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

PEx treatment characteristics.

<p>PEx treatment characteristics.</p

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

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

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

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

Additional file 8: Figure S3. of SABRE: a method for assessing the stability of gene modules in complex tissues and subject populations

Random module stability. To get a sense of the stability that could be expected of a module containing genes with minimal relation to each other, a simulation study was carried out. Modules of size 50, 100, 150, 200, 250, 300, 350, and 400 were randomly assembled by sampling from the all 2512 gene symbols in the filtered dataset. This was done 100 times for each size of module. For each random module, their best match Jaccard similarity ceofficients were computed for each of the 1000 bootstrap results previously generated, and the resulting distribution was summarized using the h-index. (PNG 51 kb

Additional file 2: Table S1. of SABRE: a method for assessing the stability of gene modules in complex tissues and subject populations

Patient demographics. Demographic characteristics of the 238 COPD patients. (CSV 495 bytes