What do we know about covid in immunocompromised people?

Is covid still a particular risk for people who are immunocompromised?

Although the morbidity and mortality of covid-19 have reduced drastically in highly vaccinated and highly previously exposed populations, the disease is still a threat to the lives of more vulnerable people, particularly those without a functioning immune system. They are the people at “greatest risk,” says Bill Schaffner, professor of preventive medicine and infectious diseases at Vanderbilt University in Nashville, Tennessee.

Around 12 000 people died of covid-19 worldwide from 1 to 28 May 2023, show data from the World Health Organization. Schaffner says that the patients who are dying are mainly immunocompromised people who are older—and therefore have weaker immune systems—or have underlying conditions such as cancer or an autoimmune disorder or are taking immunosuppressive drugs.

Alex Richter, professor in clinical immunology and director of the Clinical Immunology Service at the University of Birmingham, UK, reiterates this. “Studies are highlighting that although outcomes have improved for immune vulnerable patients, they remain at higher risk than the general population, and this is now included in risk algorithms such as QCovid,1” she says.

What we don’t know is the difference in risk between different types of immunocompromised states. The evidence is not clear cut, says Arturo Casadevall, professor of molecular microbiology and immunology at Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. “The data on [how at risk different immunocompromised people are] is fragmentary, since this group is very heterogeneous,” he says. “For example, a patient on corticosteroids is very different from a transplant recipient, who in turn is very different from a person with leukaemia.” Studies suggest that patients with malignancy or solid organ transplants are at greater risk of severe covid-19 and death.2

Immunocompromised people in general are also at risk of prolonged infection. “Some of these patients cannot clear infection once they get it, and that interferes with other therapies that they need,” says Casadevall. “They remain PCR positive, often for months—a phenomenon called ‘smouldering covid,’ where the patients are chronically infected.” These individuals pose a risk for the development of new variants and could theoretically serve as sources for new rounds of infection.3

How effective are SARS-CoV-2 vaccines in immunocompromised people?

About 2-3% of the general population have reduced immune responses, so they may be at greater risk from SARS-CoV-2 infection.4 Regulatory and governmental bodies, including the US Centers for Disease Control and Prevention and the British Society for Immunology, therefore endorse covid vaccination for immunocompromised people on the grounds that the benefits outweigh the risks (since none of the covid vaccines are live, they’re not thought to pose any more risk to this population than to immunocompetent people5). Trials in patients with HIV and those with solid organ transplants, although small in scale, have indicated that the Pfizer-BioNTech, Moderna, and Janssen vaccines are safe and effective in these groups.5

Vaccine shots may not be immediately effective, requiring boosters. Casadevall says that immunocompromised people may have a reaction that is “suboptimal since they have a compromised immune system, but [vaccination is] still recommended and some do respond after multiple shots.”

Schaffner says, “There’s a tendency for the antibodies that you’ve created to wane more rapidly [if you’re an immunocompromised person] than when someone who has an intact and robust immune system receives vaccine. The current recommendation is: if you’ve received the bivalent booster you need wait only two months to get another.” He adds that there seems to be no harm in repeatedly vaccinating immunocompromised individuals.

Close contacts of immunocompromised people are also urged to get vaccinated, but there’s little evidence to support covid prophylaxis for either immunocompromised people or their contacts.6 Richter emphasises how covid-19 has highlighted the risks among people with reduced immune response. “There was always a risk of infection for these individuals, which may not have been fully realised,” she says. “There is a real need to support patients and help them understand their risk to allow them to make individual informed choices.”

She reiterates the need for immunocompromised people to get their recommended vaccinations, to continue to wear masks, and to avoid situations that pose a high risk of infection, such as crowded or enclosed spaces.

What treatments are effective in immunocompromised patients?

Medicines to prevent the infection developing, clear the virus, or combat severe infection are vital for these patients. First line treatments have shown promise, such as the oral antivirals molnupiravir (Lagevrio) and nirmatrelvir-ritonavir (Paxlovid) and the injected antiviral remdesivir (Veklury).

One study found that molnupiravir might reduce the risk of severe covid-19 and death in elderly, female, and unvaccinated people.7 Another found that, in a small group of immunocompromised patients, those who were treated with molnupiravir had a lower incidence of hospital admission and death than those who were not.8 This was the first randomised controlled trial that showed molnupiravir’s effectiveness, although the effect size was much lower than with nirmatrelvir-ritonavir or remdesivir. The UK Panoramic study later reported that molnupiravir showed no significant reductions in mortality or hospital admission in a vaccinated “high risk” population, although that trial involved few participants considered “highest risk” (severely immunosuppressed patients).9 A review by the European Medicines Agency also questioned molnupiravir’s effectiveness and recommended refusing marketing authorisation.10

Clinical trial results from nirmatrelvir-ritonavir in patients at risk of severe illness were impressive, showing an 89% reduction in hospital admission and death.11 Real world results haven’t been quite as striking, but one recent study found that the antiviral was effective in older and immunosuppressed patients.12

People who aren’t given oral antivirals or for whom they’re ineffective can still end up in hospital with severe covid-19. The treatment options then include intravenous antivirals such as remdesivir, and/or convalescent plasma.

What’s the future of covid treatments for immunocompromised patients?

Oral versions of currently intravenous-only drugs such as remdesivir are in development, which would make them easier to access. Longer duration treatments are also needed, which could help reduce toxicity and lower the likelihood of drug resistance developing. Trials are already under way to study longer duration courses of nirmatrelvir-ritonavir—comparing the current five day course with 10 and 15 days—in immunocompromised adults.13

But as drug resistance is an ever growing worry, combination treatments seem a likely avenue for immediate exploration.14 One small scale trial has found that a combination of remdesivir and nirmatrelvir-ritonavir with monoclonal antibodies induced a good clinical response in immunocompromised patients with prolonged or relapsed covid-19. Other trials suggest that combinations of convalescent plasma with different antivirals may be effective.15

Alternatives are needed, however, particularly where contraindications have severely limited the use of existing drugs. The ritonavir part of Paxlovid, for instance, works by preventing the liver from breaking down certain compounds, but this could be a major problem with other drugs a patient might need, as these also won’t be broken down so might build to harmful levels.

Stephen Griffin, virologist at the University of Leeds, UK, says that ritonavir was part of the reason Paxlovid isn’t licensed for under 18s. He explains, “There’s such a huge raft of interactions between ritonavir and other drugs, because it acts on the liver to stop it degrading things. That is a real concern going forward for many clinically vulnerable people.

“For clinically vulnerable people on multiple medications, it’s a bit of a minefield. Referring that out to GPs to manage may be a little difficult. They’ve got to work out, ‘How does this interact with the meds my patient is on?’”