American Thoracic Association Research Articles

THE PROFILE OF THE LEVEL OF ENDOGENOUS NO IN MIGRAINE SUFFERERS

Migraine is a health problem which had big impact. A neurochemistry change in the dura, that is the increase of the amount of nitrite oxide, originated from an excessive NOS (inducible NOS) activation during ictal. Some researchers assume NO as a main cause of the pain intensity in ictal. Migraine diagnosis is guided by the International Headache Society. Hopefully, this examination can be used as a more objective diagnosis in the future. Methode of this research is descriptive analytic. This study to find the level of endogenous exhaled NO on 91 subject, consisting of 30 normal people, 31 interictal, 30 ictal. An exclusion was done previously. A validation equipment and measurement had been done in accordance with American Thoracic Association guidance. The result is level of endogenous exhaled NO on the normal group (median=5), interictal group (median=11), ictal group (median=14). Coefficient correlation between VAS and level endogenous exhaled NO was 0,815. So, there is an increase of the NO endogen level in the normal people, migraine interictal, and ictal. Strong correlation between intensity of pain (VAS) and level endogenous exhaled NO during ictal.

An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an increasingly recognized, often fatal lung disease of unknown etiology. The aim of this study was to use whole-exome sequencing to improve understanding of the genetic architecture of pulmonary fibrosis. We performed a case-control exome-wide collapsing analysis including 262 unrelated individuals with pulmonary fibrosis clinically classified as IPF according to American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines (81.3%), usual interstitial pneumonia secondary to autoimmune conditions (11.5%), or fibrosing nonspecific interstitial pneumonia (7.2%). The majority (87%) of case subjects reported no family history of pulmonary fibrosis. We searched 18,668 protein-coding genes for an excess of rare deleterious genetic variation using whole-exome sequence data from 262 case subjects with pulmonary fibrosis and 4,141 control subjects drawn from among a set of individuals of European ancestry. Comparing genetic variation across 18,668 protein-coding genes, we found a study-wide significant (P < 4.5 × 10-7) case enrichment of qualifying variants in TERT, RTEL1, and PARN. A model qualifying ultrarare, deleterious, nonsynonymous variants implicated TERT and RTEL1, and a model specifically qualifying loss-of-function variants implicated RTEL1 and PARN. A subanalysis of 186 case subjects with sporadic IPF confirmed TERT, RTEL1, and PARN as study-wide significant contributors to sporadic IPF. Collectively, 11.3% of case subjects with sporadic IPF carried a qualifying variant in one of these three genes compared with the 0.3% carrier rate observed among control subjects (odds ratio, 47.7; 95% confidence interval, 21.5-111.6; P = 5.5 × 10-22). We identified TERT, RTEL1, and PARN-three telomere-related genes previously implicated in familial pulmonary fibrosis-as significant contributors to sporadic IPF. These results support the idea that telomere dysfunction is involved in IPF pathogenesis.

High-resolution computed tomography and magnetic resonance imaging protocols in the diagnosis of fibrotic interstitial lung disease: overview for "non-radiologists".

Fibrotic interstitial lung diseases (ILDs) include a number of pulmonary disorders characterized by infiltration of inflammatory cells in lung parenchyma and fibrosis resulting in decreased lung compliance. Idiopathic pulmonary fibrosis (IPF) represents the most common ILD. ILDs can be divided in two anatomo-pathological and radiographic patterns: usual interstitial pneumonitis (UIP) and non-specific interstitial pneumonitis (NSIP). The different radiological features of UIP and NSIP are discussed. The American Thoracic Society, the European Respiratory Society, the Japanese Respiratory Society, and the Latin American Thoracic Association guidelines for the diagnosis and management of IPF have identified several characteristic high-resolution computed tomography (HRCT) features of UIP. However, even if these guidelines recommend to avoid surgical lung biopsy in case of confident UIP diagnosis on HRCT, they present some limitations, the most important of which is represented by interobserver agreement. Magnetic resonance imaging (MRI) can be considered as a radiation-free alternative to HRCT for several lung diseases. However, the clinical value of MRI for IPF diagnosis remains to be proven. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 300-306).

