RT-qPCR assays based on saliva rather than on nasopharyngeal swabs are possible but should be interpreted with caution: results from a systematic review and meta-analysis.: Diagnosis of SARS-CoV-2 through salivary fluids

RT-qPCR assays based on saliva rather than on nasopharyngeal swabs are possible but should be interpreted with caution: results from a systematic review and meta-analysis.

Diagnosis of SARS-CoV-2 through salivary fluids

Authors

  • Matteo Riccò Azienda USL di Reggio EmiliaV.le Amendola n.2 - 42122 REServizio di Prevenzione e Sicurezza negli Ambienti di Lavoro (SPSAL)Dip. di Prevenzione http://orcid.org/0000-0002-6525-2159
  • Silvia Ranzieri 2. Department of Medicine and Surgery, School of Occupational Medicine, University of Parma, I-43123 Parma (PR), Italy
  • Simona Peruzzi 3. AUSL – IRCCS di Reggio Emilia, Laboratorio Analisi Chimico Cliniche e Microbiologiche, Ospedale Civile di Guastalla, I-42016 Guastalla (RE), Italy
  • Marina Valente 4. Department of Medicine and Surgery, Unit of Clinical Surgery, University of Parma, I-43123 Parma (PR), Italy
  • Federico Marchesi 4. Department of Medicine and Surgery, Unit of Clinical Surgery, University of Parma, I-43123 Parma (PR), Italy
  • Federica Balzarini 5. University “Vita e Salute”, San Raffaele Hospital; Via Olgettina n. 58, 20132; Milan (MI), Italy
  • Nicola Luigi Bragazzi 6. Laboratory for Industrial and Applied Mathematics (LIAM), Department of Mathematics and Statistics, University of York, Toronto (ON), Canada
  • Carlo Signorelli University “Vita e Salute”, San Raffaele Hospital, Milano, Italy

Keywords:

SARS-CoV-2, COVID-19, RT-qPCR, nasopharyngeal swabs, systematic review and meta-analysis

Abstract

Background and aim of the work: The ongoing pandemic has elicited an increasing interest regarding the SARS-CoV-2 viral RNA detection in saliva specimens rather than through nasopharyngeal swabs. Our aim was to conduct a meta-analysis on the sensitivity and specificity of SARS-CoV-2 viral RNA detection through RT-qPCR based on salivary specimens compared to conventional nasopharyngeal swabs. Methods: We reported our meta-analysis according to the PRISMA statement. We searched Pubmed, Embase, and pre-print archive medRxiv.og for eligible studies published up to June 1st, 2020. Raw data included true/false positive and negative tests, and the total number of tests. Sensitivity and specificity data were calculated for every study, and then pooled in a random-effects model. Heterogeneity was assessed using the I2 measure. Reporting bias was assessed by means of funnel plots and regression analysis. Results: The systematic review eventually retrieved 14 studies including a total of 15 estimates, the were included in quantitative synthesis. We found a pooled specificity of 97.7% (95%CI 93.8-99.2) and a pooled sensitivity of 83.4% (95%CI 73.1–90.4), with an overall agreement assessed by means of Cohen’s kappa equals to 0.750, 95%CI 0.62-0.88 (i.e. moderate agreement), with high heterogeneity and risk of reporting bias. Conclusions: In conclusion, diagnostic tests based on salivary specimens are somewhat reliable, but relatively few studies have been carried out. Moreover, such studies are characterized by low numbers and low sample power. Therefore, the of salivary samples is currently questionable for clinical purposes and cannot substitute other more conventional RT-qPCR based on nasopharyngeal swabs.

Author Biography

Matteo Riccò, Azienda USL di Reggio EmiliaV.le Amendola n.2 - 42122 REServizio di Prevenzione e Sicurezza negli Ambienti di Lavoro (SPSAL)Dip. di Prevenzione

