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The small airways in chronic obstructive pulmonary disease: pathology and effects on disease progression and survival

imagePurpose of reviewChronic obstructive pulmonary disease (COPD) is caused by a mixture of small airway disease (obstructive bronchitis) and parenchymal lung tissue destruction (emphysema). The relative contributions of these two pathologic states vary from person to person. Having the ability to phenotype patients into predominately small airways disease or emphysema may affect the clinical management. Recent findingsPathologic studies have shown that the progression of COPD from Global Initiative for Chronic Obstructive Lung Disease stages 0 to 4 is most strongly associated with small airway wall thickening as a result of lung repair or remodeling. The narrowing and loss of small airways occurs prior to emphysematous destruction. There is an increase in the amount of neutrophils and CD8+ T lymphocytes (cells that induce apoptosis and necrosis) in the small airways in COPD. Small airways disease can be identified on pulmonary function testing, using multiple nitrogen breath washout testing, indirectly through high-resolution chest computed tomography (CT) imaging or MRI, or directly by using microCT of resected lung tissue. There may be increased mortality in advanced COPD and concomitant small airway disease. There are newer methods to deliver respiratory therapies to reach the small airways. SummaryThe current techniques utilized to assess patients for small airway disease need to be improved, so clinicians can more effectively phenotype patients with COPD and small airways disease. This will allow new therapies that target the small airways to be developed and tested, and positively impact on the natural progression of COPD.

Search for biomarkers in chronic obstructive pulmonary disease: current status

imageChronic obstructive pulmonary disease (COPD) is a condition principally defined by airflow limitation that is not fully reversible. The main trigger, inhalation of noxious gases or particles (usually smoke) leads to complex pathology, including inflammation of the large and small airways, and destruction of the lung parenchyma. Overlap in pathophysiology with other chronic airways diseases leads to challenges in differential diagnosis, and furthermore, periodic exacerbations of disease symptoms also increase the complexity of the disease diagnosis and prediction of outcome. There is recognized need for biomarkers to aid in the determination of disease diagnosis, progression and response to intervention.

This review describes the current status of biomarker identification in COPD.

Biomarkers of disease can take many forms other than the classical protein in serum, and their utility is dependent upon the clinical question to be addressed. No single protein marker has been adopted for routine clinical use to date. This review addresses the key issues around biomarker identification and utility in both stable and exacerbating COPD.

Biomarker identification in COPD is still a developing field, with increasing interest in patient phenotyping probably reflecting the challenges of biomarker development in a complex disease.

Immunopathogenesis of chronic obstructive pulmonary disease

imageChronic obstructive pulmonary disease (COPD) is defined by airflow obstruction and is associated with an exaggerated inflammatory response to noxious stimuli, such as cigarette smoke. Inflammation and recruitment of immune cells drives the underlying pathophysiology; however, the roles of immune cells in the pathogenesis of COPD are evolving and this review will discuss the latest advancements in this field.

Leukocytes including macrophages, neutrophils and lymphocytes are increased in the airways of COPD patients. Despite the presence of increased innate immune cells, COPD airways are often colonized with bacteria suggesting an underlying defect. Macrophages from COPD patients have reduced phagocytic ability which may drive the persistence of inflammation. Differing macrophage phenotypes have been associated with disease suggesting that the surrounding pulmonary environment in COPD may generate a specific phenotype that is permanently pro-inflammatory. COPD neutrophils are also aberrant with increased survival and motility, but lack direction which could lead to more widespread destruction during migration. Finally, an element of autoimmunity, driven by Th17 cells, and alterations in the ratios of lymphocyte subsets may also be involved in disease progression.

COPD pathogenesis is complex with contributions from both the innate and adaptive immune systems, and the interaction of these cells with their environment mediates inflammation.

Sex and race factors in early-onset COPD

imageUnlike other major diseases, mortality for chronic obstructive pulmonary disease (COPD) continues to increase. In recent years, COPD has evolved to increasingly affect women, minorities, and individuals from low socioeconomic groups. In women and African-Americans, evidence exists supporting the earlier development of COPD after less lifetime smoking. This review highlights new information on racial and sex differences in COPD.

Sex and related hormonal changes affect T-cell phenotypes, immunity, and smoking-related metabolism of toxic intermediate metabolites. Alterations in the bronchoalveolar lavage proteome of women, but not of men, have allowed the differentiation of healthy female smokers from smokers with COPD. Sex significantly influences levels of inflammatory cytokines and correlates with different clinical and physiological parameters in female COPD patients. African-Americans with COPD are younger, smoke less, are more likely to currently smoke, and have worse health-related quality of life (QOL). African-Americans are more likely to report hospitalized exacerbations that impact QOL. African-Americans with COPD and asthma are nearly four times more likely to experience exacerbations.

There are sex-specific and race-related differences in the manifestation of COPD. These differences warrant further physiologic, biologic, and genetic investigations.

Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial

Background

Patients with severe asthma are at increased risk of exacerbations and lower respiratory tract infections (LRTI). Severe asthma is heterogeneous, encompassing eosinophilic and non-eosinophilic (mainly neutrophilic) phenotypes. Patients with neutropilic airway diseases may benefit from macrolides.

 Methods

We performed a randomised double-blind placebo-controlled trial in subjects with exacerbation-prone severe asthma. Subjects received low-dose azithromycin (n=55) or placebo (n=54) as add-on treatment to combination therapy of inhaled corticosteroids and long-acting β2 agonists for 6 months. The primary outcome was the rate of severe exacerbations and LRTI requiring treatment with antibiotics during the 26-week treatment phase. Secondary efficacy outcomes included lung function and scores on the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ).

 Results

The rate of primary endpoints (PEPs) during 6 months was not significantly different between the two treatment groups: 0.75 PEPs (95% CI 0.55 to 1.01) per subject in the azithromycin group versus 0.81 PEPs (95% CI 0.61 to 1.09) in the placebo group (p=0.682). In a predefined subgroup analysis according to the inflammatory phenotype, azithromycin was associated with a significantly lower PEP rate than placebo in subjects with non-eosinophilic severe asthma (blood eosinophilia ≤200/µl): 0.44 PEPs (95% CI 0.25 to 0.78) versus 1.03 PEPs (95% CI 0.72 to 1.48) (p=0.013). Azithromycin significantly improved the AQLQ score but there were no significant between-group differences in the ACQ score or lung function. Azithromycin was well tolerated, but was associated with increased oropharyngeal carriage of macrolide-resistant streptococci.

 Conclusions

Azithromycin did not reduce the rate of severe exacerbations and LRTI in patients with severe asthma. However, the significant reduction in the PEP rate in azithromycin-treated patients with non-eosinophilic severe asthma warrants further study.

 ClinicalTrials.gov number

NCT00760838.

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