What to Do When Recovered COVID-19 Patients Still Test Positive?

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More than 1 month after she was diagnosed with COVID-19, a 44-year-old patient phoned Ana Amorim, MD, PhD, with an unexpected question: When would it be safe for her to kiss her husband and children?

This patient, diagnosed on March 11, was one of several physician colleagues of Amorim, an ear, nose, and throat specialist in Coimbra, Portugal, to contract COVID-19. She had a myriad of symptoms — cough, dyspnea, asthenia, anorexia, diarrhea, fever, anosmia — but overall, the case was mild. For 15 days she remained in quarantine in her bedroom. Then she started to move about her home, doing housework and recuperating. By the end of April, the patient was feeling normal, only slightly fatigued. She started preparing to return to work, but week after week, repeated tests came back positive for SARS-CoV-2 RNA.

As Amorim's hospital moved past the viral peak and testing became more available, recovered patients such as the physician who felt well but still tested positive became a regular problem. Seeking to help her patient and colleague get back to normal, Amorim posted to Medscape Consult, a social media platform where doctors can share cases and offer advice. "Is the test revealing dead virus or infection? Is she still contagious?"

Amorim's was one of more than a dozen recent Consult posts asking these questions. The medical director of a correctional facility wrote about keeping five persistently positive patients isolated from the other inmates. Several other doctors posted to Consult about their own positive results, asking when it was safe for them to work. CDC guidance currently requires two consecutive negative PCR tests before a patient is moved out of isolation, because false negatives are not uncommon. But clinician experience and new data show that patients can continue to test positive for months after they recover.

"We are seeing [positive PCR results] 6 and 8 weeks after first presentation," Susan Bleasdale, MD, the medical director of infection control at University of Illinois, told Medscape Medical News. "It's hard to say. Is it still transmittable? There's been some concern that if you can still find RNA, there's some virus present. But there is some argument that the amount of virus is negligible."

What the Data Say

The PCR test does what it is designed to do: detect pieces of viral RNA. That's critical information for diagnostics and preventive care. But it's a poor test of cure, emerging data suggest, and it can't tell whether someone is infectious, says John Mills, MD, an infectious disease specialist and hospital epidemiologist at the University of Michigan.

In South Korea, researchers from the country's Centers for Disease Control and Prevention traced the contacts of 285 COVID-19 patients who tested negative and were removed from isolation but who then tested positive again. The investigators concluded that none of these patients transmitted the infection after reverting to positive.

A small German study of nine COVID-19 patients that was published in Nature found that the virus collected from patients after 8 days of illness didn't grow in culture or yield subgenomic mRNA — which is only present when a virus is replicating. So, even though viral RNA was detectable, there was no evidence that it was active or infectious after the eighth day. On the basis of their cell culture results, the authors posit that for patients who are found to have fewer than 100,000 viral RNA copies/mL of sputum 10 days post symptom onset, there is "little residual risk of infectivity."

"Just because you can't grow it doesn't mean it's not there," Mills said. But the small study is an initial proof of concept, he said, and it suggests that requiring two negative PCR results is "way overkill" in many of the milder COVID-19 cases.

It's possible that for patients who feel well but test positive, the PCR test may be picking up "pieces of genetic material that are still being sloughed off by cells," said Gigi Gronvall, PhD, an immunologist at Johns Hopkins University. In other viral respiratory diseases, such as SARS, MERS, and influenza, viral RNA is detectable long after the virus is noninfectious.

There are not yet enough data on the infectiousness of SARS-CoV-2 to be sure it follows this pattern, and there's not a test that can detect only intact, infective virus, according to Gronvall. Viral cultures — such as those in the German study — can be used to tell whether the RNA is from a replicating virus, but Gronvall says culturing virus is extremely difficult and is not feasible for most hospitals.

Antibody testing can offer more context with respect to disease progression, Gronvall said. For Amorim's patient, "serology showed a good progression of IgM going down and IgG going up — last titers 16 of IgG (reactive) and 0.9 IgM (non-reactive)," she wrote in her Consult post. The progression of IgM to IgG could suggest the patient is further from the onset of infection. It is believed that viral shedding peaks early in the course of disease; if so, a patient such as Amorim's would be less infectious.

However, Jeff Martin, MD, an epidemiologist at the University of California, San Francisco, cautions against weighing serology results too heavily. He said that "for a given person we don't know how to interpret [SARS-CoV-2 antibody results], we don't know what it means." And although studying immune response is critical, at this point, "you can't at all say it has a role in clinical management."

Cycle threshold — the number of times genetic material must be replicated in the PCR test to become detectable — may also offer context on positive PCR results. A higher cycle threshold means there is less virus present in the sample, so the infection may be waning. The CDC, however, doesn't recommend using cycle threshold alone to determine infectiousness.

The Waiting Game

CDC guidance offers an alternative to testing: the symptom-based strategy, according to which a person remains in isolation for at least 10 days after symptoms start and for at least 3 days after fever subsides.

For patients who aren't hospitalized and are recovering at home, the symptom-based strategy is likely best, according to Bleasdale. It may also be a good choice for discharging hospitalized patients who don't share a home with anyone who is at high risk. But for patients returning to a congregate living situation — such as an assisted living facility, campus housing, or prison — some variation of the test-based approach is probably preferable, Bleasdale said.

Likewise, individual risk assessments are necessary to help patients get back to work, she said. "If social distance and safety measures are possible, a symptom-based [strategy] is probably okay. But if they can't maintain distance at all times, wear a mask, and disinfect surfaces — a test-based return [policy] might be a better idea." When a patient is persistently positive, antibody results, symptoms, time, and cycle threshold should be considered together on a case-by-case basis, Bleasdale said.

This is where things get hard for patients such as Amorim's — the healthcare workers. It would likely be okay for Amorim's patient to go back to work if she were in another profession, but many medical facilities have very conservative return-to-work policies. The University of Illinois, where Bleasdale works, requires two consecutive negative PCR test results to return to work. The University of Michigan, where Mills is affiliated, allows workers to return 10 days after symptom onset if the fever and respiratory symptoms markedly improve, but personnel must wear a mask and cannot care for severely immunocompromised patients. Other healthcare facilities that are facing workforce shortages during the pandemic have less conservative policies.

The CDC offers two other strategies for healthcare workers. A symptom-based approach allows healthcare workers to return to work 3 days after fever subsides and respiratory symptoms improve (at least 10 days after symptom onset). As for asymptomatic medical personnel who test positive, the time-based strategy allows them to return to work after "10 days have passed since the date of their first positive COVID-19 diagnostic test assuming they have not subsequently developed symptoms."

The reality is that we don't really have the test we want — the test of cure, Mills said. Although the data are limited and there's still a lot that is unknown about COVID-19's course, he says it is becoming clear that PCR tests are "a very poor surrogate for infectivity." He thinks time and symptom-based strategies are likely better alternatives. Epidemiologist Martin concurs: "PCR test at 14 days, I don't see the value in it."

After more than 8 weeks, Amorim's patient tested negative, and she went back to work. Amorim thinks her patient probably wasn't infectious for most of the 8-week isolation period. But without more data and a better protocol, she was not willing to send a PCR-positive doctor back into a hospital.

Donavyn Coffey is a Manhattan-based health and science journalist.

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