US taking ‘wrong approach’ to COVID-19 testing, expert warns
The American Lung Association recently held a virtual Town Hall meeting to debunk widespread misperceptions in the United States about which populations should be prioritized for COVID-19 testing and how to interpret the results.
“Far too many people have misinterpreted testing,” Michael T. Osterholm, PhD, MPH, director of the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota, said during the meeting. “While we need to greatly expand our SARS-CoV-2 testing as a critical component of our response to COVID-19, the pandemic messaging to date needs to move beyond the ‘Test, test, test!’ mantras. That is the wrong approach.”
Millions of people in the U.S. are being tested for COVID-19 each week, he added. But given the risk for false-positive or false-negative results, testing strategies require a more targeted approach. Those who are critically ill should be prioritized and tested as soon as possible after the onset of COVID-19-related symptoms, according to Osterholm.
“Then next for the prioritization for the detection of SARS-CoV-2 in people without symptoms but have recently been exposed,” he said.
Interpreting RT-PCR results
The probability of having a false-negative result with reverse transcriptase polymerase chain reaction (RT-PCR) is lowest during the first few days after symptom onset, according to research published in Annals of Internal Medicine. The analysis included data from seven studies that assessed RT-PCR performance. Results showed that the median false-negative rate decreased from 100% on the first day of infection to 67% on the fourth day of infection. The rate further decreased to 38% on day 5 — which is typically the day of symptom onset, according to the researchers — and 20% on day 8. It then increased from 21% on day 9 to 66% on day 21.
Recent data have also shown that RT-PCR may still detect SARS-CoV-2 in people who have recovered from the infection.
“There has been a lot of discussion in the last couple of weeks of people who are supposedly chronically infected with repeated PCR positives,” Osterholm said. “I hope that if nothing else, everyone is learning that having a positive PCR for this particular virus — SARS-CoV-2 — in and of itself does not mean that you’re infectious or infected for that matter.”
“Viral debris,” he added, can be detected weeks to months after infection. An investigation led by the Korean CDC (KCDC) found no evidence that people who continue to test positive for the virus after being discharged from isolation are infectious. The investigation included 285 patients who, on average, tested positive 14.3 days after discharge, as well as 790 of their contacts. In its report, the KCDC said there were no new cases that could be directly linked to the “re-positive cases.” Investigators were also were unable to isolate the virus from respiratory samples of 108 re-positive cases. Based on these findings, the KCDC report said that patients who are discharged from isolation will no longer be retested for SARS-CoV-2.
In the U.S., the CDC estimates that people who had COVID-19 are no longer contagious after 3 days of no fever and 10 days since symptoms onset. The agency recommends discontinuing isolation precautions in people who meet these symptom-based criteria or those with two consecutive negative tests taken at least 24 hours apart. However, relying on negative PCR test results has been detrimental for some people who have seemingly recovered but continue to test positive, according to Osterholm.
“People are not being allowed to go back to work,” he said. “We’ve had mothers ill at the time of delivery whose children were in the NICU and, who 2 months later, are still showing PCR positivity. [They] are not even able to visit their own child.”
The CDC will be making more statements about this issue soon, Osterholm said. In the meantime, he told Healio Primary Care that “journals should stop accepting papers that make claims of long-term infection based on PCR status only.”
“It really is unfortunate because the data does not support that,” he said. “This really is a serious problem.”
Interpreting antigen, antibody test results
RT-PCR is currently the most accurate test for COVID-19, Steven Kleiboeker, PhD, HCLD/TS/CC(ABB), vice president of research and development at Viracor Eurofins Clinical Diagnostics, previously told Healio Primary Care. Antigen tests are another option; however, these tests usually have a lower sensitivity, so they have a greater risk for producing false-negative results, according to Osterholm. Antigen tests detect the presence of proteins on the surface of the virus, whereas RT-PCR tests detect the unique genetic sequences of the virus.
“Antigen tests can give you a quick result, but it’s very important that you have a backup test,” Osterholm said during the meeting. “The antigen tests that they were using at the White House had a number of false negatives, meaning people were really positive when they tested negative. So, that is not the right test by itself.”
In contrast to RT-PCR and antigen tests that detect the virus, antibody tests can measure antibodies to the virus in the blood.
“The antibody testing remains a Wild, Wild West situation,” Osterholm said. “We discourage a lot of antibody testing because of the erroneous results that we’re getting.”