Dipartimento di Sanità Pubblica

Dirigente Medico di Medicina del Lavoro

References

1. Guan W, Liang W, Zhao Y, Liang H, Chen Z, Li Y, et al. Comorbidity and its impact on 1590 patients with Covid-19 in China: A Nationwide Analysis. Eur Respir J 2020 14;55(5):2000547. doi: 10.1183/13993003.00547-2020
2. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan , China. Lancet 2020; 395(10223):497-506. doi: 10.1016/ S0140-6736(20)30183-5
3. Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N Engl J Med. 2020; 382(13):1199-1207 doi: 10.1056/NEJMoa2001316
4. Riccò M, Ferraro P, Gualerzi G, Ranzieri S, Bragazzi NL, Balzarini F, et al. Point-of-Care diagnostic of SARS-CoV-2: knowledge, attitudes, and beliefs (KAP) of medical workforce in Italy. Acta Biomed. 2020; 91(2):57-67. doi: 10.23750/abm.v91i2.9573.
5. European Centre for Diseases Prevention and Control (ECDC). An overview of the rapid test situation for COVID-19 diagnosis in the EU / EEA. Stockholm; 2020. available from: https://www.ecdc.europa.eu/en/publications-data/overview-rapid-test-situation-covid-19-diagnosis-eueea (accessed June 9, 2020)
6. Lippi G, Mattiuzzi C, Bovo C, Plebani M, Services S. Current laboratory diagnostics of coronavirus disease 2019 ( COVID-19). Acta Biomed. 2019;91(2):137–145. doi: 10.23750/abm.v91i2.9548
7. Tang Y-W, Schmitz JE, Persing DH, Stratton CW. The Laboratory Diagnosis of COVID-19 Infection: Current Issues and Challenges. J Clin Microbiol [Internet]. 2020;(April):1–22. Available from: http://www.ncbi.nlm.nih.gov/pubmed/32245835
8. Riccò M, Ferraro P, Gualerzi G, Ranzieri S, Henry BM, Said Y Ben, et al. Point-of-Care Diagnostic Tests for Detecting SARS-CoV-2 Antibodies : A Systematic Review and Meta-Analysis of Real-World Data. J Clin Med. 2020;9(5):E1515. doi: 10.3390/jcm9051515..
9. Vashist SK. In Vitro Diagnostic Assays for COVID-19: Recent Advances and Emerging Trends. Diagnostics (Basel) 2020;10(4):202. doi: 10.3390/diagnostics10040202.
10. Cassaniti I, Novazzi F, Giardina F, Salivaro F, Sachs M, Perlini S, et al. Performance of VivaDiagTM COVID-19 IgM/IgG Rapid Test is inadequate for diagnosis of COVID-19 in acute patients referring to emergency room department. J Med Virol 10.1002/jmv.25800. doi: 10.1002/jmv.25800. Online ahead of print.
11. 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. doi: 10.1038/s41368-020-0080-z.
12. Ceron JJ, Lamy E, Martinez-Subiela S, Lopez-Jornet P, Capela e Silva F, Eckersall PD, et al. Use of Saliva for Diagnosis and Monitoring the SARS-CoV-2: A General Perspective. J Clin Med. 2020; 9(5):E1491. doi: 10.3390/jcm9051491.
13. Azzi L, Carcano G, Dalla Gasperina D, Sessa F, Maurino V, Baj A. Two cases of COVID‐19 with positive salivary and negative pharyngeal or respiratory swabs at hospital discharge: a rising concern. Oral Dis. 2020;10.1111/odi.13368. doi: 10.1111/odi.13368. Online ahead of print.
14. Azzi L, Carcano G, Gianfagna F, Grossi P, Gasperina DD, Genoni A, et al. Saliva is a reliable tool to detect SARS-CoV-2. J Infect. 2020;S0163-4453(20)30213-9. doi: 10.1016/j.jinf.2020.04.005.
15. Food and Drug Admimistration. Coronavirus (COVID-19) Update: FDA Authorizes First Diagnostic Test Using At-Home Collection of Saliva Specimens. FDA NEWS RELEASE. 2020 (available from: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-diagnostic-test-using-home-collection-saliva; accessed on June 9, 2020).
