The treatable traits approach to adults with obstructive airways disease in primary and secondary care.

The treatable traits approach is based on the recognition that the different clinical phenotypes of asthma and chronic obstructive airways disease (COPD) are a heterogeneous group of conditions with different underlying mechanisms and clinical manifestations, and that the identification and treatment of the specific clinical features or traits facilitates a personalised approach to management. Fundamentally, it recognises two important concepts. Firstly, that treatment for obstructive lung disease can achieve better outcomes if guided by specific clinical characteristics. Secondly, that in patients with a diagnosis of asthma, and/or COPD, poor respiratory health may also be due to numerous overlapping disorders that can present with symptoms that may be indistinguishable from asthma and/or COPD, comorbidities that might require treatment in their own right, and lifestyle or environmental factors that, if addressed, might lead to better control rather than simply increasing airways directed treatment. While these concepts are well accepted, how best to implement this personalised medicine approach in primary and secondary care within existing resource constraints remains uncertain. In this review, we consider the evidence base for this management approach and propose that the priority now is to assess different prototype templates for the identification and management of treatable traits in both asthma and COPD, in primary, secondary and tertiary care, to provide the evidence that will guide their use in clinical practice in different health care systems.

Molecular markers of type 2 airway inflammation are similar between eosinophilic severe asthma and eosinophilic chronic obstructive pulmonary disease.

BACKGROUND: Airway and systemic eosinophilia are important treatable traits in both severe asthma and COPD. The molecular basis of eosinophilia in COPD is poorly understood but could involve type 2 cytokines (IL5, IL13) and prostaglandin D2 (PGD2 ). METHODS: This study included non-obstructive airways disease (OAD) controls (n = 19), a COPD cohort (n = 96) and a severe asthma cohort (n = 84). Demographics, exacerbation history, disease impact (SGRQ) and spirometry were assessed. Participants were categorized as eosinophilic using either sputum eosinophil proportion (≥3%) or blood eosinophil count (≥300/µL). Sputum type 2 inflammatory measures included PGD2 by ELISA and gene expression (qPCR) of IL5, IL13 and the haematopoietic PGD2 synthase (HPGDS). RESULTS: Type 2 markers did not differ across groups except HPGDS mRNA which was highest in non-OAD controls and lowest in COPD. IL5 and IL13 mRNA and PGD2 levels were significantly increased in eosinophilic vs non-eosinophilic severe asthma but did not differ between eosinophilic COPD and eosinophilic severe asthma or non-eosinophilic COPD. HPGDS expression was higher in eosinophilic severe asthma compared with eosinophilic COPD. Results were similar using sputum or blood eosinophil cut-offs. Sputum IL5 and IL13 were highly intercorrelated in severe asthma (r = 0.907, p < 0.001) and COPD (r = 0.824, p < 0.001), were moderately correlated with sputum eosinophils in severe asthma (IL5 r = 0.440, p < 0.001; IL13 r = 0.428, p < 0.001) and were weakly correlated in COPD (IL5 r = 0.245, p < 0.05; IL13 r = 0.317, p < 0.05). CONCLUSIONS: Molecular markers of type 2 airway inflammation do not differ between eosinophilic asthma and eosinophilic COPD; however, the relationship between eosinophilia and type 2 airway markers appears weaker in COPD than in severe asthma.

Twenty-Year Reflection on the Impact of World Trade Center Exposure on Pulmonary Outcomes in Fire Department of the City of New York (FDNY) Rescue and Recovery Workers.

