Headshots of investigators

Bina Choi, Manuela Cernadas and Jonathan Li

The case began like many others: a patient was admitted to the hospital with a fever and diagnosed with COVID-19. The individual was immunocompromised, but after a five-day course of remdesivir, deemed well enough to be discharged without need of supplemental oxygen.

Over the course of the next few months, the patient quarantined at home but would appear and reappear at the hospital with hypoxemia and other ailments. “Given the patient’s severe immunocompromised state, we were concerned that there might be recurrent disease,” said Manuela Cernadas, MD, of the Division of Pulmonary and Critical Care Medicine, an attending physician who helped treat the patient.

Indeed, the patient would test positive for COVID-19 again, and then even after the infection appeared to be resolving, once more after that. The physicians worked with researchers including Jonathan Li, MD, MMSc, of the Division of Infectious Diseases, to obtain a more detailed picture of the infection’s course by measuring the amount of viral RNA remaining in the patient. Their findings, reported in The New England Journal of Medicine in November, would be an early warning sign of the possibility that new viral strains could emerge if SARS-CoV-2 is allowed to rage within a host for months on end.

An Unusual Case of Prolonged Infection

Some COVID-19 patients continue to shed viral RNA for a week or even months after their initial diagnoses, which can lead to positive COVID-19 test results. Generally, the levels of viral RNA shed are very low, and the pieces of RNA are not considered contagious.

Five months after this patient’s initial infection, however, extraordinarily high levels of viral RNA still appeared in nasopharyngeal swabs, and this RNA was found to be infectious. Though viral levels waxed and waned over the course of the illness, investigators confirmed that the patient’s immune system, compromised from the start, was failing to halt the virus’s replication. Ultimately, the patient passed away as a result of shock and respiratory failure, 154 days after initial admission to the hospital.

Following the patient’s death, physicians and researchers continued to analyze the course of the months-long illness. Of particular note were the results of genetic analyses of the viral RNA that continued to lurk in numerous organs throughout the patient’s body. Sequencing this RNA revealed that the rate of the virus’s mutation was much higher than that observed in the general population.

“This patient generated a whole slew of new mutations—the same mutations that are now highlighted in some of the concerning new variants appearing around the world that everyone is worried about,” said Li, whose virology laboratory performed viral load assays and viral sequencing for the study. “This case really provided insight into how these new strains may be coming about.”

A Virus Under Pressure

In laboratory tests, viruses tend to develop adaptive mutations most rapidly when a small amount of antibody is added to the culture — not enough to fully suppress the virus’s replication, but enough to give it what Li describes as “immune pressure.” He believes that this phenomenon is likely what occurred with the immunocompromised patient.

“This individual had some immune response, but not enough to fully eradicate the virus,” he explained. “The patient’s immunocompromised state provided an opportunity for the virus to mutate and evolve over time.”

The specific mutations that appeared in the patient, including the 484K and N501Y mutations, have also appeared in new SARS-CoV-2 variants around the world. They occur in parts of the virus’ genome that, if altered, could allow the virus to better evade antibodies, even those induced by vaccines. The N501Y mutation, for example, is one of the mutations that characterizes the more contagious B.1.1.7 variant discovered in the United Kingdom.

“What is unusual about some of the new variants we’re seeing, like the B.1.1.7 variant, is the sheer number of mutations that they have accumulated,” Li said. “It really does make me think about this case, and whether one of these evolutionary leaps in the new strains might have originally started with a patient similar to ours, before the strain began spreading through the general population.”

Paying Attention to Persistence

Several other reports of persistent COVID-19 cases have been published, including one that described a patient who was largely asymptomatic, but continued to shed viral RNA at high levels for several months.

“Our case definitely highlights the increasing need to better understand different immune responses and the viral mutations that follow,” said Bina Choi, MD, a fellow in the Division of Pulmonary and Critical Care Medicine who was on the pulmonary consult service with Cernadas and co-authored the NEJM Correspondence. “A patient can be immunocompromised in a variety of ways and can also be on several immunosuppressive agents that target different areas of the immune system, so this is not a one-size-fits-all case for all of our immunocompromised patients.”

Still, the authors hope that the case can provide broader lessons to physicians and scientists as the pandemic continues. “There is increased awareness for the need to monitor immunocompromised patients, who may have either a stuttering course like our patient or persistently positive COVID-19 swabs,” Cernadas said. “Hopefully, this will lead to the identification of patients with persistent viral infection.”

Doing so may ultimately help curb the pandemic by ensuring that new viral strains, resistant to vaccines and the body’s arsenal of antibodies, don’t proliferate.

“We’re going to have to monitor the situation very, very closely,” Li said, emphasizing the importance of conducting more viral sequencing. “I don’t think the United States is doing enough viral sequencing, and I don’t think it’s a coincidence that we found the B.1.1.7 strain starting in the U.K., which does far more viral sequencing of cases than the U.S.”

For this to occur, collaboration between physicians caring for COIVD-19 patients and researchers with the tools to analyze their infections will be key. “We were able to put together a huge team that volunteered time and resources to look at different aspects of this case,” Choi said. “It was a great example of direct translational research at the Brigham. Having scientists and physicians who are all willing to contribute their knowledge to a case is what allows us to broaden our understanding of the disease.”