16. Sri Santosh T, Parmar R, Anand H, Srikanth K, Saritha M. A Review of Salivary Diagnostics and Its Potential Implication in Detection of Covid-19. Cureus. 2020; 12(4):e7708. doi: 10.7759/cureus.7708.
17. Thompson R, Cunniffe N. The probability of detection of SARS-CoV-2 in saliva. Stat Methods Med Res. 2020 Apr;29(4):1049–1050. doi: 10.1177/0962280220915049
18. Moher D, Liberati A, Tetzlaff J, Altman DG, Altman D, Antes G, et al. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi: 10.1371/journal.pmed.1000097.
19. Bizzaro N, Villalta D, Giavarina D, Tozzoli R. Are anti-nucleosome antibodies a better diagnostic marker than anti-dsDNA antibodies for systemic lupus erythematosus? A systematic review and a study of metanalysis. Autoimmun Rev 2012;12(2):97–106. doi: 10.1016/j.autrev.2012.07.002
20. Becker D, Sandoval E, Amin A, De Hoff P, Diets A, Leonetti N, et al. Saliva is less sensitive than nasopharyngeal swabs for COVID-19 detection in the community setting. medRxiv. 2020;2020.05.11.20092338. doi: 10.1101/2020.05.11.20092338
21. L’Helgouach N, Champigneux P, Schneider FS, Molina L, Espeut J, Alali M, et al. EasyCOV : LAMP based rapid detection of SARS‐CoV‐2 in saliva. medRxiv. 2020;2020.05.30.20117291. doi: 10.1101/2020.05.30.20117291
22. Fang Z, Zhang Y, Hang C, Ai J, Li S, Zhang W. Comparisons of viral shedding time of SARS-CoV-2 of different samples in ICU and non-ICU patients. J Infect 2020;S0163-4453(20)30139-0. doi: 10.1016/j.jinf.2020.03.013
23. Williams E, Bond K, Zhang B, Putland M, Williamson DA. Saliva as a non-invasive specimen for detection of SARS-CoV-2. J Clin Microbiol. 2020;JCM.00776-20. doi: 10.1128/JCM.00776-20. Online ahead of print.
24. Chen JH-K, Yip CC-Y, Poon RW-S, Chan K-H, Cheng VC-C, Hung IF-N, et al. Evaluating the use of posterior oropharyngeal saliva in a point-of-care assay for the detection of SARS-CoV-2. Emerg Microbes Infect. 2020;1-14. doi: 10.1080/22221751.2020.1775133
25. To KKW, Tsang OTY, Leung WS, Tam AR, Wu TC, Lung DC, 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. doi: 10.1016/S1473-3099(20)30196-1
26. Iwasaki S, Fujisawa S, Nakakubo S, Kamada K, Yamashita Y, Fukumoto T, et al. Comparison of SARS-CoV-2 detection in nasopharyngeal swab and saliva. Medrxiv 2020.05.13.20100206 doi: 10.1101/2020.05.13.20100206
27. Wyllie AL, Fournier J, Casanovas-Massana A, Campbell M, Tokuyama M, Vijayakumar P, et al. Saliva is more sensitive for SARS-CoV-2 detection in COVID-19 patients than nasopharyngeal swabs. medRxiv 2020;2020.04.16.20067835. doi: 10.1101/2020.04.16.20067835v1
28. Jamal AJ, Mozafarihashjin M, Coomes E, Powis J, Xin Liu A, Paterson A, et al. Sensitivity of nasopharyngeal swabs and saliva for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). medRxiv 2020;2020.05.01.20081026. doi: 10.1101/2020.05.01.20081026
29. SoRelle JA, Mahimainathan L, McCormick-Baw C, Cavuoti D, Lee F, Bararia A, et al. Evaluation of symptomatic patient saliva as a sample type for the Abbott ID NOW COVID-19 assay. medRxiv. 2020;2020.06.01.20119198. doi: 10.1101/2020.06.01.20119198
30. Pasomsub E, Watcharananan SP, Boonyawat K, Janchompoo P, Wongtabtim G, Suksuwan W, et al. Saliva sample as a non-invasive specimen for the diagnosis of coronavirus disease-2019 (COVID-19): a cross-sectional study. Clin Microbiol Infect. 2020;S1198-743X(20)30278-0. doi: 10.1016/j.cmi.2020.05.001.
31. McCormick-Baw C, Morgan K, Gaffney D, Cazares Y, Jaworski K, Byrd A, et al. Saliva as an Alternate Specimen Source for Detection of SARS-CoV-2 in Symptomatic Patients Using Cepheid Xpert Xpress SARS-CoV-2. J Clin Microbiol 2020;JCM.01109-20. doi: 10.1128/JCM.01109-20. Online ahead of print.
