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Original Research: COPD |

Is It Possible to Identify Exacerbations of Mild to Moderate COPD That Do Not Require Antibiotic Treatment?Antibiotics in Exacerbations of COPD FREE TO VIEW

Marc Miravitlles, MD; Ana Moragas, MD; Silvia Hernández, MD; Carolina Bayona, MD; Carl Llor, MD
Author and Funding Information

From the Servei de Pneumologia (Dr Miravitlles), Hospital Universitari Vall d’Hebron, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona; Primary Care Centre Jaume I (Drs Moragas, Hernández, and Llor), University Rovira i Virgili, Tarragona; and Primary Care Centre Valls (Dr Bayona), Tarragona, Spain.

Correspondence to: Marc Miravitlles, MD, Servei de Pneumologia, Hospital Universitari Vall d’Hebron, P Vall d’Hebron 119-129, 08035 Barcelona, Spain; e-mail: marcm@separ.es


Funding/Support: This clinical trial was supported by a grant from the Instituto de Salud Carlos III (Spanish Ministry of Health) (EC07/90333).

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;144(5):1571-1577. doi:10.1378/chest.13-0518
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Background:  Anthonisen criteria are widely used to guide the use of antibiotics in exacerbations of 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 randomized trial of amoxicillin/clavulanate for exacerbations of mild to moderate COPD. Clinical response in relation to Anthonisen criteria and point-of-care serum C-reactive protein (CRP) tests (cutoff, 40 mg/L) was assessed with multivariate logistic regression analysis.

Results:  Clinical failure without antibiotics was 19.9% compared with 9.5% with amoxicillin/clavulanate (P = .022). The only factors significantly associated with an increased risk of failure without antibiotics were the increase in sputum purulence (OR, 6.1; 95% CI, 1.5-25.0; P = .005) and a CRP concentration ≥ 40 mg/L (OR, 13.4; 95% CI, 4.6-38.8; P < .001). When both factors were present, the probability of failure without antibiotics was 63.7%. The Anthonisen criteria showed an area under the curve of 0.708 (95% CI, 0.616-0.801) for predicting clinical outcome. With the addition of CRP level, the area under the curve rose significantly to 0.842 (95% CI, 0.76-0.924; P < .001).

Conclusions:  Among the Anthonisen criteria, only an increase in sputum purulence is a significant predictor of failure without antibiotics. The use of a point-of-care CRP test significantly increases the predictive accuracy of failure. Both of these easy-to-obtain factors may help clinicians to identify patients with exacerbated mild to moderate COPD who can be safely treated without antibiotics in an ambulatory setting.

Trial registry:  ClinicalTrials.gov; No.: NCT00495586; URL: www.clinicaltrials.gov

Figures in this Article

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 usually is made on the basis of an increase in dyspnea, sputum volume, and sputum purulence, symptoms described 25 years ago by Anthonisen et al1 in a randomized placebo-controlled trial in patients with exacerbations of severe 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 patients with exacerbated mild to moderate COPD (FEV1 > 50% predicted) is lacking.2 This is particularly important because most of the patients with exacerbations in the community have mild or moderate COPD,3,4 and observational studies have consistently shown 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 side effects.7 The identification of clear symptoms or signs or the description of objective tests that reliably predict a good (or poor) outcome without antibiotics in exacerbations of mild to moderate COPD would have major clinical implications.

We recently completed a randomized, double-blind, placebo-controlled trial of 8 days of amoxicillin/clavulanate 500/125 mg tid in 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 combination among the Anthonisen criteria and the point-of-care capillary C-reactive protein (CRP) test to predict clinical success with placebo.

The methods, design, and outcomes of this trial have been previously described in detail.8 In short, 310 patients with exacerbations of mild to moderate COPD were enrolled from primary care between October 2007 and July 2010 into a multicenter, double-blind, randomized placebo-controlled trial that investigated the efficacy of amoxicillin/clavulanate 500/125 mg tid for 8 days. To investigate the predictors of failure without antibiotics, we analyzed data derived from the 152 patients included in the placebo arm.

