Assessment of vitamin A status in chronic obstructive pulmonary disease patients and healthy smokers

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Analysis of autonomic modulation after an acute session of resistance exercise at different intensities in chronic obstructive pulmonary disease patients

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Experimental Basis and New Insights for Cell Therapy in Chronic Obstructive Pulmonary Disease

Chronic Obstructive Pulmonary Disease (COPD) can be briefly described as air flow limitation and chronic dyspnea associated to an inflammatory response of the respiratory tract to noxious particles and gases. Its main feature is the obstruction of airflow and consequent chronic dyspnea. Despite recent advances, and the development of new therapeutic, medical and clinical approaches, a curative therapy is yet to be achieved. Therapies involving the use of tissue-specific or donor derived cells present a promising alternative in the treatment of degenerative diseases and injuries. Recent studies demonstrate that mesenchymal stem cells have the capacity to modulate immune responses in acute lung injury and pulmonary fibrosis in animal models, as well as in human patients. Due to these aspects, different groups raised the possibility that the stem cells from different sources, such as those found in bone marrow or adipose tissue, could act preventing the emphysematous lesion progression. In this paper, it is proposed a review of the current state of the art and future perspectives on the use of cell therapy in obstructive lung diseases.

The effect of acute magnesium loading on the maximal exercise performance of stable chronic obstructive pulmonary disease patients

OBJECTIVE: The potential influence of magnesium on exercise performance is a subject of increasing interest. Magnesium has been shown to have bronchodilatatory properties in asthma and chronic obstructive pulmonary disease patients. The aim of this study was to investigate the effects of acute magnesium IV loading on the aerobic exercise performance of stable chronic obstructive pulmonary disease patients. METHODS: Twenty male chronic obstructive pulmonary disease patients (66.2 +/- 8.3 years old, FEV1: 49.3 +/- 19.8%) received an IV infusion of 2 g of either magnesium sulfate or saline on two randomly assigned occasions approximately two days apart. Spirometry was performed both before and 45 minutes after the infusions. A symptom-limited incremental maximal cardiopulmonary test was performed on a cycle ergometer at approximately 100 minutes after the end of the infusion. ClinicalTrials.gov: NCT00500864 RESULTS: Magnesium infusion was associated with significant reductions in the functional residual capacity (-0.41 l) and residual volume (-0.47 l), the mean arterial blood pressure (-5.6 mmHg) and the cardiac double product (734.8 mmHg.bpm) at rest. Magnesium treatment led to significant increases in the maximal load reached (+8 w) and the respiratory exchange ratio (0.06) at peak exercise. The subgroup of patients who showed increases in the work load equal to or greater than 5 w also exhibited significantly greater improvements in inspiratory capacity (0.29 l). CONCLUSIONS: The acute IV loading of magnesium promotes a reduction in static lung hyperinflation and improves the exercise performance in stable chronic obstructive pulmonary disease patients. Improvements in respiratory mechanics appear to be responsible for the latter finding.

Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial

IMPORTANCE International guidelines advocate a 7- to 14-day course of systemic glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease (COPD). However, the optimal dose and duration are unknown. OBJECTIVE To investigate whether a short-term (5 days) systemic glucocorticoid treatment in patients with COPD exacerbation is noninferior to conventional (14 days) treatment in clinical outcome and whether it decreases the exposure to steroids. DESIGN, SETTING, AND PATIENTS REDUCE: (Reduction in the Use of Corticosteroids in Exacerbated COPD), a randomized, noninferiority multicenter trial in 5 Swiss teaching hospitals, enrolling 314 patients presenting to the emergency department with acute COPD exacerbation, past or present smokers (≥20 pack-years) without a history of asthma, from March 2006 through February 2011. INTERVENTIONS Treatment with 40 mg of prednisone daily for either 5 or 14 days in a placebo-controlled, double-blind fashion. The predefined noninferiority criterion was an absolute increase in exacerbations of at most 15%, translating to a critical hazard ratio of 1.515 for a reference event rate of 50%. MAIN OUTCOME AND MEASURE Time to next exacerbation within 180 days. RESULTS Of 314 randomized patients, 289 (92%) of whom were admitted to the hospital, 311 were included in the intention-to-treat analysis and 296 in the per-protocol analysis. Hazard ratios for the short-term vs conventional treatment group were 0.95 (90% CI, 0.70 to 1.29; P = .006 for noninferiority) in the intention-to-treat analysis and 0.93 (90% CI, 0.68 to 1.26; P = .005 for noninferiority) in the per-protocol analysis, meeting our noninferiority criterion. In the short-term group, 56 patients (35.9%) reached the primary end point; 57 (36.8%) in the conventional group. Estimates of reexacerbation rates within 180 days were 37.2% (95% CI, 29.5% to 44.9%) in the short-term; 38.4% (95% CI, 30.6% to 46.3%) in the conventional, with a difference of -1.2% (95% CI, -12.2% to 9.8%) between the short-term and the conventional. Among patients with a reexacerbation, the median time to event was 43.5 days (interquartile range [IQR], 13 to 118) in the short-term and 29 days (IQR, 16 to 85) in the conventional. There was no difference between groups in time to death, the combined end point of exacerbation, death, or both and recovery of lung function. In the conventional group, mean cumulative prednisone dose was significantly higher (793 mg [95% CI, 710 to 876 mg] vs 379 mg [95% CI, 311 to 446 mg], P < .001), but treatment-associated adverse reactions, including hyperglycemia and hypertension, did not occur more frequently. CONCLUSIONS AND RELEVANCE In patients presenting to the emergency department with acute exacerbations of COPD, 5-day treatment with systemic glucocorticoids was noninferior to 14-day treatment with regard to reexacerbation within 6 months of follow-up but significantly reduced glucocorticoid exposure. These findings support the use of a 5-day glucocorticoid treatment in acute exacerbations of COPD. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN19646069.

