Cheryl Lopate, MS, DVMDiplomate, American College of Theriogenologists Pyometra in the Bitch Pyometra is a condition that affects intact bitches, causing a variety of clinical signs and symptoms. Pyometra is typically pre-empted by pathologic changes in the uterus. The Greekderivation of pyometra is: pyo = pus and metra = uterus, so pyometra = an accumulation of pus inthe uterus.
Rccm2011081553oc 48.55Blood Eosinophils to Direct Corticosteroid Treatment of Exacerbations of Chronic Obstructive Pulmonary DiseaseA Randomized Placebo-Controlled Trial Mona Bafadhel1, Susan McKenna1, Sarah Terry1, Vijay Mistry1, Mitesh Pancholi1, Per Venge2,David A. Lomas3, Michael R. Barer1, Sebastian L. Johnston4, Ian D. Pavord1, and Christopher E. Brightling1 1Institute for Lung Health, University of Leicester, Leicester, United Kingdom; 2Department of Medical Sciences, Clinical Chemistry, University ofUppsala, Uppsala, Sweden; 3Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; and 4Department ofRespiratory Medicine, National Heart and Lung Institute, Centre for Respiratory Infections, Imperial College London, London, United Kingdom Rationale: Exacerbations of chronic obstructive pulmonary disease(COPD) and responses to treatment are heterogeneous.
AT A GLANCE COMMENTARY Objectives: Investigate the usefulness of blood eosinophils to directcorticosteroid therapy during exacerbations.
Scientific Knowledge on the Subject Methods: Subjects with COPD exacerbations were entered into a Current guidelines advocate systemic corticosteroids during randomized biomarker-directed double-blind corticosteroid versus exacerbations of COPD, but treatment responses are het- standard therapy study. Subjects in the standard arm received prednis- erogeneous, efficacy is marginal, and the treatment is not olone for 2 weeks, whereas in the biomarker-directed arm, predniso- without harm. Airway eosinophilia is associated with cor- lone or matching placebo was given according to the blood eosinophil ticosteroid responsiveness in COPD, and the peripheral count biomarker. Both study groups received antibiotics. Blood eosi- blood eosinophil count is a sensitive and specific biomarker nophils were measured in the biomarker-directed and standard ther- for airway eosinophilia during COPD exacerbations.
apy arms to define biomarker-positive and -negative exacerbations(blood eosinophil count . and < 2%, respectively). The primaryoutcome was to determine noninferiority in health status using the What This Study Adds to the Field chronic respiratory questionnaire (CRQ) and in the proportion of A biomarker-directed treatment strategy using the peripheral exacerbations associated with a treatment failure between subjectsallocated to the biomarker-directed and standard therapy arms.
blood eosinophil count to guide corticosteroid prescription Measurements and Main Results: There were 86 and 80 exacerba- can be safely used to treat exacerbations of COPD. Whether tions in the biomarker-directed and standard treatment groups, this peripheral blood eosinophil biomarker can be used in respectively. In the biomarker-directed group, 49% of the exacerba- severe exacerbations requiring hospitalization warrants fur- tions were not treated with prednisolone. CRQ improvement after ther investigation.
treatment in the standard and biomarker-directed therapy groupswas similar (0.8 vs. 1.1; mean difference, 0.3; 95% confidence inter-val, 0.0–0.6; P ¼ 0.05). There was a greater improvement in CRQ in treatment failures occurred in 15% given prednisolone and 2% of biomarker-negative exacerbations given placebo compared with those given placebo (P ¼ 0.04).
those given prednisolone (mean difference, 0.45; 95% confidence Conclusions: The peripheral blood eosinophil count is a promising interval, 0.01–0.90; P ¼ 0.04). In biomarker-negative exacerbations, biomarker to direct corticosteroid therapy during COPD exacerba-tions, but larger studies are required.
Clinical trial registered with www.controlled-trials.com (ISRCTN92422949).
(Received in original form August 27, 2011; accepted in final form March 8, 2012) Supported by the Medical Research Council (UK) and AstraZeneca jointly as Keywords: chronic obstructive pulmonary disease; exacerbations; prednis- a "Biomarker Call Project." C.E.B. is a Wellcome Trust Senior Clinical Fellow, olone; infection; eosinophils and the research was performed in laboratories partially funded by the EuropeanRegional Development Fund grant ERDF 05567.
Acute exacerbations of chronic obstructive pulmonary disease The Medical Research Council, Wellcome Trust, and the European Regional De- (COPD) are associated with substantial morbidity and mortality velopment Fund had no involvement in the design of the study, data collection, (1, 2) and are heterogeneous with respect to inflammation (3, 4) analysis and interpretation of the data, writing of the manuscript, or the decision and etiology (5–7). Although primarily associated with asthma, to submit the manuscript.
eosinophilic airway inflammation is present in some patients Author Contributions: S.M. and S.T. were involved in the recruitment of volunteers with COPD (8). Previous studies have shown that a sputum and in data collection. V.M. and M.P. were involved in data collection and inter- eosinophilia is associated with a positive response to corticoste- pretation. M.R.B., D.A.L., S.L.J., P.V., and I.D.P. were involved in the design of the roid treatment in stable COPD (9–11), and the sputum eosino- study and data collection and interpretation. M.B. and C.E.B. were involved in phil count can be used to titrate corticosteroid therapy to reduce the study design, volunteer recruitment, data collection, data interpretation, anddata analysis, had full access to the data, and are responsible for the integrity of exacerbations of COPD (12).