OA15.03 Comparison of Prognosis between Lobectomy and Sublobar Resection for Clinical Stage I Non-Small Cell Lung Cancer with Interstitial Lung Disease

The prognosis after standard lobectomy for non-small cell lung cancer (NSCLC) with interstitial lung disease (ILD) is poor. This study aimed to compare the prognosis after lobectomy and sublobar resection for early NSCLC with ILD. Among 794 consecutive patients with clinical stage I NSCLC who underwent complete resection, 107 patients with ILD on high-resolution computed tomography (HRCT), which was defined according to the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Association classification, were identified. Overall survival (OS) was significantly worse for patients with possible usual interstitial pneumonia (UIP) or UIP pattern than those with inconsistent with UIP pattern (3-year OS, 64.5% vs. 82.1%, respectively; P = 0.031). No significant difference existed in OS between lobectomy and sublobar resection for all patients with ILD (3-year OS, 67.1% vs. 81.9%, respectively; P = 0.14). Although in patients with inconsistent with UIP pattern, OS was similar between lobectomy and sublobar resection groups (3-year OS, 81.1% vs. 83.6%, respectively; P = 0.87), OS was better for patients who underwent sublobar resection than lobectomy in patients with possible UIP or UIP patterns (3-year OS, 81.0% vs. 50.5%, respectively; P = 0.069). Multivariate Cox analysis demonstrated that preoperative diffusing capacity of the lung for carbon monoxide (P = 0.018), not the surgical procedure (P = 0.14), was an independent prognostic factor for OS. Sublobar resection can be an alternative choice for clinical stage I NSCLC with ILD especially for UIP or possible UIP patterns on HRCT.

Clasificación de los pacientes con enfermedad pulmonar obstructiva crónica según los sistemas de estadificación de la Asociación Latinoamericana de Tórax (ALAT) y la iniciativa global para la enfermedad pulmonar obstructiva crónica (GOLD)

IntroductionSeveral classification systems use different criteria when assessing COPD stages. The objective of this study was to compare the prevalence and distribution of COPD stagesusing Global initiative for chronic Obstructive Lung Disease (GOLD) recommendationsand Latin American Thoracic Association (ALAT) guidelinesin a primary-care population. MethodsSubjects attending routine primary care visits, ≥40 years of age, current or former smokers or exposed to biomass, completed a questionnaire and performed spirometry. COPD was defined as post-bronchodilator FEV1/FVC<0.70 and categorised according to GOLD-2013 criteria and ALAT-2014 guideline. The BODEx index was used to assess the prognostic value of the stratification systems. ResultsA total of 1743 subjects completed the interview, 1540 performed acceptable spirometry. COPD prevalence according GOLD-2013 was 20.1% and had a U-shaped stage distribution (group A: 9.3%, B: 4.3%, C: 2.0%, D: 4.6%). According to ALAT, prevalence was 19.7% with a bell-shaped stage distribution (mild: 2.9%, moderate: 9%, severe: 5.4%, very-severe: 2.7%). Approximately 73% of patients were stratified as moderate (45.4%) or severe (27.3%) by ALAT guidelines, whereas using GOLD-2013 criteria the majority of subjects (approximately 69%) were in group A (46.3%) or group B (22.7%). BODE index score increased as COPD worsened according to ALAT stratification. This is not observed with GOLD2013 criteria (similar values for B and C groups). ConclusionsDisease stages differ under ALAT and GOLD-2013 criteria. ALAT identified a greater proportion of COPD subjects in the moderate and severe categories compared with GOLD-2013, where the majority were categorised in group A. Future evaluation of the ALAT classification should address its predictive ability in terms of hospitalizations and mortality.