Relationship between health-related quality of life, comorbidities and acute health care utilisation, in adults with chronic conditions

Background: There is increased interest in developing multidisciplinary ambulatory care models of service delivery to manage patients with complex chronic diseases. These programs are expensive and given limited resources it is important that care is targeted effectively. One potential screening strategy is to identify individuals who report the greatest decrement in health related quality of life (HRQoL) and thus greater need. The aim of this study was to explore the relationship between HRQoL, comorbid conditions and acute health care utilisation. Methods: A prospective, longitudinal cohort design was used to evaluate the impact of HRQoL on acute care utilisation rates over three-years of follow-up. Participants were enrolled in chronic disease management programs run by a metropolitan health service in Australia. Baseline data was collected from 2007-2009 and follow-up data until 2012. Administrative data was used to classify patients' primary reasons for enrolment, number of comorbidities (Charlson Score) and presentations to acute care. At enrolment, HRQoL was measured using the Assessment of Quality of Life (AQoL) instrument, for analysis AQoL scores were dichotomised at two standard deviations below the population norm. Results: There were 1999 participants (54% male) with a mean age of 63years (range 18-101), enrolled in the study. Participants' primary health conditions at enrolment were: diabetes 915 (46%), chronic respiratory disease 463 (23%), cardiac disease 260 (13%), peripheral vascular disease, and 181 (9%) and aged care 180 (9%). At 1-year multivariate logistic regression models demonstrated that AQOL utility score was not predictive of acute care presentations after adjusting for comorbidities. Over 3-years an AQoL utility score in the lowest quartile was predictive of both ED presentation (OR 1.58, 95% CI, 1.16-2.13, p=0.003) and admissions (OR 1.67, 95% CI.1.21 to 2.30, p=0.002) after adjusting for differences in age and comorbidities. Conclusion: This study found that both HRQoL and comorbidities were predictive of subsequent acute care attendance over 3-years of follow-up. At 1-year, comorbidities was a better predictor of acute care representation than HRQoL. To maximise benefits, programs should initially focus on medical disease management, but subsequently switch to strategies that enhance health independence and raise HRQoL.

Nutritional support in chronic obstructive pulmonary disease: a systematic review and meta-analysis

