Procalcitonin Elevation in Children with Sickle Cell Disease (SCD) Requiring Hospitalization for Acute Vaso-Occlusive Pain (VOE)

Introduction: Procalcitonin (PCT) is a plasma biomarker often used as a tool for antibiotic stewardship to help distinguish bacterial infection from other causes of infection or systemic inflammation. SCD is associated with chronic inflammation among patients who are also more susceptible to bacterial infections than the general population in-part due to functional asplenia. During VOE, it is difficult to distinguish whether a fever originates from VOE-associated inflammation or a serious bacterial infection (SBI), resulting in empiric antibiotics for all such patients. Multiple studies support procalcitonin-guided antibiotic therapy in adults and children, avoiding unnecessary antibiotic overuse and/or decreasing their duration based on established cut-off values. However, the role of PCT in VOE, particularly when associated with fever among patients with SCD remains underexplored.

Objective: To evaluate the association between PCT levels and various clinical and lab parameters, including fever and acute chest syndrome (ACS) in patients with SCD-VOE

Methods: Secondary analysis of samples collected as part of a pharmacokinetics/pharmacodynamics study and a phase II randomized controlled trial of intravenous arginine therapy in patients age 3-21 years with SCD-VOE. Plasma PCT levels were measured using enzyme-linked immunosorbent assay (ELISA) at the time of emergency department (ED) presentation and again at hospital discharge. PCT ≥0.5 ng/mL was considered elevated and ≥2ng/mL - high risk based on prior non-SCD studies of SBI risk.

Results: 102 patients (mean 13±4 years, 49% male, 66% HbSS, 70% on hydroxyurea) were included, 14% with a fever ≥38.0ºC in the ED, 18% who developed fever during their hospital stay, and 11 subjects who either presented with acute chest syndrome (ACS) in the ED (n=3) or developed ACS during their hospital stay (n=8). Mean PCT level at ED presentation was 0.9±0.8 ng/mL (range 0-5), with 69% of patients presenting with elevated PCT level ≥0.5 ng/mL, and 9% ≥2 ng/mL. PCT did not decrease significantly by discharge, with discharge levels remaining elevated in 60%. Patients with an elevated PCT were similar in demographics, clinical and lab parameters assessed, including presence of fever, development of ACS, hydroxyurea use, length of hospital stay, ED pain scores and total opioids used vs patients with a PCT <0.5 ng/mL. PCT positively correlated with hemoglobin (r=0.28, p=0.005) and glucose (r=0.36, p<0.001). No association with white blood cell, neutrophil or lymphocyte count, or temperature was noted. There were no significant differences in PCT levels between patients with and without fever, chest pain, or ACS. Among patients with an elevated PCT ≥0.5 ng/mL (n=70), 14% had fever in the ED and an additional 18% developed fever during the hospital stay, 46% had chest pain, and 11% had ACS, nearly identical to patients with normal PCT levels. Patients with the highest baseline PCT levels ≥2 mg/mL were also similar except for significantly higher creatinine (p<0.05) compared to patients with PCT <0.5 ng/mL. No febrile patients had a positive blood culture. Arginine had no impact on PCT levels at discharge vs. placebo.

Conclusion: PCT levels are commonly elevated in patients with SCD experiencing VOE requiring hospitalization, indicating a systemic inflammatory response that persists at discharge, not related to a bacterial infection. Surprisingly within our cohort, PCT elevation was not associated with fever, ACS, chest pain or other clinical/demographics parameters evaluated. However, no patients had SBI, a group that should be targeted in future studies. Although PCT is a promising biomarker for antibiotic stewardship, there are several limitations in SCD that required further prospective investigation. Baseline ranges and SBI risk cut-offs for SCD are likely different from the general population given that SCD is characterized by chronic inflammation that worsens during VOE. While the presence of fever or ACS in our VOE cohort was not associated with higher PCT levels, the sensitivity and specificity of PCT to identify patients with fever or VOE at risk for SBI remains to be determined. Alternatively, PCT levels <0.5 ng/mL may identify patients at low risk of SBI, where antibiotics may be withheld. Future studies should prospectively evaluate the role of PCT-guided antibiotic stewardship among patients with SCD with fever.