Classification of COPD Patients According to ALAT and GOLD Staging Systems Using PUMA Study Data

IntroductionSeveral classification systems use different criteria when assessing COPD stages. The objective of this study was to compare the prevalence and distribution of COPD stages using Global initiative for chronic Obstructive Lung Disease (GOLD) recommendations and Latin American Thoracic Association (ALAT) guidelines in a primary-care population. MethodsSubjects attending routine primary care visits, ≥40 years of age, current or former smokers or exposed to biomass, completed a questionnaire and performed spirometry. COPD was defined as post-bronchodilator FEV1/FVC<0.70 and categorized according to GOLD-2013 criteria and ALAT-2014 guideline. The BODEx index was used to assess the prognostic value of the stratification systems. ResultsA total of 1743 subjects completed the interview, 1540 performed acceptable spirometry. COPD prevalence according to GOLD-2013 was 20.1% and had a U-shaped stage distribution (group A: 9.3%, B: 4.3%, C: 2.0%, D: 4.6%). According to ALAT, prevalence was 19.7% with a bell-shaped stage distribution (mild: 2.9%, moderate: 9%, severe: 5.4%, very-severe: 2.7%). Approximately 73% of patients were stratified as moderate (45.4%) or severe (27.3%) by ALAT guidelines, whereas using GOLD-2013 criteria the majority of subjects (approximately 69%) were in group A (46.3%) or group B (22.7%). BODE index score increased as COPD worsened according to ALAT stratification. This is not observed with GOLD-2013 criteria (similar values for B and C groups). ConclusionsDisease stages differ under ALAT and GOLD-2013 criteria. ALAT identified a greater proportion of COPD subjects in the moderate and severe categories compared with GOLD-2013, where the majority were categorized in group A. Future evaluation of the ALAT classification should address its predictive ability in terms of hospitalizations and mortality.

Heterogeneity of incidence and outcome of acute exacerbation in idiopathic interstitial pneumonia.

Acute exacerbations (AEs) of idiopathic pulmonary fibrosis (IPF) and other idiopathic interstitial pneumonia (IIP) have a poor prognosis. This study aims to clarify the incidence and prognosis of AE in IPF and the other IIP. A total of 229 patients were enrolled, of whom 92 had IPF and 137 had 'IIP other than IPF' based on the American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association (ATS/ERS/JRS/ALAT) 2011 IPF Guidelines. IIP other than IPF included 11 patients with a surgical lung biopsy (SLB) and the remainder without such a biopsy. IIP other than IPF was further classified into IIP with a 'possible usual interstitial pneumonia (UIP)' pattern on HRCT (n = 75) and IIP with 'inconsistent with UIP' pattern (n = 62) based on published guidelines. Predictors of AE and the prognosis after AE were examined in these groups. The 1-year incidence of AE in IPF, IIP with possible UIP HRCT patterns and IIP with inconsistent with UIP HRCT patterns was 16.5%, 8.9% and 4.0%, respectively. AE occurred significantly more frequently in IPF than in IIP with possible UIP and inconsistent with UIP HRCT patterns after adjustment for BMI, modified Medical Research Council score and %forced vital capacity. Prognosis of AE-IIP with possible UIP HRCT pattern was significantly worse than that of AE-IPF. Although AE occurred significantly less frequently in IIP with possible UIP and inconsistent with UIP HRCT patterns than in IPF, the prognosis of AE-IIP with possible UIP HRCT patterns might be worse than that of AE-IPF.

An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline.

This document updates the American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guideline on idiopathic pulmonary fibrosis treatment. Systematic reviews and, when appropriate, meta-analyses were performed to summarize all available evidence pertinent to our questions. The evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and then discussed by a multidisciplinary panel. Predetermined conflict-of-interest management strategies were applied, and recommendations were formulated, written, and graded exclusively by the nonconflicted panelists. After considering the confidence in effect estimates, the importance of outcomes studied, desirable and undesirable consequences of treatment, cost, feasibility, acceptability of the intervention, and implications to health equity, recommendations were made for or against specific treatment interventions. The panel formulated and provided the rationale for recommendations in favor of or against treatment interventions for idiopathic pulmonary fibrosis.

