13.2 Immunodeficiency and its investigation
Recurrent infections, especially in the small child, are common. It can be challenging, but important, to determine which children warrant investigation to exclude an underlying immunodeficiency, and which tests are most appropriate. Primary immunodeficiencies (PID) are rare, but with increasing physician and community awareness and rapid technological advances, the number of recognized genetic defects predisposing to infection risk is increasing exponentially. Some defects are essential to diagnose early, with appropriate treatment influencing morbidity and mortality. Others contribute to our understanding of the complexity of the immune response, allow tailoring of treatment and provide an explanation to concerned families.
Susceptibility to infection varies, influenced by age, genetic and environmental factors, including atopy, siblings, daycare, exposure to cigarette smoke, drug therapies and anatomical variations, all secondary factors that may be the sole cause of increased manifestations of infection, or contribute to the severity of an underlying primary immune defect. Despite the emphasis on primary disease, the clinical significance of secondary immunodeficiencies cannot be underestimated.
The aim of this chapter is to provide an approach for differentiating primary immunodeficiency from other factors predisposing to a real or apparent increased risk of infection, based on history, examination and appropriate initial investigation. A selection of PIDs will be highlighted but it is beyond the scope of this chapter to discuss in depth the pathophysiology and specialized treatment of these disorders, or specifically to cover all potential PIDs. A list of recent references is provided for further reading.
Host factors and resistance to infection
Immune defence is provided by multiple well-orchestrated components, which can be categorized into two main groups:
1. Innate, non-antigen-specific responses are initiated early. There are an increasing number of recognized components, including:
2. Adaptive, antigen-specific immune responses are the basis of immunological memory and are essential for maturation of protective immune responses and efficacy of vaccination. The components are:
Deficiencies or disruption of any of these components can predispose to infection. These defects may be the result of immaturity, primary or acquired deficiency, influencing age and severity of presentation as well as management and prognosis. Some disorders will result in localized disease, whereas others predispose to infection with specific microorganisms, as shown in Figure 13.2.1.
The influence of atopy
When recurrent respiratory infections are the sole infectious manifestation, allergy must be considered. Features that suggest an allergic or atopic condition may be responsible include absence of fever, clear non-purulent discharge, personal and/or family history of atopic conditions such as eczema, food allergies, asthma and allergic rhinitis, seasonal or exposure-related pattern, variable response to antibiotics, and good response to antihistamines, bronchodilators and/or topical steroids. In addition, atopic tendencies can prolong and adversely modify the severity of otherwise minor, often viral, infections for which antibiotics may be prescribed, contributing to the perception of frequent severe infection.
Acquisition of immunological memory
The adaptive immune response develops with recurrent exposure to infection. Primary exposure often resulting in clinical infection occurs most frequently in infancy and early childhood. Secondary exposure in the presence of an intact adaptive immune system, results in a more rapid and efficient response, and avoidance of subsequent infection in older children and adults. In association with increasing exposure, this results in the peak number of infections between the ages of 2 and 4 years, with an average of six infections a year. Existence of siblings, daycare attendance and exposure to cigarette smoke further increase this number. Children attending daycare or preschool can experience 10 to 12 upper respiratory tract infections and 1 to 2 gastrointestinal tract infections per year.
The induction of immunological memory is the principle underlying vaccination. Not only does vaccination enable protection from and/or attenuation of the severity of targeted infections, measurement of specific antibody levels after vaccination provides a means by which the function of the immune system can be assessed.
Age of presentation, infective complications and diagnosis
Deficiencies of humoral immunity typically present after the age of 4–5 months, when maternally-derived antibody has waned. Significant deficiencies of T-cell function present earlier, within the first months. The type of infection(s) as well as associated clinical features may provide clues to the deficient immune component (see Fig. 13.2.1, Table 13.2.1). In children presenting with recurrent fever without obvious and/or identifiable infection, the possibility of an autoinflammatory syndrome should be considered. Many primary immunodeficiencies present in infancy with dermatological manifestations such as severe or atypical eczema, thrombocytopenic purpura, recalcitrant candidiasis and abscesses. Some are diagnosed in association with other conditions such as cardiac, endocrine and neurological anomalies (e.g. DiGeorge syndrome, ataxia telangiectasia). Conditions such as common variable immunodeficiency, natural killer cell and complement deficiencies can present at a range of ages, from late infancy to young adulthood.
