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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 6  |  Issue : 1  |  Page : 1-9

Review of using saliva for COVID-19 testing


Department of Oral Biology, Faculty of Dentistry, Universitas Indonesia, Indonesia

Date of Submission18-Sep-2021
Date of Decision29-Oct-2021
Date of Acceptance07-Dec-2021
Date of Web Publication21-Feb-2022

Correspondence Address:
Jessica Endriyana
Department of Oral Biology, Faculty of Dentistry, Universitas Indonesia,
Indonesia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/SDJ.SDJ_100_21

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  Abstract 

Saliva is a hypotonic solution of gingival, salivary acini, and exudate sulcus fluid from the oral mucosa. Saliva contains proteins, DNA, RNA, micro-RNA, and metabolites; hence, it can be detected early in viruses, bacteria, as well as systemic diseases. It has been reported to show an ideal role in the isolation of proteins, peptides, and batches of viruses by molecular assays. Previously, saliva has been used as a biomarker to help detect oral cancer, caries, periodontal disease, diabetes, breast cancer, and lung cancer. Investigate research on saliva development as well as the utilized laboratory techniques serving as diagnostic methods for coronavirus disease-2019 (COVID-19) are the main goals in this study, and the author utilizes the standards set out in the Preferred Reporting Item for Systematic Review and Meta-Analyses (PRISMA) guidelines. A systemic search was performed by one independent reviewer based on PubMed and Google Scholar in July 2021 using the following search terms: “Saliva” OR “saliva assay” AND “diagnosis” AND “COVID-19” OR “SARS-CoV-2” in PubMed. Notably, saliva contains a collection of analytes that show potential to be biomarkers for clinical and translational applications; hence, saliva can be used as an effective biofluid in clinical diagnostics. The passive droll saliva technique may be more homogenous than spitting, and it also can prevent the impact of the inhibitory substance. Saliva specimens are beneficial to the safety of healthcare professionals; these specimens can be a substantial source of virus in saliva for dental professionals, especially in the primary stages of illness, and cotton and calcium alginate swabs may contain compounds that interfere with polymerase chain reaction (PCR) testing and render some viruses inactive. Based on some of the above statements, the collection of only saliva can be used as an alternative specimen during the early stages of symptoms for the diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Keywords: ACE2, RT-qPCR, Saliva, SARS-CoV-2


How to cite this article:
Endriyana J, Bachtiar EW. Review of using saliva for COVID-19 testing. Sci Dent J 2022;6:1-9

How to cite this URL:
Endriyana J, Bachtiar EW. Review of using saliva for COVID-19 testing. Sci Dent J [serial online] 2022 [cited 2022 Oct 2];6:1-9. Available from: https://www.scidentj.com/text.asp?2022/6/1/1/337999




  Background Top


Saliva contains 99% water and 1% organic molecules such as mucin, mucopolysaccharide, and lysozyme, as well as inorganic content such as Na+, Ca2+, K+, Cl, and cyanate ion. Salivary acini, gingival sulcus fluid, and oral mucosa exudate are mixed in a hypotonic solution. Saliva shows several functions, for example, playing a role in cleaning the oral cavity by rinsing food remnants or bacteria to refresh the breath and catalyzing the hydrolysis of flour to maltose in saliva in the presence of salivary amylase. In addition, saliva also can be bactericidal due to the lysozyme and thiocyanate ions that make saliva a nonspecific part of the immune system. Saliva is a secretion that renders healthy conditions for diseases such as polio, rabies, and the human deficiency virus (HIV) by excreting or spreading KI, Pb, and Hg.[1]

Coronavirus disease-2019 (COVID-19) is identified as the latest disease that causes severe acute respiratory syndrome (SARS) as well as some symptoms such as fever, sore throat, heavy breathing, joint pain, dizziness, rhinorrhea, abdominal pain, diarrhea, and nausea, and even vomiting.[2],[3] This family of viruses consists of four viral genera: alpha-, beta-, gamma-, and delta-coronavirus.[4] COVID-19 can affect various biological systems in humans and vertebrates, including the respiratory system, central nervous system, hepatic system, and gastrointestinal system.[5] Noninvasive sample collection methods are required to detect COVID-19 as large-scale tests are required to investigate the development and transmission methods of different populations.[6]

