Female smokers have increased risk of chronic obstructive pulmonary disease (COPD) compared with male smokers who have a similar history of cigarette smoke exposure. We have shown previously that ...chronic smoke exposure for 6 months leads to increased airway wall remodeling in female C57BL/6 mice compared with male C57BL/6 mice. These differences, however, were not evident in female ovariectomized mice exposed to cigarette smoke. Herein, we report on the pulmonary function test results from the flexiVent system, which was used to determine the potential functional consequences of the histologic changes observed in these mice. We found that tissue damping (G) was increased in female compared to male or ovariectomized female mice after smoke exposure. At low oscillating frequencies, complex input resistance (Zrs) and impedance (Xrs) of the respiratory system was increased and decreased, respectively, in female but not in male or ovariectomized female mice after smoke exposure. Quasistatic pressure-volume curves revealed a reduction in inspiratory capacity in female mice but not in male or ovariectomized female mice after smoke exposure. The remaining lung function measurements including quasistatic compliance were similar amongst all groups. This is the first study characterizing a sexual dimorphism in respiratory functional properties in a mouse model of COPD. These findings demonstrate that increased airway remodeling in female mice following chronic smoke exposure is associated with increased tissue resistance in the peripheral airways. These data may explain the importance of female sex hormones and the increased risk of airway disease in female smokers.
Nearly 30% of all exacerbations of COPD do not have a clear etiology. Although pulmonary embolism (PE) can exacerbate respiratory symptoms such as dyspnea and chest pain, and COPD patients are at a ...high risk for PE due to a variety of factors including limited mobility, inflammation, and comorbidities, the prevalence of PE during exacerbations is uncertain.
A systematic review of the literature was performed to determine the reported prevalence of PE in acute exacerbations of COPD in patients who did and did not require hospitalization. The literature search was performed using MEDLINE, CINAHL, and EMBASE, and complemented by hand searches of bibliographies. Only cross-sectional or prospective studies that used CT scanning or pulmonary angiography for PE diagnosis were included.
Of the 2,407 articles identified, 5 met the inclusion criteria (sample size, 550 patients). Overall, the prevalence of PE was 19.9% (95% confidence interval CI, 6.7 to 33.0%; p = 0.014). In hospitalized patients, the prevalence was higher at 24.7% (95% CI, 17.9 to 31.4%; p = 0.001) than those who were evaluated in the emergency department (3.3%). Presenting symptoms and signs were similar between patients who did and did not have PE.
One of four COPD patients who require hospitalization for an acute exacerbation may have PE. A diagnosis of PE should be considered in patients with exacerbation severe enough to warrant hospitalization, especially in those with an intermediate-to-high pretest probability of PE.
The objective of the study was to examine the relationship of pathologic pattern and prognosis in hypersensitivity pneumonitis (HP). We analyzed 24 cases of subacute (cellular, nonfibrotic) and 25 ...cases of chronic (fibrotic) HP. Nineteen (79%) of the subacute cases showed a pattern of bronchiolocentric interstitial pneumonia and 5 (21%) a pattern mimicking cellular nonspecific interstitial pneumonia (NSIP). Giant cells or granulomas or Schaumann bodies were present in 19 cases (79%). Eighteen (72%) chronic cases showed a pattern resembling usual interstitial pneumonia (UIP), but, in most cases, with more peribronchiolar fibrosis than one would expect in UIP. Three fibrotic cases (12%) had only peribronchiolar fibrosis, whereas 4 (16%) resembled fibrotic NSIP. Giant cells or granulomas or Schaumann bodies were present in 22 (88%) cases. Areas of subacute HP were present in 12 cases with a UIP-like pattern. Only 2 UIP-like cases could not be morphologically distinguished from idiopathic UIP. The median survival for patients who had no fibrosis was 22.4 years; for patients with a fibrotic NSIP pattern was 2.1 years; and for those with a UIP-like pattern 2.8 years (not statistically different). Patients with a pattern of only peribronchiolar fibrosis had a median survival of 11.3 years. These data confirm that the presence of fibrosis is associated with a generally poor prognosis in patients with HP, and suggest that pure peribronchiolar fibrosis may portend a longer survival than does a UIP-like or fibrotic NSIP-like pattern of fibrosis. Most cases of chronic HP have distinctive pathologic features, but a small percentage of cases cannot be pathologically distinguished from UIP.