There are currently 18 antibody tests that have received FDA emergency use authorization, according to Osterholm, but more than 200 tests are currently on the market without being validated.
“Only 30-some tests have actually been said by the FDA to be so bad that they could no longer be marketed,” Osterholm said.
Antibody tests vary in their sensitivity and specificity. An antibody test with 95% sensitivity and 95% specificity could yield just as many false positives as true positives, according to Osterholm. The results are unable to confirm current infection or immunity to COVID-19, so experts claim the clinical implications of the results remain unclear. Osterholm said antibody testing should be limited to surveillance efforts where public health officials can take sensitivity and specificity of the tests into account.
“We need to be very, very careful about this,” he said. “I think right now, the idea of immunity passports is really not responsible. It should under no conditions ever be a reason for changing personal protective equipment status in health care workers.”
‘Smart testing’ approach
It is critically important that people understand the limitations of SARS-CoV-2 testing and carry out appropriate follow-up care based on the results, according to Osterholm. The issue extends beyond this though — the entire testing landscape needs improvement, he said.
During the Town Hall meeting, Osterholm provided a few examples of pressing needs, including the global shortage of reagents and the demand for more test machines — an increasing number of which are breaking down.
“These machines were never meant to go 24/7 for 365 days a year,” Osterholm said. “We have driven, you might say, this new car at 100 mph for the past several months and we’re all beginning to see what happens when you do that.”
Additional shortages in testing chain supplies such as personal protective equipment, as well as a lack of federal guidance and coordination efforts, are also cause for concern.
To address these issues, Osterholm and colleagues from CIDRAP outlined a “smart testing” approach for SARS-CoV-2 that will help guarantee the right test is available for the right patient at the right time. This smart testing approach requires a stronger infrastructure that ensures widespread availability of materials, supplies, skilled labor and instrument capacity.
“If you don’t have the whole thing in place — the material capacity, instrument capacity, skilled labor availability, instrument use availability, result reporting and action steps — a test is wasted,” Osterholm said. “It’s like the infection itself. If you break that chain, you end up having a situation where you are not successful with what you’re doing. At this point, it’s fair to say that we still have a long way to go for having the smart testing we want and need in this country.”
To help implement smart testing, Osterholm and colleagues called on HHS to appoint a blue-ribbon panel of experts that represent multiple disciplines, including public health, medicine, laboratory research and development, ethics, politics and more, to support testing efforts by:
- clarifying when tests should be used in clinical, surveillance, research and public health settings;
- identifying and addressing supply chain issues;
- identifying national guidance for diagnostic and antibody testing;
- establishing realistic testing strategies in light of limitations and laboratory capacity;
- determining a strategy for monitoring COVID-19 hot spots;
- establishing optimal performance characteristics of tests;
- identifying necessary steps for the creation of a national laboratory testing reporting system;
- coordinating with states to monitor testing and ensure resources are available; and
- reviewing new testing technologies and issuing recommendations for their use.
CIDRAP set a deadline of July 1 for the creation of the panel; however, the center has not yet received an update from HHS on whether the blue-panel ribbon is being considered, Osterholm said.
Regardless, a smart-testing approach that complies with CDC guidance should be implemented by states as soon as possible, “as the primary impact of this pandemic will occur in the next 12 to 18 months,” according to Osterholm and colleagues.
“This pandemic is far from over,” Osterholm told Healio Primary Care. “It is being portrayed by the administration as being over — it’s not. We’re just at the beginning of it.”
- CDC. Discontinuation of isolation for persons with COVID -19 not in health care settings. https://www.cdc.gov/coronavirus/2019-ncov/hcp/disposition-in-home-patients.html. Accessed June 13, 2020.
- Healio. RT-PCR yields high false-negative rates in early SARS-CoV-2 infection. https://www.healio.com/news/primary-care/20200609/rtpcr-yields-high-falsenegative-rates-in-early-sarscov2-infection. Accessed June 15, 2020.
- KCDC. Findings from investigation and analysis of re-positive cases. https://www.cdc.go.kr/board/board.es?mid=a30402000000&bid=0030. Accessed June 13, 2020.
- Kucirka LM, et al. Ann Intern Med. 2020;doi:10.7326/M20-1495.
- University of Minnesota. COVID-19: The CIDRAP Viewpoint; Part 3: Smart Testing for COVID-19 Virus and Antibodies. https://www.cidrap.umn.edu/sites/default/files/public/downloads/cidrap-covid19-viewpoint-part3.pdf. Accessed June 14, 2020.