Saliva contains DNA, RNA, micro-RNA, proteins, and metabolites that can be used to detect viruses, bacteria, and systemic diseases in the early stages. Saliva has been reported to show an ideal role in the isolation of proteins, peptides, and groups of viruses by molecular tests.[7],[8] Saliva has been used as a biomarker that helps in the detection of oral cancer, caries, diabetes, periodontal disease, and breast and lung cancers. Previous studies have reported that from the saliva samples of patients diagnosed with SARS-associated coronavirus, RNA can be isolated and processed by a quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) assay to estimate the level of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).[9],[10]

Saliva acts as a biological fluid that can be used as an alternative to diagnose viral infections due to its facile and rapid collection without the use of special tools and reduced discomfort, which is crucial when testing pediatric patients.[6] Saliva development, laboratory techniques for the diagnosis of COVID-19, and the diagnosis method of saliva are the goals of this study.


  Materials and Methods Top


For this study, the author used the list of requirements in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Current literature regarding saliva as a specimen for the diagnosis of COVID-19 was reviewed on the basis of the heterogeneity of the available data. The primary question was formulated as follows: How can saliva be a specimen for the diagnosis of COVID-19 and how to analyze it in laboratories? A systemic search was performed by one independent reviewer based on PubMed and Google Scholar in July 2021 using the following search terms with the Boolean search: “Saliva” OR “saliva assay” AND “diagnosis” AND “COVID-19” OR “SARS-CoV-2” in PubMed. According to the results, a manual search was conducted using the references from the included studies [Table 1]. The search results were screened and reviewed for eligibility based on the requirements that had been established previously, that is, only full-text articles in English published after December 2019. The inclusion criteria of the study included recruiting patients who are suffering from COVID-19 that using saliva as a specimen for the diagnosis of COVID-19. The exclusion criteria of the study included animal studies, incomplete publications, literature review, and summaries of reports from scientific meetings.
Table 1: Summary of papers reviewed in this paper

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  COVID-19 Top


Novel COVID-19 outbreak occurred in December 2019 in Wuhan, China. Coronavirus is a family of Coronaviradae under the order of Nidovirales, which can be divided into four main groups: α, β, γ, δ. This virus can cause fatal diseases such as pneumonia, as well as enteric, hepatic, and neurological diseases, with symptoms of fever, dizziness, dry cough, and myalgia accompanied by rhinobyon, rhinorrhea, pharyngalgia, diarrhea, and nausea, even vomiting in some patients.[2],[16]

Protein S (spike) is one of the proteins in this virus, which is a key component in determining host–pathogen interaction. It is a medium which receptors attach and membranes fuse, then releasing RNA viruses into the cytoplasm for replication. S protein can bind to ACE-2 receptors. These receptors are expressed in various organs, viz. the liver, endothelium, liver, kidneys, testicles, lungs, and other tissues.[17]

Once SARS-CoV-2 enters the human body, it interacts with the ACE-2 receptors and releases RNA into the epithelial cells, and replication and infection occur in adjacent cells, which spread to the nasal route to the alveolar region of the lungs.[18] In SARS-CoV-2, vascular tissues are damaged due to increased permeability and leakage, leading to pulmonary edema, intravascular activation of coagulation, and progressive damage to the lungs.[19] Infection worsens in patients with comorbid diseases (e.g., diabetes, hypertension, and pulmonary diseases) and age-related and immune responses. Cytokine storms occur in the body via secretions of vascular endothelial growth factor (VEGF), IL-8, monocyte chemoattractant protein–1 (MCP-1) and reduces the expression of E-cadherin in epithelial cells, which is related to permeability and vascular leakage. E-cadherin shows the potential to cause hypotension and pulmonary dysfunction in acute respiratory distress syndrome (ARDS).[20] Cytokine storms involve the excess release of cytokines (viz. TNF-α, IFN-γ, IL-10, 6, 2, and 1). Excess expression of cytokines causes damage to the lungs, leading to the death of the patient.[16]


  Role of Saliva in the Diagnosis of SARS-CoV-2 Virus Top


Currently, RT-PCR is the gold standard test for identifying SARS-CoV-2 for the diagnosis of COVID-19.[21],[22],[23] Clinical specimens might be collected from the upper respiratory tract using nasopharyngeal aspirates, swabs, washes, or oropharyngeal swabs, or from the lower respiratory tract using bronchoalveolar lavage, sputum, or tracheal aspirates. Saliva shows potential as a diagnostic tool as well as for disease monitoring due to the presence of biomarkers [Figure 1]. The RNA-dependent RNA polymerase (RdRP) gene, envelop protein (E) gene, or nucleocapsid (N) gene is one of the specific regions used as PCR targets.[22],[24],[25] A positive RT-PCR positive test confirms the presence of the virus, and a negative result may not necessarily rule out SARS-CoV-2 infection. There is a potential false-negative result that could be caused by an inadequate technique, low viral load, virus genome mutation, improper sampling region, and timings.[22]
Figure 1: PRISMA (Preferred Reporting Items for Systemic Review and Meta-Analyses) diagram for a systemic review process