the data and final decision to submit. All authors contributed to the writing of the Current guidelines advocate the use of systemic corticosteroids manuscript and have approved the final version for submission.
during acute exacerbations of COPD because of improvements in Correspondence and requests for reprints should be addressed to Mona Bafadhel, the rate of recovery (13, 14); this is despite being associated with M.B.Ch.B., Institute for Lung Health, Clinical Sciences Wing, University Hospitals significant side effects (15) and with limited benefits in reducing of Leicester, Leicester, LE3 9QP, UK. E-mail: mortality (14). Increased eosinophilic airway inflammation has This article has an online supplement, which is accessible from this issue's table of been shown to occur during exacerbations of COPD, and we have shown that the peripheral blood eosinophil count is a valid bio- Am J Respir Crit Care Med Vol 186, Iss. 1, pp 48–55, Jul 1, 2012 marker of this pattern of inflammation (16). We hypothesized that Copyright ª 2012 by the American Thoracic Society the peripheral blood eosinophil count can be used to direct sys- Originally Published in Press as DOI: 10.1164/rccm.201108-1553OC on March 23, 2012Internet address: www.atsjournals.org temic corticosteroid treatment during an exacerbation of COPD Bafadhel, McKenna, Terry, et al.: Biomarker-directed Corticosteroid Therapy in COPD Exacerbations resulting in reduced total exposure to systemic corticosteroids arm to have 80% power at the 5% level. This also provided 95% power at without adversely affecting the outcome of treatment. To test this the 5% level to show a 50% reduction in exacerbations requiring cortico- hypothesis we undertook a noninferiority study of patients ran- steroid therapy, using an exacerbation frequency (SD) of 2.8 (1.7) per year.
domized to biomarker-directed corticosteroid therapy versus stan- To exclude a change in the proportion of treatment failure of 20%, from10 to 30%, between treatment arms, 60 exacerbations in each arm would dard care in patients presenting with an exacerbation of COPD.
have a power of 90% at the 5% level. Secondary analysis of health status,symptom scores, lung function, and treatment failures was performed in (1) blood eosinophil biomarker-positive and biomarker-negative exacer-bations, (2) blood eosinophil biomarker-negative exacerbations prescribed Participants and Study Design prednisolone and placebo, and (3) blood eosinophil biomarker-positive Subjects with COPD were recruited consecutively from general respi- and -negative exacerbations prescribed prednisolone. Subjects could only ratory clinics at the Glenfield Hospital, Leicester (UK) to enter a ran- be randomized into the study once, but multiple captured exacerbations domized biomarker-directed double-blind corticosteroid therapy versus were treated as independent events.
standard care study, wherein the peripheral blood eosinophil count at Further methodology details are available in the online supplement.
exacerbation was used to guide corticosteroid treatment in thebiomarker-directed arm. At exacerbation, subjects were randomized by minimization (17) for baseline lung function, exacerbation fre-quency, and sputum eosinophil count and followed up at 2 (post- One hundred sixty-four subjects were recruited to enter the study therapy) and 6 (recovery) weeks after exacerbation (see Figure E1 in (107 men, 57 women). One hundred nine consecutive subjects with the online supplement). Randomization and minimization were per- 166 exacerbation events were captured during the study period; 55 formed by an independent clinical team. Subjects and study personnel and 54 subjects with 86 and 80 exacerbation events, respectively, involved in data collection and treatment failure assessment were were randomized to the biomarker-directed and standard therapy blinded to randomization, biomarker results, and treatment allocation.
arm, as shown in Figure 1. There were 66, 32, 8, and 3 subjects who Subjects in the biomarker-directed group received a 30-mg predniso- subsequently had one, two, three, and four captured exacerbations.
lone capsule once daily or identical-appearing placebo for 14 days There were no differences in the clinical characteristics between when the peripheral blood eosinophil count was greater than 2% andless than or equal to 2%, respectively. This cut-off was derived with subjects who were randomized or not (Table E1) or between sub- a high sensitivity aimed to ensure prednisolone treatment in all subjects jects in the biomarker-directed and standard therapy arm (Table 1).
with a sputum eosinophilia (16). Subjects in the standard group re- There were 10 severe exacerbations requiring hospitalization. A ceived a 30-mg prednisolone capsule once daily irrespective of the sputum eosinophil, virus, and bacteria culture positive-associated blood eosinophil biomarker results. All subjects received open-labeled exacerbation was identified in 17, 32, and 42% of all exacerbations, broad-spectrum oral antibiotic therapy (amoxicillin, or doxycycline if respectively. There were no differences in the proportions of spu- amoxicillin allergic) for 7 days. Blood eosinophils were measured at ex- tum eosinophil-associated, virus-associated, and bacteria culture acerbation to define blood eosinophil biomarker-positive and -negative positive-associated exacerbations in the biomarker-directed and subjects in both study groups (peripheral blood eosinophil levels < 2% standard therapy arm at randomization.
termed biomarker negative; peripheral blood eosinophil levels . 2%termed biomarker positive), but these results were not disclosed. Exacer-bation visits were defined according to the criteria of Anthonisen and colleagues (18) and healthcare use (19), and all subjects were given daily The primary outcome of noninferiority of health status in the diary cards to complete (20). Data sampling and randomization were only standard therapy and biomarker-directed groups after 2 weeks obtained in subjects who were confirmed as having COPD exacerbations of treatment was achieved (CRQ mean score change, 0.8 vs.
