Multimodal Noninvasive Assessment of C-Reactive Protein for Systemic Inflammation in Adults: Cross-Sectional Study

Accurate and accessible measurements of inflammatory biomarkers are crucial for the diagnosis and monitoring of inflammatory diseases. The gold-standard C-reactive protein (CRP) requires venipuncture, which, despite providing high-quality samples, can cause discomfort, anxiety, and pain, particularly in vulnerable populations such as older patients. It is also resource-intensive, is unsuitable for remote or at-home use, and lacks continuous monitoring capability. These limitations limit patient autonomy and self-management, potentially leading to poorer prognosis due to delays in assessment and medical treatments. As digital health technologies advance, there is increasing interest in leveraging digital biomarkers for remote and real-time monitoring of systemic inflammation. Digital biomarkers derived from noninvasive biofluids could provide a scalable solution for tracking inflammatory status, offering a patient-centered alternative to traditional blood-based assessments. To date, however, there is no consensus on the most suitable modality for assessment or its digitization potential. Therefore, a comprehensive evaluation of the feasibility, reliability, and patient acceptability toward noninvasive, digital inflammatory biomarkers is needed.

Our aim is to evaluate the feasibility of various noninvasive methods to assess inflammatory markers and identify the optimal modality for predicting serum CRP levels.

Inflammatory biomarkers were assessed in 20 participants (10 patients with systemic inflammation defined as a CRP level >5 mg/L and 10 controls) using 6 noninvasive samples (urine, sweat, saliva, exhaled breath, core body temperature, and stool samples) alongside serum samples. Patient preferences were retrieved via a questionnaire. Mann-Whitney U test, Spearman correlation, and all-subset regression were conducted to assess the relationships between serum and nonserum biomarkers and identify optimal predictive models for serum CRP levels.

CRP levels were significantly elevated in the inflammation group compared to controls in urine (median 4.5, IQR 4.15-10.3 vs median 0.69, IQR 0.24-1.39 μg/mmol; P=.001) and saliva (median 4910, IQR 2735-13,275 vs median 473, IQR 309-700 pg/mL; P=.001). Urine and saliva CRP levels strongly correlated with serum CRP (rsp=0.886; P<.001; rsp=0.709; P<.001). The multimodal model using urine and saliva CRP predicted serum CRP levels with 76.1% outperforming single-modality models. Patients favored urine and saliva tests over blood tests.

Urine and saliva represent promising noninvasive alternatives to traditional blood tests for assessing CRP, enabling more accessible and less invasive diagnostic and monitoring approaches.