Multidimensional outcome assessment of pulmonary rehabilitation in traits-based clusters of COPD patients.

BACKGROUND: Clusters of COPD patients have been reported in order to individualize the treatment program. Neither co-morbidity clusters, nor integrated respiratory physiomics clusters contributed to a better prediction of outcomes. Based on a thoroughly assessed set of pulmonary and extra-pulmonary traits at the start of a pulmonary rehabilitation (PR) program, we recently described seven clusters of COPD patients. The aims of this study are to confirm multidimensional differential response and to assess the potential of pulmonary and extra-pulmonary traits-based clusters to predict this multidimensional response to PR pulmonary in COPD patients. METHODS: Outcomes of a 40-session PR program for COPD patients, referred by a chest physician, were evaluated based on the minimal clinically important difference (MCID) for 6-minute walk distance (6MWD), cycle endurance time, Canadian Occupational Performance Measure performance and satisfaction scores, Hospital Anxiety and Depression Scale anxiety and depression scores, MRC dyspnea grade and St George's Respiratory Questionnaire. The aforementioned response indicators were used to calculate the overall multidimensional response and patients were grouped in very good, good, moderate and poor responders. In the same way, responses to pulmonary rehabilitation were compared based on seven previously identified pulmonary and extra-pulmonary traits-based clusters. RESULTS: Of the whole sample, drop out was 19% and 419 patients (55.4% males, age: 64.3 ± 8.8, FEV1% of predicted: 48.9 ± 20) completed the pulmonary rehabilitation program. Very good responders had significantly worse baseline characteristics with a higher burden of disease, a higher proportion of rollator-users, higher body mass index (BMI), more limitations of activities in daily life, emotional dysfunction, higher symptoms of dyspnea and worse quality of life. Of the seven pre-identified clusters, 'the overall best functioning cluster' and 'the low disease burden cluster' both including the best 6MWD, the lowest dyspnea score and the overall best health status, demonstrated attenuated outcomes, while in 'the cluster of disabled patients', 76% of the patients improved health status with at least 2 times MCID. This 'cluster of disabled patients' as well as 'the multimorbid cluster', 'the emotionally dysfunctioning cluster', 'the overall worst-functioning cluster' and 'the physically dysfunctioning cluster' all demonstrated improvements in performance and satisfaction for occupational activities (more than 65% of patients improved with > 1MCID), emotional functioning (more than 50% of patients improved with > 1 MCID) and overall health status (more than 58%). CONCLUSION: The current study confirms the differential response to pulmonary rehabilitation based on multidimensional response profiling. Cluster analysis of baseline traits illustrates that non-linear, clinically important differences can be achieved in the most functionally and emotionally impaired clusters and that 'the overall best functional cluster' as well as 'the low disease burden cluster' had an attenuated outcome.

Cluster-randomised trial of a nurse-led advance care planning session in patients with COPD and their loved ones.

RATIONALE: Advance care planning (ACP) is uncommon in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVES: To assess whether a nurse-led ACP-intervention can improve quality of patient-physician end-of-life care communication in patients with COPD. Furthermore, the influence of an ACP-intervention on symptoms of anxiety and depression in patients and loved ones was studied. Finally, quality of death and dying was assessed in patients who died during 2-year follow-up. METHODS: A multicentre cluster randomised-controlled trial in patients with advanced COPD was performed. The intervention group received an 1.5 hours structured nurse-led ACP-session. Outcomes were: quality of patient-physician end-of-life care communication, prevalence of ACP-discussions 6 months after baseline, symptoms of anxiety and depression in patients and loved ones and quality of death and dying. RESULTS: 165 patients were enrolled (89 intervention; 76 control). The improvement of quality of patient-physician end-of-life care communication was significantly higher in the intervention group compared with the control group (p<0.001). The ACP-intervention was significantly associated with the occurrence of an ACP-discussion with physicians within 6 months (p=0.003). At follow-up, symptoms of anxiety were significantly lower in loved ones in the intervention group compared with the control group (p=0.02). Symptoms of anxiety in patients and symptoms of depression in both patients and loved ones were comparable at follow-up (p>0.05). The quality of death and dying was comparable between both groups (p=0.17). CONCLUSION: One nurse-led ACP-intervention session improves patient-physician end-of-life care communication without causing psychosocial distress in both patients and loved ones.

