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Occupational lower airway disease in relation to World Trade Center inhalation exposure.

PURPOSE OF REVIEW: To summarize the knowledge about the occupational lower airway diseases that seem related to exposures at the World Trade Center disaster site.

RECENT FINDINGS: Those diseases have been characterized as irritant-induced asthma, chronic nonspecific bronchitis, chronic bronchiolitis/small airway disease, and aggravated preexistent chronic obstructive lung disease (most frequently chronic obstructive pulmonary disease, but also asthma), with the expected overlapping features among them. One remarkable characteristic of the irritant-induced asthma observed among these workers was the slow onset of symptoms and long delay in clinical diagnoses.

SUMMARY: Longitudinal studies suggest that both the incidence and the associated functional decline of these predominantly obstructive lung diseases stabilized several years ago, but longer follow-up is clearly necessary.

SOX5 is a Candidate Gene for COPD Susceptibility and is Necessary for Lung Development.

Chromosome 12p has been linked to chronic obstructive pulmonary disease (COPD) in the Boston Early-Onset COPD Study (BEOCOPD), but a susceptibility gene in that region has not been identified.

OBJECTIVES: We used high-density single nucleotide polymorphism (SNP) mapping to implicate a COPD susceptibility gene and an animal model to determine the potential role of SOX5 in lung development and COPD.

METHODS: On chromosome 12p, we genotyped 1387 SNPs in 386 COPD cases from the National Emphysema Treatment Trial (NETT) and 424 control smokers from the Normative Aging Study (NAS). SNPs with significant associations were then tested in the BEOCOPD Study and the International COPD Genetics Network (ICGN). Based on the human results, we assessed histology and gene expression in the lungs of Sox5(-/-) mice.

MEASUREMENTS AND MAIN RESULTS: In the case-control analysis, 27 SNPs were significant at p≤0.01. The most significant SNP in the BEOCOPD replication was rs11046966 (NETT-NAS p=6.0x10(-4), BEOCOPD p=1.5x10(-5), combined p=1.7x10(-7)), located 3' to the gene SOX5 (sex determining region Y-box 5). Association with rs11046966 was not replicated in the ICGN. Sox5(-/-) mice showed abnormal lung development, with a delay in maturation prior to the saccular stage, as early as E16.5. Lung pathology in Sox5(-/-) lungs was associated with a decrease in fibronectin expression, an extracellular matrix component critical for branching morphogenesis.

CONCLUSIONS: Genetic variation in the transcription factor SOX5 is associated with COPD susceptibility. A mouse model suggests that the effect may be due, in part, to its effects on lung development and/or repair processes.

COPD Exacerbation: Mortality Prognosis Factors in a Respiratory Care Unit.

The aim of our study was to investigate the mortality predictive factors after a severe exacerbations of COPD admitted to a Spanish respiratory intermediate care unit (IRCU).

PATIENTS AND METHODS: Prospective observational 2 years study, where we included all episodes of acute exacerbations of COPD with hypercapnic respiratory failure admitted in an IRCU. We analyzed different sociodemographic, functional and clinical variables including physical activity.

RESULTS: We collected data from 102 consecutive episodes admitted to IRCU (90.1% men). Mean age was 69.4±10.6. The mean APACHE II was 19.6±5.0 and 9.5% presented a failure of other non respiratory organ. Non invasive ventilation was applied in 75.3% of the episodes and this treatment failed in 11.6% of them. The duration of stay in the IRCU was 3.5±2.1 days and 8.0±5.3 days in the hospital. The hospital mortality rate was 6.9%, and another 12.7% after 90 days of discharged. In order to predict hospital mortality, multivariant statistics identified a model with AUC of 0.867, based in 3 variables: the number of previous year admission for COPD exacerbation (p=0,048), the respiratory rate after 2hours of treatment in the IRCU (p=0.0484) and the severity of the disease established with ADO score (p=0.0241).

CONCLUSIONS: The number of previous year admission for COPD exacerbation, the severity of the disease established with ADO score, the respiratory rate after 2hours of treatment, allow us to identified what patients with a COPD exacerbation admitted in a IRCU can die during this episode.

A View on Imaging in Drug Research and Development for Respiratory Diseases.

With the incidence of respiratory diseases increasing throughout the world, new therapies are needed.

This review provides a short overview of different imaging techniques of interest for drug discovery and development within the pulmonary disease area. The focus is on studies performed both in animals and humans, which are of importance to understand pathophysiological aspects and to evaluate new drugs. Rather than emphasizing particular lung diseases, the non-invasive diagnosis and quantification of a number of characteristics related to several pathological conditions of the lung are addressed: inflammation, mucus secretion and clearance, emphysema, ventilation, perfusion, fibrosis, airway remodeling, and pulmonary arterial hypertension.

Techniques are discussed based on their present use or potential future utilization in the context of drug studies.

Asthma endotypes: A new approach to classification of disease entities within the asthma syndrome

It is increasingly clear that asthma is a complex disease made up of number of disease variants with different underlying pathophysiologies. Limited knowledge of the mechanisms of these disease subgroups is possibly the greatest obstacle in understanding the causes of asthma and improving treatment and can explain the failure to identify consistent genetic and environmental correlations to asthma.

Here we describe a hypothesis whereby the asthma syndrome is divided into distinct disease entities with specific mechanisms, which we have called “asthma endotypes.” An “endotype” is proposed to be a subtype of a condition defined by a distinct pathophysiological mechanism. Criteria for defining asthma endotypes on the basis of their phenotypes and putative pathophysiology are suggested. Using these criteria, we identify several proposed asthma endotypes and propose how these new definitions can be used in clinical study design and drug development to target existing and novel therapies to patients most likely to benefit.

This PRACTALL (PRACtical ALLergy) consensus report was produced by experts from the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology.

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