and were treatment naive. At all study visits, the following measurements 1.1; mean difference, 0.3; 95% CI, 0.0–0.6; P ¼ 0.05; Figure were undertaken: pre- and post-bronchodilator spirometry; health qualityquestionnaires using the Chronic Respiratory Disease Interviewer- 2a). There was a similar reduction in the CRQ score from base- Administered Standardized Questionnaire (CRQ) (21) (McMaster Univer- line to exacerbation in the biomarker-directed and standard sity, Hamilton, Canada); symptom assessment of cough, breathlessness, therapy arms (0.9 vs. 0.9; mean difference, 0.0; 95% CI, 20.3 sputum production, and sputum purulence using the visual analog scale to 0.3; P ¼ 0.97). There was no difference in FEV1 or % VAS (VAS) (22); blood for measurement of cell differential and C-reactive improvement between biomarker-directed and standard ther- protein; and sputum for analysis of bacteria, colony-forming units (CFU), apy arms after treatment allocation (Figures 2b and 2b). There virus, and sputum cell differential (23–26). All subjects gave informed were 14 treatment failures associated with worsening symptoms written consent, and the study was approved by the local ethics committee of COPD after treatment during the study; 10 occurred in the and the Medicines and Healthcare Products Regulatory Agency.
standard arm and 4 in the biomarker-directed arm, demonstrat-ing at least equivalence with a trend favoring the biomarker- Statistical Analysis directed arm as there were fewer treatment failures (13 vs. 5%; Statistical analysis was performed using PRISM version 4 (GraphPad Soft- 95% CI, 21 to 16; P ¼ 0.07). In the biomarker-directed group, ware, San Diego, CA) and SPSS version 16 (SPSS, Inc., Chicago, IL). Para- 49% of the exacerbations were not treated with prednisolone.
metric and nonparametric data are presented as mean (SEM) and median There were similar proportions of subjects within the standard (interquartile range), unless stated otherwise. Log-transformed data are therapy group and the biomarker-directed therapy group that presented as geometric mean (95% confidence interval [CI]). The primary had one exacerbation (35 vs. 31), two exacerbations (13 vs. 19), objective of the study was to assess whether the blood eosinophil count can three exacerbations (5 vs. 3), and four exacerbations (1 vs. 2).
be used as a biomarker to direct corticosteroid therapy at the onset of anexacerbation. The primary outcome was to show (1) noninferiority in thehealth status score after treatment between the standard therapy and Secondary Analysis biomarker-directed therapy study groups; (2) equivalence in the propor- There were 85 exacerbations that were blood eosinophil bio- tions of exacerbations associated with a treatment failure defined as the marker positive given prednisolone, 39 exacerbations that were need to start or repeat treatment within 30 days of randomization, hospi- blood eosinophil biomarker negative given prednisolone, and 42 talization for any cause, or death, between the standard therapy andbiomarker-directed therapy study groups; and (3) demonstration of a re- exacerbations that were blood eosinophil biomarker negative duction in corticosteroid therapy prescription in the biomarker-directed given placebo. Changes in clinical characteristics for biomarker- therapy study group. To demonstrate noninferiority in health reported positive and -negative exacerbations in the biomarker-directed outcomes after 14 days of treatment, using the minimally clinical important and standard treatment arms at stable, exacerbation, post- CRQ mean change of 0.5 (SD, 0.91), 53 subjects were required in each therapy, and recovery visits are presented in Table E2.
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Figure 1. CONSORT diagram for patient enrollment and randomization. Biomarker blood eosinophil levels were measured at exacerbation in bothstudy groups, but only in the biomarker-directed arm were biomarker levels used to direct placebo or matching prednisolone treatment in additionto antibiotic therapy. In the standard arm, all subjects received prednisolone and antibiotic therapy. Four subjects in the biomarker-directed treatmentarm switched from placebo to prednisolone treatment, and two subjects switched from prednisolone to placebo. Subjects and study personnel involvedin data collection and assessment of treatment failure were blinded to study group allocation, biomarker results, and treatment allocation.
Blood eosinophil biomarker-negative and -positive exacerba- eosinophil count (>3% nonsquamous cells) at exacerbation. For tions. Baseline and exacerbation health status, lung function, all exacerbation events captured, the cutoff of 2% blood eosino- and airway inflammation characteristics in blood eosinophil phil count had a positive predictive value of 91% for identifying biomarker-positive and biomarker-negative exacerbations are a sputum eosinophilia of greater than or equal to 3%.
presented in Table 2. The mean reduction in CRQ from base- Blood eosinophil biomarker-negative exacerbations prescribed line to exacerbation was similar between biomarker-positive prednisolone and placebo. Biomarker-negative exacerbations and -negative exacerbations (CRQ units, 1.0 vs. 0.9; mean dif- given placebo compared with those given prednisolone had ference, 0.1; 95% CI, 20.2 to 0.3; P ¼ 0.54). At exacerbation, greater improvements in CRQ score after 14 days of treatment blood eosinophil biomarker-negative exacerbations had higher (mean change in CRQ [units], 1.01 vs. 0.56; mean difference, sputum neutrophils, sputum total cell counts, serum CRP, and 0.45; 95% CI, 0.01–0.90; P ¼ 0.045; Figure 3a). There were FEV1% predicted compared with blood eosinophil biomarker- positive exacerbations (mean [SEM] sputum neutrophils, 86  biomarker-negative exacerbations given prednisolone than pla- vs. 78% , P ¼ 0.03; geometric mean [95% CI] sputum cebo (15 vs. 2% [95% CI, 1–25], P ¼ 0.04). There was no differ- total cell counts 3 106 cells/g, 9.2 [6.5–13.0] vs. 5.4 [3.9–7.5], ence in FEV1 for these groups (Figure 3b). The proportion of P ¼ 0.03; median [interquartile range] CRP mg/L, 20  vs.
