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Diagnostics

Diagnosing the novel coronavirus leads to trade offs

Medical workers in China weigh the advantages and disadvantages of nucleic acid lab tests and CT lung scans

by Hepeng Jia, special to C&EN
February 20, 2020 | APPEARED IN VOLUME 98, ISSUE 8

 

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Credit: Xiao Yijiu Xinhua News Agency/Newscom
Patients infected with SARS-CoV-2 sit in a temporary hospital in Wuhan.

China continues to fight the outbreak of a novel coronavirus, called SARS-CoV-2, which has infected tens of thousands and killed more than 2,000 people since the end of 2019. The outbreak’s hot spot is in the central province of Hubei, in particular, its capital city Wuhan, where there have been more than 60,000 infections and 1,921 deaths as of this week. There, doctors and scientists are desperately struggling to find reliable ways to diagnose infected patients, to help treat them, and control the spread of the virus. The struggle has involved two diagnostic options—computed tomography (CT) scans of patients’ lungs and a nucleic acid lab test—each with advantages and disadvantages. Meanwhile, researchers are working to develop new antibody-based tests for the virus.

With “a suddenly rampant new virus, it is normal to have multiple test approaches,” says a virologist at the Chinese Center for Disease Prevention and Control (China CDC), who asked not to be named because they were not authorized to speak to the media. “The key is not which one is the best but how they can support each other.”

The lab test analyzes nucleic acids extracted from patient saliva or mucus samples, and compares them against sequences in the genomes of known coronavirus strains. The CT screening method highlights indications of the disease, such as signs that fluid has filled the lungs, but can’t specifically link those indications to the virus. Also, as a recent report notes, not all infected people have abnormal CT lung scans (Radiology 2020, DOI: 10.1148/radiol.2020200230).

Differences in data between these two methods caused a stir last week. On Feb. 12, China released data showing 15,000 newly confirmed cases of infections, mostly in Hubei, more than five times the number of cases in the previous day’s report. The magazine Caixin reported that this jump was due to Chinese officials revising the diagnostic criteria for confirming infections. The new criteria allowed doctors in Hubei to use clinical CT screening alone to confirm infections, instead of waiting for confirmation from the lab test.

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In response, the World Health Organization (WHO), which had been reporting only cases confirmed by lab tests, started to release data separately from the lab tests and clinical diagnoses. On Feb. 17, the WHO stopped reporting the numbers separately and combined them into one statistic. Both WHO and the Chinese health authority also include viral genome sequencing in their diagnostic criteria to confirm COVID-19—the disease caused by SARS-CoV-2—but the method is practically infeasible due to the lengthy time of sequencing and high cost.

Scott Dowell, an infectious disease specialist at the Bill & Melinda Gates Foundation and a former official at the US CDC, points out that the lab test has proved much more accurate than clinical confirmation. “We are not criticizing China’s move, but it is important to keep the epidemic information accurate and consistent,” Dowell said at a session on the coronavirus at the American Association for the Advancement of Science annual meeting in Seattle on Feb. 14.

Tarik Jašarević, a WHO spokesperson, agrees that the use of clinical signs or symptoms, including CT scans, to diagnose a patient is often less specific than lab tests, but the clinical diagnoses enable surveillance to continue when the number of patients exceedsf laboratory diagnostic capacity.

However, Chinese medical workers must hospitalize and treat large numbers of highly infectious suspected patients. So the change in diagnostic approach seemed inevitable.

The Chinese government quarantined the entire of city of Wuhan on Jan. 23. Facing increasing numbers of patients and dwindling availability of hospital beds, the local government decided to hospitalize only those patients with confirmed infections. Fever and a CT scan showing signs of deteriorating lung conditions were considered criteria to judge suspected infections, but confirmation required two positive nucleic acid kit tests.

The lab test requirement soon led to problems. Demand for the testing kits skyrocketed and led to shortages. Media and social media posts reported dozens of suspected deaths from COVID-19 before the patients could be confirmed as infected due to a lack of test kits. In at least one confirmed case, a family of four died before most family members could be admitted to the hospital.

“The early undersupply of nucleic acid kits can be overcome relatively easily, but it is hard to solve the bottleneck of testing capacity,” the China CDC virologist says.

The test requires highly specialized expertise that doctors and nurses have not been trained for. It also relies on polymerase chain reaction technology to amplify nucleic acids in a sample, and that process can take up to 6 h, meaning labs struggle to deal with thousands of tests each day. Also, handling patient samples can be risky for medical workers. So far, 3,000 Chinese doctors and nurses have been infected by the virus, mostly in Hubei, leading to at least five deaths.

Shortages and long testing times are just part of the problem. Wang Chen, a pulmonologist at the Peking Union Medical College, told China’s central television on Feb. 5 that the nucleic acid test’s accuracy is less than 50%. The China CDC virologist explains that coronavirus is often concentrated in the lower part of the respiratory system, meaning viral loads in a saliva or mucus sample may not be concentrated enough to be detected by the test.

Despite the nucleic acid test’s downsides, scientists note that it is still the most definitive way to identify an infected patient. But including CT scans as a diagnostic tool not only helps get patients treated faster, but also controls the spread of the virus.

Quickly hospitalizing COVID-19 patients has become a priority for controlling the outbreak to prevent infected people from passing the virus to others. The strategy of relying on CT screening alone to admit patients is a compromise, says the China CDC virologist, who points out that those who have been hospitalized with CT screening alone also get tested using other lab methods when conditions allow it.

At a news conference held by China’s National Health Commission on Feb. 17, Wang Guiqiang, an expert on infectious disease at the First Affiliated Hospital of Peking University, said that scientists are working to improve the nucleic acid test’s sensitivity and specificity. One way is to collect more of a patients’ saliva and mucus.

Jašarević says that WHO and partners are working to understand when to test viral samples, which bodily fluids should be tested, and which PCR assays are most efficient to use for the test.

While experts have debated the pros and cons of the nucleic acid test and CT screening, several Chinese labs, both in academic institutions and commercial firms, announced that they have developed antibody test methods. These tests would detect the presence of antibodies against SARS-CoV-2 produced by a patient’s immune system. Unlike the nucleic acid tests, antibody tests would work on blood samples.

The tests involve using part of a protein from the virus to try to snag antibodies the person has developed. When a patient’s antibody binds to the protein, other components in the test mixture produce a visible signal. The hardest part of developing such a test is finding and purifying the viral protein that will lead to the most effective test.

Most labs claim that their tests can produce results in 15 min. A group at the State Key Lab of Respiratory Disease in Guangzhou announced that its antibody test has been tested on several hundred COVID-19 patients. The antibody test and nucleic acid tests agreed on more than 90% of the cases.So far, none of the antibody methods have been approved as a formal COVID-19 test in China.

However, WHO’s Jašarević cautions that antibody-based diagnostics are typically less sensitive than nucleic acid–based tests. Also, because antibody-based diagnostics detect the body’s immune response to a pathogen, which takes time to develop, these tests may not detect early stages of the illness.

UPDATE

This story was updated on Feb. 21, 2020, to include comments from Tarik Jašarević, a WHO spokesperson.

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