ANNALS OF MEDICINE 2020, VOL. 52, NO. 5, 207–214 https://doi.org/10.1080/07853890.2020.1763449 ORIGINAL ARTICLE Multi-tiered screening and diagnosis strategy for COVID-19: a model for sustainable testing capacity in response to pandemic Michael S. Puliaa, Terrence P. O’Brienb, Peter C. Houc, Andrew Schumand and Robert Samburskye aBerbeeWalsh Department of Emergency Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; bCharlotte Breyer Rodgers Distinguished Chair Ocular Microbiology Laboratory, Infection Control Unit, Bascom Palmer Eye Institute, University of Miami, Miller School of Medicine, Miami, Florida, U.S.A; cDivision of Emergency Critical Care Medicine, Department of Emergency Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; dDepartment of Pediatrics, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA; eLumos Diagnostics, Inc., Sarasota, FL, USA ABSTRACT ARTICLE HISTORY Coronavirus disease 2019 (COVID-19), caused by novel enveloped single stranded RNA corona- Received 8 April 2020 virus (SARS-CoV-2), is responsible for an ongoing global pandemic. While other countries Revised 27 April 2020 deployed widespread testing as an early mitigation strategy, the U.S. experienced delays in Accepted 28 April 2020 development and deployment of organism identification assays. As such, there is uncertainty KEYWORDS surrounding disease burden and community spread, severely hampering containment efforts. COVID-19; Coronavirus; COVID-19 illuminates the need for a tiered diagnostic approach to rapidly identify clinically sig- SARS-CoV-2; myxovirus nificant infections and reduce disease spread. Without the ability to efficiently screen patients, resistance protein A (MxA); hospitals are overwhelmed, potentially delaying treatment for other emergencies. A multi-tiered, C-reactive protein (CRP); diagnostic strategy incorporating a rapid host immune response assay as a screening test, molecular diagnostics; molecular confirmatory testing and rapid IgM/IgG testing to assess benefit from quarantine/fur- serology; rapid diagnostic ther testing and provide information on population exposure/herd immunity would efficiently tests; point-of-care test evaluate potential COVID-19 patients. Triaging patients within minutes with a fingerstick rather than hours/days after an invasive swab is critical to pandemic response as reliance on the exist- ing strategy is limited by assay accuracy, time to results, and testing capacity. Early screening and triage is achievable from the outset of a pandemic with point-of-care host immune response testing which will improve response time to clinical and public health actions. KEY MESSAGES Delayed testing deployment has led to uncertainty surrounding overall disease burden and community spread, severely hampering public health containment and healthcare system preparation efforts. A multi-tiered testing strategy incorporating rapid, host immune point-of-care tests can be used now and for future pandemic planning by effectively identifying patients at risk of dis- ease thereby facilitating quarantine earlier in the progression of the outbreak during the weeks and months it can take for pathogen specific confirmatory tests to be developed, vali- dated and manufactured in sufficient quantities. The ability to triage patients at the point of care and support the guidance of medical and therapeutic decisions, for viral isolation or confirmatory testing or for appropriate treatment of COVID-19 and/or bacterial infections, is a critical component to our national pandemic response and there is an urgent need to implement the proposed strategy to combat the current outbreak. Background visits annually in the United States [2]. Community- Acute respiratory infection (ARI) is responsible for acquired bacterial pneumonia (CABP), which is com- more than 100 million adult ambulatory care visits [1] monly associated with ARI, is the second most com- and 29 million paediatric emergency department (ED) mon cause of hospitalization and the most common CONTACT Michael S. Pulia [email protected] Emergency Care for Infectious Diseases (ECID) Research Program, BerbeeWalsh Department of Emergency Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA This article has been republished with minor changes. These changes do not impact the academic content of the article. ß 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by- nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. 