exacerbations with no improvement in symptoms after 7 days of 9 , P , 0.01; mean [SEM] FEV1% predicted, 46  vs. 39 treatment was higher in biomarker-negative treated with prednis- ; P ¼ 0.03). There was a significant difference in absolute and olone compared with biomarker-negative treated with placebo percentage blood eosinophil counts at baseline, exacerbation, (21 vs. 4% [95% CI, 0–31], P ¼ 0.03). In biomarker-negative post-therapy, and recovery between biomarker-positive and -neg- exacerbations treated with prednisolone or placebo, there were ative exacerbations (for each visit between groups, P , 0.01; no differences in the proportions of those associated with bacteria Table 3 and Table E2). There were similar proportions of (44 vs. 49%, P ¼ 0.70) or virus (36 vs. 38%, P ¼ 0.87).
bacteria-associated biomarker-positive and biomarker-negative Blood eosinophil biomarker-positive and -negative exacerbations exacerbations (38 vs. 46%, P ¼ 0.31) and virus-associated prescribed prednisolone. There was a statistical and clinically signif- biomarker-positive and -negative exacerbations (26 vs. 37%, P ¼ icant difference in the CRQ improvement after prednisolone therapy 0.16). The colony forming units (CFU) at exacerbation were sig- in blood eosinophil biomarker-positive compared with biomarker- nificantly higher in biomarker-negative exacerbations compared negative exacerbations (mean improvement in CRQ [units], 1.11 with biomarker-positive exacerbations (CFU cells/ml geometric vs. 0.56; mean difference, 0.56; 95% CI, 0.15–0.96; P , 0.01). There mean [95% CI], 1.1 3 107 [6.2 3 106 to 1.9 3 107] vs. 2.9 3 106 was no difference in treatment failure rates between the biomarker- [1.6 3 106 to 5.3 3 106]; P ¼ 0.002). A sputum eosinophil–asso- positive and -negative exacerbations treated with prednisolone (8 ciated exacerbation was found in more biomarker-positive than vs. 15%; 95% CI, 210 to 43; P ¼ 0.23). There was a greater recov- biomarker-negative exacerbations (31 vs. 2%, P , 0.001), ery over 14 days in biomarker-positive exacerbations treated with whereas only one patient treated with placebo had a sputum prednisolone compared with biomarker-negative exacerbations Bafadhel, McKenna, Terry, et al.: Biomarker-directed Corticosteroid Therapy in COPD Exacerbations TABLE 1. CLINICAL CHARACTERISTICS OF PATIENTS IN RANDOMIZED PLACEBO CONTROLLED-TRIAL Current smoker, n (%) Pack-year history† Exacerbation frequency in previous yr† Body mass index, kg/m2 Inhaled corticosteroid usage, n (%) Inhaled corticosteroid dose, mg‡ FEV1/FVC ratio, %k Reversibility, ml Sputum total cell count, x 106/g¶ Sputum neutrophils, % Sputum eosinophils, %¶ Sputum eosinophil–associated exacerbation, % Virus-associated exacerbation, % Bacteria-associated exacerbation, % Definition of abbreviations: CI ¼ confidence interval; CRQ ¼ Chronic Respiratory Disease Questionnaire, scores range between 1 and 7 with higher score representing better health quality; VAS ¼ Visual Analog Scale, performed on 100-mmline from "no symptoms" to "worst symptoms." Higher scores represent worse symptoms (total score addition of measureddomains: cough, dyspnea, sputum production, and sputum purulence).
Data presented as mean (SD), unless otherwise stated.
* t Test or Mann-Whitney for continuous variables or x2 for proportions.
y Mean (range).
x Median (interquartile range).
z Beclomethasone dipropionate equivalent.
¶ Geometric mean (95% CI).
treated with prednisolone (area under the % change in VAS curve treatment with corticosteroids, was not associated with an in- [95% CI], 516 [449–583] vs. 350 [241–458]; P , 0.01) (Figure 3c).
crease in treatment failure or worsening of symptoms compared Biomarker phenotype stability. The blood eosinophil biomarker with standard conventional therapy. More important, we have status at baseline had an odds ratio (OR) (95% CI) of 5.5 (2.7–11.0) shown that a biomarker-directed strategy using the peripheral for predicting the blood eosinophil biomarker status at exacerba- blood eosinophil count can safely reduce prednisolone prescrip- tion; specifically, blood eosinophil biomarker negative at baseline tion at exacerbations. There was a trend for outcomes to be bet- had an OR of 2.9 (1.6–5.0) for a blood eosinophil biomarker- ter in the group randomized to biomarker-directed treatment negative exacerbation, and blood eosinophil biomarker-positive versus standard care. Critically, in the subgroup of patients at baseline had an OR 2.2 (1.5–3.2, P , 0.01) for a blood eosinophil who were blood eosinophil biomarker negative, corticosteroid biomarker-positive exacerbation. A blood eosinophil biomarker- treatment resulted in worse outcomes compared with placebo.