Little is known about the impact of exacerbations on COPD progression or whether inhaled corticosteroid (ICS) use and blood eosinophil count (BEC) affect progression. We aimed to assess this in a ...prospective observational study.
The study population included patients with mild to moderate COPD, aged ≥35 years, with a smoking history, who were followed up for ≥3 years from first to last spirometry recording using two large UK electronic medical record databases: Clinical Practice Research Datalink (CPRD) and Optimum Patient Care Research Database (OPCRD). Multilevel mixed-effects linear regression models were used to determine the relationship between annual exacerbation rate following initiation of therapy (ICS vs non-ICS) and FEV
decline. Effect modification by blood eosinophils was studied through interaction terms.
Of 12178 patients included (mean age 66 years; 48% female), 8981 (74%) received ICS. In patients with BEC ≥350 cells/µL not on ICS, each exacerbation was associated with subsequent acceleration of FEV
decline of 19.4 mL/year (95% CI 12.0 to 26.7, p<0.0001). This excess decline was reduced by 15.1 mL/year (6.6 to 23.6) to 4.3 mL/year (1.9 to 6.7, p<0.0001) in those with BEC ≥350 cells/µL treated with ICS.
Exacerbations are associated with a more rapid loss of lung function among COPD patients with elevated blood eosinophils, defined as ≥350 cells/µL, not treated with ICS. More aggressive prevention of exacerbations using ICS in such patients may prevent excess loss of lung function.
The prevalence, morbidity, and mortality of inflammatory lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) are increasing in women. There is a dearth ...of data on the biological mechanisms to explain such observations. However, some large epidemiologic studies suggest that lung function fluctuates during the menstrual cycle in female patients with airways disease but not in women without disease, suggesting that circulating estradiol and progesterone may be involved in this process.
In asthma, estradiol shuttles adaptive immunity towards the TH2 phenotype while in smokers estrogens may be involved in the generation of toxic intermediate metabolites in the airways of female smokers, which may be relevant in COPD pathogenesis. In CF, estradiol has been demonstrated to up-regulate MUC5B gene in human airway epithelial cells and inhibit chloride secretion in the airways. Progesterone may augment airway inflammation.
Taken together, clinical and in-vivo data have demonstrated a sex-related difference in that females may be more susceptible to the pathogenesis of lung diseases. In this paper, we review the effect of female sex hormones in the context of these inflammatory airway diseases.
Accumulated high-quality data from randomised controlled trials (RCTs) indicate that long-acting muscarinic antagonist (LAMA)/long-acting β2 agonist (LABA) combination therapy significantly improves ...clinical symptoms and health status in patients with chronic obstructive pulmonary disease (COPD) and reduces exacerbation risk. However, there is a growing concern that LAMA/LABA therapy may increase the risk of cardiovascular disease in patients with COPD. The aim of this paper is to determine whether the use of LAMA/LABA combination therapy modifies the risk of cardiovascular disease in patients with COPD.
Two reviewers independently searched Embase, PubMed and Cochrane Library to identify relevant RCTs of LAMA/LABA or LABA/LAMA/inhaled corticosteroids (ICS) for the management of patients with COPD that reported on cardiovascular end-points. The primary outcome was major adverse cardiovascular events (MACE), which was a composite of cardiovascular death, myocardial infarction or stroke.
A total of 51 RCTs enrolling 91 021 subjects were analysed. Both dual LAMA/LABA (1.6%
1.3%; relative risk 1.42, 95% CI 1.11-1.81) and triple therapy (1.6%
1.4%; relative risk 1.29, 95% CI 1.03-1.61) significantly increased the risk of MACE compared with ICS/LABA. The excess risk was most evident in RCTs in which the average underlying baseline risk for MACE was >1% per year. Compared with LAMA only, LABA only or placebo, dual LAMA/LABA therapy did not significantly increase the risk of MACE, though these comparisons may have lacked sufficient statistical power.
