Navigating Immunosuppression and Infection Risk

Modern immunosuppressive therapies have transformed the treatment of autoimmune diseases, allowing many people to live healthier, more active lives. At the same time, these medications can increase susceptibility to certain infections, making prevention and early recognition especially important.

As seasonal viruses, emerging infections, and vaccine-preventable disease outbreaks continue, many people taking immunosuppressive medications are left wondering how to protect themselves from infection while keeping their autoimmune disease under control.

Rosemary Ainley developed rheumatoid arthritis in 2007 and started treating it with methotrexate, a medication designed to reduce swelling and inflammation. By 2008, methotrexate wasn’t enough on its own, and she needed a second-line treatment as well. She applied to participate in a clinical trial for a biologic drug. During the screening process, she had a routine chest X-ray. To her surprise, the X-ray showed a lump in her lung about the size of a thumb nail. She didn’t have any respiratory symptoms, and tests were inconclusive for cancer. After three long months, she had the lump removed, and doctors found out it was cryptococcosis, a fungal infection caused by breathing in cryptococcus fungal spores. “[These spores are] in the air all around us and everybody breathes [them] in and out all the time,” she says. For most people, cryptococcus doesn’t cause problems. So what was different in Ainley’s case?

What Are Opportunistic Infections?

Because Ainley was taking methotrexate, her immune system was suppressed, meaning that her body couldn’t fight off infections as well. The fungus may have been in her system for years, but it became active after she started methotrexate. These types of infections that occur in people with weakened immune systems are called opportunistic infections. For example, people who take biologics to treat an autoimmune disease, those with HIV/AIDS, those undergoing cancer treatment, or those who are immunosuppressed due to organ transplants are at higher risk of these infections. Common opportunistic infections can be caused by fungi, bacteria, viruses, and parasites. In addition to opportunistic infections, those who are immunocompromised can have more serious complications from other infections like the flu or COVID-19.

How Do I Know My Risk for Opportunistic Infections When I’m Treating My Autoimmune Disease?

Not all immunosuppressive therapies for autoimmune diseases carry the same level of infection risk. “A short course of steroids is not really going to increase your risk as much as long-term immunologic drugs,” says Joshua Hill, an associate professor at Fred Hutch Cancer Center and the University of Washington School of Medicine. However, he cautions that sometimes a short steroid course can balloon into a longer course if someone doesn’t respond initially. This can increase the risk of infection and calls for a preventative antibiotic, he adds.

However, it’s hard to determine risk. “There’s a lot of heterogeneity in immunocompromised patient populations,” Hill says. This risk depends on the underlying disease and type of therapy. Even in the same individual patient, the degree they are immunocompromised can change over time.

“We don’t have a great test that we can do that says ‘you are this [level of] immunocompromised and as a result, this is what your risk profile looks like,'” he explains.

While it is possible to measure counts of different types of immune cells, Hill says that these numbers “aren’t that predictive.”

I’m Immunocompromised. How Should I Navigate Life and Medical Decisions While Avoiding Opportunistic Infections?

Since her diagnosis nearly 20 years ago, Ainley has navigated many medical decisions while treating rheumatoid arthritis and other autoimmune conditions that she subsequently developed. She had a bout of pneumonia and bronchitis while waiting for back surgery. She needed to go off her immunosuppressant medications and delay her surgery to allow her immune system to recover. Soon after, she had to go off her immunosuppressants again before her surgery due to the high risk of infection from the procedure. Overall, she was off her immunosuppressants for about five out of seven months. Her rheumatoid arthritis and ankylosing spondylitis, which she developed in 2017, were “pretty well controlled” before then, but since she got back on the drugs after surgery, she noticed “they never worked one hundred percent since.”

Ainley calls the decision to go off medication a “tricky balance” and only does this for major or persistent infections or for surgeries.

For more routine medical appointments, Ainley makes it known right away that she is immunocompromised. “That means they are more alert and start to take my infection risk seriously,” she says. She brings a list of all medications and conditions when she goes to a new doctor.

Ainley takes other precautions daily. To minimize the risk of opportunistic infections, she prefers to wear a mask when she is at the doctor’s or when she sings in her choir, avoids meeting people who are sick, gets all recommended vaccinations, and is aware of how her body is feeling and of possible signs of infection. She has found counseling helpful and manages two support groups for arthritis. “I believe connecting with other people with similar conditions who ‘get’ what you’re going through is very important for mental health,” she explains.

