Saliva and other oral fluids (e.g., gingival crevicular fluid, combined secretions of minor salivary glands) support the health of soft and hard tissues in the oral cavity.1-7 The protective functions of saliva include maintaining a neutral oral pH, cleaning and remineralizing teeth, facilitating swallowing and digestion, and protecting oral tissue against desiccation and invasion by microorganisms.2, 7 Adequate saliva is essential for maintaining oral health, and reduced salivary secretion (i.e., hyposalivation) or xerostomia (i.e., dry mouth) can contribute to oral problems such as dental caries, mucositis, fungal infections, and periodontal diseases.8-11
Potential advantages of using saliva for disease diagnostics include ease of access, noninvasive sample collection, increased acceptance by patients, and reduced risks of infectious disease transmission.12-14 Readily accessible fluids include whole saliva, secretions from specific glands, mucosal transudate or gingival crevicular fluid.13 However, the various techniques and durations of collecting saliva and other oral fluids (e.g., spitting, drooling, dribbling, and collection with or without coughing) can affect the precision and determination of biomarkers of interest.
Saliva is a heterogeneous biofluid that can also include epithelial cells and leukocytes.15 Composition of saliva is variable as specimens will be affected by the time of day they are collected, the location where oral fluid is collected, and the sample storage conditions, including the time to analysis.16-19 To date, there are no established uniform criteria for the collection of human saliva.2
There continues to be interest in oral fluid as a non-invasive diagnostic medium for rapid, point-of-care testing.12-14 Interest in saliva tests expanded significantly with emergence of the coronavirus disease 2019 (COVID-19) pandemic, which fueled development of rapid diagnostic tests using alternative sample specimens, such as saliva, for improved detection of individuals with SARS CoV-2 infection.20 During early stages of the pandemic, initial studies showed detectable viral loads of SARS CoV-2 in saliva21-24 and in individuals showing no symptoms of COVID-19 (asymptomatic).25 Subsequently, studies that evaluated saliva specimens using polymerase chain reaction (PCR) testing for COVID-19 showed that such tests performed relatively well.26-30 One meta-analysis31 reported 91% sensitivity for saliva tests of previously confirmed COVID-19 patients compared with 98% sensitivity for nasopharyngeal swabs (a commonly used specimen type for COVID-19 diagnosis).
Sampling oral fluids, instead of blood, provides an accessible medium for detecting a range of candidate biomarkers, such as proteins, electrolytes, hormones, antibodies and DNA/RNA, as well as other substances such as therapeutic or recreational drugs.1 While oral fluid assessment has been suggested to be useful in screening for or diagnosing oral or systemic diseases, monitoring viral or fungal infections, detecting drug exposure, and evaluating endocrine disorders and cancer risk, evidence of utility for most of these purposes is limited, and further clinical validation research is required.
Currently, oral fluid testing by clinical laboratories is regulated under the Clinical Laboratory Improvement Amendments of 1988 (CLIA). The federal CLIA regulatory standards apply to clinical laboratories and any facility examining human specimens for diagnosis, prevention, treatment of a disease or for assessment of health. CLIA regulations are designed to help ensure test results are accurate and reliable.32 However, the CLIA program does not address the clinical validity of any test—that is, the accuracy with which the test identifies, measures, or predicts the presence or absence of a clinical condition or predisposition in a patient.32
To make a claim of clinical validity, a test must be submitted to the U.S. Food and Drug Administration (FDA), which regulates tests under the Federal Food Drug, and Cosmetic Act. The clinical validity of a test is evaluated by FDA in its premarket clearance and approval processes.32
As of mid-2021, several tests have received FDA emergency use authorization for detection of SARS CoV-2 infection using saliva collected from individuals with COVID-19 symptoms. Some of the tests allow saliva specimens to be self-collected at home (and/or in special collection devices), or to be collected in a health care setting (when determined to be appropriate by a health care provider).33
In addition, there are two direct-to-consumer (DTC), oral fluid tests that have received marketing authorization from FDA, which test for gene alleles associated with increased cancer risk. The FDA includes more information on DTC genomic tests at the following website: https://www.fda.gov/medical-devices/in-vitro-diagnostics/direct-consumer-tests.