After the terrorist attacks on September 11, 2001 (9/11), many rescue/recovery workers developed respiratory symptoms and pulmonary diseases due to their extensive World Trade Center (WTC) dust cloud exposure. Nearly all Fire Department of the City of New York (FDNY) workers were present within 48 h of 9/11 and for the next several months. Since the FDNY had a well-established occupational health service for its firefighters and Emergency Medical Services workers prior to 9/11, the FDNY was able to immediately start a rigorous monitoring and treatment program for its WTC-exposed workers. As a result, respiratory symptoms and diseases were identified soon after 9/11. This focused review summarizes the WTC-related respiratory diseases that developed in the FDNY cohort after 9/11, including WTC cough syndrome, obstructive airways disease, accelerated lung function decline, airway hyperreactivity, sarcoidosis, and obstructive sleep apnea. Additionally, an extensive array of biomarkers has been identified as associated with WTC-related respiratory disease. Future research efforts will not only focus on further phenotyping/treating WTC-related respiratory disease but also on additional diseases associated with WTC exposure, especially those that take decades to develop, such as cardiovascular disease, cancer, and interstitial lung disease.

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.

Quantitative lung morphology: semi-automated measurement of mean linear intercept.

BACKGROUND: Quantifying morphologic changes is critical to our understanding of the pathophysiology of the lung. Mean linear intercept (MLI) measures are important in the assessment of clinically relevant pathology, such as emphysema. However, qualitative measures are prone to error and bias, while quantitative methods such as mean linear intercept (MLI) are manually time consuming. Furthermore, a fully automated, reliable method of assessment is nontrivial and resource-intensive. METHODS: We propose a semi-automated method to quantify MLI that does not require specialized computer knowledge and uses a free, open-source image-processor (Fiji). We tested the method with a computer-generated, idealized dataset, derived an MLI usage guide, and successfully applied this method to a murine model of particulate matter (PM) exposure. Fields of randomly placed, uniform-radius circles were analyzed. Optimal numbers of chords to assess based on MLI were found via receiver-operator-characteristic (ROC)-area under the curve (AUC) analysis. Intraclass correlation coefficient (ICC) measured reliability. RESULTS: We demonstrate high accuracy (AUCROC > 0.8 for MLIactual > 63.83 pixels) and excellent reliability (ICC = 0.9998, p < 0.0001). We provide a guide to optimize the number of chords to sample based on MLI. Processing time was 0.03 s/image. We showed elevated MLI in PM-exposed mice compared to PBS-exposed controls. We have also provided the macros that were used and have made an ImageJ plugin available free for academic research use at https://med.nyu.edu/nolanlab. CONCLUSIONS: Our semi-automated method is reliable, equally fast as fully automated methods, and uses free, open-source software. Additionally, we quantified the optimal number of chords that should be measured per lung field.

End-of-life care in general practice: A cross-sectional, retrospective survey of 'cancer', 'organ failure' and 'old-age/dementia' patients.

BACKGROUND: End-of-life care is often provided in primary care settings. AIM: To describe and compare general-practitioner end-of-life care for Dutch patients who died from 'cancer', 'organ failure' and 'old-age or dementia'. DESIGN: A cross-sectional, retrospective survey was conducted within a sentinel network of general practitioners. General practitioners recorded the end-of-life care of all patients who died (1 January 2009 to 31 December 2011). Differences in care between patient groups were analysed using multivariate logistic regressions performed with generalised linear mixed models. SETTING/PARTICIPANTS: Up to 63 general practitioners, covering 0.8% of the population, recorded the care of 1491 patients. RESULTS: General practitioners personally provided palliative care for 75% of cancer, 38% of organ failure and 64% of old-age/dementia patients (adjusted odds ratio (confidence interval): cancer (reference category); organ failure: 0.28 (0.17, 0.47); old-age/dementia: 0.31 (0.15, 0.63)). In the week before death, 89% of cancer, 77% of organ failure and 86% of old-age/dementia patients received palliative treatments: (adjusted odds ratio (confidence interval): cancer (reference category); old-age/dementia: 0.54 (0.29, 1.00); organ failure: 0.38 (0.16, 0.92)). Options for palliative care were discussed with 81% of cancer, 44% of organ failure and 39% of old-age/dementia patients (adjusted odds ratio (confidence interval): cancer (reference category); old-age/dementia: 0.34 (0.21, 0.57); organ failure: 0.17 (0.08, 0.36)). CONCLUSION: The results highlight the need to integrate palliative care with optimal disease management in primary practice and to initiate advance care planning early in the chronic disease trajectory to enable all patients to live as well as possible with progressive illness and die with dignity and comfort.

