Primary Immunodeficiencies

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Primary immunodeficiencies (PIDs) are inherited defects in the development and function of the immune system. The clinical hallmark of PIDs is an increased susceptibility to recurrent and/or severe infections, though some PIDs present with autoimmunity or lymphoproliferation1-5. The molecular basis of more than 150 PIDs has been established, which are categorized into eight categories based on which part of the immune system is affected (Table 1)1,2. The majority of PIDs follow a simple Mendelian inheritance, though some PIDs originate from a more complex polygenic inheritance3. Defects in the adaptive arm of the immune system include antibody deficiency syndromes and combined immunodeficiencies (CIDs)3. Defects in the innate arm of the immune system comprise disorders of phagocytes, Toll-like receptor (TLR)-mediated signaling, and complement pathways3.

Table 1. The eight PID categories2

Disease Category

Diagnoses

Combined B and T cell immunodeficiencies (predominantly T cell)

(Severe) combined immunodeficiency (S)CID; many different genetic defects

CD40L deficiency

Predominantly antibody deficiencies

X-linked or AR agammaglobulinemia

Common variable immunodeficiency disorders (CVIDs)

Specific antibody deficiencies

IgG subclass deficiency

Selective IgA deficiency

Other well-defined immunodeficiency syndromes

Wiskott Aldrich syndrome

Ataxia telangiectasia and other DNA repair disorders

Hyper-IgE syndromes

Disease of immune dysregulation

Immunodeficiencies with hypopigmentation

Familial hemophagocytic lymphohistiocytosis syndromes (HLH)

X-linked lymphoproliferative syndrome

Autoimmune lymphoproliferative syndrome (ALPS)

Congenital defects of phagocyte number, function, or both

Severe congenital neutropenia

Cyclic neutropenia

X-linked or AR chronic granulomatous disease (CGD)

Defects in innate immunity

Anhidrotic ectodermal dysplasia with immunodeficiency

IL-1 receptor-associated kinase 4 deficiency (IRAK-4 deficiency)

Chronic mucocutaneous candidiasis

Autoinflammatory disorders

Familial Mediterranean fever

TNF receptor-associated periodic syndromes

Complement deficiencies

Broad spectrum of deficiencies of classical and alternative pathway complement factors

Hereditary angioedema (C1 esterase inhibitor deficiency)

The severity and spectrum of symptoms varies widely from asymptomatic to fatal without treatment. More than 50% of the reported PID diagnoses are of primary antibody deficiencies2. IgA deficiency, for example, has a prevalence of 1:500 and is often asymptomatic2. Severe forms of PIDs, such as severe combined immunodeficiency (SCID), immune dysregulation syndromes, and complement deficiencies  are much more rare with a prevalence of 1:100,0002. PIDs can be challenging to diagnose, as they often present with common and/or aspecific symptoms2,4. Combined with the relative rarity of PIDs, diagnostic delay is common. However, early diagnosis and treatment of PIDs has been shown to save lives, improve quality of life, and prevent morbidity2.

The clinical hallmark of PIDs is an increased susceptibility to recurrent and/or severe infections1-5. Atypical presentation of infection, impaired response to treatment, and infections caused by opportunistic pathogens also point towards the presence of a PID2. The type of infection identified in medical history may indicate the nature of the immunodeficiency, as distinctive susceptibility to particular pathogens has been shown to correlate with the underlying immune deficiency, as shown in Table 23. Patients with a PID often appear to be chronically ill, thus physical examination in conjunction with medical history can be revealing2. Common physical signs include pallor, malaise, and a distended abdomen caused by hepatosplenomegaly2.

Table 2. Infections associated with major categories of PIDs3

Organism

Antibody Deficiencies

CIDs

Phagocytic Defects

Complement Deficiencies

Viruses

Enteroviruses

All, especially: CMV, RSV, EBV, parainfluenza 3

No

No

Bacteria

Streptococcus pneumoniae, Haemophilus influenza, Moraxella catarrhalis, Pseudomonas aeruginosa, Staphylococcus aureus, Neisseria meningitides, Mycoplasma pneumoniae

Same as antibody deficiencies, also: Salmonella typhi, Listeria monocytogenes, enteric flora

S. aureus, P. aeruginosa, Nocardia asteroids, S. typhi

Same as antibody deficiencies, especially N. meningitides in deficiency of late components

Mycobacteria

No

Nontuberculous, including BCG

Nontuberculous, including BCG

No

Fungi

No

Candida species, Aspergillus species, Cryptococcus neoformans, Histoplasmosis capsulatum

Candida species, Aspergillus species

No

Protozoa

Giardia lamblia

Pneumocystis jiroveci, Toxoplasma gondii, Cryptosporidium parvum

No

No

Clinical immunologic laboratory tests are critical to validate suspicion of PID3,4. Viracor-IBT offers an extensive menu of immunological and infectious disease assays to assist clinicians in the diagnosis of PIDs, from providing supporting evidence of a presumptive diagnosis to providing necessary information required to establish a definitive diagnosis (Table 3).

