Uncoupling of macrophage inflammation from self-renewal modulates host recovery from respiratory viral infection.

Tissue macrophages self-renew during homeostasis and produce inflammatory mediators upon microbial infection. We examined the relationship between proliferative and inflammatory properties of tissue macrophages by defining the impact of the Wnt/ß-catenin pathway, a central regulator of self-renewal, in alveolar macrophages (AMs). Activation of ß-catenin by Wnt ligand inhibited AM proliferation and stemness, but promoted inflammatory activity. In a murine influenza viral pneumonia model, ß-catenin-mediated AM inflammatory activity promoted acute host morbidity; in contrast, AM proliferation enabled repopulation of reparative AMs and tissue recovery following viral clearance. Mechanistically, Wnt treatment promoted ß-catenin-HIF-1α interaction and glycolysis-dependent inflammation while suppressing mitochondrial metabolism and thereby, AM proliferation. Differential HIF-1α activities distinguished proliferative and inflammatory AMs in vivo. This ß-catenin-HIF-1α axis was conserved in human AMs and enhanced HIF-1α expression associated with macrophage inflammation in COVID-19 patients. Thus, inflammatory and reparative activities of lung macrophages are regulated by ß-catenin-HIF-1α signaling, with implications for the treatment of severe respiratory diseases.

Shape-Sensing Robotic-Assisted Bronchoscopy versus Computed Tomography-Guided Transthoracic Biopsy for the Evaluation of Subsolid Pulmonary Nodules.

INTRODUCTION: Lung cancer remains the leading cause of cancer death worldwide. Subsolid nodules (SSN), including ground-glass nodules (GGNs) and part-solid nodules (PSNs), are slow-growing but have a higher risk for malignancy. Therefore, timely diagnosis is imperative. Shape-sensing robotic-assisted bronchoscopy (ssRAB) has emerged as reliable diagnostic procedure, but data on SSN and how ssRAB compares to other diagnostic interventions such as CT-guided transthoracic biopsy (CTTB) are scarce. In this study, we compared diagnostic yield of ssRAB versus CTTB for evaluating SSN. METHODS: A retrospective study of consecutive patients who underwent either ssRAB or CTTB for evaluating GGN and PSN with a solid component less than 6 mm from February 2020 to April 2023 at Mayo Clinic Florida and Rochester. Clinicodemographic information, nodule characteristics, diagnostic yield, and complications were compared between ssRAB and CTTB. RESULTS: A total of 66 nodules from 65 patients were evaluated: 37 PSN and 29 GGN. Median size of PSN solid component was 5 mm (IQR: 4.5, 6). Patients were divided into two groups: 27 in the ssRAB group and 38 in the CTTB group. Diagnostic yield was 85.7% for ssRAB and 89.5% for CTTB (p = 0.646). Sensitivity for malignancy was similar between ssRAB and CTTB (86.4% vs. 88.5%; p = 0.828), with no statistical difference. Complications were more frequent in CTTB with no significant difference (8 vs. 2; p = 0.135). CONCLUSION: Diagnostic yield for SSN was similarly high for ssRAB and CTTB, with ssRAB presenting less complications and allowing mediastinal staging within the same procedure.

RNA Sequencing of Idiopathic Subglottic Stenosis Tissues Uncovers Putative Profibrotic Mechanisms and Identifies a Prognostic Biomarker.

Idiopathic subglottic stenosis (iSGS) is a localized airway disease that almost exclusively affects females. Understanding the molecular mechanisms involved may provide insights leading to therapeutic interventions. Next-generation sequencing was performed on tissue sections from patients with iSGS (n = 22), antineutrophil cytoplasmic antibody-associated vasculitis (AAV; n = 5), and matched controls (n = 9) to explore candidate genes and mechanisms of disease. Gene expression changes were validated, and selected markers were identified by immunofluorescence staining. Epithelial-mesenchymal transition (EMT) and leukocyte extravasation pathways were the biological mechanisms most relevant to iSGS pathogenesis. Alternatively activated macrophages (M2) were abundant in the subepithelium and perisubmucosal glands of the airway in iSGS and AAV. Increased expression of the mesenchymal marker S100A4 and decreased expression of the epithelial marker epithelial cell adhesion molecule (EPCAM) further supported a role for EMT, but to different extents, in iSGS and antineutrophil cytoplasmic antibody-associated subglottic stenosis. In patients with iSGS, high expression of prostate transmembrane protein, androgen induced 1 (PMEPA1), an EMT regulator, was associated with a shorter recurrence interval (25 versus 116 months: hazard ratio = 4.16; P = 0.041; 95% CI, 1.056-15.60). Thus, EMT is a key pathogenetic mechanism of subglottic stenosis in iSGS and AAV. M2 macrophages contribute to the pathogenesis of both diseases, suggesting a shared profibrotic mechanism, and PMEPA1 may be a biomarker for predicting disease recurrence in iSGS.

