The need for physiological phenotyping to develop new drugs for airways disease.

Asthma and COPD make up the majority of obstructive airways diseases (OADs), which affects ∼11 % of the population. The main drugs used to treat OADs have not changed in the past five decades, with advancements mainly comprising variations on existing treatments. The recent biologics are beneficial to only specific subsets of patients. Part of this may lie in our inability to adequately characterise the tremendous heterogeneity in every aspect of OAD. The field is currently moving towards the concept of personalised medicine, based on a focus on treatable traits that are objective, measurable and modifiable. We propose extending this concept via the use of emerging clinical tools for comprehensive physiological phenotyping. We describe, based on published data, the evidence for the use of functional imaging, gas washout techniques and oscillometry, as well as potential future applications, to more comprehensively assess and predict treatment response in OADs. In this way, we hope to demonstrate how physiological phenotyping tools will improve the way in which drugs are prescribed, but most importantly, will facilitate development of new drugs for OADs.

Steroid insensitive fixed airflow obstruction is not related to airway inflammation in older non-smokers with asthma.

There is limited evidence linking airway inflammation and lung function impairment in older non-smoking asthmatics with fixed airflow obstruction (FAO), which can develop despite treatment with inhaled corticosteroids (ICS). We assessed lung function (spirometry, forced oscillation technique (FOT)), lung elastic recoil and airway inflammation using bronchoalveolar lavage (BAL) in non-smoking adult asthmatics with FAO, following 2 months treatment with high-dose ICS/long-acting beta-agonist. Subjects demonstrated moderate FAO, abnormal FOT indices and loss of lung elastic recoil. This cross-sectional study showed a lack of a relationship between BAL neutrophils, eosinophils, inflammatory cytokines and lung function impairment. Other inflammatory pathways or the effect of inflammation on lung function over time may explain FAO development.

Greater parallel heterogeneity of airway narrowing and airway closure in asthma measured by high-resolution CT.

BACKGROUND: Heterogeneous airway narrowing and closure are characteristics of asthma. However, they have never been quantified by direct measurements of parallel sister airways obtained from image data, and the anatomical basis of these processes remains unknown. METHODS: Seven normal and nine asthmatic subjects underwent high-resolution CT, before and after methacholine challenge. Mean lumen areas of the entire airways were measured in 28 and 24 parallel sister airway pairs (a pair of airways arising from the same bifurcation) respectively (range 1.0-8.7 mm diameter). Heterogeneous narrowing was defined as the median difference in percentage narrowing between parallel sister airways. Forced oscillatory respiratory resistance (Rrs) and spirometry were measured before and after methacholine challenge conducted while supine. RESULTS: The airways of asthmatics were smaller at baseline, and following bronchoconstriction there were similar decreases in FEV1, increases in Rrs and mean narrowing of airways for asthmatic and non-asthmatic groups. Non-asthmatics required higher doses of methacholine than asthmatics to achieve the same changes. However, parallel heterogeneity (median (IQR) 33% (27-53%) vs 11% (9-18%), p<0.001) and airway closure (24.1% and 7.7%, p=0.001, χ(2)) were greater in asthmatics versus non-asthmatics. CONCLUSION: We found clear evidence of differences in airway behaviour in the asthmatic group. Asthmatic airways were narrower at baseline and responded to inhaled methacholine by more heterogeneous narrowing of parallel sister airways and greater airway closure.

Small airways function declines after allogeneic haematopoietic stem cell transplantation.

Bronchiolitis obliterans (BO) following allogeneic haematopoietic stem cell transplantation (HSCT) affects peripheral airways. Detection of BO is presently delayed by the low sensitivity of spirometry. We examined the relationship between peripheral airway function and time since HSCT, and compared it with spirometry and clinical indices in 33 clinically stable allogeneic HSCT recipients. The following measurements were performed: lung function, exhaled nitric oxide, forced oscillatory respiratory system resistance and reactance, acinar (S(acin)) and conductive airways ventilation heterogeneity and lung clearance index (LCI) measured by multiple breath nitrogen washout. 22 patients underwent repeat visits from which short-term changes were examined. Median time post HSCT was 12 months. Eight patients were clinically diagnosed as having BO. In multivariate analysis, time since HSCT was predicted by S(acin) and forced expiratory volume in 1 s % predicted. 20 patients had abnormal S(acin) with normal spirometry, whereas none had airflow obstruction with normal S(acin). S(acin) and LCI were the only measures to change significantly between two visits, with both worsening. Change in S(acin) was the only parameter to correlate with change in chronic graft-versus-host disease grade. In conclusion, peripheral airways ventilation heterogeneity worsens with time after HSCT. S(acin) may be more sensitive than spirometry in detecting BO at an early stage, which needs confirmation in a prospective study.

