What is the diagnostic accuracy of antibody tests for the detection of infection with the COVID‐19 virus?
Background
COVID‐19 is an infectious disease caused by the SARS‐CoV‐2 virus that spreads easily between people in a similar way to the common cold or ‘flu’. Most people with COVID‐19 have a mild‐to‐moderate respiratory illness, and some may have no symptoms (asymptomatic infection). Others experience severe symptoms and need specialist treatment and intensive care.
In response to COVID‐19 infection, the immune system develops proteins called antibodies that can attack the virus as it circulates in their blood. People who have been vaccinated against COVID‐19 also produce these antibodies against the virus. Tests are available to detect antibodies in peoples' blood, which may indicate that they currently have COVID‐19 or have had it previously, or it may indicate that they have been vaccinated (although this group was not the focus of this review).
Why are accurate tests important?
Accurate testing allows identification of people who need to isolate themselves to prevent the spread of infection, or who might need treatment for their infection. Failure of diagnostic tests to detect infection with COVID‐19 when it is present (a false negative result) may delay treatment and risk further spread of infection to others. Incorrect diagnosis of COVID‐19 when it is not present (a false positive result) may lead to unnecessary further testing, treatment, and isolation of the person and close contacts. Accurate identification of people who have previously had COVID‐19 is important in measuring disease spread and assessing the success of public health interventions.
To determine the accuracy of an antibody test in identifying COVID‐19, test results are compared in people known to have (or have had) COVID‐19 and in people known not to have (or have had) COVID‐19. The criteria used to determine whether people are known or not known to have COVID‐19 is called the ‘reference standard’. Many studies use a test called reverse transcriptase polymerase chain reaction (RT‐PCR) as the reference standard, with samples taken from the nose and throat. Additional tests that can be used include measuring symptoms, like coughing or high temperature, or ‘imaging’ tests like chest X‐rays. People known not to have COVID‐19 are sometimes identified from stored blood samples taken before COVID‐19 existed, or from patients with symptoms confirmed to be caused by other diseases.
What did the review study?
We wanted to find out whether antibody tests:
‐ are able to diagnose infection in people with or without symptoms of COVID‐19, and
‐ can be used to find out if someone has already had COVID‐19.
The studies we included in our review looked at three types of antibodies. Most commonly, antibody tests measure two types known as IgG and IgM, but some tests only measure a single type of antibody or different combinations of the three types of antibodies (IgA, IgG, IgM).
What did we do?
We looked for studies that measured the diagnostic accuracy of antibody tests to detect current or past COVID‐19 infection and compared them with reference standard criteria. Since there are many antibody tests available, we included studies assessing any antibody test compared with any reference standard. People could be tested in hospital or in the community. The people tested may have been confirmed to have, or not to have, COVID‐19 infection, or they may be suspected of having COVID‐19.
Study characteristics
We found 178 relevant studies. Studies took place in Europe (94), Asia (45), North America (35), Australia (2), and South America (2).
Seventy‐eight studies included people who were in hospital with suspected or confirmed COVID‐19 infection and 14 studies included people in community settings. Several studies included people from multiple settings (35) or did not report where the participants were recruited from (39).
One hundred and forty‐one studies included recent infection cases (mainly week 1 to week 3 after onset of symptoms), and many also included people tested later (from day 21 onwards after infection) (117).
Main results
In participants that had COVID‐19 and were tested one week after symptoms developed, antibody tests detected only 27% to 41% of infections. In week 2 after first symptoms, 64% to 79% of infections were detected, rising to 78% to 88% in week 3. Tests that specifically detected IgG or IgM antibodies were the most accurate and, when testing people from 21 days after first symptoms, they detected 93% of people with COVID‐19. Tests gave false positive results for 1% of those without COVID‐19.
Below we illustrate results for two different scenarios.
If 1000 people were tested for IgG or IgM antibodies during the third week after onset of symptoms and only 20 (2%) of them actually had COVID‐19:
‐ 26 people would test positive. Of these, 8 people (31%) would not have COVID‐19 (false positive result).
‐ 974 people would test negative. Of these, 2 people (0.2%) would actually have COVID‐19 (false negative result).
If 1000 people with no symptoms for COVID‐19 were tested for IgG antibodies and 500 (50%) of them had previously had COVID‐19 infection more than 21 days previously:
‐ 455 people would test positive. Of these, 6 people (1%) would not have been infected (false positive result).
‐ 545 people would test negative. Of these, 51 (9%) would actually have had a prior COVID‐19 infection (false negative result).
How reliable were the results of the studies of this review?
We have limited confidence in the evidence for several reasons. The number of samples contributed by studies for each week post‐symptom onset was often small, and there were sometimes problems with how studies were conducted. Participants included in the studies were often hospital patients who were more likely to have experienced severe symptoms of COVID‐19. The accuracy of antibody tests for detecting COVID‐19 in these patients may be different from the accuracy of the tests in people with mild or moderate symptoms. It is not possible to identify by how much the test results would differ in other populations.
Who do the results of this review apply to?
A high percentage of participants were in hospital with COVID‐19, so were likely to have more severe disease than people with COVID‐19 who were not hospitalised. Only a small number of studies assessed these tests in people with no symptoms. The results of the review may therefore be more applicable to those with severe disease than people with mild symptoms.
Studies frequently did not report whether participants had symptoms at the time samples were taken for testing making it difficult to fully separate test results for early‐phase infection as opposed to later‐phase infections.
The studies in our review assessed several test methods across a global population, therefore it is likely that test results would be similar in most areas of the world.
What are the implications of this review?
The review shows that antibody tests could have a useful role in detecting if someone has had COVID‐19, but the timing of test use is important. Some antibody tests may help to confirm COVID‐19 infection in people who have had symptoms for more than two weeks but who have been unable to confirm their infection using other methods. This is particularly useful if they are experiencing potentially serious symptoms that may be due to COVID‐19 as they may require specific treatment. Antibody tests may also be useful to determine how many people have had a previous COVID‐19 infection. We could not be certain about how well the tests work for people who have milder disease or no symptoms, or for detecting antibodies resulting from vaccination.
How up‐to‐date is this review?
This review updates our previous review. The evidence is up‐to‐date to September 2020.
Fox T, Geppert J, Dinnes J, Scandrett K, Bigio J, Sulis G, Hettiarachchi D, Mathangasinghe Y, Weeratunga P, Wickramasinghe D, Bergman H, Buckley BS, Probyn K, Sguassero Y, Davenport C, Cunningham J, Dittrich S, Emperador D, Hooft L, Leeflang MMG, McInnes MDF, Spijker R, Struyf T, Van den Bruel A, Verbakel JY, Takwoingi Y, Taylor-Phillips S, Deeks JJ. Antibody tests for identification of current and past infection with SARS‐CoV‐2. Cochrane Database of Systematic Reviews 2022, Issue 11. Art. No.: CD013652. DOI: 10.1002/14651858.CD013652.pub2.
The editorial base of the Cochrane Infectious Diseases Group is funded by UK aid from the UK government for the benefit of low- and middle-income countries (project number 300342-104). The views expressed do not necessarily reflect the UK government's offical policies.