negative status at baseline was identified in 59% of all subjects These findings make it very unlikely that we have missed an im- randomized. In the biomarker-directed group, 80% of patients portant difference in outcome in favor of standard, non– who were initially assigned prednisolone therapy would have been assigned prednisolone from the baseline blood eosinophil A peripheral blood eosinophilia has been previously shown to count. Similarly, 59% of patients assigned to placebo at exac- be associated with an increase in all-cause mortality in patients erbation would have been assigned this treatment from the with airways disease (27–29), and we have previously shown that baseline blood eosinophil count. In subjects with repeated ex- the peripheral blood eosinophils are a highly sensitive and spe- acerbation events, comparison of the first and second exacer- cific marker of a sputum eosinophilia during exacerbations of bation event demonstrated that 22% switched biomarker COPD (16). It is an attractive biomarker to use in clinical prac- status (from blood eosinophil biomarker negative to bio- tice as it is simple to measure, widely available at the time of an marker positive or vice versa), whereas the remainder stayed exacerbation, and reliable. Current guidelines advocate the use in the same blood eosinophil biomarker group.
of corticosteroids during exacerbations in patients who haveincreasing symptoms of breathlessness (14). Although studies have shown that corticosteroids can improve lung function In this study we have shown that a biomarker-directed strategy, and dyspnea scores in the short term (13), these improvements which used the peripheral blood eosinophil count to guide are marginal (30) and need to be weighed against the potential
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Figure 2. Standard group (red) and biomarker-directed therapy group (blue).
(a) Chronic Respiratory DiseaseQuestionnaire total score atbaseline, exacerbation, after14-day placebo or prednisolonetreatment (2 wk after exacerba-tion) and recovery (6 wk afterexacerbation) in standard ther-apy arm (n ¼ 80) and biomarker-directed therapy arm (n ¼ 86).
Data presented as mean (SEM).
(b) FEV1 at baseline, exacerba-tion, after 14 days of placebo orprednisolone treatment (2 wkafter exacerbation) and recov-ery (6 wk after exacerbation)in standard therapy arm (n ¼80) and biomarker-directed ther-apy arm (n ¼ 86). (c) Percentimprovement in visual analogscale total score from exacerba-tion and for duration of treat-ment period in exacerbations instandard therapy arm (n ¼ 80)and biomarker-directed therapyarm (n ¼ 86). Data points pre-sented as mean (SEM). CRQ ¼Chronic Questionnaire; VAS ¼ visual an-alog scale.
for harm in a population who often have significant comorbid- (14). Our findings suggest that a biomarker-directed strategy for ities (14, 15). This, together with evidence in stable COPD that initiating corticosteroid therapy would result in maintenance of patients with eosinophilic airway inflammation respond better the benefits of therapy with a simultaneous reduction in the to corticosteroid treatment (9–11), provides a strong rationale number harmed by this treatment. Using the peripheral blood for a study investigating biomarker-directed therapy. Pooled eosinophil count as a surrogate marker of eosinophilic airway data analysis has shown that the number needed to harm using inflammation, we have shown similar findings of corticosteroid corticosteroid therapy in COPD exacerbations is 5, whereas for responsiveness in a COPD eosinophilic phenotype but impor- every 13 patients treated, 1 will develop significant hyperglycemia tantly demonstrated this during exacerbations.
TABLE 2. LUNG FUNCTION AND INFLAMMATION AT BASELINE AND EXACERBATION IN ALL EXACERBATIONS CAPTURED CATEGORIZEDAS BLOOD EOSINOPHIL BIOMARKER POSITIVE AND BIOMARKER NEGATIVE Biomarker Negative (n ¼ 56, nE ¼ 81) Biomarker Positive (n ¼ 53, nE ¼ 85) Mean Difference (95% CI)* Mean Difference (95% CI)* 20.13 (20.19 to 20.07) ,0.01 1.16 (0.42) 20.17 (20.22 to 20.12) FEV1, % predicted† 20.88 (21.06 to 20.70) ,0.01 3.99 (1.20) 20.96 (21.16 to 20.77) Sputum total cell count, 3106/g‡ Sputum neutrophils, % Sputum eosinophils, %‡ Blood total cell count, 3109 cells/L‡ 10.3 (9.5–11.1) Blood neutrophil count, 3109 cells/L‡ Blood eosinophil count, 3109 cells/L‡ 0.15 (0.13–0.17) 0.11 (0.10–0.13) ,0.01 0.30 (0.26–0.34) 0.34 (0.31–0.38) Blood eosinophil % 20.9 (21.1 to 20.7) Definition of abbreviations: CI ¼ confidence interval; CRQ ¼ Chronic Respiratory Disease Questionnaire score; CRP ¼ C-reactive protein; n ¼ number of patients; nE ¼ number of exacerbation events.
Statistical analysis performed using a paired t test analysis or Wilcoxon signed rank test. Differences between exacerbation and baseline presented as mean difference (95% CI of difference), fold difference (95% CI of fold difference), and median (interquartile range) of differences as appropriate. Data presented as mean (SD) unlessotherwise stated.
* Mean, median, or fold difference as appropriate.
z Geometric mean (95% CI).