Acute bilateral phrenic nerve neuropathy causing hypercapnic respiratory associated with checkpoint inhibitor immunotherapy.

We present two cases of acute hypercapnic respiratory failure due to diaphragmatic dysfunction secondary to bilateral phrenic nerve paralysis, in patients who were receiving immunotherapy for melanoma. Bilateral diaphragmatic paralysis is an uncommon cause of acute or sub-acute hypercapnic respiratory failure which causes severe breathlessness, orthopnoea and potentially death. Immune checkpoint inhibitors are now standard of care in several solid organ malignancies. However, their use is associated with a risk of developing autoimmune toxicities, which includes mononeuritis. Our two cases demonstrate the potential difficulties in recognising acute hypercapnic respiratory failure and diagnosis of the rare disorder of bilateral diaphragmatic dysfunction, with consequent delays in appropriate management. The occurrence of this rare condition in association with checkpoint inhibitor immunotherapy suggests a possible autoimmune mechanism. Awareness that this rare cause of respiratory failure may occur in patients receiving checkpoint inhibitor therapy might facilitate earlier diagnosis and treatment.

Obesity alters the topographical distribution of ventilation and the regional response to bronchoconstriction.

Obesity is associated with reduced operating lung volumes that may contribute to increased airway closure during tidal breathing and abnormalities in ventilation distribution. We investigated the effect of obesity on the topographical distribution of ventilation before and after methacholine-induced bronchoconstriction using single-photon emission computed tomography (SPECT)-computed tomography (CT) in healthy subjects. Subjects with obesity (n = 9) and subjects without obesity (n = 10) underwent baseline and postbronchoprovocation SPECT-CT imaging, in which Technegas was inhaled upright and followed by supine scanning. Lung regions that were nonventilated (Ventnon), low ventilated (Ventlow), or well ventilated (Ventwell) were calculated using an adaptive threshold method and were expressed as a percentage of total lung volume. To determine regional ventilation, lungs were divided into upper, middle, and lower thirds of axial length, derived from CT. At baseline, Ventnon and Ventlow for the entire lung were similar in subjects with and without obesity. However, in the upper lung zone, Ventnon (17.5 ± 10.6% vs. 34.7 ± 7.8%, P < 0.001) and Ventlow (25.7 ± 6.3% vs. 33.6 ± 5.1%, P < 0.05) were decreased in subjects with obesity, with a consequent increase in Ventwell (56.8 ± 9.2% vs. 31.7 ± 10.1%, P < 0.001). The greater diversion of ventilation to the upper zone was correlated with body mass index (rs = 0.74, P < 0.001), respiratory system resistance (rs = 0.72, P < 0.001), and respiratory system reactance (rs = -0.64, P = 0.003) but not with lung volumes or basal airway closure. Following bronchoprovocation, overall Ventnon increased similarly in both groups; however, in subjects without obesity, Ventnon only increased in the lower zone, whereas in subjects with obesity, Ventnon increased more evenly across all lung zones. In conclusion, obesity is associated with altered ventilation distribution during baseline and following bronchoprovocation, independent of reduced lung volumes.NEW & NOTEWORTHY Using ventilation SPECT-computed tomography imaging in healthy subjects, we demonstrate that ventilation in obesity is diverted to the upper lung zone and that this is strongly correlated with body mass index but is independent of operating lung volumes and of airway closure. Furthermore, methacholine-induced bronchoconstriction only occurred in the lower lung zone in individuals who were not obese, whereas in subjects who were obese, it occurred more evenly across all lung zones. These findings show that obesity-associated factors alter the topographical distribution of ventilation.

Increased airway closure is a determinant of airway hyperresponsiveness.

In order to investigate whether increased airway closure is a component of airway hyperresponsiveness (AHR), airway closure was compared during induced bronchoconstriction in 62 asthmatic, 41 nonasthmatic nonobese (control) and 20 nonasthmatic obese (obese) subjects. Airway closure and airway narrowing were measured by spirometry as percentage change in forced vital capacity (%DeltaFVC) and change in forced expiratory ratio (DeltaFER), respectively. Multiple regression analyses were used to assess the determinants of AHR, assessed by the dose response slope (DRS). The DRS was significantly increased in asthmatics compared with controls but did not differ between obese and controls. The spirometric predictors of logDRS were baseline FER, DeltaFER, body mass index (BMI) and %DeltaFVC. There was a negative relationship between BMI and logDRS in the regression, suggesting a protective effect. The present findings suggest that the extent of airway closure during induced bronchoconstriction is a determinant of airway hyperresponsiveness, independent of the level of airway narrowing. However, after adjusting for airway closure, obesity appears to protect against airway hyperresponsiveness.

