Airway Caliber Research Articles

Awake Laser Laryngeal Stenosis Surgery.

Awake Laser Laryngeal Stenosis Surgery.

Asthmatics with concordant eosinophilic disease classified according to their serum IgE status

BackgroundEosinophilic inflammation has long been associated with asthma. Looking at systemic and airway eosinophilia, we have recently identified a group of patients exhibiting diffuse eosinophilic inflammation. Among the mechanisms governing eosinophilic inflammation, IgE-mediated mast cell activation is a key event leading to eosinophilia in atopic asthmatics. MethodsWe conducted a retrospective study on our asthma clinic database containing more than 1500 patients and identified 205 asthmatics with successful sputum induction and concordant eosinophilic phenotype. This phenotype was defined as a sputum eosinophil count≥3% and a blood eosinophils concentration≥400cells/mm3. IgE-high atopic phenotype was characterized by the presence of at least one positive specific IgE (>0.35kU/L) to common aeroallergens and a raised total serum IgE (≥113kU/L). ResultsThe largest group of asthmatics displaying concordant eosinophilic phenotype had a raised total serum IgE and atopy (45%). IgE-low non-atopic concordant eosinophilic asthma was a predominantly late onset disease, exhibited a more intense airway eosinophilic inflammation (P<0.05), required more often maintenance treatment with oral corticosteroids (P<0.05) but, surprisingly, had a reduced level of bronchial hyperresponsiveness to methacholine (P<0.05) despite similar baseline airway calibre impairment. ConclusionThe more severe airway eosinophilic inflammation in IgE-low non-atopic asthmatics despite similar treatment with ICS and a higher burden of OCS points to a certain corticosteroid resistance in this asthma phenotype.

Effects of Obesity and Asthma on Lung Function and Airway Dysanapsis in Adults and Children

Obesity increases the risk of developing asthma in children and adults. Obesity is associated with different effects on lung function in children and adults. In adults, obesity has been associated with reduced lung function resulting from a relatively small effect on forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), with the FEV1/FVC ratio remaining unchanged or mildly increased (restrictive pattern). In contrast, in children, obesity is associated with normal or higher FEV1 and FVC but a lower FEV1/FVC ratio (obstructive pattern). This anomaly has recently been associated with a phenomenon known as dysanapsis which results from a disproportionate growth between lung parenchyma size and airway calibre. The mechanisms that promote disproportionate lung parenchyma growth compared with airways in obese children remain to be elucidated. Obesity and dysanapsis in asthma patients might contribute to asthma morbidity by increasing airway obstruction, airway hyper-reactivity and airway inflammation. Obesity and dysanapsis in asthma patients are associated with increased medication use, more emergency department visits, hospitalizations and systemic corticosteroid burst than patients with normal weight. Dysanapsis may explain the reduced response to asthma medications in obese children. Weight loss results in a significant improvement in lung function, airway reactivity and asthma control. Whether these improvements are associated with the changes in the dysanaptic alteration is as yet unclear.

UFP exposure and biomarkers of exposure/effect on small airways in school children

Background/Aim Ultrafine particles (UFP) are of health concern due to their small size and ability to diffuse into the circulatory system once inhaled. However, epidemiological studies of adverse respiratory effects from UFP exposure are uncommon and evidence is varied. There is a scarcity of data on its effects on small airways. We aimed to study associations between UFP exposure and markers of small airways exposure/impacts in school children. Methods We used a time-integrated model for particle number count (PNC) (UFP indicator), which combined measurements at schools and modelled PNC at home using land use and time trends, to assign annual average daily exposure. We measured biomarkers of small airways exposure/impact: respiratory system resistance (Rrs); respiratory system reactance (Xrs); and lung clearance index (LCI); in 577 children recruited from 25 schools. We estimated the effect of exposure to PNC on these outcomes using Bayesian generalised linear mixed effects regression models. Analyses adjusted for potential confounders, using three models: 1) age, sex, height; 2) Model 1 plus BMI, home air conditioning, carpet, garage, gas cooking, gas heating; home flooded or with visible mould (&lt;12 months); blood cotinine levels (ETS); 3) Model 2 plus PM2.5 mass (24 h prior to clinical testing) and annual average daily NO2 exposure. Results The PNC model explained 26% of the variability of PNC measured at the schools. No statistically significant associations were observed between PNC and LCI or Xrs. Protective statistically significant associations were observed for respiratory resistance in Models 1 and 2, but not 3. Conclusions These results do not demonstrate a detrimental effect of UFP on biomarkers of small airways exposure/impact, and the results for resistance (reflecting airway calibre) are counter-intuitive to expected. This might be due to the low predictive capacity of the exposure model, therefore improved exposure measures are needed in future studies.

