Salivary Biomarkers, Primary Care, and Inflammatory Diseases

Introduction

Primary care physicians (PCPs) are tasked with providing comprehensive, patient-centered care. With the increasing prevalence of chronic diseases that are driven by inflammation and dysregulated stress responses, there is a growing need for tools that can detect subclinical changes before overt pathology manifests. Traditional blood-based assays, while invaluable, often require invasive procedures and may not fully capture the dynamic nature of stress and inflammation. Saliva offers a readily accessible, low-stress medium for assessing many biomarkers involved in neuroendocrine and immune regulation. The measurement of analytes such as cortisol, dehydroepiandrosterone (DHEA), α-amylase, C-reactive protein (CRP), interleukins, and immunoglobulin A (IgA) can help clinicians to evaluate patients’ allostatic load—the cumulative physiological wear and tear from chronic stress—and potentially predict inflammatory disease progression.

Incorporating salivary biomarker analysis into primary care settings may enable earlier detection of dysregulation, more precise monitoring of treatment efficacy, and an overall shift toward preventive care. This article synthesizes data from recent studies and pilot projects while discussing challenges and strategies for practical implementation. In addition, we consider how noninvasive biomarker evaluation complements existing primary care paradigms, including those related to the scope of practice for PCPs in both urban and rural communities.

The Science Behind Salivary Biomarkers

Saliva is an ultrafiltrate of blood that contains enzymes, hormones, antibodies, and various other proteins and peptides. Because many of these analytes reflect systemic physiological processes, their measurement provides a window into the body’s response to chronic stress and inflammation.

Key Salivary Biomarkers

Several biomarkers have received widespread attention for their roles in reflecting the activity of the neuroendocrine system and immune function:

• Cortisol: A hormone released by the adrenal cortex in response to stress, cortisol displays a distinct diurnal rhythm with a robust peak shortly after waking (the cortisol awakening response) and declining levels throughout the day. Healthy diurnal patterns typically feature a high morning peak with a steep decline; alterations in this pattern could indicate chronic stress or dysregulated hypothalamic–pituitary–adrenal (HPA) axis function.

• α-Amylase: As an enzyme involved in carbohydrate digestion, salivary α-amylase is also a marker of sympathetic nervous system (SNS) activity. Its rapid response to acute stress events and subsequent diurnal fluctuations make it a useful index of autonomic regulation.

• Dehydroepiandrosterone (DHEA): This steroid hormone has neuroprotective, antioxidant, and anti-inflammatory properties. Low salivary DHEA levels have been linked to negative mood states, depression, and chronic stress.

• C-Reactive Protein (CRP): Although more commonly measured in blood, CRP is an acute-phase protein measurable in saliva. Elevated CRP levels indicate systemic inflammation and have been associated with increased allostatic load.

• Proinflammatory Cytokines (Interleukin-1β and Interleukin-6): These signaling proteins modulate immune responses and inflammation. Their concentrations in saliva, although sometimes lower than in blood, are sensitive to acute changes in inflammatory status.

• Total Immunoglobulin A (IgA): IgA is a key component of the mucosal immune system. In response to stressors, total salivary IgA can increase and serves as an indicator of changes in immune readiness.

Researchers have combined several of these biomarkers into composite indices that describe overall “physiological dysregulation” or “allostatic load.” One recent pilot study constructed an Inflammation and Physiological Dysregulation Index (IPDI) from seven salivary biomarkers, dichotomized at distribution-based cutoffs. Such composite measures may enable clinicians to quantify subtle changes that occur in response to chronic social or environmental stressors.

Biomarker Table

Below is a summary table of select salivary biomarkers, their role in stress regulation, and their typical diurnal patterns:

Table 1. Overview of primary salivary biomarkers and their physiological relevance.

Salivary Biomarkers in Inflammatory Diseases

Inflammatory diseases—from asthma and atopic dermatitis to chronic sinusitis—are marked by underlying dysregulation of neuroendocrine and immune responses. The inflammatory process triggers cascades that lead not only to tissue damage but also to remodeling in affected organs. Salivary biomarkers are particularly valuable in inflammatory conditions because they offer real-time insights into these processes without subjecting the patient to invasive procedures.