Fibrosing Interstitial Lung Disease. A Practical High-Resolution Computed Tomography–based Approach to Diagnosis and Management and a Review of the Literature

Establishing the etiology of fibrosing interstitial lung disease (FILD) remains a clinical challenge. This is because many disorders resulting in lung fibrosis may be similar in their initial clinical and radiographic appearances. High-resolution computed tomography (HRCT) studies are now almost always obtained for patients who present with otherwise nonspecific clinical symptoms and chest radiographic findings. In the majority of cases presenting with FILD, differential diagnosis typically requires differentiating among three most commonly encountered clinical entities: idiopathic pulmonary fibrosis with usual interstitial pneumonia, nonspecific interstitial pneumonia, and chronic hypersensitivity pneumonitis. As a consequence, the development of a simplified diagnostic algorithmic approach initially focusing on the interpretation of HRCT findings may prove of considerable value provided thorough familiarity with optimal HRCT techniques and methods of interpretation. For this purpose, in patients with FILD in whom an underlying etiology is not initially apparent, the recently proposed American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines for the diagnosis of IPF have been modified to create a straightforward, clinically practicable algorithmic approach to clinical management based on the initial interpretation and classification of HRCT findings.

Importance of Idiopathic Pulmonary Fibrosis Staging for Clinical Trial Endpoints

We welcome the Pulmonary Perspective on the evaluation of clinically meaningful primary endpoints for idiopathic pulmonary fibrosis (IPF) (1). However, the logic of this discussion is weakened by the failure to acknowledge that the disease progression is influenced by the burden of disease at presentation. The burden of disease is normally described by a staging system, which is currently absent for IPF. One specific endpoint will clearly be insufficient if applied to “all comers with IPF.” Therefore, the definition of endpoints is heavily dependent on the staging of the disease (2). Regrettably, we have not seen a formal staging system emerge from the American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guideline publication (3). We have learned from randomized controlled studies that change in FVC is a very pragmatic endpoint to be applied in patients with “mild to moderate disease,” which equates with a limited burden of disease. In patients with limited disease, defined as a gas transfer of greater than 40% predicted (2), mortality as an endpoint has a very low frequency. In contrast, mortality as an endpoint is more common in patients with advanced disease, defined as a gas transfer less than 40%. Therefore the relative endpoints are dependent on the stage of the disease. This burden/stage of disease can be defined on the basis of simple lung function testing. We would encourage the debate to consider that the appropriate endpoints should be defined on the basis of the burden or stage of disease, and that the discussions highlight the need for a simple reproducible staging system for IPF in a manner comparable to the Global Initiative for Chronic Obstructive Lung Disease classification for chronic obstructive pulmonary disease.

Idiopathic pulmonary fibrosis: current challenges and future perspectives

Idiopathic pulmonary fibrosis (IPF) is the most prevalent of the idiopathic interstitial pneumonias and its incidence seems to be increasing [1–4]. IPF is generally considered to be unresponsive to “standard” therapies and carries a poor prognosis with most patients dying within at least 5 years following diagnosis [5–7]. An accurate diagnosis of IPF is essential for the optimal management of patients with IPF. The original IPF management guidelines, published in 2000 [8], have been superseded recently by the evidence-based international recommendations jointly sponsored by the European Respiratory Society (ERS), the American Thoracic Association (ATS), the Japanese Respiratory Society (JRS) and the Latin American Thoracic Association (ALAT) [9]. Nonetheless, despite this and other major accomplishments over the last decade, the diagnosis and the management of IPF remain a major medical challenge. Diagnostic uncertainties remain due, at least in part, to variability in the natural history of the disease and co-existing complicating comorbidities, interpretation and widespread application of the guideline recommendations, and analysis of …

