Introduction
What are primary immunodeficiencies?
Primary immunodeficiencies can be hereditary disorders that are caused by a mutation in a single gene or by a genetic vulnerability combined with environmental factors. PID can be caused by genetic mutations that affect the development or function of immune cells, including T cells, B cells, and natural killer cells.2 PID can also be caused by defects in the proteins that regulate immune cell function, such as cytokines and complement proteins.3
PIDs are a heterogeneous group of over 400 disorders caused by defects in immune system development and/or function.1
Prevalence
Prevalence
Around 6 million people worldwide are estimated to have a PID, but between 70% and 90% of these are undiagnosed. It is estimated that about 5,000 individuals within the UK suffer from PID disorder.
PID can present in infancy, childhood, or adulthood, depending on the specific genetic mutation or protein defect. Most PIDs are diagnosed in later life, even though some can be detected in infancy or childhood. Diagnosing PID requires good clinical awareness and specialized laboratory testing, and early diagnosis may help reduce morbidity and mortality.5
Signs and symptoms
Several signs can lead a clinician to suspect an immunodeficiency. They are often diagnosed after “too many infections”. Due to the defects in their immune systems, people with PID are more prone to infections caused by microorganisms such as bacteria, viruses, fungi and protozoa. In addition, a poorly regulated immune system can lead to autoimmunity. PID should be considered in patients with severe, persistent, recurrent, or unusual infections (SPUR for short).
Over the last few decades, the understanding and awareness of PID has improved significantly. Often associated with recurrent infections, PID can also be associated with sporadic infections, autoimmunity, autoinflammation, allergy and malignancy.
Released by the Jeffrey Modell foundation, the ‘10 warning signs of primary immunodeficiency’ ) aims to increase awareness.6,7
These warning signs include:
- Four or more new ear infections within a year
- Two or more serious sinus infections within a year
- Being on antibiotics for two or more months with little effect
- Two or more pneumonias within a year
- Failure of an infant to gain weight or grow normally
- Recurrent, deep skin or organ abscesses
- Persistent oral thrush or fungal infections of skin
- Frequent need for intravenous antibiotics to clear infections
- Two or more deep-seated infections including septicaemia
- A family history of primary immunodeficiency12,13
It is advisable to consider early child and adult referral to an immunologist when ≥ 2 of the following warning signs are experienced.6,7,8,10
Classification of PID manifestations
PID can present in many different ways depending on the specific genetic mutation or protein defect. PIDs are classified according to the predominant immune mechanism that is defective.
Based on the component of the immune system involved, PID can be categorised as follows:8,11
- Predominantly antibody deficiencies
- Predominantly T-cell Deficiencies
- Phagocytic Disorders
- Complement deficiencies
- Other well defined PIDs
- Autoimmune and immune dysregulation syndromes
- Autoinflammatory disorders
- Defects in innate immunity
- Unclassified PIDs
Examples of PIDs
As the predominant group of PID, antibody disorders are characterized by absent, low or faulty antibodies. The main symptoms include recurrent infections, including recurrent sinopulmonary infections with encapsulated bacteria (pneumonia, sinusitis, otitis media), recurrent viral respiratory tract infections or gastrointestinal infections, with chronic or recurrent diarrhea being the most common clinical presentation sometimes accompanied by malabsorption and weight loss. Autoimmune disorders are another symptom of antibody disorders including autoimmune hemolytic anemia, neutropenia or thrombocytopenia.
Here are a few examples:11
Adapted from the ESID Registry, working definitions for clinical diagnosis of PID, 2019.12
Complement disorders account for a small percentage of PIDs (<2%) and are characterized by absent or low levels of individual complement proteins, or by the presence of non-functional proteins. The complement system has a number of different functions, and the symptoms of a deficiency therefore depend on the specific complement protein that is absent or non-functional. Complement deficiencies can result in inadequate coating of bacteria with antibody (opsonization), reduced or absent phagocytosis and/or lysis of microorganisms. These defects can lead to severe sepsis. They may coexist with autoimmune disease.8,11
Examples would include:
- Deficiencies in the proteins that form the membrane attack complex (such as C5/C6/C7/C8) can lead to increased susceptibility to particular infections, including those with Neisseria meningitidis.
- Deficiencies in the early complement components (C1q/C1r/C1s/C4) is linked with the development of Systemic Lupus Erythematous (SLE)
- C1 inhibitor deficiency, also known as Type I and Type II Hereditary Angioedema (HAE)
Diagnosis
These tests are of great clinical importance because they allow the physician to know whether the lymphocyte, neutrophil and platelet counts are normal. This is often a first stage screening requested before more specialised tests are performed.
Because antibody defects are more common than any other immune defect, the first emphasis should be placed on investigation of serum immunoglobulins and antibody production. Because immunoglobulin values increase with age, comparison to age-matched controls is necessary for correct interpretation.
Following total immunoglobulins, the subclasses can be determined. IgG1 accounts for 60-70% of total IgG, therefore most cases of IgG1 deficiency will be apparent as hypogammaglobulinemia without the need to test for IgGSC’s. However, substantial deficiencies of IgG2, IgG3 and IgG4 may exist with normal IgG levels. Important anti-polysaccharide antibodies are often located in the IgG2 subclass.
It is important to determine if antibodies which are being produced are functionally relevant. This can be performed by using vaccination as a diagnostic test for specific antibody formation. These tests are of crucial importance in determining whether there is truly an antibody deficiency disorder, especially when the serum immunoglobulins are not very low. It is important to test for antibodies to both protein (i.e., tetanus or diphtheria) and polysaccharide (i.e., pneumococcal polysaccharides) antigens.
Evaluation of the complement system is appropriate for patients with episodes of bacteremia, meningitis or systemic Neisserial infections. CH50 is an excellent screening test for the classical pathway, Alternative Pathway defects can be screened for with the AH50 test.
Analysis of lymphocyte surface markers, using monoclonal antibodies and flow cytometry, can identify T and B cells, subpopulations of T cells and NK cells and monocytes and macrophages.
Assessment of the presence of monoclonal proteins to rule out lymphoproliferative disease.
Delays in diagnosis
There is often a significant delay in the diagnosis of immunodeficiency. PID is widely under-diagnosed in most countries. In PID, delays of over seven years between first presentation and final diagnosis are common. The main reasons for a delayed or missed diagnosis of PID include the complex nature of PID, and the variety and diversity of symptoms and clinical manifestations. Patients are often reviewed by several physicians without the diagnosis being considered. Individuals with PID are often diagnosed after >3 hospital visits. There is a relatively low awareness of symptoms among primary care doctors. Delays in diagnosis and treatment are associated with poor outcomes and serious complications. Organ damage is possible if PID is not diagnosed early enough.15,16
Complications of delayed diagnosis4,6,8,17 include:
- Severe, persistent infections
- Autoimmune disorders
- Damage to the lungs, heart, nervous system, or digestive tract
- Growth disorders
- Increased risk of cancer
- Death from serious infection
Early diagnosis comes with many benefits for both the clinicians or laboratories and the patients. Healthcare expenditure can actually be reduced by over 50% after the diagnosis of PID. And for patients an early diagnosis can improve their health, quality of life and even their lifespan. The longer the delay, the worse the prognosis can be for these patients.
A word on treatment
Treatment of PID depends on the specific genetic mutation or protein defect. Antibiotics may be used to prevent certain infections, while immunoglobulin replacement therapy and interferon-gamma therapy may be used to help the immune system function better.17 In some cases, bone marrow or stem cell transplantation may be necessary.
References
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