The Open Dentistry Journal




ISSN: 1874-2106 ― Volume 14, 2020
EDITORIAL

SARS-CoV-2: A Promising Path in Salivary Diagnosis



Larissa Leci Fernandes1, Leandro Borges2, Valeria Bordallo Pacheco1, Alessandra Bernardes1, Rafaela Rosa Ribeiro3, Manuel Jimenez4, Debora Heller1, 3, *
1 Post Graduate Program in Dentistry, Universidade Cruzeiro do Sul, São Paulo, Brazil
2 Post Graduate Program in Health Sciences, Universidade Cruzeiro do Sul, São Paulo, Brazil.
3 Experimental Research, Instituto Israelita de Ensino e Pesquisa, Hospital Israelita Albert Einstein, São Paulo, Brazil.
4 Departamento de Didáctica de la Educación Física y Salud, Universidad Internacional de La Rioja, Logroño, Spain


Article Information


Identifiers and Pagination:

Year: 2020
Volume: 14
First Page: 343
Last Page: 344
Publisher Id: TODENTJ-14-343
DOI: 10.2174/1874210602014010343

Article History:

Electronic publication date: 21/07/2020
Collection year: 2020

© 2020 Fernandes et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Post Graduate Program in Dentistry, Universidade Cruzeiro do Sul, São Paulo, Brazil; E-mail: debora_heller@hotmail.com





Since March 2020, the World Health Organization (WHO) established the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; previously provisionally named 2019 novel coronavirus or 2019-nCoV) disease (COVID-19) as a pandemic, with nearly 239.604 deaths and with a range of confirmed diagnosis that presently exceeded 3.435.894 people worldwide [1WHO. Coronavirus Disease 2019. (COVID-19) Situation Report-105 https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports (accessed May 4, 2020). ]. Coronavirus is a large family of respiratory viruses ranging from relatively mild (similar to the common cold) to severe (bronchitis, pneumonia, and renal involvement) respiratory syndromes [2Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382(8): 727-33.
[http://dx.doi.org/10.1056/NEJMoa2001017] [PMID: 31978945]
].

Accurate and rapid diagnosis of COVID-19 is essential to manage the outbreak in this pandemic. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of respiratory tract swabs is currently recognized as the gold standard for the diagnosis of SARS-CoV-2 infection [3Wang Y, Kang H, Liu X, Tong Z. Combination of RT-qPCR testing and clinical features for diagnosis of COVID-19 facilitates management of SARS-CoV-2 outbreak. J Med Virol 2020; 92(6): 538-9.
[http://dx.doi.org/10.1002/jmv.25721] [PMID: 32096564]
]. However, studies demonstrated issues regarding the persistence of the virus in the body after the pharyngeal swab conversion or false-negative outcomes [4Li Z, Yi Y, Luo X, et al. Development and clinical application of a rapid IgM-IgG combined antibody test for SARS-CoV-2 infection diagnosis. J Med Virol 2020.
[http://dx.doi.org/10.1002/jmv.25727] [PMID: 32104917]
]. Moreover, oropharyngeal nasopharyngeal tests cause discomfort to patients and require trained professionals to be carried out and close contact between health professionals and patients, which represents a high risk of transmission of the virus to professionals [5To KKW, Yip CCY, Lai CYW, et al. Saliva as a diagnostic specimen for testing respiratory virus by a point-of-care molecular assay: A diagnostic validity study. Clin Microbiol Infect 2019; 25(3): 372-8.
[http://dx.doi.org/10.1016/j.cmi.2018.06.009] [PMID: 29906597]
, 6To KK-W, Tsang OT-Y, Chik-Yan Yip C, et al. Consistent detection of 2019 novel Coronavirus in saliva. Clin Infect Dis 2020. Feb 12; ciaa149
[PMID: 32047895]
]. Therefore, the purpose of salivary fluids in the detection of SARS-CoV-2 is a subject that has gained attention from current literature [6To KK-W, Tsang OT-Y, Chik-Yan Yip C, et al. Consistent detection of 2019 novel Coronavirus in saliva. Clin Infect Dis 2020. Feb 12; ciaa149
[PMID: 32047895]
].

