Clinical utility of C-reactive protein to predict treatment response during cystic fibrosis pulmonary exacerbations

<div><p>Rationale</p><p>C-reactive protein (CRP) is a systemic marker of inflammation that correlates with disease status in cystic fibrosis (CF). The clinical utility of CRP measurement to guide pulmonary exacerbation (PEx) treatment decisions remains uncertain.</p><p>Objectives</p><p>To determine whether monitoring CRP during PEx treatment can be used to predict treatment response. We hypothesized that early changes in CRP can be used to predict treatment response.</p><p>Methods</p><p>We reviewed all PEx events requiring hospitalization for intravenous (IV) antibiotics over 2 years at our institution. 83 PEx events met our eligibility criteria. CRP levels from admission to day 5 were evaluated to predict treatment non-response, using a modified version of a prior published composite definition. CRP was also evaluated to predict time until next exacerbation (TUNE).</p><p>Measurements and main results</p><p>53% of 83 PEx events were classified as treatment non-response. Paradoxically, 24% of PEx events were characterized by a ≥ 50% increase in CRP levels within the first five days of treatment. Absolute change in CRP from admission to day 5 was not associated with treatment non-response (p = 0.58). Adjusted for FEV₁% predicted, admission log₁₀ CRP was associated with treatment non-response (OR: 2.39; 95% CI: 1.14 to 5.91; p = 0.03) and shorter TUNE (HR: 1.60; 95% CI: 1.13 to 2.27; p = 0.008). The area under the receiver operating characteristics (ROC) curve of admission CRP to predict treatment non-response was 0.72 (95% CI 0.61–0.83; p<0.001). 23% of PEx events were characterized by an admission CRP of > 75 mg/L with a specificity of 90% for treatment non-response.</p><p>Conclusions</p><p>Admission CRP predicts treatment non-response and time until next exacerbation. A very elevated admission CRP (>75mg/L) is highly specific for treatment non-response and might be used to target high-risk patients for future interventional studies aimed at improving exacerbation outcomes.</p></div

ROC curve for the prediction of treatment non-response based on admission log₁₀ CRP adjusted for baseline FEV₁% predicted.

<p>As can be seen from the ROC curve, a CRP cut-off of >75 mg/L corresponds to a test specificity of 90% and sensitivity of 70%.</p

Clinical characteristics of included patients at the time of first PEx.

<p>Clinical characteristics of included patients at the time of first PEx.</p

PEx treatment characteristics.

<p>PEx treatment characteristics.</p

Flow diagram for cohort selection based on study inclusion and exclusion criteria.

<p>Flow diagram for cohort selection based on study inclusion and exclusion criteria.</p

Evaluation of CRP and WBC to predict PEx treatment non-response.

<p>Evaluation of CRP and WBC to predict PEx treatment non-response.</p

Scatterplot of admission (day 0) C-reactive protein (CRP) levels and WBC count.

<p>CRP and WBC are significantly correlated but 45% of pulmonary exacerbation events are characterized by an elevated CRP (>3.1 mg/L) and normal WBC (<11 x 10⁹ cells/L).</p

Trial Profile.

<p>Trial Profile.</p

Pulmonary Exacerbations and Hospitalizations by Treatment Group - 24 Week Treatment Period.

<p>Pulmonary Exacerbations and Hospitalizations by Treatment Group - 24 Week Treatment Period.</p

Time to First Pulmonary Exacerbation Requiring Oral or Intravenous Antibiotics.

<p>Blue dashed line = placebo-treated patients. Black solid line = itraconazole-treated patients. The median time to first exacerbation was 77 days for the itraconazole group and 134 days for the placebo group, log-rank P = 0.35. Hash marks = censored observations.</p