Primary immunodeficiency (PI) is a group of more than 400 disorders that affect the immune system. In people with PI, the immune system is weakened or missing important components, making it harder for the body to fight off infection and certain diseases, including autoimmune diseases and cancers. Some forms of primary immunodeficiency are so mild they go undiagnosed until adulthood, while other types are severe enough that they are discovered soon after birth.e60dc2a1-f33c-4a05-9b50-8e3e8e59762948b444b9-7732-4f86-adac-5d65aa7ff47a Primary immunodeficiency is sometimes called other names, including primary immunodeficiency disease, primary immunodeficiency disorder, and inborn errors of immunity.e60dc2a1-f33c-4a05-9b50-8e3e8e597629f7c4b487-0c8b-496b-89de-49539b700063 Treatments for PI boost the immune system and can help many people live healthy lives. Keep reading to find out what you need to know about primary immunodeficiency symptoms, causes, treatments, and outlook.
Types of Primary Immunodeficiency Types Unlike secondary immunodeficiencies, which are caused by other health issues (such as HIV or cancer treatments ), primary immunodeficiency is present from birth and can result in frequent, severe, or unusually hard-to-cure infections. There are many different types of primary immunodeficiency, categorized based on which part of the immune system is affected. B-cell Deficiencies These affect the body’s ability to produce antibodies, the proteins that normally fight harmful bacteria, leading to increased risk of infections like pneumonia , sinus infections , and ear infections . Defects in B cells make up 50 to 60 percent of primary immunodeficiency; common variable immunodeficiency (CVID), in which B cells don’t work normally, is the most common primary immunodeficiency in adults.e60dc2a1-f33c-4a05-9b50-8e3e8e597629dfdee220-25c4-4529-95cb-497135e190de T-cell Deficiencies These affect the function of T cells, which are essential for fighting infections. People with T-cell deficiencies are more vulnerable to bacterial and fungal infections. Conditions include DiGeorge syndrome, also known as congenital thymic aplasia, and chronic mucocutaneous candidiasis. Combined Immunodeficiencies A mix of B-cell and T-cell problems, these cause a higher risk of serious infections. Conditions include severe combined immunodeficiency disease (SCID), Wiskott-Aldrich syndrome, immunodeficiency with ataxia-telangiectasia, and major histocompatibility complex deficiency. Defective Phagocyte These affect white blood cells that help “eat” and destroy invaders, leading to frequent bacterial infections. Conditions include chronic granulomatous disease and leukocyte adhesion deficiency syndrome. Complement Deficiencies This involves problems with the proteins that assist in immune responses, increasing vulnerability to certain infections and autoimmune diseases. Conditions include hereditary angioedema, deficiency of C3, deficiency of membrane attack complex, and C2 or C4 deficiency secondary to autoimmunity.e60dc2a1-f33c-4a05-9b50-8e3e8e5976298d9de429-b417-4419-9c3f-68430156c7cd Unknown (Idiopathic) In some cases, the underlying cause of primary immunodeficiency is unknown.e60dc2a1-f33c-4a05-9b50-8e3e8e597629863361da-cd87-4dca-baf4-ebcfebd44f08
Signs and Symptoms of Primary Immunodeficiency Symptoms Often the first signs of primary immunodeficiency are having repeated, persistent, or unusual infections that are hard to treat. Other symptoms vary depending on the type of immune cells affected and may include: Certain types of infections : These may include ear infections, sinus infections, pneumonia, bronchitis , meningitis , skin infections, and thrush (a fungal infection of the mouth or skin, also called candidiasis).e60dc2a1-f33c-4a05-9b50-8e3e8e59762921b4b6c4-332b-4f0a-af5f-569f3c804b01 Infections that don’t respond well to treatment : This includes infections that take a long time to get better, need multiple courses of antibiotics to overcome, or require hospitalization, or infections that come back after treatment is stopped. Enlarged spleen : Symptoms can include vague abdominal discomfort or pain in the left upper abdomen or left shoulder.e60dc2a1-f33c-4a05-9b50-8e3e8e5976291fa8cfc0-c0f2-4815-871d-9b5fa799eb3d Sickness after a live vaccine : Live vaccines include the MMR and MMRV , chicken pox (varicella) , bacille Calmette–Guérin (used to prevent tuberculosis ), infant rotavirus , and oral polio virus . Failure to thrive in infants and children : This includes slower than expected growth and physical development. Chronic diarrhea or digestive issues : Some types of PI affect the gut, leading to ongoing digestive problems. Autoimmune conditions : Some types of PI can lead to the body mistakenly attacking its own cells, tissues, and organs and cause autoimmune conditions such as lupus , rheumatoid arthritis , or type 1 diabetes .e60dc2a1-f33c-4a05-9b50-8e3e8e597629d22b9791-c77f-42d6-8885-df181e8e424a
