Concomitant therapy with Cineole (Eucalyptole) reduces exacerbations in COPD: A placebo-controlled double-blind trial

Background

The clinical effects of mucolytics in patients with chronic obstructive pulmonary disease (COPD) are discussed controversially. Cineole is the main constituent of eucalyptus oil and mainly used in inflammatory airway diseases as a mucolytic agent. We hypothesised that its known mucolytic, bronchodilating and anti-inflammatory effects as concomitant therapy would reduce the exacerbation rate and show benefits on pulmonary function tests as well as quality of life in patients with COPD.

Methods

In this double-blind, placebo-controlled multi-center-study we randomly assigned 242 patients with stable COPD to receive 200 mg of cineole or placebo 3 times daily as concomitant therapy for 6 months during winter-time. The frequency, duration and severity of exacerbations were combined as primary outcome measures for testing as multiple criteria. Secondary outcome measures included changes of lung function, respiratory symptoms and quality of life as well as the single parameters of the exacerbations.

Results

Baseline demographics, lung function and standard medication of both groups were comparable. During the treatment period of 6 months the multiple criteria frequency, severity and duration of exacerbations were significantly lower in the group treated with cineole in comparison to placebo. Secondary outcome measures validated these findings. Improvement of lung function, dyspnea and quality of life as multiple criteria were statistically significant relative to placebo. Adverse events were comparable in both groups.

Conclusion

Concomitant therapy with cineole reduces exacerbations as well as dyspnea and improves lung function and health status. This study further suggests cineole as an active controller of airway inflammation in COPD by intervening in the pathophysiology of airway inflammation of the mucus membrane.

Trial registration

ISRCTN07600011     

Future Impact of Various Interventions on the Burden of COPD in Canada: A Dynamic Population Model

Background

Chronic obstructive pulmonary disease (COPD) is a growing economic burden worldwide. Smoking cessation is thought to be the single most effective way of reducing the economic burden of COPD. The impact of other strategies such as interventions that predict risk of disease, reduce progression of disease, or reduce exacerbations has not been systematically studied.

Objectives

We estimated the economic and clinical burden of COPD over the next 25 years in Canada and the impact of three potential interventions (screening test for predisposition to COPD, new drugs to avoid progression into more severe disease stages, and predictive test for exacerbations) on COPD burden.

Methods

Using a dynamic simulation model, we projected the total burden of COPD (cost, morbidity, and mortality) from 2011 to 2035 using the population of Canada as a case study. The model stratified population based on sex, age, smoking status, respiratory symptoms, and their COPD stage. The cost and quality adjusted life years (QALYs) associated with each intervention were estimated.

Results

The model indicates that annual societal cost of COPD is $4.52 billion (B) Canadian dollars in 2011 and will reach $3.61B ($7.33B undiscounted) per year in 2035. Over the next 25 years, COPD will be responsible for approximately $101.4B in societal costs ($147.5B undiscounted) and 12.9 million QALYs lost (19.0 million undiscounted). Our results suggested that the best strategy to reduce the financial burden of COPD is by reducing exacerbations. Smoking cessation, while it is the cornerstone of COPD prevention, has only a modest effect in attenuating the financial burden of COPD over the next 25 years in Western countries such as Canada.

Conclusion

Our data suggest that any intervention that can reduce the number of exacerbations has a substantial impact on morbidity and costs of COPD and should be considered in conjunction with the ongoing efforts to reduce smoking rates.     

Characterisation of COPD heterogeneity in the ECLIPSE cohort

Background

Chronic obstructive pulmonary disease (COPD) is a complex condition with pulmonary and extra-pulmonary manifestations. This study describes the heterogeneity of COPD in a large and well characterised and controlled COPD cohort (ECLIPSE).

Methods

We studied 2164 clinically stable COPD patients, 337 smokers with normal lung function and 245 never smokers. In these individuals, we measured clinical parameters, nutritional status, spirometry, exercise tolerance, and amount of emphysema by computed tomography.

