ProPublica, a non-profit news organization, said in an article today that due to many factors, the COVID-19 test results in the United States are unreliable, and the false negative rate is estimated to be as high as 25%. Subsequent antibody serum test results may be even more unreliable, affecting the reopening of social activities.
The following is the full text of the article:
The medical staff are collecting samples.
Kendra Borov, 7 1 year-old, thought she was infected with COVID-19. She was infected by the waiter when she went out to eat with her family on February 20th, because the waiter had cough symptoms at that time.
Four days later, Borov developed symptoms of fever and sore throat. I had difficulty breathing and coughing, she recalled.
For the next three weeks, Borov felt cold and nauseous. Many doctors have diagnosed bronchitis and pneumonia as possibly caused by a cold.
Borov underwent a series of tests: the flu test was negative, and chest X-rays showed lung damage, including white spots called frosted glass opacity.
On March 7, Borov was convinced that she was infected with COVID-19 virus, but it was not until March 19 that she was tested for COVID-19 virus in the emergency room of the University of Cincinnati Medical Center. In addition, she had a high fever of 39.5℃ and decreased blood oxygen saturation, and was diagnosed on the spot.
About a week later, Borov's condition gradually stabilized, and her COVID-19 test results came out: negative.
Borov was puzzled, but the doctor diagnosed that no matter what the test results were, she was really infected with COVID-19. She recalled what the doctor said at that time: My diagnosis was that she was infected with COVID-19 virus, not other diseases.
Public health experts told ProPublica that all the symptoms indicated that the patient was infected with COVID-19 virus, but the test results were negative. In the past 1 month, hospitals all over the United States are putting on such a drama.
At present, researchers are not clear about two problems: how high the false negative ratio is; Is the false negative caused by external factors or the design of the test kit itself?
Neither the US Food and Drug Administration nor the US Centers for Disease Control and Prevention disclosed the proportion of false negatives. Although FDA requires testing institutions to report false negative cases, relevant data have not been disclosed yet.
The lack of false negative data of COVID-19 test results makes people increasingly worried that inaccurate test results will make it more difficult for the United States to relax social distance control measures. After all, the ability to track and find infected people is crucial to any strategy to restart social activities.
The U.S. Congress already knew about it, and Lloyd doggett, a Democrat from the Texas House of Representatives, heard a doctor in his district complain about the accuracy of the COVID-19 test.
He and House Democrat Rosa Delalleau wrote to the FDA on Thursday, demanding the accuracy of COVID-19's data and antibody test results.
Doggett said that if there are too many false negatives, the virus will spread quickly again when measures to control social distance are relaxed.
FDA relaxes regulatory standards.
COVID-19 test kit
One of the things that the FDA was spit out was that at the beginning of the epidemic, it did not take timely measures to popularize testing. For most of February, only the Centers for Disease Control and Prevention in the United States can conduct the COVID-19 test. The FDA didn't announce the new policy until February 29th, so that private laboratories and academic medical centers can also provide testing services.
After that, the demand for testing in various parts of the United States prompted the FDA to relax the supervision of COVID-19 test kits.
Usually, manufacturers need to collect evidence of product quality through experiments, which may last for months or even years. At present, FDA has simplified the approval process by granting emergency use authorization.
At present, FDA requires COVID-19 test kit manufacturers to conduct reagent tests on samples of at least 30 confirmed cases and 30 healthy people. Manufacturers must prove to the FDA that the accuracy of their products is 95% or above, which means that 95% of confirmed cases can be detected; The specificity reaches 100%, that is, all samples that are not infected with COVID-19 must be detected.
However, manufacturers have done something to prove the quality of test kits by using artificial samples. Artificial samples refer to viral RNA cultured in the laboratory and then put into simulated snot.
Benjamin Pinski, medical director of clinical virus laboratory at Stanford University Medical Center, said that artificial samples were used to simulate swab samples, but they were not from real confirmed cases. There is a difference between the two.
At present, it is not clear whether the viral load in artificial samples is equivalent to that in samples taken from patients. However, Pinski pointed out that given the time constraints, it is not wrong for the FDA to allow the use of manual samples.
He also said: We need to evaluate the performance of the test kit in practical application to see if there are any products with poor sensitivity and specificity. At present, these problems have not been solved.
Alberto Gutierrez, former director of the FDA's office of in vitro diagnosis and radiology, said: Especially in diagnostic tests, it is difficult to judge whether the results are accurate or not.
Roche, a Swiss manufacturer of test kits, told ProPublica that it could not give the exact ratio of false negatives to false positives, and research showed that its products could detect COVID-19 at a very low load.
Mike West, a spokesman for Roche, said in an email that we will continue to cooperate with the FDA to carry out research related to the quality of test kits.
Abbott, a manufacturer of rapid test kits, also said that the quality data of test kits, including accuracy, are still being collected.
Abbott, LabCorp and Quest Diagnostics all told ProPublica that the test results are only one of the basis for doctors to make a diagnosis.
The testing process is compliant and the results may be unreliable.
There are many factors that lead to inaccurate test results.
Clinicians and researchers say that many factors will lead to inaccurate COVID-19 test results, some of which have nothing to do with the design of the kit.
First, when patients are tested, opportunities will affect the results. Pinski explained: It takes too long from the beginning of infection, and the viral load decreases.
Viral load refers to the number of viruses released by cells of confirmed cases. If the viral load drops to a certain level, even patients with symptoms may have negative test results.
Another factor is the location of the virus in the patient. Researchers believe that with the development of the disease, the virus will migrate to the lungs of patients, and the possibility of positive nasal swab test results will be reduced.
Although it is technically feasible to collect lung samples from patients through respiratory tract, it is difficult to operate and brings great pain to patients, so some anesthetic measures need to be taken.
