On January 19, 2020, a 35-year-old man with a 4-day history of cough, subjective fever, and recent travel history to Wuhan, China, presented to an urgent care clinic in Snohomish County, Washington. A health alert from the United States Centers for Disease Control and Prevention (CDC) regarding a novel coronavirus outbreak in China1 – in conjunction with his symptoms and travel history – prompted him to seek care. On January 20, 2020, the CDC confirmed that samples from the patient’s nasopharyngeal and oropharyngeal swabs tested positive for that virus, now known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), making this man the first confirmed case of the coronavirus disease of 2019 (COVID-19) in the United States.2,3
Close to 3 months later, >1 million individuals in the United States have tested positive for SARS-CoV-2.5 This rapid spread has been attributed to a number of factors including the high transmissibility of the virus,6,7 especially among asymptomatic or minimally symptomatic carriers;8,9 the apparent absence of any cross-protective immunity from related viral infections; and a delayed public health response.10,11,12
The overall confirmed case number, however, is primarily a function of the scope of testing, which is dependent on the case definition for COVID-19 and the number of tests available. Both factors have proved to be a point of contention as the virus continues its spread throughout the United States, and as a review published in Annals of Internal Medicine pointed out, there is a critical need for ample, accurate diagnostic testing in the face of this historic pandemic.13
Why Testing Matters
Until an effective vaccine or treatment is available, mitigating the spread of a virus as infectious as SARS-CoV-2 requires taking steps to minimize transmission. The review authors noted that these considerations necessitate reducing the number of people exposed to the virus as well as reducing the basic reproductive number (R0) of the virus. This is most effectively accomplished by employing high rates of testing for infection. In the United States, community transmission began to occur before adequate testing measures were implemented. As such, Americans were forced to follow a population-based mitigation strategy for COVID-19 via measures such as social distancing and stay-at-home orders. A robust testing strategy, however, will support the United States’ to transition to the case-based mitigation strategy seen in a number of other countries. This strategy would allow for:
- Detecting infected individuals.
- Interrupting transmission through isolation of contagious individuals.
- Contact tracing of infected individuals to further mitigate transmission.
In the clinical setting, testing also aids in triage, allocation of personal protective equipment, prevention of nosocomial infections and, once available, decisions regarding treatment. This strategy, however, is contingent on the types of tests available, the resources required for testing, and turnaround time to results.
The review authors highlight that testing strategies have varied from country to country and are contingent on both the public health resources available as well as the degree of viral spread within respective communities.
In the United States, testing was arguably slow to ramp up, a fact that has been attributed to a narrow testing indication, limited testing capacity, and regulatory hurdles for developing and conducting tests.13,14,15 Early in the course of the outbreak, the only approved test for SARS-CoV-2 was the CDC assay developed under Emergency Use Authorization (EUA) from the US Food and Drug Administration (FDA), which required samples to be sent directly to the CDC lab in Atlanta, Georgia. Kits developed by the CDC were eventually sent to state and local public health laboratories to improve access and mitigate spread, but shortly thereafter, the CDC reported several labs had difficulties in validating results due to a faulty reagent.16,17 As such, guidance to send samples directly to CDC remained, and concerns regarding scope and turnaround time for confirming diagnoses persisted.
After delays in re-issuing validated CDC test kits, the FDA sought to improve access to testing by announcing on February 29, 2020 that they would allow laboratories certified to perform high-complexity testing to “develop and begin to use validated COVID-19 diagnostics before the FDA [had] completed review of their [EUA] requests.” 18 By March 21, EUAs had been granted to >20 diagnostic tests and the number of samples tested per day increased from 32 to >44000.14 The FDA has continued to update their approval process; as of April 30, EUAs have been granted to >50 tests for SARS-CoV-2,19 testing capacity has increased to >230,000 per day,14 with >1 million Americans testing positive.4,5
Improving the Testing Paradigm
Although real-time reverse transcriptase polymerase chain reaction (RT-PCR) based assays of respiratory specimens have been the predominant mode of diagnostic testing in the United States, a number of novel and complementary diagnostic strategies are also being considered. RT-PCR can be resource-intensive and slow; delays also put the contacts of patients under investigation at risk for infection. As the review authors noted, innovative testing strategies such as point of care testing, serologic testing, and home specimen collection, may help expedite both the collection and testing of specimen.
