Activated PI3K-delta syndrome (APDS)

APDS is a primary immunodeficiency, an inherited problem with the immune system. PI3K-delta is an enzyme, a protein that speeds up chemical reactions, found in white blood cells. It helps these cells grow and mature. In APDS, a gene change keeps the enzyme switched on too much. As a result, B cells, which make antibodies, and T cells, which attack infected cells, do not develop or work properly.

So APDS causes two kinds of trouble at once. Parts of the immune system are too weak to fight some germs (immune deficiency). Other parts are overactive and build up where they should not (immune dysregulation).

APDS was first described in 2013. There are two types. APDS1 is caused by changes in the PIK3CD gene, and APDS2 by changes in the PIK3R1 gene. It is sometimes first mistaken for common variable immunodeficiency (CVID) or another antibody problem, because the signs overlap.

APDS follows an autosomal dominant pattern. That means one changed copy of PIK3CD or PIK3R1 is enough to cause it. A person with APDS has a 50% chance of passing the change to each child. A dominant condition can also start with a new gene change in a child whose parents do not have it.

Family members with the same gene change can have very different health. In England, a mother told NICE that her child had APDS and that she herself had only recently been diagnosed. The Immune Deficiency Foundation says relatives of a person with APDS should have genetic testing, because they may carry the change without the same symptoms. APDS is not caused by anything a parent did, and it cannot spread from person to person.

Most people have repeated infections of the ears, sinuses and lungs, often starting in childhood. In an international group of 53 people with APDS1, 98% had repeated chest or sinus infections. Six in 10 had bronchiectasis, lasting damage that widens the airways. About half had severe or long-lasting infections with herpes-family viruses, such as Epstein-Barr virus (EBV) or cytomegalovirus (CMV).

Lymph glands, the spleen and the liver often swell because immune cells build up. Lumps of immune tissue can also form in the lining of the airways and gut. These growths are not cancer, but APDS does raise the risk of lymphoma, a cancer of immune cells. Some people develop autoimmune problems, where the immune system attacks the body's own tissues. About 1 in 5 people in that group had delays in development.

Signs usually start early, but the diagnosis often comes years later. In the UK registry, the median age at the first problem was 1 year, and the median age at diagnosis was about 9 years. Problems tend to add up with age, and by adulthood lung disease is common.

Doctors start to suspect APDS in a child or adult with repeated sinus and lung infections. The suspicion grows when there are also swollen lymph glands, a large spleen or liver, or long-lasting herpes-family virus infections. Bronchiectasis and lymphoma are other clues. Because the signs overlap with CVID and other immune disorders, the diagnosis is often delayed.

Blood tests often show low numbers of CD4 T cells and a high level of the antibody IgM. They may also show many transitional B cells, young B cells that have not finished maturing. Some people also have low IgG. In a study of 53 people with APDS1, 84% had low CD4 T cells and 78% had high IgM. No single blood result predicted how sick a person would be.

Genetic testing confirms the diagnosis by finding a disease-causing change in PIK3CD or PIK3R1. The Immune Deficiency Foundation says genetic testing is the only way to be sure. When the effect of a gene change is unclear, specialized labs can check whether the PI3K-delta pathway is overactive in the person's cells.

Everyday care aims to prevent and treat infections and calm symptoms. It can include antibiotics to prevent infection, antibody replacement called immunoglobulin, and medicines that calm the immune system. Sirolimus (also called rapamycin), a type of medicine called an mTOR inhibitor, has been used off-label to shrink swollen glands. Off-label means for a use not on the drug's label. None of these fix the cause.

Leniolisib (brand name Joenja) is a pill taken twice a day that blocks the overactive PI3K-delta enzyme. It is the first medicine approved for APDS. The U.S. FDA approved it in 2023 for people 12 and older. In September 2026, the FDA announced its approval for children aged 4 to 11 who weigh at least 27 kg (about 60 pounds). The European Union authorized it in May 2026 for people 12 and older who weigh at least 45 kg (about 99 pounds). Because APDS is so rare, the EU asked the company to keep collecting long-term data. In a 12-week trial of 31 people aged 12 and older, leniolisib shrank swollen lymph nodes. It also raised the share of new (naive) B cells compared with a placebo, a pill with no medicine in it. A study in children aged 1 to 6 is under way.

An allogeneic stem cell transplant, using blood-forming cells from a donor, can replace the immune system and reverse APDS. It carries serious risks. In England, experts told NICE they are hesitant to offer it because of those risks. NICE reported in 2025 that transplant is mainly used for children and that very few people aged 12 or older have one. In the largest transplant study, every person had serious APDS problems first; no one was transplanted because of a gene result alone.

APDS can shape daily life. In a UK survey run by Immunodeficiency UK and NICE, only 31% of people said they were satisfied with their quality of life. People described feeling drained, spending a lot of time in hospital and worrying that the disease would get worse. To avoid infections, some miss school, work and time with friends. Because APDS runs in families, a parent may be caring for an unwell child while unwell themselves.

For those who have a transplant, conditioning treatment, a long hospital stay and months of close follow-up are part of it. In the international study, 96% of the people who could be assessed, and whose new cells had taken hold, were alive and well with APDS reversed. Some needed extra donor cells or a second transplant. About 1 in 10 developed kidney failure that needed dialysis, and the study authors suggest the kidneys may need closer watching after transplant.

A transplant needs blood-forming cells from a donor with a close HLA match. Because APDS is dominant and can be mild, a brother, sister or parent could carry the same gene change without knowing it. European transplant guidelines say family donors should be checked for the same genetic defect, especially in conditions whose signs can start late or vary.

Unrelated volunteers were the most common donors in the largest study. There, 41 of 66 transplants (62%) used an unrelated adult donor, 15 used a half-matched relative and 7 used a matched brother or sister. Survival did not differ significantly by donor type.

In England, NICE noted that people from ethnic minority backgrounds may have fewer suitable donors. New registry members widen the choices for patients who need an unrelated donor, though joining cannot promise a match for any one person.

When a transplant from a donor is planned, the team usually tests brothers and sisters first. Each full sibling has about a one in four chance of being a full match.

Most patients do not have a matched relative. In the words of NMDP, the U.S. registry, “75% of patients don’t have a fully matched donor in their own family.” The team then searches registries of volunteer donors around the world and banks of donated cord blood. In some transplants, a half-matched parent, child or sibling can also be the donor.

Matching depends on inherited tissue markers called HLA, so a patient is most likely to match someone who shares their ancestry. Every person who joins makes the search a little more likely to succeed, especially for patients from groups that are underrepresented on registries.

APDS varies a great deal. Some people have few symptoms and are found only after a relative is diagnosed. Others become very ill as young children. In general, problems add up with age. Lung damage and lymphoma are the main long-term worries.

Before leniolisib, care could only treat symptoms. Leniolisib has been studied for up to about 6 years in a small number of adults. Its long-term effect on lymphoma and organ damage is still being studied. A transplant can reverse APDS for most people whose new cells take hold, but graft failure and kidney problems are real risks.

These figures describe groups of people, many diagnosed or treated years ago. They cannot predict how any one person will do.