Approximately 99% of saliva is water and 1% includes a wide group of elements for the function of taste, digesting, the balance of mineralization, and anti-microorganisms [7Dawes C, Wong DTW. Role of saliva and salivary diagnostics in the advancement of oral health. J Dent Res 2019; 98(2): 133-41.
[http://dx.doi.org/10.1177/0022034518816961] [PMID: 30782091]
]. This oral fluid is one of the simplest ways to collect body fluids and represents an important source for the analysis of biomarkers with multiple functions. The benefits of saliva over conventional fluids are that collection is relatively easy to perform and almost noninvasive [7Dawes C, Wong DTW. Role of saliva and salivary diagnostics in the advancement of oral health. J Dent Res 2019; 98(2): 133-41.
[http://dx.doi.org/10.1177/0022034518816961] [PMID: 30782091]
]. Additionally, saliva specimen collection has the advantage of being more secure for healthcare workers during the diagnosis of coronavirus [8Xu R, Cui B, Duan X, Zhang P, Zhou X, Yuan Q. Saliva: potential diagnostic value and transmission of 2019-nCoV. Int J Oral Sci 2020; 12(1): 11.
[http://dx.doi.org/10.1038/s41368-020-0080-z] [PMID: 32300101]
].

In patients with COVID-19, studies suggest saliva as a promising sample type for diagnosis, monitoring, and infection control [8Xu R, Cui B, Duan X, Zhang P, Zhou X, Yuan Q. Saliva: potential diagnostic value and transmission of 2019-nCoV. Int J Oral Sci 2020; 12(1): 11.
[http://dx.doi.org/10.1038/s41368-020-0080-z] [PMID: 32300101]
, 9Azzi L, Carcano G, Gianfagna F, et al. Saliva is a reliable tool to detect SARS-CoV-2. J Infect 2020.S0163-4453(20)30213-9
[http://dx.doi.org/10.1016/j.jinf.2020.04.005] [PMID: 32298676]
]. This oral fluid has a great concordance rate higher than 90% with nasopharyngeal specimens in the identification of respiratory viruses, including coronaviruses [5To KKW, Yip CCY, Lai CYW, et al. Saliva as a diagnostic specimen for testing respiratory virus by a point-of-care molecular assay: A diagnostic validity study. Clin Microbiol Infect 2019; 25(3): 372-8.
[http://dx.doi.org/10.1016/j.cmi.2018.06.009] [PMID: 29906597]
]. Moreover, in two studies on coughed out saliva, a total of 91.67% (11 cases out of 12) [6To KK-W, Tsang OT-Y, Chik-Yan Yip C, et al. Consistent detection of 2019 novel Coronavirus in saliva. Clin Infect Dis 2020. Feb 12; ciaa149
[PMID: 32047895]
] and 86.96% (20 cases out of 23) [10To KK-W, Tsang OT-Y, Leung W-S, et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis 2020; 20(5): 565-74.
[http://dx.doi.org/10.1016/S1473-3099(20)30196-1] [PMID: 32213337]
] COVID-19 patients were SARS-CoV-2 RNA affirmative in saliva, respectively. While regarding the use of saliva directly from the salivary gland duct, Chen et al. showed that four cases out of 13 COVID-19 patients were SARS-CoV-2 RNA affirmative in saliva [11Chen L, Zhao J, Peng J, et al. Detection of 2019-NCoV in Saliva and Characterization of Oral Symptoms in COVID-19 Patients 2020. Available from https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3557140].

