Less sensitive rapid tests may miss asymptomatic/presymptomatic SARS-CoV-2 infection

The rapid transmissibility of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a significant challenge to COVID-19 containment measures, especially because of the high percentage of asymptomatic and presymptomatic infections.

As a result, transmission often occurs before the individual is known to be infected. This has spurred intensive research into methods of early diagnosis, which should be both accurate and reliable. This would be one of the best methods to protect high-risk vulnerable populations, provided they fulfill certain key assumptions.

A new preprint appeared on the medRxiv* server in December 2020, describing a documented presymptomatic transmission event. This provides a slender thread of evidence as to how the viral load increases.


SARS-CoV-2. Image Credit: Kateryna Kon/Shutterstock.com

Earlier Studies

Many studies show that up to ~75% of transmission occurs before symptoms develop in non-healthcare settings such as parties, sports meets, prisons, religious meetings, and family visits.

The researchers cite a Wisconsin outbreak affecting over 100 campers beginning with a single student who became symptomatic a day after arriving at the camp. Despite quarantining 11 close contacts until the rapid test results were available, and despite the negative test results of these contacts, resulting in their release from quarantine, 6 out of 11 later became symptomatic, spreading the infection to the rest of the campers.

Conversely, repeated PCR testing of nursing home occupants, after three of them tested positive for COVID-19, led to its further transmission to only 19 out of 99 residents over two weeks. Early reliable testing can help to effectively isolate infected individuals before they infect others.

Sensitivity vs Rapid Results

The most sensitive tests now available have a limit of detection (LOD) of 102-103 RNA copies/mL. These include reverse transcription-quantitative polymerase chain reactions (RT qPCR). These mostly depend on intensive sample preparation methods, with RNA extraction and purification, and require centralized laboratories, though a few point-of-care tests are available.

The other tests category are those with low sensitivity, which require LODs of 105 to 107 copies/mL, such as molecular or antigen tests. These are rapid tests, not requiring rigorous sample preparation, and cheaper and suitable for outside laboratories. These are important for early detection by surveillance and have received FDA approval for use in symptomatic individuals. However, they may not be able to pick up asymptomatic or presymptomatic patients.

Earlier, studies have reported the ability of rapid tests to provide rapid early diagnosis. However, a vital issue with rapid tests is their low sensitivity, which precludes their surveillance use. As a result, they can be used to detect early infection only if it is assumed that viral load rapidly rises to high levels (>105-106 RNA copies/mL) after infection and remains elevated. However, there is insufficient data to confirm these conditions.

Study Details

The current study focused on a household where one member was diagnosed with COVID-19. The index patient's contacts within the household were followed up by twice-daily saliva testing, from which the absolute viral load was quantified. They used RT-qPCR and RT digital droplet PCR (RT ddPCR) tests.

The household had four members, including two parents and their two children. One of the children had close contact with a COVID-19 person just before both of them returned home after an out-of-state trip. Both were tested by RT-qPCR the following day, with the contact turning up a positive result and the other negative.

The positive sibling was isolated, and the rest of the household quarantined. Later, the negative sibling and one parent became positive, and viral sequencing supported the virus's spread from the index case to the rest.

Study Observations Indicate Slow Rise

Rigorous follow-up for study purposes showed that the viral loads, in at least some cases, rise over days and not hours, indicating a slow rise. This is beneficial if highly sensitive tests detect infection before the viral load rises to infectious levels. Such tests include PCR.

However, the second sibling's viral load took three days to cross the limit of detection (LOD) for rapid tests. The results showed a viral load between 103-105 copies/mL in six successive samples before reaching a 107 copies/mL peak. This slow rise would make it difficult to assess the individual's infectivity. It may promote the assumption that such people are not likely to be infectious and need not self-isolate.

Secondly, the peak level may be below the LOD of rapid COVID-19 tests, with only 1/88 being above it. Moreover, the index patient never showed a viral load above this even while the household transmission was taking place, as presumed by the investigators.

Thirdly, of the 52 samples that tested positive from the first 10 days of the study, only three were near or above the LOD (9.3x106 copies) of the least sensitive rapid test. However, 33 exceeded it for the more sensitive rapid test. During the presymptomatic period of both the infected parent and the second sibling, they would probably have tested positive for RT-qPCR but been negative or had unreliable results, with many of the tests with lower sensitivity.

What are the Implications?

These results agree with an earlier study on basketball players, showing a slow rise in viral loads for up to five days from the first PCR test that showed positive until the time that they crossed the LOD of the rapid tests. Very few of the tests in this study crossed the LOD of rapid antigen tests by much.

The researchers suggest that low-sensitivity tests are useful to confirm COVID-19 in symptomatic infections at point-of-care testing, consistent with the FDA authorization. On the other hand, based on this small dataset, these tests are not suitable for routine large-scale surveillance of asymptomatic individuals.

The current study dealt only with saliva, but this sample's sensitivity to nasopharyngeal swabs is still in question, despite several studies. More quantitative studies will be required to define viral loads in different respiratory specimens and determine the protocol for sensitive determination of viral loads from saliva.

The relationship between viral RNA in a specimen and the live viral titer, which indicates infectivity, can be determined only by head-to-head comparison studies. Much data is therefore still awaited to shape the best testing strategies for viral containment in this pandemic.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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