Novel modes of non-invasive ventilation in chronic respiratory failure: a narrative review.

Home non-invasive ventilation (NIV) is central in the management of chronic hypercapnic respiratory failure and is associated with improvements in clinically relevant outcomes. Home NIV typically involves delivery of fixed positive inspiratory and expiratory airway pressures. These pressures do not reflect physiological changes to respiratory mechanics and airway calibre during sleep, which may impact on physiological efficacy, subsequent clinical outcomes, and therapy adherence. Novel ventilator modes have been designed in an attempt to address these issues. Volume-assured pressure support modes aim to automatically adjust inspiratory pressure to achieve a pre-set target tidal volume. The addition of auto-titrating expiratory pressure to maintain upper airway calibre is designed for patients at risk of upper airway collapse, such as obese patients and those with obstructive sleep apnoea complicating their hypercapnic failure. Heterogeneity in setup protocols, patient selection and trial design limit firm conclusions to be drawn on the clinical efficacy of these modes. However, there are data to suggest that compared to fixed-pressure NIV, volume-assured modes may improve nocturnal carbon dioxide, sleep quality and ventilator adherence in select patients. The use of the forced oscillation technique to identify expiratory flow limitation and adjust expiratory pressure to eliminate it is the most recent addition to these advanced modes and is yet to be assessed in formal clinical trials.

IMPENDING DANGERS IN PATIENTS WITH TRACHEOMALACIA WITH ANXIETY DISORDER/PTSD

SESSION TITLE: Medical Student/Resident Respiratory Care SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Trachea is a D-shaped structure with incomplete cartilaginous rings anteriorly and laterally and straight membranous wall posteriorly. Tracheomalacia is a pathological process that happens due to flaccidity of the supporting cartilage and widening of posterior membranous wall with reduced anterior-posterior airway caliber leading to tracheal collapse. Our case enlightens that adequate control of anxiety symptoms plays an important role in trach management in tracheomalacia patients. CASE PRESENTATION: An 84-year-old man with HTN, COPD, A.fib, HFrEF, PTSD, severe anxiety disorder, h/o CVA with hemorrhagic conversion after tPA, severe L-carotid artery stenosis s/p endarterectomy, stage 1 T1N0M0 SCC of left vocal cord s/p laser resection/XRT, tracheostomy with tracheomalacia. Multiple rapid responses were called because of sudden tachypnea, hypoxemia with cyanosis leading to hypoxic respiratory failure. After each episode he gets transferred to ICU for mechanical ventilation management. Infections were ruled out in most of the case, mucous plugs rarely blocked the tracheostomy tube. Almost all episodes occurred while he was off his anxiety medications. DISCUSSION: The thought of underlying cause leading to hypoxemic respiratory failure was whenever he felt anxious/agitated he flexed his neck and together with the collapse of tracheal wall over the opening of tracheostomy tube this prevented air flow. This is similar to mucus plugs blocking the tube opening. Once his anxiety is well controlled, he relaxes and improves air entry through Tracheostomy tube. CONCLUSIONS: In tracheostomy dependent tracheomalacia patients with anxiety disorder; it is of utmost importance to control anxiety symptoms. Extreme anxiety/agitation from PTSD and anxiety disorder along with flexion of the neck, can compromise air entry into tracheostomy tube, which can result in hypoxemic respiratory failure and within minutes one can have clinical deterioration with death. Reference #1: Carden KA, Boiselle PM, Waltz DA, Ernst A. Tracheomalacia and tracheobronchomalacia in children and adults: an in-depth review. chest. 2005 Mar.127(3):984-1005 DISCLOSURES: No relevant relationships by Moses Bachan, source=Web Response No relevant relationships by Zinobia Khan, source=Web Response No relevant relationships by swetha Nadella, source=Web Response No relevant relationships by Robert Siegel, source=Web Response

Low-Frequency Intrapulmonary Percussive Ventilation Increases Aerosol Penetration in a 2-Compartment Physical Model of Fibrotic Lung Disease.

