Repeatedly negative PCR results in patients with COVID-19 symptoms: Do they have SARS-CoV-2 infection or not?

Česká verze

Authors: J. Beneš ¹; O. Džupová ¹; A. Poláková ²; N. Sojková ²
Authors place of work: 3. lékařská fakulta Univerzity Karlovy, Klinika infekčních nemocí, Nemocnice Na Bulovce, Praha ¹; Oddělení klinické mikrobiologie, Nemocnice Na Bulovce, Praha ²
Published in the journal: Epidemiol. Mikrobiol. Imunol. 70, 2021, č. 1, s. 3-9
Category: Původní práce

Summary

Objective: To point out possible infection with SARS-CoV-2 in symptomatic patients despite repeated negative nasopharyngeal swab tests for SARS-CoV-2.

Material and methods: A retrospective observational study carried out at the Na Bulovce Hospital from the beginning of the pandemic until November 2020 included patients (1) who had symptoms compatible with COVID-19; (2) whose nasopharyngeal swab PCR tests in the presence of acute respiratory infection symptoms yielded two consecutive negative results; (3) in whom SARS-CoV-2 infection was subsequently confirmed by serology. Basic demographic and epidemiological data, symptoms, laboratory test results, X-ray findings and timing of virological tests were analysed for these patients.

Results: Seventeen patients met the inclusion criteria, 14 men and three women, aged 19-84 years with a median of 59 years, of whom 14 were hospitalized and three were treated as outpatients. Only seven patients were aware of the previous contact with an infected person. The main symptoms were fever, cough, headache, weakness, fatigue and shortness of breath. Pneumonia was found in 12 patients, four of whom developed respiratory insufficiency requiring ventilatory support. Most patients showed a uniform combination of haematological, biochemical and radiological findings: absence of eosinophils and increased polymorphonuclear/lymphocyte ratio; elevation of serum lactate dehydrogenase; elevation of CRP without rise of procalcitonin; typical chest CT or X-ray findings. All patients recovered. Coronavirus antigen test was performed in six patients, with all of them testing negative. SARS-CoV-2 infection was confirmed serologically by the detection of specific IgG and IgA in all 17 patients and also IgM in six patients, not before day 8 of the onset of symptoms.

Conclusions: Our study showed that some patients with acute COVID-19 may test repeatedly negative by nasopharyngeal swab PCR. These cases should be interpreted as a low viral load in the upper respiratory tract rather than false negativity of PCR. Such alternative is not envisaged in the algorithms used. Considering our results, the following recommendation can be made: If, despite negative PCR tests, COVID-19 is still suspected based on clinical symptoms and epidemiological evidence, preliminary diagnosis can be made on the basis of comprehensive assessment of the laboratory test and X-ray findings. Final confirmation of the aetiology relies on serological tests performed two weeks after the onset of symptoms.

Keywords:

COVID-19 – diagnostics – PCR tests – Serology

Zdroje

1. He X, Lau EHY, Wu P, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat Med., 2020;26(5):672–675.

2. Sethuraman N, Jeremiah SS, Ryo A. Interpreting diagnostic tests for SARS-CoV-2. JAMA, 2020;323(22):2249–2251.

3. Arevalo-Rodriguez I, Buitrago-Garcia D, Simancas-Racines D, et al. False-negative results of initial RT-PCR assays for COVID-19: a systematic review. (Document ahead of print.) Dostupný na www: https://doi.org/10.1101/2020.04.16.20066787.

4. WHO: Diagnostic testing for SARS-CoV-2: Interim guidance, 11 September 2020. Dostupný na www: https://www.who.int/publications/i/item/diagnostic-testing-for-sars-cov-2.

5. Beneš J. Příspěvek k diagnostice covidu-19 pomocí PCR. Dostupný na www: https://www.infekce.cz/zprava20-112.htm.

6. Wang G, Yu N, Xiao W, et al. Consecutive false‐negative rRT‐PCR test results for SARS‐CoV‐2 in patients after clinical recovery from COVID‐19. J Med Virol., 2020;92:2887–2890.

7. Xiao AT, Tong YX, Zhang S. False negative of RT-PCT and prolonged nucleic acid conversion in COVID-19: rather than recurrence. J Med Virol., 2020;92:1755–1756.

8. International Federation of Clinical Chemistry and Laboratory Medicine. IFCC Information Guide on COVID-19. Dostupný na www: https://www.ifcc.org/ifcc-news/2020-03-26-ifcc-information-guide-on-covid-19/.

