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Quick Uptakes

February 14, 2024

When It Comes to SARS-CoV-2 Clearance, People Who are Immunocompromised Are Not All Alike

Rita Rubin

JAMA. Published online February 14, 2024. doi:10.1001/jama.2024.1014

For people who are immunocompromised, the COVID-19 pandemic is not over.

In general, their immune system’s response to COVID-19 vaccines and to SARS-CoV-2 infection is blunted compared with individuals who are not immunocompromised, leading to more severe disease.

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But not all people with compromised immune systems are alike, and some are able to vanquish COVID-19 about as handily as people who aren’t immunocompromised, a recently published study in Science Translational Medicine found.

For those patients, “I hope that this paper will provide a little reassurance,” senior author Jonathan Li, MD, an infectious diseases specialist at Brigham and Women’s Hospital and Harvard Medical School, told JAMA in an interview.

The Methods

The study compared 56 people who were immunocompromised with 184 who weren’t. Participants were enrolled in the Post-Vaccination Viral Characteristics Study (POSITIVES), a longitudinal cohort study of adults who tested positive for COVID-19 or received a prescription for a COVID-19 treatment in the Mass General Brigham health care system. Three patients, all of whom were severely immunocompromised, died of COVID-19 or its complications during the study.

The researchers divided the people who were immunocompromised into 3 groups:

• Severely immunocompromised due to a solid organ transplant, a hematopoietic stem cell transplant, lymphoma or leukemia, or cancer treated with multiple immunosuppressants.

• Severely immunocompromised due to B-cell–targeted therapy for an autoimmune disease or congenital or late-onset B-cell deficiency.

• Immunocompromised but not severely, as a result of receiving immunosuppressants such as antitumor necrosis factor for autoimmune diseases.

People in both the immunocompromised and nonimmunocompromised groups had received 3 COVID-19 vaccine doses on average. Both groups also included some people who had received COVID-19 monoclonal antibodies and antivirals outside of the study; those who were immunocompromised were more likely to have received the treatments. All but 1 of the participants collected their own nasal swabs for analysis.

The Results

The researchers assessed differences among the 3 immunocompromised groups and the nonimmunocompromised groups in 2 main areas:

• How likely the virus was to mutate, specifically among participants who had a viral genome available at baseline and at least 1 follow-up time point. Persistent SARS-CoV-2 infection in individuals who are severely immunosuppressed “most people would agree represents a key driver of viral evolution,” Li said.

• How many days they shed the virus.

Among participants with viral sequences, 39% of those who were immunocompromised had evidence of changes in the gene that encodes the SARS-CoV-2 spike protein, compared with 12% of the nonimmunocompromised group.

In addition, clearance rates of nasal viral RNA and culturable SARS-CoV-2 differed among the immunocompromised groups. Nasal viral RNA can include SARS-CoV-2 fragments that aren’t infectious, but viral RNA that can be grown in culture is infectious. On average, this was how long it took the different groups to clear viral RNA and culturable virus from their nose:

• For the group that included solid organ transplant recipients, 72 days for viral RNA, 40 days for culturable virus.

• For the other severely immunocompromised group, 10 days for nasal viral RNA, 6.5 days for culturable virus.

• For the less severely immunocompromised group, 12 days for nasal viral RNA, 6 days for culturable virus.

• For the nonimmunocompromised group, 13 days for nasal viral RNA, 7 days for culturable virus.

Taking It Seriously

The findings about persistent SARS-CoV-2 infection in the severely compromised group confirm case reports and case series, the authors noted.

“Persistent symptoms past 10 days need to be taken seriously,” Li said. One danger, he noted, is that patients might mistakenly attribute their persistent symptoms to post–COVID-19 condition, commonly called long COVID, and assume they can no longer spread the virus.

The National Institutes of Health’s COVID-19 treatment guidelines suggest longer or additional courses of the antivirals nirmatrelvir-ritonavir (Paxlovid) or remdesivir (Veklury) only for patients who are immunocompromised and then only if symptoms persist and there is evidence of ongoing SARS-CoV-2 replication.

For everyone else, treatment with nirmatrelvir-ritonavir is supposed to be a single 5-day course, while the standard treatment with remdesivir for nonhospitalized patients is 3 consecutive daily infusions. The guidelines, last updated in early November 2023, acknowledged that definitive data to support extending treatment are lacking.

