COVID-19 Diagnostic Use Cases

The intended use is to determine if a symptomatic individual in an epidemic setting has a reasonable likelihood of a current infection warranting temporary isolation pending confirmation testing (Use Case 4). For Group 1 Sites, use examples include locations with known infections such as cruise ships, hospitals, assisted living centers and quarantine facilities. These are locations where multiple people are at least temporary residents (days). Group 2 sites include public health clinics, primary care facilities, urgent care clinics, and emergency departments, where symptomatic individuals will visit temporally unless they are found to be positive. Note that primary care as used here includes community-level settings in low to middle income country (LMIC) regions referred to as Level I and Level 0. These two groups of sites offer different issues for testing. In Group 1 sites, residents can be isolated and confirmation testing can be conducted remotely; however, the Group 2 sites are more problematic since unless the confirmation testing can be conducted locally and rapidly, it will not be possible to keep patients on site long enough to isolate them to prevent potential transmissions. If the Group 2 site were associated with a quarantine location (e.g., emergency department in a hospital) it would be possible to quarantine triaged patients until confirmation-testing results were received within a few hours. In any event, a triage test that permits the majority of symptomatic patients to leave if they have a negative result (low probability of a false negative result; high sensitivity and high negative predictive value) would limit the need to isolate and test for confirmation of infection. On the other hand, the test requires an acceptable false positive rate (high specificity and high positive predictive value) so that few people are unnecessarily quarantined. Even in an epidemic setting, it is likely that most persons with respiratory disease symptoms do not have COVID-19, likely >99%. The balance of clinical performance characteristics and test requirements should be analyzed and justified within an impact model including economic parameters (e.g., hospital and testing costs) and clinical measures (e.g., QALYs). Please contact us for details if you are interested.

The triage test would need to be in a point of care format. Given the sites of use, an instrumentfree solution would be desirable, but a small processing/reading instrument would also be possible for most sites. In either case, a test or system designed to meet CLIA waiver requirements is essential. It is also highly desirable to use information and communication technologies (ICT) to permit test results to be reported remotely, for example, to national health authorities or the WHO. End user price targets for the test are likely to be <$25 for the US, but considerably less for low and middle-income countries (LMICs). For comparison, prices for Ebola PCR-based tests used during the 2018 outbreak in the Democratic Republic of Congo ranged from $10-$79 (estimates) depending on whether they were used in batch mode (20 tests) or as single tests (Cnops, et al.).

We must remember that healthcare professionals today send samples out and wait for results. In any scenario where a test will be performed at the point of care, it is possible the trained professionals will be wearing substantial PPE. In this case, they must be able to perform the test while gloved, gowned and masked, which has implications for the type of sample that can be obtained (e.g., finger prick blood or nasal swabs while wearing gloves), how it can be processed (e.g., micro-capillary manipulation observation while wearing a mask), and the operator interfaces on the devices used (e.g., touch screen while wearing gloves).

The potential use of a triage test in an epidemic is tied to the availability of an acceptable confirmation test. Without rapid availability of confirmatory testing results, quarantine restrictions, even if temporary, will have significant, perhaps unrealistic, impact on the sites and the individuals tested. Also, healthcare professionals will need to maintain PPE requirements until the individual is confirmed to be negative. If the confirmation test can be performed locally, the second set of sites with temporary visiting capacity would benefit greatly. Until there are rapid point of care confirmation tests available, there are likely to be a large number of sample send outs for lab tests, presenting logistical challenges

The intended use is to determine if a symptomatic individual in an endemic or epidemic setting has a reasonable likelihood of a current infection warranting temporary isolation pending confirmation testing (Use Case 4). It is not clear that the endemic scenario will become a reality. Is Wuhan now an endemic site? Or, like SARS-CoV, will SARS-CoV-2 disappear? Although no one can say, for the purpose of discussing the implications for test design, we will assume that COVID-19 will remain a recurring threat, perhaps akin to seasonal flu. We will not address the epidemic scenario again here, but we assume that a test that works in the endemic setting will work in the epidemic setting, if the PPE encumbrances are considered.

The sites of testing are the same as for Use Case 1, except that there will likely be a much broader set of sites that will wish to test. It is also likely that more testing will occur in Group 2 sites (temporary visits) than the Group 1 sites (residents or inpatients). Regulatory requirements, for example the need for CLIA waiver, will again be important considerations. Most of the individuals presenting with respiratory symptoms at the sites are less likely to be infected with SARS-CoV-2 than with other more common respiratory pathogens such as common cold or flu viruses than persons presenting in Use Case 1. The need for high sensitivity remains, but there is now a need for higher specificity since in a low prevalence (e.g., <1%) environment, the majority of positive results could be false positives. For example, with a specificity of 95%, five false positives would be expected for each true positive person. At a 99% specificity, the ratio of false positives to true positives would be 1 to 1, a far more acceptable result. Price targets for the test are likely to be less than for epidemic settings, <$15 for the US, but considerably less for LMICs.