32. Kojima N, Turner F, Klausner. Self-Collected Oral Fluid and Nasal Swabs Demonstrate Comparable Sensitivity to Clinician Collected Nasopharyngeal Swabs for Covid-19 Detection. medRxiv 2020;2020.04.11.20062372. doi: 10.1101/2020.04.11.20062372
33. To KKW, Tsang OTY, Chik-Yan Yip C, Chan KH, Wu TC, Chan JMC, et al. Consistent detection of 2019 novel coronavirus in saliva. Clin Infect Dis. 2020;ciaa149. doi: 10.1093/cid/ciaa149
34. Czumbel LM, Kiss S, Farkas N, Mandel I, Hegyi A, Nagy Á, et al. Saliva as a Candidate for COVID-19 Diagnostic Testing : A Meta-Analysis. medRxiv 2020;2020.05.26.20112565 doi: 10.1101/2020.05.26.20112565
35. Liu L, Wei Q, Alvarez X, Wang H, Du Y, Zhu H, et al. Epithelial Cells Lining Salivary Gland Ducts Are Early Target Cells of Severe Acute Respiratory Syndrome Coronavirus Infection in the Upper Respiratory Tracts of Rhesus Macaques. J Virol. 2011;85(8):4025–30. doi: 10.1128/JVI.02292-10
36. Wang W-K, Chen S-Y, Liu I-J, Chen Y-C, Chen H-L, Yang C-F, et al. Detection of SARS-associated Coronavirus in Throat Wash and Saliva in Early Diagnosis. Emerg Infect Dis 2004;10(7):1213–9. doi: 10.3201/eid1007.031113
37. Khurshid Z, Asiri FYI, Al Wadaani H. Human saliva: Non-invasive fluid for detecting novel coronavirus (2019-nCoV). Int J Environ Res Public Health. 2020 Apr 1;17(7):2225. doi: 10.3390/ijerph17072225.
38. Bae S, Kim M-C, Kim J-Y, Cha H-H, Lim JS, Kim M-J, et al. Notice of Retraction: Effectiveness of Surgical and Cotton Masks in Blocking SARS-CoV-2. Ann Intern Med. 2020;L20-0745. doi: doi: 10.7326/L20-0745
39. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. Jama [Internet]. 2020;323(11):1061-1069. doi: 10.1001/jama.2020.1585
40. Woloshin S, Patel N, Kesselheim AS. False Negative Tests for SARS-CoV-2 Infection. N Eng J Med. 2020; doi: 10.1056/NEJMp2015897. Online ahead of print.
41. Bourgonje AR, Abdulle AE, Timens W, Hillebrands J, Navis GJ, Gordijn SJ, et al. Angiotensin‐converting enzyme‐2 ( ACE2 ), SARS‐CoV ‐2 and pathophysiology of coronavirus disease 2019 ( COVID ‐19) . J Pathol. 2020;10.1002/path.5471. doi: 10.1002/path.5471.
42. Joung J, Ladha A, Saito M, Segel M, Bruneau R, Schwartz L, et al. Point-of-care testing for COVID-19 using SHERLOCK diagnostics. medRxiv 2020;2020.05.04.20091231. doi: 10.1101/2020.05.04.20091231
43. Reusken CB, Buiting A, Bleeker-Rovers C, Diederen B, Hooiveld M, Friesema I, et al. Rapid assessment of regional SARS-CoV-2 community transmission through a convenience sample of healthcare workers, the Netherlands, March 2020. Euro Surveill 2020;25(12):2000334. doi: 10.2807/1560-7917.ES.2020.25.12.2000334
44. Hirotsu Y, Maejima M, Shibusawa M, Nagakubo Y, Hosaka K, Amemiya K, et al. Pooling RT-PCR test of SARS-CoV-2 for large cohort of “healthy” and infection-suspected patients: A prospective and consecutive study on 1,000 individuals. medRxiv 2020;2020.05.04.20088146. doi: 10.1101/2020.05.04.20088146

Downloads

Published

07-09-2020

Issue

Section

REVIEWS/FOCUS ON - SPECIAL COVID19

How to Cite

1.
RT-qPCR assays based on saliva rather than on nasopharyngeal swabs are possible but should be interpreted with caution: results from a systematic review and meta-analysis.: Diagnosis of SARS-CoV-2 through salivary fluids. Acta Biomed [Internet]. 2020 Sep. 7 [cited 2024 Mar. 29];91(3):e2020025. Available from: https://www.mattioli1885journals.com/index.php/actabiomedica/article/view/10020