1887
Research Open Access
Like 0

Abstract

Background

Reverse-transcription PCR (RT-PCR) assays are used to test for infection with the SARS-CoV-2 virus. RT-PCR tests are highly specific and the probability of false positives is low, but false negatives are possible depending on swab type and time since symptom onset.

Aim

To determine how the probability of obtaining a false-negative test in infected patients is affected by time since symptom onset and swab type.

Methods

We used generalised additive mixed models to analyse publicly available data from patients who received multiple RT-PCR tests and were identified as SARS-CoV-2 positive at least once.

Results

The probability of a positive test decreased with time since symptom onset, with oropharyngeal (OP) samples less likely to yield a positive result than nasopharyngeal (NP) samples. The probability of incorrectly identifying an uninfected individual due to a false-negative test was considerably reduced if negative tests were repeated 24 hours later. For a small false-positive test probability (<0.5%), the true number of infected individuals was larger than the number of positive tests. For a higher false-positive test probability, the true number of infected individuals was smaller than the number of positive tests.

Conclusion

NP samples are more sensitive than OP samples. The later an infected individual is tested after symptom onset, the less likely they are to test positive. This has implications for identifying infected patients, contact tracing and discharging convalescing patients who are potentially still infectious.

Loading

Article metrics loading...

/content/10.2807/1560-7917.ES.2020.25.50.2000568
2020-12-17
2021-01-21
http://instance.metastore.ingenta.com/content/10.2807/1560-7917.ES.2020.25.50.2000568
Loading
Loading full text...

Full text loading...

/deliver/fulltext/eurosurveillance/25/50/eurosurv-25-50-4.html?itemId=/content/10.2807/1560-7917.ES.2020.25.50.2000568&mimeType=html&fmt=ahah

