POCT modalities and SARS-CoV2 in theory
There are four POC testing approaches for SARS-CoV2 with different
decision-making implications:
- Class I: POCTs for the presence of SARS-CoV2 antigens to identify
active infection (7).
- Class II: molecular POCTs to identify active infection but with
shorter turn-around times than conventional RT-PCR.
- Class III: serological antibody tests (IgG and/or IgM) for
confirmation of infection. This includes most SARS-CoV2-specific
POCTs.
- Class IV: surrogate tests (including FebriDx) that do not directly
diagnose SARS-CoV2 but can be used as screening tests.
POCT utility varies according to time from symptom onset. PCR-based
tests offer better sensitivity in the first few days but performance
declines from as early as day 5 (8). Class III POCTs likely offer value
only from day 7-8 because of the time taken to generate a detectable
antibody response (9–11). All POCTs are, for now, used to guide interim
decision-making pending final diagnosis via RT-PCR.
While class I, II and III modalities test for SARS-CoV2-specific
antigens, RNA or antibodies respectively, FebriDx is a composite tool
that detects both Myxovirus resistance protein A (MxA – elevated in
acute viral infections) and C-reactive protein (CRP – elevated in
either viral or bacterial infections). The test uses fixed thresholds
for “positive” MxA and CRP levels; any positive MxA result, with or
without positive CRP, indicates viral infection (4). These markers are
used because: [i] CRP production is stimulated by Interleukin-6
(IL-6), produced in higher quantities in bacterial infections; [ii]
MxA expression is exclusively driven by Type 1 Interferons (IFN-1),
secreted in response to detection of viral signatures by host
intracellular receptors. IFN-1, and consequently MxA, are thought to be
specific to viral infection (4).
There may be grounds for caution in interpreting FebriDx results at the
extremes of the clinical course. Early SARS-CoV infection appears not to
activate MxA and IFN-1 transcription in the normal way (12), and if
SARS-CoV2 similarly attenuates early MxA expression, FebriDx may have
low sensitivity in at least the first few days following infection. The
low MxA threshold for a positive result (40ng/mL) means FebriDx may
nevertheless be positive even with weak MxA activation.