There is No Fast Track to Identify Fast Decliners in Alpha-1 Antitrypsin Deficiency by Spirometry: A Longitudinal Study of Repeated Measurements.

BACKGROUND: It is known that lung function decline in Alpha-1 Antitrypsin Deficiency (AATD) varies. Those with a rapid decline are at highest risk of poorer outcomes but may benefit most from targeted treatments including augmentation therapy. Current evidence suggests rapid decliners can be identified after 3 years of serial follow-up. It would be advantageous to identify these patients over a shorter time period, especially in mild disease. METHODS: Post-bronchodilator spirometry was performed every 6 months for a total of 18 months (4 measurements) by PiZZ AATD patients (ex- or never-smokers) either without spirometric COPD or with mild COPD. Where possible, retrospective spirometry data were included. Decline was assessed using 2 (baseline and 6 month) or four measurements (including baseline, 6, 12 and 18 months) and compared to retrospective decline rates using annual measurements over 3 years. RESULTS: Seventy-two PiZZ AATD patients were included, with 27 having at least three years of retrospective, annual spirometry. 18-month progression obtained by linear regression showed variable degrees of change with 29 showing no decline, 8 showing slow decline and 35 showing rapid decline. Bland-Altman plots showed that there was no overall agreement between predicted rate of decline using data obtained over 6 months and that obtained over 18 months. Furthermore, there was no agreement between rate of decline from either 6 or 18 months' data when compared to data collected over 3 years. The positive predictive value for rapid decline with 18 months of data compared to 3 years was only 50.0%. CONCLUSION: This study suggests serial lung function over 18 months cannot identify AATD patients who have rapidly declining lung function. There is an urgent need for different biomarkers to help identify these patients at the earliest opportunity.

Acute hypercapnic respiratory failure and its management on the acute medical take.

Acute hypercapnic respiratory failure accounts for 50 000 hospital admissions each year in the UK. This article discusses the pathophysiology and common causes of acute hypercapnic respiratory failure, and provides practical considerations for patient management in acute medical settings. Non-invasive ventilation for persistent acute hypercapnic respiratory failure is widely recognised to improve patient outcomes and reduce mortality. National audits highlight a need to improve patients' overall care and outcomes through appropriate patient selection and treatment initiation. Multidisciplinary involvement is essential, as this underpins inpatient care and follow up after hospital discharge. New non-invasive ventilation modalities may offer better patient comfort and compensate better for sleep-related changes in respiratory mechanics. Emerging therapies, such as nasal high flow, may offer an alternative treatment approach in those who cannot tolerate non-invasive ventilation, but more research is required to completely understand its effectiveness in treating acute hypercapnic respiratory failure.

"A breath of fresh air" for tackling chronic disease in Ireland? An evaluation of a self-management support service for people with chronic respiratory diseases.

OBJECTIVE: To describe the impact of a nurse-led telephone self-management support (SMS) service for people with asthma and COPD in Ireland. METHODS: A cross-sectional survey of all (442) SMS users, July 2016 to May 2017, described user demographics, self-reported experience, process and outcome. Population utilisation was estimated and compared across groups. Factors associated with key outcomes were identified. RESULTS: The response rate was 162 (36.7%). Utilisation varied across population groups. Reported satisfaction was high, and 56.0% of users without a written action plan reported developing one. Most users reported positive cognitive and affective outcomes indicating effective patient activation. Information pack receipt was independently associated with better outcomes (odds ratio = 11.4 (95% CI, 2.0, 216.6), p < 0.05). CONCLUSION: A nurse-led telephone SMS intervention positively impacted self-management for people with asthma and COPD in Ireland. PRACTICE IMPLICATIONS: Roll-out of SMS should include staff training to promote positive service user experience and should include routine monitoring and evaluation to assure equitable reach and quality of key evidence-based care processes.

Fractal Analysis of Lung Structure in Chronic Obstructive Pulmonary Disease.