The study population comprised patients aged at least 40 years with mild to moderate COPD (defined as having a smoking history of at least 10 pack-years, a postbronchodilator FEV1/FVC ratio < 70%, and a postbronchodilator FEV1 > 50% predicted) and an exacerbation defined as the occurrence of at least one of the following symptoms: increased dyspnea, increased sputum volume, and increased sputum purulence. Patients with all three symptoms were classified as type 1, those with two symptoms as type 2, and those with one symptom as type 3.1 The most relevant exclusion criteria were antibiotic use in the previous 2 weeks; bronchial asthma; active neoplasm; hospital admission; immunosuppression; and hypersensitivity to β-lactams, clavulanate, or lactose.

The study protocol was approved by the Research and Ethics Committee of Primary Care Fundació Jordi Gol i Gurina (Barcelona, Spain; number: P6/031). Written informed consent was obtained from all the participants.

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, oral corticosteroids, or hospitalization.8 Evaluation was performed at the end-of-therapy visit on days 9 to 11.

Serum CRP Level

On the inclusion visit, a CRP rapid test in capillary blood was performed with QuikRead (Orion Diagnostica Oy) CRP analyzers.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 cutoff for CRP serum concentrations to predict clinical success was set at 40 mg/L on the basis of a previous analysis.8

Statistical Analysis

To identify the factors significantly associated with clinical failure without antibiotics, univariate and multivariate logistic regression analyses were performed. The first analysis focused on investigating signs and symptoms of the exacerbation that could potentially identify episodes more likely to fail and included the three Anthonisen criteria (ie, increased dyspnea, increased sputum volume production, increased sputum purulence) together with temperature > 38°C, baseline peak flow, and the presence of elevated CRP levels (≥ 40 mg/L). The second analysis focused on the risk factors of the patient that could be associated with an increased risk of clinical failure and included age > 65 years, sex, pack-years, ischemic heart disease, cardiac insufficiency, diabetes, and FEV1 < 65% predicted. Variables with P < .1 in the univariate analysis were selected to be included in the multivariate model, and final selection of variables was performed by the backward stepwise selection analysis.

The predictive value for clinical failure of the Anthonisen criteria alone and with the addition of CRP level ≥ 40 mg/L was calculated by means of receiver operating characteristic (ROC) curves. Comparisons between the areas under the curves (AUCs) were assessed according to the method of Hanley and McNeil.12 All analyses were performed with the SPSS, version 15 (IBM) software.

Baseline Characteristics

In the original randomized trial, 310 patients were enrolled. The placebo group of this trial, comprising 152 patients, was used for the current study. Table 1 shows the baseline characteristics of the population treated with placebo according to the type of exacerbation.1 The mean ± SD age of the patients in the placebo group was 67.8 ± 11 years, and 78.3% were men. The mean FEV1 was 65.9 ± 12.1% predicted, and most patients had either a type 2 (47.4%) or a type 1 (29.6%) exacerbation. The median CRP level was 17 mg/L (interquartile range, 5.5-28.5 mg/L).

Table Graphic Jump Location
Table 1 —Baseline Characteristics of the Population Treated Without Antibiotics According to the Exacerbation Type

Data are presented as mean ± SD, No. (%), or median (interquartile range). CRP = C-reactive protein.

a 

Type 1: all Anthonisen criteria present (increased dyspnea, increased sputum volume, and increased sputum purulence).

b 

Type 2: only two Anthonisen criteria present.

c 

Type 3: only one Anthonisen criterion present.

Anthonisen Criteria and Prediction of Failure Without Antibiotics

At the end-of-therapy visit, the overall clinical success rates for the antibiotic and placebo arms were 80.9% and 90.5%, respectively (P = .022), and the clinical cure rates were 59.9% and 74.1%, respectively (P = .016). Considering the 9.5% failure rate with antibiotic, the aim was to identify factors that could predict a failure rate of < 10% in the placebo arm.

Among patients not receiving antibiotics, those with type 3 exacerbations had a failure rate of 2.8% (one of 35 patients); none of the 19 patients presenting only with increased dyspnea failed. In general, patients with types 2 or 3 exacerbations had a failure rate of 5.6% (three of 53 patients) when no increase in sputum purulence was one of the criteria; in contrast, all other patients had a failure rate of > 10%. When increased sputum purulence was one of the criteria, type 2 and 3 exacerbations had a failure rate of 20.3% (11 of 54 patients), and type 1 exacerbations had a failure rate of 33.3% (15 of 45 patients) (Fig 1).