Robotic-assisted bronchoscopy versus CT-guided transthoracic biopsy for diagnosis of pulmonary nodules.

BACKGROUND AND OBJECTIVE: Currently, computed tomography-guided transthoracic biopsy (CTTB) is the most accurate diagnostic approach for pulmonary nodules suspected of malignancy. Traditional bronchoscopy has shown suboptimal diagnostic sensitivity, but the emergence of robotic-assisted bronchoscopy (RAB) has the potential to improve diagnostic accuracy, maximize diagnostic yield and complete mediastinal and hilar staging in a single procedure. We aim to assess the efficacy and diagnostic performance of RAB compared to CTTB for diagnosing pulmonary nodules suspected of lung cancer. METHODS: A multicenter retrospective review of consecutive patients who underwent RAB and CTTB for evaluating pulmonary nodules from January 2019 to March 2021 at Mayo Clinic Florida and Mayo Clinic Rochester, United States. Clinical and demographic information, nodule characteristics, outcomes and complications were compared between RAB and CTTB. RESULTS: A total of 225 patients were included: 113 in the RAB group and 112 in the CTTB group. Overall diagnostic yield was 87.6% for RAB and 88.4% for CTTB. For malignant disease, RAB had a sensitivity of 82.1% and a specificity of 100%, CTTB had a sensitivity of 88.5% and a specificity of 100%. Complication rate was significantly higher for CTTB compared to RAB (17% vs. 4.4%; p = 0.002). CONCLUSION: RAB, when available, can be as accurate as CTTB for sampling pulmonary nodules with similar or reduced complications and should be considered as a means for nodule biopsy, particularly when mediastinal staging is also clinically warranted.

Complications following laser wedge excision for idiopathic subglottic stenosis.

OBJECTIVES: Endoscopic laser wedge excision (LWE) is an effective treatment option for idiopathic subglottic stenosis (iSGS); however, data regarding complications following LWE are limited. The aim of the following analysis was to provide a review of frequency and type of complications that occur with LWE in patients with iSGS. STUDY DESIGN: Retrospective review. METHODS: Patients with iSGS undergoing LWE between January 2002 and September 2021 were performed. Demographic data were recorded. Complications were stratified into major and minor categories. The frequency of these complications and the respective treatment for them was analyzed. RESULTS: 212 patients within the study period underwent a total of 573 LWE procedures. All but two patients were female, with a median age of 54 years at time of LWE. Of these patients, 43 (20 %) patients experienced a complication. Of these, only 7 (15 %) of the reported complications were considered major while the rest were minor in nature. Major complications included 3 cases of post-operative hemoptysis, 1 case of tracheitis, and 3 cases of reduced vocal fold hypomobility with concurrent glottic stenosis. Minor complications consisted of 2 cases of tooth fracture and 34 cases of tongue paresthesia post-operatively that was self-limited. There were no mortalities. CONCLUSION: Major complications occur in <5 % of LWE procedures based off the analysis. All major complications were managed without significant long-term morbidity. Minor complications with the LWE are self-limited in nature. Our data supports the LWE as a safe treatment option for iSGS.

Optimizing clinical cytology touch preparations for next generation sequencing.

Intraoperative diagnosis is routinely performed on cytology touch preparations (TPs) from core needle biopsies (CNBs). Current interest promotes their utility as an important source of patient tissue for clinical genomic testing. Herein we present whole genome structural variant analysis (SVA) from mate-pair sequencing (MPseq) and whole exome sequencing (WES) mutation calling in DNA directly whole genome amplified (WGA) from TPs. Chromosomal copy changes and somatic DNA junction detection from MPseq of TPs were highly consistent with associated CNBs and bulk resected tissues in all cases. While increased frequency coverage noise from limitations of amplification of limited sample input was significant, this was effectively compensated by natural tumor enrichment during the TP process, which also enhanced variant detection and loss of heterozygosity evaluations from WES. This novel TP methodology enables expanded utility of frequently limited CNB for both clinical and research genomic testing.