For instance, in asthma and chronic respiratory conditions, inflammation driven by the release of cytokines such as IL-1β and IL-6 plays a role in airway remodeling via processes like epithelial-to-mesenchymal transition (EMT) (Zhang et al., 2025). Monitoring such cytokine levels in saliva could supplement clinical assessments and enable early intervention before irreversible structural changes occur. Similarly, in conditions such as atopic dermatitis and even drug-induced adverse responses (e.g., the paradoxical development of psoriasis during immunomodulatory therapy), fluctuations in cortisol, DHEA, and IgA may help gauge the underlying inflammatory state (Dupilumab-induced psoriasis case report, 2025).

A notable advantage of salivary biomarker sampling is its noninvasive nature. This is especially important in pediatric and geriatric populations, or in patients with intellectual or physical disabilities, where blood draws may be stressful or impractical. Moreover, saliva-based assessments facilitate repeated measurements over time, allowing for the tracking of disease progression or the effects of therapeutic interventions.

Integration of Salivary Biomarkers into Primary Care Practice

Primary care settings are often the first point of contact for patients with chronic illnesses. With the growing emphasis on preventive care and early detection of disease processes, the integration of salivary biomarker testing into routine practice represents a paradigm shift toward precision medicine. Several factors support this integration:

Advantages for Primary Care

• Noninvasive Sampling: Saliva collection avoids the discomfort and logistical challenges associated with venipuncture. This favorability improves patient compliance, especially when frequent serial measurements are needed.

• Rapid Turnaround Time: Advances in assay technologies mean that many salivary biomarkers can be quantified quickly, allowing PCPs to obtain actionable data during routine visits.

• Comprehensive Health Assessment: Primary care providers are responsible for understanding a patient’s overall health. A composite index such as the IPDI, based on multiple salivary analytes, offers insight into cumulative physiological stress and inflammatory burden. This approach can assist in guiding lifestyle modifications, therapy adjustments, and referrals to specialists when necessary.

• Scope in Diverse Settings: Data from a study on the scope of practice of Japanese primary care physicians indicate that those who embrace broad practice and pursue specialized training tend to offer more comprehensive services (Scope of Practice of Japanese Primary Care Physicians, 2025). Similarly, the use of salivary biomarker indices could become one of those broadened services that not only expand diagnostic capabilities but also reinforce the role of the PCP in preventive care.

Clinical Application and Workflow

A potential workflow in a busy primary care clinic might include the following steps:

1. Patient Selection: Identify patients at high risk for chronic inflammatory diseases or those who may benefit from a noninvasive assessment of stress and inflammation (e.g., patients with poorly controlled asthma, atopic conditions, or those with multiple comorbidities).

2. Saliva Collection: Provide patients with standardized saliva collection kits and clear instructions. Patients could collect samples at home over the course of one day, following a well-defined schedule to capture diurnal variations.

3. Laboratory Analysis: Saliva samples are then sent to a laboratory capable of high-sensitivity, enzyme-linked immunosorbent assays (ELISAs) or immunoassays for the measurement of biomarkers such as cortisol, α-amylase, DHEA, CRP, IL-1β, IL-6, and IgA.

4. Composite Index Calculation: The laboratory can compute a composite Inflammation and Physiological Dysregulation Index (IPDI) based on preset cutoffs for “unhealthy” biomarker values. For example, values above the 75th percentile (or below the 25th for markers like DHEA) may be assigned one point, and the sum of these points indicates the level of dysregulation.

5. Clinical Interpretation: PCPs review the results alongside the patient’s history and clinical findings. Elevated IPDI values may prompt further evaluations or interventions such as referral to specialists, lifestyle modifications, or adjustment of medications.

6. Follow-Up and Monitoring: Regular reassessment using salivary biomarkers can help measure response to interventions, enabling dynamic adjustments to the treatment plan.

Practice-Related Challenges

Despite these advantages, several challenges exist:

• Standardization: To be clinically useful, collection protocols and assay methodologies must be standardized across laboratories.

