In the JournalsPerspective

C-reactive protein testing safely reduces antibiotic use for COPD exacerbations

The use of point-of-care testing for C-reactive protein to guide treatment lessened the use of antibiotics for COPD exacerbations without worsening clinical outcomes, according to a study published in The New England Journal of Medicine.

“Recommendations for antibiotic prescribing in primary care practice are generally based on clinical features alone (eg, the Anthonisen criteria, which include increased dyspnea, increased sputum volume, and increased sputum purulence), but these features are subjective and insufficiently accurate in predicting which patients can be treated safely without antibiotics,” the researchers wrote.

In contrast, C-reactive protein (CRP) testing may serve as a more objective indicator of whether antibiotics are necessary for treating some COPD exacerbations, they noted.

In the multicenter, open-label, controlled PACE trial, the researchers randomly assigned 653 patients with COPD exacerbations seen at 86 general medical practices in England and Wales to usual care guided by CRP point-of-care testing or usual care alone. Patients aged at least 40 years with a diagnosis of COPD in their primary care clinical record who presented with an acute exacerbation with at least one of the Anthonisen criteria were eligible for enrollment.

The two primary outcomes were patient-reported use of antibiotics for acute COPD exacerbations within 4 weeks of randomization and COPD-related health status at 2 weeks after randomization using the Clinical COPD Questionnaire (CCQ) score, with a minimal clinically important difference of 0.4 points.

For the CRP-guided group, the researchers advised clinicians that antibiotics were unlikely to benefit patients whose CRP levels were lower than 20 mg/L, likely to benefit patients whose CRP level is higher than 40 mg/L and may possibly benefit patients whose CRP levels fell between the two cutoffs. They also asked clinicians to use judgment when determining treatment course as opposed to solely basing their decisions on CRP levels.

Reduced antibiotic use

Among the 317 patients who underwent CRP testing, 76% had values lower than 20 mg/L, 12% had values between 20 mg/L and 40 mg/L and 12% had values higher than 40 mg/L.

At 4 weeks, patients in the CRP-guided group were less likely to report antibiotic use than the usual care group (57% vs. 77.4%; adjusted OR = 0.31; 95% CI, 0.2-0.47), and at 2 weeks, the adjusted mean difference in total CCQ score (–0.19 points; two-sided 90% CI, –0.33 to –0.05) favored CRP testing.

In looking at clinician prescribing, the CRP-guided group was less likely than the usual care group to receive an antibiotic prescription at the initial consultation (47.7% vs. 69.7%; aOR = 0.31; 95% CI, 0.21-0.45) as well as during the first 4 weeks of follow-up (59.1% vs. 79.7%; aOR = 0.3; 95% CI, 0.2-0.46).

“Between-group differences in the scores on the Clinical COPD Questionnaire during follow-up were smaller than the published minimal clinically important difference of 0.4, which indicates that less antibiotic use and fewer prescriptions from clinicians did not compromise patient-reported disease-specific quality of life,” the researchers wrote.

During 6-month follow-up, the researchers also found no significant differences between groups in other health measures.

“Health care–seeking behavior or measures of patient well-being at 6 months did not differ meaningfully between the trial groups, nor did secondary clinical, microbiologic, disease-specific quality of life or health care utilization outcomes with respect to primary and secondary care,” the researchers wrote.

Two deaths occurred in the usual care group during the 4-week follow-up, of which neither was considered to be related to the trial interventions or procedures by the researchers. There also appeared to be no clinically important differences between groups in adverse effects from antibiotics (aOR = 0.79; 95% CI, 0.44-1.39).

Clinical implications

The researchers concluded that their findings suggest patient-reported use of antibiotics and clinicians’ prescribing of antibiotics may decline with the use of point-of-care CRP testing to guide treatment of COPD exacerbations in the primary care setting.

Reducing antibiotic use likely has several benefits, as it mitigates some risks associated with treatment, such as potentially increasing the predisposition for airway colonization by multidrug-resistant bacteria, which can lead to pneumonia in some patients, according to Allan S. Brett, MD, from the division of general internal medicine, and Majdi N. Al-Hasan, MBBS, from the division of infectious diseases, both at the University of South Carolina School of Medicine in Columbia.

They noted, however, that the implementation of CRP testing in primary care may hit some roadblocks.

“Whether primary care practices in the United States would embrace point-of-care CRP testing is another matter, given the regulatory requirements for in-office laboratory testing and uncertainty about reimbursement,” Brett and Al-Hasan wrote in an accompanying editorial.

This is particularly true because COPD exacerbations account for a small number of patients seen in primary care practices. Nevertheless, there is potential for broader application, as data show that CRP testing may reduce antibiotic prescribing in more common clinical scenarios, such as suspected lower respiratory infection, they added.