Point of Care Test
A low-complexity, rapid molecular diagnostic test that can be conducted at the point of care, thus not requiring a complex lab or specially trained personnel, will be an important tool for mitigating the spread of COVID-19. On March 21, 2020, the FDA granted its first EUA to the Xpert Xpress SARS-CoV-2 point-of-care test developed by Cepheid, which claims to provide results 45 min.20
“Having a test that will tell you the disease you have, but in 5 days, will not help with decisions about triage and where you are going to put patients. We need an answer quickly, ideally we need an answer right away, but any answer that is in less than an hour is something that can be actionable,” noted David Alland, MD, MSc, whose team has been working with Cephied to validate their rapid point of care test.
Dr Alland, professor of medicine, chief of infectious disease, and the director of the Center for Emerging Pathogens and the Rutgers Regional Biocontainment Laboratories at Rutgers New Jersey Medical School, has been a pioneer in the diagnosis, treatment, and molecular study of mycobacterium tuberculosis. He noted that “this is the same problem we had with drug resistant tuberculosis [TB] 10, 20 years before. We were cohorting patients, taking people who were coming into the hospital to get better and making them worse because they were infected with a drug resistant form of TB.”
In the setting of COVID-19, Dr Alland believes a similar concern exists. Patients not infected with SARS-CoV-2 requiring admission to a hospital may, inadvertently, fall ill and possibly die as a result of COVID-19.
The FDA has since granted EUAs to 3 additional point of care tests for rapid detection of SARS-CoV-2.19 Although point-of-care tests are not meant to replace traditional RT-PCR tests conducted in high throughput laboratories, they will likely play an important role in critical decision making for patients. Moreover, they can help minimize the number of healthcare workers being exposed to the virus and potentially falling ill. “In the immediate time frame, a point of care test is not going to help ‘flatten the curve.’ It is going to help keep patients and healthcare workers alive,” said Dr Alland. “In the longer term, a point of care test that can go out and detect cases in the community can help ‘flatten the curve’ and help keep it flat.”
What can clinicians in the US accomplish with point of care testing? Listen to the Weekly Rounds’ discussion, with further insight from David Alland, MD, MSc, Professor of Medicine and the Chief of Infectious Disease at Rutgers New Jersey Medical School.
Serologic tests analyze specimens, such as blood or saliva, for the presence of antibodies, and can indicate whether or not an individual has mounted a response to an infection rather than detect the virus itself. The review authors caution that their utility in diagnosing acute infections is limited, as antibody response to infection can take days to weeks to be reliably detectable. Serologic assays may be more relevant in scenarios in which patients present with late complications of COVID-19 and RT-PCR may be falsely negative due to a decrease in viral shedding.21
In March 2020, the FDA issued a policy allowing the developers of certain serologic tests to begin administering them once accuracy and reliability has been established.22 FDA Commissioner Stephan M. Hahn, MD noted in a statement that “serological tests can play a critical role in the fight against COVID-19 by helping healthcare professionals to identify individuals who have overcome an infection in the past and have developed an immune response.” He added that, “in the future, this may potentially be used to help determine, together with other clinical data, that such individuals are no longer susceptible to infection and can return to work.”22
Serologic testing may also aid in epidemiologic studies, ongoing surveillance, vaccine studies, and risk assessment of health care workers.