References

  1. Xie X, Zhong Z, Zhao W, Zheng C, Wang F, Liu J. Chest CT for Typical 2019-nCoV Pneumonia: Relationship to Negative RT-PCR Testing. Radiology. 2020;200343.  https://doi.org/10.1148/radiol.2020200343 
  2. Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, et al. Correlation of Chest CT and RT-PCR Testing for Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology. 2020;296(2):E32-40.  https://doi.org/10.1148/radiol.2020200642  PMID: 32101510 
  3. Fang Y, Zhang H, Xie J, Lin M, Ying L, Pang P, et al. Sensitivity of Chest CT for COVID-19: Comparison to RT-PCR. Radiology. 2020;296(2):E115-7.  https://doi.org/10.1148/radiol.2020200432  PMID: 32073353 
  4. Yang Y, Yang M, Shen C, Wang F, Yuan J, et al. Evaluating the accuracy of different respiratory specimens in the laboratory diagnosis and monitoring the viral shedding of 2019-nCoV infections. medRxiv. 11 Feb 2020.  https://doi.org/10.1101/2020.02.11.20021493 
  5. Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, et al. SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients. N Engl J Med. 2020;382(12):1177-9.  https://doi.org/10.1056/NEJMc2001737  PMID: 32074444 
  6. Wölfel R, Corman VM, Guggemos W, Seilmaier M, Zange S, Müller MA, et al. Virological assessment of hospitalized patients with COVID-2019. Nature. 2020;581(7809):465-9.  https://doi.org/10.1038/s41586-020-2196-x  PMID: 32235945 
  7. Zhao J, Yuan Q, Wang H, Liu W, Liao X, Su Y, et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clin Infect Dis. 2020;ciaa344.  https://doi.org/10.1093/cid/ciaa344  PMID: 32221519 
  8. Liu L, Liu W, Zheng Y, Jiang X, Kou G, Ding J, et al. A preliminary study on serological assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 238 admitted hospital patients. Microbes Infect. 2020;22(4-5):206-11.  https://doi.org/10.1016/j.micinf.2020.05.008  PMID: 32425648 
  9. Wu H, Hao Q, Wang Q. Difficulties in False Negative Diagnosis of Coronavirus Disease 2019: A Case Report. Research Square. 13 Mar 2020.  https://doi.org/10.21203/rs.3.rs-17319/v1 
  10. Cao G, Tang S, Yang D, Shi W, Wang X, Wang H, et al. The potential transmission of SARS-CoV-2 from patients with negative RT-PCR swab tests to others: two related clusters of COVID-19 outbreak. Jpn J Infect Dis. 2020;73(6):399-403.  https://doi.org/10.7883/yoken.JJID.2020.165  PMID: 32475877 
  11. Luo L, Liu D, Liao X-L, Wu X-B, Jing Q-L, Zheng J-Z, et al. Modes of contact and risk of transmission in COVID-19 among close contacts. MedRxiv.2020;26.  https://doi.org/10.1101/2020.03.24.20042606 
  12. Kujawski SA, Wong KK, Collins JP, Epstein L, Killerby ME, Midgley CM, et al. Clinical and virologic characteristics of the first 12 patients with coronavirus disease 2019 (COVID-19) in the United States. Nat Med. 2020;26(6):861-8.  https://doi.org/10.1038/s41591-020-0877-5  PMID: 32327757 
  13. Danis K, Epaulard O, Bénet T, Gaymard A, Campoy S, Botelho-Nevers E, et al. Cluster of coronavirus disease 2019 (Covid-19) in the French Alps, 2020. Clin Infect Dis. 2020;71(15):825-32.  https://doi.org/10.1093/cid/ciaa424  PMID: 32277759 
  14. Seah IYJ, Anderson DE, Kang AEZ, Wang L, Rao P, Young BE, et al. Assessing Viral Shedding and Infectivity of Tears in Coronavirus Disease 2019 (COVID-19) Patients. Ophthalmology. 2020;127(7):977-9.  https://doi.org/10.1016/j.ophtha.2020.03.026  PMID: 32291098 
  15. Wyllie AL, Fournier J, Casanovas-Massana A, Campbell M, Tokuyama M, Vijayakumar P, et al. Saliva or Nasopharyngeal Swab Specimens for Detection of SARS-CoV-2. N Engl J Med 2020; 383:1283-1286. medRxiv. 2020; 2020.04.16.20067835. https://doi.org/ 10.1056/NEJMc2016359 
  16. Young BE, Ong SWX, Kalimuddin S, Low JG, Tan SY, Loh J, et al. Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore. JAMA. 2020;323(15):1488-94.  https://doi.org/10.1001/jama.2020.3204  PMID: 32125362 
  17. Lescure F-X, Bouadma L, Nguyen D, Parisey M, Wicky P-H, Behillil S, et al. Clinical and virological data of the first cases of COVID-19 in Europe: a case series. Lancet Infect Dis. 2020;20(6):697-706.  https://doi.org/10.1016/S1473-3099(20)30200-0  PMID: 32224310 
  18. van Kampen JJA, van de Vijver DAMC, Fraaij PLA, Haagmans BL, Lamers MM, Okba N, et al. Shedding of infectious virus in hospitalized patients with coronavirus disease-2019 (COVID-19): duration and key determinants. medRxiv. 9 Jun 2020.  https://doi.org/10.1101/2020.06.08.20125310 
  19. Kim ES, Chin BS, Kang CK, Kim NJ, Kang YM, Choi JP, et al. Clinical Course and Outcomes of Patients with Severe Acute Respiratory Syndrome Coronavirus 2 Infection: a Preliminary Report of the First 28 Patients from the Korean Cohort Study on COVID-19. J Korean Med Sci. 2020;35(13):e142.  https://doi.org/10.3346/jkms.2020.35.e142  PMID: 32242348 
  20. Wood SN. Fast stable restricted maximum likelihood and marginal likelihood estimation of semiparametric generalized linear models. J R Stat Soc Series B Stat Methodol. 2011;73(1):3-36.  https://doi.org/10.1111/j.1467-9868.2010.00749.x 
  21. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, 2020. Available from: https://www.R-project.org/
  22. Bi Q, Wu Y, Mei S, Ye C, Zou X, Zhang Z, et al. Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study. Lancet Infect Dis. 2020;20(8):911-9.  https://doi.org/10.1016/S1473-3099(20)30287-5  PMID: 32353347 
