Molecular Mechanisms and Physiological Changes behind Benign Tracheal and Subglottic Stenosis in Adults.

Laryngotracheal stenosis (LTS) is a complex and heterogeneous disease whose pathogenesis remains unclear. LTS is considered to be the result of aberrant wound-healing process that leads to fibrotic scarring, originating from different aetiology. Although iatrogenic aetiology is the main cause of subglottic or tracheal stenosis, also autoimmune and infectious diseases may be involved in causing LTS. Furthermore, fibrotic obstruction in the anatomic region under the glottis can also be diagnosed without apparent aetiology after a comprehensive workup; in this case, the pathological process is called idiopathic subglottic stenosis (iSGS). So far, the laryngotracheal scar resulting from airway injury due to different diseases was considered as inert tissue requiring surgical removal to restore airway patency. However, this assumption has recently been revised by regarding the tracheal scarring process as a fibroinflammatory event due to immunological alteration, similar to other fibrotic diseases. Recent acquisitions suggest that different factors, such as growth factors, cytokines, altered fibroblast function and genetic susceptibility, can all interact in a complex way leading to aberrant and fibrotic wound healing after an insult that acts as a trigger. However, also physiological derangement due to LTS could play a role in promoting dysregulated response to laryngo-tracheal mucosal injury, through biomechanical stress and mechanotransduction activation. The aim of this narrative review is to present the state-of-the-art knowledge regarding molecular mechanisms, as well as mechanical and physio-pathological features behind LTS.

Pulmonary Stretch and Lung Mechanotransduction: Implications for Progression in the Fibrotic Lung.

Lung fibrosis results from the synergic interplay between regenerative deficits of the alveolar epithelium and dysregulated mechanisms of repair in response to alveolar and vascular damage, which is followed by progressive fibroblast and myofibroblast proliferation and excessive deposition of the extracellular matrix. The increased parenchymal stiffness of fibrotic lungs significantly affects respiratory mechanics, making the lung more fragile and prone to non-physiological stress during spontaneous breathing and mechanical ventilation. Given their parenchymal inhomogeneity, fibrotic lungs may display an anisotropic response to mechanical stresses with different regional deformations (micro-strain). This behavior is not described by the standard stress-strain curve but follows the mechano-elastic models of "squishy balls", where the elastic limit can be reached due to the excessive deformation of parenchymal areas with normal elasticity that are surrounded by inelastic fibrous tissue or collapsed induration areas, which tend to protrude outside the fibrous ring. Increasing evidence has shown that non-physiological mechanical forces applied to fibrotic lungs with associated abnormal mechanotransduction could favor the progression of pulmonary fibrosis. With this review, we aim to summarize the state of the art on the relation between mechanical forces acting on the lung and biological response in pulmonary fibrosis, with a focus on the progression of damage in the fibrotic lung during spontaneous breathing and assisted ventilatory support.

Incidental finding of bronchial diverticula in a non-smoker population: evaluation on thin-section CT.

Bronchial diverticula have been described as a common radiological finding in smoker patients with COPD, but the specificity of this sign should be further investigated. Thus, the aim of our study was to evaluate the prevalence of diverticula in a cohort of non-smoker subjects. Between February and July 2012, 2438 patients were admitted to our Radiology Unit to undergo a chest CT. Among them, we enrolled 121 non-smoking patients (78/121-64.5% females, 43/121-35.5% males), of different age (57.0±20.7 years-range: 12-88), without any respiratory symptoms, submitted to chest CT for several reasons (oncologic evaluation: 59/121-48.8%; follow up of lung nodules: 27/121-22.3%; screening in connectivitis: 12/121-9.9%; others: 23/121-19.0%). We considered thin-section CT scan on axial, coronal and sagittal plans to evaluate prevalence, numbers and level of bronchial diverticula. Diverticula were found in 41/121-33.9% patients, with a slight major prevalence in males (p=0.048), but no significant difference on age. In 31/41-75.6% the number was <3, whereof 17/31-54.8% with just one diverticulum assessed. Regarding the level, in 30/41-73.2% they were subcarinal, but they were also detected in mainstem (2/41-4.9%) and lobar bronchi (with the right upper lobe bronchus most frequently involved- 12/41-29.3%). Bronchial diverticula can be observed in non-smokers, as well as in smoker patients with COPD. However, their prevalence seems to be lower than in smokers and they tend to be isolated and subcarinal. The age of patients does not influence their finding. More studies should be proposed to better define a cut-off between smokers and healthy subjects.