Managing diagnostic procedures in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF), the most prevalent of the idiopathic interstitial pneumonias, is associated with a poor prognosis. An accurate diagnosis of IPF is essential for its optimal management. The 2011 American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) recommendations on the diagnosis and management of IPF were developed from a systematic review of the published literature. High-resolution computed tomography (HRCT) scanning has a central role in the IPF diagnostic pathway, with formal designation of criteria for an HRCT pattern of usual interstitial pneumonia. In the correct clinical context, a usual interstitial pneumonia pattern on HRCT is indicative of a definite diagnosis of IPF and negates the need for a surgical lung biopsy. However, although the 2011 ATS/ERS/JRS/ALAT statement is a major advance, the application of the guideline recommendations by clinicians has identified limitations that should be addressed in future statements. Key problems include: 1) HRCT misdiagnosis, particularly by less experienced radiologists; 2) lack of management recommendations for the highly prevalent clinical scenarios of "probable" or "possible" IPF; 3) ongoing confusion concerning the diagnostic role of bronchoalveolar lavage; and 4) the lack of integration of clinical data in the designation of the diagnostic likelihood of IPF, including the treated course of disease. These issues become evident as the recommendations are applied and highlight the need for continued guideline adjustments.

Influence of physical activity level on Saudi reference values of 6 min walk test

The 6 min walk test (6-MWT) is widely used to evaluate exercise capacity in several cardiopulmonary diseases due to its simplicity, applicability and low cost. Establishing reference value is essential to guide the diagnostic and prognostic use of the 6-MWT and previous study showed that the Saudi subject’s age and height were the most significant predictors for 6 min walked distance (6-MWD). On the other hand, physical activity level proved to have direct effect on the exercise capacity. This study aimed to answer the question: Does the physical activity level influence the Saudi reference values of 6-MWT? The main outcome measure was the 6 min walked distance (6-MWD) which was measured by the 6-MWT following the protocol of the American Thoracic Association. The demographic characters, including age, gender, weight, and height, of the participants were collected and their body mass index (BMI) was calculated. Participant’s physical activity level was calculated using the Last 7 days International Physical Activity Questionnaire (IPAQ) and was expressed as high, moderate and low levels. For each participant the following cardiovascular variables were measured before and after the test; the heart rate, systolic and diastolic blood pressure, and arterial oxygen saturation. The percent from the predicted maximum heart rate (%PMHR) was calculated for each participant. The predictive power of the studied demographic and cardiovascular characters to estimate the 6-MWD was evaluated using the statistical program SPSS version 17. Participants in the current study are 359 Saudi health subjects (70.5% female). They aged from 18 to 71 years (31.0 ± 14.0 years). Results showed a significant ( P = 0.0001) decrease in 6-MWD with increasing the age. In addition, within the different age groups, male participants showed longer 6-MWD than females (503.3 and 471.1 m respectively). This longer male’s 6-MWD was significant in the younger age groups. From the age of 50 years up to 71 years there was no significant gender difference in the 6-MWD. In all age groups, there were significant increase in 6-MWD from low, moderate, to high physical activity level. Moreover, the interaction between age, gender, and level of physical activity was significant ( P = 0.0001). Younger male with high level of activity had the best 6-MWD. Older age, female gender, and lower physical activity level was accompanied with significant shorter 6-MWD. The 6-MWD was positively correlated to the subject’s height, heart rate, arterial oxygen saturation, and physical activity level. It was negatively correlated to age, weight, BMI, % PMHR, systolic and diastolic blood pressure. Out of all these correlations within the studied demographic and cardiovascular factors; physical activity level, age and gender were working as a predictive factors for 6-MWD of Saudi healthy subjects and were significantly included in the regression equation to estimate the 6-MWD [6-MWD = (74.31 X physical activity level) + (33.88 X gender) − (4.25 X age) + 342.650]. This equation explained 67.8% of the distance variance. It is not only the subject’s age and gender which predict the 6- MWD but the physical activity level as well. This necessitates considering the subject’s physical activity level when establishing ethnic reference values.

