Four medical professionals with COVID-19 who met the criteria for hospital release or lifting of quarantine in China had positive real-time reverse transcriptase-polymerase chain reaction (RT-PCR) results 5 to 13 days later, according to a research letter published yesterday in JAMA.

The researchers said the results suggest that current criteria for hospital release or lifting of quarantine and continued treatment should be reevaluated. "These findings suggest that at least a proportion of recovered patients may still be virus carriers," they wrote.

Other new research involving the novel coronavirus includes two large clinical studies highlighting the extent of severe cases and common comorbidities, and a UK report notes that its first two COVID-19 cases would not have gotten tested using case definitions.

Serial positive RT-PCR results

In the small JAMA study, throat swabs from one hospitalized patient and three patients in home quarantine treated at Zhongnan Hospital of Wuhan University from Jan 1 to Feb 15 were tested with RT-PCR for COVID-19 nucleic acid to determine if the patients could return to work.

Criteria for hospital release or return to work included normal temperature for at least 3 days, resolved respiratory symptoms, substantially improved lesions on chest computed tomography (CT), and two consecutive negative RT-PCR test results at least 1 day apart.

RT-PCR results of the patients, two men and two women aged 30 to 36 years, were positive, and CT scans showed mild to moderate areas of fluid buildup. The patients were given antiviral medication and recovered 12 to 32 days after symptom onset. After meeting the criteria for hospital release or lifting of quarantine, the patients were asked to remain at home for another 5 days.

RT-PCR was performed again 5 to 13 days later and repeated three times over the next 4 or 5 days—and all tests were positive. Another RT-PCR test with a kit from a different manufacturer confirmed the results. The patients were asymptomatic, CT showed no changes, and they reported no contact with anyone with respiratory symptoms or infected family members.

"Further studies should follow up patients who are not healthcare professionals and who have more severe infection after hospital discharge or discontinuation of quarantine," the authors noted. "Longitudinal studies on a larger cohort would help to understand the prognosis of the disease."

Experts recommend cautious interpretation

Although the results are interesting, it should be noted that RT-PCR measures viral genomic material but doesn't necessarily indicate contagiousness, said Stanley Perlman, MD, PhD, professor of microbiology and immunology at the University of Iowa Hospitals and Clinics in Iowa City.

"Genomic material comes from virus, of course, but it does not indicate that infectious virus is present," Perlman said, adding that a positive test means that virus or was present a day or two before. "Certainly [RT-PCR] is useful diagnostically; it is less useful for telling us whether someone is contagious." He was not involved in the study.

He added, "The patients may be patient carriers or they may just have viral genomic material without any infectious virus. It is hard to know—and hard to know if they are infectious as well. This is all murky at present."

Florian Krammer PhD, virologist and vaccinologist in the Department of Microbiology at the Icahn School of Medicine at Mount Sinai in New York City, said on Twitter that the RNA of many viruses can be detected months after viral shedding has ended.

"Follow-up tests can turn positive after a few negative tests, eg because sampling was better," Krammer said. "Also, and this is a very important point, just because somebody still tests positive in a nuclei acid-based test does not mean they are still shedding infectious virus."

Some patients lack fever, CT findings at first

In other research news, investigators at Guangzhou Institute of Respiratory Disease in China published a report on COVID-19 symptoms and severity today in The New England Journal of Medicine, noting a 1.4% death in hospitalized patients and the fact that some patients had no fever or radiographic abnormalities initially.

The investigators mined the medical records of 1,099 patients with laboratory-confirmed COVID-19 from 522 hospitals in 30 Chinese provinces from December 2019 to Jan 29. The patients' median age was 47 years, and 41.9% were women.

Sixty-seven (6.1%) of the patients reached the primary composite end point of admission to the intensive care unit (ICU) (5.0%), mechanical ventilation (2.3%), or death (1.4%). Only 1.9% had contact with wildlife, while 72.3% of non-Wuhan residents had contact with Wuhan residents, including 31.3% who had traveled to the city.

The most common symptoms were fever (43.8% on hospitalization and 88.7% during hospitalization) and cough (67.8%). Diarrhea occurred in only 3.8%. While fluid buildup was commonly seen on chest CT (56.4%), no radiographic or CT abnormalities were seen in 157 of 877 patients (17.9%) with nonsevere disease and five of 173 patients (2.9%) with severe disease. Lymphocytopenia (low white blood cell count) was seen in 83.2% of patients at admission.

"Some patients with COVID-19 do not have fever or radiologic abnormalities on initial presentation, which has complicated the diagnosis," the authors wrote.

Comorbidities and risk for poor outcomes

Meanwhile, a retrospective non–peer-reviewed article by much the same group of researchers in Guangzhou, China, found that co-existing diseases are found in about one quarter of hospitalized COVID-19 patients and tend to worsen the patients' prognosis.

The study of 1,590 patients with lab-confirmed COVID-19 from 575 hospitals across China, published yesterday on medRxiv, collected data from Nov 21, 2019, to Jan 31.

Mean patient age was 48.9 years, and 686 (42.7%) were women. Severe cases made up 16.0% of the study population, and 131 (8.2%) reached the primary end points of ICU admission, mechanical ventilation, or death. (The fatality rate was 3.1%.)

At least one comorbidity was reported in 399 (25.1%) of patients, the most common of which were high blood pressure (269, 16.9%) and cardiovascular disease (59, 3.7%). Two or more comorbidities were reported in 130 (8.2%) of patients, who had a significantly elevated risk of reaching an end point compared with those with one comorbidity and an even higher risk than those with none (P < 0.05).

After adjusting for age and smoking status, patients with chronic obstructive pulmonary disease (hazard ratio [HR], 2.7; 95% confidence interval [CI],1.4-5.0), diabetes (HR, 1.6; 95% CI, 1.0-2.5), high blood pressure (HR, 1.6; 95% CI, 1.1-2.3), and cancer (HR, 3.5, 95% CI 1.6-7.6) were most likely to reach an end point than those without those diseases.

The death rate among COVID-19 patients with one or more comorbidities was 5.6%.

UK's first patients did not meet testing criteria

Finally, researchers at Hull University in Hull, England, published a letter yesterday in The Lancet describing how their country's first two COVID-19 patients tested positive for the virus even though they didn't meet current case definitions.

The patients were identified as at-risk while still in the community and transported from their hotel to the university hospital, where they were tested.

The researchers said that the case highlights important points about the management of COVID-19. "Had [clinical] criteria been strictly applied, testing might not have been done," they wrote, noting that applying case definitions is the best way to target testing. "However, with any newly emerging infection, case definitions must evolve rapidly as information accrues."