Table 3. Selective Viracor-IBT immunodiagnostic and infectious disease menu

Classification

Test

Preliminary Immune Status Check     

IgG Subclasses

Immunoglobulin E (IgE)

Immunoglobulin A (IgA)

Immunoglobulin G (IgG)

Immunoglobulin M (IgM)

 Vaccine Antibody Response    

Diphtheria Antibody

Tetanus Antibody

Haemophilus influenza b Antibody

Pneumococcal Antibody

Pneumococcal Antibody Avidity

 T-cell Development and Function   

T Cell Fx™ Select

T Cell Fx™ Complete

ImmuKnow®

T-cell Receptor Excision Circle (TREC) Test

 Autoantibodies    

Anti IgA

Anti IgE

CU Index™

Anti-Thyroid Peroxidase IgG

Anti-Thyroglobulin IgG

Complement Assessment    

MBL Protein

MBL Pathway Function

C1 Esterase Inhibitor Functional

C1 Esterase Inhibitor Protein

C1q Complement

Innate Immunity Development and Function  

Oxidative Burst

TLR Function

 Angioedema   

C1 Esterase Inhibitor Functional

C1 Esterase Inhibitor Protein

C1q Complement

C4

Gene Mutation Analysis      

ProGenotyper® MBL Panel

Inflammatory Markers                 

GM-CSF

Interferon-gamma

Interleukin-10

Interleukin-12p70

Interleukin-13

Interleukin-1 beta

Interleukin-2

Interleukin-4

Interleukin-5

Interleukin-6

Interleukin-8

TNF-alpha

Eotaxin-3

Soluble IL-2 Receptor Alpha

Eosinophil Cationic Protein

Eosinophil Derived Neurotoxin

Common Infections

Aspergillus Real-time PCR Panel

Platelia™ Aspergillus Galactomannan EIA

Atypical Pneumonia Real-time PCR Panel (Mycoplasma pneumoniae and Chlamydophila pneumoniae)

Cytomegalovirus (CMV) Quantitative Real-time PCR

Enterovirus Quantitative Real-time RT-PCR

Epstein-Barr Virus (EBV) Quantitative Real-time PCR

Fungitell® β-D Glucan

Legionella pneumophila Real-time PCR

Pneumocystis jiroveci Quantitative Real-time PCR

Respiratory Viral Panel (RVP) PCR utilizing Luminex® xTAG™

Toxoplasma gondii Quantitative Real-time PCR

 

 

Infections are the main clinical threat in patients with PID, thus successful prevention of infections is the goal of treatment and determines patient outcomes. Antibody and complement deficiencies can be effectively managed by IVIG treatment and prophylactic antibiotics and these patients are able to have near normal life spans2,3. More severe forms of PID, such as phagocytic and combined deficiencies, usually result in guarded prognoses. These patients are generally critically ill and require intensive treatment with IVIG, prophylactic antibiotics/antifungals, IFNγ, immunosuppression when autoimmunity is present, or gene therapy which is becoming increasingly available2,3. Severe forms of PID, such as SCID, can only be treated by hematopoietic stem cell transplant (HSCT)2,5. HSCT performed early with an HLA-matched donor has demonstrated a survival rate of over 90%2.

References

 

1.  International Union of Immunological Societies Expert Committee on Primary Immunodeficiencies, Notarangelo LD, Fischer A, Geha RS, et al. Primary immunodeficiencies: 2009 update. J Allergy Clin Immunol. 2009;124:1161-1178.

2.  Vries ED, Driessen G. Primary immunodeficiencies in children: a diagnostic challenge. Eur J Pediatr. 2011;170:169-177.

3.  Notarangelo LD. Primary immunodeficiencies. J Allergy Clin Immunol. 2010;125:S182-194.

4.  O’Gorman MRG. Recent developments related to the laboratory diagnosis of primary immunodeficiency diseases. Curr Opin Pediatr. 2008;20:688-697.

5.  Szabolcs P, Cavazzana-Calvo M, Fischer A, Veys P. Bone marrow transplantation for primary immunodeficiency diseases. Pediatr Clin N Am. 2010:207-237.