Results

COPD patients were slightly older than controls and had more pack years of smoking than smokers with normal lung function. Co-morbidities were more prevalent in COPD patients than in controls, and occurred to the same extent irrespective of the GOLD stage. The severity of airflow limitation in COPD patients was poorly related to the degree of breathlessness, health status, presence of co-morbidity, exercise capacity and number of exacerbations reported in the year before the study. The distribution of these variables within each GOLD stage was wide. Even in subjects with severe airflow obstruction, a substantial proportion did not report symptoms, exacerbations or exercise limitation. The amount of emphysema increased with GOLD severity. The prevalence of bronchiectasis was low (4%) but also increased with GOLD stage. Some gender differences were also identified.

Conclusions

The clinical manifestations of COPD are highly variable and the degree of airflow limitation does not capture the heterogeneity of the disease.     

Severe vitamin D deficiency is associated with frequent exacerbations and hospitalization in COPD patients

Background

Acute exacerbations of COPD (AECOPD) are common and strongly influence disease severity and relative healthcare costs. Vitamin D deficiency is frequent among COPD patients and its contributory role in disease exacerbations is widely debated. Our aim was to assess the relationship of serum vitamin D levels with COPD severity and AECOPD.

Methods

Serum vitamin D (25-hydroxyvitamin D) levels were measured in 97 COPD patients and related to lung function, comorbidities, FEV1 decline, AECOPD and hospital admission during the previous year.

Results

Most patients (96%) had vitamin D deficiency, which was severe in 35 (36%). No significant relationship was found between vitamin D and FEV1 or annual FEV1 decline. No difference between patients with and without severe vitamin D deficiency was found in age, gender, BMI, smoking history, lung function, and comorbidities, apart from osteoporosis (60.9% in severe deficiency vs 22.7%, p = 0.001). In multiple logistic regression models, severe deficiency was independently associated with AECOPD [adjusted odds ratios (aOR) of 30.5 (95% CI 5.55, 168), p < 0.001] and hospitalization [aOR 3.83 (95% CI 1.29, 11.4), p = 0.02]. The odds ratio of being a frequent exacerbator if having severe vitamin D deficiency was 18.1 (95% CI 4.98, 65.8) (p < 0.001), while that of hospitalization was 4.57 (95% CI 1.83, 11.4) (p = 0.001).

Conclusions

In COPD patients severe vitamin D deficiency was related to more frequent disease exacerbations and hospitalization during the year previous to the measurement of vitamin D. This association was independent of patients’ characteristics and comorbidities.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0131-0) contains supplementary material, which is available to authorized users.     

Withdrawal of inhaled corticosteroids can be safe in COPD patients at low risk of exacerbation: a real-life study on the appropriateness of treatment in moderate COPD patients (OPTIMO)

Background

It has been suggested that withdrawal of inhaled corticosteroids (ICS) in COPD patients on maintenance treatment results in deterioration of symptoms, lung function and exacerbations. The aim of this real-life, prospective, multicentric study was to investigate whether withdrawal of ICS in COPD patients at low risk of exacerbation is linked to a deterioration in lung function and symptoms and to a higher frequency of exacerbations.

Methods

914 COPD patients, on maintenance therapy with bronchodilators and ICS, FEV₁>50% predicted, and <2 exacerbations/year were recruited. Upon decision of the primary physicians, 59% of patients continued their ICS treatment whereas in 41% of patients ICS were withdrawn and regular therapy was continued with long-acting bronchodilators mostly (91% of patients). FEV₁, CAT (COPD Assessment Test), and occurrence of exacerbations were measured at the beginning (T0) and at the end (T6) of the 6 months observational period.

Results

816 patients (89.3%) concluded the study. FEV₁, CAT and exacerbations history were similar in the two groups (ICS and no ICS) at T0 and at T6. We did not observe any deterioration of lung function symptoms, and exacerbation rate between the two groups at T0 and T6.

Conclusions

We conclude that the withdrawal of ICS, in COPD patients at low risk of exacerbation, can be safe provided that patients are left on maintenance treatment with long-acting bronchodilators.     