Effect of obesity on breathlessness and airway responsiveness to methacholine in non-asthmatic subjects.

BACKGROUND: Obesity is associated with increased prevalence and incidence of asthma, but the mechanism is unknown. Obesity reduces lung volumes, which can increase airway responsiveness, and increases resistive and elastic work of breathing, which can increase dyspnea. OBJECTIVE: To determine if the intensity of dyspnea due to airway narrowing or if airway responsiveness is increased in obese, non-asthmatic subjects. SUBJECTS: Twenty-three obese (BMI (body mass index) > or =30 kg m(-2)) and 26 non-obese (BMI <30 kg m(-2)) non-asthmatic subjects, aged between 18 and 70 years. METHODS: High-dose methacholine challenge was used to determine the sensitivity and the maximal response to methacholine. Respiratory system resistance (Rrs) and reactance were measured, using the forced oscillation technique, as indicators of resistive and elastic loads during challenge. Perception of dyspnea was measured by the Borg score during challenge. Static lung volumes were measured by body plethysmography. RESULTS: Static lung volumes were reduced in the obese subjects. There were no significant differences in the sensitivity or maximal response to methacholine between obese and non-obese subjects. The magnitude of change in Rrs was similar in both groups, but obese subjects had more negative reactance after challenge (P=0.002) indicating a greater elastic load. The intensity of dyspnea was greater in obese subjects (P=0.03). CONCLUSIONS: Obesity reduces lung volumes, but does not alter the sensitivity or maximal response to methacholine. However, obese subjects have enhanced perception of dyspnea, associated with greater apparent stiffness of the respiratory system, and may therefore be at greater risk of symptoms.

Pulmonary embolism: comparison of gadolinium-enhanced MR angiography with contrast-enhanced spiral CT in a porcine model.

RATIONALE AND OBJECTIVES: The purpose of this study was to compare gadolinium-enhanced magnetic resonance (MR) angiography with contrast material-enhanced computed tomography (CT) for the detection of small (4-5-mm) pulmonary emboli (PE), with a methacrylate cast of the porcine pulmonary vasculature used as the diagnostic standard. MATERIALS AND METHODS: In 15 anesthetized juvenile pigs, colored methacrylate beads (5.2 and 3.8 mm diameter-the size of segmental and subsegmental emboli in humans) were injected via the left external jugular vein. After embolization, MR angiographic and CT images were obtained. The pigs were killed, and the pulmonary arterial tree was cast in clear methacrylate, allowing direct visualization of emboli. Three readers reviewed CT and MR angiographic images independently and in random order. RESULTS: Forty-nine separate embolic sites were included in the statistical analysis. The mean sensitivity (and 95% confidence intervals) for CT and MR angiography, respectively, were 76% (68%-82%) and 82% (75%-88%) (P > .05); the mean positive predictive values, 92% (85%-96%) and 94% (88%-97%) (P > .05). In this porcine model, PE were usually seen as parenchymal perfusion defects (98%) with MR angiography and as occlusive emboli (100%) with CT. CONCLUSION: MR angiography is as sensitive as CT for the detection of small PE in a porcine model.

Asthma programmes in diverse regions of the world: challenges, successes and lessons learnt.

International surveys have demonstrated that asthma is still underdiagnosed and undertreated in many parts of the world. Despite improvements in the standard of asthma care delivered in many areas, as evidenced by improved global asthma mortality data, much information on projects and programmes undertaken in resource-limited regions of the world is not in the public domain. The aim of this report is to review projects and programmes in diverse regions around the world so that health care providers, planners and consumers may draw on the successes, failures and lessons learnt. Such real world experiences may contribute to achieving Global Initiative for Asthma goals of asthma control. Asthma projects and programmes in Argentina, Australia, Brazil, China, Japan, Mexico, Philippines, Russia, South Africa and Turkey were discussed by a group of experts in asthma care, the Advancing Asthma Care Network, from their respective countries, over a course of three satellite meetings in 2010. Collective analyses consistently identified low rates of dissemination and implementation of national and international treatment guidelines, low levels of continuing medical education and training of primary health care professionals and access and distribution of inhaled corticosteroids to be major barriers that are critical to the overall success of a national asthma management programme. In the less developed asthma programmes, under-recognition and undertreatment further limited the success of the programmes. Evidence from well-established national asthma management programmes suggests that establishment of a successful programme entails a logical progression through specific developmental stages, starting with political/stakeholder endorsement and commitment, followed by epidemiological evaluation, evaluation of disease burden, evaluation of access to care and best therapy, and finally optimisation and maintenance therapy for individual patients.