At present, there are no home testing kits approved by the FDA. However on April 21, 2020 the FDA reissued the EUA for a RT-PCR assay developed by LabCorp for COVID-19, which allows for a home collection option of samples. “We worked with LabCorp to ensure the data demonstrated from at-home patient sample collection is as safe and accurate as sample collection at a doctor’s office, hospital or other testing site,” Dr Hahn remarked in a statement from the FDA.23
Scaling Up Tests
EUAs have allowed for local public health laboratories and academic diagnostic laboratories in the United States to rapidly perform assays for SARS-CoV-2. However, the authors of the Annals review noted that it will be important to continue advancing solutions that can be implemented in less well-equipped laboratories to mitigate the spread of the pandemic on a global scale. Antigen-based tests, for example, may prove useful in both low-resource and home settings to guide quarantine and social distancing measures, especially among patients who are mildly symptomatic. Further, novel diagnostic tools such as Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR) may prove useful to nontraditional and resource-limited settings, such as airports and border crossings. Finally, the review authors emphasized that efforts should be made to leverage existing surveillance networks. The CDC has already begun modifying existing systems used to track annual influenza infections and other respiratory viruses to monitor the spread of COIVD-19.24
Current Testing Guidance
For clinicians who may be considering a test for a person under investigation, the CDC recommends working with local and state health departments to coordinate testing through public health laboratories; alternatively, they may use laboratory tests for COVID-19 that have been granted an EUA by the FDA.25
Clinicians are advised to use their best judgment to determine whether or not a patient has signs and symptoms compatible with a diagnosis of COVID-19 and whether the patient should be tested. Tests for other causes of respiratory illness should be considered as needed. At present, the CDC recommends COVID-19 priority testing for:
- Hospitalized patients with presentations compatible with COVID-19, including but not limited to fever, cough, shortness of breath, chills, muscle pain, new loss of taste or smell, vomiting or diarrhea or sore throat. [High]
- Healthcare workers, workers in congregate living settings, and first responders with symptoms. [High]
- Residents in long-term care facilities or other congregate living settings, including prisons and shelters, with symptoms. [High]
- Persons identified through public health clusters and selected contact investigations. [High]
- Individuals with symptoms of compatible with COVID-19.
- Individuals without symptoms who are prioritized by health departments or clinicians, for any reason, including but not limited to: public health monitoring, sentinel surveillance, or screening of other asymptomatic individuals according to state and local plans.
Recommended infection prevention and control practices should be implemented if a patient is suspected of having COVID-19. The CDC advises clinicians to notify infection control personnel at their healthcare facility and their state or local health department if a patient is classified as a person under investigation for COVID-19. (Note: guidance is subject to change and the latest information can be found on the CDC’s page for evaluating and testing persons with COVID-19)
“Urgent clinical and public health needs now drive an unprecedented global effort to increase SARS-CoV-2 testing capacity,” noted the review authors in a concluding remark. They emphasized that “the blinding speed with which COVID-19 has spread illustrates the need for preparedness and long-term investments in diagnostic testing.”
Accordingly, the CDC announced on April 23, 2020 that they will be awarding $631 million to state and local jurisdictions using funds from the Coronavirus Aid, Relief and Economic Security (CARES) Act of 2020,26 with the goal of:
- Establishing or enhancing the ability to aggressively identify cases, conduct contact tracing and follow up, and implement appropriate containment measures.
- Improving morbidity and mortality surveillance.
- Enhancing testing capacity.
- Controlling COVID-19 in high-risk settings and protecting vulnerable or high-risk populations.
- Working with healthcare systems to manage and monitor system capacity
Robert R. Redfield, MD, director of the CDC, believes “this infusion of additional funding into the nation’s public health infrastructure will strengthen our capacity to implement tried and true containment measures.” He also noted that “the ability to implement aggressive contact tracing, surveillance and testing will be fundamental to protecting vulnerable populations as the nation takes steps to reopen and Americans begin returning to their daily lives.”26
Weekly Rounds Podcast
- Centers for Disease Control and Prevention. Outbreak of pneumonia of unknown etiology (PUE) in Wuhan, China. Updated January 8, 2020. Accessed May 1, 2020. https://emergency.cdc.gov/han/han00424.asp
- Holshue ML. DeBolt C, Lindquist S, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020; 382:929-936
- Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol. 2020;5:536-544
- Johns Hopkins University School of Medicine. Coronavirus COVID-19 global cases. Updated April 2, 2020. Accessed April 20, 2020. https://coronavirus.jhu.edu/map.html
- Centers for Disease Control and Prevention. Cases in the U.S. Updated April 30, 2020. Accessed May 1, 2020. https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/cases-in-us.html
- Li Q, Guan X, Wu P, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med. 2020;382:1199-1207
- Mizumoto K, Kagaya K, Chowell G. Early epidemiological assessment of the transmission potential and virulence of coronavirus disease 2019 (COVID-19) in Wuhan City: China, January-February, 2020. Posted online March 13, 2020. medRxiv. doi:10.1101/2020.02.12.20022434
- Bai Y, Yao L, Wei T, et al. Presumed asymptomatic carrier transmission of COVID-19 [published online February 21, 2020]. JAMA. doi:10.1001/jama.2020.2565
- Li R, Pei S, Chen B, et al. Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2). Science. doi:10.1126/science.abb3221
- Wells CR, Sah P, Moghadas SM, et al. Impact of international travel and border control measures on the global spread of the novel 2019 coronavirus outbreak. Proc Natl Acad Sci USA. 2020;117:7504-7509.