Risk Factors for Pulmonary Air Leak and Clinical Prognosis in Patients With COVID-19 Related Acute Respiratory Failure: A Retrospective Matched Control Study.

Background: The role of excessive inspiratory effort in promoting alveolar and pleural rupture resulting in air leak (AL) in patients with SARS-CoV-2 induced acute respiratory failure (ARF) while on spontaneous breathing is undetermined. Methods: Among all patients with COVID-19 related ARF admitted to a respiratory intensive care unit (RICU) and receiving non-invasive respiratory support, those developing an AL were and matched 1:1 [by means of PaO2/FiO2 ratio, age, body mass index-BMI and subsequent organ failure assessment (SOFA)] with a comparable population who did not (NAL group). Esophageal pressure (ΔPes) and dynamic transpulmonary pressure (ΔPL) swings were compared between groups. Risk factors affecting AL onset were evaluated. The composite outcome of ventilator-free-days (VFD) at day 28 (including ETI, mortality, tracheostomy) was compared between groups. Results: Air leak and NAL groups (n = 28) showed similar ΔPes, whereas AL had higher ΔPL (20 [16-21] and 17 [11-20], p = 0.01, respectively). Higher ΔPL (OR = 1.5 95%CI[1-1.8], p = 0.01), positive end-expiratory pressure (OR = 2.4 95%CI[1.2-5.9], p = 0.04) and pressure support (OR = 1.8 95%CI[1.1-3.5], p = 0.03), D-dimer on admission (OR = 2.1 95%CI[1.3-9.8], p = 0.03), and features suggestive of consolidation on computed tomography scan (OR = 3.8 95%CI[1.1-15], p = 0.04) were all significantly associated with AL. A lower VFD score resulted in a higher risk (HR = 3.7 95%CI [1.2-11.3], p = 0.01) in the AL group compared with NAL. RICU stay and 90-day mortality were also higher in the AL group compared with NAL. Conclusion: In spontaneously breathing patients with COVID-19 related ARF, higher levels of ΔPL, blood D-dimer, NIV delivery pressures and a consolidative lung pattern were associated with AL onset.

Stenting versus balloon dilatation in patients with tracheal benign stenosis: The STROBE trial.

Background: It is well known that benign tracheal stenosis represents an obstacle to open surgery, and that its treatment could be challenging. Two endoscopic techniques have so far been adopted to restore tracheal patency: balloon dilatation (BA) through laryngoscopy, and tracheal stenting (ST) with rigid bronchoscopy. The main objective of this study was to compare the efficacy of BA and ST to treat benign tracheal stenosis not eligible for surgery. We also compared the rate of adverse events in the two treatment groups. Methods: A retrospective, observational cohort study was carried out at the University Hospital of Modena (Italy) from November 2012 to November 2017 in two separate departments. Patients were considered to be "stabilized" (primary outcome) if they did not report significant respiratory symptoms, or restenosis in the long-term (2 years) following the endoscopic procedure. Results: Sixty-six patients were included in the study (33 in the BA and 33 in the ST group, respectively). Unadjusted Kaplan-Meier estimates showed a greater therapeutic effect of ST compared to BA at 2 years (hazard ratio = 3.9 95%CI [1.5-9.8], p = .01). After adjusting for confounders, stratified analyses showed that this effect was significant in patients with complex stenosis, idiopathic etiology, and degree of stenosis >70%. Compared with BA, ST showed a higher rate of adverse events (p = .01). Conclusions: Compared to BA, ST seems to be more effective in achieving stabilization of tracheal patency in complex benign tracheal stenosis, although burdened with a significantly higher number of adverse effects. These findings warrant future prospective study for confirmation. Level of evidence: 3.