Effectiveness of Pulmonary Rehabilitation in Patients With Chronic Obstructive Pulmonary Disease With Different Degrees of Static Lung Hyperinflation.

OBJECTIVE: To evaluate the effect of pulmonary rehabilitation (PR) on exercise performance and quality of life in patients with chronic obstructive pulmonary disease (COPD) with different degrees of static lung hyperinflation (LH). DESIGN: Retrospective cohort study. SETTING: PR network. PARTICIPANTS: A cohort of 1981 patients with COPD (55% men; age: 66.8±9.3y; forced expiratory volume in the first second%: 50.7±19.5; residual volume [RV]%: 163.0±49.7). INTERVENTION: An interdisciplinary PR program for patients with COPD consisting of 40 sessions. MAIN OUTCOME MEASURES: Participants were stratified into 5 quintiles according to baseline RV and were evaluated on the basis of pre- and post-PR 6-minute walk distance (6MWD), constant work rate test (CWRT), and Saint George's Respiratory Questionnaire (SGRQ), among other clinical parameters. RESULTS: With increasing RV quintile, patients were younger, more frequently women, had lower forced expiratory volume in the first second%, lower body mass index and fat-free mass index, shorter 6MWD, shorter CWRT, and worse SGRQ scores (P<.01). All RV strata improved after PR in all 3 outcomes (P<.001). Nevertheless, higher, compared to lower RV categories, had lower ΔCWRT (P<.01) but similar Δ6MWD (P=.948) and ΔSGRQ (P=.086) after PR. CONCLUSIONS: LH in COPD is related to younger age, female sex, lower body weight, worse exercise capacity and health status, but did not prevent patients from benefitting from PR. LH, however, influences walking and cycling response after PR differently.

Differential response to pulmonary rehabilitation in COPD: multidimensional profiling.

The aim of the present study was to profile a multidimensional response to pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD).Dyspnoea, exercise performance, health status, mood status and problematic activities of daily life were assessed before and after a 40-session pulmonary rehabilitation programme in 2068 patients with COPD (mean forced expiratory volume in 1 s of 49% predicted). Patients were ordered by their overall similarity concerning their multidimensional response profile, which comprises the overall response on MRC dyspnoea grade, 6MWD, cycle endurance time, Canadian Occupational Performance Measure performance and satisfaction scores, Hospital Anxiety and Depression Scale anxiety and depression, and St George's Respiratory Questionnaire total score, using a novel non-parametric regression technique.Patients were clustered into four groups with distinct multidimensional response profiles: n=378 (18.3%; "very good responder"), n=742 (35.9%; "good responder"), n=731 (35.4%; "moderate responder"), and n=217 (10.5%; "poor responder"). Patients in the "very good responder" cluster had higher symptoms of dyspnoea, number of hospitalisations <12 months, worse exercise performance, worse performance and satisfaction scores for problematic activities of daily life, more symptoms of anxiety and depression, worse health status, and a higher proportion of patients following an inpatient PR programme compared to the other three clusters.A multidimensional response outcome needs to be considered to study the efficacy of pulmonary rehabilitation services in patients with COPD, as responses to regular outcomes are differential within patients with COPD.

Six-minute walk distance in patients with chronic obstructive pulmonary disease: Which reference equations should we use?

