Does CRP Help Reduce Antibiotic Prescriptions in Acute COPD Exacerbations?

Background: Unwarranted use of antibiotics has several deleterious effects which include, antimicrobial resistance, wasted resources, adverse effects, negative affect on the microbiome of patients, and distracts from potentially more effective interventions. There has recently been a huge push for tests such as procalcitonin to help in curtailing the use of antibiotics when it is not warranted. Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend only prescribing antibiotics in moderately or severely ill patients with acute COPD exacerbations, increased cough, and/or sputum purulence [2]. The authors of this trial wanted to test another such marker, point of care CRP in patients with acute COPD exacerbations. Along with bronchodilators and steroids, antibiotic prescriptions seem to be a common treatment modality as well. CRP is an acute-phase protein that is readily available and can be measured quickly with point of care testing. The authors of this trial hypothesized that the results of POC CRP may help inform prescribing decisions for acute COPD exacerbations, however RCTs regarding clinical effectiveness of this test are lacking.

What They Did:

• Multicenter, open-label, randomized controlled trial
• Patients recruited from 86 general medical practices in the UK
• Patients with a diagnosis of COPD seen by a physician for an acute COPD exacerbation were randomized to:
  • Usual care guided by CRP POC testing (CRP-guided group)
  • Usual care alone (Usual care group)
• CRP Levels & Recommendations:
  • CRP <20mg/L àAntibiotics unlikely to be beneficially
  • CRP 20 – 40mg/L àAntibiotics may be beneficial if purulent sputum present
  • CRP >40mg/L àAntibiotics are likely to be beneficial

Outcomes:

• Primary:
  • Patient-reported use of antibiotics for acute COPD exacerbations within 4 weeks after randomization
  • COPD-related health status 2 weeks after randomization defined by the Clinical COPD Questionnaire (10 item scale with scores ranging from 0 = very good COPD health status to 6 = extremely poor COPD health status)
• Secondary:
  • Antibiotic prescription at initial consultation
  • Adverse effects potentially attributable to antibiotics (Any of the following: n/v, stomach upset, headache, diarrhea, thrush, rash)
  • Incidence of PNA at 4wks and 6mos

Inclusion:

• ≥40 years of age
• Diagnosis of COPD in the primary care clinical record
• Presenting with an acute exacerbation of COPD between 24hrs and 21d duration
• At least one of the Anthonisen criteria

Exclusion:

• Required urgent hospital admission
• Severe illness (i.e. suspected PNA, tachypnea >30BPM)
• Concurrent infection at another site (i.e UTI)
• Past history of respiratory failure or mechanical ventilation
• Currently taking antibiotics ar had already taken antibiotics for this exacerbation
• Active inflammatory condition
• Cystic fibrosis
• Tracheostomy
• Bronchiectasis
• Immunocompromised
• Pregnant
• Previously participated in study

Anthonisen Criteria:

• Increased dyspnea
• Increased sputum volume
• Increased sputum purulence

Results:

• 653 patients randomized
• CRP values <20mg/L = 241/317 pts (76.0%)
  • 79/241 (32.8%) still received an antibiotic prescription
• Patient Reported Use of Antibiotics for Acute COPD Exacerbation by 4 Weeks:
  • CRP-Guided Group: 57.0%
  • Usual Care Group: 77.4%
  • aOR 0.31; 95% CI 0.20 – 0.47
• Difference in Clinical COPD Questionnaire at 2 weeks was -0.19, in favor of the CRP-guided group
• Antibiotic Prescription for Acute COPD Exacerbation at Initial Visit:
  • CRP-Guided Group: 47.7%
  • Usual Care Group: 69.7%
  • aOR 0.31; 95% CI 0.21 – 0.45
• No difference in PNA diagnosis at 4 weeks of follow up (aOR 1.57; 95% CI 0.28 – 8.84) or 6 months of follow up (aOR 0.73; 95% CI 0.29 – 1.82)
• Serious Clinically Important Events:
  • Hospitalization:
    • CRP-Guided Group: 35 events
    • Usual Care Group: 34 events
  • Death:
    • CRP-Guided Group: 0 events
    • Usual Care Group: 2 events
  • No difference in adverse effects from antibiotics (aOR 0.79; 95% CI 0.44 – 1.39)

Strengths:

• Multicenter randomized controlled trial
• Alere, now Abbott loaned Afinion desktop devices for CRP POC at no extra cost, and had no role in the design, the analysis, interpretation of the data, or in the preparation of the manuscript for this trial
• Trial groups well matched at baseline

Limitations:

• Unblinded trial without the use of sham testing (i.e. awareness of receiving POC testing may have contributed to enhanced COPD-related health status on questionnaire by patients)
• Non-ED setting, meaning these patients may not be as sick as the patients we see in the ED and therefore makes the results of this study not generalizable to a sicker cohort of patients
• Use of sputum purulence in the middle CRP group (20 – 40mg/L) adds bias favoring antibiotic prescriptions
• No comparison to education regarding GOLD criteria, which may have reduced antibiotic prescriptions by itself
• The primary outcome of patient-reported use of antibiotics for acute COPD exacerbations within 4 weeks after randomization is a strange endpoint. A better primary outcome would have been use of antibiotics by the physician the patient visited and not just any antibiotics within 4 weeks after randomization. This was one of the secondary outcomes but would have been a more appropriate primary outcome

Discussion:

• Most common bacterial pathogens cultured from sputum samples:
  • influenzae = 53/391
  • catarrhalis = 50/391
  • pneumoniae = 35/391
• An important point worth mentioning is it would have been interesting to have another arm where all practitioners studying in the study were educated regarding GOLD criteria for antibiotic prescriptions and see if CRP added anything to that education or education alone would have been just as good at reducing unnecessary antibiotic prescriptions (i.e. gestalt being as good when that gestalt is educated by best practice).

Author Conclusion: “CRP-guided prescribing of antibiotics for exacerbations of COPD in primary care clinics resulted in lower percentage of patients who reported antibiotic use and who received antibiotic prescriptions from clinicians, with no evidence of harm.”

Clinical Take Home Point: With an antibiotic prescription rate of almost 80% in the usual care group, just about any intervention that pushes antibiotic stewardship would make a difference in prescribing habits, and therefore there is no surprise that POC CRP reduced the number of antibiotic prescriptions in patients with acute COPD.

References:

1. Butler CC et al. C-Reactive Protein Testing to Guide Antibiotic Prescribing for COPD Exacerbations. NEJM 2019. PMID: 31291514
2. Global Initiative for Chronic Obstructive Lung Disease (GOLD) Home Page. [Link is HERE]

For More Thoughts on This Topic Checkout:

• EM Lite of Note: CRP for COPD

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)

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