Changes in Clinical Characteristics and Outcomes of Patients Admitted to Inpatient Cardiac Rehabilitation.

AIMS: Cardiac rehabilitation (CR) has proven to be effective and beneficial in middle-aged and older patients. However, solid data in large cohorts of elderly individuals are yet to be explored. This retrospective study investigated the general characteristics, outcomes, and the level of response of patients referred to CR over 13 consecutive years. METHODS: We reviewed the medical records of patients admitted to Villa Pineta Rehabilitation Hospital for exercise-based CR from 2006 to 2018. The patients' baseline characteristics and changes following CR in an upper-limb weightlifting test (ULW), 30-s sit-to-stand test (30STS), and the 6-min walking test (6MWT) with associated Borg-related dyspnea (D) and fatigue (F) were collected. We also calculated the number of individuals that reached the minimal clinically relevant change (MCRC) following CR for each outcome. RESULTS: One thousand five hundred and fifty-one patients (70.2 ± 9.7 years, 66% men) with complete datasets were included in the analysis. Coronary artery bypass graft and cardiac valve replacement surgery were the most frequent surgical procedures leading to CR referral (41.1% and 35.8%, respectively). The patients' age (p = 0.03), number of total comorbidities (p < 0.0001), and post-surgical complications (p = 0.02) significantly increased over time. In contrast, the average absolute changes in ULW, 30STS, and 6MWT with associated D and F, and the proportion of patients that reached their respective MCRC, remained constant over the same period. CONCLUSION: The patients admitted to exercise-based CR were older and had more comorbidities and complications over time. The outcomes, however, were not influenced in terms of the absolute change or clinically meaningful response.

A retrospective review of the role of B-mode and color Doppler ultrasonography in the investigation of primary hyperparathyroidism: Features that differentiate benign from malignant lesions.

PURPOSE: To identify the variant features encountered in parathyroid abnormalities and document those suggesting malignant change. MATERIALS AND METHODS: Data were collected from a cohort of patients who underwent investigation for primary hyperparathyroidism over a 10-year period. Ultrasonographic features: shape, presence of calcification, cystic changes, heterogeneous echogenicity, vascularity, capsular thickening, local invasion, and vascularity were reviewed retrospectively and were used to correlate with final histological findings. RESULTS: One hundred forty-seven patients with histology and concurrent ultrasonographic scans were reviewed, and divided into benign parathyroid lesions (nodular hyperplasia (n = 44), adenoma (n = 93)) and parathyroid carcinoma (n = 10). Parathyroid carcinomas were significantly larger than benign parathyroid lesions (P = 0.030). Benign parathyroid lesions showed variant sonographic features: irregular shape (16.8%), heterogenous echogenicity (24.1%), calcification (1.5%), capsular thickening (1.5%), and cystic change (19.7%). A significantly higher proportion of parathyroid carcinomas demonstrated heterogenous echogenicity (P = 0.022), capsular thickening (P = 0.023), and infiltrative margin (P < 0.0001) than benign parathyroid lesions. Of the 137 benign parathyroid lesions, 38 (27.7%), 76 (55.5%), 23 (16.8%) were avascular, vascular, and hypervascular, respectively. Of the 10 parathyroid carcinomas, 4 (40%), 3 (30%), and 3 (30%) of lesions were avascular, vascular, and hypervascular, respectively. The vascularity of the lesions did not differ significantly between the parathyroid carcinoma and benign parathyroid lesions (P = 0.281). CONCLUSION: Ultrasonographic features such as irregular shape, heterogeneous echogenicity, cystic change, and vascularity are nondiscriminatory features between benign or malignant lesions. Large lesion size together with the presence of calcification, capsular thickening, or infiltrative margin strongly raises the suspicion of a malignant parathyroid lesion, and management should be altered.