208 M. S. PULIA ET AL. infectious cause of death in the United States [3]. uncomfortable for the patient when administered cor- Viruses cause over 85% of ARIs [1] with seasonal influ- rectly, and specialized training is suggested for those enza typically affecting 3–8% of the U.S. population administering the test. After swabbing, the provider each year [4]. Common bacterial infections such as mixes the specimen with liquid in an open container group A streptococcus pharyngitis and CABP comprise which could release a highly contagious pathogen, the remaining minority of ARI [1]. Coronavirus disease spread by droplets, into the air. NP swabs may also be 2019 (COVID-19), caused by novel enveloped single- considered an aerosol generating procedure (AGP), stranded RNA coronavirus (SARS-CoV-2), has a similar which may induce a cough and repeatedly expose nucleotide identity to other novel coronavirus out- healthcare workers to droplets transmission. Thus, breaks causing ARI in humans, 2003 SARS-CoV and healthcare workers who perform this testing may 2012 MERS-CoV [5–7]. SARS-CoV-2 is responsible for a need additional protective equipment, which remains global pandemic that began in the winter of 2019. in short supply, to safely perform this testing. Although overall COVID-19 mortality rates are low Inadequate sample collection may also contribute to relative to other recent viral epidemics (e.g. SARS, the reduced sensitivity of molecular tests [17,18]. Ebola) [8,9], older adults and those with chronic dis- Increasingly, false negative molecular test results ease are at substantially increased risk of morbidity are of concern to clinicians on the frontlines who see and mortality and increasingly, younger adults (<50) patients with clear clinical presentations of COVID-19 are requiring critical care hospital resources [10]. The (e.g. cough, fever, characteristic chest imaging) and sudden spike in patients requiring ventilator support test negative for SARS-CoV-2 on day one but test posi- overwhelmed local healthcare systems in several areas tive days later [17,18]. Recently released data from the of the world including Wuhan, China and most Cleveland Clinic showed a false negative rate of 14.8% recently northern Italy and New York City [11,12]. Per of the 239 specimens tested with a rapid PCR test Institute of Healthcare Metrics and Evaluation, the [19]. The risk for false negative results requires repeat peak of daily COVID-19 deaths was 2,688 on April 15, molecular testing, potentially adding days to a con- 2020 and over 55,000 people have died in the U.S. as firmatory diagnosis. Additionally, as PCR is theoretically of April 27, 2020 [13,14]. capable of detecting small amounts of pathogen, it is While other countries deployed widespread testing yet to be elucidated what a positive result means in early during the SARS-CoV-2 pandemic (e.g. South terms of infectivity, colonization, and active infection, Korea, Germany), the U.S. has experienced significant especially among those who are asymptomatic. delays in the development and deployment of organ- The requirement of ancillary equipment and com- ism identification assays. As such, there is uncertainty plex technical operation by trained professionals in surrounding overall disease burden and community certified labs subjects molecular RT-PCR tests to limita- spread, severely hampering public health containment tions. These include the procurement of expensive and healthcare system preparation efforts. COVID-19 materials and equipment. In addition, these assays illuminates the need for a tiered and coordinated take 1 to 3 h to perform and total turnaround time diagnostic approach to rapidly identify clinically sig- can take upwards of 24 hours if the local lab does not nificant infections and reduce the spread of disease. have molecular testing capabilities in-house. Without the ability to efficiently screen patients, Considering that specimens often need to be trans- healthcare facilities will become overwhelmed, poten- ported to a testing facility, there can be a delay in tially delaying treatment for other emergency condi- establishing a diagnosis. tions (e.g. bacterial sepsis). Finally, concerns about testing capacity, including Molecular pathogen detection using real-time poly- reagent shortages, have resulted in the Centres for merase chain reaction (PCR) has been established as Disease Control and Prevention issuing guidelines rec- the gold standard for confirmatory diagnosis of SARS- ommending testing be restricted to only select popu- CoV-2 infections. This technology is designed to be a lation (e.g. high risk) [20]. This limits front line