Blood-based lung cancer biomarkers identified through proteomic discovery in cancer tissues, cell lines and conditioned medium.

BACKGROUND: Support for early detection of lung cancer has emerged from the National Lung Screening Trial (NLST), in which low-dose computed tomography (LDCT) screening reduced lung cancer mortality by 20 % relative to chest x-ray. The US Preventive Services Task Force (USPSTF) recently recommended annual screening for the high-risk population, concluding that the benefits (life years gained) outweighed harms (false positive findings, abortive biopsy/surgery, radiation exposure). In making their recommendation, the USPSTF noted that the moderate net benefit of screening was dependent on the resolution of most false-positive results without invasive procedures. Circulating biomarkers may serve as a valuable adjunctive tool to imaging. RESULTS: We developed a broad-based proteomics discovery program, integrating liquid chromatography/mass spectrometry (LC/MS) analyses of freshly resected lung tumor specimens (n = 13), lung cancer cell lines (n = 17), and conditioned media collected from tumor cell lines (n = 7). To enrich for biomarkers likely to be found at elevated levels in the peripheral circulation of lung cancer patients, proteins were prioritized based on predicted subcellular localization (secreted, cell-membrane associated) and differential expression in disease samples. 179 candidate biomarkers were identified. Several markers selected for further validation showed elevated levels in serum collected from subjects with stage I NSCLC (n = 94), relative to healthy smoker controls (n = 189). An 8-marker model was developed (TFPI, MDK, OPN, MMP2, TIMP1, CEA, CYFRA 21-1, SCC) which accurately distinguished subjects with lung cancer (n = 50) from high risk smokers (n = 50) in an independent validation study (AUC = 0.775). CONCLUSIONS: Integrating biomarker discovery from multiple sample types (fresh tissue, cell lines and conditioned medium) has resulted in a diverse repertoire of candidate biomarkers. This unique collection of biomarkers may have clinical utility in lung cancer detection and diagnoses.

Myhre-LAPs syndrome and intubation related airway stenosis: keys to diagnosis and critical therapeutic interventions.

OBJECTIVES: Myhre-LAPS syndrome is a recently recognized disease caused by a mutation in the SMAD4 gene. This results in a range of pathology including laryngotracheal stenosis, arthropathy, prognathism and short stature, or LAPS syndrome. We aim to delineate the role of intubation in development of airway stenosis in these patients as well as provide insight into diagnosis and management of this syndrome. Herein we present four patients with Myhre-LAPS syndrome complicated by airway stenosis and perform a systematic review of all cases of Myhre-LAPS syndrome with reported airway pathology. STUDY DESIGN: Retrospective review METHODS: All patients diagnosed with Myhre-LAPS syndrome and airway stenosis at a single institution from 1981 to 2014 were reviewed. RESULTS: Four patients (4F, median age 42) were identified that met inclusion criteria. Initial presenting signs included progressive shortness of breath, dyspnea on exertion and respiratory distress. All four (100%) patients had multi-level airway stenosis most commonly in the subglottic and glottic regions and all patients had undergone at least one endotracheal intubation prior to presentation. One patient with a history of nasal tracheal intubation presented with nasal obstruction and was found to have choanal as well as subglottic stenosis. Two of the four (50%) patients are tracheostomy tube dependent, 1/4 (25%) died of a fatal cardiac arrhythmia and 1/4 (25%) has had 6 endoscopic treatments for subglottic stenosis in 4 years with rapid symptom recurrence. CONCLUSIONS: Myhre-LAPS syndrome is characterized by progressive systemic fibrosis and patients are diagnosed by characteristic findings of prognathism, short stature, abnormal facies, and thick skin among other abnormalities. Airway management is complicated by recurrent, refractory subglottic stenosis often preceded by elective intubation as well as maxillary hypoplasia, trismus, and limited neck extension. Endotracheal intubation and surgical intervention should be approached with caution in these patients and multidisciplinary care teams are necessary to address all manifestations of this syndrome.

