Note: This is the thirty-eighth of a series of clinical briefs on the coronavirus outbreak. The information on this subject is continually evolving. The content within this activity serves as a historical reference to the information that was available at the time of this publication. We continue to add to the collection of activities on this subject as new information becomes available.

Clinical Context

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third outbreak of coronavirus known to affect humans in recent times but has been unlike its predecessors in its exponential spread. There is still much to be discovered regarding the natural history of COVID-19. One of the big unknowns is whether contracting the virus infers immunity. There are emerging concerns that patients are retesting positive.

A study by He and colleagues assessed the results of reverse-transcriptase polymerase chain reaction (RT-PCR) from daily throat swabs of 94 patients admitted for COVID-19 in China. Testing continued for up to 32 days after the onset of illness.

The research, which was published in the April 15 issue of Nature,^[1] estimated that the incubation period for COVID-19 before the onset of symptoms was 5.2 days. Viral loads for COVID-19 were highest shortly after the onset of symptoms and then gradually decreased toward the detection limit by day 21. Sex, age, and disease severity did not substantially affect these findings.

The authors estimated that infectiousness of COVID-19 began 2.3 days before the onset of symptoms and peaked at 0.7 days after symptom onset. They further estimated that up to 44% of cases of COVID-19 could be a result of viral transmission before the onset of symptoms.

In the current study by Wu and colleagues, with results published in the May 22 issue of JAMA,^[2] researchers performed a larger analysis after 2 cases of positive testing for COVID-19 after hospital discharge among patients previously diagnosed with COVID-19.

What does that mean? Are patients immune after contracting the virus?

Study Synopsis and Perspective

Patients who are discharged from isolation after recovering from COVID-19 and who again test positive are unlikely to be infectious, according to a report from the KCDC.^[3]

"There's no relapse," Laila E. Woc-Colburn, MD, DTM&H, associate professor and director of medical education, National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, told Medscape Medical News.

Although the disease is now known to linger and affects more than one system of the body, other viral diseases, such as influenza and mononucleosis, also "work that way," explained Woc-Colburn, who was not involved in the study.

As of May 15, the Korean researchers identified 447 patients who again tested positive on real-time RT-PCR testing for viral RNA. Of those patients, 285 (63.8%) had undergone epidemiologic investigation and contact investigation. Among the tested individuals, 59.6% were tested for screening purposes and 37.5% underwent testing as a result of symptoms. Almost half (44.7%) of the 284 patients who underwent symptom investigation were symptomatic.

According to data concerning 3 groups of patients from different cities, the investigators found that between 25.9% and 48.9% of patients again tested positive after they had been discharged.

Among the 226 patients who were symptomatic when their case was initially confirmed, a repeat positive test result after discharge occurred an average of 44.9 (range, 8-82) days) from the date symptoms initially developed. It took an average of 14.3 (range, 1-37) days from the time of discharge to the time of the second positive test.

More than half (59.6%) of patients who tested positive a second time were tested for screening, without regard for symptoms. Of patients who again tested positive, 44.7% had symptoms that included cough and sore throat.

No Evidence of Infectivity

To help determine whether a positive result on a second test is associated with infectivity, the Korean researchers investigated 790 contacts of the 285 patients who tested positive a second time. Of those patients, 351 were family members, and 439 were others. Among the contacts, the researchers identified 3 new cases; however, for all 3 patients, other sources of infection were possible. These sources included religious groups or family groups that were confirmed to have COVID-19.

The researchers tried to culture virus from 108 patients who tested positive a second time; all such cultures were negative.

Further, investigators obtained first and second serum samples from 23 patients who had tested a second time. Of those patients, 96% tested positive for neutralizing antibodies.

"Based on active monitoring, epidemiological investigation, and laboratory testing of re-positive cases and their contacts, no evidence was found that indicated infectivity of re-positive cases," the authors wrote.

For patients who tested positive a second time, the KCDC employed the same protocol used for patients who initially tested positive. That protocol requires the patient to be isolated and to undergo further testing; however, according to current findings, the KCDC revised its protocol for managing such patients.

The agency now maintains that patients who have been discharged from isolation need no further testing and are not likely to be infective, even if they again test positive on RT-PCR assay.

Although reporting, investigation, and contact tracing of patients who again test positive will continue "for the purposes of research and investigation," the patients will no longer be regarded as "re-positive cases" but as patients with "PCR re-detected after discharge from isolation."

The recent study by Xi He et al^[1] studied the infectiousness profile of COVID-19. The authors determined that the virus indicated an infectious nature early on, with substantial potential for transmission before onset of symptoms. Previous studies have suggested that transmission of the virus spreads after onset of illness, with viral loads peaking approximately 10 days after symptom onset.^[4]

Whether antibodies for coronavirus infer immunity is still unknown. Previous studies on severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) showed antibodies in persons affected may persist for a while.^[5,6] Antibodies could still be measured in blood for up to 2 years for individuals with SARS and almost 3 years for MERS. Measurements of antibodies in the blood of people who have survived those infections suggest that these defenses persist for some time: however, it was noted that the neutralizing ability of these antibodies was already declining during the study periods. The neutralizing ability is a measure of how well antibodies are able to inhibit virus replication.

Regarding whether people who recover from COVID-19 can be reinfected with SARS-CoV-2, the Centers for Disease Control and Prevention (CDC) stated that the immune response to SARS-CoV-2, including duration of immunity, is not yet understood.^[7]

The CDC provides guidance on COVID-19 test results via viral testing or antibody testing.^[8]

Clinical Implications

• A previous study by He and colleagues of patients hospitalized with COVID-19 followed with daily oral testing found that viral loads for COVID-19 were highest shortly after the onset of symptoms and then gradually decreased toward the detection limit by day 21. Sex, age, and disease severity did not substantially affect these findings. The authors estimated that infectiousness of COVID-19 began 2.3 days before the onset of symptoms and peaked at 0.7 days after symptom onset.
• In the current study by Wu and colleagues, nearly 17% of patients discharged after hospital admission for COVID-19 had a repeat RT-PCR test that was positive for SARS-CoV-2.
• Implications for the Healthcare Team: The healthcare team needs to mind the prolonged viral shedding of COVID-19 in terms of advising patients about repeat testing and the threat of infecting others. More research is needed to determine the infective potential of virus shed weeks or months after the onset of initial symptoms of COVID-19.

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