Prediction and course of symptoms and lung function around an exacerbation in chronic obstructive pulmonary disease

Background

Frequent exacerbations induce a high burden to Chronic Obstructive Pulmonary Disease (COPD). We investigated the course of exacerbations in the published COSMIC study that investigated the effects of 1-year withdrawal of fluticasone after a 3-month run-in treatment period with salmeterol/fluticasone in patients with COPD.

Methods

In 373 patients, we evaluated diary cards for symptoms, Peak Expiratory Flow (PEF), and salbutamol use and assessed their course during exacerbations.

Results

There were 492 exacerbations in 224 patients. The level of symptoms of cough, sputum, dyspnea and nocturnal awakening steadily increased from 2 weeks prior to exacerbation, with a sharp rise during the last week. Symptoms of cough, sputum, and dyspnea reverted to baseline values at different rates (after 4, 4, and 7 weeks respectively), whereas symptoms of nocturnal awakening were still increased after eight weeks. The course of symptoms was similar around a first and second exacerbation. Increases in symptoms and salbutamol use and decreases in PEF were associated with a higher risk to develop an exacerbation, but with moderate predictive values, the areas under the receiver operating curves ranging from 0.63 to 0.70.

Conclusions

Exacerbations of COPD are associated with increased symptoms that persist for weeks and the course is very similar between a first and second exacerbation. COPD exacerbations are preceded by increased symptoms and salbutamol use and lower PEF, yet predictive values are too low to warrant daily use in clinical practice.     

Matrix metalloproteinase-9 predicts pulmonary status declines in α1-antitrypsin deficiency

Background

Matrix metalloproteinase-9 (MMP-9) may be important in the progression of emphysema, but there have been few longitudinal clinical studies of MMP-9 including pulmonary status and COPD exacerbation outcomes.

Methods

We utilized data from the placebo arm (n = 126) of a clinical trial of patients with alpha₁-antitrypsin deficiency (AATD) and emphysema to examine the links between plasma MMP-9 levels, pulmonary status, and COPD exacerbations over a one year observation period. Pulmonary function, computed tomography lung density, incremental shuttle walk test (ISWT), and COPD exacerbations were assessed at regular intervals over 12 months. Prospective analyses used generalized estimating equations to incorporate repeated longitudinal measurements of MMP-9 and all endpoints, controlling for age, gender, race-ethnicity, leukocyte count, and tobacco history. A secondary analysis also incorporated highly-sensitive C-reactive protein levels in predictive models.

Results

At baseline, higher plasma MMP-9 levels were cross-sectionally associated with lower FEV₁ (p = 0.03), FVC (p < 0.001), carbon monoxide transfer factor (p = 0.03), resting oxygen saturation (p = 0.02), and ISWT distance walked (p = 0.02) but were not associated with radiographic lung density or total lung capacity (TLC). In longitudinal analyses, MMP-9 predicted a further decline in transfer factor (p = 0.04) and oxygen saturation (p < 0.001). MMP-9 also predicted worsening lung density (p = 0.003), increasing TLC (p = 0.02), and more frequent COPD exacerbations over follow-up (p = 0.003). Controlling additionally for hs-CRP levels did not substantively change the longitudinal associations between MMP-9 and these outcomes.

Conclusions

Increased plasma MMP-9 levels generally predicted pulmonary status declines, including worsening transfer factor and lung density as well as greater COPD exacerbations in AATD-associated emphysema.     

Long-term air pollution exposure and living close to busy roads are associated with COPD in women

Background

Lung function and exacerbations of chronic obstructive pulmonary disease (COPD) have been associated with short-term exposure to air pollution. However, the effect of long-term exposure to particulate matter from industry and traffic on COPD as defined by lung function has not been evaluated so far. Our study was designed to investigate the influence of long-term exposure to air pollution on respiratory symptoms and pulmonary function in 55-year-old women. We especially focused on COPD as defined by GOLD criteria and additionally compared the effects of air pollution on respiratory symptoms by questionnaire data and by lung function measurements.