Figure Jump LinkFigure 1. Percentage of failure rates in exacerbations of mild to moderate COPD not treated with antibiotics according to Anthonisen criteria.Grahic Jump Location

Table 2 shows the results of the univariate and multivariate analyses of the association of Anthonisen criteria with failure. Only an increase in sputum purulence was significantly associated with failure in both analyses.

Table Graphic Jump Location
Table 2 —Univariate and Multivariate Logistic Regression Analysis of Exacerbation Factors That Predict Clinical Failure of Exacerbations of Mild to Moderate COPD Not Treated With Antibiotics

NA = not assessed. See Table 1 legend for expansion of other abbreviation.

CRP Level and Anthonisen Criteria for Prediction of Failure Without Antibiotics

Previous analysis of the data based on ROC curves indicated that a CRP level cutoff of 40 mg/L provided the best prediction for clinical failure in the whole population.8 In the placebo arm, 77.3% of CRP tests resulted in concentrations < 40 mg/L. In these cases, the failure rate was 12.4% (15 of 121 patients), which was significantly lower than the 65.5% failure rate observed among the 34 patients with CRP levels ≥ 40 mg/L (P < .001).

In the multivariate analysis that included the Anthonisen criteria together with the CRP test results, only an increase in sputum purulence and CRP concentrations ≥ 40 mg/L were significant predictors of failure. The ROC curve analysis for Anthonisen criteria produced an AUC of 0.708 (95% CI, 0.616-0.801) that was significantly improved when the CRP measurement was included in the model (AUC, 0.842; 95% CI, 0.760-0.924; P = .033) (Fig 2). In logistic regression analysis, the probability of failure without antibiotics was only 2.7% when CRP level was < 40 mg/L, and no increase in sputum purulence was present. This probability rose to 12.4% when only sputum purulence was present, to 25.6% when only CRP level was ≥ 40 mg/L, and to 63.7% when both factors were present.

Figure Jump LinkFigure 2. Receiver operating characteristic curves showing the predictive value for clinical failure of Anthonisen criteria (dotted line) (area under the curve, 0.708; 95% CI, 0.616-0.801) and with the addition of a C-reactive protein level ≥ 40 mg/L (solid line) (area under the curve, 0.842; 95% CI, 0.760-0.924) among patients with exacerbations of mild to moderate COPD not treated with antibiotics. Differences between curves were significant at P = .033.Grahic Jump Location
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 those not treated with antibiotics, we observed that only FEV1 < 65% predicted was independently associated with an increased risk of failure in the multivariate analysis (OR, 3.0; 95% CI, 1.3-7.2; P = .012) (Table 3).

Table Graphic Jump Location
Table 3 —Univariate and Multivariate Logistic Regression Analysis of Patient Factors That Predict Clinical Failure of Exacerbations of Mild to Moderate COPD Not Treated With Antibiotics

The analysis of the placebo arm results of a randomized, double-blind, antibiotic trial in exacerbated mild to moderate COPD provided a unique opportunity to investigate the factors associated with clinical outcomes and to identify patients who can be safely treated without antibiotics in an ambulatory setting.8 We revisited the classic Anthonisen criteria for antibiotic treatment1 and demonstrated that only an increase in sputum purulence was associated with a significant increase in the risk of failure without antibiotics and that the use of point-of-care testing of CRP level significantly increased the predictive accuracy for the need of antibiotics in ambulatory patients with exacerbations of mild to moderate COPD.

