominoplasty combined with flank liposuction. Erythema and/or epidermolysis was seen in 4.8 percent of the abdominoplasty patients and 10 percent of the abdominoplasty/ flank liposuction group. The rate of seroma formation in both groups was approximately 16.5 percent. CONCLUSIONS: Direct excision of subscarpal fat does not subject any zone of the abdominoplasty flap to increased risks of vascular compromise. It is a safe technique that provides excellent abdominoplasty results.