Methods

In consecutive cross sectional studies conducted between 1985–1994, we investigated 4757 women living in the Rhine-Ruhr Basin of Germany. NO₂ and PM₁₀ exposure was assessed by measurements done in an 8 km grid, and traffic exposure by distance from the residential address to the nearest major road using Geographic Information System data. Lung function was determined and COPD was defined by using the GOLD criteria. Chronic respiratory symptoms and possible confounders were defined by questionnaire data. Linear and logistic regressions, including random effects were used to account for confounding and clustering on city level.

Results

The prevalence of COPD (GOLD stages 1–4) was 4.5%. COPD and pulmonary function were strongest affected by PM₁₀ and traffic related exposure. A 7 μg/m₃ increase in five year means of PM₁₀ (interquartile range) was associated with a 5.1% (95% CI 2.5%–7.7%) decrease in FEV₁, a 3.7% (95% CI 1.8%–5.5%) decrease in FVC and an odds ratio (OR) of 1.33 (95% CI 1.03–1.72) for COPD. Women living less than 100 m from a busy road also had a significantly decreased lung function and COPD was 1.79 times more likely (95% CI 1.06–3.02) than for those living farther away. Chronic symptoms as based on questionnaire information showed effects in the same direction, but less pronounced.

Conclusion

Chronic exposure to PM₁₀, NO₂ and living near a major road might increase the risk of developing COPD and can have a detrimental effect on lung function.     

Interactions between HIV infection and chronic obstructive pulmonary disease: Clinical and epidemiological aspects

Introduction

An association between HIV infection and chronic obstructive pulmonary disease (COPD) has been observed in several studies.

Objective and methods

we conducted a review of the literature linking HIV infection to COPD, focusing on clinical and epidemiological data published before and during widespread highly active antiretroviral therapy (HAART).

Results

Interactions between HIV infection and COPD appear to be influenced by multiple factors. In particular, the bronchopulmonary tract can be damaged by HIV infection, the immunodeficiency it induces, and the resulting increase in the risk of pulmonary infections. In addition, the prevalence of smoking and intravenous drug use is higher in HIV-infected populations, also increasing the risk of COPD. Before the advent of HAART, respiratory tract infections probably played a major role. Since the late 1990s and the widespread use of HAART, the frequency of opportunistic infections has fallen but new complications have emerged as life expectancy has increased.

Conclusion

given the high prevalence of smoking among HIV-infected patients, COPD may contribute significantly to morbidity and mortality in this setting.     

Characterisation of exacerbation risk and exacerbator phenotypes in the POET-COPD trial

Background

Data examining the characteristics of patients with frequent exacerbations of chronic obstructive pulmonary disease (COPD) and associated hospitalisations and mortality are scarce.

Methods

Post-hoc analysis of the Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, targeting exacerbations as the primary endpoint. Patients were classified as non-, infrequent, and frequent exacerbators (0, 1, or ≥ 2 exacerbations during study treatment), irrespective of study treatment. A multivariate Cox regression model assessed the effect of covariates on time to first exacerbation.

Results

In total, 7376 patients were included in the analysis: 63.5% non-exacerbators, 22.9% infrequent, 13.6% frequent exacerbators. Factors significantly associated with exacerbation risk were age, sex, body mass index, COPD duration and severity, smoking history, baseline inhaled corticosteroid use, and preceding antibiotic or systemic corticosteroid courses. Frequent exacerbators had greater severity and duration of COPD, received more pulmonary medication, and ≥ 2 systemic corticosteroid or antibiotic courses in the preceding year, and were more likely to be female and ex-smokers. The small proportion of frequent exacerbators (13.6%) accounted for 56.6% of exacerbation-related hospitalisations, which, overall, were associated with a three-fold increase in mortality.

Conclusion

The frequent exacerbator phenotype was closely associated with exacerbation-related hospitalisations, and exacerbation-related hospitalisations were associated with poorer survival.

