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Is it possible to identify exacerbations of mild to moderate COPD that do not

require antibiotic treatment?

Short title: Antibiotics in exacerbations of COPD

Authors: Marc Miravitlles (1), Ana Moragas (2), Silvia Hernndez (2), Carolina

Bayona (3), Carl Llor (4).

Center:1. Pneumology Department, Hospital Universitari Vall dHebron, Barcelona.

Spain. CIBER de Enfermedades Respiratorias (CIBERES), Barcelona,

Spain.([email protected]) 2. Primary Care Centre Jaume I, Tarragona, Spain.

([email protected]) ([email protected]) 3. Primary Care Centre Valls,

Spain.([email protected]). 4. Primary Care Centre Jaume I, University

Rovira i Virgili, Tarragona, Spain.([email protected])

Conflicts of interest: MM reports receiving: honoraria for lectures from Bayer-

Schering, Boehringer-Ingelheim, Pfizer, Nycomed, AstraZeneca, and Novartis, payment

for development of educational presentations from Bayer-Schering, serving on the

advisory boards of Bayer-Schering, Boehringer-Ingelheim, Pfizer, Nycomed,

GlaxoSmithKline, Almirall, AstraZeneca, and Novartis; and receiving consulting fees

from Bayer-Schering, Boehringer-Ingelheim, Pfizer, Nycomed, GlaxoSmithKline,

Almirall, AstraZeneca, and Novartis. CL reports receiving research grants from the

European Commission (Sixth and Seventh Programme Frameworks), Catalan Society of

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Family Medicine, and Instituto de Salud Carlos III (Spanish Ministry of Health). AM

reports receiving research grants from the Spanish Society of Family Medicine,

Fundaci Jordi Gol i Gurina, and Instituto de Salud Carlos III (Spanish Ministry of

Health). The other authors do not have conflicts of interest to disclose.

Correspondence:Marc Miravitlles

Servei de Pneumologia. HospitalVall dHebron

P. Vall dHebron 119-129, 08035 Barcelona, Spain

e-mail: [email protected]

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ABSTRACT

Background: Anthonisens criteria are widely used to guide the need for antibiotics in

exacerbations of chronic obstructive pulmonary disease (COPD). We evaluated the best

predictors of outcomes in exacerbations of mild to moderate COPD not treated with

antibiotics.

Methods:We used data from 152 patients of the placebo arm of a randomised trial of

amoxicillin/clavulanate for exacerbations of mild to moderate COPD. Clinical response

in relation to Anthonisens criteria and point-of-test serum C-reactive protein (CRP)

levels (cut off 40 mg/L) was assessed with multivariate logistic regression analysis.

Results: Clinical failure without antibiotics was 19.9% compared to 9.5% with

amoxicillin/clavulanate (p=0.022). The only factors significantly associated with an

increased risk of failure without antibiotics were the increase in purulence of sputum

(OR=6.1, 95% confidence interval: 1.5 to 25.0; p=0.005) and a CRP concentration >40

mg/L (OR=13.4, 95%CI: 4.6 to 38.8; p


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Keywords: COPD; exacerbations; antibiotics; risk factors; clinical trial; C-reactive

protein

ABBREVIATIONS

AUC: Area under the curve

CI: Confidence interval

COPD: Chronic obstructive pulmonary disease

CRP: C-reactive protein

EOT: End of therapy

FEV1: Forced expiratory volume in the first second

FVC: Forced vital capacity

L: Liter

Mg: Milligrams

OR: Odds ratio

t.i.d: Three times a day (ter in die)

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INTRODUCTION

The decision to prescribe an antibiotic for a patient with an exacerbation of COPD is

one of the most frequent dilemmas encountered by physicians. This decision is usually

taken with the aid of the combination of the three cardinal symptoms: increase in

dyspnoea, in sputum volume and sputum purulence, described 25 years ago by

Anthonisen et al (1) in a randomised placebo controlled trial in severe patients with

exacerbated COPD (mean FEV1=33% predicted). These criteria have been extrapolated

to all patients with COPD irrespective of the severity of airflow obstruction, but

information about their predictive validity in mild to moderate patients (FEV1>50%

predicted) is lacking (2). This is particularly important because most of the patients with

exacerbations of COPD in the community are mild or moderate (3,4) and observational

studies consistently show that most of these patients are treated with antibiotics

irrespective of guidelines (5,6).

