Towards salivary C-reactive protein as a viable biomarker of systemic inflammation

Abstract

C-reactive protein (CRP) is a commonly used marker of systemic inflammation, routinely measured in serum blood samples. However salivary samples offer a noninvasive and easily accessible alternative which would improve point of care (POC) testing for inflammation. Two major challenges restrict the use of saliva: the influence of the oral environment on CRP and its local production; and collecting a standardised sample given patient-dependent salivary flow rates. Here we review the reported studies of salivary CRP in humans as a potential marker of systemic inflammation and how the challenges can be overcome. Salivary CRP currently poorly reflects systemic inflammation as it does not consistently and strongly correlate with serum CRP. The mean and one standard deviation reported R 2 values are 0.53  0.23 from 14 studies. An improved understanding of the key challenges and implemented solutions are needed to optimise salivary CRP use. Firstly, control for the effects of local oral inflammation. Screening for oral trauma is one option, however this could drastically limit the number of patients suitable for salivary CRP testing and the number of professionals able to use the POC test. Secondly, the role of a dilution biomarker is considered controlling for salivary flow rate which dilutes serum CRP by ~10 4 ; a variable and likely-patient specific factor. The ideal dilution biomarker should have many of the pharmacokinetic, sensitivity and specificity characteristics of CRP. The potential for positive acute phase protein serum amyloid A (SAA) and negative acute phase protein albumin is considered and the characteristics of any correction function discussed. Currently, however, there are no available strategies to make salivary CRP a reliable quantitative measure of serum CRP and hence POC systemic inflammation testing.

Salivary Cytokines in Children with Nephrotic Syndrome versus Healthy Children: A Comparative Study

“…Therefore, despite the increased permeability of the glomerular filter in NS, capillary permeability of the salivary gland appears to be unaffected. Decreased serum protein levels correlate with changes in saliva composition that are evident in other diseases [10,11] and corroborate the intimate relation between serum and saliva characteristics. Furthermore, similar correlations have been shown between saliva and systemic markers for various conditions such as diabetes [8] and autoimmune disorders [9] in adults.…”

Salivary cytokines in children with nephrotic syndrome versus healthy children: a comparative study

“…Therefore, despite the increased permeability of the glomerular lter in NS, capillary permeability of the salivary gland appears to be unaffected. Decreased serum protein levels correlate with changes in saliva composition that are evident in other diseases [10,11], and corroborate the intimate relation between serum and saliva characteristics. Furthermore, similar correlations have been shown between saliva and systemic markers for various conditions such as diabetes [8] and autoimmune disorders [9] in adults.…”

Directed Transport of CRP Across In Vitro Models of the Blood-Saliva Barrier Strengthens the Feasibility of Salivary CRP as Biomarker for Neonatal Sepsis

“…Patients with samples drawn at several time points ( Figure 1B) in this study showed a median ratio between salivary and serum concentration of 1600 (5300 ± 10,100, mean ± SD) similar to the ratio found in a clinical study with 61 healthy volunteers by Ouellet-Morin et al [23] reporting a ratio of 1633. This ratio was below the assumed factor of 10,000 described by Pay and Shaw [41].…”

“…The most recent study correlating neonatal sepsis with elevated levels of CRP and IL-6 was published by Cortes et al and demonstrated that CRP could be a useful biomarker in combination with other inflammatory biomarkers, especially for late-onset neonatal sepsis [40]. Recently, 14 clinical studies were summarized by Pay and Shaw [41] ) showing a correlation of salivary CRP and serum CRP levels with R 2 of 0.53 ± 0.23, comparable to the result of our study with a R 2 value of 0.52 ( Figure 1A). Patients with samples drawn at several time points ( Figure 1B) in this study showed a median ratio between salivary and serum concentration of 1600 (5300 ± 10,100, mean ± SD) similar to the ratio found in a clinical study with 61 healthy volunteers by Ouellet-Morin et al [23] reporting a ratio of 1633.…”

“…However, Pay and Shaw [41] also stressed the necessity to understand the correlation of salivary and serum concentrations as local oral inflammation cannot be excluded in clinical set-ups. Even though clinical studies linked salivary CRP positively as a marker for metabolic syndrome [42], detection of obesity in children [43], or pneumonia in neonates [17], a study published in 2019 with 37 healthy young males showed no clear correlation between salivary and serum concentrations of CRP [44].…”