Bafadhel, McKenna, Terry, et al.: Biomarker-directed Corticosteroid Therapy in COPD Exacerbations TABLE 3. LUNG FUNCTION AND INFLAMMATION (ABSOLUTE DATA) AT BASELINE, EXACERBATION, 2WEEKS AFTER EXACERBATION (POST-THERAPY) AND 6 WEEKS AFTER EXACERBATION (RECOVERY), FORALL EXACERBATIONS CATEGORIZED INTO BIOMARKER POSITIVE GIVEN PREDNISOLONE, BIOMARKERNEGATIVE GIVEN PREDNISOLONE, AND BIOMARKER NEGATIVE GIVEN PLACEBO Biomarker Positive Given Prednisolone FEV1, % predicted* Sputum total cell count, 3106/g† Sputum neutrophils, % Sputum eosinophils, %† Blood total cell count, 3109 cells/L† 11.6 (10.9–12.4) Blood neutrophil count, 3109 cells/L† Blood eosinophil count, 3109 cells/L† 0.30 (0.26–0.34) 0.34 (0.31–0.38) 0.19 (0.15–0.23) 0.26 (0.19–0.34) Blood eosinophil % Biomarker Negative Given Prednisolone FEV1, % predicted* Sputum total cell count, 3106/g† 10.6 (7.0–16.1) Sputum neutrophils, % Sputum eosinophils, %† Blood total cell count, 3109 cells/L† 10.8 (9.8–12.0) 11.9 (10.4–13.7) Blood neutrophil count, 3109 cells/L† Blood eosinophil count, 3109 cells/L† 0.15 (0.12–0.18) 0.10 (0.09–0.12) 0.11 (0.09–0.14) 0.12 (0.09–0.15) Blood eosinophil % Biomarker Negative Given Placebo FEV1, % predicted* Sputum total cell count, 3106/g† Sputum neutrophils, % Sputum eosinophils, %† Blood total cell count, 3109 cells/L† Blood neutrophil count, 3109 cells/L† Blood eosinophil count, 3109 cells/L† 0.15 (0.12–0.17) 0.12 (0.10–0.13) 0.14 (0.11–0.15) 0.17 (0.13–0.18) Blood eosinophil % Definition of abbreviation: CI ¼ confidence interval; CRP ¼ C-reactive protein; n ¼ number of patients; nE ¼ number of Data presented as mean (SD) unless otherwise stated.
y Geometric mean (95% CI).
z Median (interquartile range).
We identified that patients who were biomarker positive had a reduced and possibly detrimental response. We also found that higher peripheral blood and sputum eosinophil counts and recovered biomarker-positive exacerbations were more likely to have more quickly with prednisolone than patients who were biomarker higher blood eosinophils during stable state compared with negative. In contrast, prednisolone treatment in biomarker-negative biomarker-negative exacerbations. Further interrogation of the patients was associated with more treatment failures and less im- data also showed that subjects who were biomarker negative at provement of health status or symptoms compared with placebo.
stable state were also more likely to be biomarker negative at This finding was unexpected and may have arisen by chance.
the exacerbation event and that repeated exacerbation events However, it raises the possibility that the absence of the blood remained in the same blood eosinophil biomarker subgroup.
eosinophil biomarker identifies a COPD population whose re- Previous work investigating the heterogeneity of COPD exacer- covery is adversely affected by corticosteroid therapy, indepen- bations has shown that the presence of airway eosinophilic inflam- dent of the presence of bacteria or virus at exacerbation. There is mation or bacterial pathogen at stable state could predict the increasing evidence that inhaled corticosteroids are associated exacerbation phenotype (16). In this study, we have determined with an increased risk of pneumonia in COPD (31–33). These that a blood eosinophil biomarker status in stable state can predict findings would suggest that in blood eosinophil biomarker- the exacerbation blood eosinophil biomarker status, highlighting negative COPD exacerbations, infection may be a primary a blood biomarker that has repeatability, has a high predictive driver, and thus treatment with corticosteroids is associated with value, and is indicative of treatment responsiveness. Whether
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Figure 3. (a) Chronic Respira-tory total score at baseline, exacer-bation, after 14 days of treat-ment (2 wk after exacerbation)and recovery (6 wk after exac-erbation) in exacerbations thatwere biomarker-positive trea-ted with prednisolone (green),biomarker and biomarker negative trea-ted with placebo (purple). Datapresented as mean (SEM). (b)FEV1 at baseline, exacerbation,after 14 days of placebo orprednisolone treatment (2 wkafter exacerbation) and recov-ery (6 wk after exacerbation)in exacerbations that werebiomarker with prednisolone (green), bio-marker negative treated withprednisolone biomarker negative treated withplacebo (purple). Data pre-sented as mean (SEM). (c) Per-cent improvement in visualanalog scale total score from ex-acerbation and for duration oftreatment period in exacerba-tions that were biomarker posi-tive treated with prednisolone(green), treated with prednisolone (or-ange), and biomarker negativetreated with placebo (purple).
Data points presented as mean(SEM). CRQ ¼ Chronic Respi-ratory Disease Questionnaire;VAS ¼ visual analog scale.
these patients represent a specific phenotype that can be identified in our study were low, probably reflecting the moderate severity a priori and whether baseline knowledge of blood eosinophil bio- of the exacerbations. It is therefore important that our hypoth- marker status could direct treatment at the onset of an exacerba- esis is tested in larger studies including patients hospitalized tion requires further study in larger randomized controlled trials.
with severe exacerbations of COPD. These studies should also A limitation of this study is that the majority of the exacerba- investigate whether outcomes of biomarker-directed therapy tions studied were moderate and did not require hospitalization.
differ by the presence of features such as tapered prednisolone We would be cautious in extrapolating our findings beyond this treatment; duration of treatment; and the presence of infection, group. However, the population we studied reflects a population emphysema, and chronic bronchitis. This study was not pow- of patients who exacerbate and present to clinics and primary care, ered to study health economic impact of biomarker-directed and our findings are likely to be relevant and applicable in this corticosteroid therapy, and this important potential benefit setting (34). Furthermore, our study population had to have a requires further study. A final concern is that our population prior history of exacerbations, and therefore they are likely to may have included patients who had fixed airflow obstruction as reflect predominately a frequent exacerbator group. Whether a result of asthma and may not be relevant to settings where differences in response to therapy exist between infrequent and diagnostic abilities are greater. We acknowledge that this is frequent exacerbator groups requires future study.
