Primary Immunodeficiency Syndrome

Primary immunodeficiency syndrome refers to a large group of disorders where the body’s immune system doesn’t work properly, making it harder to fight off infections and leading to various health complications throughout life.

Table of contents

• What is Primary Immunodeficiency Syndrome?
• How Many Types Exist?
• What Causes These Conditions?
• Signs and Symptoms
• Possible Complications
• How It Is Diagnosed
• Treatment Options
• Prevention and Daily Care
• Living With Primary Immunodeficiency

What is Primary Immunodeficiency Syndrome?

Primary immunodeficiency syndrome, also called primary immunodeficiency diseases (PIDD) or inborn errors of immunity (IEI), describes a group of disorders where part of the body’s immune system is missing or does not function correctly^[1][2]. Your immune system is your body’s defense against germs, bacteria, viruses, and other harmful invaders. When you have a primary immunodeficiency, this defense system is weakened from birth.

These conditions are called “primary” because they result from inherited problems in the immune system itself, not from other diseases or medications^[4]. This makes them different from secondary immunodeficiencies, which develop later due to other health conditions like HIV/AIDS, diabetes, cancer, or medications such as chemotherapy^[2].

People with primary immunodeficiency get sick more often than most people. Their infections tend to be more frequent, last longer, are harder to treat, or are more severe than what others typically experience^[1][3]. Because the immune system doesn’t have all the tools it needs to fight off germs, even common infections that are usually minor can lead to serious complications^[2].

Primary immunodeficiency diseases, PIDD, inborn errors of immunity, IEI, primary immune disorders

How Many Types Exist?

More than 400 to 550 different types of primary immunodeficiency have been identified by researchers, and new ones continue to be recognized^[3][6][8]. Some are very rare, while others are more common. These disorders vary widely in how serious they are and when they appear.

Some forms are so severe that they cause problems in infancy and are discovered soon after a baby is born. Other types are mild enough that they may not be noticed until adulthood^[1][4]. Most people with a primary immunodeficiency experience symptoms before turning 20, but symptoms can develop at any point in life^[2].

Around 1 in 500 to 1 in 2,000 people in the United States are born with a primary immunodeficiency^[5][8]. These conditions can affect anyone, regardless of age, gender, or ethnicity^[3]. However, they are more common in males^[2].

Primary immunodeficiencies are broadly classified based on which part of the immune system is affected. They may involve disorders of adaptive immunity (problems with T-cells, B-cells, or both) or disorders of innate immunity (problems with phagocytes, which are cells that eat germs, or complement proteins, which help fight infection)^[6].

What Causes These Conditions?

Primary immunodeficiencies are caused by genetic changes, also called genetic variants or mutations, that occur before birth^[2][3]. These genetic changes prevent the immune system from developing and working correctly. The immune system might be less active than it should be, missing certain cells it usually has, or completely missing^[2].

You cannot control these genetic changes. They happen during development before you are born. Which genes are changed will determine which disorder you develop^[2]. Most primary immunodeficiencies result from inherited defects, and over 430 genes have been identified as causing these conditions^[6][14].

The genetic changes that cause primary immunodeficiencies often run in biological families. If your biological parents or siblings have a primary immunodeficiency, you may be more likely to have one too^[2][4]. Knowing your family medical history can be important, as sometimes symptoms do not arise until adulthood^[5].

It’s important to remember that these disorders are caused by genes, and they are not due to anything you or your family has or has not done^[5].

Signs and Symptoms

The main sign of primary immunodeficiency is having infections that are more frequent, longer lasting, or harder to treat than what most people experience^[1][2]. You might catch infections more easily than people around you, and when you get sick, you may experience more severe symptoms or complications^[2].

You might notice that it takes you longer to recover from an illness than others. Infections may go away and come back, even after you start treatment^[2]. People with primary immunodeficiency may also get infections that most people don’t get, called opportunistic infections^[1][4].