Causes and Risk Factors of Primary Immunodeficiency Causes Primary immunodeficiency is caused by genetic changes that affect one or many components of the immune system, including cells and proteins. The genetic changes can make the immune system less active than normal, defective, or totally absent. Most, but not all, of these genetic changes are inherited. So although anyone can develop primary immunodeficiency, it’s more likely to happen in people with a biological family history. It typically occurs in people before they are 20 years old, and it’s more common in males.e60dc2a1-f33c-4a05-9b50-8e3e8e597629f00f29a9-87a6-422a-ae01-3b94a328475d
How Is Primary Immunodeficiency Diagnosed? Diagnosis Getting a diagnosis of primary immunodeficiency — especially for adults — can be difficult. People average 9 to 15 years from symptom onset to diagnosis, and experts believe that more than 70 percent of people with a PI are undiagnosed. “A lot of times people just think having frequent infections is normal, and so they may not seek a diagnosis,” says John Ramey, MD , an immunologist at Roper St. Francis Healthcare in Charleston, South Carolina. There’s also evidence that a diagnosis of an autoimmune condition may delay PI diagnosis, though people can have both.e60dc2a1-f33c-4a05-9b50-8e3e8e597629a616edd8-7996-4fdc-a5b4-02850346f900 If you’re having the same type of infection over and over again, it may be an immune problem that makes you more susceptible, and you may want to talk with your doctor about a referral to an allergist or immunologist to get further testing, says Dr. Ramey. Other signs that may indicate primary immunodeficiency can include enlarged lymph nodes, failure to thrive (in both children and adults), nonhealing skin ulcers, and recurrent fevers for no clear reason.e60dc2a1-f33c-4a05-9b50-8e3e8e597629710bd06e-8d3f-44ea-b7c7-e4c7f476a798 Diagnosing primary immunodeficiency involves a combination of medical history, physical exams, and specialized blood tests to evaluate immune system function. Diagnostic Procedures Several tests help doctors confirm a diagnosis of primary immunodeficiency. Blood Tests Blood tests can measure levels of immunoglobulins (infection-fighting proteins), as well as the levels of blood cells and immune system cells. People who have levels of certain blood cells that are outside the standard range may have PI. A blood test can also show if the immune system is working as it should and making proteins that identify and kill harmful germs.e60dc2a1-f33c-4a05-9b50-8e3e8e5976293570e050-97fa-400a-b1cd-14595a3702b8 Flow Cytometry This laser-based lab test can detect chemical physical differences of cells or particles and may also be used to check the number and types of immune cells. A blood, tissue, or bone marrow sample may be used. Genetic Testing These tests can help identify specific genetic differences that are causing the immune system dysfunction.e60dc2a1-f33c-4a05-9b50-8e3e8e59762958b46479-bf5a-4230-be8b-7926fdf8abe4 Prenatal Testing Parents who have a child with primary immunodeficiency may choose to be tested for certain immunodeficiency disorders during future pregnancies. Samples of the amniotic fluid, blood cells, or cells from the tissue that will become the placenta are tested. In some cases, DNA testing is performed to look for a genetic defect that can provide information to guide medical decisions.e60dc2a1-f33c-4a05-9b50-8e3e8e59762999245c1a-4e9e-4893-a7ee-100e6df26c5c
Treatment and Medication Options for Primary Immunodeficiency Treatment Treatments vary depending on the type of primary immunodeficiency. For most people, treatment involves managing infections and treating the underlying disease to prevent future infections. Although there aren’t many disease-specific medications, there are newly approved treatments for two types of PI. In some cases, people with PI also have another serious condition such as an autoimmune condition or cancer, which would require additional treatments. Managing Infections Preventing and treating infections is central to the treatment of PI. Treating Infections Infections need rapid and aggressive treatment with antibiotics, antifungals, or antivirals, as appropriate, sometimes with a longer course (taking the medicine for more days or weeks) than is usually prescribed. Infections