• Interpretation of Composite Scores: Composite indices such as IPDI require validation in large, diverse populations to confirm their predictive power and to establish normative ranges.

• Training Needs: As illustrated by studies on the scope of practice among Japanese PCPs, ongoing training and comprehensive education are imperative so that physicians can adeptly incorporate novel diagnostic tests into their practice (Scope of Practice of Japanese Primary Care Physicians, 2025).

A table summarizing practice attributes associated with broad scope and complementary noninvasive diagnostic practices is provided below.

Table 2. Selected factors influencing the scope of practice among primary care physicians and their relation to the uptake of innovative noninvasive diagnostic tests.

Emerging Trends in Noninvasive Diagnostics

The development of sensitive immunoassays and multiplex platforms has accelerated the use of saliva for diagnostic purposes. Ongoing research in the field of environmental health and stress biology has validated multiple salivary biomarkers as reliable indicators of neuroendocrine and immune functions (Pilot application of an inflammation and physiological dysregulation index based on noninvasive salivary biomarkers, 2025). Such findings open avenues for the following innovations:

• Composite Indices: By combining multiple biomarker measurements into indices like IPDI, clinicians can capture a holistic picture of physiological dysregulation. This method has the potential to streamline risk stratification and guide preventive strategies.

• Point-of-Care Devices: Future developments may yield rapid point-of-care devices that allow for on-site analysis of salivary biomarkers, reducing turnaround time and integrating seamlessly into routine clinical practice.

• Remote Monitoring: Telemedicine platforms could be integrated with home saliva collection systems to remotely monitor high-risk patients, ensuring continuous care and timely interventions without the need for frequent clinic visits.

• Personalized Therapeutic Strategies: Given that chronic inflammatory diseases often share common pathways such as dysregulated cortisol rhythms or proinflammatory cytokine production, personalized treatment regimens could be developed based on an individual’s salivary biomarker profile.

Salivary Biomarkers and Inflammatory Diseases: Case Perspectives

A number of recent case reports and pilot studies have highlighted the role of noninvasive salivary diagnostics in inflammatory diseases:

• A pilot study conducted among economically disadvantaged populations in Denver demonstrated that exposure to chronic stressors—such as loss of employment or difficulty adjusting to pandemic restrictions—was associated with higher values of a saliva-based composite index (IPDI). In this study, elevated levels of inflammatory biomarkers (e.g., CRP, IL-1β, and IgA) were linked with self-reported allergies and chronic medical conditions, underscoring the potential of salivary assays in real-world settings (Pilot application of an inflammation and physiological dysregulation index based on noninvasive salivary biomarkers, 2025).

• In another clinical context, inflammatory skin diseases such as atopic dermatitis (AD) and even paradoxical presentations like dupilumab-induced psoriasis highlight the complexity of immune regulation in inflammatory conditions. While these observations are more directly related to dermatology, they emphasize the need for accurate, accessible biomarkers to guide treatment. Although blood tests are traditionally used in these scenarios, salivary diagnostics may pave the way for monitoring inflammatory status noninvasively.

• Furthermore, in respiratory diseases such as asthma, the pathological process of airway remodeling is associated with chronic inflammation. Recent research on epithelial-mesenchymal transition (EMT) has shown that inflammatory cytokines and growth factors drive structural changes in the lung. Salivary cytokine levels may serve as surrogate markers for these processes, allowing earlier detection and intervention before irreversible changes occur (Epithelial-mesenchymal transition in asthma, 2025).

Future Perspectives and Integration into Healthcare

As the field of salivary diagnostics evolves, several potential changes in primary care practice may be anticipated:

• Enhanced Preventive Care: Routine screening using salivary biomarkers may allow early identification of individuals at risk for chronic inflammatory diseases. Such proactive interventions can reduce morbidity and healthcare costs over time.

• Training and Continuing Medical Education: To effectively incorporate these new tools, primary care physicians will require training both during residency and as part of ongoing professional development. Studies from Japan have underscored the importance of comprehensive training programs and rotational experiences in expanding the scope of practice (Scope of Practice of Japanese Primary Care Physicians, 2025).