Chest CT is often used for localizing and quantitating pathologies associated with chronic obstructive pulmonary disease (COPD). While simple measurements of areas and volumes of emphysema and airway structure are common, these methods do not capture the structural complexity of the COPD lung. Since the concept of fractals has been successfully applied to evaluate complexity of the lung, this review is aimed at describing the fractal properties of airway disease, emphysema, and vascular abnormalities in COPD. An object forms a fractal if it exhibits the property of self-similarity at different length scales of evaluations. This fractal property is governed by power-law functions characterized by the fractal dimension (FD). Power-laws can also manifest in other statistical descriptors of structure such as the size distribution of emphysema clusters characterized by the power-law exponent D. Although D is not the same as FD of emphysematous clusters, it is a useful index to characterize the spatial pattern of disease progression and predict clinical outcomes in patients with COPD. The FD of the airway tree shape and the D of the size distribution of airway branches have been proposed indexes of structural assessment and clinical predictions. Simulations are also useful to understand the mechanism of disease progression. Therefore, the power-law and fractal analysis of the parenchyma and airways, especially when combined with computer simulations, could lead to a better understanding of the structural alterations during the progression of COPD and help identify subjects at a high risk of severe COPD.

Longstanding tracheobronchomalacia: A forgotten cause of severe cough and its response to roflumilast.

This case report describes a patient with moderately severe tracheobronchomalacia following mycoplasma pneumonia. The patient was considered to have obstructive lung disease despite no prior smoking or lung disease and failure to respond to standard treatment. The possibility of tracheal pathology causing cough and sputum was not considered in 23yrs confirming this to be a "forgotten zone". The patient was treated with Roflumilast to reduce airway secretions with great success and the Immunology of Roflumilast is discussed.

Real-life treatment of rhinitis in Australia: a historical cohort study of prescription and over-the-counter therapies for patients with and without additional respiratory disease.

BACKGROUND: The aim of the study was to explore rhinitis therapy purchases in different Australian regions for patients with and without additional respiratory disease, using both doctor's prescriptions and over-the-counter (OTC) medications. PATIENTS AND METHODS: It was a historical cohort study of pharmacy-related claims that included prescription or OTC rhinitis therapy, with or without asthma/COPD therapy, from January 2013 to December 2014. RESULTS: Overall, 4,247,193 prescription and OTC rhinitis treatments were purchased from 909 pharmacies over a calendar year; the majority were single-therapy purchases for rhinitis only patients. More multiple-therapy was purchased for rhinitis and asthma/COPD patients (4.4%) than for rhinitis only patients (4.0%), with a greater proportion purchased in VIC, SA and TAS (4.7% of rhinitis only patients and 4.5% of rhinitis and asthma/COPD patients) than in other areas. Dual therapy of oral antihistamine (OAH) and intranasal corticosteroid (INS) were the most frequently purchased multiple-therapy, with higher purchasing rates for rhinitis and asthma/COPD patients (2.6%) than for rhinitis only patients (1.6%). The most frequently purchased single therapy was OAH (70.1% of rhinitis only patients and 57.3% of rhinitis and asthma/COPD patients). First-line INS therapy was more likely to be purchased for rhinitis and asthma/COPD patients (15.3% by prescription and 11.7% OTC) than for rhinitis only patients (5.0% by prescription and 9.2% OTC); however, geographical differences in the proportion of therapies purchased OTC were noted, with a lower proportion of OTC OAH and INS purchases in Queensland and the Northern Territory for patients with and without comorbid respiratory disease. CONCLUSION: Purchases of first-line INS therapy are more likely for patients with comorbid respiratory disease if they have received prescriptions and information/advice from their general practitioner. The study results indicate a need for patient information/education at the point-of-sale of OTC OAHs to enable patients to assess their nasal symptoms and receive treatment support from pharmacists. Greater availability to INSs in pharmacies as well as guidance from current guidelines and instruction in correct intranasal technique may also lead to greater uptake of INSs.

Occupational exposure to vapor, gas, dust, or fumes and chronic airflow limitation, COPD, and emphysema: the Swedish CArdioPulmonary BioImage Study (SCAPIS pilot).