that don’t get better may require hospitalization and high-dose, IV treatment. Preventing Infections Some people take long-term antibiotics for weeks or even years to prevent infections that could cause permanent damage to the lungs and ears.e60dc2a1-f33c-4a05-9b50-8e3e8e5976293de3b09b-a3b0-4928-8658-cf65b817ca62 Immunoglobulin Replacement Therapy (IgG) Immunoglobin is a type of antibody found in blood plasma. IgG is a blood product that comes from a donor, is purified, and then delivered to the patient via an IV or subcutaneous injection weekly, biweekly, or monthly. The replacement IgG helps the person fight infections.e60dc2a1-f33c-4a05-9b50-8e3e8e597629818cc352-98d3-4345-a41f-7ef96e3472fd Interferon-Gamma Therapy Interferon gamma-1b injections are used to lower the frequency and severity of serious infections in chronic granulomatous disease. Interferon gamma-1b is a man-made version of a substance naturally produced by cells in the body to help fight infections and tumors.e60dc2a1-f33c-4a05-9b50-8e3e8e5976295da1d55a-5bf4-4592-8d6a-86cc813e1c74 Treatments to Restore the Immune System In some cases, the immune system can be essentially rebuilt or reconstituted with a stem cell transplant or via gene therapy. Hematopoietic Stem Cell Transplantation (HSCT) Also known as a bone marrow transplant, HSCT may be the best treatment option for people with forms of primary immunodeficiency that is causing very poor quality of life or even life-threatening. To “fix” the immune system, hematopoietic stem cells — immature cells that can develop into all types of blood cells — are taken from a donor and transferred to the patient to help them make their own blood and immune system cells.e60dc2a1-f33c-4a05-9b50-8e3e8e5976299970caa8-372c-46be-9c45-d54882e45757 Gene Therapy Although gene therapy has been approved by the U.S. Food and Drug Administration (FDA) for a few rare genetic diseases, it’s not yet approved for any type of PI. In the United States, it’s only available through enrollment in a clinical trial. If approved in the future, gene therapy will offer an important alternative to HSCT when a suitable donor cannot be found.e60dc2a1-f33c-4a05-9b50-8e3e8e597629e0d2f3e1-5262-45b8-870d-efd663fac95b Enzyme Replacement Therapy For some infants with certain types of SCID, treatment can include enzyme replacement therapy, which involves providing the body with the missing enzyme.e60dc2a1-f33c-4a05-9b50-8e3e8e59762942e42e40-48dc-4339-9b81-e293d101dbc1 Drugs for Specific Types of PI In recent years, two drugs have been approved for two ultra-rare forms of PI. Xolremdi (mavorixafor) is approved for the treatment of WHIM syndrome, which causes recurrent respiratory, ear, and skin infections and extensive warts from human papillomavirus (HPV).e60dc2a1-f33c-4a05-9b50-8e3e8e59762910a8ba0b-13b4-4eea-b07b-070b0c8de900 Joenja (leniolisib) is approved to treat activated PI3K delta syndrome (ADPS), also known as PASLI disease, a combined immunodeficiency affecting both B cells and T cells. People who have with APDS have frequent respiratory tract infections that can lead to lung damage, chronic infection with herpesviruses, and increased generation of white blood cells, which tends to progress to lymphoma , a type of cancer.e60dc2a1-f33c-4a05-9b50-8e3e8e597629519dd236-1b5b-4ebc-9dde-c93b100875a5
Lifestyle Recommendations Lifestyle Changes Certain lifestyle habits can reduce the chances of getting an infection or developing complications. Avoid infections. It’s especially important for people living with primary immunodeficiency to take precautions to avoid infections. These actions can help. Wash your hands frequently. Take good care of your teeth and see your dentist regularly for checkups. Practice good health habits, including getting the recommended amount of physical activity, eating a balanced diet with plenty of fruits and vegetables, and get enough sleep. Avoid crowds and close contact with people who are sick. Get the appropriate vaccinations. Check with your healthcare provider about which vaccinations are safe for you to get. People with some types of PI can’t get live vaccines such as rotavirus, chicken pox, oral polio, and MMR (measles, mumps, rubella).e60dc2a1-f33c-4a05-9b50-8e3e8e597629c9a5d1ba-5be7-47be-9710-aaf7e0a967c6 Ongoing Care See your doctor regularly and seek treatment right away if you think you have an infection. “We ask our patients with primary immunodeficiency to call us as soon as they feel like they’re getting sick so we can get them on the appropriate treatment. Don’t wait a few days, because you’re likely to get sicker than normal patients,” says Ramey.