The use of different 6-min walk distance (6MWD) reference equations probably results in different predicted 6MWD reference values. We wished to investigate the impact of several 6MWD reference equations for adults in patients with chronic obstructive pulmonary disease (COPD) and factors accountable for different 6MWD% predicted values. Twenty-two 6MWD reference equations were applied to a data set of 2757 patients with COPD. The predicted 6MWD reference value of Troosters and colleagues was used as the point of reference. Four out of 21 remaining equations resulted in comparable 6MWD% predicted, 16 equations resulted in significantly higher 6MWD% predicted and 1 equation resulted in a significantly lower 6MWD% predicted. Similar differences in 6MWD% predicted were observed after stratification by sex. Body mass index and global initiative for chronic obstructive lung disease (GOLD) stage classification demonstrated varying results within and between the groups; 9 out of 21 equations resulted in comparable 6MWD% predicted in underweight patients but only 1 equation demonstrated comparable result in obese. Eight equations in GOLD I, whilst 5 out of 21 equations in GOLD IV resulted in comparable 6MWD% predicted. Existing 6MWD reference equations will give varying results. The choice of 6MWD reference equation should consider the consistency of 6-min walk test operating procedures and at least be specific for the country/region of origin.

The effect of a multispecies probiotic on the composition of the faecal microbiota and bowel habits in chronic obstructive pulmonary disease patients treated with antibiotics.

Short-term antibiotic treatment profoundly affects the intestinal microbiota, which may lead to sustained changes in microbiota composition. Probiotics may restore such a disturbance. The objective of the present study was to investigate the effect of a multispecies probiotic on the faecal microbiota during and after antibiotic intake in patients with a history of frequent antibiotic use. In this randomised, placebo-controlled, double-blind study, thirty chronic obstructive pulmonary disease (COPD) patients treated with antibiotics for a respiratory tract infection received 5 g of a multispecies probiotic or placebo twice daily for 2 weeks. Faecal samples were collected at 0, 7, 14 and 63 d. Changes in the composition of the dominant faecal microbiota were determined by PCR-denaturing gradient gel electrophoresis (DGGE). Changes in bacterial subgroups were determined by quantitative PCR and culture. Bowel movements were scored daily according to the Bristol stool form scale. During and after antibiotic treatment, DGGE-based similarity indices (SI) were high ( >/= 84 %) and band richness was relatively low, both remaining stable over time. No difference in SI was observed between patients with and without diarrhoea-like bowel movements. The multispecies probiotic had a modest effect on the bacterial subgroups. Nevertheless, it affected neither the composition of the dominant faecal microbiota nor the occurrence of diarrhoea-like bowel movements. The dominant faecal microbiota was not affected by antibiotics in this COPD population, suggesting an existing imbalance of the microbiota, which may also have contributed to the lack of effect by probiotic intake.

Poly (ADP-ribose) polymerase-1-inhibiting flavonoids attenuate cytokine release in blood from male patients with chronic obstructive pulmonary disease or type 2 diabetes.

Recently, we identified several flavonoids as inhibitors of the nuclear enzyme poly(ADP-ribose) polymerase (PARP)-1 in vitro and in vivo. PARP-1 is recognized as coactivator of nuclear factor-kappaB and plays a role in the pathophysiology of diseases with low-grade systemic inflammation, such as chronic obstructive pulmonary disease (COPD) and type 2 diabetes (T2D). In this study, we assessed the antiinflammatory effects of flavonoids with varying PARP-1-inhibiting effects in whole blood from male patients with COPD or T2D and healthy men. A total of 10 COPD, 10 T2D patients, and 10 healthy volunteers matched for age and BMI were recruited. Blood from each participant was exposed to 1 microg/L lipopolysaccharide (LPS) over 16 h with or without preincubation with 10 micromol/L of flavone, fisetin, morin, or tricetin. Concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, -8, and -10 were measured in the supernatant. Preincubation with fisetin and tricetin strongly attenuated LPS-induced increases in concentrations of TNFalpha in blood from COPD patients [mean (+/- SEM): -41 +/- 4% (fisetin) and -31 +/- 4% (tricetin); P < 0.001] and IL-6 in blood from T2D patients [-31 +/- 5% (fisetin) and -29 +/- 6% (tricetin); P < or = 0.001]. Moreover, LPS-induced changes in TNFalpha and IL-6 concentrations were positively correlated with the extent of reduction by fisetin and tricetin. The PARP-1-inhibiting flavonoids fisetin and tricetin were able to attenuate LPS-induced cytokine release from leukocytes of patients with chronic systemic inflammation, indicating a potential application as nutraceutical agents for these patient groups.