Adequate antibiotic prescription is necessary to prevent the development of bacterial

resistance and unnecessary side effects (7). The identification of clear symptoms or

signs, or the description of objective tests that could reliably predict a good (or poor)

outcome without antibiotics in exacerbations of mild to moderate COPD would have

major clinical implications.

We have recently completed a randomised, double-blind, placebo-controlled trial of 8

days of amoxicillin/clavulanate 500/125 mg t.i.din patients with acute exacerbations of

mild to moderate COPD attended in primary care (8). The results indicate that treatment

with amoxicillin/clavulanate is associated with a higher clinical success rate and a

significantly longer period to the next exacerbation. However, up to 80% of patients

were successfully treated with placebo. We used data from this trial to assess the best

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combination among the Anthonisen criteria and the point-of-care capillary C-reactive

protein (CRP) test to predict clinical success with placebo.

METHOD

The methods, design, and outcomes of the above-mentioned trial have been described

previously in detail (8). In short, 310 patients were enrolled between October 2007 and

July 2010 into a multicentre, double-blind, randomised placebo-controlled trial

investigating the efficacy of amoxicillin/clavulanate 500/125 mg three times daily for 8

days in patients with exacerbations of mild to moderate COPD recruited in primary

care. To investigate the predictors of failure without antibiotics, we analyzed data

derived from the 152 patients included in the placebo arm.

The study population consisted of patients that were at least 40 years of age, had a

diagnosis of mild to moderate COPD (defined as having a smoking history of at least 10

pack-years, a ratio of post-bronchodilator FEV1 to FVC of 50% of the predicted value), and with an exacerbation defined as

the occurrence of at least one of the following criteria: increase in dyspnoea, increase in

sputum volume and/or sputum purulence. When the patients presented with the three

symptoms, the exacerbations was classified as type I, with two symptoms as type II and

with only one symptom as type III (1).The most relevant exclusion criteria were

antibiotic use in the previous two weeks, bronchial asthma, active neoplasm, hospital

admission, immunosuppression and hypersensitivity to beta-lactams, clavulanate or

lactose.

The study protocol was approved by the Research and Ethics Committee of Primary

Care Fundaci Jordi Gol i Gurina (Barcelona, Spain; number: P6/031). Written

informed consent was obtained from all the participants.

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Definition of clinical outcome

Treatment success was defined as cure (a complete resolution of signs and symptoms

associated with the exacerbation) or improvement (a resolution or reduction of the

symptoms and signs without new symptoms and signs associated with the

exacerbation). Clinical success was considered when either cure or improvement was

observed (9). Failure was defined as incomplete resolution, persistence or worsening of

symptoms that required a new course of antibiotics and/or oral corticosteroids or

hospitalization (8). Evaluation was performed at the end of therapy visit (EOT) at days

9 to11.

Serum C-reactive protein

On the inclusion visit, a C-reactive protein (CRP) rapid test in capillary blood was

performed using Quik Read CRP

analyzers (Orion Diagnostica, Espoo, Finland) (10).

Studies comparing this rapid test with the routine CRP laboratory test have shown a

very good correlation thereby demonstrating its reliability (11). The best cut off for

CRP serum concentrations to predict clinical success was set at 40 mg/L based on

previous analysis (8).