Detection of Immunoglobulin M (IgM) antibodies tends to suggest recent exposure to infection, whereas the identification of IgG antibodies suggests virus exposure in the past [12Racine R, Winslow GM. IgM in microbial infections: taken for granted? Immunol Lett 2009; 125(2): 79-85.
[http://dx.doi.org/10.1016/j.imlet.2009.06.003] [PMID: 19539648]
]. The rapid recognition of both IgG and IgM antibodies could give additional immunological information for physicians in the diagnosis along with others assays and to begin COVID-19 patient treatment. In this sense, posterior oropharyngeal saliva specimens could be useful in assays involving Enzyme-linked Immunosorbent Assay (EIA) of IgG and IgM against internal viral nucleoprotein [10To KK-W, Tsang OT-Y, Leung W-S, et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis 2020; 20(5): 565-74.
[http://dx.doi.org/10.1016/S1473-3099(20)30196-1] [PMID: 32213337]
]. It is important to mention that mucosal immune responses seem to be characterized first by the production of secretory IgA, while systemic antibodies occur posteriorly. For instance, Guo et al. demonstrated that 92.7% of the participants tested presented with anti-SARS-CoV-2 nuclear capsid IgA, whilst only 85.4% obtained IgM and 77.9% IgG [13Guo L, Ren L, Yang S, et al. Profiling early humoral response to diagnose novel coronavirus disease (COVID-19). Clin Infect Dis 2020. Mar 21;ciaa310.
[PMID: 32198501]
]. Therefore, it is suggested that IgA in saliva could be a promising path to salivary research in the diagnosis of COVID-19 and that the monitoring of anti-viral secretory IgA (associated with specific T cells and immune complexes) [14Béné MC, de Carvalho M, Eveillard M, et al. Good IgA Bad IgG in SARS-CoV-2 Infection? Clin Infect Dis 2020. Apr 11;ciaa426
[PMID: 32280952]
] could supply mechanistic insights in the pathophysiology of SARS-CoV-2 infection. However, further saliva studies on its role in immunopathology or antiviral therapy and the possible cross-reactivity with other coronaviruses and flu viruses are warranted.

Since there is the expression of angiotensin-converting enzyme II (ACE2) receptor on the mucosa of the oral cavity [15Xu H, Zhong L, Deng J, et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci 2020; 12(1): 8.
[http://dx.doi.org/10.1038/s41368-020-0074-x] [PMID: 32094336]
], theoretically, ACE2-positive cells in salivary glands could be the target cells of SARS-CoV-2 and produce saliva containing this virus [11Chen L, Zhao J, Peng J, et al. Detection of 2019-NCoV in Saliva and Characterization of Oral Symptoms in COVID-19 Patients 2020. Available from https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3557140]. Another speculation involves the fact that the tongue has an increased risk of coronavirus infection and that furin is greatly expressed in lung tissue, probably inducing a gain-of-function to the infectivity of COVID-19 [16Mallapaty S. Why Does the Coronavirus Spread so Easily between People? Nature 2020 Mar; 579(7798): 183.
[http://dx.doi.org/10.1038/d41586-020-00660-x] [PMID: 32157230]
]. Nevertheless, while it indicates that cells expressing furin have reduced restriction for virus entry speculatively, it should still be prudent whether the furin-like cleavage site implies a significant function in COVID-19 infection [16Mallapaty S. Why Does the Coronavirus Spread so Easily between People? Nature 2020 Mar; 579(7798): 183.
[http://dx.doi.org/10.1038/d41586-020-00660-x] [PMID: 32157230]
]. Moreover, the molecular mechanism of SARS-CoV-2 infection is not completely known and we should not overstate the present virus-invade-host hypothesis.

The diagnostic importance of saliva specimens for the COVID-19 assessment is auspicious, and much desired in a time that many populations require extensive testing in order to return to work and their daily routines. More research is needed to assess the potential diagnostic of SARS-CoV-2 in saliva, studies with a large number of participants, possibly including saliva biobanks and preferably comparing the different stages of SARS-CoV-2 infection and during the infection (viral charge) and after the infection (immune signature of the patient). In this way, our group leads an international salivary research initiative in order to establish a universal collection, processing, and storage protocols for saliva of COVID-19 patients. It is also important to emphasize that a complete diagnosis should be reinforced with full information regarding epidemiological history, symptoms, and analysis of multiple clinical evaluations [8Xu R, Cui B, Duan X, Zhang P, Zhou X, Yuan Q. Saliva: potential diagnostic value and transmission of 2019-nCoV. Int J Oral Sci 2020; 12(1): 11.
[http://dx.doi.org/10.1038/s41368-020-0080-z] [PMID: 32300101]
, 9Azzi L, Carcano G, Gianfagna F, et al. Saliva is a reliable tool to detect SARS-CoV-2. J Infect 2020.S0163-4453(20)30213-9
[http://dx.doi.org/10.1016/j.jinf.2020.04.005] [PMID: 32298676]
].

