Overview

Primary immunodeficiency, also known as primary immunodeficiency disorder, and primary immunodeficiency disease, refers to a large group of genetic disorders which result from defects in the development or function of the immune system. As a result, patients are more vulnerable to infections (which may become chronic), allergies, autoimmune diseases and cancer. Since there are more than 430 different primary immunodeficiencies, the symptoms, diagnosis, and treatments vary depending on the specific disorder. 

The Immune System

The immune system is made up of different organs, cells, and proteins which  work together to protect the body from bacteria, viruses, fungi, cancer, etc. The immune system is divided into two parts: the innate immune system and the adaptive immune system. 

The innate immune system

The innate immune system is the first line of defence. It acts very quickly and attacks any foreign substance immediately. The cells that belong to the innate immune system do not learn to differentiate between different invaders, so they respond in the same way to all foreign substances. Moreover, these cells do not have a memory so they do not offer protection against specific invaders in the future. Some important innate immune cells, such as neutrophils and monocytes, belong to the category of phagocytes, meaning these cells engulf and destroy invaders. 

The adaptive immune system

The adaptive immune system, also known as the acquired immune system, targets a specific invader, meaning the cells have to identify the invader. Even though this is slower than the innate immunity, it is more accurate. A key characteristic of the adaptive immune system is that these cells have the ability to remember the invaders. Thus, if the cells encounter the same invader at a later time point, they will respond faster. This memory feature is why people become “immune” to certain diseases. Once the adaptive immune system has responded to an invader, the next time it is encountered, the body will react immediately, and subsequent infections will usually go unnoticed. 

The adaptive immune system is made up of T cells and B cells, also known as T lymphocytes and B lymphocytes, respectively. T cells destroy specific invaders and send signals to other cells in the immune system to coordinate an attack. B cells produce antibodies which circulate in the bloodstream and quickly detect and neutralise specific invaders, and attract other cells in the immune system to help. 

Types of primary immunodeficiency 

Primary immunodeficiencies occur due to defects in the immune system. Some disorders are inherited defects, meaning they are passed down within families. However, there are several cases when the genetic defects occur sporadically. Although primary immunodeficiencies can affect both adults and children, they are more common during childhood.¹

There are several ways of classifying the different disorders. According to the 2014 International Union of Immunodeficiency Society, primary immunodeficiencies can be classified into 9 categories.² Below are some examples of primary immunodeficiency disorders. 

Chronic granulomatous disease (CGD)

CGD is a disorder that affects phagocytes. It is caused by a mutation in the gene for NADPH oxidase, a key protein which phagocytes need to kill some bacteria and fungi. As a result, patients with CGD are highly susceptible to bacterial and fungal infections. CGD patients may develop abscesses (collections of pus) with granulomas (masses of cells) that can obstruct the bowel or urinary tract. Most patients are diagnosed when they are 3 years old, which is when they start developing symptoms.³ 

X-linked agammaglobulinemia (XLA)

XLA was discovered in 1952 and was the first primary immunodeficiency described. It is caused by a mutation in the gene for Bruton tyrosine kinase (BTK), which is involved in the development and maturation of B cells, a key adaptive immune system component. This condition is characterised by recurrent infections in the respiratory and gastrointestinal tracts.¹ 

Common variable immunodeficiency (CVID)

CVID is a heterogeneous disorder characterised by having low levels of antibodies in the bloodstream. This condition usually appears around 10 years of age and affects people assigned female at birth (AFAB) and people assigned male at birth (AMAB) equally. Patients diagnosed with CVID may suffer from recurrent infections in the ears and sinuses, gastrointestinal complications, and have a higher risk of developing cancer.⁴ 

Severe combined immunodeficiency (SCID)

SCID is a rare disorder in which patients have a marked reduction of T cells, and variable amounts of B cells. The first year of life of a SCID patient is characterised by chronic diarrhoea, skin rashes, and serious bacterial, fungal, and viral infections.² SCID has a very poor prognosis and is fatal if left untreated. Immune-restoring treatments such as bone marrow transplantation or gene therapy can be life-saving. 

