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Primary immunodeficiency (PID)

Find out more about the warning signs of primary immunodeficiencies, the different manifestations and the best diagnosis practice

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).

 

Thumbnail of a gold and silver 3-D antibody structure
Image of a primary immunodeficiency multicolored venn diagram
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:

  1. Four or more new ear infections within a year
  2. Two or more serious sinus infections within a year
  3. Being on antibiotics for two or more months with little effect
  4. Two or more pneumonias within a year
  5. Failure of an infant to gain weight or grow normally
  1. Recurrent, deep skin or organ abscesses
  2. Persistent oral thrush or fungal infections of skin
  3. Frequent need for intravenous antibiotics to clear infections
  4. Two or more deep-seated infections including septicaemia
  5. 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

Multiple Myeloma
A number of guidelines exist for the diagnosis of primary immunodeficiency which recommend the tests required.¹¹𝄒¹²𝄒¹³ Each of these serves as a guideline of what testing should be completed based on the clinical presentation by following this diagnostic pathway.¹²𝄒¹³𝄒¹⁴
Multiple Myeloma
Adapted from the ESID guideline by De Vries, the above algorithm shows the tests commonly used when an immunodeficiency is suspected.¹²

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.

 

Photo of a pediatric immunodeficiency patient holding a teddy bear
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Inborn errors of immunity (IEI)
Find out more about this terminology, the link with primary immunodeficiencies and the phenotypical classification.
References
  1. Immunodeficiency Disorders. NIH National Library of Medicine. MedlinePlus. Available from: https://medlineplus.gov/ency/article/000818.htm
  2. Meyts Isabelle, Bousfiha Aziz, Duff Carla, Singh Surjit, Lau Yu Lung, Condino-Neto Antonio, Bezrodnik Liliana, Ali Adli, Adeli Mehdi, Drabwell Jose, Primary Immunodeficiencies: A Decade of Progress and a Promising Future, JOURNAL=Frontiers in Immunology, VOLUME 11, Year 2021. DOI=10.3389/fimmu.2020.625753, ISSN=1664-3224 Available from https://www.frontiersin.org/articles/10.3389/fimmu.2020.625753
  3. Bonilla, Francisco A, and Raif S Geha. “Primary immunodeficiency diseases.” The Journal of allergy and clinical immunology vol. 111,2 Suppl (2003): S571-81. doi:10.1067/mai.2003.86
  4. Megan a. Cooper, Thomas l. Pommering, and Katalin Korányi, Primary Immunodeficiencies, Am Fam Physician. 2003;68(10):2001-2009
  5. Condino-Neto A, Espinosa Rosales FJ. Changing the lives of people with primary mmunodeficiencies (PI) with early testing and diagnosis. Frontiers in Immunology. 2018;9:1439. DOI: 10.3389/fimmu.2018.01439
  6. Clinical Working Party 10 Warning Signs of PID - General. European Society for Immunodeficiencies (ESID) Available from: https://esid.org/Working-Parties/Clinical-Working-Party/Resources/10-Warning-Signs-of-PID-General Accessed on 27 APR 2023
  7. 2021 Jeffrey Modell foundation. Available from: https://res.cloudinary.com/info4pi/image/upload/v1662306263/JMF_10_Signs_Illustrated_ENGLISH_082421_v1_a6bb7981cb.pdf?updated_at=2022-09-04T15:44:24.369Z
