title: Stable COPD: predicting benefit from high-dose inhaled corticosteroid treatment Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea COPD association and repeatability of blood biomarkers in the ECLIPSE cohort Clinically important differences in the intensity of chronic refractory breathlessness. Short-term opioids for breathlessness in stable chronic heart failure: a randomized controlled trial. Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial Morphine for the relief of breathlessness in patients with chronic heart failure—a pilot study Once-daily opioids for chronic dyspnea: a dose increment and pharmacovigilance study. Does the use of a handheld fan improve chronic dyspnea? A randomized, controlled, crossover trial. Sputum eosinophilia predicts benefit from prednisone in smokers with chronic obstructive bronchitis.
abstract: The role of inhaled corticosteroids in the management of chronic obstructive pulmonary disease ( COPD ) remains controversial . The purpose of this study was to evaluate whether sputum eosinophilia ( defined as eosinophils ≥3 % ) predicts clinical benefit from inhaled corticosteroid treatment in patients with smoking-related clinical ly stable moderate-to-severe COPD . Forty consecutive patients with effort dyspnoea ( mean age 67 yrs ; 52 pack-yr smoking history ; post-bronchodilator forced expiratory volume in one second ( FEV1 ) < 60 % predicted , consistent with moderate-to-severe smoking-related chronic airflow limitation ) were enrolled . Subjects were treated with inhaled placebo followed by inhaled budesonide ( Pulmicort Turbuhaler ® 1,600 µg·day−1 ) , each given for 4 weeks . While the treatment was single-blind ( subject level ) , sputum cell counts before and after treatment interventions were double-blind , thus removing bias . Outcome variables included spirometry , quality -of-life assessment and 6-min walk test . Sputum eosinophilia was present in 38 % of subjects . In these , budesonide treatment normalised the eosinophil counts and , in comparison to placebo treatment , result ed in clinical ly significant improvement in the dyspnoea domain of the disease-specific chronic respiratory question naire ( 0.8 versus 0.3 ) and a small but statistically significant improvement in post-bronchodilator spirometry ( FEV1 100 mL versus 0 mL ; p<0.05 ) . In conclusion , sputum eosinophilia predicts short-term clinical benefit from high-dose inhaled corticosteroid treatment in patients with stable moderate-to-severe chronic obstructive pulmonary disease & NA ;  Pain intensity is frequently measured on an 11‐point pain intensity numerical rating scale ( PI‐NRS ) , where 0=no pain and 10=worst possible pain . However , it is difficult to interpret the clinical importance of changes from baseline on this scale ( such as a 1‐ or 2‐point change ) . To date , there are no data driven estimates for clinical ly important differences in pain intensity scales used for chronic pain studies . We have estimated a clinical ly important difference on this scale by relating it to global assessment s of change in multiple studies of chronic pain . Data on 2724 subjects from 10 recently completed placebo‐controlled clinical trials of pregabalin in diabetic neuropathy , postherpetic neuralgia , chronic low back pain , fibromyalgia , and osteoarthritis were used . The studies had similar design s and measurement instruments , including the PI‐NRS , collected in a daily diary , and the st and ard seven‐point patient global impression of change ( PGIC ) , collected at the endpoint . The changes in the PI‐NRS from baseline to the endpoint were compared to the PGIC for each subject . Categories of ‘ much improved ’ and ‘ very much improved ’ were used as determinants of a clinical ly important difference and the relationship to the PI‐NRS was explored using graphs , box plots , and sensitivity/specificity analyses . A consistent relationship between the change in PI‐NRS and the PGIC was demonstrated regardless of study , disease type , age , sex , study result , or treatment group . On average , a reduction of approximately two points or a reduction of approximately 30 % in the PI‐NRS represented a clinical ly important difference . The relationship between percent change and the PGIC was also consistent regardless of baseline pain , while higher baseline scores required larger raw changes to represent a clinical ly important difference . The application of these results to future studies may provide a st and ard definition of clinical ly important improvement in clinical trials of chronic pain therapies . Use of a st and ard outcome across chronic pain studies would greatly enhance the comparability , validity , and clinical applicability of these studies RATIONALE Exacerbations of chronic obstructive pulmonary disease ( COPD ) and responses to treatment are heterogeneous . OBJECTIVES Investigate the usefulness of blood eosinophils to direct corticosteroid therapy during exacerbations . METHODS Subjects with COPD exacerbations were entered into a r and omized biomarker-directed double-blind corticosteroid versus st and ard therapy study . Subjects in the st and ard arm received prednisolone for 2 weeks , whereas in the biomarker-directed arm , prednisolone or matching placebo was given according to the blood eosinophil count biomarker . Both study groups received antibiotics . Blood eosinophils were measured in the biomarker-directed and st and ard therapy arms to define biomarker-positive and -negative exacerbations ( blood eosinophil count > and ≤ 2 % , respectively ) . The primary outcome was to determine noninferiority in health status using the chronic respiratory question naire ( CRQ ) and in the proportion of exacerbations associated with a treatment failure between subjects allocated to the biomarker-directed and st and ard therapy arms . MEASUREMENTS AND MAIN RESULTS There were 86 and 80 exacerbations in the biomarker-directed and st and ard treatment groups , respectively . In the biomarker-directed group , 49 % of the exacerbations were not treated with  prednisolone . CRQ improvement after treatment in the st and ard and biomarker-directed therapy groups was similar ( 0.8 vs. 1.1 ; mean difference , 0.3 ; 95 % confidence interval , 0.0 - 0.6 ; P = 0.05 ) . There was a greater improvement in CRQ in biomarker-negative exacerbations given placebo compared with those given prednisolone ( mean difference , 0.45 ; 95 % confidence interval , 0.01 - 0.90 ; P = 0.04 ) . In biomarker-negative exacerbations , treatment failures occurred in 15 % given prednisolone and 2 % of those given placebo ( P = 0.04 ) . CONCLUSIONS The peripheral blood eosinophil count is a promising biomarker to direct corticosteroid therapy during COPD exacerbations , but larger studies are required Abstract Objective To determine the efficacy of oral morphine in relieving the sensation of breathlessness in patients in whom the underlying aetiology is maximally treated . Design R and omised , double blind , placebo controlled crossover study . Setting Four outpatient clinics at a hospital in South Australia . Participants 48 participants who had not previously been treated with opioids ( mean age 76 , SD 5 ) with predominantly chronic obstructive pulmonary disease ( 42 , 88 % ) were r and omised to four days of 20 mg oral morphine with sustained release followed by four days of identically formulated placebo , or vice versa . Laxatives were provided as needed . Main outcome measures Dyspnoea in the morning and evening as shown on a 100 mm visual analogue scale , quality of sleep , wellbeing , performance on physical exertion , and side effects as measured at the end of the four day treatment period . Results 38 participants completed the study ; three withdrew because of definite and two because of possible side effects of morphine  ( nausea , vomiting , and sedation ) . Participants reported significantly different dyspnoea scores when treated with morphine : an improvement of 6.6 mm ( 95 % confidence interval 1.6 mm to 11.6 mm ) in the morning and of 9.5 mm ( 3.0 mm to 16.1 mm ) in the evening ( P = 0.011 and P = 0.006 , respectively ) . During the period in which they were taking morphine participants also reported better sleep ( P = 0.039 ) . More participants reported distressing constipation while taking morphine ( 9 v 1 , P = 0.021 ) in spite of using laxatives . All other side effects were not significantly worse with morphine , although the study was not powered to address side effects . Conclusions Sustained release , oral morphine at low dosage provides significant symptomatic improvement in refractory dyspnoea in the community setting Background There is a need for biomarkers to better characterise individuals with COPD and to aid with the development of therapeutic interventions . A panel of putative blood biomarkers was assessed in a subgroup of the Evaluation of COPD Longitudinally to Identify Surrogate Endpoints ( ECLIPSE ) cohort . Methods Thirty-four blood biomarkers were assessed in 201 subjects with COPD , 37 ex-smoker controls with normal lung function and 37 healthy non-smokers selected from the ECLIPSE cohort . Biomarker repeatability was assessed using baseline and 3-month sample s. Intergroup comparisons were made using analysis of variance , repeatability was assessed through Bl and -Altman plots , and correlations between biomarkers and clinical characteristics were assessed using Spearman correlation coefficients . Results Fifteen biomarkers were significantly different in individuals with COPD when compared to former or non-smoker controls . Some biomarkers , including tumor necrosis factor-α and interferon-γ , were measurable in only a minority of subjects whilst others such as C-reactive protein showed wide variability over the 3-month replication period . Fibrinogen was the most repeatable biomarker and exhibited a weak correlation with 6-minute walk distance , exacerbation rate , BODE index and MRC dyspnoea score in COPD subjects . 