A case series of 11 patients with persistent SARS-CoV-2 infection, published by researchers in Ireland and the UK in December 2023, suggested that prolonged nirmatrelvir-ritonavir treatment can effectively treat persistent SARS-CoV-2 infection in people who are immunocompromised.

Ten of the patients were hospitalized, 7 with severe COVID-19 (nirmatrelvir-ritonavir is approved only for outpatients with mild to moderate COVID-19 but can be prescribed off-label). On average, the patients, 9 of whom had a blood cancer, were treated with the antiviral pills for 10 days. None of the patients died, and 9 of them completely cleared the virus.

The Bs and Ts of Immunity

It might be surprising that some individuals who were immunocompromised in Li’s study cleared SARS-CoV-2 even sooner than people who weren’t.

But there were hints that it could happen from the earliest days of the pandemic, he noted. For example, a reportpublished in May 2020 described 2 young adults with X-linked agammaglobulinemia (XLA) who developed COVID-19-related interstitial pneumonia. People with XLA, an inborn error of immunity, have no circulating B cells. B cells, one of the 2 main types of lymphocytes, produce neutralizing antibodies that attack viruses and other invaders, so there was speculation that patients with the condition would likely become very ill if infected with SARS-CoV-2.

“Neutralizing antibodies are protective,” Charles Hackett, PhD, deputy director of the Division of Allergy, Immunology, and Transplantation at the National Institute of Allergy and Infectious Diseases, explained in an interview with JAMA. “If you have enough of them, you don’t even get infected.”

But even though they lacked antibody-producing B cells, the 2 patients with XLA recovered without the need for intensive care or ventilation, suggesting that the T-cell response is probably important for protection against SARS-CoV-2, the authors wrote.

T cells are the other main type of lymphocyte. Unlike B cells, T cells don’t recognize viruses until they infect cells, so they can’t block infection, Hackett noted. Instead, T cells destroy infected cells.

One hypothesis is that when B cells are depleted, T cells rev up to compensate, Hackett said, adding, “I hope that’s true.”

Hackett noted that he’s known people infected with SARS-CoV-2 who had low neutralizing antibody titers. “I was scared to death [for them], but they got over COVID just like an average person,” he said.

In people who are severely immunocompromised due to a solid organ or stem cell transplant or leukemia or lymphoma, however, “you kind of disarm all of their weapons,” Yijia Li, MD, said in an interview, referring to the effects of the immunosuppressive therapies such patients receive. The treatments leave behind neither a robust B-cell nor robust T-cell immune response, explained the University of Pittsburgh Medical Center infectious diseases physician, who was the first author on the new POSITIVES article coauthored by Jonathan Li (no relation).

The Upshot

Both Hackett and transplant surgeon Dorry Segev, MD, PhD, codirector of the NYU Langone Center for Surgical and Transplant Applied Research, praised the study.

“The study showed, in a very interesting way, qualitatively different selection pressure put on the virus by people who have differences in their immune system,” Hackett said.

“It gives us a mechanistic underpinning for what we had observed clinically, and I think that’s really important,” Segev noted in an interview.

Unfortunately, Segev said, clinicians lack the tools to precisely assess where a patient who’s immunocompromised falls on the scale of risk of severe and persistent COVID-19. “What patients and their providers still dream of are some clinical correlates of the immune milieu,” he pointed out.

Segev acknowledged that he used to think antibody tests were the way to go for transplant recipients and others with compromised immune systems who were concerned about their ability to fend off SARS-CoV-2. Before “things went off the rails” with the Omicron variant, “we knew that detectable circulating antibody correlated with neutralizing antibody,” Segev said.

Today, though, he said, the sources of circulating antibodies can be numerous and vary from patient to patient, due to combinations of COVID-19 vaccines and infections with different variants. As a result, circulating antibody titers no longer reflect neutralizing antibody titers, except in people found to have no circulating antibody, Segev explained. In that case, he said, “I can guarantee you you’re not going to have neutralizing antibodies.”

Perhaps if effective anti–SARS-CoV-2 monoclonal antibodies were to become available for preexposure prophylaxis, there would be increased interest in developing tests to help determine which patients with compromised immune systems should be at the front of the line to get such treatments, Segev observed. “We really need to step up our game in terms of patient-level clinical testing.”