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letter
. 2024 May 16;390(19):1835–1836. doi: 10.1056/NEJMc2403409

False Positive Covid-19 Rapid Antigen Tests

PMCID: PMC11156229  PMID: 38749053
letter N Engl J Med. 2024 May 16;390(19):1835–1836.
Chengliang Yang 1, Estefanía Espín 1, Scott J Tebbutt 1,✉

To the Editor: The letter by Herbert et al. (Feb. 22 issue)1 explores persistent false positive results on SARS-CoV-2 rapid antigen tests but overlooks various factors, such as interfering substances and testing conditions.2 Structural similarities between pathogens such as dengue virus and SARS-CoV-2 imply potential cross-reactivity.3

The potential for IgM cross-reactivity with rheumatoid factor–positive serum samples was observed in blood tests used to detect IgM SARS-CoV-2 by means of gold immunochromatographic and enzyme-linked immunosorbent assays.4 SARS-CoV-2 rapid antigen tests differ from antibody tests, with the former identifying SARS-CoV-2 viral proteins and the latter detecting human IgM SARS-CoV-2 antibodies. Thus, the possible link between false positive rapid antigen tests, which use nasal swabs, not blood samples, and antibody cross-reactivity with rheumatoid factor deserves reconsideration.

The absence of discussion about patients with negative results on reverse-transcriptase–polymerase-chain-reaction (RT-PCR) testing for SARS-CoV-2 but positive results on SARS-CoV-2 rapid antigen tests raises questions about persistent viral infection. For instance, despite negative results on RT-PCR testing of nasopharyngeal swabs or bronchoalveolar-lavage samples, autopsies revealed continued shedding of SARS-CoV-2 in lung tissue up to 300 days after the remission of infection.5 Overall, the letter provides insights into persistent false positive results on rapid antigen testing but neglects factors of relevance for the accurate interpretation of SARS-CoV-2 test results.

Footnotes

No potential conflict of interest relevant to this letter was reported.

References

  • 1.Herbert C, McManus DD, Soni A. Persistent false positive Covid-19 rapid antigen tests. N Engl J Med 2024;390:764-765. [DOI] [PubMed] [Google Scholar]
  • 2.Patriquin G, Davidson RJ, Hatchette TF, et al. Generation of false-positive SARS-CoV-2 antigen results with testing conditions outside manufacturer recommendations: a scientific approach to pandemic misinformation. Microbiol Spectr 2021;9(2):e0068321-e0068321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Lustig Y, Keler S, Kolodny R, et al. Potential antigenic cross-reactivity between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and dengue viruses. Clin Infect Dis 2021;73(7):e2444-e2449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Vinyé Bausà M, Bausà Peris R, Corominas H. Cross-reactions between rheumatoid factor and IgM SARS-CoV-2. Med Clin (Engl Ed) 2020;155:417-418. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Bussani R, Zentilin L, Correa R, et al. Persistent SARS-CoV-2 infection in patients seemingly recovered from COVID-19. J Pathol 2023;259:254-263. [DOI] [PMC free article] [PubMed] [Google Scholar]
N Engl J Med. 2024 May 16;390(19):1836.
Carly Herbert 1, David D McManus 1, Apurv Soni 1,✉

The authors reply: In our letter, we describe persistent false positive SARS-CoV-2 rapid antigen tests and suggest rheumatoid factor as a potential mechanism. Our postulation was based on previous reports of cross-reactivity and the observation that IgM and IgA rheumatoid factors are detected in saliva and nasal secretions.1 It is important to underscore that our findings were observational and that we did not investigate causal relationship. Yang and colleagues raise important considerations about persistent viral shedding in lung tissue. However, all the participants in our study were asymptomatic and reported that they had not tested positive for SARS-CoV-2 in the previous 3 months. By contrast, viral shedding is commonly observed in persons with prolonged olfactory dysfunction after infection.2

Finally, we received more than 30 accounts from patients and providers in response to our letter sharing similar experiences of persons with autoimmune conditions who had persistent positive results on specific SARS-CoV-2 rapid antigen tests without positive PCR tests. We believe that such anecdotal evidence, combined with our findings and previous reports,3 warrants further investigation of the potential associations between autoimmunity and persistent false positive results on SARS-CoV-2 rapid antigen tests.

Footnotes

Since publication of the letter, the authors report no further potential conflict of interest.

References

  • 1.Elkon KB, Gharavi AE, Patel BM, Hughes GR, Frankel A. IgA and IgM rheumatoid factors in serum, saliva and other secretions: relationship to immunoglobulin ratios in systemic sicca syndrome and rheumatoid arthritis. Clin Exp Immunol 1983;52:75-84. [PMC free article] [PubMed] [Google Scholar]
  • 2.Costa Dos Santos J, Ximenes Rabelo M, Mattana Sebben L, et al. Persistence of SARS-CoV-2 antigens in the nasal mucosa of eight patients with inflammatory rhinopathy for over 80 days following mild COVID-19 diagnosis. Viruses 2023;15:899-899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Vinyé Bausà M, Bausà Peris R, Corominas H. Cross-reactions between rheumatoid factor and IgM SARS-CoV-2. Med Clin (Engl Ed) 2020;155:417-418. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The New England Journal of Medicine are provided here courtesy of Massachusetts Medical Society

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