Introduction

Primary Immunodeficiency (PID) describes a group of over 450 disorders that affect the body’s immune system and are broadly categorised as those affecting the adaptive or innate immune systems.¹ The presentation of PIDs is highly variable, but frequently involves increased susceptibility to infections, causing them to become recurrent, persistent, unusual, and severe.² PIDs are usually diagnosed in early childhood but can be identified at any stage of life. Treatment provided is specific to the type of PID and how it affects your immune system. PIDs are rare diseases, affecting over 4,500 people in the UK, and it is important to raise awareness to help support individuals and their families who are affected.¹

Causes of Primary Immunodeficiency

Genetic factors

All primary immunodeficiencies are caused by genetic mutations that impact the functioning of the individual’s immune system, with many PIDs also being genetically inherited.³ Genes can be described as the functional sequences of the DNA that determine our physical development including the everyday functioning of the immune system. Genes can suffer from ‘mutations’ that affect the sequence of DNA and may result in the gene’s function being altered or removed completely.⁴ 

Genetic mutations can occur at random due to a mistake during DNA replication or may be inherited from a parent due to the sperm or fertilised egg carrying an inheritable mutation. In the case of a primary immunodeficiency disorder, a genetic mutation may, for example, affect the genes responsible for the production and functioning of T-cells, leading to the development of an adapted primary immunodeficiency disorder.

Types of Primary Immunodeficiency

Innate immunity deficiencies

Innate primary immunodeficiencies affect our ‘innate immune system’ which acts as the body’s first ‘line of defence’ against pathogens and infections. The innate immune system is non-specific, meaning it does not target specific types or species of pathogens, and acts quickly to reduce the opportunity for infection. The innate immune system is made up of immune cells including neutrophils, monocytes, and natural killer (NK) cells that can non-specifically target pathogens or foreign bodies rapidly and reliably. 

Innate immune responses are very important in newborns, who are not able to produce their antibodies for several weeks. During this period, they rely on the nonspecific action of innate immunity until they can develop ‘adaptive immunity’. Infants who have inherited a genetic mutation affecting the innate immune system may have defects in the normal functioning of innate immune cells. For example, NEMO deficiency syndrome is an innate PID arising from genetic variants in the X-linked NEMO gene, affecting the development and proliferation of lymphocytes.

Adaptive immunity deficiencies

Adaptive primary immunodeficiencies affect our ‘adaptive immune system’, which is responsible for developing immunity to specific pathogens as we are exposed to pathogens or receive vaccinations. The adaptive immune system creates ‘memory responses’ to increase the effectiveness of the immune response to specific pathogens, enabling a more rapid and robust response upon each subsequent exposure. The adaptive immune system is made up of specialised cells such as B-cells (or B-lymphocytes) and T-cells, which carry out a wide range of functions including antibody production and immunogenic memory. 

Severe combined immunodeficiency (SCID) is an example of an adaptive PID that results in a depleted number of B-cells, causing babies to be born without a functional immune system and therefore, extremely vulnerable to infection. 

Symptoms of Primary Immunodeficiency

Recurrent infections

As previously mentioned, primary immunodeficiency causes infections to become recurrent, severe and unusual. Recurrent infections, particularly ones that are so severe as to require the use of intravenous (IV) antibiotics, are a common sign of PIDs. Intravenous antibiotics are medications delivered directly into a vein to ensure rapid and high concentration of the drug to combat severe infections. 

Due to the impact of genetic mutations on the immune system, people with PID may not be able to produce a functional immune response to pathogens, leading to recurrent infections. Immunodeficiency UK describes how this may present in the form of having two or more types of pneumonia within three years, having four or more new ear infections within one year, or spending two or more months on at least two antibiotics with little effect. 

Delayed growth and development

Primary immunodeficiency can cause the failure of a baby or child to gain weight or grow normally, sometimes described as a ‘failure to thrive’. There are many reasons why a baby or child may not be developing as expected, and PIDs are a rare cause of this. In newborns,  ‘failure to thrive’ due to PID may present in various ways, including chronic diarrhoea, hepatosplenomegaly (enlargement of the liver and spleen), abdominal distention and lung or cardiac problems. 