  23. Our world in data. Statistics and Research. Coronavirus (COVID-19) testing. [Accessed: 3 Apr 2020]. Available from: https://ourworldindata.org/covid-testing
  24. Verity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. 2020;20(6):669-77.  https://doi.org/10.1016/S1473-3099(20)30243-7  PMID: 32240634 
  25. Wu JT, Leung K, Bushman M, Kishore N, Niehus R, de Salazar PM, et al. Estimating clinical severity of COVID-19 from the transmission dynamics in Wuhan, China. Nat Med. 2020;26(4):506-10.  https://doi.org/10.1038/s41591-020-0822-7  PMID: 32284616 
  26. Cohen J, Kupferschmidt K. Countries test tactics in ‘war’ against COVID-19. Science. 2020;367(6484):1287-8.  https://doi.org/10.1126/science.367.6484.1287  PMID: 32193299 
  27. Lee D, Lee J. Testing on the move: South Korea’s rapid response to the COVID-19 pandemic. Transportation Research Interdisciplinary Perspectives. 2020. p. 100111.  https://doi.org/10.1016/j.trip.2020.100111 
  28. Wu F, Wang A, Liu M, Wang Q, Chen J, Xia S, et al. Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. medRxiv. 20 Apr 2020.  https://doi.org/10.1101/2020.03.30.20047365 
  29. Vabret N, Britton GJ, Gruber C, Hegde S, Kim J, Kuksin M, et al. Immunology of COVID-19: Current State of the Science. Immunity. 2020;52(6):910-41.  https://doi.org/10.1016/j.immuni.2020.05.002  PMID: 32505227 
  30. Kellam P, Barclay W. The dynamics of humoral immune responses following SARS-CoV-2 infection and the potential for reinfection. J Gen Virol. 2020;101(8):791-7.  https://doi.org/10.1099/jgv.0.001439  PMID: 32430094 
  31. Cervia C, Nilsson J, Zurbuchen Y, Valaperti A, Schreiner J, Wolfensberger A, et al. Systemic and mucosal antibody secretion specific to SARS-CoV-2 during mild versus severe COVID-19. bioRxiv. 2020;23.  https://doi.org/10.1101/2020.05.21.108308 
  32. Staines HM, Kirwan DE, Clark DJ, Adams ER, Augustin Y, Byrne RL, et al. Dynamics of IgG seroconversion and pathophysiology of COVID-19 infections. medRxiv. 9 Jun 2020.  https://doi.org/10.1101/2020.06.07.20124636 
  33. Solbach W, Schiffner J, Backhaus I, Burger D, Staiger R, Tiemer B, et al. Antibody Profiling of COVID-19 Patients in an Urban Low-Incidence Region in Northern Germany. Front Public Health. 2020;8:570543.  https://doi.org/10.3389/fpubh.2020.570543  PMID: 33072707 
  34. World Health Organization (WHO). Laboratory testing for coronavirus disease 2019 (‎COVID-19)‎ in suspected human cases: interim guidance, 2 March 2020. Geneva: WHO; 2Mar 2020. Available from: https://apps.who.int/iris/handle/10665/331329
  35. European Centre for Disease Prevention and Control (ECDC). Novel coronavirus (SARS-CoV-2). Discharge criteria for confirmed COVID-19 cases – When is it safe to discharge COVID-19 cases from the hospital or end home isolation? Stockholm: ECDC. [Accessed: 4 Apr 2020]. Available from: https://www.ecdc.europa.eu/sites/default/files/documents/COVID-19-Discharge-criteria.pdf
  36. Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, et al. Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA. 2020;323(18):1843-4.  https://doi.org/10.1001/jama.2020.3786  PMID: 32159775 
  37. Liu W-D, Chang S-Y, Wang J-T, Tsai M-J, Hung C-C, Hsu C-L, et al. Prolonged virus shedding even after seroconversion in a patient with COVID-19. J Infect. 2020;81(2):318-56. PMID: 32283147 
  38. Bullard J, Dust K, Funk D, Strong JE, Alexander D, Garnett L, et al. Predicting infectious SARS-CoV-2 from diagnostic samples. Clin Infect Dis. 2020;ciaa638.  https://doi.org/10.1093/cid/ciaa638  PMID: 32442256 
  39. He X, Lau EHY, Wu P, Deng X, Wang J, Hao X, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat Med. 2020;26(5):672-5.  https://doi.org/10.1038/s41591-020-0869-5  PMID: 32296168 
  40. van Kasteren PB, van der Veer B, van den Brink S, Wijsman L, de Jonge J, van den Brandt A, et al. Comparison of seven commercial RT-PCR diagnostic kits for COVID-19. Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology. 2020. p. 104412.
  41. Chan JF-W, Yip CC-Y, To KK-W, Tang TH-C, Wong SC-Y, Leung K-H, et al. Improved Molecular Diagnosis of COVID-19 by the Novel, Highly Sensitive and Specific COVID-19-RdRp/Hel Real-Time Reverse Transcription-PCR Assay Validated In Vitro and with Clinical Specimens. J Clin Microbiol. 2020;58(5):58.  https://doi.org/10.1128/JCM.00310-20  PMID: 32132196 
  42. Cohen AN, Kessel B. False positives in reverse transcription PCR testing for SARS-CoV-2. MedRxiv.2020;28.  https://doi.org/10.1101/2020.04.26.20080911 
  43. Cereda D, Tirani M, Rovida F, Demicheli V, Ajelli M, Poletti P, et al. The early phase of the COVID-19 outbreak in Lombardy, Italy. arXiv. 2003.09320. Available from: https://arxiv.org/abs/2003.09320
  44. Li R, Pei S, Chen B, Song Y, Zhang T, Yang W, et al. Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2). Science. 2020.368(6490):489-93.  https://doi.org/10.1126/science.abb3221 
  45. Tong Z-D, Tang A, Li K-F, Li P, Wang H-L, Yi J-P, et al. Potential Presymptomatic Transmission of SARS-CoV-2, Zhejiang Province, China, 2020. Emerg Infect Dis. 2020;26(5):1052-4.  https://doi.org/10.3201/eid2605.200198  PMID: 32091386 
/content/10.2807/1560-7917.ES.2020.25.50.2000568
Loading

Data & Media loading...

Supplementary data

Submit comment
Close
Comment moderation successfully completed
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error