Early in the Covid19 pandemic, doctors noticed that some immunocompromised patients had persistent infections from SARS-CoV-2, some of which lasted weeks or months at a time. This has raised concerns that one of these cases could be the source of an emerging virus variant that has benefited from a long battle with the immune system.
A prospective study, “SARS-CoV-2 shedding and Evolution in Patients who were immunocompromised during the omicron period: a multicenter, prospective analysis,” provides greater clarity on which patient populations are at greatest risk for prolonged infections – and suggests that this fear is probably unjustified.
The results of research were published in the journal Lancet Microbe.
Prolonged Covid19 infections in at-risk patients
The study, led by Adam Lauring, MD, Ph.D., of Michigan Medicine's Division of Infectious Diseases, is part of the larger IVY Network study sponsored by the CDC and led by Vanderbilt University.
The collaborative team followed 150 immunocompromised patients with COVID infections from five US healthcare systems in 2022. Each patient was screened and tested using nasal swabs collected from the onset of Covid19 infection until they tested negative.
“We were specifically looking at who was at risk for prolonged infection, so that we never eliminated the virus,” Lauring said.
Study participants had a diverse set of immunocompromising conditions, ranging from people with B-cell tumors or receiving anti-B-cell therapy; subjects undergoing solid organ or stem cell transplants; people living with AIDS; and those with non-B cell tumors and autoimmune or autoinflammatory conditions.
The team found that only 25% of patients tested positive using the highly sensitive, gold standard PCR test for 21 days or more after disease onset.
Only 8% tested positive for live virus for 21 days or longer. The median time to last positive test overall was nine days. “Unlike many reported cases, we found that very few people had a prolonged infection,” Lauring said.
Specifically, people with AIDS and those with B-cell cancers, such as some leukemias and lymphomas, were more likely to have prolonged infections than patients with autoimmune diseases or non-B-cell cancers. And of the 59 patients enrolled with a transplant of solid organ with T cell immunosuppression, only one had an infection that lasted longer than 56 days.
The extensive infection also appeared to coincide with some immunosuppressive therapies.
Patients treated with rituximab or CAR-T therapy, which targets B cells, were more likely to have longer-lasting infections, underscoring the importance of antibodies (produced by B cells) for immunity.
Importantly, the team also notes that mutations within the subgroup of patients who had prolonged infections rarely, if ever, matched those of variants circulating within the broader global community.
“A lot of what makes a virus effective is its ability to escape immunity,” Lauring said.
“However, immunity is heterogeneous: what might cause a virus to escape the immune system in an immunocompromised patient versus patients at a population level is different.”
As global immunity changes due to vaccination and infection, surveillance of this particular patient population for new variants may not be practical, he explained.
The study provides much-needed information about which immunocompromised patients are at greatest risk, Lauring says. He hopes the study will also lead to refocusing efforts to develop better therapies for these patients.
Immunocompromised individuals are at risk for worse Covid19 outcomes and may have a less robust response to vaccination than non-immunocompromised individuals. But the term “immunocompromised” refers to a wide range of conditions, and not all patients in this category may be at the same risk.
Mass General Brigham researchers studied a population of 56 immunocompromised individuals that included patients severely immunocompromised due to hematologic malignancy/organ transplant or autoimmune/B-cell deficiency, as well as patients who were not severely immunocompromised. The team compared these groups with each other and with patients who were not immunocompromised.
They found that patients' ability to clear the virus differed based on the extent of their immunosuppression. Patients immunocompromised due to a hematologic malignancy or organ transplant were more likely to have a chronic, prolonged infection. This finding suggests the importance of T cells in clearing Covid19 infection, which has implications for patient monitoring and improved vaccine design. Severely immunocompromised participants also had a higher risk of developing resistance to therapeutic monoclonal antibodies.
“Providers and patients should be aware that protracted symptoms may signify persistent Covid19 disease requiring further testing and potential treatments,” said corresponding author Jonathan Li, MD, of the Division of Infectious Diseases at Brigham and Women's Hospital.
Patients with a history of organ transplantation or hematologic malignancy had the greatest delay in viral clearance; patients with B-cell immunodeficiency were at intermediate risk; and the 31 study patients with mild, non-severe immunocompromise, such as those with autoimmune diseases receiving anti-tumor necrosis factor (TNF) treatment, had viral shedding dynamics similar to those of non-immunocompromised participants.
“Although our sample size is limited, these results provide reassurance that most patients with mild/moderate immunosuppression (including those undergoing B-cell depletion therapy) will be able to clear the virus during the acute phase of the infection,” Li said.
Comorbid conditions affecting individuals diagnosed with Covid19 may impact how long they continue to receive positive SARS-CoV-2 polymerase chain reaction (PCR) test results.
Individuals diagnosed with Covid19 who are over age 60, have three or more chronic medical conditions, particularly diabetes, obesity, rheumatologic disease, or an organ transplant, have positive PCR tests for longer periods of time than younger individuals without these comorbidities. However, the data showed no significant differences in the duration of positive PCR test results based on the degree of immunocompromise or for subjects receiving chemotherapy or steroids to treat COVID.
“There is limited data on how long immunocompromised individuals continue to test positive for Covid19 after initial infection,” said Rachel Epstein, MD, MScE, an infectious disease physician at Boston Medical Center and corresponding author of the study.
“This study calls into question the need for current recommendations to consider retesting severely immunocompromised individuals and to use negative Covid19 PCR test results to end isolation.”
According to the Centers for Disease Control and Prevention (CDC), severely immunocompromised individuals are likely to have sustained positive Covid19 PCR test results. Conditions causing the immunocompromised state represented in the CDC definition include: people on chemotherapy or high-dose steroids; those with untreated HIV; those with a primary immunodeficiency; or those who have recently received an organ transplant.
The researchers examined data from 3,758 individuals who were retested using the Covid19 PCR test after an initial positive result. Individuals were separated into groups based on age and severity of compromised immune system:
Severe: active chemotherapy, HIV with a CD4 count less than 200, organ transplant within the past year, or chronic high-dose steroids (7.4% of study group)
Moderate: Solid organ transplant recipient for more than 1 year, HIV with a CD4 count greater than 200, and others taking chronic biologics (4.2% of study group)
Non-immunocompromised (88.4% of study group)
The median length of time it took severely immunocompromised patients to receive a negative Covid19 PCR test result was 22 days; for moderately and non-immunocompromised individuals, the time was 20 and 16 days, respectively. For individuals who have undergone a solid organ transplant, are over age 60, have diabetes, obesity, or rheumatologic disease, as well as those with more than three comorbid conditions, it took longer for a negative SARS PCR test result -CoV-2.
“Retesting individuals to end isolation precautions may delay treatment and may not be necessary for even the most severely immunocompromised people, particularly because most transmission studies show that it is highly unlikely that someone will transmit the infection for more than 20 days after the onset of the illness,” said Epstein. , assistant professor of medicine and pediatrics at Boston University School of Medicine.
The authors note that recommendations for retesting should perhaps consider a combination of conditions or include only certain groups of extremely immunocompromised individuals.
There have been a few cases in the literature showing positive Covid19 test results months after initial infection in patients who have undergone a solid organ or bone marrow transplant or received antigen receptor T cell therapy chimeric (CAR).
Additional studies directly measuring transmission or transmissibility from individuals with a positi
ve PCR test result from more than 20 days of illness with Covid19 would be helpful to better inform current CDC guidelines.
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