Effect of infliximab on local and systemic inflammation in chronic obstructive pulmonary disease: a pilot study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) with cachexia is characterized by inflammation reflected by increased levels of tumor necrosis factor-alpha (TNF-alpha). OBJECTIVES: In this study, infliximab, an anti-TNF-alpha antibody, was evaluated for its effects on systemic (plasma) and local (exhaled breath condensate, EBC) inflammation in cachectic patients with COPD. Also, baseline levels of new inflammatory markers were compared to control subjects. METHODS: Sixteen cachectic patients with moderate to severe COPD were examined for inflammatory status at baseline and compared to 25 control subjects. Patients were randomized (1:1) to receive infliximab (5 mg/kg) or placebo at weeks 0, 2 and 6. Patients were evaluated at weeks 8 and 12 and followed through week 26. RESULTS: EBC analysis revealed increased levels of several novel inflammatory markers, including macrophage migration inhibitory factor, IL-12, RANTES and sICAM-1, in patients with COPD compared to controls. EBC levels of inflammatory markers were unchanged in patients receiving infliximab. In addition, systemic levels of acute-phase proteins (C-reactive protein, fibrinogen and lipopolysaccharide-binding protein), IL-6 and soluble TNF receptor (sTNFR) 55 had not changed at weeks 8 or 12. Small increases in circulating levels of sTNFR75, myeloperoxidase and Clara cell protein 16 were seen at week 8, but not at week 12. CONCLUSIONS: In this small study, infliximab did not produce an observable decrease in local inflammation in cachectic patients with COPD and had minor effects on systemic inflammation. The detection of new inflammatory markers in EBC can help to further characterize local inflammatory processes in COPD.

Extra-pulmonary features in COPD patients entering rehabilitation after stratification for MRC dyspnea grade.

Experts have stated that referral for rehabilitation of patients with chronic obstructive pulmonary disease (COPD) becomes appropriate when these patients become aware of their disability (e.g. usually grade 3 to 5 on the Medical Research Council (MRC) dyspnea scale). However, patients with MRC dyspnea grade 1/2 may also suffer from extra-pulmonary features, such as abnormal body composition, exercise intolerance and reduced disease-specific health status. In the present study, we have studied whether and to what extent chronic obstructive pulmonary disease (COPD) patients with MRC dyspnea grade 1/2 have extra-pulmonary features compared to patients with grade 3, 4 or 5? Pulmonary function, body composition, 6-min walking distance, peak exercise capacity, anxiety, depression and disease-specific health status have been assessed in 333 outpatients who had been referred for pulmonary rehabilitation. On average, patients with MRC dyspnea grade 1/2 had a better exercise tolerance and disease-specific health status compared to patients with grade 4 or 5. Nevertheless, grade 1/2 patients had a higher prevalence of muscle mass depletion. In addition, these patients did still have aberrant values in one or more of the aforementioned outcomes. On average, patients with MRC dyspnea grade 1/2 may clearly suffer from extra-pulmonary features, indicating the necessity to refer these patients for rehabilitation. Therefore, MRC dyspnea scale alone does not appear to be a suitable measure to identify most patients with COPD who have to be referred for rehabilitation.

