The 47-year-old woman couldn’t shake her cough and shortness of breath, baffling Veronique Nussenblatt, an infectious disease specialist at the National Institutes of Health (NIH). Her patient had been hospitalized at NIH with COVID-19 in spring 2020; as summer turned to fall and fall to winter, the woman should have mostly recovered. But she continued to need supplemental oxygen at home. “Sometimes she felt better, sometimes she felt worse,” Nussenblatt says.
Repeated COVID-19 tests were positive for the virus, but barely. Nussenblatt and other doctors assumed they were picking up nonviable viral fragments, as has been documented in other people after a bout with COVID-19. In fact, the woman’s medical ordeal, lasting nearly 1 year, turned out to be a unique case study in how long an active infection can endure, and how the virus can evolve inside one person’s body.
Along with her lingering symptoms, Nussenblatt’s patient was unusual in another important respect: She’d had cancer—lymphoma—and been successfully treated with an aggressive treatment, CAR-T cell therapy, 3 years earlier. That treatment left her with vanishingly few B cells, a type of immune cell that churns out antibodies and helps the immune system function normally.
In March, a COVID-19 test showed her virus levels, barely detectable before, had jumped. Had the woman been reinfected, or had she never cleared her first infection? Nussenblatt says chronic COVID-19 wasn’t on her radar in part because her patient, although ailing, wasn’t in dire straits. In addition, she hadn’t seen anything quite like this with other pathogens. “I’ve never heard of a transplant patient with flu for a year,” Nussenblatt says. “That’s a really long time.”
She asked for help from Elodie Ghedin, a molecular virologist who runs an NIH lab that studies the genomes of SARS-CoV-2 virus from infections. Ghedin and computational biologist Allison Roder sequenced samples from the patient and confirmed the virus had continued to replicate. Then, they compared those sequences with ones from the patient stored 10 months earlier.
“It was the same virus,” Ghedin says. The patient had been infected in 2020 by one of the first versions of SARS-CoV-2, which by early this year was no longer circulating. Samples from later in the infection allowed the team to trace how the virus evolved as her weakened immune system combated it. Nussenblatt, Ghedin, and their colleagues posted a report this month on the preprint server medRxiv and are submitting it for publication.
“There’s very few systematic studies of immune-suppressed patients and how long they continue to shed virus,” says Jonathan Li, an infectious disease specialist at Brigham and Women’s Hospital and Harvard Medical School. “We need to study them so we can help these patients and prevent the virus from mutating further.” With colleagues, Li published a case study in The New England Journal of Medicine about a 45-year-old immune-compromised man infected for about 5 months, who ultimately died of the disease in late summer 2020. “Even now,” Li says, more than 1 year later, “I still find places where that patient has continued to teach us.”
In Li’s patient, the virus developed mutations that are hallmarks of the Alpha, Gamma, and Delta variants of SARS-CoV-2, none of which had yet taken hold in the general population. Immune-suppressed patients “give you a window on how the virus explores the genetic space,” Ghedin says.
In the NIH patient, sequencing revealed two genetic deletions that caught the researchers’ eyes. One was in the RNA that codes for the spike protein, which helps the virus enter cells. Because of the spike protein’s critical role in how SARS-CoV-2 causes infection, mutations in that sequence have garnered a lot of interest. But it was the other that especially struck the team: a large deletion, almost 500 nucleotides out of the virus’ 30,000, that lay outside the spike sequence.
Some scientists think nonspike mutations merit more attention than they’ve gotten. “It is spike, spike, spike all the time, but spike only makes up 13% of the viral genome,” Li says. In June in Clinical Infectious Diseases, Li and his colleagues analyzed previously published case reports of chronic infections and reinfections and found that a deletion similar to the large one Ghedin and Nussenblatt identified was among the most common mutations described. Other genes, Li says, lack spike’s role in transmission and infection, but “they are likely of importance when the virus is trying to fight against our immune response.”
Thankfully, chronic COVID-19 infections appear relatively rare, doctors say, but they are also important to study. “New variants are still a threat,” says Ravindra Gupta, an infectious disease specialist at the University of Cambridge, and “chronic infection is what drives” at least some of them. Work by Gupta suggests the Alpha variant, which surged in the United Kingdom in December 2020 before spreading elsewhere, may have first appeared in an immune-compromised individual. Furthermore, Gupta and his team reported, convalescent plasma that patient received, which is rich in antibodies, appeared to drive viral evolution. Nussenblatt’s patient received convalescent plasma as well, both when she first got sick and this spring, when her symptoms worsened again.
For Gupta, an important question is whether monoclonal antibody therapies, which are now recommended as a treatment for COVID-19 in high-risk patients, can also speed viral evolution in immune-compromised people. It’s “very important to limit the potential of these immune-compromised patients getting infected” in the first place, Gupta says—both to protect them from the risk of severe infection and to reduce the likelihood of new viral variants arising.
As for Nussenblatt’s patient, her story has a happy ending. After a second hospitalization and more treatment, her lungs improved and blood markers of inflammation dropped. Since April, she’s had multiple negative COVID-19 tests, and those, combined with the easing of symptoms, convinced Nussenblatt that “the infection is gone.” Nussenblatt Facetimed with her patient in early summer. “She was walking on the beach,” Nussenblatt says, no oxygen tube in sight.
Source: Science Mag