Medical Maintenance Therapy Following Laser Excision in Patients With Granulomatosis With Polyangiitis (GPA)-Associated Subglottic Stenosis.

OBJECTIVE: To report on a series of patients with cANCA/PR3-positive, granulomatosis with polyangiitis (GPA)-associated subglottic stenosis (SGS) and evaluate response to medical maintenance therapy with rituximab versus other immunosuppressants following initial endoscopic laser excision. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary academic center. METHODS: A retrospective chart review of patients with SGS and cANCA/PR3-positive GPA who received immunosuppressive maintenance therapy following endoscopic laser excision at our institution from June 1989 to March 2020 was performed. Data pertaining to patient demographics, clinical features, medications, and endoscopic laser procedures were collected. RESULTS: A total of 27 patients (15 women) with mean age (range) of 40 (19-59) years and mean (range) follow-up of 12.6 years (1.5-28.6) were identified. Sixteen patients (60%) had limited GPA. Six patients (24%) had previously received local intervention with open surgery (n = 1, 4%) or endoscopic techniques (n = 5, 20%). All patients experienced symptom improvement following initial CO2 laser excision at our institution without any procedural complications or adverse events. Following initial laser excision, 15 patients (60%) were treated with rituximab and 10 patients (40%) were treated with nonrituximab immunosuppressive agents. Patients treated with rituximab were less likely to recur (P = 0.040). Limited GPA was associated with an increased incidence of recurrence (P = 0.031). Median time (years) to recurrence (range) was 3.2 (0.3-19.3) and was not significantly associated with treatment or GPA subtype. CONCLUSION: Endoscopic CO2 laser excision is a safe and effective local intervention for GPA-associated SGS. Medical maintenance therapy with rituximab reduces risk of recurrence following initial laser excision relative to treatment with non-rituximab agents.

Symptom-Free Intervals Following Laser Wedge Excision for Recurrent Idiopathic Subglottic Stenosis.

OBJECTIVE: Analyze the duration of symptom-free intervals following laser wedge excision (LWE) for recurrent idiopathic subglottic stenosis (iSGS). Secondary aim includes evaluating the influence of patient-related or disease factors. STUDY DESIGN: Retrospective review. SETTING: Tertiary center. METHODS: Review of iSGS patients who underwent LWE between 2002 and 2021. LWE patients without prior airway surgery were labeled LWE primary (LWEP) and those with prior history of dilation were labeled LWE secondary (LWES). A conditional frailty repeated events model was used to analyze the median time to recurrence (MTR) for each nth recurrence. Secondary analysis included stratification by use of medical therapy and initial preoperative characteristics of scar (Myer-Cotton grade, distance between the glottis and superior-most aspect of scar, DGS; length of scar, DL). RESULTS: Two hundred and ten iSGS patients underwent LWE (131 LWEP, 79 LWES). The proportion of patients experiencing at least 1, 3, 6, and 12 recurrences, respectively, was 68.0% (n = 143), 40.7% (n = 85), 20.0% (n = 42), and 5.2% (n = 11). There was exponential time-shortening from the 1st to 12th recurrence (P < .0001). While MTR was 4.1 years after the first LWE, this fell to 2.8, 1.7, 1.0, and 0.7 years for the 2nd, 3rd, 6th, and 12th recurrences. Furthermore, LWEP patients experienced longer MTR than LWES counterparts within the first 6 recurrences (P < .01). There was no significant relationship between intersurgical interval and medication adherence, DL, DGS, or grade for recurrences beyond the first (P = .207, P = .20, P = .43, P = .16). CONCLUSION: Symptom-free intervals in iSGS shorten with each subsequent recurrence and LWE. The difference in MTR between LWEP and LWES groups was significant within the first 6 recurrences with LWEP having longer MTR.

Accuracy of Preliminary Pathology for Robotic Bronchoscopic Biopsy.

