Symptomatic patients
Current practices and
guidelines/recommendations
The priority for symptomatic patients is the need to know if their
symptoms are due to COVID-19; in these cases, NAATs for COVID-19 should
be performed when possible (Figure 1). NAATs are the most sensitive
class of tests available, and this method will help to ensure that cases
are not missed among symptomatic patients.26,40 In
this context we are talking about RT-PCR testing and TMA, not LAMP, as
sensitivity data are still variable (Table
1).17-20,23,41-43 In settings where testing resources
are available but limited, many laboratories have adopted sample pooling
strategies that allow conservation of resources.44Several commercially available assays have regulatory authorization for
pooling and offer guidance regarding the optimal number of samples to
pool and the volume per sample to include in the
pool.45,46 The methods and benefits of pooling are
highly influenced by the prevalence in the population being tested. For
example, creating pools of 10 samples in a population of 10% positivity
would require repeat testing of all of the individual samples in most
pools, thus resulting in extra testing and an extended time to results.
Conversely, pooling only 3 samples in a population with 1% positivity
does not realize all of the reagent savings possible. Pooling strategies
must be evaluated at each laboratory based on the population(s) they
serve and can even be applied to sub-groups of samples sent to the
laboratory to minimize time to results and maximize reagent
conservation.47-49
In settings where NAATs are unavailable, antigen testing is also
acceptable for the diagnosis of symptomatic patients as an option that
is more informative than no testing. Antigen tests detect viral proteins
in a patient’s serum or plasma, and whilst they have a lower sensitivity
than NAATs, they are most sensitive when viral loads are high, which may
correlate with infectivity.50 If symptoms are strongly
indicative of COVID-19, a negative test should also be confirmed with a
NAAT.51-54 The authors consider that specificity is
not an issue with currently available antigen tests, and that whilst
retesting is not needed to confirm positivity, NAATs may be performed to
provide semi-quantitative cycle threshold (Ct) values to aid
understanding of infection status.26,28,52,54-56 The
utility of Ct values is currently unclear and the use of Ct values to
assess infection status is currently only deployed in certain regions,
and only then in patients who require medical intervention for COVID-19.
Depending on the local prevalence and patient-specific risk of
influenza, dual-target NAATs for influenza and COVID-19 may be useful
for differential diagnosis, particularly if an initial NAAT result is
negative and clinical suspicion of respiratory infection is high (Figure
1). However, in many regions the prevalence of influenza is very low,
possibly due to infection control measures for COVID-19, and the risk of
influenza is lower than the normal risk expected for many regional flu
seasons.57-61
If a patient repeatedly tests negative, but their clinical presentation
is highly suggestive of COVID-19 and a diagnosis is required to enable
medical care, a low-dose chest-computed tomography (CT) scan could be
used to diagnose or rule out COVID-19.62-64 However,
this is recommended with caution, as chest-CT scans are less sensitive
than NAATs for COVID-19, and specificity is often over-estimated due to
selection bias and the low prevalence of other pulmonary disease in
retrospective studies. The data suggest that chest-CT scans can be used
to complement diagnostic testing but are not an effective standalone
assessment.62,63
Key considerations
The key determinants of the test for use in symptomatic patients include
the patient’s symptoms/clinical presentation; whether the patient needs
to be admitted for their symptoms or can manage their symptoms at home
with isolation; and in the setting where patients are accessing
testing/sampling and presenting to the healthcare
system.65 Globally, there are vast differences in how
and where symptomatic individuals access healthcare, such as
walk-in/fever clinics, drive-through testing centers, at-home testing
squads, postal testing, and in the hospital/emergency department
(ED)/general (not COVID-specific) clinic/COVID-specific clinic. If
patients are accessing testing in a setting where they could possibly
pass infection on to others, strict hygiene measures need to be applied
and sample collection needs to be done as quickly as possible. If
patients are well enough not to require urgent admission, then
centralized testing is acceptable. However, if patients need urgent
medical care for their symptoms, then rapid testing at the point of care
is required. Several NAATs have been developed that can be performed in
near-patient settings and, if available and affordable, these offer
advantages over antigen-based assays. In symptomatic individuals, test
sensitivity is important to ensure that infectious individuals are not
missed and do not continue to spread their infection, whilst also
ensuring that those who need medical care are appropriately triaged.