In patients with fibrotic pulmonary disease such as idiopathic pulmonary fibrosis (IPF), inhaled aerosols deposit mostly in the less affected region of the lungs, resulting in suboptimal pharmacokinetics of airway-delivered treatments. Refinement of aerosol delivery technique requires new models to simulate the major alterations of lung physiology associated with IPF, i.e., heterogeneously reduced lung compliance and increased airway caliber. A novel physical model of the respiratory system was constructed to simulate aerosol drug delivery in spontaneously breathing (negative pressure ventilation) IPF patients. The model comprises upper (Alberta ideal throat) and lower airway (plastic tubing) models and branches into two compartments (Michigan lung models) which differ in compliance and caliber of conducting airway. The model was able to reproduce the heterogeneous, compliance-dependent reduction in ventilation and aerosol penetration (using NaF as a model aerosol) seen in fibrotic lung regions in IPF. Of note, intrapulmonary percussive ventilation induced a 2–3-fold increase in aerosol penetration in the low-compliance/high airway caliber compartment of the model, demonstrating the responsiveness of the model to therapeutic intervention.

Fetal Origins of Asthma: A Longitudinal Study from Birth to Age 36 Years.

Rationale: Deficits in infant lung function-including the ratio of the time to reach peak tidal expiratory flow to the total expiratory time (tptef/te) and maximal expiratory flow at FRC (V̇maxFRC)-have been linked to increased risk for childhood asthma.Objectives: To examine the individual and combined effects of tptef/te and V̇maxFRC in infancy on risk for asthma and abnormalities of airway structure into mid-adult life.Methods: One hundred eighty participants in the Tucson Children's Respiratory Study birth cohort had lung function measured by the chest-compression technique in infancy (mean age ± SD: 2.0 ± 1.2 mo). Active asthma was assessed in up to 12 questionnaires between ages 6 and 36 years. Spirometry and chest high-resolution computed tomographic (HRCT) imaging were completed in a subset of participants at age 26. The relations of infant tptef/te and V̇maxFRC to active asthma and airway structural abnormalities into adult life were tested in multivariable mixed models.Measurements and Main Results: After adjustment for covariates, a 1-SD decrease in infant tptef/te and V̇maxFRC was associated with a 70% (P = 0.001) and 55% (P = 0.005) increased risk of active asthma, respectively. These effects were partly independent, and two out of three infants who were in the lowest tertile for both tptef/te and V̇maxFRC developed active asthma by mid-adult life. Infant V̇maxFRC predicted reduced airflow and infant tptef/te reduced HRCT airway caliber at age 26.Conclusions: These findings underscore the long-lasting effects of the fetal origins of asthma, support independent contributions by infant tptef/te and V̇maxFRC to development of asthma, and link deficits at birth in tptef/te with HRCT-assessed structural airway abnormalities in adult life.

Thoracic Imaging at Exacerbation of Chronic Obstructive Pulmonary Disease: A Systematic Review.

Exacerbations of chronic obstructive pulmonary disease (COPD) are currently diagnosed based on changes in respiratory symptoms. Characterizing the imaging manifestation of exacerbations could be useful for objective diagnosis of exacerbations in the clinic and clinical trials, as well as provide a mechanism for monitoring exacerbation treatment and recovery. In this systematic review, we employed a comprehensive search across three databases (Medline, EMBASE, Web of Science) to identify studies that performed imaging of the thorax at COPD exacerbation. We included 51 from a total of 5,047 articles which met all our inclusion criteria. We used an adapted version of the Modified Newcastle-Ottawa Quality Assessment Scale for cohort studies to assess the quality of the included studies. Conclusions were weighted towards higher-quality articles. We identified a total of 36 thoracic imaging features studied at exacerbation of COPD. Studies were generally heterogeneous in their measurements and focus. Nevertheless, considering studies which performed consecutive imaging at stable state and exacerbation, which scored highest for quality, we identified salient imaging biomarkers of exacerbations. An exacerbation is characterized by airway wall and airway calibre changes, hyperinflation, pulmonary vasoconstriction and imaging features suggestive of pulmonary arterial hypertension. Most information was gained from CT studies. We present the first ever composite imaging signature of COPD exacerbations. While imaging during an exacerbation is comparatively new and not comprehensively studied, it may uncover important insights into the acute pathophysiologic changes in the cardiorespiratory system during exacerbations of COPD, providing objective confirmation of events and a biomarker of recovery and treatment response.