Trial registration

{"type":"clinical-trial","attrs":{"text":"NCT00563381","term_id":"NCT00563381"}}NCT00563381; Study identifier: BI 205.389.     

The Effect of Azithromycin in Adults with Stable Neutrophilic COPD: A Double Blind Randomised,Placebo Controlled Trial

Background

Chronic Obstructive Pulmonary Disease (COPD) is a progressive airway disease characterised by neutrophilic airway inflammation or bronchitis. Neutrophilic bronchitis is associated with both bacterial colonisation and lung function decline and is common in exacerbations of COPD. Despite current available therapies to control inflammation, neutrophilic bronchitis remains common. This study tested the hypothesis that azithromycin treatment, as an add-on to standard medication, would significantly reduce airway neutrophil and neutrophils chemokine (CXCL8) levels, as well as bacterial load. We conducted a randomised, double-blind, placebo-controlled study in COPD participants with stable neutrophilic bronchitis.

Methods

Eligible participants (n = 30) were randomised to azithromycin 250 mg daily or placebo for 12 weeks in addition to their standard respiratory medications. Sputum was induced at screening, randomisation and monthly for a 12 week treatment period and processed for differential cell counts, CXCL8 and neutrophil elastase assessment. Quantitative bacteriology was assessed in sputum samples at randomisation and the end of treatment visit. Severe exacerbations where symptoms increased requiring unscheduled treatment were recorded during the 12 week treatment period and for 14 weeks following treatment. A sub-group of participants underwent chest computed tomography scans (n = 15).

Results

Nine participants with neutrophilic bronchitis had a potentially pathogenic bacteria isolated and the median total bacterial load of all participants was 5.22×10⁷ cfu/mL. Azithromycin treatment resulted in a non-significant reduction in sputum neutrophil proportion, CXCL8 levels and bacterial load. The mean severe exacerbation rate was 0.33 per person per 26 weeks in the azithromycin group compared to 0.93 exacerbations per person in the placebo group (incidence rate ratio (95%CI): 0.37 (0.11,1.21), p = 0.062). For participants who underwent chest CT scans, no alterations were observed.

Conclusions

In stable COPD with neutrophilic bronchitis, add-on azithromycin therapy showed a trend to reduced severe exacerbations sputum neutrophils, CXCL8 levels and bacterial load. Future studies with a larger sample size are warranted.

Trial Registration

Australian New Zealand Clinical Trials Registry ACTRN12609000259246     

Circulating Progenitor Cells and Vascular Dysfunction in Chronic Obstructive Pulmonary Disease

Background

In chronic obstructive pulmonary disease (COPD), decreased progenitor cells and impairment of systemic vascular function have been suggested to confer higher cardiovascular risk. The origin of these changes and their relationship with alterations in the pulmonary circulation are unknown.

Objectives

To investigate whether changes in the number of circulating hematopoietic progenitor cells are associated with pulmonary hypertension or changes in endothelial function.

Methods

62 COPD patients and 35 controls (18 non-smokers and 17 smokers) without cardiovascular risk factors other than cigarette smoking were studied. The number of circulating progenitors was measured as CD45⁺CD34⁺CD133⁺ labeled cells by flow cytometry. Endothelial function was assessed by flow-mediated dilation. Markers of inflammation and angiogenesis were also measured in all subjects.

Results

Compared with controls, the number of circulating progenitor cells was reduced in COPD patients. Progenitor cells did not differ between control smokers and non-smokers. COPD patients with pulmonary hypertension showed greater number of progenitor cells than those without pulmonary hypertension. Systemic endothelial function was worse in both control smokers and COPD patients. Interleukin-6, fibrinogen, high sensitivity C-reactive protein, vascular endothelial growth factor and tumor necrosis factor were increased in COPD. In COPD patients, the number of circulating progenitor cells was inversely related to the flow-mediated dilation of systemic arteries.

Conclusions

Pulmonary and systemic vascular impairment in COPD is associated with cigarette smoking but not with the reduced number of circulating hematopoietic progenitors. The latter appears to be a consequence of the disease itself not related to smoking habit.     