BACKGROUND: The efficacy of nutritional support in the management of malnutrition in chronic obstructive pulmonary disease (COPD) is controversial. Previous meta-analyses, based on only cross-sectional analysis at the end of intervention trials, found no evidence of improved outcomes. OBJECTIVE: The objective was to conduct a meta-analysis of randomized controlled trials (RCTs) to clarify the efficacy of nutritional support in improving intake, anthropometric measures, and grip strength in stable COPD. DESIGN: Literature databases were searched to identify RCTs comparing nutritional support with controls in stable COPD. RESULTS: Thirteen RCTs (n = 439) of nutritional support [dietary advice (1 RCT), oral nutritional supplements (ONS; 11 RCTs), and enteral tube feeding (1 RCT)] with a control comparison were identified. An analysis of the changes induced by nutritional support and those obtained only at the end of the intervention showed significantly greater increases in mean total protein and energy intakes with nutritional support of 14.8 g and 236 kcal daily. Meta-analyses also showed greater mean (±SE) improvements in favor of nutritional support for body weight (1.94 ± 0.26 kg, P < 0.001; 11 studies, n = 308) and grip strength (5.3%, P < 0.050; 4 studies, n = 156), which was not shown by ANOVA at the end of the intervention, largely because of bias associated with baseline imbalance between groups. CONCLUSION: This systematic review and meta-analysis showed that nutritional support, mainly in the form of ONS, improves total intake, anthropometric measures, and grip strength in COPD. These results contrast with the results of previous analyses that were based on only cross-sectional measures at the end of intervention trials.

The influence of smoking status on malnutrition risk and 1-year mortality in outpatients with chronic obstructive pulmonary disease.

Introduction:  Smoking status in outpatients with chronic obstructive pulmonary disease (COPD) has been associated with a low body mass index (BMI) and reduced mid-arm muscle circumference (Cochrane & Afolabi, 2004). Individuals with COPD identified as malnourished have also been found to be twice as likely to die within 1 year compared to non-malnourished patients (Collins et al., 2010). Although malnutrition is both preventable and treatable, it is not clear what influence current smoking status, another modifiable risk factor, has on malnutrition risk. The current study aimed to establish the influence of smoking status on malnutrition risk and 1-year mortality in outpatients with COPD. Methods:  A prospective nutritional screening survey was carried out between July 2008 and May 2009 at a large teaching hospital (Southampton General Hospital) and a smaller community hospital within Hampshire (Lymington New Forest Hospital). In total, 424 outpatients with a diagnosis of COPD were routinely screened using the ‘Malnutrition Universal Screening Tool’, ‘MUST’ (Elia, 2003); 222 males, 202 females; mean (SD) age 73 (9.9) years; mean (SD) BMI 25.9 (6.4) kg m−2. Smoking status on the date of screening was obtained for 401 of the outpatients. Severity of COPD was assessed using the GOLD criteria, and social deprivation determined using the Index of Multiple Deprivation (Nobel et al., 2008). Results:  The overall prevalence of malnutrition (medium + high risk) was 22%, with 32% of current smokers at risk (who accounted for 19% of the total COPD population). In comparison, 19% of nonsmokers and ex-smokers were likely to be malnourished [odds ratio, 1.965; 95% confidence interval (CI), 1.133–3.394; P = 0.015]. Smoking status remained an independent risk factor for malnutrition even after adjustment for age, social deprivation and disease-severity (odds ratio, 2.048; 95% CI, 1.085–3.866; P = 0.027) using binary logistic regression. After adjusting for age, disease severity, social deprivation, smoking status, malnutrition remained a significant predictor of 1-year mortality [odds ratio (medium + high risk versus low risk), 2.161; 95% CI, 1.021–4.573; P = 0.044], whereas smoking status did not (odds ratio for smokers versus ex-smokers + nonsmokers was 1.968; 95% CI, 0.788–4.913; P = 0.147). Discussion:  This study highlights the potential importance of combined nutritional support and smoking cessation in order to treat malnutrition. The close association between smoking status and malnutrition risk in COPD suggests that smoking is an important consideration in the nutritional management of malnourished COPD outpatients. Conclusions:  Smoking status in COPD outpatients is a significant independent risk factor for malnutrition and a weaker (nonsignificant) predictor of 1-year mortality. Malnutrition significantly predicted 1 year mortality. References:  Cochrane, W.J. & Afolabi, O.A. (2004) Investigation into the nutritional status, dietary intake and smoking habits of patients with chronic obstructive pulmonary disease. J. Hum. Nutr. Diet.17, 3–11. Collins, P.F., Stratton, R.J., Kurukulaaratchym R., Warwick, H. Cawood, A.L. & Elia, M. (2010) ‘MUST’ predicts 1-year survival in outpatients with chronic obstructive pulmonary disease. Clin. Nutr.5, 17. Elia, M. (Ed) (2003) The ‘MUST’ Report. BAPEN. http://www.bapen.org.uk (accessed on March 30 2011). Nobel, M., McLennan, D., Wilkinson, K., Whitworth, A. & Barnes, H. (2008) The English Indices of Deprivation 2007. http://www.communities.gov.uk (accessed on March 30 2011).