0164 Evidence Suggesting Early Airway Collapse as Cause of Spontaneous Arousals

Abstract Introduction Spontaneous arousals can occur in response to a number of stimuli like noise, movement, hypoxia, or airway obstruction. Some arousals occur “spontaneously” and in individuals donning a hyper-arousable phenotype, spontaneous arousals can dominate the sleep architecture. While arousal mechanisms for some stimuli have been well described, there is a profound lack of knowledge to explain spontaneous arousals. During clinical testing of a device that was designed by SleepMethods, Inc. to anticipate obstructive sleep apnea events by the ability to sense minute airway caliber changes, it was noted, incidentally that the device would signal impeding airway collapse but a spontaneous arousal followed the signal before an obstructive airway event ever developed. This phenomenon was observed many times within and between subjects, suggesting the possibility that very early airway changes are causing “spontaneous arousals” Methods Ten adults (7M;3F) aged 18-80y/o (avg. 54.7y/o) with a known AHI ≥ 15/hr (avg. AHI = 42.6/hr) underwent 1 overnight PSG recording while wearing the device. Patients were required to forego their usual CPAP therapy on the night of study in efforts to expose the device to an adequate number of total obstructive events (defined as apneas and hypopneas; RERAs and snores were excluded). Standard PSG analysis was performed. Scoring rules were applied to determine whether signals were true/false positives and/or true/false negatives based on pre-clinical data showing anticipation accuracy for up to 45 seconds prior to an obstructive airway event. Signals designed to herald obstructive events were noted, incidentally, appearing prior to spontaneous arousals. Results Preliminary results suggest that early phases of airway collapse, as the airway progresses from patency to clinically significant obstruction, are causing EEG arousals which, by current standards, are considered “spontaneous”. Because these findings were incidental to another primary purpose of the clinical study, data analysis is in early stages but currently suggesting at least an associative relationship. Conclusion If final data analysis shows statistically significant correlation between early airway collapse and “spontaneous arousals”, it may have tremendous implications for patients with hyper-arousability, insomnia, and/or pathologically elevated spontaneous arousal indices by proposing therapies aimed at airway patency maintenance. Support N/A

Asthma: A Loss of Post-natal Homeostatic Control of Airways Smooth Muscle With Regression Toward a Pre-natal State.

The defining feature of asthma is loss of normal post-natal homeostatic control of airways smooth muscle (ASM). This is the key feature that distinguishes asthma from all other forms of respiratory disease. Failure to focus on impaired ASM homeostasis largely explains our failure to find a cure and contributes to the widespread excessive morbidity associated with the condition despite the presence of effective therapies. The mechanisms responsible for destabilizing the normal tight control of ASM and hence airways caliber in post-natal life are unknown but it is clear that atopic inflammation is neither necessary nor sufficient. Loss of homeostasis results in excessive ASM contraction which, in those with poor control, is manifest by variations in airflow resistance over short periods of time. During viral exacerbations, the ability to respond to bronchodilators is partially or almost completely lost, resulting in ASM being “locked down” in a contracted state. Corticosteroids appear to restore normal or near normal homeostasis in those with poor control and restore bronchodilator responsiveness during exacerbations. The mechanism of action of corticosteroids is unknown and the assumption that their action is solely due to “anti-inflammatory” effects needs to be challenged. ASM, in evolutionary terms, dates to the earliest land dwelling creatures that required muscle to empty primitive lungs. ASM appears very early in embryonic development and active peristalsis is essential for the formation of the lungs. However, in post-natal life its only role appears to be to maintain airways in a configuration that minimizes resistance to airflow and dead space. In health, significant constriction is actively prevented, presumably through classic negative feedback loops. Disruption of this robust homeostatic control can develop at any age and results in asthma. In order to develop a cure, we need to move from our current focus on immunology and inflammatory pathways to work that will lead to an understanding of the mechanisms that contribute to ASM stability in health and how this is disrupted to cause asthma. This requires a radical change in the focus of most of “asthma research.”