Selective IgA deficiency

Selective IgA deficiency is a milder disorder characterised by low levels of IgA, a specific type of antibody. Most patients with selective IgA deficiency are asymptomatic their whole life; however, some patients develop recurrent infections in the ears and sinuses, allergies, and gastrointestinal disorders, among other symptoms.⁵

Hemophagocytic lymphohistiocytosis (HLH)

HLH is a life-threatening disorder characterised by a deregulated immune activity of different immune cells, which results in inflammation and multi-organ failure. If left untreated all major organs, including lungs, heart, kidney, and brain, will undergo extreme problems which are deadly. Treatment for HLH focuses on suppressing the immune system with a combination of different drugs. Some of the HLH symptoms are fever, cytopenias (reduction of red blood cells, immune cells, or platelets) and enlargement of the spleen.⁶ 

Symptoms of primary immunodeficiency

The symptoms for primary immunodeficiencies are highly variable and depend on the specific type of disorder. However, many disorders involve higher susceptibility to infections and persistent disease.⁷ Other common symptoms are:⁴

• Enlargement of the spleen
• Autoimmune diseases
• Recurrent pneumonias
• Failure to thrive, meaning infants have a problem gaining weight or growing
• Chronic diarrhoea
• A family history of primary immunodeficiency

Diagnosis of primary immunodeficiency

It is important to diagnose primary immunodeficiencies in a timely manner to prevent further complications or even death. According to a survey performed by the Immune Deficiency Foundation in the United States, around 60% of patients with primary immunodeficiency are not diagnosed until their adult years even though many reported serious or chronic health conditions prior to diagnosis.⁴

If a primary immunodeficiency is suspected, a specialist will thoroughly examine the immune system condition by doing a complete blood count and blood smear to evaluate the quantity and characteristics of the immune cells in the bloodstream. Another important diagnostic tool is flow cytometry, which detects the specific chemical and physical characteristics of cells.⁴ 

If a patient is suspected of having an antibody deficiency, a specialist will measure the antibody levels in the serum. A more precise diagnosis is done by measuring the levels of IgG, a specific antibody, in response to a vaccine.⁴ 

Another important way of diagnosing disorders consists of genetic testing to find specific mutations that are associated with the different disorders.⁴ 

Treatment and management of primary immunodeficiency

Once a primary immunodeficiency has been diagnosed, it is crucial to begin therapy as soon as possible to prevent permanent organ damage or even death. Treatment of primary immunodeficiencies is variable and depends on the specific disorder. 

Disorders that affect the innate immune system are treated with prophylactic antibiotics and antifungal therapies, meaning patients receive these treatments to prevent bacterial and fungal infections. 

For disorders involving antibody deficiencies, treatment options depend on the specific symptoms. Asymptomatic patients are monitored with no further treatment. Symptomatic patients receive immunoglobulin replacement therapy which consists of receiving antibodies from healthy donors either in an intravenous (injection into the vein) or subcutaneous (injection under the skin) manner. Patients receive this treatment for the duration of their life.

Some primary immunodeficiency disorders, like SCID, are treated with stem cell transplants. This technique consists of administering healthy stem cells to patients with dysfunctional or absent stem cells. This way the healthy stem cells build a new and functional immune system.⁴  Clinical trials involving a specific type of SCID have shown that gene therapy could also be beneficial. This is a technique that consists of introducing a correct copy of the mutated gene into the appropriate cells. Currently, newer techniques are being evaluated in clinical trials. 

Importantly, lifestyle changes such as having good hygiene and avoiding contact with sick or non-immunised people, can be crucial in reducing primary immunodeficiency complications. Moreover, depending on the disorder type, patients should receive some or all immunisations like influenza vaccination to prevent possible infections. Lastly, maintaining a healthy lifestyle with a balanced diet and moderate physical activity can ensure an optimal quality of life.² 

FAQs

How common are primary immunodeficiencies?

Approximately 1 in 10,000 people suffer from primary immunodeficiencies. Over 6 million children and adults are affected worldwide, of which 70% to 90% are undiagnosed.⁷ 

Can primary immunodeficiency be prevented?

Since primary immunodeficiencies are caused by genetic mutations that are inherited, it is not possible to prevent them.

What is the difference between primary and secondary immunodeficiencies? 

Primary immunodeficiencies occur due to inherited defects in the immune system, whereas secondary immunodeficiencies are due to other causes, including age, medications, infections, and malnutrition. 

What is the most common primary immunodeficiency?

The most common disorder is IgA deficiency. In the United States, 1 out of every 300–500 people suffer from IgA deficiency. 

Summary

Primary immunodeficiencies involve many different types of disorders that are caused by defects in the immune system. Symptoms vary, but most disorders involve high susceptibility to infection. Early consultation with a specialist is essential, since timely diagnosis and treatment are crucial for preventing severe complications that can result in death.