The bottom line: At this point, sensitivity and specificity of respiratory swabs for SARS-CoV2 is unknown. Although the rate of false negative results is currently unknown, false negatives do occur, so there may be clinical scenarios in which physicians could consider repeating the test.
Strength of evidence: Inadequate. Comparisons to a meaningful gold standard in a population-based setting are needed.
Discussion: In the U.S. right now, a positive test for SARS-CoV-2 RNA by reverse-transcription polymerase chain reaction (RT-PCR) at the CDC or in a CDC-qualified lab confirms the diagnosis of COVID-19. In other words, the PCR–based assay is the gold standard for COVID-19 diagnosis. We were unable to find any studies comparing PCR–based assays for SARS-CoV-2 infection from naso- or oropharyngeal samples (“respiratory swabs”) to any other clinically adequate gold standard. Clinicians may see studies reporting “positive rates” from PCR respiratory swabs, but the methods used need to be reviewed carefully. For example, a recent study estimated the positive rate of PCR from respiratory swabs for SAR-CoV-2 infection at 38% among individuals in Wuhan, China “fever clinics” thought to have clinical likely COVID-19 infection based on (1) typical respiratory infection symptoms such as fever, cough and dyspnea, or (2) close contact with an individual with COVID-19 (1). Similarly, a study published in JAMA compared detection of SARS-CoV-2 in a variety of samples taken from hospitalized patients in China including respiratory swabs to a gold standard of COVID-19 based on a clinical case definition plus a SARS-CoV-2–positive PCR results from some site, reporting a positive rate of 63% for nasal swabs (5 out of 8 samples) and 32% for oral swabs (126 out of 398 samples) (2). These results should be interpreted with care. Individuals with asymptomatic or mild infection from COVID-19 would be inappropriately excluded from the denominator, and individuals with respiratory disease from other causes would be inappropriately included in the denominator, and results in true negatives are not evaluated. Another potential source of misunderstanding is other accepted uses of the term “sensitivity. In laboratory protocols for RT-PCR-based assays “sensitivity” is a measure of the limits of detection of the assay (how many copies of the viral RNA per micro/L can the assay detect, for example), not the ability to correctly identify individuals with COVID-19.
False negatives have been reported on SARS-CoV2 respiratory swabs, notably in this recent case report (3), detailing a 69yo man with persistently negative respiratory swabs despite evidence of SARS-CoV2 from sputum and BAL samples. Knowledge gained from studies published during the SARS epidemic also supports the idea. Serologic response to SARS CoV is thought to be a sensitive and specific retrospective tool for diagnosis of SARS CoV infection, but are often not detectable until day 10 of illness or later. During the SARS epidemic, PCR-based assays from Artus and Roche were 87% and 85% sensitive for respiratory specimens respectively for SARS CoV compared to serologic response from paired acute- and convalescent-phase serum samples (4). Based on knowledge of test performance characteristics for influenza and SARS, factors such as adequacy of sample collection and decline in viral load over time may also play a role in the test performance characteristics of RT-PCR–based assays for SARS-CoV-2 infection.
Authors: Pandora “Luke” Wander, MD, MS, FACP
URLs:
https://www.ncbi.nlm.nih.gov/pubmed/15797361
https://wwwnc.cdc.gov/eid/article/26/6/20-0299_article
Date last reviewed: 3/18/20
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References:
1. Liu R, Han H, Liu F, Lv Z, Wu K, Liu Y, Feng Y, Zhu C: Positive rate of RT-PCR detection of SARS-CoV-2 infection in 4880 cases from one hospital in Wuhan, China, from Jan to Feb 2020. Clinica chimica acta; international journal of clinical chemistry 2020;505:172-175
2. Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, Tan W: Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA : the journal of the American Medical Association 2020;
3. Wu X, Cai Y, Huang X, Yu X, Zhao L, Wang F, Li Q, Gu S, Xu T, Li Y, Lu B, Zhan Q: Co-infection with SARS-CoV-2 and Influenza A Virus in Patient with Pneumonia, China. Emerg Infect Dis 2020;26
4. Yam WC, Chan KH, Chow KH, Poon LL, Lam HY, Yuen KY, Seto WH, Peiris JS: Clinical evaluation of real-time PCR assays for rapid diagnosis of SARS coronavirus during outbreak and post-epidemic periods. J Clin Virol 2005;33:19-24