• Research and Standardization: Large-scale validation studies are needed to establish reference ranges and confirm the predictive power of composite indices such as IPDI. Joint efforts between academic institutions, government agencies, and industry will be crucial for standardizing assays and integrating them into clinical workflows.

• Patient Engagement: Because saliva sampling is minimally invasive, patients may be more willing to engage in frequent monitoring. This can empower patients with chronic conditions by involving them in self-management strategies and providing timely feedback on treatment effectiveness.

Conclusion

Salivary biomarkers offer a promising, noninvasive approach for assessing physiological dysregulation and inflammation in primary care settings. Their ability to provide real-time, actionable insights into stress, neuroendocrine activity, and immune function makes them especially valuable for early detection and management of chronic inflammatory diseases. While challenges remain regarding assay standardization and clinical integration, emerging composite indices—such as the Inflammation and Physiological Dysregulation Index (IPDI)—demonstrate the potential of these biomarkers to serve as practical tools in everyday clinical practice. Ultimately, the incorporation of salivary diagnostics into primary care may lead to improved preventive care, personalized treatment strategies, and a more comprehensive approach to health management.

Frequently Asked Questions (FAQ)

What are salivary biomarkers?
Salivary biomarkers are measurable substances present in saliva that can provide insights into various physiological processes. They include hormones like cortisol and DHEA, enzymes such as α-amylase, acute-phase proteins like CRP, cytokines (IL-1β, IL-6), and antibodies such as IgThese markers reflect the activity of the neuroendocrine and immune systems and can be used to assess stress and inflammation.

Why is saliva an attractive medium for diagnostic tests?
Saliva collection is noninvasive, simple, and can be performed by patients themselves. It avoids the pain and discomfort of blood draws, making it especially suitable for children, older adults, and patients with needle phobiAdditionally, the ease of repeated sampling allows for monitoring diurnal patterns and long-term changes in physiological status.

How can salivary biomarkers help in managing inflammatory diseases?
Inflammatory diseases often involve chronic dysregulation of immune and stress responses. By measuring salivary biomarkers, clinicians can detect subclinical inflammation and stress-related changes early on, enabling proactive management. Composite indices such as the IPDI can summarize overall physiological dysregulation, guiding treatment adjustments and monitoring disease progression.

Are salivary biomarkers used in primary care today?
While salivary biomarker testing is not yet a routine component of primary care, research and pilot studies have demonstrated its feasibility. As assays become more standardized and validated, it is anticipated that these tests will be integrated into primary care settings to support preventive and personalized medicine.

What are the challenges with using salivary biomarkers in clinical practice?
Key challenges include the need for standardization of collection protocols and assay methods, validation of composite indices across diverse populations, and ensuring that primary care physicians are adequately trained to interpret and act upon the test results. Ongoing research is addressing these issues to enhance clinical reliability.

How do composite indices like the IPDI work?
Composite indices are calculated by summing the number of biomarkers that fall into an “unhealthy” range based on predetermined cutoffs. For instance, values exceeding the 75th percentile (or falling below the 25th percentile for certain markers) are assigned a score, and the total sum represents the overall level of physiological dysregulation or inflammation. This approach mirrors the concept of allostatic load.

References

1. Oxidative stress and reactive oxygen species in otorhinolaryngological diseases: insights from pathophysiology to targeted antioxidant therapies. (2025). Retrieved from https://pubmed.ncbi.nlm.nih.gov/11792148/

2. Dupilumab-induced psoriasis in a patient with atopic dermatitis successfully treated with Upadacitinib: A case report. (2025). Retrieved from https://pubmed.ncbi.nlm.nih.gov/11792007/

3. Pilot application of an inflammation and physiological dysregulation index based on noninvasive salivary biomarkers. (2025). Retrieved from https://doi.org/10.1186/s13104-024-07056-4

4. Scope of practice of Japanese primary care physicians and its associated factors: A cross-sectional study. (2025). Retrieved from https://pubmed.ncbi.nlm.nih.gov/11795410/

5. Epithelial-mesenchymal transition in asthma: Its role and underlying regulatory mechanisms. (2025). Retrieved from https://doi.org/10.3389/fimmu.2025.1519998