Compared with ICS/LABA, dual LAMA/LABA or triple therapy increases cardiovascular risk in patients with COPD. This should be considered in the context of the incremental benefits of these therapies for symptoms and exacerbation rates in patients with COPD, especially in those with a MACE risk of >1% per year.
Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide ...association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion.
To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations.
We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.
We identified and replicated three new genome-wide significant (
< 5 × 10
) signals of association with IPF susceptibility (associated with altered gene expression of
,
, and
) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as yet unreported IPF susceptibility variants contribute to IPF susceptibility.
The observation that decreased
expression associates with increased susceptibility to IPF supports recent studies demonstrating the importance of mTOR signaling in lung fibrosis. New signals of association implicating
and
suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.
Asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent chronic obstructive lung diseases with an associated high burden of disease. Asthma, which is often allergic in origin, ...frequently begins in infancy or childhood with variable airflow obstruction and intermittent wheezing, cough, and dyspnea. Patients with COPD, in contrast, are usually current or former smokers who present after the age of 40 years with symptoms (often persistent) including dyspnea and a productive cough. On the basis of age and smoking history, it is often easy to distinguish between asthma and COPD. However, some patients have features compatible with both diseases. Because clinical studies typically exclude these patients, their underlying disease mechanisms and appropriate treatment remain largely uncertain. To explore the status of and opportunities for research in this area, the NHLBI, in partnership with the American Thoracic Society, convened a workshop of investigators in San Francisco, California on May 14, 2016. At the workshop, current understanding of asthma-COPD overlap was discussed among clinicians, pathologists, radiologists, epidemiologists, and investigators with expertise in asthma and COPD. They considered knowledge gaps in our understanding of asthma-COPD overlap and identified strategies and research priorities that will advance its understanding. This report summarizes those discussions.
Cigarette Smoking and Asthma Thomson, Neil C.; Polosa, Riccardo; Sin, Don D.
The journal of allergy and clinical immunology in practice (Cambridge, MA),
11/2022, Letnik:
10, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Globally, around half the adult asthma population are current or former cigarette smokers. Cigarette smoking and asthma interact to induce an “asthma-smoking phenotype(s),” which has important ...implications for diagnosis, pathogenic mechanisms, and management. The lack of progress in understanding the effects of smoking on adults with asthma is due in part to their exclusion from most investigative studies and large clinical trials. In this review, we summarize the adverse clinical outcomes associated with cigarette smoking in asthma, highlight challenges in diagnosing asthma among cigarette smokers with chronic respiratory symptoms, particularly in older individuals with a long-standing smoking history, and review pathogenic mechanisms involving smoking- and asthma-related airway inflammation, tissue remodeling, corticosteroid insensitivity, and low-grade systemic inflammation. We discuss the key components of management including the importance of smoking cessation strategies, evidence for the effectiveness of the Global Initiative for Asthma recommendations on treatment in cigarette smokers, and the role of treatable traits such as type 2 eosinophilic airway inflammation. Lastly, we provide an algorithm to aid clinicians to manage current and former smokers with asthma. In the future, controlled and pragmatic trials in real-world populations should include cigarette smokers with asthma to provide an evidence base for treatment recommendations.
Acute and chronic lung inflammation is an underrecognized risk factor for cardiovascular disease. Yet, there are compelling epidemiological data to indicate that airway exposures to cigarette smoke, ...air pollution particles, and viral and bacterial pathogens are strongly related to acute ischemic events. Over the past 10 years, there have been important human and animal studies that have provided experimental evidence to support a causal link. In this article, we review the epidemiological data for the relationship between lung inflammation and cardiovascular disease and provide plausible mechanistic pathways by which acute and chronic inflammation contributes to the development of acute cardiovascular syndromes.
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