possible but maintain that we made stringent efforts to reduce Although bacteria are believed to play a role in up to 50% of a population with characteristics of asthma and were careful to exacerbations (7), evidence on the benefits of antibiotics is con- ensure that our population met current diagnostic criteria for flicting (35–37). In our study, we have concentrated on targeting COPD (1). It is notable that, as we have shown before (16), corticosteroid therapy and thereby standardized the effects of features such as atopy and bronchodilator responsiveness were any bacterial etiology by prescribing open-labeled antibiotic not related to eosinophilic airway inflammation.
therapy in an aim to eliminate any confounding effects of bac- In conclusion, a biomarker-directed strategy using the periph- teria within exacerbations. We found no difference in bacteria eral blood eosinophil count can be used to direct corticosteroid culture-positive rates in the biomarker-directed and standard therapy during acute exacerbations of COPD and allows the iden- therapy arms, so this variable is unlikely to have confounded tification of subgroups that have benefit and detriment from the our comparison between these groups. Treatment failure rates use of prednisolone treatment. This simple stratification allows for Bafadhel, McKenna, Terry, et al.: Biomarker-directed Corticosteroid Therapy in COPD Exacerbations the identification of clinically important phenotypes of COPD and 17. Treasure T, MacRae KD. Minimisation: the platinum standard for trials? may identify groups for whom modified therapy is needed. Our Randomisation doesn't guarantee similarity of groups; minimisation data suggest that in the outpatient treatment of exacerbations does. BMJ 1998;317:362–363.
of COPD, systemic corticosteroids should be only be given to 18. Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, those who have a peripheral blood eosinophil count greater than Nelson NA. Antibiotic therapy in exacerbations of chronic obstruc-tive pulmonary disease. Ann Intern Med 1987;106:196–204.
2%, but a larger confirmatory study is required. Whether this ap- 19. Rodriguez-Roisin R. Toward a consensus definition for COPD exacer- proach can also be used for patients with severe COPD exacerba- bations. Chest 2000;117:398S–401S.
tions who require hospitalization warrants further investigation.
20. Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA.
Time course and recovery of exacerbations in patients with chronic are available with the text of this article at .
obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161: Acknowledgment: The authors thank all the research volunteers who participated in the study. They also thank the following people for their contributions during the study: 21. Guyatt G. Measuring health status in chronic airflow limitation. Eur J. Agbetile, M. Bourne, D. Desai, P. Dodson, B. Hargadon, T. Kebadze, M. McCormick, Respir J 1988;1:560–564.
P. Newbold, H. Patel, A. Riding, P. Rugman, M. Saunders, M. Shelley, and A. Singapuri.
22. Brightling CE, Monterio W, Green RH, Parker D, Morgan MD, Wardlaw AJ, Pavord ID. Induced sputum and other outcome measures in chronic obstructive pulmonary disease: safety and repeatability. RespirMed 2001;95:999–1002.
1. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi 23. Health Protection Agency. Investigation of bronchoalveolar lavage, sputum Y, Jenkins C, Rodriguez-Roisin R, van Weel C, et al. Global strategy and associated specimens [Internet]. National Standard Method BSOP for the diagnosis, management, and prevention of chronic obstructive 57 Issue 2.3. c2009 [accessed 2010 Aug]. Available from: pulmonary disease: GOLD executive summary. Am J Respir Crit Care 24. Pye A, Stockley RA, Hill SL. Simple method for quantifying viable 2. Halpin D. NICE guidance for COPD. Thorax 2004;59:181–182.
bacterial numbers in sputum. J Clin Pathol 1995;48:719–724.
3. Bhowmik A, Seemungal TA, Sapsford RJ, Wedzicha JA. Relation of 25. Bisgaard H, Zielen S, Garcia-Garcia ML, Johnston SL, Gilles L, Menten sputum inflammatory markers to symptoms and lung function changes J, Tozzi CA, Polos P. Montelukast reduces asthma exacerbations in in COPD exacerbations. Thorax 2000;55:114–120.
2- to 5-year-old children with intermittent asthma. Am J Respir Crit 4. Saetta M, Di SA, Maestrelli P, Turato G, Ruggieri MP, Roggeri A, Care Med 2005;171:315–322.
Calcagni P, Mapp CE, Ciaccia A, Fabbri LM. Airway eosinophilia in 26. Pizzichini MM, Popov TA, Efthimiadis A, Hussack P, Evans S, chronic bronchitis during exacerbations. Am J Respir Crit Care Med Pizzichini E, Dolovich J, Hargreave FE. Spontaneous and induced sputum to measure indices of airway inflammation in asthma. Am J 5. Papi A, Bellettato CM, Braccioni F, Romagnoli M, Casolari P, Caramori Respir Crit Care Med 1996;154:866–869.
G, Fabbri LM, Johnston SL. Infections and airway inflammation in 27. Hospers JJ, Schouten JP, Weiss ST, Postma DS, Rijcken B. Eosinophilia chronic obstructive pulmonary disease severe exacerbations. Am J is associated with increased all-cause mortality after a follow-up of 30 Respir Crit Care Med 2006;173:1114–1121.
6. Seemungal T, Harper-Owen R, Bhowmik A, Moric I, Sanderson G, years in a general population sample. Epidemiology 2000;11:261–268.