Peripheral compartment innate immune response to Haemophilus influenzae and Streptococcus pneumoniae in chronic obstructive pulmonary disease patients.

Alterations in innate immunity that predispose to chronic obstructive pulmonary disease (COPD) exacerbations are poorly understood. We examined innate immunity gene expression in peripheral blood polymorphonuclear leukocytes (PMN) and monocytes stimulated by Haemophilus influenzae and Streptococcus pneumoniae. Thirty COPD patients (15 rapid and 15 non-rapid lung function decliners) and 15 smokers without COPD were studied. Protein expression of IL-8, IL-6, TNF-α and IFN-γ (especially monocytes) increased with bacterial challenge. In monocytes stimulated with S. pneumoniae, TNF-α protein expression was higher in COPD (non-rapid decliners) than in smokers. In co-cultures of monocytes and PMN, mRNA expression of TGF-β1 and MYD88 was up-regulated, and CD14, TLR2 and IFN-γ down-regulated with H. influenzae challenge. TNF-α mRNA expression was increased with H. influenzae challenge in COPD. Cytokine responses were similar between rapid and non-rapid decliners. TNF-α expression was up-regulated in non-rapid decliners in response to H. influenzae (monocytes) and S. pneumoniae (co-culture of monocytes and PMN). Exposure to bacterial pathogens causes characteristic innate immune responses in peripheral blood monocytes and PMN in COPD. Bacterial exposure significantly alters the expression of TNF-α in COPD patients, although not consistently. There did not appear to be major differences in innate immune responses between rapid and non-rapid decliners.

Nutritional support and functional capacity in chronic obstructive pulmonary disease: A systematic review and meta-analysis

Currently there is confusion about the value of using nutritional support to treat malnutrition and improve functional outcomes in chronic obstructive pulmonary disease (COPD). This systematic review and meta-analysis of randomised controlled trials (RCTs) aimed to clarify the effectiveness of nutritional support in improving functional outcomes in COPD. A systematic review identified 12 RCTs (n = 448) in stable COPD patients investigating the effects of nutritional support [dietary advice (1 RCT), oral nutritional supplements (ONS; 10 RCTs), enteral tube feeding (1 RCT)] versus control on functional outcomes. Meta-analysis of the changes induced by intervention found that whilst respiratory function (FEV(1,) lung capacity, blood gases) was unresponsive to nutritional support, both inspiratory and expiratory muscle strength (PI max +3.86 SE 1.89 cm H(2) O, P = 0.041; PE max +11.85 SE 5.54 cm H(2) O, P = 0.032) and handgrip strength (+1.35 SE 0.69 kg, P = 0.05) were significantly improved, and associated with weight gains of ≥ 2 kg. Nutritional support produced significant improvements in quality of life in some trials, although meta-analysis was not possible. It also led to improved exercise performance and enhancement of exercise rehabilitation programmes. This systematic review and meta-analysis demonstrates that nutritional support in COPD results in significant improvements in a number of clinically relevant functional outcomes, complementing a previous review showing improvements in nutritional intake and weight.

The effect of deprivation and disease-severity on malnutrition risk in chronic obstructive pulmonary disease (COPD)

Deprivation has previously been shown to be an independent risk factor for the high prevalence of malnutrition observed in COPD (Collins et al., 2010). It has been suggested the socioeconomic gradient observed in COPD is greater than any other chronic disease (Prescott & Vestbo, 1999). The current study aimed to examine the infl uence of disease severity and social deprivation on malnutrition risk in outpatients with COPD. 424 COPD outpatients were screened using the ‘Malnutrition Universal Screening Tool’ (‘MUST’). COPD disease severity was recorded in accordance with the GOLD criteria and deprivation was established according to the patient’s geographical location (postcode) at the time of nutritional screening using the UK Government’s Index of Multiple Deprivation (IMD). IMD ranks postcodes from 1 (most deprived) to 32,482 (least deprived). Disease severity was posi tively associated with an increased prevalence of malnutrition risk (p < 0.001) both within and between groups, whilst rank IMD was negatively associated with malnutrition (p = 0.020), i.e. those residing in less deprived areas were less likely to be malnourished. Within each category of disease severity the prevalence of malnutrition was two-fold greater in those residing in the most deprived areas compared to those residing in the least deprived areas. This study suggests that deprivation and disease severity are independent risk factors for malnutrition in COPD both contributing to the widely variable prevalence of malnutrition. Consideration of these issues could assist with the targeted nutritional management of these patients.