Relationship between periodontitis-related antibody and frequent exacerbations in chronic obstructive pulmonary disease

Background

To identify patients with chronic obstructive pulmonary disease (COPD) who are susceptible to frequent exacerbations is important. Although periodontitis aggravated by poor oral hygiene might increase the risk of lower respiratory tract infection, the relationship between periodontitis and COPD exacerbations remains unknown. This prospective cohort study investigates the relationship between periodontitis-related antibody and exacerbation frequency over a one-year period.

Methods

We assessed an IgG antibody titer against Porphyromonas gingivalis, which is a major pathogen of periodontitis, and then prospectively followed up 93 individuals over one year to detect exacerbations.

Results

The numbers of exacerbations and the rate of individuals with frequent exacerbations (at least two per year) were significantly lower in patients with higher IgG titer than those with normal IgG titer (0.8 vs. 1.2 per year, p  = 0.045 and 14.3 vs. 38.6%, p  = 0.009, respectively). Multivariate logistic regression analysis showed that being normal-IgG titer for periodontitis-related antibody significantly increased the risk of frequent exacerbations (relative risk, 5.27, 95% confidence interval, 1.30–25.7; p  = 0.019) after adjusting for other possible confounders, such as a history of exacerbations in the past year, disease severity, COPD medication and smoking status.

Conclusions

Normal-IgG titer for periodontitis-related antibody can be an independent predictor of frequent exacerbations. Measuring periodontitis-related antibody titers might be useful to identify patients with susceptibility to frequent exacerbations so that an aggressive prevention strategy can be designed.     

Vitamin D deficiency exacerbates COPD-like characteristics in the lungs of cigarette smoke-exposed mice

Background

Chronic obstructive pulmonary disease (COPD) is characterized by excessive inflammation and disturbed bacterial clearance in the airways. Although cigarette smoke (CS) exposure poses a major risk, vitamin D deficiency could potentially contribute to COPD progression. Many in vitro studies demonstrate important anti-inflammatory and antibacterial effects of vitamin D, but a direct contribution of vitamin D deficiency to COPD onset and disease progression has not been explored.

Methods

In the current study, we used a murine experimental model to investigate the combined effect of vitamin D deficiency and CS exposure on the development of COPD-like characteristics. Therefore, vitamin D deficient or control mice were exposed to CS or ambient air for a period of 6 (subacute) or 12 weeks (chronic). Besides lung function and structure measurements, we performed an in depth analysis of the size and composition of the cellular infiltrate in the airways and lung parenchyma and tested the ex vivo phagocytic and oxidative burst capacity of alveolar macrophages.

Results

Vitamin D deficient mice exhibited an accelerated lung function decline following CS exposure compared to control mice. Furthermore, early signs of emphysema were only observed in CS-exposed vitamin D deficient mice, which was accompanied by elevated levels of MMP-12 in the lung. Vitamin D deficient mice showed exacerbated infiltration of inflammatory cells in the airways and lung parenchyma after both subacute and chronic CS exposure compared to control mice. Furthermore, elevated levels of typical proinflammatory cytokines and chemokines could be detected in the bronchoalveolar lavage fluid (KC and TNF-α) and lung tissue (IP-10, MCP-1, IL-12) of CS-exposed vitamin D deficient mice compared to control mice. Finally, although CS greatly impaired the ex vivo phagocytic and oxidative burst function of alveolar macrophages, vitamin D deficient mice did not feature an additional defect.

Conclusions

Our data demonstrate that vitamin D deficiency both accelerates and aggravates the development of characteristic disease features of COPD. As vitamin D deficiency is highly prevalent, large randomized trials exploring effects of vitamin D supplementation on lung function decline and COPD onset are needed.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-015-0271-x) contains supplementary material, which is available to authorized users.     

Prevalence and Burden of Breathlessness in Patients with Chronic Obstructive Pulmonary Disease Managed in Primary Care

Background & Aims

Breathlessness is a primary clinical feature of chronic obstructive pulmonary disease (COPD). We aimed to describe the frequency of and factors associated with breathlessness in a cohort of COPD patients identified from the Clinical Practice Research Datalink (CPRD), a general practice electronic medical records database.