- Tuite AR, Bogoch II, Sherbo R, et al. Estimation of coronavirus disease 2019 (COVID-19) burden and potential for international dissemination of infection from Iran [published online March 16, 2020]. Ann Intern Med. doi:10.7326/M20-0696
- Lee VJ, Chiew CJ, Khong WX. Interrupting transmission of COVID-19: lessons from containment efforts in Singapore [published online March13, 2020]. J Travel Med. doi:10.1093/jtm/taaa039
- Cheng MP, Papenburg J, Desjardins M, et al. Diagnostic testing for severe acute respiratory syndrome–related coronavirus-2: a narrative review [published online April 13, 2020]. Ann Intern Med. doi:10.7326/M20-1301
- The COVID Tracking Project. US historical data. Updated May 1, 2020. Accessed May 1, 2020. https://covidtracking.com/data/us-daily
- Cohen J. The United States badly bungled coronavirus testing—but things may soon improve [published February 28, 2020]. Science. doi:10.1126/science.abb5152
- Shear MD, Goodnough A, Kaplan S, Fink S, Thomas K, Weiland N. The lost month: how a failure to test blinded the U.S. to Covid-10. The New York Times. March 28, 2020. https://www.nytimes.com/2020/03/28/us/testing-coronavirus-pandemic.html?action=click&module=RelatedLinks&pgtype=Article. Accessed May 1, 2020.
- Weaver C, McKay B, Abott. America needed coronavirus tests. The government failed. The Wall Street Journal. March 19, 2020. https://www.wsj.com/articles/how-washington-failed-to-build-a-robust-coronavirus-testing-system-11584552147?mod=article_inline. Accessed May 1, 2020.
- Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Issues New Policy to Help Expedite Availability of Diagnostics. Updated February 29, 2020. Accessed May 1, 2020. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-new-policy-help-expedite-availability-diagnostics
- Food and Drug Administration. Emergency use authorizations. Updated May 1, 2020. Accessed May 1, 2020. https://www.fda.gov/medical-devices/emergency-situations-medical-devices/emergency-use-authorizations#covid19ivd
- Coronavirus (COVID-19) update: FDA issues new policy to help expedite availability of diagnostics [news release]. White Oak, MD: Food and Drug Administration. Published February 29, 2002. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-first-emergency-use-authorization-point-care-diagnostic. Accessed May 1, 2020.
- To KK, Tsang OT, Leung WS, et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis. 2020;20(5):565-574
- Coronavirus (COVID-19) update: serological tests [news release]. White Oak, MD: Food and Drug Administration. Published April 7, 2020. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-serological-tests. Accessed May 1, 2020.
- Coronavirus (COVID-19) update: FDA authorizes first test for patient at-home sample collection [news release]. White Oak, MD: Food and Drug Administration. Published April 21, 2020. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-test-patient-home-sample-collection. Accessed May 1, 2020.
- Centers for Disease Control and Prevention. COVIDView: a weekly surveillance summary of U.S. COVID-19 activity. Updated May 1, 2020. Accessed May 1, 2020. https://www.cdc.gov/coronavirus/2019-ncov/covid-data/covidview/index.html
- Centers for Disease Control and Prevention. Evaluating and Testing Persons for Coronavirus Disease 2019 (COVID-19). Updated May 1, 2020. Accessed May 1, 2020. www.cdc.gov/coronavirus/2019-nCoV/hcp/clinical-criteria.html.
- HHS announces CARES act funding distribution to states and localities in support of COVID-19 response [press release]. Washington DC, MD: United States Department of Health and Human Services. Published April 23, 2020. https://www.cdc.gov/media/releases/2020/p0423-CARES-act.html. Accessed May 1, 2020.