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Saliva is a biological fluid that can be used as an alternative for the diagnosis of viral infections because it can be collected easily and rapidly without special tools and reduces discomfort, which is key when conducting tests on pediatric patients.[6] This fluid is secreted in the salivary glands, and it shows a considerable function. Some of the functions include cleansing and protection, as well as antibacterial and digestive functions. Saliva contains urea, ammonia, glucose, cholesterol, fatty acids, amylase, neutral lipids, glycolipids, amino acids, lysozyme, steroid hormones, triglycerides, mucin, lectin, glycoprotein, peroxidase, and lactoferrin; hence, saliva has a complex composition.[1] Interestingly, saliva also contains analytes, such as mRNA, DNA, proteins, and some metabolites that can be prospective biomarkers in scientific and clinical research for use as effective biofluids in clinical diagnostics. As a specimen, saliva is a good specimen as it is safe, does not clot, affordable, and also non-invasive.[27],[28] Salivaomics is the science of the integration of saliva and its associated elements, functions, and techniques. Salivaomics comprises genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiomics. The three main groups or omics include DNA circulation (genomics), RNA (transcriptomics), and protein (proteomics).[23]

Over the last few decades, saliva has been utilized more often to assess human health.[29] As both fluids include cellular and molecular linkages, some earlier studies have suggested that blood and saliva are related directly.[30] Saliva contains DNA, RNA, microRNA, proteins, and metabolites for the early detection in viruses, bacteria, and systemic diseases, and it has been reported to play an ideal role in the isolation of proteins, peptides, and groups of viruses via molecular testing.[7],[8] Saliva is a mix of salivary gland secretions, gingival crevicular fluid, desquamated oral epithelia, and various bacteria. A significant variety of proteins, including immunoglobulins, especially secretory IgA, mucins, enzymes, metabolites, hormones, and electrolytes are also present in saliva [Figure 2].[6],[29] This formula permits the identification of pathogens in saliva and quantification of biomarkers, which can provide information about inflammatory, immunological, metabolic, and endocrine conditions of individuals.[31] Currently, nasal and oropharyngeal swabs are the two diagnostic tests most often utilized by clinicians, and COVID-19 has been isolated from a sample of the upper respiratory tract.[10],[29],[32] In addition, the US Food and Drug Administration has authorized this test to determine RNA in saliva samples.[33]
Figure 2: Saliva biomarkers with the potential to be a diagnostic and a disease monitoring tool for COVID-19[26]
ACE2 = angiotensin-converting enzyme 2, ADA = adenosine deaminase, IgG = immunoglobulin G, IgM = immunoglobulin M, RNA = ribonucleic acid, sIgA = secretory immunoglobulin A


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Antibodies are directly produced when the body fights SARS-CoV-2 in saliva, which can be used as specimens for antibody detection. One advantage of saliva compared to blood is the presence of IgA antibodies because these antibodies are secreted by the mucosa, and IgM and IgG antibodies higher in the blood concentration.[34] In 28 studies, SARS-CoV-2 RNA has been found in the saliva samples of patients, which have been detected by various techniques, including unstimulated saliva, cough saliva, posterior oropharyngeal saliva, and swab saliva. Differences in the saliva flow rate can affect the amount of virus collected from saliva, but the prevalence of the severity disease and patients that experiencing cough symptoms in observation, viral RNA detected in their saliva. Viral RNA is identified in more than half of asymptomatic individuals and before symptoms appear. A previous study has reported that apart from throat and nasopharyngeal swabs, saliva obtained in the early stages of symptoms is reliable and can be utilized to identify and diagnose COVID-19.[35] At about 20 days or more, viral RNA has been reportedly found in a third of the patient’s posterior oropharyngeal (deep throat) saliva samples.[36]