Methods

Patients with a record of COPD diagnosis after January 1 2008 were identified in the CPRD. Breathlessness was assessed using the Medical Research Council (MRC) dyspnoea scale, with scoring ranging from 1–5, which has been routinely administered as a part of the regular assessment of patients with COPD in the general practice since April 2009. Stepwise multivariate logistic regression estimated independent associations with dyspnoea. Negative binomial regression evaluated a relationship between breathlessness and exacerbation rate during follow-up.

Results

The total cohort comprised 49,438 patients diagnosed with COPD; 40,425 (82%) had any MRC dyspnoea grade recorded. Of those, 22,770 (46%) had moderate-to-severe dyspnoea (MRC≥3). Breathlessness increased with increasing airflow limitation; however, moderate-to-severe dyspnoea was also observed in 32% of patients with mild airflow obstruction. Other factors associated with increased dyspnoea grade included female gender, older age (≥70 years), obesity (BMI ≥30), history of moderate-to-severe COPD exacerbations, and frequent visits to the general practitioner. Patients with worse breathlessness were at higher risk of COPD exacerbations during follow-up.

Conclusions

Moderate-to-severe dyspnoea was reported by >40% of patients diagnosed with COPD in primary care. Presence of dyspnoea, including even a perception of mild dyspnoea (MRC = 2), was associated with increased disease severity and a higher risk of COPD exacerbations during follow-up.     

Systemic inflammation,depression and obstructive pulmonary function: a population-based study

Background

Levels of Interleukin-6 (IL-6) and C-creative protein (CRP) indicating systemic inflammation are known to be elevated in chronic diseases including chronic obstructive pulmonary disease (COPD) and depression. Comorbid depression is common in patients with COPD, but no studies have investigated whether proinflammatory cytokines mediate the association between pulmonary function and depressive symptoms in healthy individuals with no known history of obstructive pulmonary diseases.

Methods

In a population-based sample (n = 2077) of individuals aged 55 and above with no known history of obstructive pulmonary disease in the Singapore Longitudinal Ageing Study (SLAS), we analyzed the relationships between IL-6 and CRP, depressive symptoms (GDS-15 ≥5) and obstructive pulmonary function (FEV1% predicted and FEV1/FVC% predicted).

Results

High serum levels of IL-6 and CRP were associated with greater prevalence of depressive symptoms (p < 0.05). High IL-6, high CRP and depressive symptoms were independently associated with decreased FEV1% predicted and FEV1/FVC% predicted after adjusting for smoking status, BMI and number of chronic inflammatory diseases. Increasing grades of combination of inflammatory markers and/or depressive symptoms was associated with progressive increases in pulmonary obstruction. In hierarchical models, the significant association of depressive symptoms with pulmonary obstruction was reduced by the presence of IL-6 and CRP.

Conclusions

This study found for the first time an association of depressive symptoms and pulmonary function in older adults which appeared to be partly mediated by proinflammatory cytokines. Further studies should be conducted to investigate proinflammatory immune markers and depressive symptoms as potential phenotypic indicators for chronic obstructive airway disorders in older adults.     

Vitamins A & D inhibit the growth of mycobacteria in radiometric culture

Background

The role of vitamins in the combat of disease is usually conceptualized as acting by modulating the immune response of an infected, eukaryotic host. We hypothesized that some vitamins may directly influence the growth of prokaryotes, particularly mycobacteria.

Methods

The effect of four fat-soluble vitamins was studied in radiometric Bactec® culture. The vitamins were A (including a precursor and three metabolites,) D, E and K. We evaluated eight strains of three mycobacterial species (four of M. avium subspecies paratuberculosis (MAP), two of M. avium and two of M. tb. complex).