What New Research Can Help People Who Are Immunocompromised Reduce Infection Risk?

While there are day-to-day precautions to help manage opportunistic infection risks on an individual level, researchers around the world are devising new ways to better treat or understand opportunistic infections and to prevent common infections from becoming serious. 

Monoclonal Antibodies: An Alternative to Vaccines?

One of these methods are monoclonal antibodies (mAbs) that can be used when vaccine responses are muted in people who are immunocompromised. Hill notes that this dampened response to vaccines is a problem because immunocompromised patients are already vulnerable, and vaccines cannot protect them well if they can’t mount a strong immune response. There have been studies on timing vaccinations around biologic infusions, but results have been mixed. For example, the 2022 American College of Rheumatology guidelines recommend waiting two weeks after influenza vaccination before restarting methotrexate if possible and that vaccines other than influenza should be administered at least six months after a rituximab dose (1). Yet another study in IBD patients found that giving an inactivated influenza vaccine resulted in a similar response regardless of whether it was given at the time of infliximab infusion or in between (2).

This is where mAbs can help. Instead of asking the body to generate its own antibodies, mAbs given to a patient can act as natural antibodies against infectious agents they target. mAbs can stick around in the body for the length of a flu season, for example, so giving someone mAbs against flu at the start of flu season would protect them.

“There’s a lot of research happening in this space and a lot of drug development happening to make monoclonal antibodies for some of the common respiratory viruses that can be severe in patients with autoimmune and other conditions,” said Hill. He mentioned that a cocktail of antibodies, for example against flu, RSV, and COVID, that’s given before the respiratory virus season begins could be helpful.

Engineering B Cells to Make Antibodies

Another approach would be giving patients engineered B cells that are designed to make antibodies against a specific group of pathogens. This is a new area of research with studies in preclinical phases. For example, one study found that when introduced in immunodeficient mice, engineered B cells could protect against RSV infection (3).

Expanding Clinical Trial Inclusion

Clinical trials have often focused on healthy populations as participants because they minimize any confounding variables. Yet, this doesn’t represent the real world where 6.6% of people in the US are immunocompromised (4). When clinical trials only focus on healthy populations, it makes it difficult to know how the drug or treatment would work in immunocompromised populations. Hill cites the COVID-19 pandemic as a prime example of this. “In the first year, almost all of the trials excluded higher-risk individuals for those vaccine studies, but those are the patients that are at the highest risk for bad outcomes,” he says. “The consequence of that is that we don’t know how to give vaccines [against COVID] to patients with suppressed immune systems.” Studies of how people who are immunocompromised respond to therapies can help inform dosing amount or interval. “That work just isn’t done very much and that’s a key limitation. We’re just stuck doing the same thing for our immunocompromised patients as we do for everyone else and that’s really not sufficient,” he says. Hill is trying to change that by building a clinical trial network, ImmunOptimize Network, which would test therapies targeting infections in people who are immunocompromised on a larger scale.

Targeted Therapies Instead of Widespread Immunosuppression

Rather than addressing how to protect from opportunistic infections, another strategy focuses on eliminating the need for widespread immunosuppression. Nanotechnology-based therapies could help bring immunosuppressive drugs to the sites where they’re needed most as opposed to widespread delivery to the body. While work in this area is still new, it is a promising avenue to reduce the risk of opportunistic infections caused by other types of therapies.

Sources

1. Sources

   1. Bass, A. R., et al. (2023). 2022 American College of Rheumatology Guideline for Vaccinations in Patients With Rheumatic and Musculoskeletal Diseases. Arthritis Care & Research, 75(3), 449–464. https://doi.org/10.1002/acr.25045

   2. deBruyn, J., et al. (2016). Immunogenicity of Influenza Vaccine for Patients with Inflammatory Bowel Disease on Maintenance Infliximab Therapy: A Randomized Trial. Inflammatory Bowel Dis, 22(3), 638–647. https://doi.org/10.1097/MIB.0000000000000615

   3. Moffett, H. F., et al. (2019). B cells engineered to express pathogen-specific antibodies protect against infection. Sci Immunol, 4(35), eaax0644. https://doi.org/10.1126/sciimmunol.aax0644

   4. Martinson, M. L., & Lapham, J. (2024). Prevalence of Immunosuppression Among US Adults. JAMA, 331(10), 880–882. https://doi.org/10.1001/jama.2023.28019