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma.

Excessive airway obstruction is the cause of symptoms and abnormal lung function in asthma. As airway smooth muscle (ASM) is the effecter controlling airway calibre, it is suspected that dysfunction of ASM contributes to the pathophysiology of asthma. However, the precise role of ASM in the series of events leading to asthmatic symptoms is not clear. It is not certain whether, in asthma, there is a change in the intrinsic properties of ASM, a change in the structure and mechanical properties of the noncontractile components of the airway wall, or a change in the interdependence of the airway wall with the surrounding lung parenchyma. All these potential changes could result from acute or chronic airway inflammation and associated tissue repair and remodelling. Anti-inflammatory therapy, however, does not "cure" asthma, and airway hyperresponsiveness can persist in asthmatics, even in the absence of airway inflammation. This is perhaps because the therapy does not directly address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM. In the present study, a central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored.

Airway dimensions measured from micro-computed tomography and high-resolution computed tomography.

Volume averaging results in both over- and underestimation of airway dimensions when they are measured by high-resolution computed tomography (HRCT). The current authors calibrated computerised measurements of airway dimensions from HRCT against a novel three-dimensional micro-computed tomography (CT) standard, which has a 50-fold greater resolution, as well as against traditional morphometry. Inflation-fixed porcine lung cubes were scanned by HRCT and micro-CT. A total of 59 lumen area (Ai), 30 wall area (A(aw)) and 11 lumen volume (Vi) measurements were made. Ai was measured from the cut surface of 11 airways by morphometry. Airways in scanned images were matched using branching points. After calibration, the errors of Ai, A(aw) and Vi HRCT measurements were determined. The current authors found a systematic, size-dependent underestimation of Ai and overestimation of A(aw) from HRCT measurements. This was used to calibrate an HRCT measurement algorithm. The 95% limits of agreement of subsequent measurements were +/-3.2 mm2 for Ai, +/-4.3 mm2 for A(aw), and +/-11.2 mm3 for Vi with no systematic error. Morphometric measurements agreed with micro-CT (+/-2.5 mm2) without systematic error. In conclusion, micro-computed tomography image data from inflation-fixed airways can be used as calibration standards for three-dimensional lumen volume measurements from high-resolution computed tomography, while morphometry is acceptable for two-dimensional measurements. The image dataset could be used to validate other developmental three-dimensional segmentation algorithms.

(1S)-1-ethyl-2-methylpropyl 3,13-dimethylpentadecanoate: major sex pheromone component of Paulownia bagworm, Clania variegata.

The Paulownia bagworm, Clania variegata Snell. (Lepidoptera: Psychidae), is one of the most significant forest defoliators in China. In gas chromatographic (GC)-electroantennographic detection analyses of pheromone gland extracts of female C. variegata on three GC columns (DB-5, DB-23, DB-210), two compounds (A and B) elicited strong responses from male antennae. The more abundant component B was isolated by high-performance liquid chromatography and identified as 1-ethyl-2-methylpropyl 3,13-dimethylpentadecanoate by transesterification, GC-mass spectrometry (MS), and comparison of its spectral and GC retention characteristics with those of synthetic compounds. In field trapping experiments in China, racemic and (1S)-1-ethyl-2-methylpropyl 3,13-dimethylpentadecanoate [but not the (1R)-stereoisomer] attracted male C. variegata. The absolute configuration of B (a molecule with three chiral centers) and the structure of component A remain to be determined.

The effects of body weight on airway calibre.