Recommendations on treatment for IPF

Patient management in Idiopathic Pulmonary Fibrosis (IPF) is largely based on societal guidelines and recommendations. A recent update by the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS) and Latin American Thoracic Association (ALAT) provided updated guidance on the diagnosis and management of IPF, along with recommendations on pharmacologic and non-pharmacologic approaches to patient management. The treatment guidance is based on GRADE criteria, which rates the quality of evidence according to previously published methodology. Here we discuss how to interpret the recent guideline updates and the implications of this guidance for clinical practice. In addition we discuss the assessment and recommendations for a number of pharmacological agents that have been the focus of clinical trials over the past years. Although no single pharmacological agent was recommended by the guidelines committee, we discuss how since then, more recent data have resulted in the approval of pirfenidone in Europe, and preliminary negative findings regarding the safety of a triple therapy regimen consisting of prednisone, azathioprine and N-acetylcysteine have raised the question of whether it is no longer a treatment option. As clinicians, we must interpret the available guidance and recommendations as we consider each individual patient and as we discuss the available clinical data and the patient’s own preferences in our approach to the management of this disease.

An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.

This document is an international evidence-based guideline on the diagnosis and management of idiopathic pulmonary fibrosis, and is a collaborative effort of the American Thoracic Society, the European Respiratory Society, the Japanese Respiratory Society, and the Latin American Thoracic Association. It represents the current state of knowledge regarding idiopathic pulmonary fibrosis (IPF), and contains sections on definition and epidemiology, risk factors, diagnosis, natural history, staging and prognosis, treatment, and monitoring disease course. For the diagnosis and treatment sections, pragmatic GRADE evidence-based methodology was applied in a question-based format. For each diagnosis and treatment question, the committee graded the quality of the evidence available (high, moderate, low, or very low), and made a recommendation (yes or no, strong or weak). Recommendations were based on majority vote. It is emphasized that clinicians must spend adequate time with patients to discuss patients' values and preferences and decide on the appropriate course of action.

Possession of the macrophage-induced gene by isolates of the Mycobacterium avium complex is not associated with significant clinical disease

The Mycobacterium avium complex (MAC) is the most frequently isolated species among non-tuberculous mycobacteria (NTM) clinical isolates. Physicians pay attention to the differential diagnosis of the disease caused by MAC from tuberculosis because of their similar clinical presentations. Expression of the macrophage-induced gene (mig) is one of the virulence phenotypes in MAC, but it has not been determined whether the presence of the mig gene itself has any relationship with clinical disease or whether it is merely a marker for MAC. To uncover the significance of the mig gene among MAC clinical isolates, positive cultures from respiratory specimens from patients in a tertiary referral centre were identified by sequencing the 16S rRNA gene. The mig gene was also evaluated using PCR and sequence analysis. The medical records from the patients were reviewed retrospectively. The diagnostic criteria from the American Thoracic Association were adopted for the diagnosis of NTM lung disease. A total of 45 MAC clinical isolates were identified over a period of 1 year. Following 16S rRNA sequencing, all of the 23 M. avium isolates were categorized as sequevar I. Among the 22 Mycobacterium intracellulare isolates, 18 strains were identified as M. intracellulare sequevar I and the remaining four consisted of one each of sequevars II, III, IV and V. The proportion of cases that fitted the diagnostic criteria of NTM lung disease was 26.7 % (12/45). The mig PCR results were 100 % positive for the MAC isolates studied, irrespective of their species, sequevar or disease-causing properties. However, following bootstrap analysis of the mig sequences, we observed definite grouping between M. avium and M. intracellulare. Thus the mig gene is a species-specific marker with distinct sequence diversity between the two species M. avium and M. intracellulare, but there is poor correlation between disease-causing properties and specific mig sequences.