Common infections seen in people with primary immunodeficiency include^[1][4]:

• Ear infections
• Sinus infections
• Pneumonia (lung infection)
• Bronchitis (infection of the airways)
• Meningitis (infection of the brain or spinal cord)
• Skin infections
• Thrush, also called candidiasis (a fungal infection of the mouth or skin)

Other symptoms that may indicate primary immunodeficiency include^[1][2][3]:

• Needing antibiotics longer than usual
• Infections that require hospitalization or intravenous (IV) antibiotics
• Swollen lymph nodes or an enlarged spleen
• Unexplained weight loss or poor growth, especially in infants (called failure to thrive)
• Digestive problems, such as cramping, loss of appetite, nausea, diarrhea, or chronic diarrhea
• Delayed growth and development
• Experiencing more side effects after getting a live vaccine

In addition to frequent infections, primary immunodeficiencies can involve problems with immune system regulation. This may lead to autoimmune disorders, where the immune system attacks the body’s own tissues, or autoinflammatory symptoms, such as inflammatory bowel disease^[1][3][14].

Possible Complications

People with primary immunodeficiency are more likely to have certain health problems beyond frequent infections. Because the immune system protects the body against cancer, people with these conditions are more likely to develop certain cancers^[4].

They are also more likely to have autoimmune disorders and certain blood disorders, such as low platelet count or anemia^[1][4]. Some primary immunodeficiencies involve problems affecting other organs or systems, such as heart defects, facial features, or the skeletal system^[8].

Left untreated, some types of primary immunodeficiency can result in serious health problems, including organ damage and even death^[4]. That’s why early diagnosis and treatment are so important. With proper medical care and treatment, many people with primary immunodeficiency are able to live healthy, active, and independent lives^[1][9].

How It Is Diagnosed

Diagnosing primary immunodeficiency requires the expertise of a healthcare provider with specialized knowledge and experience, usually a clinical immunologist, who is a doctor specializing in the immune system^[4][5].

A healthcare provider will diagnose a primary immunodeficiency based on several factors, including your medical history, whether any close relatives have an inherited immune system disorder, and a physical examination^[10][2]. Because primary immunodeficiency often has a genetic cause and can run in families, sharing your family history with your healthcare provider can be very important^[4].

The basic tests performed when an immunodeficiency is suspected include^[8][10]:

• A full blood count, including accurate counts of infection-fighting white blood cells called lymphocytes and granulocytes
• Measurement of immunoglobulin levels (IgG, IgA, and IgM), which are the three most important types of antibodies in your blood
• Tests to check if your immune system is responding properly by measuring antibodies to routine immunizations and commonly acquired infections

Additional tests may be performed depending on the suspected disorder^[8][10]:

• Tests that count different types of white blood cells in the blood
• Tests for T-cell function, which help coordinate the immune response
• Tests for B-cell function, which produce antibodies
• Tests for phagocyte function, which are cells that eat germs
• Genetic testing to identify specific genetic changes

In the United States, all states include testing for one type of primary immunodeficiency called severe combined immunodeficiency (SCID) as part of newborn screening. This allows infants with this very serious condition to be diagnosed early, before they face potentially life-threatening infections^[4][12].

Parents who have a child with a primary immunodeficiency might want to be tested during future pregnancies. Samples of the amniotic fluid, blood, or cells from the tissue that will become the placenta can be tested for problems. In some cases, DNA testing is done to check for a genetic issue^[10].

Treatment Options

Treatments for primary immunodeficiency involve preventing and treating infections, boosting the immune system, and treating the underlying cause of the immune problem^[10]. The treatment is complex and generally requires both supportive and definitive strategies^[6]. Which treatment works best depends on the type of primary immunodeficiency a person has^[4].

Managing Infections

Infections in people with primary immunodeficiency need to be treated promptly at the first sign of infection. They need fast and aggressive treatment with antibiotics. Treatment might require a longer course of antibiotics than is usually prescribed^[10][15].

Some people may need to take antibiotics, anti-fungals, or anti-virals as a preventative measure to prevent infections. This is called prophylactic treatment^[15].

Immunoglobulin Replacement Therapy

Immunoglobulin replacement therapy, often called Ig replacement therapy, is the main treatment for people with antibody deficiencies. This treatment provides antibodies that help prevent infection in those who cannot make enough antibodies on their own^[6][9].

Immunoglobulin is a blood-based treatment that provides the infection-fighting proteins your body needs. In 2020-2021, 7,275 people with immunodeficiency were prescribed immunoglobulin therapy in a single database^[15]. This therapy is also an important supportive treatment for many patients with combined immunodeficiency disorders^[6].