BACKGROUND: Diagnosis and treatment of peripheral pulmonary lesions (PPLs) currently require at least 2 procedures. An all-in-1 approach would require diagnosing malignancy with preliminary cytology results. This study investigated the concordance between preliminary cytology and final pathology results in biopsies of PPLs obtained by shape-sensing robotic-assisted bronchoscopy (ssRAB). METHODS: This study was a retrospective, consecutive, single-arm, single-center study of 110 ssRABs for PPLs. Concordance was defined as agreement between preliminary cytology and final pathology results. Accuracy, sensitivity, specificity, positive and negative predictive values, and safety outcomes were examined. RESULTS: The concordance was 89% for needle biopsies, 85% for forceps biopsies, and 92% overall, with substantial agreement. There was no significant association of concordance with patients' demographics or lesion characteristics. Preliminary cytology resulted in a malignant diagnosis in 70%, a nonmalignant diagnosis in 4%, and a nondiagnostic result in 26%, with accuracy of 86% and sensitivity of 84%. The total complication rate was 3.6%, with a pneumothorax rate of 1.8%. CONCLUSIONS: This study compared the concordance of preliminary pathology results with final pathology results for ssRAB biopsies in PPLs. The results showed that preliminary samples have a high concordance with final pathology results and may enable management of PPLs with a single anesthetic procedure including biopsy, staging, and treatment.

Bronchoscopic Lung Volume Reduction: Highlighting the Patient Selection Process.

Patients with advanced emphysema frequently experience severe dyspnea that is inadequately treated with medical therapy alone. Over the past 4 years, we have seen increased usage of bronchoscopic lung volume reduction (BLVR) with endobronchial valves. Success of the procedure is dependent on patient selection because it is not necessarily appropriate for all patients with severe emphysema. (Table 1) The purpose of this review is to highlight the selection process at a single institution. We also discuss the influence of this process on outcomes. Between March 1, 2019, and October 12, 2021, 2402 patients were referred to a dedicated chronic obstructive pulmonary disease clinic at Mayo Clinic - Rochester, whereas 161 patients were subsequently referred for multidisciplinary BLVR review. Of those patients, 53 (32.9%) were selected to receive valves and 35 (21.7%) ultimately underwent the procedure. The main reasons for exclusion included an incompatible quantitative computed tomography analysis (n=37, 34.3%), presence of pulmonary nodule or active malignancy (n=14, 13.0%), or need for completion of pulmonary rehabilitation (n=9, 8.3%). Full or partial (>70%) target lobe collapse was observed in 58.6% of patients who received valves. Those with collapse experienced statistically significant improvements in spirometric measures. Twelve patients experienced a pneumothorax (34.3%), with 10 patients requiring thoracostomy tube placement and prolonged hospitalization (median, 11 days; range, 4-39 days). Nineteen patients required a secondary procedure within the first year. The study highlights how a multidisciplinary approach to the BLVR selection process enables individualization of a complex procedure and enhances the exclusion of inappropriate candidates.

Proximal Scar Progression in Idiopathic Subglottic Stenosis After Wedge Excision: Does it Happen?

OBJECTIVE: To compare the incidence of glottic stenosis in idiopathic subglottic stenosis (iSGS) patients with no prior surgical intervention to those with a history of endoscopic dilation and characterize the incidence of glottic involvement, changes in scar length, and progression of scar toward glottis following laser wedge excision (LWE). METHODS: A retrospective review of iSGS patients who underwent LWE between 2002 and 2021 was performed. Patients without prior airway surgery were labeled LWE primary (LWEP) and operative findings for LWEP patients were reviewed for glottic involvement, scar length (DL ), and distance from the glottis to superior-most aspect of scar (DGS ). Rates (in mm/procedure) of DΔL , reflecting an increase in length, and D-ΔGS , reflecting proximal migration, were calculated by dividing DΔL and D-ΔGS by the number of LWE procedures. RESULTS: 213 iSGS patients underwent LWE, with 132 being LWEP patients. LWEP had a lower incidence of baseline glottic involvement (n = 6, 4.5%) than LWE secondary (LWES; n = 6, 7.5%). Four new cases of glottic involvement were noted in LWEP patients following LWE, with only one being clinically significant resulting in permanently decreased vocal fold mobility. With each procedure, scar length increased by 1.0 mm and DGS decreased by 0.7 mm, reflecting a migration or decrease in DGS of 9.5% with each procedure with respect to initial DGS . Overall rates of glottic stenosis following operations were similar between LWEP and LWES cohorts, 7.6% and 7.5% respectively. CONCLUSION: There appears to be a low risk of glottic involvement resulting from the LWE procedure in iSGS patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:875-882, 2023.

