Overview

Primary Immunodeficiency (PI/PID) is the result of a range of disorders which cause aspects of your child's immune system to be missing or faulty. This in turn affects their ability to fight off infections, such as viruses, bacteria and fungi successfully.¹ They are called primary as they are genetic errors affecting the immune system, predetermined at birth, whereas secondary immunodeficiency is acquired later in life.² Primary immunodeficiency disorders (PIDDs) can affect both the innate and adaptive immune systems, and symptoms can show up at any age with innate disorders.³

Causes

As of 2023, there are 485 recognised types of PIDDs.⁴ These disorders cause immunodeficiency by affecting different components of the adaptive or innate immune system. The innate immune system consists of defences we are born with. The adaptive immune system, however, keeps track of all the infections you’ve encountered. Cells of the adaptive immune system make antibodies to enable us to clear infections upon future exposure.

Adaptive immune system component defects

• B-cell defects
• T-cell defects
• Combined immunodeficiency (CID)³

Innate immune system component defects

• Macrophages
• Complement system 
• Neutrophils
• Dendritic cells¹

Most PIDs are caused by a single gene defect, but some are also caused by inheriting multiple genes that cause defects in the innate or adaptive immune system.¹ Occasionally however, certain types of PIDs can be acquired.³ There are also differences in how common PIDDs are; Selective IgA for example is more common, whereas severe combined immunodeficiency (SCID) is very rare.⁶ 

Well-known adaptive immune system PIDDs 

B cell immunodeficiency

• CVID (common variable immunodeficiency)
• XLA (X-linked agammaglobulinemia)
• Selective IgA (immunoglobulin A) deficiency 
• Specific antibody deficiency 
• IgG (immunoglobulin G) subclass deficiency³

T cell immunodeficiency

• IFN-γ (interferon-γ) /IL-12 (Interleukin-12) - these are involved in immune responses
• AIRE (autoimmune regulator) gene mutations - these regulators prevent autoimmunity³

Combined immunodeficiency

• SCID (severe combined immunodeficiency disease) 
• Wiskott-Aldrich syndrome
• Ataxia telangiectasia
• DiGeorge syndrome
• Hyper IgE (immunoglobulin E) syndrome³

Well-known innate immune system PIDDS

• Chronic granulomatous disease
• Leukocyte adhesion deficiency
• Complement pathway component deficiency (early, late or regulatory)³

Your innate immune system is your first line of defence against potential pathogens. PIDDs that affect your child’s innate immune system can mean that they have a harder time identifying and then clearing infections, creating worse outcomes.³

Signs and symptoms 

Depending on the PID severity, symptoms can be seen as early as the neonatal period to late childhood. The most common age of presentation however is infancy and early childhood.¹  

The most severe types of PIDs are recognised and diagnosed in childhood. However, it is vital for individuals with other types of PIDDs to get an early diagnosis. The Jeffrey Modell Foundation (JMF) came up with the 10 warning signs to identify and diagnose children with a PID diagnosis:⁵

• At least four new ear infections within one year
• At least two serious sinus infections within one year
• At least two months on antibiotics with little effect
• At least two pneumonias within one year
• Failure to gain weight or grow normally
• Recurring, deep skin or organ abscesses
• Persistent mouth thrush or skin fungal infection
• A need for intravenous antibiotics to clear infections
• At least two deep-seated infections, including septicemia
• A family history of PID

As one-third of patients may not show the usual symptoms, your GP may ask you if you have a family history of PID, and further information about your child’s medical records including weight and height since birth to make an informed diagnosis.⁶

Symptoms and factors your GP will look for:⁶

• Family history of PID
• Frequent infections 
• Severe and unusual infections
• Autoimmunity
• Autoinflammation
• Long-standing diarrhoea
• Severe eczema 
• Weight loss
• Bronchiectasis

Depending on the PID severity, symptoms can be seen as early as the neonatal period to late childhood. The most common age of presentation, however, is infancy and early childhood.¹ Dermatological skin conditions are common symptoms in children. Eczema is the most common dermatological symptom seen in children with PID.¹

Diagnosis

Diagnosis can happen from your GP spotting PID symptoms and going for further evaluation. Early detection of PID dramatically improves quality of life and life expectancy.⁹