BACKGROUND: The aim of this study was to estimate the occupational burden of airflow limitation, chronic airflow limitation, COPD, and emphysema. MATERIALS AND METHODS: Subjects aged 50-64 years (n=1,050) were investigated with forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC). Airflow limitation was defined as FEV1/FVC <0.7 before bronchodilation. Chronic airflow limitation was defined after bronchodilation either according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) as FEV1/FVC <0.7 or according to the lower limit of normal (LLN) approach as FEV1/FVC < LLN. COPD was defined as chronic airflow limitation (GOLD) in combination with dyspnea, wheezing, or chronic bronchitis. Emphysema was classified according to findings from computed tomography of the lungs. Occupational exposure was defined as self-reported occupational exposure to vapor, gas, dust, or fumes (VGDF). Odds ratios (OR) were calculated in models adjusted for age, gender, and smoking; population-attributable fractions and 95% CI were also calculated. RESULTS: There were significant associations between occupational exposure to VGDF and COPD (OR 2.7, 95% CI 1.4-51), airflow limitation (OR 1.8, 95% CI 1.3-2.5), and emphysema (OR 1.8, 95% CI 1.1-3.1). The associations between occupational exposure to VGDF and chronic airflow limitation were weaker, and for the OR, the CIs included unity. The population-attributable fraction for occupational exposure to VGDF was 0.37 (95% CI 0.23-0.47) for COPD and 0.23 (95% CI 0.05-0.35) for emphysema. CONCLUSION: The occupational burden of COPD and computed tomography-verified emphysema is substantial.

The Effect of World Trade Center Exposure on the Timing of Diagnoses of Obstructive Airway Disease, Chronic Rhinosinusitis, and Gastroesophageal Reflux Disease.

OBJECTIVES: In a cohort of rescue/recovery workers exposed to the dust that resulted from the collapse of the World Trade Center (WTC), we assessed how a diagnosis of obstructive airways disease (OAD) affected the likelihood of a subsequent diagnosis of chronic rhinosinusitis (CRS) or gastroesophageal reflux disease (GERD). We also assessed whether OAD acted as a mediator of the association between exposure to the WTC rescue/recovery effort and CRS and GERD diagnoses. METHODS: In this prospective cohort study, we analyzed Fire Department of the City of New York physician diagnoses of OAD, CRS, and GERD that were first documented between September 11, 2001, and September 10, 2011, among 8,968 WTC-exposed firefighters. We used piecewise exponential survival models to evaluate whether OAD was a risk factor for either CRS or GERD and to assess OAD as a possible mediator. RESULTS: An OAD diagnosis significantly increased the risks for subsequent CRS [relative rate (RR), 4.24; 95% CI, 3.78-4.76] and GERD (RR, 3.21; 95% CI, 2.93-3.52) diagnoses. Further, 21% of the WTC exposure effect (high vs. low intensity) on GERD and 13% of the effect (high vs. low intensity) on CRS were mediated by a prior OAD diagnosis. CONCLUSION: Individuals with an OAD diagnosis had elevated risks for subsequent diagnoses of CRS or GERD. Part of the effect of WTC exposure on CRS and GERD diagnoses is mediated by prior diagnoses of OAD; this mediation effect of OAD may reflect biological pathways or healthcare utilization practices.

A case series evaluating the serological response of adult asthma patients to the 23-valent pneumococcal polysaccharide vaccine.