Table 13.2.1 Clinical features suggestive of some immune defects
Clinical feature | Immunodeficiency |
---|---|
Recurrent sinopulmonary infections/chronic diarrhoea and failure to thrive (and, less commonly, cytopenias, arthritis, hepatitis, coeliac disease, inflammatory bowel disease, granuloma formation, malignancy) | Humoral |
Recurrent fungal, opportunistic infections/chronic diarrhoea, failure to thrive, neonatal hypocalcaemia | Cellular |
Recurrent periodontal disease, gingivitis, skin and deep abscesses, fungal pneumonia, osteomyelitis | Phagocytic |
Recurrent or severe meningococcal or pneumococcal infection | Complement |
Defects associated with prematurity and delays in immunological development
In the absence of intrauterine infection, the fetus exists in a sterile environment until birth, at which time specific immune responses begin to develop. Active transplacental transport of immunoglobulin (Ig) G (but not IgA, IgM or IgE) occurs during the third trimester, providing humoral protection to the newborn.
Physiological hypogammaglobulinaemia of infancy occurs between 3 and 6 months of life at the nadir of waning maternal IgG balanced by increasing infant production of IgG (Fig. 13.2.2). This can be accentuated and prolonged in premature infants by a reduced store of maternally derived IgG, or alternatively by delay in IgG production, the latter termed transient hypogammaglobulinaemia of infancy.

Fig. 13.2.2 Evolution of serum immunoglobulin (Ig)G, IgA and IgM levels in utero and during the first year after birth, illustrating the contribution of maternal and neonatal IgG. Levels of IgM reach adult equivalents by approximately 3 years of age, IgG by 5–6 years and IgA by 9–12 years.
In most cases, these measurable abnormalities are asymptomatic and resolve completely, usually by 9–15 months of age, but in some cases low levels of IgG, and sometimes also IgA and IgM, may persist for longer. With more sophisticated follow-up, spontaneous resolution has been documented up to the end of the first decade. Immunoglobulin replacement therapy may rarely be required in affected infants experiencing significant infections despite prophylactic antibiotics, such as co-trimoxazole. If commenced, a trial of cessation of intravenous immunoglobulin (IVIG) should be undertaken after a period free of significant infection. A small number of these children continue to have immune abnormalities and require ongoing IVIG, the diagnosis evolving to common variable immunodeficiency (CVID). This diagnosis cannot be made definitively before the age of 2 years.
T cell-independent antibody responses, for example to polysaccharide antigens, which are important for humoral protection from encapsulated microorganisms such as pneumococcus, Haemophilus and meningococcus, are poor in infants aged less than 2 years. Protein-conjugated vaccines induce T cell-dependent antibody production in younger infants, enabling vaccination from 2 months of age.
Neonates have relatively low levels of complement and impairment of neutrophil chemotaxis, both of which mature rapidly during early infancy. T-cell proliferative responses are reasonable but cytokine production, particularly of proinflammatory (T-helper type 1, Th1) cytokines such as interferon (IFN)-γ, is immature, which may compromise T-cell help. This immaturity may persist in some infants with an atopic tendency, potentially contributing to infection risk.
Thomas presented at 12 months of age with a history of six episodes of otitis media associated with green nasal discharge since the age of 6 months. Each responded to antibiotics with recurrence soon after cessation. There was discharge from the left ear on two occasions from which Streptococcus pneumoniae and non-typeable Haemophilus influenzae were isolated. Thomas was thriving and had no other symptoms. He was an only child, his immunizations were up to date, and he did not attend daycare. There was no significant family history.
Examination revealed a perforated left tympanic membrane. Tonsillar tissue was present. Full blood count was unremarkable. Serum IgG (2.5 g/L, normal range 3.4–11.6 g/L) and IgA (0.1 g/L, normal range 0.2–1.2 g/L) were moderately reduced but IgM level was normal for age. Both IgG1 and IgG2 levels were slightly below the normal range. T-and B-cell numbers were normal. Levels of antibodies to vaccine antigens (tetanus, diphtheria, and conjugated Haemophilus influenzae B and pneumococcal vaccines) were acceptable.
A provisional diagnosis of transient hypogammaglobulinaemia of infancy was made. A trial of prophylactic, daily, low-dose co-trimoxazole successfully prevented further recurrences of ear infection, until an attempt to cease therapy after a year. Antibiotic prophylaxis was ceased uneventfully at 3 years of age. Serum IgG and IgA levels rose gradually into the lower end of the normal range by the age of 2 and 5 years respectively.
Primary and secondary immunodeficiencies
More than 150 primary immunodeficiencies (PID) have been identified and characterized, and the number is growing constantly. An expert international committee of the International Union of Immunological Societies (IUIS) meets regularly to update continually the known primary immunodeficiencies and, where identified, the underlying genetic cause. The publication by Notarangelo and co-workers, summarizing the most recent meeting in 2009, contains detailed tables summarizing clinical features, laboratory findings, genetics and relative frequency of known PIDs. Although, individually, most are rare or extremely rare, many affect similar pathways or categories of immune function and thus collectively are not uncommon. Table 13.2.2 lists these conditions as categorized by IUIS and, where known, the mode of inheritance.