33 % ( 66/201 ) of the COPD subjects reported at least 1 exacerbation over the 3 month study with 18 % ( 36/201 ) reporting the exacerbation within 30 days of the 3-month visit . CRP , fibrinogen interleukin-6 and surfactant protein-D were significantly elevated in those COPD subjects with exacerbations within 30 days of the 3-month visit compared with those individuals that did not exacerbate or whose exacerbations had resolved . Conclusions Only a few of the biomarkers assessed may be useful in diagnosis or management of COPD where the diagnosis is based on airflow obstruction ( GOLD ) . Further analysis of more promising biomarkers may reveal utility in subsets of patients . Fibrinogen in particular has emerged as a potentially useful biomarker from this cohort and requires further investigation . Trial Registration SCO104960 , clinical trials.gov identifier CONTEXT Clinical ly important differences in chronic refractory breathlessness are ill defined but important in clinical practice and trial design . OBJECTIVES To estimate the clinical relevance of differences in breathlessness intensity using distribution and patient anchor methods . METHODS This was a retrospective data analysis from 213 data sets from four clinical trials for refractory breathlessness .  Linear regression was used to explore the relationship between study effect size and change in breathlessness score ( 0 - 100 mm visual analogue scale ) and to estimate the change in score equivalent to small , moderate , and large effect sizes . Pooled individual blinded patient preference data from three r and omized controlled trials were analyzed . The difference between the mean change in Day 4 minus baseline scores between preferred and non-preferred arms was calculated . RESULTS There was a strong relationship between change in score and effect size ( P = 0.001 ; R(2 ) = 0.98 ) . Values for small , moderate , and large effects were -5.5 , -11.3 , and -18.2 mm . The participant preference change in score was -9 mm ( 95 % CI , -15.8 , -2.1 ) ( P = 0.008 ) . CONCLUSION This larger data set supports a clinical ly important difference of 10 mm . Studies should be powered to detect this difference AIMS To assess the effect of oral opioids vs. placebo on breathlessness in patients with chronic heart failure ( CHF ) . METHODS AND RESULTS Oral morphine ( Oramorph ) , oral oxycodone ( Oxynorm ) , and placebo were studied in an outpatient setting . Once r and omized , participants received all three interventions in a controlled double-blind crossover trial for 4 days each , with a 3-day washout between interventions . Patients known to the Hull and East Yorkshire Academic Cardiology department with CHF ( New York Heart Association Grade III-IV ) were invited to participate . Participants were eligible if they were on st and ard medical therapy with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers , and diuretics .  Participant-rated change in 11-point numerical rating scale ( NRS ) ( average over previous 24 h ) breathlessness severity score from baseline ( Day 1 ) to Day 4 of treatment was the primary outcome measure . The study was powered to detect a one-point change in severity . Thirty-nine patients were r and omized and 35 completed all three study arms . Breathlessness severity was reduced from baseline with all three interventions . There was no statistically significant difference between active intervention and placebo or between the two types of opioid for the primary endpoint [ -1.37 in NRS score for placebo group vs. -0.41 in morphine group ( P = 0.13 ) and -1.29 for oxycodone group ( P = 0.90 ) ] . The response to treatment was not affected by aetiology , severity of CHF , or concurrent drug therapy . Opioid administration did not cause detrimental changes in clinical observations and was well tolerated . CONCLUSION We demonstrated no benefit over placebo for the relief of breathlessness with short-term low-dose oral opioids for CHF patients . Trial registered prior to the recruitment of the first participant with Current Controlled Trials ( www.controlled-trials.com ; Trial number IS RCT N 85268059 ) Evidence suggests that eosinophilic airway inflammation is important in the pathogenesis of severe chronic obstructive pulmonary disease ( COPD ) exacerbations . The present authors tested the hypothesis that a management strategy that aims to reduce sputum eosinophil counts is associated with a reduction in exacerbations of COPD . A total of 82 patients with COPD were r and omised into two groups . One group was treated according to traditional guidelines ( British Thoracic Society ( BTS ) group ) and the other ( sputum group ) was treated with the additional aim of minimising eosinophilic airway inflammation , assessed using the induced sputum eosinophil count . The primary outcome was exacerbations , which were categorised as mild , moderate or severe . The frequency of severe exacerbations per patient per year was 0.5 and 0.2 in the BTS and sputum groups , respectively ( mean reduction 62 % ) . The majority of this benefit was confined to patients with eosinophilic airway inflammation .  