Sensitivity and specificity of C-reactive protein and α1-acid glycoprotein for episodes of acute infection among children in Kilimanjaro, Tanzania

C-reactive protein (CRP) and α1-acid glycoprotein (AGP; also called orosomucoid) are acute phase reactants and biomarkers of inflammation. CRP binds to the surface of bacterial and damaged host cells, activates complement, and facilitates phagocytosis; the physiological role of AGP in the acute phase response is not yet well-understood. Production of these proteins increases dramatically during the acute phase response to infection (Vigushin et al., 1993; Fournier et al., 2000; Pepys and Hirshfield, 2003). CRP and AGP stand to be useful biomarkers of acute infectious disease (ID): they are physiologically-based and objective, and not subject to variability in reporting of ID symptoms; they can be elevated in the absence of clinical symptoms, allowing for detection of sub-clinical ID; and they remain elevated in the presence of interventions (e.g., antipyretics) which might obscure other indicators. They can be measured in blood collected by finger stick and stored as dried blood spots (DBS), facilitating use among young children and in challenging field settings. However, the utility of CRP and AGP is limited by the lack of reliable and agreed-upon cutpoints defining acute ID. Multiple conventions have developed for using CRP and AGP to define acute infection, summarized in Table 1. The most widely-used biomarker definition of acute infection is CRP ≥ 10 mg/L (e.g., Frohlich et al., 2000; Pearson et al., 2003; Cushman et al., 2005). Early CRP assays could not detect concentrations lower than ~10 mg/L, and, for this reason, 10 mg/L is considered the upper limit of the normal range of CRP (Wilkins et al., 1998); values over this cutpoint are assumed to reflect acute infection. A better means of selecting cutpoints would be to consider their sensitivity and specificity for acute infection. Such analysis has been performed for CRP, but has focused on distinguishing bacterial from viral infections among severely ill children; cutpoints suggested by such analyses, ranging from 10–70 mg/L (McWilliam and Riordan, 2010), are unlikely to be useful outside of a clinical setting. Table 1 Utilization of CRP and AGP to identify acute infection Efforts to employ biomarkers to identify acute ID are further complicated by variability in specimen type. In western research settings, serum is the most commonly analyzed fluid; population-based studies in the developing world are increasingly employing DBS. Although high correlation between serum and DBS CRP values is reported (Pearson R = 0.96, McDade et al., 2004; Pearson R = 0.979, Brindle et al., 2010), DBS estimates are consistently lower than serum, suggesting a recovery of ~69% (Brindle et al., 2010). For this reason, definitions of elevated CRP or AGP based on serum may not transfer perfectly to DBS. McDade and colleagues (2008) and Wander and colleagues (2009) defined acute ID as CRP > 2.0 mg/L measured in DBS. This cutpoint, while associated with report of ID symptoms (McDade et al., 2008), was not explicitly selected to optimize sensitivity and specificity for ID episodes. We assessed sensitivity and specificity of CRP and AGP measured in DBS for acute ID among children in Kilimanjaro, Tanzania, and identified appropriate cutpoints. We compared CRP and AGP definitions of acute ID against the standard of a morbidity history interview. Although imperfect, morbidity histories provided a means of identifying acute ID episodes for the purpose of selecting cutpoints for biomarker definitions of acute ID.