The previously published results of the clinical trial showed the superiority of amoxicillin/clavulanate compared with placebo in terms of significantly higher clinical cure and success rates compared with placebo. However, up to 80% of patients were successfully treated with placebo.8 It has been widely recognized that not all exacerbations of COPD require antibiotic treatment13,13 and that excessive and unnecessary antibiotic use is causing an increase in bacterial resistance.7 Moreover, microbiologic analysis of respiratory samples that could potentially be used to direct antibiotic therapy in the ambulatory setting usually is not available.3 In this context, the clinical criteria described by Anthonisen et al1 have been incorporated in guidelines for the past 25 years to help with selecting patients for empirical antibiotic therapy.14,15 However, these criteria were identified in a population with severe COPD with a mean FEV1 of only 33% predicted. Therefore, validation of these criteria or identification of new criteria for using (or not using) antibiotics in ambulatory patients with mild to moderate COPD is still required.2

More current studies have identified a change in color or an increase in purulence as a good surrogate marker for the presence of bacteria in sputum16,17 or in BAL18 of patients with exacerbations of COPD. The present results show that an increase in sputum purulence was the only sign or symptom associated with the exacerbation that was significantly and independently related to a worse outcome in patients not receiving antibiotics, whereas an increase in dyspnea and sputum volume were not. This clear difference among the three cardinal symptoms also confirms the reliable identification of the increase in sputum purulence by primary care physicians. In this study, no color chart or specific instructions were provided to the investigators; they had to fill in the case report form according to their understanding of the meaning of an increase in sputum purulence, as in real-life clinical practice. Of interest, when no increase in purulence was documented, the probability of failure without antibiotics was always inferior to the failure rate observed in the group treated with antibiotics (10%).

Despite the good predictive value of the increase in sputum purulence, it would be of interest to investigate whether any objective and easy-to-obtain measurement could improve the discriminative power for identifying patients who can be safely managed without antibiotics. We used the point-of-care testing of CRP level that has been demonstrated to be a useful strategy for improving the prescription of antibiotics for lower respiratory tract infections19,20 and a good tool to improve patient adherence to antibiotic therapy.21

CRP level has been demonstrated to be the best biomarker to differentiate between stable and exacerbated COPD, but its accuracy is poor,22 and CRP concentrations decrease significantly with recovery from exacerbations.23 Moreover, persistently elevated CRP levels are associated with recurrence of COPD exacerbations,24 and previous studies observed that CRP levels were significantly increased in purulent vs mucoid exacerbations.25 Finally, increased CRP concentrations have been linked to the presence of bacteria in sputum from COPD exacerbations.2529 Increased CRP level has also been observed in association with the acquisition of a new bacterial strain in patients with COPD,30 a mechanism associated with the development of a new exacerbation.31 Up to four different phenotypes of exacerbations in COPD have been described, and the best serum biomarker for the phenotype of bacterial exacerbations is a high CRP level.29 In contrast, in the same study, increased CRP levels were not observed in the phenotype of viral exacerbations.29 Previous studies also reported this same lack of increase (or minor increase) in CRP levels in viral exacerbations of COPD.32,33

In accordance with the present results, Daniels et al28 demonstrated that CRP levels (but not procalcitonin levels) predicted the response to antibiotics in exacerbations of severe COPD, with increasing effects of antibiotics compared with placebo in patients with higher CRP levels. We have extended their findings by analyzing the predictive value of CRP levels in patients not treated with antibiotics and observed that low CRP levels are associated with success without antibiotics. Another important difference between these studies is the severity of the population studied, whereas all the present patients had an FEV1 > 50% predicted, only 30% of the patients in Daniels et al28 had an FEV1 > 50% predicted. This difference is relevant because severity of airflow obstruction is a risk factor of poor outcome in ambulatory exacerbations in COPD34; furthermore, bacterial etiology of exacerbations is related to the degree of airflow obstruction.35 Nevertheless, most guidelines have extrapolated the results of the previous studies in patients with exacerbations of severe COPD to establish their recommendations of antibiotic treatment in patients with mild to moderate COPD.14,15