Real-word experience with mepolizumab: Does it deliver what it has promised?

Randomized control trials performed in selected populations of severe eosinophilic asthmatics have shown that mepolizumab, an anti-IL5 therapy, was able to reduce exacerbations and OCS maintenance dose and in some studies, to improve asthma control and lung function. The aim of this study was to confirm the results of the RCTs in real-life in a population of 116 severe eosinophilic asthmatics treated with mepolizumab and who were followed up at the asthma clinic every month for at least 18 months. Severe asthmatics underwent FENO, lung function, asthma control and quality of life questionnaires, sputum induction and gave a blood sample at baseline, after 6 months and then every year. We found a significant reduction in exacerbations by 85% after 6 months (P < .0001), which was maintained over time. We also found a significant and maintained reduction by 50% in the dose of oral corticosteroids (P < .001). Patients improved their ACT (+5.31pts, p<0.0001) ACQ (-1.13pts, P < .0001) and their AQLQ score (+1.24, P < .0001) at 6 months and this was maintained during follow-up. Only 37% reached asthma control (ACQ <1.5, ACT> 20). We observed a progressive increase in post-BD FEV1 that reached significance after 18 months (190ml or 11%, P < .01). Patients improving their FEV1had higher baseline sputum eosinophils than those not improving airway caliber. We found a significant reduction in sputum eosinophil counts by 60% after 6 months (P < .01) and a maintained reduction in blood eosinophil counts by 98% (P < .0001). In our real-life study, we confirm the results published in the RCTs showing a sharp reduction in exacerbation and oral corticosteroids dose and an improvement in asthma control and quality of life. Mepolizumab is efficient in severe eosinophilic asthma in real life.

Effectiveness of omalizumab on patient reported outcomes, lung function, and inflammatory markers in severe allergic asthma

BackgroundOmalizumab arose as a therapeutic option in patients suffering from moderate to severe refractory allergic asthma. It acts as a humanized monoclonal antibody neutralizing circulating IgE antibodies. Randomized clinical trials and real life clinical studies have already confirmed benefits, cost-effectiveness and applicability of the medication. MethodOur study retrospectively reports on the clinical outcomes and airway inflammation in 157 severe allergic asthmatics who were initiated with omalizumab between 2007 and 2019. ResultsAfter 4 months of therapy, 76% of the patients were judged to have benefited from omalizumab and were admitted to prolonged treatment. During follow-up, we observed an improvement in asthma control, quality of life and spirometric performance. There was also a sustained reduction in exacerbation rate over the years. As for T2 biomarkers, FeNO significantly decreased and, in a subgroup of patients who had repeated sputum inductions, there was also significant reduction in sputum eosinophils but no change in blood eosinophil count. Lastly, we found a correlation between high FeNO levels at baseline and reduction in ACQ scores at 1 year. ConclusionWe conclude that omalizumab shows effectiveness in severe allergic asthma in a real life setting, by reducing exacerbation rate, improving patient perspective outcomes and airway calibre, together with reducing type-2 airway inflammation.

Corticomotor control of airway calibre in obstructive sleep apnoea syndrome.

Corticomotor control of airway calibre in obstructive sleep apnoea syndrome.

Spirometry in Central Asian Lowlanders and Highlanders, a Population Based Study.