Statistical Analyses

To identify the factors significantly associated with clinical failure without antibiotics,

univariate and multivariate logistic regression analysis were performed. The first

analysis was focused on investigating signs and symptoms of the exacerbation that

could potentially identify episodes more likely to fail and included the three Anthonisen

criteria: Increasing dyspnoea, increasing production of sputum and increasing purulence

of sputum, together with fever >38, baseline peak flow and the presence of elevated

CRP blood concentrations (>40 mg/L). The second model was focused on the risk

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factors of the patient that could be associated with an increased risk of clinical failure

and included: age older than 65 years, sex, pack-years, ischaemic heart disease, cardiac

insufficiency, diabetes and FEV1


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respectively (p=0.016). Considering the 9.5% failure rate with antibiotic, the aim was to

identify factors that could predict a failure rate 10%. When increased purulence was

one of the criteria, types II and III exacerbations had a failure rate of 20.3% (11 out of

54), and type I exacerbations a failure rate of 33.3% (15 out of 45) (Figure 1).

Table 2 shows the results of the univariate and multivariate analysis of the association

of Anthonisens criteria with failure. Only an increase in sputum purulence was

significantly associated with failure in both analyses.

CRP and Anthonisens criteria for prediction of failure without antibiotics

Previous analysis of our data based on ROC curves indicated that a cut off of 40 mg/L

provided the best prediction for clinical failure in the whole population (8). In the

placebo arm, a total of 77.3% of CRP determinations presented concentrations lower

than 40 mg/L. In these cases, the failure rate was 12.4% (15 out of 121), being

significantly lower than the 65.5% of failure rate observed among the 34 patients with

CRP40 mg/L (P< 0.001).

In the multivariate analysis including the Anthonisen criteria together with the CRP test

results, only an increase in purulence and CRP concentrations >40mg/L were significant

predictors of failure. The ROC curve analysis for Anthonisens criteria provided an area

under the curve (AUC) of 0.708 (95% confidence interval (CI): 0.616-0.801) that was

significantly improved when the CRP measurement was included in the model [AUC=

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0.842 (95%CI: 0.760-0.924), p=0.033] (figure 2). In logistic regression analysis the

probability of failure without antibiotics was only 2.7% when CRP was 40 mg/L and finally to 63.7%

when both factors were present.

Other risk factors of failure without antibiotics

On analyzing the influence of other risk factors of the patients in the evolution of the

exacerbation in patients not treated with antibiotics, we observed that only FEV1(%) 50%, only 30% of the patients included in the former study had an

FEV1(%)>50% (28). This difference is relevant because severity of airflow obstruction

is a risk factor of poor outcome in ambulatory exacerbations in COPD (34);

furthermore, bacterial aetiology of exacerbations is related to the degree of airflow

obstruction (35). Nevertheless, most guidelines have extrapolated the results of the

previous studies in severe or very severe patients to establish their recommendations of

antibiotic treatment including mild to moderate COPD patients (14,15).

Our study has some limitations. We could not investigate the relationship between

symptoms and CRP levels and the presence of bacteria in sputum, because

microbiological analysis of sputum was not readily available in the participating

primary care centers. However, our results are consistent with previous studies that

analyzed the presence of bacteria in sputum related to purulence and CRP

concentrations (16-18,27-29).We cannot rule out some placebo effect because the

criteria for success are based on clinical evaluation. However, the significant

relationship between failure and increasing purulence, higher CRP and worse FEV1(%)

suggest that most of the clinical assessments were correct. Finally, there was not a

protocol for the administration of comedications, but the low percentage of use of oral

corticosteroids, similar to that observed in other series in our country (5,6) most likely

did not influence our results.

In summary, ambulatory patients with exacerbations of mild to moderate COPD

(FEV1>50% predicted) can be safely treated without antibiotics when no increase in

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purulence is present, and the point of test CRP is


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TABLE 1. Baseline characteristics of the population treated without antibiotics

according to the exacerbation type.