Regardless, more study will be important, according to Brett and Al-Hasan.

“The PACE study only suggests a way to reduce antibiotic prescribing without compromising clinical outcomes,” they wrote. “It does not establish which patients (if any) truly benefit from antibiotic therapy or which antibiotics are most appropriate for COPD exacerbations. Additional clinical trials will be necessary to address these uncertainties.” – by Melissa Foster

Disclosures: The study was funded by the National Institute for Health Research (NIHR) Health Technology Assessment Program. One author reports he has received advisory board fees from Roche Molecular Systems and grant support from Roche Molecular Diagnostics. A second author reports she has received lecture fees from Merck Sharp and Dohme. A third author reports he has received grant support from Abbott Diagnostics. All other authors report no relevant financial disclosures. Al-Hasan and Brett report no relevant financial disclosures.

 

The use of point-of-care testing for C-reactive protein to guide treatment lessened the use of antibiotics for COPD exacerbations without worsening clinical outcomes, according to a study published in The New England Journal of Medicine.

“Recommendations for antibiotic prescribing in primary care practice are generally based on clinical features alone (eg, the Anthonisen criteria, which include increased dyspnea, increased sputum volume, and increased sputum purulence), but these features are subjective and insufficiently accurate in predicting which patients can be treated safely without antibiotics,” the researchers wrote.

In contrast, C-reactive protein (CRP) testing may serve as a more objective indicator of whether antibiotics are necessary for treating some COPD exacerbations, they noted.

In the multicenter, open-label, controlled PACE trial, the researchers randomly assigned 653 patients with COPD exacerbations seen at 86 general medical practices in England and Wales to usual care guided by CRP point-of-care testing or usual care alone. Patients aged at least 40 years with a diagnosis of COPD in their primary care clinical record who presented with an acute exacerbation with at least one of the Anthonisen criteria were eligible for enrollment.

The two primary outcomes were patient-reported use of antibiotics for acute COPD exacerbations within 4 weeks of randomization and COPD-related health status at 2 weeks after randomization using the Clinical COPD Questionnaire (CCQ) score, with a minimal clinically important difference of 0.4 points.

For the CRP-guided group, the researchers advised clinicians that antibiotics were unlikely to benefit patients whose CRP levels were lower than 20 mg/L, likely to benefit patients whose CRP level is higher than 40 mg/L and may possibly benefit patients whose CRP levels fell between the two cutoffs. They also asked clinicians to use judgment when determining treatment course as opposed to solely basing their decisions on CRP levels.

Reduced antibiotic use

Among the 317 patients who underwent CRP testing, 76% had values lower than 20 mg/L, 12% had values between 20 mg/L and 40 mg/L and 12% had values higher than 40 mg/L.

At 4 weeks, patients in the CRP-guided group were less likely to report antibiotic use than the usual care group (57% vs. 77.4%; adjusted OR = 0.31; 95% CI, 0.2-0.47), and at 2 weeks, the adjusted mean difference in total CCQ score (–0.19 points; two-sided 90% CI, –0.33 to –0.05) favored CRP testing.

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In looking at clinician prescribing, the CRP-guided group was less likely than the usual care group to receive an antibiotic prescription at the initial consultation (47.7% vs. 69.7%; aOR = 0.31; 95% CI, 0.21-0.45) as well as during the first 4 weeks of follow-up (59.1% vs. 79.7%; aOR = 0.3; 95% CI, 0.2-0.46).

“Between-group differences in the scores on the Clinical COPD Questionnaire during follow-up were smaller than the published minimal clinically important difference of 0.4, which indicates that less antibiotic use and fewer prescriptions from clinicians did not compromise patient-reported disease-specific quality of life,” the researchers wrote.

During 6-month follow-up, the researchers also found no significant differences between groups in other health measures.

“Health care–seeking behavior or measures of patient well-being at 6 months did not differ meaningfully between the trial groups, nor did secondary clinical, microbiologic, disease-specific quality of life or health care utilization outcomes with respect to primary and secondary care,” the researchers wrote.

Two deaths occurred in the usual care group during the 4-week follow-up, of which neither was considered to be related to the trial interventions or procedures by the researchers. There also appeared to be no clinically important differences between groups in adverse effects from antibiotics (aOR = 0.79; 95% CI, 0.44-1.39).

Clinical implications

The researchers concluded that their findings suggest patient-reported use of antibiotics and clinicians’ prescribing of antibiotics may decline with the use of point-of-care CRP testing to guide treatment of COPD exacerbations in the primary care setting.