Message S, Maccallum P, Meade TW, Jeffries DJ, Johnston SL, et al.
28. Hospers JJ, Schouten JP, Weiss ST, Rijcken B, Postma DS. Asthma Respiratory viruses, symptoms, and inflammatory markers in acute attacks with eosinophilia predict mortality from chronic obstructive exacerbations and stable chronic obstructive pulmonary disease. Am J pulmonary disease in a general population sample. Am J Respir Crit Respir Crit Care Med 2001;164:1618–1623.
Care Med 1999;160:1869–1874.
7. Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic 29. Hospers JJ, Rijcken B, Schouten JP, Postma DS, Weiss ST. Eosinophilia and obstructive pulmonary disease. N Engl J Med 2008;359:2355–2365.
positive skin tests predict cardiovascular mortality in a general population 8. Saha S, Brightling CE. Eosinophilic airway inflammation in COPD. Int J sample followed for 30 years. Am J Epidemiol 1999;150:482–491.
Chron Obstruct Pulmon Dis 2006;1:39–47.
30. Aaron SD, Vandemheen KL, Hebert P, Dales R, Stiell IG, Ahuja J, 9. Shim C, Stover DE, Williams MH Jr. Response to corticosteroids in Dickinson G, Brison R, Rowe BH, Dreyer J, et al. Outpatient oral chronic bronchitis. J Allergy Clin Immunol 1978;62:363–367.
prednisone after emergency treatment of chronic obstructive pulmo- 10. Pizzichini E, Pizzichini MM, Gibson P, Parameswaran K, Gleich GJ, nary disease. N Engl J Med 2003;348:2618–2625.
Berman L, Dolovich J, Hargreave FE. Sputum eosinophilia predicts 31. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, benefit from prednisone in smokers with chronic obstructive bron- Yates JC, Vestbo J. Salmeterol and fluticasone propionate and survival in chitis. Am J Respir Crit Care Med 1998;158:1511–1517.
chronic obstructive pulmonary disease. N Engl J Med 2007;356:775–789.
11. Brightling CE, Monteiro W, Ward R, Parker D, Morgan MD, Wardlaw 32. Ernst P, Gonzalez AV, Brassard P, Suissa S. Inhaled corticosteroid use AJ, Pavord ID. Sputum eosinophilia and short-term response to in chronic obstructive pulmonary disease and the risk of hospitaliza- prednisolone in chronic obstructive pulmonary disease: a randomised tion for pneumonia. Am J Respir Crit Care Med 2007;176:162–166.
controlled trial. Lancet 2000;356:1480–1485.
33. Kardos P, Wencker M, Glaab T, Vogelmeier C. Impact of salmeterol/ 12. Siva R, Green RH, Brightling CE, Shelley M, Hargadon B, McKenna S, fluticasone propionate versus salmeterol on exacerbations in severe Monteiro W, Berry M, Parker D, Wardlaw AJ, et al. Eosinophilic chronic obstructive pulmonary disease. Am J Respir Crit Care Med airway inflammation and exacerbations of COPD: a randomised controlled trial. Eur Respir J 2007;29:906–913.
34. National Clinical Guideline Centre. Chronic obstructive pulmonary dis- 13. Davies L, Angus RM, Calverley PM. Oral corticosteroids in patients ease: management of chronic obstructive pulmonary disease in adults admitted to hospital with exacerbations of chronic obstructive pul- in primary and secondary care [Internet]. London: National Clinical monary disease: a prospective randomised controlled trial. Lancet Guideline Centre; c2010 [accessed 2010 Aug]. Available from: http:// 14. Walters JA, Gibson PG, Wood-Baker R, Hannay M, Walters EH. Sys- 35. Rothberg MB, Pekow PS, Lahti M, Brody O, Skiest DJ, Lindenauer PK.
temic corticosteroids for acute exacerbations of chronic obstructive Antibiotic therapy and treatment failure in patients hospitalized for pulmonary disease. Cochrane Database Syst Rev 2009;CD001288.
acute exacerbations of chronic obstructive pulmonary disease. JAMA 15. Niewoehner DE, Erbland ML, Deupree RH, Collins D, Gross NJ, Light RW, Anderson P, Morgan NA. Effect of systemic glucocorticoids on exacer- 36. Puhan MA, Vollenweider D, Steurer J, Bossuyt PM, Ter RG. Where is bations of chronic obstructive pulmonary disease. Department of Veterans the supporting evidence for treating mild to moderate chronic ob- Affairs Cooperative Study Group. N Engl J Med 1999;340:1941–1947.
structive pulmonary disease exacerbations with antibiotics? A sys- 16. Bafadhel M, McKenna S, Terry S, Mistry V, Reid C, Haldar P, McCormick tematic review. BMC Med 2008;6:28.
M, Haldar K, Kebadze T, Duvoix A, et al. Acute exacerbations of 37. Sethi S. The problems of meta-analysis for antibiotic treatment of chronic COPD: identification of biological clusters and their biomarkers. Am J obstructive pulmonary disease, a heterogeneous disease: a commentary Respir Crit Care Med 2011;184:662–671.
on Puhan et al. BMC Med 2008;6:29.
DAROU PAKHSH PHARMACEUTICAL MFG. CO. SITE MASTER FILE Issued Date: 09/05/2015 CODE : DPSMF422 Validation Date: 09/05/2016 Rev. No:3 This Site Master File was prepared on the basis of the PIC/S document "Explanatory notes for industry on the preparation of a Site Master File" PE 008-4. Contents: Chapter 1: General information 1.1