Medical staff can also ask patients to expectorate, but this will greatly increase the risk of infection of medical staff. Even obtaining nasopharyngeal swab samples has certain technical difficulties.
Daniel Brooke, a historian in New Orleans, said that he thought his test result was false negative because the swab collection method was improper.
During the carnival in New Orleans, he played with a friend from Manhattan. A few days later, he began to have night sweats and chills, and a friend sent a message saying that his COVID-19 test result was positive.
Brooke suffers from asthma, so when he has symptoms of dyspnea, he will go to the emergency room for treatment. Unfortunately, the detection ability of the emergency room is not enough to detect him.
Four days later, Brooke found her symptoms more serious, and even went upstairs out of breath. He and his girlfriend also developed symptoms. They received a letter from the emergency doctor and could go to the physical examination point for testing.
Brooke said that when taking the nasal swab, the cotton swab hardly reached into the nose, which may be one of the problems. Nine days later, the test results of both of them came out: negative.
Brooke is confused. He once told all his close contacts, including the barber, that they might be infected with COVID-19. Now, he has shared with many people the good news that his test result is negative.
But the doctor told him that clinically, he showed all the symptoms of COVID-19, and the diagnosis result would not be changed by the test results.
Even if there is no problem with sample collection, the treatment that does not meet the requirements will lead to wrong results. RNA is similar to DNA, but its chemical structure is different, so it is easier to be destroyed and degraded.
COVID-19 is an RNA virus, which is basically an RNA chain covered with a thin film.
Abbott suggested that the storage time of samples should not exceed 8 hours at 16 to 30℃ and 72 hours at the frozen state. In a statement to ProPublica, Abbott said: Samples should be tested in time.
This is obviously a difficult problem for many testing laboratories with a large number of samples to be tested.
A laboratory technician who asked not to be named said that he witnessed the improper handling of samples, which may destroy the test results of dozens of people.
He told ProPublica: We have many problems in testing COVID-19, but I don't understand why. For example, every time we test dozens of samples, samples will leak out from time to time, which may pollute other samples. If one accidentally leaked sample is positive, the results of other samples may be positive.
This laboratory is not the only one with this problem. At the end of March, hundreds of samples were destroyed on the way to the Alabama laboratory.
The possible dangers caused by inaccurate test results.
Inaccurate test results may lead to the resurgence of the epidemic.
Due to the lack of data, doctors and public health officials can only estimate the proportion of false negatives, which will have serious consequences for individuals and curb the spread of the virus.
Gutierrez said: If a person infected with COVID-19 virus is told that the test result is negative, he will continue to infect others. Even if 5 out of 100 samples even fail to report 1, the problem is very serious.
In addition, false negatives make it more difficult to trace the route of transmission in COVID-19, because they will not be listed as confirmed cases and will not be included in the mortality rate after COVID-19's death.
Not only false negatives, but also false positives are problematic. Pinski said that if the patient is wrongly classified as a confirmed case in COVID-19, it will cause a run on medical resources, waste personal protective materials and waste the time and energy of medical staff. In addition, it will also cause anxiety of patients.
Pinski expressed the hope that relevant departments would collect data on the accuracy of test kits in actual use, especially in the case of more and more test kits on the market. With these data, testing institutions can choose products with higher accuracy.
Yukari Manabe, deputy director of the Center for Global Health Research and Innovation at Johns Hopkins University School of Medicine, estimates that false negatives account for 20%-25% of all test results.
However, she warned that this estimate was not supported by data. She found that in the Johns Hopkins University hospital system, many people whose test results do not match the symptoms will be tested more than once.
Like others, Manabe admits that the FDA needs to simplify the approval process so that people can test quickly. However, she said that the government did not encourage enterprises to develop test kits earlier and detect more people earlier.
Unfortunately, the shortage of test kits makes doctors only test the most serious patients. With the increase of supply, many people can test at the beginning of symptoms, which may help to reduce the false negative rate, because it is easier to detect the virus by nasal swab as soon as possible after infection.
Antibody serum test results may be even more unreliable.
The results of antibody serum test are related to whether the control measures can be relaxed.
With the listing of antibody serum test kits, the problem of low accuracy of COVID-19 test results may not disappear. The FDA has approved the first batch of such test kits. Unlike nucleic acid detection kit to detect viruses, antibody serum detection kit detects whether the immune system has encountered viruses in the past.
Antibody testing is considered to play a key role in the decision to relax control measures, because it can be used to estimate who has been immunized against COVID-19. In antibody detection, false positive is even more worrying, because it may make people who have not actually gained immunity return to normal work and life, and increase the risk of infection.
Pinski warned that before antibody test results can be used as the basis for relaxation control measures, several problems still need to be solved: How high level of antibodies can make patients immune? How long can immunity last? The answers to these questions are still unknown. The World Health Organization (WHO) issued diagnostic guidelines this week, and antibody testing is not recommended as a clinical diagnostic standard.
The FDA is further lowering the threshold for testing kits. It issued a new guide on March 65438+6, 2006, allowing manufacturers to sell test kits within a reasonable time without emergency use approval, provided that internal testing is completed.
Local governments are so eager for testing tools that they will buy them even if the accuracy of testing cannot be guaranteed. The media reported that Chicago ordered 1. 1, 000 sets of Korean antibody detection kits. Although they have not been approved by the FDA, they can also be legally used in the United States because they contain several exemption clauses.
Catherine Troissy, an epidemiologist at the University of Texas Medical Science Center, said there was no time to investigate what the problem was. Such a question. I'm not saying that the test is not good, but what's the use of a test with unreliable results? No one can answer this question.
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