(112) Calprotectin predicts cystic fibrosis pulmonary exacerbations in equivocal cases

Background: Cystic fibrosis (CF) patients frequently experience pulmonary exacerbations (PEx) characterized by uncontrolled airway infection and inflammation. Without a consensus definition of PEx, these events can be overlooked by clinicians which can impact long-term lung function, quality of life and life expectancy. The decision to treat with antibiotics is straightforward when the patient presents with increased respiratory symptoms (e.g., cough, mucus, breathlessness) and decreased lung function, However, adjunctive approaches to PEx diagnosis are needed in equivocal cases where the clinical course of action is unclear. C-reactive protein (CRP) and calprotectin are promising candidates to aid PEx diagnosis. The objective of this study is to evaluate the utility of CRP and calprotectin to effectively differentiate patients who will eventually require treatment with antibiotics when they present to CF clinic with discordant changes in symptoms and lung function.

Methods: We retrospectively identified patients from the CF Biomarker (CFB) study at St. Paul’s Hospital (Vancouver, Canada) who presented to the CF clinic with discordant changes in respiratory symptoms and lung function and were not prescribed antibiotics (index visit) between 2012 and 2019. Discordant visits were defined as visits with 1) Cystic Fibrosis Respiratory Symptom Diary-Chronic Respiratory Infection Symptom Score (CFRSD-CRISS) ≥ 39 and a relative forced expiratory volume in 1 second (FEV1) drop of < 5% (symptomatic, stable FEV1) or 2) CFRSD-CRISS score < 30 and a relative FEV1 drop of >10% (silent decline in FEV1). Using biobanked blood samples, we quantified plasma calprotectin levels through an enzyme-linked immunosorbent assay (ELISA) and plasma CRP levels using an electrochemiluminescence assay. We measured the samples in duplicate and used mean values for analysis. We used a generalized estimating equations (GEE) model including age, sex, and baseline percent predicted FEV1 to examine the association between log2 transformed CRP or calprotectin levels and subsequent risk of PEx requiring antibiotics within 4 months of index visit.

Results: We identified 52 discordant visits (77% symptomatic, stable FEV1) from 36 patients (61% male) with a median age of 28 years [IQR: 25, 38] and a median baseline percent predicted FEV1 of 80% [IQR: 50, 97]. Patients had a range of 1 to 4 discordant visits with 75% of patients having only a single discordant visit. The 52 visits had a median CRP concentration of 5.16 mg/L [IQR: 2.15, 10.58] and a median calprotectin concentration of 0.81 mg/L [IQR: 0.62, 1.71]. In our adjusted GEE model, there was no association between log CRP levels and PEx requiring antibiotics within 4 months of the index visit (OR = 1.10, 95% CI [0.77, 1.57]). However, we found a significant association between log calprotectin levels and PEx requiring antibiotics (OR = 2.51, 95% CI [1.08, 5.80]).

Conclusions: The independent association between calprotectin levels and the risk of PEx in our cohort in the presence of other important covariates demonstrates its potential value as a biomarker of PEx in discordant cases. Use of calprotectin as an objective add-on test could help improve PEx diagnosis and facilitate timelier treatment. Validation in an external cohort is currently in progress and diagnostic cut-offs will need to be defined.

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