Hematopoietic Stem Cell Transplantation

For some of the most serious primary immunodeficiencies, hematopoietic stem cell transplantation (HSCT), more commonly known as bone marrow transplant, can be curative. This treatment replaces the defective white blood cells and reconstitutes the immune system^[5][9].

When primary immunodeficiency is likely to cause significant harm or death, HSCT may be the best treatment option. The disorders involving the T-cell part of the immune system, such as severe combined immunodeficiency, require immune reconstitution as soon as possible^[6][9].

Early diagnosis allows infants to proceed to definitive therapy such as stem cell transplantation prior to facing potentially life-threatening infections^[12]. While stem cell transplantation continues to carry significant risks, knowledge gained over recent decades is allowing for improved survival with less toxicity^[12].

Gene Therapy

Gene therapy is in clinical trials for several types of primary immunodeficiency and offers an alternative to HSCT when a suitable donor is not available^[9]. This newer approach has opened new horizons through new technologies^[14]. Research is ongoing, leading to improved treatments and enhanced quality of life for people with these conditions^[1].

Other Treatments

The treatment of other types of primary immunodeficiency varies depending on the type of defect. It may involve antifungal and antibiotic prevention measures, replacement of specific proteins called cytokines, vaccinations, and in some cases bone marrow transplantation^[6].

In some cases, primary immune disorders are linked to a serious illness, such as an autoimmune disorder or cancer, which also needs to be treated^[10]. Precision medicine with specific drugs for altered immune pathways is already a reality for several immune defects^[14].

Prevention and Daily Care

Taking steps to prevent infection is very important if you have primary immunodeficiency. Early diagnosis can help prevent or delay some of the health problems caused by these conditions^[4].

Important prevention steps include^[4][19]:

• Washing your hands the right way using soap and hot water for at least 20 seconds
• Taking good care of your teeth with regular dental visits, proper brushing, and flossing
• Maintaining healthy habits, including being physically active, eating healthy, and getting enough sleep
• Avoiding crowds and exposure to people who are sick, especially during flu or respiratory virus season
• Asking your healthcare provider which vaccinations are safe for you

In some cases, people with primary immunodeficiency cannot have live vaccines such as rotavirus, chickenpox, oral polio, and measles, mumps, rubella. Newborn screening can find babies with certain conditions early, before they receive these vaccines, so that they are not given live vaccines that could make them sick^[4].

Diet and Nutrition

A healthy diet is essential to maintaining health and preventing infections. A regular diet is usually sufficient, but modifications may be needed during illness. Special diets are not typically necessary unless the person has another condition such as diabetes^[19].

Use extreme caution when taking nutritional supplements, vitamins, herbal supplements, or probiotics. Many of these are not regulated by health authorities, and their claims are not based on scientific data. Probiotics contain live microorganisms that could be harmful. You should always ask your healthcare provider before taking any supplements^[19].

Hygiene and Environment

Proper hygiene is crucial for people with primary immunodeficiency and their families to prevent exposure to germs and infections. This involves regular bathing and hand washing^[19].

To avoid infectious diseases, people with primary immunodeficiency should minimize their exposure to people or places that carry a risk of infection, such as crowded indoor spaces during flu or respiratory virus surges^[19].

Living With Primary Immunodeficiency

A primary immunodeficiency diagnosis is a milestone along the journey for answers and the beginning of the journey to manage the condition. Some lifestyle changes may be necessary, but most people with primary immunodeficiency can lead full lives^[19].

Living with primary immunodeficiency can be challenging, but you’re not alone. Many people with these conditions lead full and active lives. With the right support and resources, you can too^[18].

Living with primary immunodeficiency can impact your mental health, so it’s important to seek support, share your diagnosis when appropriate, and practice self-compassion^[2][18]. It can be comforting to share your diagnosis with others, but it can also be stressful. You have control over how, where, and when you share this information^[18].

With early diagnosis and aggressive treatment, there is an excellent chance to continue living an active, productive life^[5]. Many people with primary immunodeficiency successfully navigate work, school, travel, and family life with proper planning and support^[18].