In the minor and major salivary glands, viral particles are released into the saliva duct. A previous study has reported that in epithelial cells of the oral cavity, angiotensin-converting enzyme expression 2 (ACE2), which is the primary receptor involved in SARS-CoV-2 infection in cells, is detected.[26] Compared with the expression of ACE2 in the lungs, that in the minor salivary glands is higher. Before the occurrence of lesions in the lungs, saliva contains SARS-CoV-2 RNA, which can be utilized as a marker in asymptomatic infections. Saliva samples can be used to culture the virus. Based on observations of specific antibodies, SARS-CoV-2 can be used to detect seropositive saliva. Generally, antibodies detected in saliva, IgA is discharged locally by plasma cells in salivary glands and IgG derived from cervical gingiva. In fact, IgA identified in saliva has not been linked with IgA serum in three individuals who had high levels of IgA serum but did not have IgA in saliva.[37]

SARS-CoV-2 binds to ACE2 receptors in the epithelium of the salivary glands, followed by replication, fusion, and cell lysis to trigger symptoms such as inflammation, pain, and discomfort in the major salivary glands. After the cytolytic activity of SARS-CoV-2, acinar cells develop for lysis that causes the release of amylase in saliva in the peripheral bloodstream. Cytokine secretion facilitates inflammatory reactions that destroy tissues in the salivary glands and continues as a form of immunopathological process; as a result, sialadenitis occurs in patients with SARS-CoV-2.[38] Based on some of the above statements, saliva collected by itself in the early stages of symptoms can be confirmed to be used as an alternative specimen for the diagnosis of SARS-CoV-2.[35],[39]

According to Azzi et al.,[40] high sensitivity is produced from saliva samples. Saliva samples can be collected during the initial phase of the onset of symptoms to increase sensitivity.[41] Sakanashi et al.[42] have reported that the sensitivity of saliva specimens by the passive drool method is greater than that of the samples obtained by nasopharyngeal swabs, which has been proposed to diagnose patients with COVID-19, and saliva may be utilized as the first step. In patients with wet cough, sputum can be used as a specimen for a diagnostic test of COVID-19, but sputum induction is not suggested.[22],[23] A previous study has revealed that replicating SARS-CoV-2 in cells is obtained by throat wash from SARS patients, which is a beneficial feature of sputum and saliva.[22]


  Screening Principle of COVID-19 by Saliva-based Diagnosis Top


The TaqPath SARS-CoV Assay for the qualitative detection of RNA from virus is a saliva-based COVID-19 testing kit that has been authorized previously. Nucleic acid extraction buffers and collection methods have been changed. Saliva specimen can be transported and kept at room temperature, but these samples must be processed within 48 h after collection.[22]

Ideally, the assays employed should be sufficiently sensitive to identify low levels of analytes present in saliva; some procedures to process diagnosis from saliva are shown in [Figure 3]. Extremely sensitive immunoassays, such as those based on time-resolved fluorescence or similar technologies, should be employed to quantify immunoglobulins and acute-phase proteins.[33] By using quantitative reverse transcription-PCR (RT-qPCR), it is critical to select an appropriate housekeeping gene and determine if a cell-free or cell-associated virus is found in saliva. Overall, the test should be thoroughly validated to minimize analytical errors caused by technological constraints in the assay.[33]
Figure 3: COVID-19 salivary diagnosis procedures[40]
The drooling technique is employed to collect saliva without expectoration or coughing. (a) Real-time reverse transcription polymerase chain reaction (rRT-PCR): This assay is employed for the diagnosis of COVID-19, and it is typically done for respiratory specimens, although it may also be conducted on saliva. (b) Direct rRT-PCR provides more rapid diagnosis. (c) Colorimetric reverse transcription loop-mediated isothermal amplification (RT-LAMP) permits the rapid detection of viral DNA. (d) The enzyme-linked immunosorbent assay (ELISA) or lateral flow assay can employed to detect antibodies in saliva. (e) The rapid salivary test is an antigen test based on the lateral flow assay that shows immense potential for mass screening


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Güçlü et al.[15] have shown that saliva samples can be used instead of oropharyngeal swab samples for the diagnosis of COVID-19 as the kappa value (0.744) was in substantial agreement and quite parallel to the results obtained for the oro-pharyngeal sample. From saliva we can get more samples rather than samples that collected from oropharyngeal swab. Saliva may have a lower viral load than the oropharynx and nasopharynx, and salivary enzymes might prevent the replication of the virus in the mouth.[15] Notably, a similar result has been reported by To et al.[13] and Pasomsub et al.,[14] and RT-PCR has been reported to show good sensitivity and performance similar to those of the existing nasopharyngeal and throat swab standards. The comparison of the nasal swab to the bronchoalveolar lavage fluid revealed that the positive test rate of the nasal swab (63%) is less than that of the bronchoalveolar lavage fluid (93%). SARS-CoV-2 has been detected in the posterior oropharyngeal saliva samples, with a high viral load at the time of illness onset.[13],[14] Samples were collected early in the morning after coughing up and cleaning the throat, according to their routine. Individuals generated this sample without the necessity for coughing.[14]