  8. Nizar Mahlaoui, Benjamin Gathmann, Gerhard Kindle, Stephan Ehl. The European Society for Immunodefciencies (ESID) Registry: recent advancements in the epidemiology of Primary Immunodefciencies and how does that translate in clinical care. RARE DISEASES AND ORPHAN DRUGS An International Journal of Public Health. December 2014, Volume 1, Number 4, Supplement4.
  9. Reda SM, El-Ghoneimy DH, Afifi HM. Clinical predictors of primary immunodeficiency diseases in children. Allergy Asthma Immunol Res. 2013 Mar;5(2):88-95. doi: 10.4168/aair.2013.5.2.88. Epub 2012 Nov 2. PMID: 23450209; PMCID: PMC3579097.
  10. Secondary Immunodeficiency Diseases. LibreTexts Biology™ Available from: https://bio.libretexts.org/Bookshelves/Microbiology/Microbiology_(Boundless)/12%3A_Immunology_Applications/12.06%3A_Immunity_Disorders-_Immunodeficiencies/12.6B%3A_Secondary_Immunodeficiency_Diseases
  11. ESID Registry (2019) – Working Definitions for Clinical Diagnosis of PID. Available from: https://esid.org/content/download/17141/463543/file/ESID%20Clin%20Crit_omim_orpha_hpo_11_2019fin.pdf
  12. de Vries E; European Society for Immunodeficiencies (ESID) members. Patient-centred screening for primary immunodeficiency, a multi-stage diagnostic protocol designed for non-immunologists: 2011 update. Clin Exp Immunol. 2012 Jan;167(1):108-19. doi: 10.1111/j.1365-2249.2011.04461.x. PMID: 22132890; PMCID: PMC3248092.
  13. Bonilla FA, Khan DA, Ballas ZK, Chinen J, Frank MM, Hsu JT, Keller M, Kobrynski LJ, Komarow HD, Mazer B, Nelson RP Jr, Orange JS, Routes JM, Shearer WT, Sorensen RU, Verbsky JW, Bernstein DI, Blessing-Moore J, Lang D, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph CR, Schuller D, Spector SL, Tilles S, Wallace D; Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma & Immunology; and the Joint Council of Allergy, Asthma & Immunology. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015 Nov;136(5):1186-205.e1-78. doi: 10.1016/j.jaci.2015.04.049. Epub 2015 Sep 12. PMID: 26371839.
  14. Orange JS, Hossny EM, Weiler CR, Ballow M, Berger M, Bonilla FA, Buckley R, Chinen J, El-Gamal Y, Mazer BD, Nelson RP Jr, Patel DD, Secord E, Sorensen RU, Wasserman RL, Cunningham-Rundles C; Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 2006 Apr;117(4 Suppl):S525-53. doi: 10.1016/j.jaci.2006.01.015. Erratum in: J Allergy Clin Immunol. 2006 Jun;117(6):1483. Dosage error in article text. PMID: 16580469.
  15. Hartog Nicholas L., Williams Kelli W., Abraham Roshini S. “The State of the Union”: Current and Future Perspectives on Patient-Centric Care for Primary Immunodeficiencies and Immune Dysregulatory Diseases. Frontiers in Immunology 2019 10. doi:10.3389/fmmu.2019.01783 https://www.frontiersin.org/articles/10.3389/fimmu.2019.01783
  16. Slade CA, Bosco JJ, Binh Giang T, Kruse E, Stirling RG, Cameron PU, Hore-Lacy F, Sutherland MF, Barnes SL, Holdsworth S, Ojaimi S, Unglik GA, De Luca J, Patel M, McComish J, Spriggs K, Tran Y, Auyeung P, Nicholls K, O'Hehir RE, Hodgkin PD, Douglass JA, Bryant VL, van Zelm MC. Delayed Diagnosis and Complications of Predominantly Antibody Deficiencies in a Cohort of Australian Adults. Front Immunol. 2018 May 14;9:694. doi: 10.3389/fimmu.2018.00694. PMID: 29867917; PMCID: PMC5960671.
  17. Paris K, Wall LA. The Treatment of Primary Immune Deficiencies: Lessons Learned and Future Opportunities. Clin Rev Allergy Immunol. 2022 Jul 1:1–12. doi: 10.1007/s12016-022-08950-0. Epub ahead of print. PMID: 35776401; PMCID: PMC9247903.


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