9. Hueston L, Kok J, Guibone A, et al. The Antibody Response to SARS-CoV-2 Infection. Open Forum Infect Dis., 2020;7(9):ofaa387.

10. Kowitdamrong E, Puthanakit T, Jantarabenjakul W, et al. Antibody responses to SARS-CoV-2 in patients with differing severities of coronavirus disease 2019. PLoS One, 2020;15(10):e0240502.

11. Van Praet JT, et al. Comparison of four commercial SARS-CoV-2 IgG immuno-assays in RT-PCR negative patients with suspect CT findings. Infection, 2020;PMID:32910322.

12. Kucirka LM, Lauer SA, Laeyendecker O, et al. Variation in false-negative rate of reverse transcriptase polymerase chain reaction-based SARS-CoV-2 tests by time since exposure. Review Ann Intern Med., 2020;173(4):262–267.

13. Zhang JJ, Cao YY, Dong X, et al. Distinct characteristics of COVID-19 patients with initial rRT-PCR-positive and rRT-PCR-negative results for SARS-CoV-2. Allergy, 2020;75(7):1809–1812.

14. Ziegler K, Steininger P, Ziegler R, et al. SARS-CoV-2 samples may escape detection because of a single point mutation in the N gene. Euro Surveill., 2020;25(39):2001650.

15. Tavare AN, Braddy A, Brill S, et al. Managing high clinical suspicion COVID-19 inpatients with negative RT-PCR: a pragmatic and limited role for thoracic CT. Thorax, 2020;75(7):537–538.

16. Salzberger B, Buder F, Lampl B, et al. Epidemiology of SARS--CoV-2. Infection, 2020;8:1–7.

17. Stein RA. Super-spreaders in infectious diseases. Int J Infect Dis., 2011;15(8):e510–e513.

18. Lechien JR, Chiesa-Estomba CM, Place S, et al. Clinical and epidemiological characteristics of 1420 European patients with mild-to-moderate coronavirus disease 2019. J Intern Med, 2020;288(3):335–344.

19. Grebenyuk V, Roháčová H, Trojánek M. Klinické a laboratorní nálezy u pacientů s COVID-19. Farmakoterap Revue, 2020;5(Suppl 1):37–44.

20. Zahorec R, Hulin I, Zahorec P. Rationale use of neutrophil-to-lymphocyte ratio for early diagnosis and stratification of COVID-19. Bratisl Lek Listy, 2020;121(7):466–470.

21. Liu J, Liu Y, Xiang P, et al. Neutrophil-to-lymphocyte ratio predicts critical illness patients with 2019 coronavirus disease in the early stage. J Transl Med., 2020;18(1):206.

22. Xie G, Ding F, Han L, et al. The role of peripheral blood eosinophil counts in COVID-19 patients. Allergy, 2020;10.1111/all.14465.

23. Panteghini M. Lactate dehydrogenase: an old enzyme reborn as a COVID-19 marker (and not only). Clin Chem Lab Med., 2020;58(12):1979–1981.

24. Kočová E. Doporučený postup pro zobrazování pacientů s potvrzeným onemocněním covid-19 ve Fakultní nemocnici Hradec Králové. Dostupný na www: https://www.infekce.cz/zprava20-53.htm.

25. Ferda J, Mírka H, Baxa J, et al. Urgentní výpočetní tomografie při podezření na onemocnění COVID-19. Ces Radiol., 2020;74(1):577–583.

26. Rubin GD, Ryerson CJ, Haramati LB, et al. The role of chest imaging in patient management during the COVID-19 pandemic: a multinational consensus statement from the Fleischner Society. Chest, 2020;58(1):106–116.

27. Xie X, Zhong Z, Zhao W, et al. Chest CT for typical coronavirus disease 2019 (COVID-19) pneumonia: relationship to negative RT-PCR testing. Radiology, 2020;296(2):E41–E45.

28. Yang HS, Hou Y, Vasovic LV, et al. Routine laboratory blood tests predict SARS-CoV-2 infection using machine learning. Clin Chem., 2020;66(11):1396–1404.

29. Kurstjens S, van der Horst A, Herpers R, et al. Rapid identification of SARS-CoV-2-infected patients at the emergency department using routine testing. Clin Chem Lab Med., 2020;58(9):1587–1593.

30. Joshi RP, Pejaver V, Hammarlund NE, et al. A predictive tool for identification of SARS-CoV-2 PCR-negative emergency department patients using routine test results. J Clin Virol., 2020;129:104502.