Not only serum antibodies but also locally generated IgA class antibodies may be obtained from saliva. Aita et al.[11] have reported that 67% of patients tested positive for salivary IgA. This state evaluates IgA class antibodies in saliva induced by the domain of the spike protein S1, which is implicated by ACE2 receptor binding and positive IgA class more frequently in patients with pneumonia. Unexpectedly, salivary samples from two individuals have been reported to be positive, although they showed negative respiratory swabs on the same day.[12]

Hung et al.[22] have reported that utilizing spit saliva is conceivable due to numerous targets, such as desquamative oropharyngeal mucous epithelial cells and respiratory secretions containing shedding viruses. In contrast, Sakanashi et al.[42] have reported that the passive droll saliva method may be more homogeneous than the spitting method and avoid inhibitory substances. Sputum should be collected before brushing teeth and breakfast.[12]


  Advantages of Saliva-based Diagnosis for Screening of COVID-19 Top


According to FDA guidelines, an accurate test must show high sensitivity (above 90%) and specificity (95%). Sensitivity refers to a test’s capacity to detect accurate positive results while minimizing the risk of false negatives. Specificity refers to a test’s capacity to read negative samples to reduce false-positive results.[43] Pasomsub et al.[14] have used saliva as a specimen for the diagnosis of COVID-19, with a sensitivity of 84.2% and a specificity of 98.9%. The reference standard is a nasopharyngeal swab and throat-swab RT-PCR due to the 9.5% prevalence of COVID-19 diagnosed by this method. The chance of a positive test result being genuinely positive (PPV/real positive) is 98% based on combined findings, whereas the probability of a negative test result being an actual negative result (NPV/false positive) is 86% based on the combined result.[44]

Use of saliva for the diagnosis of COVID-19 renders several advantages. The key benefit is the safety of healthcare professionals. During sampling, healthcare workers are exposed to secretions from the upper respiratory tract. The patient might sneeze or cough during the appropriate swabbing techniques because the nasopharynx and oropharynx are stimulated. Patient saliva samples are up to significantly minimize the likelihood of COVID-19 infection because this non-invasive saliva collection procedure may produce fewer aerosols and reduce the possibility of infections in clinic.[13],[14],[15]

The second saliva for the diagnosis of COVID-19 is crucial for dental professionals. Previous studies have reported that in rhesus macaques, salivary glands of the epithelial cells can be infected rapidly with SARS-CoV after infection and can be a significant source of the virus in saliva, especially in early infection.[13],[45] Third, calcium alginate and cotton swabs as well as wooden shafts may include chemicals that hinder PCR testing and inactivate certain viruses. In addition, swabs should not be used for the diagnosis of COVID-19. Standard oro-pharyngeal samples should be collected using polyester-flocked swabs or Dacron with plastic shafts.[15],[46]


  Conclusion Top


Saliva is a biofluid for diagnosis that can be collect easily, and it is not invasive and contains high-quality DNA with a sensitivity of 84.2% and a specificity of 98.9%. However, which collection method can provide the best result is not clear. In patients with SARS-CoV-2, there is a representative level of antibodies and immunoglobulin in saliva because the salivary glands also have ACE2 receptors that can bind to coronavirus. Saliva is beneficial for the initial diagnosis of SARS-CoV-2. On the contrary, saliva is an easy-to-obtain and a non-invasive sample. Hence, saliva can be utilized to diagnose SARS-CoV-2 infection, and the best method to process saliva is RT-PCR, which shows good sensitivity and performance. Further research needs to be conducted to search for an accurate method for collecting and manipulating saliva for the next step of the assay.

Financial support and sponsorship

This study was supported by: PDUPT gran from KEMENTRISTEK/BRIN 2021 No. NKB-144/UN2.RST/HKP.05.00/2021.

Conflicts of interest

There are no conflicts of interest.



 
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COVID-19
Role of Saliva i...
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