It is likely that isolation will become a major annoyance for persons tested, healthcare professionals, and facilities, especially when PPE and patient isolation is required during the clinical encounter and until the test results are received. Therefore, confirmation testing would need to be very rapid. In fact, it might not be practical to use triage testing in some settings like emergency departments. See Use Case 5 as an alternative. Use Case 3: Triage of at-risk pre-symptomatic and symptom

The intended use is to determine if an at-risk individual with or without symptoms in an endemic setting has a reasonable likelihood of a current infection warranting temporary isolation pending confirmation testing. The sites for testing symptomatic individuals remain the same as Use Case 2; however, the site for testing pre-symptomatic persons is far more problematic. General testing of the population is costly and unacceptable for a variety of reasons including access, adherence, awareness, training and cost. In an endemic setting, occasionally a cluster of new symptomatic cases could appear and initiate a broad testing protocol of recent contacts. A point of care triage test could be used to process and identify infected, pre-symptomatic persons for temporary isolation pending rapid confirmation testing, potentially even at ports of entry or at large public gatherings. Send-out testing taking days would probably not be useful except possibly within confined populations. With very high sensitivity and specificity triage testing (e.g., >99%), it would be possible to eliminate confirmation testing altogether and initiate extended quarantine immediately upon test completion. Such a triage test would be nearly indistinguishable from a diagnostic test (Use Case 5). Price targets for the test are likely to be ~$25 for the US since there would be a premium value for identifying pre-symptomatic patients, but considerably less for LMICs.

The intended use is to confirm that an individual is currently infected with SARS-CoV-2 after positive results from triage testing. Sites of testing would be dependent upon the sites of triage testing. Where the patients are residents or inpatients, patients can remain confined for a few days enabling sample send out; however, in sites of temporary visits, local confirmation testing is preferred, for instance, in a qualified lab near an emergency room or primary care facility. Rapid turnaround of two hours or less would be preferable. It is possible that a mobile lab could be employed. The test could be conducted by a trained laboratorian, but it is preferable that a trained nurse perform testing.

Sensitivity and specificity goals are less than for a diagnostic test, since after triage testing the population will be greatly enriched for infected persons. If the triage test had specificity of 95%, only one in 20 persons would be false positive in the triaged population to be confirmed. Price could be as high as $100 for testing, depending in part (rightly or wrongly) on the assay technology used, but preferably lower. Again, if the triage test were of high enough clinical performance it would not be necessary to use a confirmation test.

The intended use is to diagnose a symptomatic individual with a SARS-CoV-2 infection in an endemic or an epidemic setting. Sites include emergency rooms, urgent care clinics, hospitals, and primary healthcare facilities. The test could be CLIA-waivable for a minimally trained healthcare worker or a moderately complex system for a small lab performed by a laboratorian. The turnaround time needs to be no more than one hour, but preferably 15 minutes or less.

Sensitivity and specificity will need to be quite high (≥ 99%). A false negative result, particularly in the elderly, could result in high morbidity and mortality rates, while increasing the risk of transmissions. False positive results would lead to unnecessary and costly quarantine or hospitalization. Cross reactivity with other respiratory pathogens would be highly problematic. Price targets should be $30-$50 in the US, probably less in LMICs.

The intended use is to diagnose an individual with other upper or lower respiratory infections, such as Influenza A, Influenza B, RSV, pneumonia, bronchitis or SARS-CoV-2 infection in a COVID-19 endemic or epidemic setting. Optimally, the test would also include the four coronaviruses associated with upper respiratory infections and the common cold: HCoV 229E, NL63, OC43, HKU1. The Use Case testing sites and users are the same as Use Case 5, but in this case will require additional high-performing tests run simultaneously. A test result indicating that a person is not infected with SARS-CoV-2 but is infected with an alternative respiratory pathogen would have a great advantage. Even in the absence of a therapy for SARS-CoV-2, this would lead to great comfort for both the patient and the caregiver, although a flu diagnosis shouldn’t be treated lightly. Note that if the test is designed for an endemic setting, it should also be useful in the epidemic setting, since the performance needs are higher for an endemic setting. Acceptable test costs are likely somewhat more than Use Case 5 at $30-$120, depending on the complexity of the test and the assay technology used.