BACKGROUND: Asthma is an independent risk factor for invasive pneumococcal disease; however, the immune response of adult asthma patients to pneumococcal vaccination is unknown. We explore the serologic response of patients with moderate to severe asthma to the 23-valent pneumococcal polysaccharide vaccine (PPSV23). METHODS: Seventeen moderate to severe adult asthma patients that had not been vaccinated against pneumococcus over the 5 previous years were prospectively recruited from a tertiary care asthma clinic. Serum was analyzed for the presence of antibodies to five capsular polysaccharide (CP) antigens (6B, 9V, 19A, 19F, 23F) before and 4 weeks after PPSV23 vaccination. RESULTS: There was a wide variability in baseline anti-CP antibody concentrations. Other than for serotype 19A, our patients frequently have baseline anti-CP antibody concentrations below 1 µg/mL (35% for serotype 19F, 41% for serotypes 9V and 23F, and 59% for serotype 6B). All post-vaccination geometric mean antibody concentrations were significantly higher than baseline. In the 31 tests where the baseline antibody concentration was <1 µg/mL, 77.4% had at least a twofold increase post-vaccination. Despite this, a large proportion of post-vaccination anti-CP antibody concentrations remained <1 µg/mL (51.6% of tests). Nine patients had at least one anti-CP antibody concentration <1 µg/mL post-vaccination. There was no difference between these patients and the remaining eight patients in demographic or clinical variables. CONCLUSIONS: Patients with moderate to severe asthma have variable baseline and low post-vaccination antibody concentrations to common CP antigens included in the PPSV23 vaccine. The clinical relevance of these observations remains to be determined since the threshold concentration in adults required for clinical protection from invasive pneumococcal disease is uncertain.

No change in prevalence of symptoms of COPD between 1996 and 2006 in Finnish adults - a report from the FinEsS Helsinki Study.

BACKGROUND: The age-dependent increase of chronic obstructive pulmonary disease (COPD) prevalence caused by smoking and other inhalational exposures in the general population is well-known worldwide. However, time trends are poorly known, due to lower number of high-quality studies especially following nationwide efforts on diminishing exposure levels. This study aimed to compare the prevalence of COPD symptoms and their major determinants in Finnish adults in 1996 and 2006. METHODS: Two identical postal surveys were conducted among two random population samples from Helsinki using identical methodologies in 1996 and 2006, with 6,062 (76%) and 2,449 (62%) participants, respectively. RESULTS: The physician-diagnoses of COPD remained at 3.7%, whereas physician-diagnoses of asthma and use of asthma medicines increased in both genders. Current smoking reduced from 33.4 to 27.3% (p<0.001), and the amount of cigarettes smoked also reduced significantly. The crude prevalence of chronic productive cough was 12.1 and 11.1%, wheezing with dyspnoea without a cold (wheezing triad) 7.3 and 7.7%, and dyspnoea grade II 13.8 and 13.6%, in 1996 and 2006, respectively. Among subjects with physician-diagnosed COPD, the prevalences of chronic productive cough and recurrent wheeze reduced significantly, from 60.6 to 40.7% and 53.5 to 38.5%, respectively. CONCLUSION: From 1996 to 2006, the prevalence of obstructive airway symptoms common in different phenotypes of COPD did not increase in Finnish adults. This suggests that the upward trend of COPD prevalence might have reached a plateau. Current smoking and the quantities smoked diminished suggesting a wider impact of stronger legislation and smoking-cessation efforts during the Finnish National Programme for COPD.

Chronic obstructive pulmonary disease part 2: non-pharmacological therapy.

Chronic obstructive pulmonary disease (COPD) is a common, progressive and disabling disease that causes significant burden to patients, their families, and the NHS. Research suggests that the complexity of factors contributing to the disease requires a deeper understanding of the patient experience and a more holistic approach to care provision. This, the second of two articles, discusses the non-pharmacological therapies for managing patients with COPD and explores the concept of mindfulness as a therapy in the management of breathlessness.

Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Pulmonary hypertension due to lung diseases and/or hypoxia.

Chronic lung diseases are common causes of pulmonary hypertension. It ranks second after the left heart disease. Both obstructive and restrictive lung diseases are know to cause pulmonary hypertension. The pathophysiology of the disease is complex, and includes factors affecting the blood vessels, airways, and lung parenchyma. Hypoxia and the inhalation of toxic materials are another contributing factors. Recent guidelines have further clarified the association between pulmonary hypertension and chronic lung disease and made general guidelines concerning the diagnosis and management. In this article, we will provide a detailed revision about the new classification and give general recommendations about the management of pulmonary hypertension in chronic lung diseases.