Increased granzyme A expression in type II pneumocytes of patients with severe chronic obstructive pulmonary disease.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is associated with increased numbers of CD8(+) cytotoxic T lymphocytes (CTLs) in the lung, but the functional activity of CTLs remains unknown. Granzyme A (GrA) and B (GrB) are serine proteases considered to be important effector molecules of CTLs and natural killer cells. OBJECTIVE: To investigate protein and mRNA expression of GrA and GrB in peripheral lung tissue from patients with COPD and control subjects with normal lung function. METHODS: Paraffin-embedded sections of surgical lung specimens from 22 patients with COPD (FEV(1), 22% predicted; GOLD stage 4) and 15 control subjects (FEV(1), 108% predicted) were immunostained for GrA and GrB, and semiquantified on a 3-point scale. Messenger RNA expression in total lung, specific cell types enriched for by laser capture microdissection, and freshly isolated primary cells were determined by reverse transcriptase-polymerase chain reaction. MEASUREMENTS AND MAIN RESULTS: GrA and GrB immunoreactivity was observed in CD8(+) CTLs and CD57(+) natural killer cells, but also in type II pneumocytes and alveolar macrophages in both groups. Bronchiolar epithelium stained positive for GrA, but negative for GrB. These observations were confirmed by reverse transcriptase-polymerase chain reaction on total lung, laser capture microdissection-enriched specific cell types and freshly isolated primary type II pneumocytes. The scores of GrA-expressing type II pneumocytes were significantly higher in patients with COPD versus control subjects. CONCLUSIONS: GrA and GrB mRNA and protein are detectable in human lung tissue. GrA expression is increased in type II pneumocytes of patients with very severe COPD. These results indicate that GrA may be important in the development of COPD.

Systemic poly(ADP-ribose) polymerase-1 activation, chronic inflammation, and oxidative stress in COPD patients.

Oxidative stress and systemic inflammation in chronic obstructive pulmonary disease (COPD) strongly suggest a role for the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1, E.C.2.4.2.30) in the disease pathophysiology. PARP-1 is highly activated by reactive oxygen species-induced DNA strand breaks, upon which it forms extensive poly(ADP-ribose) (PAR) polymers from its substrate NAD(+). We hypothesized that in COPD, chronic inflammation and oxidative stress would lead to systemic PARP-1 activation and to a reduced NAD(+) status. In a patient-control study, systemic PARP-1 activation was assessed by immunofluorescent detection of PAR polymers in peripheral blood lymphocytes. The percentage of PAR polymer-positive lymphocytes appeared to be higher in COPD patients (27 +/- 3%) than in healthy age-matched controls (17 +/- 2%, p <.05). Trolox equivalent antioxidant capacity (TEAC) of deproteinized plasma (p <.001), plasma uric acid (p <.05), as well as blood NAD(+) (p <.01) of stable COPD patients were significantly reduced when compared to controls. In addition, levels of proinflammatory cytokines IL-6, IL-8, and sICAM-1 were increased (p <.005) in COPD patients. In this study, evidence was found for the presence of systemic inflammation, chronic oxidative stress, and systemic PARP-1 activation in stable COPD patients. These data support a contribution of oxidative stress-induced PARP-1 activation to the pathophysiology of COPD.

Tumor necrosis factor-alpha +489G/A gene polymorphism is associated with chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by a chronic inflammatory process, in which the pro-inflammatory cytokine Tumor Necrosis Factor (TNF)-alpha is considered to play a role. In the present study the putative involvement of TNF-alpha gene polymorphisms in pathogenesis of COPD was studied by analysis of four TNF-alpha gene polymorphisms in a Caucasian COPD population. METHODS: TNF-alpha gene polymorphisms at positions -376G/A, -308G/A, -238G/A, and +489G/A were examined in 169 Dutch COPD patients, who had a mean forced expiratory volume in one second (FEV1) of 37 +/- 13%, and compared with a Dutch population control group of 358 subjects. RESULTS: The data showed that the TNF-alpha +489G/A genotype frequency tended to be different in COPD patients as compared to population controls, which was due to an enhanced frequency of the GA genotype. In line herewith, carriership of the minor allele was associated with enhanced risk of development of COPD (odds ratio = 1.9, p = 0.009). The other TNF-alpha gene polymorphisms studied revealed no discrimination between patients and controls. No differences in the examined four TNF-alpha polymorphisms were found between subtypes of COPD, which were stratified for the presence of radiological emphysema. However, comparison of the COPD subtypes with controls showed a significant difference in the TNF-alpha +489G/A genotype in patients without radiological emphysema (chi2-test: p < 0.025 [Bonferroni adjusted]), while no differences between COPD patients with radiological emphysema and controls were observed. CONCLUSION: Based on the reported data, it is concluded that COPD, and especially a subgroup of COPD patients without radiological emphysema, is associated with TNF-alpha +489G/A gene polymorphism.