Autoimmune disorders

Autoimmunity occurs when the immune system produces an immune response against itself using antibodies, with the effects being either localised to a specific area or causing a generalised inflammatory condition such as Lupus. 

Autoimmune disorders are primarily observed in people with primary antibody deficiencies (adaptive), including common variable immunodeficiency (CVID), but have also been associated with patients with innate primary immunodeficiency. 

Signs of an autoimmune disorder vary by the disorder, but some common symptoms include swollen joints, fatigue, weight loss, and muscle weakness.⁵ Experiencing autoimmunity whilst also suffering from a primary immunodeficiency disorder can have a significant impact on a patient’s quality of life.

Allergic reactions

Due to the altered functioning of the immune system, primary immunodeficiencies can make individuals more susceptible to allergies, which are immune responses to specific triggers or allergens. Susceptibility to allergens is sometimes referred to as ‘atopy’, and people affected by the condition often have multiple allergic diseases such as rhinitis (hay fever), asthma and eczema. Severe atopy in children can be a symptom of an underlying primary immunodeficiency, especially if it occurs alongside an increased susceptibility to infections. 

Chronic inflammation

Inflammation is critical to the immune response against foreign bodies and pathogens, and can be either acute or chronic. 

Acute inflammation is a normal response involving the action of inflammatory cells within the immune system that have reached a site of infection or injury. 

Chronic inflammation, on the other hand, describes inflammation that lasts for prolonged periods and commonly arises from both autoimmune disorders and defects in the immune system, such as in primary immunodeficiency. 

Chronic inflammation may present itself as body aches and pain, depression and anxiety, frequent infections, fatigue, and more.⁶ 

Chronic inflammation can cause damage to healthy cells and tissues, contributing to a wide range of symptoms. 

Diagnosis

Clinical evaluation

Swift and accurate diagnosis of primary immunodeficiencies is critical to reducing the disease burden associated with these disorders and protecting individuals’ quality of life. Suspected diagnoses of primary immunodeficiencies are typically provided in primary care and paediatric healthcare settings when a clinician has identified some of the symptoms outlined above, particularly recurrent and severe infections. To help aid diagnosis, your healthcare practitioner may want to gather an accurate medical and family history, and perform a physical examination. 

Laboratory tests

Laboratory tests are often necessary to determine if you have a primary immunodeficiency disorder, and your healthcare practitioner should refer you for them as appropriate. Common laboratory tests include screening for antibody and complement deficiencies in the blood serum as well as identifying T cell and neutrophil disorders.⁷ 

These blood tests help to identify the levels of immune cells and molecules, which may be abnormal in the case of a primary immunodeficiency. In some cases, genetic testing may be requested to identify the presence of genetic mutations that are known to cause PIDs, helping to accelerate your diagnosis.⁸

Imaging studies (if necessary)

A history of recurrent infections, such as respiratory infections like pneumonia, can be the first sign of primary immunodeficiencies and can be evaluated using imaging. CT scans are the common first radiological approach to diagnosing PIDs and can be performed on the chest to identify common PID complications such as interstitial lung disease and bronchiectasis.⁹ 

Summary

Primary immunodeficiency describes a group of over 450 rare disorders of the innate and adaptive immune system, affecting approximately 4,500 people in the UK. Signs and symptoms of PIDs can vary between each condition but typically include the recurrence of severe and unusual infections, multiple allergies, autoimmune disorders, as well as abnormal growth and development in babies and children. As with all health conditions, a swift and accurate diagnosis of primary immunodeficiency can help to reduce the disease burden and improve the quality of life of the affected individual. To aid with your diagnosis, your clinician may refer you for a wide range of laboratory, genetic, and imaging tests which will also determine what treatment may be available and appropriate for your disorder.