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.