Remotely operated robotic microscopy for rapid diagnosis of bronchoscopic cytology specimens.

BACKGROUND: Obtaining a diagnosis and treating pulmonary malignancies during the same anesthesia requires either an on-site pathologist or a system for remotely evaluating microscopic images. Cytology specimens are challenging to remotely assess given the need to navigate through dispersed and three-dimensional cell clusters. Remote navigation is possible using robotic telepathology, but data are limited on the ease of use of current systems, particularly for pulmonary cytology. METHODS: Air dried modified Wright-Giemsa stained slides from 26 touch preparations of transbronchial biopsies and 27 smears of endobronchial ultrasound guided fine needle aspirations were scored for ease of adequacy assessment and ease of diagnosis on robotic (rmtConnect Microscope) and non-robotic telecytology platforms. Diagnostic classifications were compared between glass slides and the robotic and non-robotic telecytology assessments. RESULTS: Compared to non-robotic telecytology, robotic telecytology had a greater ease of adequacy assessment and non-inferior ease of diagnosis. The median time to diagnosis using robotic telecytology was 85 s (range 28-190 s). Diagnostic categories were concordant for 76% of cases in robotic versus non-robotic telecytology and 78% of cases in robotic telecytology versus glass slide diagnosis. Weighted Cohen's kappa scores for agreement in these comparisons were 0.84 and 0.72, respectively. CONCLUSIONS: Use of a remote-controlled robotic microscope improved the ease of adequacy assessment compared to non-robotic telecytology and enabled strongly concordant diagnoses to be expediently rendered. This study provides evidence that modern robotic telecytology is a feasible and user-friendly method of remotely and potentially intraoperatively rendering adequacy assessments and diagnoses on bronchoscopic cytology specimens.

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.

Risk of aortic valve replacement in patients with aortic stenosis and chronic obstructive pulmonary disease.

BACKGROUND AND AIM OF THE STUDY: Patients with aortic stenosis (AS) and chronic obstructive pulmonary disease (COPD) have been considered at high risk for aortic valve replacement (AVR), which results in some patients being denied this life-saving operation. Hence, the study aim was to assess the operative, 30-day, and long-term mortality in individuals with COPD undergoing AVR for AS in the modern surgical era. METHODS: This retrospective cohort of patients had documented COPD (FEV1/FVC < 70%), and underwent isolated AVR for severe AS between 1993 and 2007 at the Mayo Clinic in Rochester, MN. RESULTS: Of the 68 patients who met the study criteria, 27 had mild/moderate COPD (FEV1 > 50%), 35 had severe COPD (FEV1 30-50%), and six had very severe COPD (FEV1 < 30%). The overall operative and 30-day mortality was 4.8%. More severe COPD was associated with a longer stay in the intensive care unit (42 h for mild/moderate versus 115 h for severe/very severe: p = 0.02), but did not influence the operative or 30-day mortalities. Female gender was associated with an increased length of hospital stay. Long-term mortality was significantly higher in patients with a history of cerebrovascular disease (HR 4.3, p < 0.001), NYHA class III or IV heart failure (class III HR 2.79, p = 0.05; class IV HR 3.97, p = 0.03), and increased age (HR 1.06, p = 0.003). The severity of COPD was an independent risk factor for long-term mortality. CONCLUSION: Patients with severe AS and COPD are at an acceptable risk for AVR (30-day mortality < 5%). The severity of COPD is not associated with an increased in-hospital or 30-day mortality, but does influence long-term mortality.

Recurrence Following Endoscopic Laser Wedge Excision and Triple Medical Therapy for Idiopathic Subglottic Stenosis.