If PID in your child is suspected, blood tests will be taken by your doctor, and these samples will be sent off to the hospital to conduct diagnostic tests. These tests are looking for faults in the immune system, such as:³

• Low levels of T cells, B cells, and neutrophils
• Immune cells not working correctly
  • Such as B cells not producing antibodies
  • Or producing non-functioning antibodies

Standard laboratory tests

• Assay of blood cells- leukocyte, lymphocyte, thrombocytes and haemoglobin protein
• Serum immunoglobulins (Ig) levels- main classes IgG, IgA and IgM
• Levels of blood minerals and substances- e.g. sodium, potassium, creatinine⁶

Further diagnostic testing can include more expensive tests such as immunoassay and genetic testing.⁶ There has been research into different diagnostic tests to confirm PID, such as newborn screening, molecular diagnosis and gene sequencing to confirm the suspected diagnosis.⁸ 

Newborn screening

Newborn screening for SCID involves T-cell receptor excision circles (TRECs)⁹ in an assay that evaluates for T-cell lymphopenia, using a dried newborn blood spot (NBS).¹¹ If the test is positive then your child will be referred to a specialist, such as a clinical immunologist.¹¹

In the UK, the National Health Service NHS evaluation of screening of newborn babies for SCID started on the 6th of September 2021 and initially was conducted for 2 years on two-thirds of the newborn population, which is being extended to collect more data. This report will then be evaluated by the UK National Screening Committee (UK NSC) to decide whether SCID should be a part of the NHS NBS screening programme.¹⁰

Treatments

Haematopoietic stem cell transplantation (HSCT)

HSCT from the bone marrow or blood is the only cure for severe cellular lymphocyte disorders in early childhood and infants.⁶ For severe conditions such as SCID, early diagnosis and HSCT can be curative.¹¹ 

Antimicrobial therapy

Antimicrobial therapy using antibiotics is a treatment for all forms of immunodeficiency. This is to help your child fight off infections and pathogens.¹² To prevent infections in severe conditions like SCID, antimicrobial prophylaxis can be used whilst waiting for curative treatment, such as HSCT or gene therapy.¹²

Gene therapy

Gene therapy uses stem cells harvested from a child with PID that has a faulty gene. The cells are then genetically transformed to have the normal gene. These cells are then re-infused back into the child, which then develop into immune cells that work correctly.¹² Gene therapy has progressed over the recent decades, and has successfully treated several PIDDs like SCID, and also has been seen to have better safety and efficacy than HSCT.¹³

Immunoglobulin (Ig) replacement therapy

Ig replacement therapy uses blood with antibodies for PID patients who have improper antibody production. This prevents serious infections, and usually, IgG antibodies are administered either under the skin by subcutaneous (SC) or in the veins by intravenous (IV) infusion.¹⁴ 

In early childhood, the therapy can be administered by your doctor by IV. As the child ages, you can switch to at-home administration using SC therapy to suit your family's lifestyle better.¹² This is a successful prescribed treatment in the UK. It is known that there are common side effects, but they can be managed with medicines such as antihistamines.⁶ 

Risks

Misdiagnosed and untreated PIDs are chronic severe diseases, and can even be fatal.⁶ A common issue is that PIDs can go undiagnosed, and treatment is prescribed for recurring symptoms, such as infections, instead of looking deeper to get to the root cause.⁶ However, PIDs are becoming more diagnosed, due to increased awareness, and education, leading to further diagnosis.⁸

Having PID increases the risk of the following problems:¹²

• Infections
• Autoimmunity
• Lymphoproliferation and malignancies⁹
• Autoinflammation 
• Immune dysregulation, which can impact multiple organ systems

Children with PID are also at higher risk of developing cancer,² so early diagnosis, treatment and management are key to prevention. Good personal hygiene is also recommended to help prevent infections.⁶ 

Summary

Although PIDs are seen as very rare, they are more common than initially thought.⁷ With more research and increased awareness of PIDs, our knowledge is continuing to grow and diagnosis of PID is constantly improving. PIDDs are treatable and in some cases can be curable, therefore early diagnosis is essential to preventing the development of further symptoms.⁶ Contact your local healthcare professional if your child has symptoms of primary immunodeficiency.