There was no difference in the frequency of mild and moderate exacerbations . The average daily dose of inhaled or oral corticosteroids during the trial did not differ between the groups . Out of 42 patients in the sputum group , 17 required regular oral corticosteroids to minimise eosinophilic airway inflammation . A management strategy that aims to minimise eosinophilic airway inflammation , as well as symptoms , is associated with a reduction in severe exacerbations of chronic obstructive pulmonary disease BACKGROUND Some patients with chronic obstructive pulmonary disease ( COPD ) respond to corticosteroid therapy . Whether these patients have different airway pathology from other COPD patients is unclear . We tested the hypothesis that response to prednisolone is related to the presence of eosinophilic airway inflammation . METHODS We did a r and omised , double-blind , crossover trial . Patients who had COPD treated with bronchodilators only were assigned placebo and 30 mg prednisolone daily for 2 weeks each , in a r and om order , separated by a 4-week washout period . Before and after each treatment period , we assessed patients with spirometry , symptom scores , the chronic respiratory disease question naire ( CRQ ) , incremental shuttle walk test , and induced sputum .  Analysis was done by intention to treat . FINDINGS 83 patients were recruited , of whom 67 were r and omised . The geometric mean sputum eosinophil count fell significantly after prednisolone ( from 2.4 % to 0.4 % ; mean difference six-fold [ 95 % CI 3.1 - 11.4 ] ) but not after placebo . Other sputum cell counts did not change . After stratification into tertiles by baseline eosinophil count , postbronchodilator forced expiratory volume in 1 s ( FEV1 ) and total scores on the CRQ improved progressively after prednisolone from the lowest to the highest eosinophilic tertile , compared with placebo . The mean change in postbronchodilator FEV1 , total CRQ score , and shuttle walk distance with prednisolone compared with placebo in the highest tertile was 0.19 L ( 0.06 - 0.32 ) , 0.62 ( 0.31 - 0.93 ) , and 20 m ( 5 - 35 ) , respectively . INTERPRETATION Our findings suggest that eosinophilic airway inflammation contributes to airflow obstruction and symptoms in some patients with COPD and that the short-term effects of prednisolone are due to modification of this feature of the inflammatory response . The possibility that sputum eosinophilia identifies a subgroup of patients who particularly respond to long-term treatment with inhaled corticosteroids should be investigated Chronic heart failure ( CHF ) patients can experience significant breathlessness despite maximum medication for their heart failure . Morphine has long been used to relieve symptoms in acute failure , but there is little evidence about this potentially useful palliative therapy in CHF CONTEXT R and omized controlled trials can answer questions of efficacy , but long-term pharmacovigilance studies generate complementary safety data . OBJECTIVES Level I evidence supports short-term efficacy of opioids in reducing  chronic refractory dyspnea .  This study aim ed to determine the minimum effective once-daily dose of sustained-release morphine , and whether net clinical benefits are sustained safely . METHODS In a Phase II dose increment study , 10 mg daily of sustained-release morphine was administered , and increased in nonresponders by 10 mg daily each week to a maximum of 30 mg daily . The participant was withdrawn if there were unacceptable side effects or no response to maximum dose . If participants had a 10 % improvement in dyspnea over their own baseline , they joined a long-term Phase IV effectiveness/safety study at that dose . Complying with Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) guidelines , response and side effects are described , with demographic and clinical characteristics of responders . RESULTS Eighty-three participants ( 53 males , mean age 75 years , 54 % with chronic obstructive pulmonary disease ) provided more than 30 patient-years of data . Fifty-two participants derived ≥ 10 % benefit ( on average 35 % improvement over baseline ) , giving a response rate of 62 % ( number needed to treat of 1.6 : number needed to harm 4.6 ) ; for 70 % , this dose was 10mg/24h . Benefit was maintained at three months for 28 ( 33 % ) people . Ranking of breathlessness was reduced significantly ( P<0.001 ) , but constipation increased ( P<0.001 ) despite laxatives . There were no episodes of respiratory depression or hospitalizations as a result of the sustained-release morphine . Overall , one in three people continued to derive benefit at three months . CONCLUSION Ten milligrams of sustained-release oral morphine once daily is safe and effective for most people who respond CONTEXT Dyspnea is a disabling distressing symptom that is common in advanced disease affecting millions of people worldwide . Current palliative strategies are partially effective in managing this symptom ; facial cooling has been shown to reduce the sensation of breathlessness when induced in volunteers but has not been formally investigated in dyspnea associated with disease . OBJECTIVE The objective of this study was to investigate whether a h and held fan reduces the sensation of breathlessness in such patients , enhancing palliative approaches . METHODS The effectiveness of a h and held fan ( blowing air across the nose and mouth ) in reducing the sensation of breathlessness was assessed in patients with advanced disease . Fifty participants were r and omized to use a h and held fan for five minutes directed to their face or leg first and then crossed over to the other treatment . The primary outcome measure was a decrease of greater than 1 cm in breathlessness recorded on a 10 cm visual analog scale ( VAS ) . RESULTS There was a significant difference in the VAS scores between the two treatments , with a reduction in breathlessness when the fan was directed to the face ( P=0.003 ) . CONCLUSION This study supports the hypothesis that a h and held fan directed to the face reduces the sensation of breathlessness . The fan was acceptable to participants : it is inexpensive , portable , enhances self-efficacy , and available internationally . It should be recommended as part of a palliative management strategy for reducing breathlessness associated with advanced disease A reliable predictor of benefit from corticosteroid treatment in patients with chronic airflow limitation is needed . In a single-blind , sequential crossover trial of placebo and prednisone ( 30 mg/day ) treatment , with each given for 2 wk , we investigated whether an increased proportion of sputum eosinophils ( > = 3 % ) predicts a beneficial effect of prednisone in smokers with severe obstructive bronchitis . Patients were seen before and after each treatment . Clinical measurements were made blind to the laboratory findings and vice-versa . Eighteen of 20 patients completed the study . Eight had sputum eosinophilia and similar clinical and physiologic characteristics to those of 10 patients without a finding of sputum eosinophilia . Only in patients with sputum eosinophilia did prednisone , as compared with placebo , produce a statistically significant and clinical ly important mean effect on effort dyspnea of 0.8 ( 95 % confidence interval [ CI ] : 0.3 to 1.2 ) , p = 0.008 , and in quality of life of 1.96 ( 95 % CI : 0.5 to 3.3 ) , p = 0.01 , associated with a small improvement in FEV1 of 0.11 L ( 95 % CI : - 0.04 to 0.23 L ) , p = 0.05 . In these patients , prednisone also produced a significant decline in the median sputum eosinophil percentage , from 9.7 % to 0.5 % ( p = 0.002 ) , eosinophil cationic protein ( ECP ) , from 6 , 000 microgram/L to 1,140 microgram/L ( p < 0.001 ) , and fibrinogen , from 25 . 3 mg/L to 5.4 mg/L ( p < 0.001 ) . These findings indicate that in smokers with severe airflow limitation , sputum eosinophilia predicts a beneficial effect of prednisone treatment . Improvement in FEV1 , after prednisone treatment in this population , is small , and may not be appreciated in clinical practice
target: Thus the distribution method can only be used to calculate an absolute MCID as there is no st and ard deviation of baseline score for a relative measure .
  The anchor-based method relates the change in
background: To the Editor : The same patient outcome data from clinical trial results , when presented as absolute or relative changes , may appear different in magnitude .
  Recommendations are to report both absolute and relative , or at least baseline , data from which to calculate absolute values [ 1 , 2 ] .
  To inform clinical practice , outcome improvements , whether relative or absolute , must be statistically significant and clinical ly meaningful .
  A minimal clinical ly important difference ( MCID ) should inform sample size calculations for clinical trials .