REFERENCES

[1] WHO. Coronavirus Disease 2019. (COVID-19) Situation Report-105 https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports (accessed May 4, 2020).
[2] Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382(8): 727-33.
[http://dx.doi.org/10.1056/NEJMoa2001017] [PMID: 31978945]
[3] Wang Y, Kang H, Liu X, Tong Z. Combination of RT-qPCR testing and clinical features for diagnosis of COVID-19 facilitates management of SARS-CoV-2 outbreak. J Med Virol 2020; 92(6): 538-9.
[http://dx.doi.org/10.1002/jmv.25721] [PMID: 32096564]
[4] Li Z, Yi Y, Luo X, et al. Development and clinical application of a rapid IgM-IgG combined antibody test for SARS-CoV-2 infection diagnosis. J Med Virol 2020.
[http://dx.doi.org/10.1002/jmv.25727] [PMID: 32104917]
[5] To KKW, Yip CCY, Lai CYW, et al. Saliva as a diagnostic specimen for testing respiratory virus by a point-of-care molecular assay: A diagnostic validity study. Clin Microbiol Infect 2019; 25(3): 372-8.
[http://dx.doi.org/10.1016/j.cmi.2018.06.009] [PMID: 29906597]
[6] To KK-W, Tsang OT-Y, Chik-Yan Yip C, et al. Consistent detection of 2019 novel Coronavirus in saliva. Clin Infect Dis 2020. Feb 12; ciaa149
[PMID: 32047895]
[7] Dawes C, Wong DTW. Role of saliva and salivary diagnostics in the advancement of oral health. J Dent Res 2019; 98(2): 133-41.
[http://dx.doi.org/10.1177/0022034518816961] [PMID: 30782091]
[8] Xu R, Cui B, Duan X, Zhang P, Zhou X, Yuan Q. Saliva: potential diagnostic value and transmission of 2019-nCoV. Int J Oral Sci 2020; 12(1): 11.
[http://dx.doi.org/10.1038/s41368-020-0080-z] [PMID: 32300101]
[9] Azzi L, Carcano G, Gianfagna F, et al. Saliva is a reliable tool to detect SARS-CoV-2. J Infect 2020.S0163-4453(20)30213-9
[http://dx.doi.org/10.1016/j.jinf.2020.04.005] [PMID: 32298676]
[10] To KK-W, Tsang OT-Y, Leung W-S, et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis 2020; 20(5): 565-74.
[http://dx.doi.org/10.1016/S1473-3099(20)30196-1] [PMID: 32213337]
[11] Chen L, Zhao J, Peng J, et al. Detection of 2019-NCoV in Saliva and Characterization of Oral Symptoms in COVID-19 Patients 2020. Available from https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3557140
[12] Racine R, Winslow GM. IgM in microbial infections: taken for granted? Immunol Lett 2009; 125(2): 79-85.
[http://dx.doi.org/10.1016/j.imlet.2009.06.003] [PMID: 19539648]
[13] Guo L, Ren L, Yang S, et al. Profiling early humoral response to diagnose novel coronavirus disease (COVID-19). Clin Infect Dis 2020. Mar 21;ciaa310.
[PMID: 32198501]
[14] Béné MC, de Carvalho M, Eveillard M, et al. Good IgA Bad IgG in SARS-CoV-2 Infection? Clin Infect Dis 2020. Apr 11;ciaa426
[PMID: 32280952]
[15] Xu H, Zhong L, Deng J, et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci 2020; 12(1): 8.
[http://dx.doi.org/10.1038/s41368-020-0074-x] [PMID: 32094336]
[16] Mallapaty S. Why Does the Coronavirus Spread so Easily between People? Nature 2020 Mar; 579(7798): 183.
[http://dx.doi.org/10.1038/d41586-020-00660-x] [PMID: 32157230]
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