Introduction: The purpose of the study was to establish spirometric reference values for a Central Asian population of highlanders and lowlanders.Methods: Spirometries from a population-based cross-sectional study performed in 2013 in rural areas of Kyrgyzstan were analyzed. Using multivariable linear regression, Global Lung Function Initiative (GLI) equations were fitted separately for men and women, and altitude of residence (700–800 m, 1,900–2,800 m) to data from healthy, never-smoking Kyrgyz adults. The general GLI equation was applied: Predicted value=ea0+a1× ln(Height)+a2× ln(Age)+b1× ln(Age100)+b2× ln(Age100)2+b3× ln(Age100)3 +b4× ln(Age100)4+b5× ln(Age100)5Results: Of 2,784 screened Kyrgyz, 448 healthy, non-smoking highlanders (379 females) and 505 lowlanders (368 females), aged 18–91 years, were included. Predicted FVC in Kyrgyz fit best with GLI “North-East Asians,” predicted FEV1 fit best with GLI “Other/Mixed.” Predicted FEV1/FVC was lower than that of all GLI categories. Age- and sex-adjusted mean FVC and FEV1 were higher in highlanders (+0.138l, +0.132l) than in lowlanders (P < 0.001, all comparisons), but FEV1/FVC was similar.Conclusion: We established prediction equations for an adult Central Asian population indicating that FVC is similar to GLI “North-East Asian” and FEV1/FVC is lower than in all other GLI population categories, consistent with a relatively smaller airway caliber. Central Asian highlanders have significantly greater dynamic lung volumes compared to lowlanders, which may be due to environmental and various other effects.

Regional lung deflation with increased airway volume underlies the functional response to bronchodilators in chronic obstructive pulmonary disease.

Bronchodilators, including long‐acting muscarinic antagonists (LAMAs), improve airflow limitation and lung hyperinflation in patients with chronic obstructive pulmonary disease (COPD). While bronchodilators increase airway caliber and deflate the lungs, little is known about the effects of the local interaction between airway dilation and lung deflation on functional improvements resulting from bronchodilator therapy. This study aimed to explore whether lung deflation with increased airway volume in the upper and lower lung regions would produce different physiological responses to LAMA therapy. Using the clinical data of 41 patients with COPD who underwent spirometry and inspiratory computed tomography (CT) before and 1 year after LAMA treatment, we measured the 1‐year change in the airway tree to lung volume percentage ratio (AWV%) for the right upper, middle, and lower lobes (RUL, RML, and RLL) and the left upper and lower lobes (LUL and LLL), and total airway count (TAC) identifiable on CT in relation to the forced expiratory volume in 1 s (FEV1). The results showed that LAMA treatment significantly increased the FEV1 and AWV% of the RUL, RML, RLL, LUL, and LLL. Increased AWV% in the RLL and LLL, but not in the RUL and LUL, was correlated with increased FEV1. In the multivariate analysis, the increased AWV% in the RLL was associated with the increased FEV1 independent of the change in TAC in the RLL after treatment. This is the first study to show that the physiological improvements after bronchodilator treatment in COPD could be mainly due to the combination of regional deflation and increased airway volume of the lower lobes.

Children with Asthma Have Fixed Airway Obstruction through Childhood Unaffected by Exacerbations

Children with asthma may have a disease course with or without exacerbations, but the relationship between exacerbations and lung function development is poorly understood. To compare lung function trajectories from birth till adolescence in asthmatic children with and without exacerbations. Children with asthma from the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) birth cohort had lung function and bronchial reactivity assessed repeatedly from 1 month to 13 years. Exacerbations were diagnosed at the COPSAC clinic defined as symptoms requiring hospitalization, oral or high-dose inhaled corticosteroid treatment. Mixed models were applied to analyze lung function trajectories. Children with asthma with exacerbations (N= 50) had a trajectory of increased, fixed airway obstruction compared with children without exacerbations (N= 47): z-score difference in airway resistance (sRawz) (95% confidence interval [CI]):+0.34 (+0.03;+0.66), P= .03, and maximal mid-expiratory flow (MMEFz):-0.41 (-0.69;-0.13), P= .004, but no differences in forced expiratory volume (FEVz):-0.14 (-0.41;+0.13), P= .29, or bronchial reactivity to methacholine (PDz):+0.08 (-0.26;+0.42), P= .65. This did not change comparing lung function trajectories before and after exacerbations: z-score difference (95% CI) sRawz:-0.04 (-0.35; 0.27), P= .80; MMEFz: 0.01 (-0.02; 0.04), P= .55; FEVz: 0.02 (-0.02; 0.05), P= .42; and PDz:-0.01 (-0.06; 0.05), P= .88. Children with asthma with exacerbations compared with children with asthma without exacerbations are characterized by increased airway obstruction since infancy through childhood. The airway obstruction is a fixed trajectory without progression due to exacerbations, suggesting that exacerbations are a consequence rather than a cause of diminished airway caliber in childhood.