Reducing antibiotic use likely has several benefits, as it mitigates some risks associated with treatment, such as potentially increasing the predisposition for airway colonization by multidrug-resistant bacteria, which can lead to pneumonia in some patients, according to Allan S. Brett, MD, from the division of general internal medicine, and Majdi N. Al-Hasan, MBBS, from the division of infectious diseases, both at the University of South Carolina School of Medicine in Columbia.

They noted, however, that the implementation of CRP testing in primary care may hit some roadblocks.

“Whether primary care practices in the United States would embrace point-of-care CRP testing is another matter, given the regulatory requirements for in-office laboratory testing and uncertainty about reimbursement,” Brett and Al-Hasan wrote in an accompanying editorial.

This is particularly true because COPD exacerbations account for a small number of patients seen in primary care practices. Nevertheless, there is potential for broader application, as data show that CRP testing may reduce antibiotic prescribing in more common clinical scenarios, such as suspected lower respiratory infection, they added.

PAGE BREAK

Regardless, more study will be important, according to Brett and Al-Hasan.

“The PACE study only suggests a way to reduce antibiotic prescribing without compromising clinical outcomes,” they wrote. “It does not establish which patients (if any) truly benefit from antibiotic therapy or which antibiotics are most appropriate for COPD exacerbations. Additional clinical trials will be necessary to address these uncertainties.” – by Melissa Foster

Disclosures: The study was funded by the National Institute for Health Research (NIHR) Health Technology Assessment Program. One author reports he has received advisory board fees from Roche Molecular Systems and grant support from Roche Molecular Diagnostics. A second author reports she has received lecture fees from Merck Sharp and Dohme. A third author reports he has received grant support from Abbott Diagnostics. All other authors report no relevant financial disclosures. Al-Hasan and Brett report no relevant financial disclosures.

 

    Perspective
    David Mannino

    David Mannino

    The average patient with COPD experiences about one to two exacerbations per year. They are typically treated with a combination of antibiotics and/or steroids. However, there has always been a concern that we may be using too many antibiotics. The core of this study is determining whether biomarker-directed therapy — specifically using the biomarker CRP, which, when elevated, suggests an infectious process — can aid a clinician in deciding whether a patient requires antibiotics as opposed to steroids only for treatment of their exacerbation. CRP has been used for many years in the evaluation of disease, but the difference here is the use of point-of-service testing. This type of testing allows the physician to make an immediate decision based on the quick assessment of CRP in the office.

    In this study, the researchers offered guidance on the appropriate cut points for CRP but also urged clinicians to use clinical judgment in determining treatment. As was shown, antibiotic use was lower in the CRP-guided group vs. the usual care group. Additionally, despite the lower use of antibiotics in the CRP-guided group, there was little difference in COPD severity level between groups, and there were no safety concerns. According to the study, the bottom line is that this type of biomarker testing, particularly when available at the point of service, might be useful in guiding therapy.

    What is interesting, though, is that although more than three-quarters of patients in the CRP-guided group were below the CRP threshold for antibiotic treatment, more than half of all patients in the CRP-guided group received antibiotics anyway. This is where clinician judgment comes into play.

    Looking ahead, the question is: Could point-of-service CRP testing gain traction? In some parts of the pulmonary world — cystic fibrosis, for example — CRP is already being used to guide therapy, but there are several other ways in which point-of-service CRP testing could aid clinicians. First, we know when exacerbations begin, but we do not really know when they end; CRP testing may provide additional guidance as to duration of exacerbation. It may also provide additional guidance as to what therapies patients need. Currently, one of the debates in this space is: Which patients need to be on triple therapy or an inhaled corticosteroid, which patients may benefit from suppressive antibiotics or which patients are appropriate for weaning off inhaled steroids? If something like CRP testing becomes more commonly available as a point-of-service assessment, it will be able to help take some of the guesswork out of deciding which course of treatment is best for which patient. This of course must be validated in future studies, but it is entirely possible that CRP testing could become more popular. Once again, though, it is worth noting that the clinicians in this study did not seem to pay a great deal of attention to the CRP values when deciding to prescribe antibiotics.

    Overall, the PACE trial was a nicely done, real-world study. It answered the basic question that use of point-of-service CRP testing can decrease antibiotic exposure in patients with COPD exacerbations. At this point, I do not think it will dramatically change clinical practice because this type of testing is not yet widely available. At present, however, it is a nice concept that could help us make clinical decisions based on data rather than by the seat of our pants, which is common nowadays.

    • David Mannino, MD
    • Part-time Professor of Medicine
      University of Kentucky, Lexington

    Disclosures: Mannino reports he is a consultant, stockholder and employee for GlaxoSmithKline.