OBJECTIVE: We present the outcomes for patients with idiopathic subglottic stenosis (iSGS) following their first carbon dioxide laser wedge excision (LWE) procedure, additionally examining the effect of compliance with adjuvant medical therapy (triple therapy) after the operation. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary center. METHODS: A retrospective review was performed on 183 patients with iSGS following their first LWE and their compliance to adjuvant medical therapy (inhaled corticosteroid, proton pump inhibitor, trimethoprim-sulfamethoxazole) following the operation, with all reviewed to December 31, 2020. The primary outcome variable was median time to recurrence (MTR). Patients were stratified by whether the LWE was their first operation (LWE primary or secondary), by compliance to triple therapy, and by compliance with trimethoprim-sulfamethoxazole. Kaplan-Meier analysis and Cox proportional hazards were used to evaluate the MTR across the stratifications. RESULTS: An overall 113 patients underwent their first LWE, while 70 received the procedure after having undergone 1 to 13 procedures. The MTR between LWE primary and secondary was 4.6 and 2.9 years, respectively. Adjusted Cox proportional hazards comparing these 2 groups revealed the number of prior operations to be a confounding variable. A statistically increased MTR was demonstrated with greater degrees of medical compliance. CONCLUSION: LWE conferred an MTR of 4.1 years in the iSGS cohort. The number of prior procedures preceding LWE behaved as a confounding variable. Patients who were completely or partially compliant to triple therapy appear to demonstrate increased intervals prior to recurrence.

Prevention of acute exacerbation of chronic obstructive pulmonary disease after bronchoscopic lung volume reduction with endobronchial valves.

INTRODUCTION: Bronchoscopic lung volume reduction (BLVR) with endobronchial valves (EBVs) has emerged as an important treatment method for patients with severe chronic obstructive pulmonary disease (COPD). Acute exacerbations of COPD (AECOPD) are a frequent complication following BLVR with EBV. However, there is no consensus on the prevention of AECOPD. OBJECTIVES: Our study aims to compare the outcomes of different prophylactic measures on the occurrence of AECOPD after BLVR with EBV. METHODS: We conducted a multicenter, retrospective study of patients who underwent BLVR with EBV at six different institutions. Emphasis was directed towards the specific practices aimed at preventing AECOPD: antibiotics, steroids, antibiotics plus steroids, or no prophylaxis. Subgroups were compared, and odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated. RESULTS: A total of 170 patients were reviewed. The rate of AECOPD was 21.2% for the full cohort. Patients who received prophylaxis had a significantly lower rate of AECOPD compared with those who did not (16.7% vs. 46.2%; p = 0.001). The rate was lowest in patients who received antibiotics alone (9.2%). There was no significant difference in the rate of AECOPD between patients who received steroids alone or antibiotics plus steroids, compared with the other subgroups. The OR for AECOPD was 4.3 (95% CI: 1.8-10.4; p = 0.001) for patients not receiving prophylaxis and 3.9 (95% CI: 1.5-10.1; p = 0.004) for prophylaxis other than antibiotics alone. CONCLUSIONS: Administration of antibiotics after BLVR with EBV was associated with a lower rate of AECOPD. This was not observed with the use of steroids or in combination with antibiotics.

Respiratory mucosal immunity against SARS-CoV-2 after mRNA vaccination.

SARS-CoV-2 mRNA vaccination induces robust humoral and cellular immunity in the circulation; however, it is currently unknown whether it elicits effective immune responses in the respiratory tract, particularly against variants of concern (VOCs), including Omicron. We compared the SARS-CoV-2 S-specific total and neutralizing antibody responses, and B and T cell immunity, in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19-vaccinated individuals and hospitalized patients. Vaccinated individuals had significantly lower levels of neutralizing antibody against D614G, Delta (B.1.617.2), and Omicron BA.1.1 in the BAL compared with COVID-19 convalescents despite robust S-specific antibody responses in the blood. Furthermore, mRNA vaccination induced circulating S-specific B and T cell immunity, but in contrast to COVID-19 convalescents, these responses were absent in the BAL of vaccinated individuals. Using a mouse immunization model, we demonstrated that systemic mRNA vaccination alone induced weak respiratory mucosal neutralizing antibody responses, especially against SARS-CoV-2 Omicron BA.1.1 in mice; however, a combination of systemic mRNA vaccination plus mucosal adenovirus-S immunization induced strong neutralizing antibody responses not only against the ancestral virus but also the Omicron BA.1.1 variant. Together, our study supports the contention that the current COVID-19 vaccines are highly effective against severe disease development, likely through recruiting circulating B and T cell responses during reinfection, but offer limited protection against breakthrough infection, especially by the Omicron sublineage. Hence, mucosal booster vaccination is needed to establish robust sterilizing immunity in the respiratory tract against SARS-CoV-2, including infection by the Omicron sublineage and future VOCs.