A comment by Peeling and Olliaro published March 25th in The Lancet Infectious Diseases suggests that scaling up testing in tandem with appropriate public health measures and vaccine rollout might effectively contribute to all our lives returning to some level of normality.
Molecular testing is the method of choice for detecting SARS-CoV-2 infection.
When capacity is restricted, supplies are inconsistent, or delays are experienced in providing results, one needs to look at other testing modalities.
Boum and colleagues presented the results of PCR, antigen based and antibody based rapid diagnostic tests in individuals with symptomatic COVID-19 during the first, second, and third week after onset of symptoms, and in asymptomatic individuals who volunteered for testing or were contacts of COVID-19 cases.
Antigen based rapid diagnostic test sensitivity was 80% in the first seven days after symptom onset and 76% in the second week post symptom onset, dropping to 19% by week three, compared with PCR.
Conversely, the sensitivity of antibody based rapid diagnostic testing increased with duration of illness, from 26.8% sensitivity in week one to 76.4% 14 days after symptom onset.
Boum and colleagues developed a diagnostic algorithm combining use of antigen rapid diagnostic tests with PCR confirmation of samples negative at antigen rapid diagnostic tests.
In week one 60% of symptomatic patients tested positive by PCR and 54% of symptomatic patients tested positive by antigen based rapid diagnostic tests.
The advantages of this approach are that it is not only highly sensitive, 94% on days 0-7 after onset of symptoms, providing most patients with results in 15 minutes, but also cost effective reducing the cost of PCR testing by almost 50% if antigen rapid testing detects 54% of infected people in this population then PCR is only required for the remaining 46% of people who test antigen negative – compared with using PCR on everyone, which clearly has a cost saving of nearly 50%.
However, after the first week post symptom onset, although use of antigen based rapid diagnostic testing improved the sensitivity of case attention, it is limited by low specificity, which translates into high numbers of false positives samples that require PCR confirmation.
Therefore, timing is everything.
The reduced costs and quicker turnaround times of this diagnostic algorithm should prompt decision makers to encourage people to present for testing early.
Early diagnosis and isolation of individuals with COVID-19 in order to interrupt transmission remains the key strategy for pandemic control.
The screening of asymptomatic individuals, the usefulness of antigen based rapid diagnostic tests depends on both the purpose of testing and the prevalence of COVID-19 in the population to be screened.
This can be used for triaging of those who can return to school, work, attend mass gatherings or travel, it is important that antigen based rapid diagnostic tests have a high negative predictive value, so those who test negative are truly negative.
When used instead for case funding amongst say contacts of cases as in the Boum and colleagues study, it is important that individuals identified as antigen base rapid diagnostic test positive are truly infected with SARS-CoV-2 meaning a high positive predictive value.
Boum and colleagues evaluated an algorithm combining antigen based rapid diagnostic test screening with antibody based rapid diagnostic test screening of those who tested antigen based test negative, followed by PCR confirmation of IgM positive samples.
This case finding strategy only had a sensitivity of 35%, which is marginally better than PCR alone, with a specificity of 92%, yielding a low positive predictive value.
The use of antibody based tests in an algorithm to increase sensitivity of detection in people presenting late in their illness or who are asymptomatic is also useful but requires tests with specificity of 98% or more to be effective.
In Boum and colleagues’ study, none of the antibody based rapid diagnostic tests appear to have had sufficiently high specificity compared with a laboratory based assay for this algorithm to be helpful.
Combining antibody based rapid diagnostic tests with antigen based diagnostic tests might also be useful to increase sensitivity of case detection, as has been shown in dengue fever.
This combination might also be useful in determining the phase of an individual’s infection and derive information on potential for transmission andf protection.
Diagnostic algorithms that maximise the advantage of each type of test and use them in combination to mitigate risks of under diagnosing and over diagnosing COVID-19 are important tools for pandemic control, especially when we are concerned about the rapid spread of variants of concern.
As the diagnostic target of most antigen tests is the nucleocapsid protein and most of the mutations of the variants of concern are on the spike protein, countries should not hesitate to roll out antigen testing.
Scaling up testing in tandem with appropriate public health measures and vaccine rollout will effectively contribute to us returning to as normal a life as possible
The London General Practice has developed COVID testing regimes involving lateral flow antigen tests, rapid antigen tests, within all populations to ensure that as much as possible a workforce, mass gathering, social interaction can take place so that those infected with SARS-CoV-2 can be identified as quickly, efficiently and as cost effective way as soon as possible.
Dr Paul Ettlinger
BM, DRCOG, FRCGP, FRIPH, DOccMed