Increased wheeze and asthma diagnosis in obesity may be due to reduced lung volume with subsequent airway narrowing. Asthma (wheeze and airway hyperresponsiveness), functional residual capacity (FRC) and airway conductance (Gaw) were measured in 276 randomly selected subjects aged 28-30 yrs. Data were initially adjusted for smoking and asthma before examining relationships between weight and FRC (after adjustment for height), and between body mass index (BMI = weight.height(-2)) and Gaw (after adjustment for FRC) by multiple linear regression, separately for females and males. For males and females, BMI (+/-95% confidence interval) was 27.0+/-4.6 kg.m(-2) and 25.6+/-6.0 kg.m(-2) respectively, Gaw was 0.64+/-0.04 L.s(-1).cmH2O(-1) and 0.57+/-0.03 L.s(-1).cmH2O(-1), and FRC was 85.3+/-3.4 and 84.0+/-2.9% of predicted. Weight correlated independently with FRC in males and females. BMI correlated independently and inversely with Gaw in males, but only weakly in females. In conclusion, obesity is associated with reduced lung volume, which is linked with airway narrowing. However, in males, airway narrowing is greater than that due to reduced lung volume alone. The mechanisms causing airway narrowing and sex differences in obesity are unknown.

The mechanics of exaggerated airway narrowing in asthma: the role of smooth muscle.

Although non-specific bronchial hyperresponsiveness (NSBH) is a basic mechanism underlying the excessive, labile airway narrowing which is characteristic of asthma, its mechanism remains unknown. It is still unclear if the phenomenon is due to fundamental changes in the phenotype of the smooth muscle or is caused by structural and/or mechanical changes in the non-contractile elements of the airway wall or by alterations in the relationship of the airway wall to the surrounding lung parenchyma. Although airway wall remodeling may contribute to NSBH there is increasing evidence that the bronchodilating response to cyclic and periodic stretch is impaired in asthma. There are at least two different mechanisms by which periodic length and force oscillations could influence airway smooth muscle shortening and airway narrowing. These processes which have been called 'perturbed equilibrium of myosin binding' and 'plasticity' have different biochemical and mechanical mechanisms and consequences. They have the potential to interact and to have a fundamental effect on the shortening capacity of airway smooth muscle and its ultimate ability to cause excessive airway narrowing.

Self-organization in a multicore fiber laser array.

We explain an observed spontaneous transition to the high-brightness, in-phase array state of a seven-core ytterbium-doped fiber laser array [IEEE Photonics Technol. Lett. 13, 439 (2001)]. The responsible mechanism is nonlinear refraction, and either in-phase or antiphase array modes can be selected by control of pump intensity. The phenomenon appears to be robust and scalable.

Carbamazepine-induced pneumonitis.

OBJECTIVE: To present a case of a rare pulmonary reaction to carbamazepine. CLINICAL FEATURES: One month after starting carbamazepine therapy, a previously well 38-year-old man developed pulmonary interstitial pneumonitis associated with debilitating systemic symptoms, the cause of which was not diagnosed for a further three months. Transbronchial lung biopsy showed granulomatous inflammation consistent with an allergic drug reaction. INTERVENTION AND OUTCOME: The patient's clinical status, chest x-ray appearance and arterial blood gas tensions all normalised after withdrawal of the drug without any specific therapy. CONCLUSION: Pneumonitis is a rare adverse reaction to carbamazepine therapy. However, awareness may reduce delays in both diagnosis and withdrawal of the drug.

Optical isomers of 3,13-dimethylheptadecane: Sex pheromone components of the western false hemlock looper,Nepytia freemani (Lepidoptera: Geometridae).

(3S, 13R)-3, 13-Dimethylheptadecane [(3S, 13R)-3, 13-dime-17Hy] is the major pheromone component of the western false hemlock looper (WFHL),Nepytia freemani. In comparative gas chromotographic-electroantennographic detection (GC-EAD) analyses of stereoselectively synthesized isomers, 1 pg of (3S, 13R)-dime-17Hy elicited significantly stronger electrophysiological responses by male WFHL antennae than did 1 pg of separately injected (3R, 13R)-, (3R, 13S)- or (3S, 13S)-3, 13-dime-17Hy. In field experiments with individually tested stereoisomers. (3S, 13R)-3, 13-dime-17Hy was the only stereoisomer to attract males, but the four-stereoisomer blend was 3.6 times more attractive. Quaternary and all binary combinations of (3S, 13R)-3, 13-dime-17Hy with the other stereoisomers were equally attractive, suggesting that synergisytic behavioral activity in WFHL resided with either one of (3R, 13R)-, (3R, 13S)-, or (3S, 13S)-3, 13-dime-17Hy. Because optical isomers of (di)methylhydrocarbons do not separate on currently available columns, it remains unknown whether female WFHL also produce a four-stereoisomer pheromone blend. Substitutionality of pheromone stereoisomers without loss of behavioural activity has not previously been reported, but favorably compares with the concept of pheromone redundancy that was first suggested for the multiple pheromone component blend of the cabbage looper moth,Trichoplusia ni.