The present study has some limitations. We could not investigate the relationship between symptoms and CRP levels and the presence of bacteria in sputum because microbiologic analysis of sputum was not readily available in the participating primary care centers. However, the results are consistent with previous studies that analyzed the presence of bacteria in sputum related to purulence and CRP concentrations.1618,2729 We cannot rule out some placebo effect because the criteria for success are based on clinical evaluation. However, the significant relationship among failure and increasing purulence, higher CRP levels, and worse FEV1 (%) predicted suggests that most of the clinical assessments were correct. Finally, there was no protocol for the administration of comedications, but the low percentage of use of oral corticosteroids, similar to that observed in other series in Spain,5,6 most likely did not influence the 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 sputum purulence is present and the point-of-care CRP level is < 40 mg/L (probability of failure, 2.7%). In cases where a point-of-care CRP test is not available, the presence of the cardinal symptoms of an increase in dyspnea, an increase in sputum volume, or both (without an increase in sputum purulence) is associated with a probability of failure of < 8% without antibiotics, which is inferior to the 10% failure rate observed for the whole population treated with antibiotics. These simple rules may help physicians with their empirical choice of therapy in this frequently treated group of patients.

Author contributions: Dr Miravitlles had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Miravitlles: contributed to the study design, participant recruitment and follow-up, and drafting and review of the manuscript.

Dr Moragas: contributed to the study design, trial coordination, and review of the manuscript.

Dr Hernández: contributed to the participant recruitment and follow-up and revision and approval of the manuscript.

Dr Bayona: contributed to the supervision of the packaging and labeling of the study medication, data analysis, and revision and approval of the manuscript.

Dr Llor: contributed to the study design, trial coordination, participant recruitment and follow-up, and drafting and review of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Miravitlles received honoraria for lectures from Bayer AG, Boehringer Ingelheim GmbH, Pfizer Inc, Takeda Nycomed AS, AstraZeneca, and Novartis Corporation; received payment for the development of educational presentations from Bayer AG; and served on the advisory boards of and received consulting fees from Bayer AG, Boehringer Ingelheim GmbH, Pfizer Inc, Takeda Nycomed AS, GlaxoSmithKline, Almirall SA, AstraZeneca, and Novartis Corporation. Dr Moragas received research grants from the Spanish Society of Family Medicine, Fundació Jordi Gol i Gurina, and Instituto de Salud Carlos III (Spanish Ministry of Health). Dr Llor received research grants from the European Commission (Sixth and Seventh Programme Frameworks), Catalan Society of Family Medicine, and Instituto de Salud Carlos III (Spanish Ministry of Health). Drs Hernández and Bayona have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

Other contributions: The authors thank all the study coordinators, the study investigators in the different primary health-care centers, and the nurses who performed the spirometric studies. They also thank Albert Gabarrús, MSc (IDIBAPS, Hospital Clínic, Barcelona, Spain) for assistance with the data analysis.

AUC

area under the curve

CRP

C-reactive protein

ROC

receiver operating characteristic

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Figures

Figure Jump LinkFigure 1. Percentage of failure rates in exacerbations of mild to moderate COPD not treated with antibiotics according to Anthonisen criteria.Grahic Jump Location
Figure Jump LinkFigure 2. Receiver operating characteristic curves showing the predictive value for clinical failure of Anthonisen criteria (dotted line) (area under the curve, 0.708; 95% CI, 0.616-0.801) and with the addition of a C-reactive protein level ≥ 40 mg/L (solid line) (area under the curve, 0.842; 95% CI, 0.760-0.924) among patients with exacerbations of mild to moderate COPD not treated with antibiotics. Differences between curves were significant at P = .033.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Baseline Characteristics of the Population Treated Without Antibiotics According to the Exacerbation Type

Data are presented as mean ± SD, No. (%), or median (interquartile range). CRP = C-reactive protein.

a 

Type 1: all Anthonisen criteria present (increased dyspnea, increased sputum volume, and increased sputum purulence).

b 

Type 2: only two Anthonisen criteria present.

c 

Type 3: only one Anthonisen criterion present.

Table Graphic Jump Location
Table 2 —Univariate and Multivariate Logistic Regression Analysis of Exacerbation Factors That Predict Clinical Failure of Exacerbations of Mild to Moderate COPD Not Treated With Antibiotics

NA = not assessed. See Table 1 legend for expansion of other abbreviation.

Table Graphic Jump Location
Table 3 —Univariate and Multivariate Logistic Regression Analysis of Patient Factors That Predict Clinical Failure of Exacerbations of Mild to Moderate COPD Not Treated With Antibiotics

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