Prevention of Primary Immunodeficiency Prevention Genetic mutations cause most types of PI. Since primary immunodeficiency is usually inherited and present from birth, it’s not preventable. If primary immunodeficiency runs in your family, you may want to see a genetic counselor to discuss your risk for passing on the condition.e60dc2a1-f33c-4a05-9b50-8e3e8e5976297a482ae2-ef6a-47de-8b2e-5398a0f2d177
Prognosis and Outlook Prognosis and Outlook With appropriate treatment, most people with primary immunodeficiency can lead relatively normal lives. The outlook depends on the type and severity of PI, but many people have fewer infections as they get older, especially with ongoing care. For people who develop an autoimmune condition or cancer, the prognosis will depend on the severity of their condition.e60dc2a1-f33c-4a05-9b50-8e3e8e5976291b8d65fb-5152-4ae2-93d0-dc1336521d79
Research and Statistics: How Many People Have Primary Immunodeficiency? Research and Statistics It’s estimated that more than six million people worldwide, or 1 in 10,000 people, have a type of primary immunodeficiency, though the majority of cases go undiagnosed. Researchers are still learning about the condition, but it appears to be more common in certain countries, though it isn’t clear why.e60dc2a1-f33c-4a05-9b50-8e3e8e597629a9115f60-9260-4c64-810b-23246a3814cf
Complications of Primary Immunodeficiency Complications Primary immunodeficiency may increase the risk of developing other conditions later in life, including: Autoimmune Diseases People with PI may have a higher risk of developing autoimmune conditions such as lupus or rheumatoid arthritis. Cancer Some types of PI increase the risk of developing certain types of cancer, especially lymphoma.e60dc2a1-f33c-4a05-9b50-8e3e8e597629875c2f01-5735-4010-aab1-9dd16b5605eb
Support for People With Primary Immunodeficiency Support Life with primary immunodeficiency can be challenging. Frequent illnesses and hospitalizations can be demoralizing and isolating. Support groups can be helpful, as well as other social support options, such as social workers or therapists. Organizations that provide support and information for people living with PI include: Immune Deficiency Foundation (IDF) This patient-focused organization supports people living with primary immunodeficiency through education, advocacy, and community. Jeffrey Modell Foundation / Primary Immunodeficiency Resource Center This foundation provides a range of tools and resources tailored for both patients and doctors. The site offers educational materials, awareness campaigns, and access to a global network of expert centers. International Patient Organization for Primary Immunodeficiencies (IPOPI) A global patient advocacy group, IPOPI empowers individuals and families living with primary immunodeficiencies. Their site includes educational resources, patient stories, and support tools tailored for a worldwide audience.
The Takeaway Primary immunodeficiency (PI) is a group of more than 400 rare genetic disorders that weaken the immune system, making people more vulnerable to infections, autoimmune diseases, and certain cancers. Because symptoms can vary and mimic other conditions, PI often goes undiagnosed, sometimes for years. With timely diagnosis and ongoing care, most people with PI can live healthy, active lives. If you experience frequent or unusual infections that don’t respond well to treatment, talk to a healthcare provider about getting evaluated by an immunologist.
Resources We Trust: Cleveland Clinic: Primary ImmunodeficiencyImmune Deficiency Foundation: Living With Primary ImmunodeficiencyAmerican Academy of Allergy, Asthma, and Immunology: Primary Immunodeficiency DiseaseWorld PI Week: About Primary ImmunodeficienciesJeffrey Modell Foundation: Find an Expert Immunologist
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