Kaley Karaffa had just turned 28 when the reality of having a weakened immune system as a cancer patient started to sink in. A few weeks earlier, at an annual medical exam, Karaffa had expressed concern to her doctor about enlarged lymph nodes near her collarbone. Testing showed that Karaffa had a type of B-cell lymphoma, a cancer that affects the white blood cells, which are essential to fighting off infections.

“I had to become cautious about who I saw, the activities I was involved in and even the kind of food I ate,” said Karaffa, now 37.

Even a seemingly minor threat like a cold can lead to a serious illness in someone with a compromised immune system. For Karaffa, getting sick would also mean having to pause the clinical trial she was participating in to receive cancer treatment.

The COVID-19 pandemic made many people familiar with the term “immunocompromised.” But while public health messaging around COVID-19, flu season or even food-borne illness outbreaks may make those who are immunocompromised sound like a homogeneous group with the same kinds of conditions and a similarly high risk of illness, there is a broad spectrum of vulnerability.

And their numbers appear to be going up. A study published this year suggests that about 7% of U.S. adults — or about 18 million people — have immune systems that are suppressed in some way, up from about 3% in 2013. Researchers have different theories to explain the rise in immune suppression. Some believe it may be caused by an increase in autoimmune diseases, while others blame increasing rates of cancer and chronic diseases that require immunosuppressive treatment and the broader use of medications that can affect the immune system.

“It’s no longer a niche group,” said Dr. Joshua Hill, a specialist who treats infectious diseases in immunocompromised cancer patients at Fred Hutch Cancer Center in Seattle. “These are people walking around in the community that you might not know are immunocompromised.”

What makes someone immunocompromised?

Experts often liken the immune system to an army that protects you from foreign enemies, like viruses and bacteria, as well as domestic ones, like cancer cells. But some people have an immune army that is not working as it should — because they were born that way or because of something that occurred later in life.

Researchers have identified more than 430 primary immunodeficiencies, rare conditions caused by genetic variants that weaken the immune system. Some of these can be detected through routine newborn screenings or other blood tests shortly after birth.

People with severe immunodeficiencies sometimes require bone marrow transplants, which essentially replace their immune system with a new one from a donor. The nature of their illness and the treatment mean these individuals tend to be among the most immunocompromised, said Dr. Paibel Aguayo-Hiraldo, medical director of transplant and cellular therapy at Children’s Hospital Los Angeles.

“Most of our young patients are home-schooled,” Aguayo-Hiraldo said. “They have to be isolated and try to prevent infections, limit who visits their home and take other precautionary measures. For at least a year after a bone-marrow transplant, they must live in a bubble because any infection can be fatal.”

People who get certain blood or immune-cell cancers like leukemias, lymphomas or myelomas are also considered severely immunocompromised because the disease and the treatment wipe out the immune system, Aguayo-Hiraldo said. Similarly, people who receive organ transplants have to take immunosuppressive drugs so their bodies don’t reject the new organ. This makes it hard to fight off infections too.

Certain chronic conditions, such as multiple sclerosis, lupus, rheumatoid arthritis and AIDS, can also leave people mildly immunocompromised. These diseases are often driven by an overactive immune system that starts damaging the body’s own cells, making it less capable of fighting off actual pathogens, said Dr. Carl Fichtenbaum, a professor of infectious diseases at the University of Cincinnati.

How are your body’s defenses affected?

Depending on why someone is immunocompromised, different parts of the immune army may be temporarily or permanently out of commission.

Adriano Ortiz, 9, was born with Fanconi anemia, a rare genetic condition that predisposed him to an immunodeficient condition. Neither his T cells, which identify and attack pathogens, nor his B cells, which should remind the body how it dealt with past infections, were functioning properly. After a bone-marrow transplant in 2019, he had to remain in the hospital for more than a year to heal and avoid infections. Even after that, he had to go back to the hospital every time he got sick over the next several years.

Biologic drugs, such as those taken by people with rheumatoid arthritis, only block specific parts of the immune system, Fichtenbaum said.

Some of these drugs may make patients susceptible to particular types of respiratory infections; others may raise the risk of infections in the gastrointestinal tract or skin.

Does the immune system ever bounce back?

Luckily, the immune system can recover from many types of damage. Once a person completes chemotherapy and achieves remission from cancer or is able to stop taking biologics or steroids, the immune system can restore itself within a few weeks or months.

If the underlying cause of immunosuppression is a condition like AIDS, antiretroviral therapy can help restore immune function by controlling the virus and giving the body time to make healthy immune cells again. For people with severely compromised systems, it can take months or even a few years for bone-marrow or stem-cell transplants to rebuild the immune system, Aguayo-Hiraldo said.

When Karaffa was done with her cancer treatment, she had blood tests every few months to check how her immune system was recovering. She eventually resumed traveling and volunteer work, but she still carries hand sanitizer everywhere and puts on a mask whenever someone sniffles nearby.