Type I

n= 45

Type II

n = 72

Type III

n = 35

p

Age (years), mean (SD) 71.3 (8.7) 65.9 (11.8) 68.1 (10.7) 0.058

Male sex, n (%) 41 (91.1) 52 (72.2) 26 (74.3) 0.044

Smoking status:

- Current, n (%)- Former, n (%)

30 (66.7)

15 (33.3)

43 (59.7)

29 (40.3)

16 (45.7)

19 (54.3)

0.162

Pack-years, mean (SD) 41.8 (13.7) 36.1 (21.0) 36.4 (21.0) 0.260

High blood pressure, n (%) 24 (53.3) 33 (45.8) 16 (45.7) 0.697

Diabetes mellitus, n (%) 10 (22.2) 12 (16.7) 6 (17.1) 0.734

Coronary heart disease, n (%) 8 (17.8) 7 (9.7) 4 (11.4) 0.429

FVC (ml), mean (SD) 2552.0 (865.0) 2961.5 (1017.2) 2627.7 (874.4) 0.049

FVC (%), mean (SD) 69.4 (17.9) 73.9 (18.6) 68.9 (18.2) 0.280

FEV1 (ml), mean (SD) 1523.1 (574.9) 1879.0 (673.5) 1656.0 (586.3) 0.010

FEV1 (%), mean (SD) 62.6 (11.2) 68.1 (13.4) 65.5 (9.5) 0.056

FEV1/FVC ratio, mean (SD) 59.5 (5.8) 63.5 (5.8) 63.0 (4.7) 0.001

Treatment of the exacerbation:

- Short-acting -agonists, n(%)

- Oral corticosteroids, n (%)

20 (44.4)

15 (33.3)

19 (26.4)

9 (12.5)

14 (40.0)

3 (8.6)

0.105

0.004

CRP, median (IQR) 42.0 (36.5) 21.9 (25.5) 20.7 (18.8)


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Type I: all the Anthonisen criteria present (increased dyspnoea, increased sputum volume and

purulent sputum); type II: only two criteria present; type III: only one criterion present

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Table 2. Univariate and multivariate logistic regression analysis of factors related to the exacerbation that predic

of mild to moderate COPD not treated with antibiotics.

Variable Univariate Multivariate

OR CI95% P value OR CI95% P value

Increased dyspnoea 1.6 0.6-3.8 0.32 2.3 0.9-5.9 0.078

Increased volume of sputum 2.1 0.7-6.5 0.20 1.8 0.6-6.1 0.32

Increased purulence of sputum 5.9 1.7-20.7 0.005 6.3 1.8-22.5 0.005

CRP >40 mg/L 13.4 5.3-34.3


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Table 3. Univariate and multivariate logistic regression analysis of factors related to the

patient that predict clinical failure of exacerbations of mild to moderate COPD not

treated with antibiotics.

Variable Univariate Multivariate

OR CI95% P value OR CI95% P value

Pack-years (>20) 1.4 0.9-2.1 0.094

High blood pressure 2.0 0.9-4.6 0.096

Coronary heart disease 2.9 1.0-8.3 0.042

FEV1(%) < 65% 3.0 1.3-7.2 0.012 3.0 1.3-7.2 0.012

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FIGURES

Figure 1. Percentage of failure rates in exacerbations of mild to moderate COPD not

treated with antibiotics, according to Anthonisens criteria.

Figure 2. ROC curves showing the predictive value for clinical failure of a)

Anthonisens criteria (dotted line) and b) with the addition of CRP 40 mg/l

(continuous line), among mild-to-moderate COPD patients with exacerbations not

treated with antibiotics.

Footnote: a) Anthonisens criteria AUC= 0.708 (95% confidence interval (CI): 0.616-

0.801); b) with the addition of CRP 40 mg/l AUC= 0.842 (95%CI: 0.760-0.924).

Differences between curves were significant at p=0.033.

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254x190mm (72 x 72 DPI)

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254x190mm (72 x 72 DPI)

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predictores de exacerbaciones en epoc

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