Associations of Prenatal Dietary Inflammatory Potential with Childhood Respiratory Outcomes in Project Viva

Inflammation during pregnancy may be a factor in the developmental programming of asthma and wheeze in childhood. To examine associations of inflammatory potential of prenatal diet with respiratory outcomes in early childhood and midchildhood. Among 1424 mother-child pairs in Project Viva, a prebirth cohort, we examined associations of Dietary Inflammatory Index (DII®) (first trimester, second trimester, and average of first and second trimesters) scores in relation to ever asthma and wheezing in the past year (early childhood and midchildhood); current asthma and lung function (midchildhood), and wheeze trajectory during 1 to 9 years. We used multivariable linear and logistic regression modeling, adjusting for relevant confounders. In a fully adjusted analysis, a more proinflammatory diet was associated with an early versus never wheeze trajectory (first- and second-trimester average fourth vs first quartile: odds ratio, 1.89; 95% CI, 1.14-3.13). A more proinflammatory diet during pregnancy also was associated with lower forced expiratory flow (forced expiratory flow at 25%-75%) in midchildhood (first- and second-trimester average fourth vs first quartile: β,-132 mL; 95% CI,-249 to-14). Results were evident for first-, but not second-, trimester DII and wheeze trajectory and midchildhood forced expiratory flow at 25% to 75%. Other child respiratory outcomes, including ever asthma, were not related to any DII measure during pregnancy. Proinflammatory diet during pregnancy is associated with wheeze trajectory during early childhood and decrements in small airways caliber in midchildhood, but not other respiratory outcomes in the offspring.

Ensifentrine (RPL554): an investigational PDE3/4 inhibitor for the treatment of COPD

ABSTRACTIntroduction: A compound that simultaneously inhibits PDE3 and PDE4 should increase airway caliber by relaxing the smooth muscle and, simultaneously, suppress airway inflammatory responses. Ensifentrine (RPL554) is considered a PDE3/4 inhibitor, although its affinity for PDE3 is 3,440 times higher than that for PDE4, that is under clinical development for the treatment of asthma and COPD and, potentially, cystic fibrosis.Areas covered: We analyze the development of this molecule from its basic pharmacology to the present clinical Phase II studies.Expert opinion: Ensifentrine is an interesting drug but there is a lack of solid studies that still does not allow us to correctly allocate this molecule in the current COPD and even asthma therapeutic armamentarium. Furthermore, apparently ensifentrine has not yet entered Phase III clinical development and, in any case, there is no reliable evidence of its ability to elicit an anti-inflammatory activity in patients with COPD or asthma. Therefore, the real anti-inflammatory profile of ensifentrine must be clarified with new studies of basic pharmacology and adequate clinical studies specifically designed. However, at present the most intriguing perspective is linked to its possible use in the treatment of cystic fibrosis, also considering the lack of valid therapeutic options for this disease.Trial registration: ClinicalTrials.gov identifier: NCT03937479.

Laryngo-tracheal stenosis in a woman with ablepharon macrostomia syndrome

BackgroundAblepharon macrostomia syndrome (AMS) is a rare congenital malformation disorder caused by the autosomal-dominant mutations in gene TWIST2. Patients affected by the disease present abnormalities in ectoderm-derived structures mainly consisting in major facial dysmorphic features and rarely in visceral anomalies. The only laryngo-tracheal defect reported is malacia, with no reference to any anatomical stenosis. We describe a unique case of laryngo-tracheal stenosis in a woman, with genetically confirmed AMS currently followed at our Department.Case presentationA 37-year-old Caucasian woman was admitted to the intensive care unit for acute dyspnea that required orotracheal intubation followed by tracheostomy.The bronchoscopy revealed abnormal tracheal tissue at the level of the cricoid and the first three tracheal rings reducing airway caliber by 80% (grade III according to the Cotton-Meyer classification). Treatment of the stenosis by means of temporary tracheostomy and corticosteroids therapy resulted in airway patency restoration and patient’s return to her normal activities. Bronchoscopy at four and five months showed disappearance of the abnormal tissue and a residual anatomical laryngo-tracheal stenosis of about 20% (grade I according to the Cotton-Meyer classification) of the normal airway caliber.ConclusionsTo our knowledge, this is the first patient affected by AMS presenting with laryngo-tracheal stenosis.