Journal Logo

What to D.O.

What to D.O.

A Confusing COVID-19 Testing Landscape

Pescatore, Richard DO

doi: 10.1097/01.EEM.0000688824.38191.27
    Figure
    Figure:
    coronavirus, COVID-19, testing
    Figure
    Figure

    For months, we've heard repeated calls for better COVID-19 testing availability. Emergency physicians have struggled with accessibility to testing, more often than not relying on peripheral markers of illness (radiographic findings, elevations in inflammatory markers, etc.) than any timely and actionable viral PCR data.

    As supply chains have improved, availability has exploded and turnaround times on viral test results have narrowed, though many areas of the country are still left wanting, a baffling disparity, but one that emergency physicians will be forced to contend with for the duration of the pandemic.

    I spend much of my day in my public health role focused on the growing list of testing modalities and their varied pros and cons. Understanding the types of tests available to patients—whether inside the ED, throughout the hospital or ambulatory care offices, or at wider-access community testing sites—is important for emergency physicians to navigate an increasingly confusing testing landscape. I make no assertions that this discussion would pass a laboratorian's sniff test, but believe it provides a bit more insight for my fellow EPs.

    PCR Testing

    Molecular testing utilizing reverse transcriptase polymerase chain reaction (rt-PCR) is the foundation of testing for SARS-CoV-2 at present. These tests can be performed through a variety of methods, with the most preferred beginning with a nasopharyngeal swab, though the world quickly moved to accept oropharyngeal swabs, collection via nostrils, and recently even buccal swabs or saliva.

    In the earliest phases of the pandemic, this first step—collection—was an unexpected hurdle for many because existing supplies of collection kits were exhausted nearly immediately. Hospitals and health authorities moved quickly to cobble together swabs from every corner, and assembly lines of volunteers or the National Guard formed around the country, pipetting viral transport media (and, later on, sterile saline) into transport tubes to pair with a patchwork of repurposed collection swabs.

    Collected specimens can then be processed through a number of methods, each with its own list of advantages, disadvantages, and challenges and with varying accessibility and turnaround time. For most of these processes, an extraction step is required prior to processing. This piece posed—and continues to pose—a rate-limiting step in processing patient samples. Extraction can be performed manually (through a labor-intensive process that also introduces increased possibility for error), robotically (though supplies are expensive and limited), or through proprietary processes that marry this step with others. Some of the faster turnaround and more popularized machines (e.g., the Abbott ID NOW or the Cepheid Xpert Xpress) utilize this latter method, but they have their own downsides including reagent availability and throughput (the Abbott ID NOW, for example, can process just one patient sample at a time). The FDA has granted emergency use authorizations to an increasing number of extraction platforms, some of which have already significantly improved the process.

    The amplification and detection steps of PCR suffered an early setback when test kits shipped by the CDC were found to have faulty negative controls and a primer and probe set (the now-infamous N3 set) was subsequently removed from the SARS-CoV-2 diagnostic panel. Beyond this, the sensitivity of available PCR assays—CDC-delivered and commercially-available alike—has been questioned, with some studies finding that nearly 30 percent of positive cases could be missed. Indeed, social media abounds recently with EMR snapshots showing staccato and unpredictable SARS-CoV-2 results in single patients, and many of us have had the experience of glaringly obvious COVID-19 patients with multiple negative test results, only to turn positive with either a BAL specimen or a nasopharyngeal swab performed with just the right flick of the wrist.

    Antibody Testing

    Few topics have received as much attention (and, frankly, as much misunderstanding) as the role of antibody testing. Statistical purists have saturated the conversation with warnings about specificity shortcomings and the harms that can result in low-prevalence populations, important considerations but too often lacking operational context important to implementation. We have little knowledge about the clinical effects of serologic immunity, but nonetheless can use antibody testing to help inform population-level public health efforts, such as supervised outbreak investigations among congregate settings.

    Antibody testing generally comes in point-of-care lateral flow immunoassays (rapid antibody tests), traditional quantitative serology such as enzyme-linked immunosorbent assay (ELISA, common to many commercially available antibody tests), or chemiluminescent microparticle immunoassay (CMIA, as in the case of the Abbott SARS-CoV-2 IgG assay). The former can provide nearly instantaneous information at the bedside or within the ambulatory care setting, but it has been plagued by a sluice of poorly manufactured and unreliable tests released onto the market following regulatory relaxation by the FDA. Much conversation was had about cross-reactivity of these assays with previously circulating coronavirus strains (namely, HKU1, NL63, OC43, or 229E), but such cross-reactivity was never well documented among validated tests.

    In the early phases of the pandemic, assays that were validated in high-complexity labs to have high specificity for SARS-CoV-2 IgM served as a reasonable surrogate for a positive PCR, a helpful tool when and where PCR was extremely limited. Nonetheless, the use of lateral flow immunoassays to identify durable immunity with IgG would be a risky venture at best. Some practitioners may have purchased these devices for use in offices or even among friends and family, but all would be well-advised to be mindful of regulations that restrict use to laboratories certified to certain complexity under the Clinical Laboratory Improvement Amendments of 1988 (CLIA).

    Quantitative serology with ELISA or CMIA is an area that remains largely unexplored, but one into which we have tiptoed as I write this in mid-May. These tests call for a blood tube for serum or plasma to be run on a large lab-based machine. Throughput and turnaround are generally quite quick, and supplies for testing seem fairly plentiful at the moment. Analytical performance numbers are reportedly very high (as close to perfect as we're likely to get), and the numbers are believable based on the technology being utilized. By the time this article is published, it is likely that widespread IgG testing will have commenced. At present, however, there are more questions than answers, including what serological immunity means clinically, what (if any) the role of “immunity passports” might play (there is significant concern among bioethicists that such documents might lead to a perverse incentive for infection, spurring COVID parties and risky behavior), and who (if anyone) should be prioritized for immunologic testing.

    “Testing,” is, in reality, a complex web of multiple different testing types, vendors, steps, and processes. Emergency physicians stand at the front line of COVID-19 treatment, but we may continue to have difficulty accessing testing for many weeks to come, and once it becomes available, will need to understand the advantages, disadvantages, and proper implementation of testing for our patients, friends, and families

    Dr. Pescatoreis the chief physician for the Delaware Division of Public Health and an emergency physician in New Jersey and the host with Ali Raja, MD, of the podcast EMN Live, which focuses on hot topics in emergency medicine:http://bit.ly/EMNLive. Follow him on Twitter@Rick_Pescatore, and read his past columns athttp://bit.ly/EMN-Pescatore.

    Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.