Principal Findings

Vitamins A and D cause dose-dependent inhibition of all three mycobacterial species studied. Vitamin A is consistently more inhibitory than vitamin D. The vitamin A precursor, β-carotene, is not inhibitory, whereas three vitamin A metabolites cause inhibition. Vitamin K has no effect. Vitamin E causes negligible inhibition in a single strain.

Significance

We show that vitamin A, its metabolites Retinyl acetate, Retinoic acid and 13-cis Retinoic acid and vitamin D directly inhibit mycobacterial growth in culture. These data are compatible with the hypothesis that complementing the immune response of multicellular organisms, vitamins A and D may have heretofore unproven, unrecognized, independent and probable synergistic, direct antimycobacterial inhibitory activity.     

Differential Effects of Concomitant Use of Vitamins C and E on Trophoblast Apoptosis and Autophagy between Normoxia and Hypoxia-Reoxygenation

Background

Concomitant supplementation of vitamins C and E during pregnancy has been reportedly associated with low birth weight, the premature rupture of membranes and fetal loss or perinatal death in women at risk for preeclampsia; however, the cause is unknown. We surmise that hypoxia-reoxygenation (HR) within the intervillous space due to abnormal placentation is the mechanism and hypothesize that concomitant administration of aforementioned vitamin antioxidants detrimentally affects trophoblast cells during HR.

Methodology/Principal Findings

Using villous explants, concomitant administration of 50 µM of vitamins C and E was observed to reduce apoptotic and autophagic changes in the trophoblast layer at normoxia (8% oxygen) but to cause more prominent apoptosis and autophagy during HR. Furthermore, increased levels of Bcl-2 and Bcl-xL in association with a decrease in the autophagy-related protein LC3-II were noted in cytotrophoblastic cells treated with vitamins C and E under standard culture conditions. In contrast, vitamin treatment decreased Bcl-2 and Bcl-xL as well as increased mitochondrial Bak and cytosolic LC3-II in cytotrophoblasts subjected to HR.

Conclusions/Significance

Our results indicate that concomitant administration of vitamins C and E has differential effects on the changes of apoptosis, autophagy and the expression of Bcl-2 family of proteins in the trophoblasts between normoxia and HR. These changes may probably lead to the impairment of placental function and suboptimal growth of the fetus.     

Acute exacerbations of COPD are associated with significant activation of matrix metalloproteinase 9 irrespectively of airway obstruction,emphysema and infection

Background

Acute exacerbations of chronic obstructive pulmonary disease (AE-COPD) are associated with accelerated aggravation of clinical symptoms and deterioration of pulmonary function. The mechanisms by which exacerbations may contribute to airway remodeling and declined lung function are poorly understood. In this study, we investigated if AE-COPD are associated with differential expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in bronchoalveolar lavage (BAL).

Methods

COPD patients undergoing diagnostic bronchoscopy, with either stable disease (n = 53) or AE-COPD (n = 44), matched for their demographics and lung function parameters were included in this study. Protein levels of MMP-2,–9,–12 and of TIMP-1 and -2 in BAL were measured by ELISA. Enzymatic activity of MMP-2 and -9 was assessed by gelatin zymography.

Results

We observed that MMP-9, TIMP-1 and TIMP-2 were significantly increased in BAL during AE-COPD. Furthermore, there was a significant negative correlation of MMP-9, TIMP-1 and TIMP-2 with FEV1% predicted and a significant positive correlation of TIMP-1 and TIMP-2 with RV% predicted in AE-COPD. None of MMPs and TIMPs correlated with DLCO% predicted, indicating that they are associated with airway remodeling leading to obstruction rather than emphysema. In AE-COPD the gelatinolytic activity of MMP-2 was increased and furthermore, MMP-9 activation was significantly up-regulated irrespective of lung function, bacterial or viral infections and smoking.

Conclusions

The results of this study indicate that during AE-COPD increased expression of TIMP-1, TIMP-2, and MMP-9 and activation of MMP-9 may be persistent aggravating factors associated with airway remodeling and obstruction, suggesting a pathway connecting frequent exacerbations to lung function decline.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-015-0240-4) contains supplementary material, which is available to authorized users.