Table 13.2.2 International Union of Immunological Societies (IUIS) classification of primary immunodeficiencies
Disease | Inheritance |
---|---|
Combined T- and B-cell immunodeficiency | |
T− B+ SCID | |
γc deficiency | XL |
JAK3 deficiency | AR |
IL-7 receptor α deficiency | AR |
CD45 deficiency | AR |
CD3δ/CD3ε/CD3ζ deficiency | AR |
Coronin-1A deficiency | AR |
T− B− SCID | |
RAG1/RAG2 deficiency | AR |
DCLREIC (Artemis) deficiency | AR |
DNA PKcs deficiency | AR |
Adenosine deaminase (ADA) deficiency | AR |
Reticular dysgenesis | AR |
Omenn syndrome | AR (most) |
DNA ligase IV deficiency | AR |
Cernunnos deficiency | AR |
CD40 ligand deficiency | XL |
CD40 deficiency | AR |
Purine nucleoside phosphorylase deficiency | AR |
CD3γ deficiency | AR |
CD8 deficiency | AR |
ZAP-70 deficiency | AR |
Ca2+ channel deficiency | AR |
MHC class I deficiency | AR |
MHC class II deficiency | AR |
Winged helix deficiency (nude) | AR |
CD25 deficiency | AR |
STAT5b deficiency | AR |
Itk deficiency | AR |
DOCK8 deficiency | AR |
Predominantly antibody deficiencies | |
Severe reduction in all serum Ig isotypes with profoundly decreased or absent B cells | |
Btk deficiency | XL |
μ heavy chain deficiency | AR |
λ5 deficiency | AR |
Igα deficiency | AR |
Igβ deficiency | AR |
BLNK deficiency | AR |
Thymoma with immunodeficiency | None |
Severe reduction in at least 2 serum Ig isotypes with normal or low numbers of B cells | |
Common variable immunodeficiency disorders | Variable |
ICOS deficiency | AR |
CD19 deficiency | AR |
TACI deficiency | AD or AR |
BAFF receptor deficiency | AR |
Severe reduction in serum IgG and IgA with normal/raised IgM and normal B-cell numbers | |
CD40L deficiency | XL |
CD40 deficiency | AR |
AID deficiency | AR |
UNG deficiency | AR |
Isotype or light chain deficiencies with normal numbers of B cells | |
Ig heavy chain mutations or deletions | AR |
κ chain deficiency | AR |
Isolated IgG subclass deficiency | Variable |
IgA with IgG subclass deficiency | Variable |
Selective IgA deficiency | Variable |
Specific antibody deficiency with normal Ig concentrations and normal B cell numbers | Variable |
Transient hypogammaglobulinaemia of infancy with normal B-cell numbers | Variable |
Other well defined immunodeficiency syndromes | |
Wiskott–Aldrich syndrome | XL |
DNA repair defects | |
Ataxia telangectasia | AR |
Ataxia telangectasia-like disease | AR |
Nijmegen breakage syndrome | AR |
Bloom syndrome | AR |
Immunodeficiency with centromeric instability and facial anomalies (ICF) | AR |
PMS2 deficiency | AR |
Thymic defects | |
DiGeorge anomaly | De novo/AD |
Immune osseous dysplasias | |
Cartilage hair hypoplasia | AR |
Schimke syndrome | AR |
Comel–Netherton syndrome | AR |
Hyper-IgE syndromes (HIES) | |
AD-HIES | AD |
AR-HIES | AR |
Chronic mucocutaneous candidiasis | AD/AR/sporadic |
Hepatic veno-occlusive disease with immunodeficiency | AR |
XL dyskeratosis congenita | XL |
Diseases of immune dysregulation | |
Immunodeficiency with hypopigmentation | |
Chediak–Higashi syndrome | AR |
Griscelli syndrome, type 2 | AR |
Hermansky–Pudlak syndrome, type 2 | AR |
Familial haemophagocytic lymphohistiocytosis | |
Perforin deficiency | AR |
UNC13-D deficiency | AR |
Syntaxin 11 deficiency | AR |
Lymphoproliferative syndromes | |
XLP1, SH2D1A deficiency | XL |
XLP2, XIAP deficiency | XL |
Itk deficiency | AR |
Syndromes with autoimmunity | |
Autoimmune lymphoproliferative syndrome (ALPS) | |
CD95 (Fas) defects, ALPS type 1a | AD |
CD95L (Fas ligand) defects, ALPS type 1b | AR |
Caspase 10 deficiency, ALPS type 2a | AR |
Caspase 8 deficiency, ALPS type 2b | AR |
Activating N-ras, N-ras-dependent ALPS | AD |
APECED (autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy) | AR |
IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) | XL |
CD25 deficiency | AR |
Congenital defects of phagocyte number, function or both | |
Severe congenital neutropenias | AD |
Kostman disease | AR |
Neutropenia with cardiac and urogenital malformations | AR |
Glycogen storage disease type 1b | AR |
Cyclic neutropenia | AR |
X-linked neutropenia/myelodysplasia | AR |
P14 deficiency | AR |
Leukocyte adhesion deficiency type 1 | AR |
Leukocyte adhesion deficiency type 2 | AR |
Leukocyte adhesion deficiency type 3 | AR |
Rac2 deficiency | AR |
β-Actin deficiency | AR |
Localized juvenile periodontitis | AR |
Papillon–Lefèvre syndrome | AR |
Specific granule deficiency | AR |
Schwachman–Diamond syndrome | AR |
X-linked chronic granulomatous disease | AR |
Autosomal chronic granulomatous diseases | AR |
IL-12 and IL-23 receptor β1-chain deficiency | AR |
IL-12p40 deficiency | AR |
IFN-γ receptor 1 deficiency | AR, AD |
IFN-γ receptor 2 deficiency | AR |
STAT1 deficiency | AR |
AR hyper-IgE syndrome | AR |
AD hyper-IgE syndrome | AD |
Pulmonary alveolar proteinosis | Bi-allelic |
Defects in innate immunity | |
Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) | XL |
AD EDA-ID | AD |
IL-1 receptor-associated kinase 4 (IRAK4) deficiency | AR |
MyD88 deficiency | AR |
WHIM (warts, hypogammaglobulinaemia, infections, myelokathexis syndrome) | AD |
Epidermodysplasia verruciformis | AR |
Herpes simplex encephalitis (HSE) – UNC93B1 | AR |
HSE – TLR3 | AD |
Chronic mucocutaneous candidiasis – CARD9 | AR |
Trypanosomiasis | AD |
Autoinflammatory disorders | |
Familial Mediterranean fever | AR |
TNF receptor-associated periodic fever syndrome (TRAPS) | AD |
Hyper-IgD syndrome | AR |
Muckle–Wells syndrome | AD |
Familial cold autoinflammatory syndrome | AD |
NOMID/CINCA | AD |
Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome | AD |
Blau syndrome | AD |
Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed) | AR |
DIRA (deficiency of IL-1 receptor antagonist) | AR |
Complement deficiencies | |
C1q deficiency | AR |
C1r deficiency | AR |
C1s deficiency | AR |
C4 deficiency | AR |
C2 deficiency | AR |
C3 deficiency | AR |
C5 deficiency | AR |
C6 deficiency | AR |
C7 deficiency | AR |
C8 deficiency | AR |
C9 deficiency | AR |
C1 inhibitor deficiency | AR |
Factor I deficiency | AR |
Factor H deficiency | AR |
Factor D deficiency | AR |
Properdin deficiency | AR |
Mannose-binding lectin deficiency | AR |
MASP2 deficiency | AR |
Complement receptor 3 (CR3) deficiency | AR |
Membrane cofactor protein (CD46) deficiency | AR |
Membrane attack complex inhibitor (CD59) deficiency | AR |
Paroxysmal nocturnal haemoglobinuria | Acquired |
Immunodeficiency associated with ficolin-3 deficiency | AR |
AD, autosomal dominant; AR, autosomal recessive; IFN, interferon; Ig, immunoglobulin; IL, interleukin; XL, X-linked.
Modified from: Notarangelo LD, Fischer A, Geha RS et al 2009 Primary immunodeficiencies: 2009 update. Journal of Allergy and Clinical Immunology 124:1161–1178.
An underlying PID may be suggested by the frequency, severity and type of infection, the response or lack of response to antimicrobial therapy, associated failure to thrive and existence of significant family history (Box 13.2.1).
Box 13.2.1 Warning signs of primary immunodeficiency
Patients are advised to seek medical review if affected by 2 or more of the following 10 warning signs of primary immunodeficiency (Jeffrey Modell Foundation, New York):
1. Eight or more new ear infections within 1 year
2. Two or more serious sinus infections within 1 year
3. Two or more months on antibiotics with little effect
4. Two or more pneumonias within 1 year
5. Failure of an infant to gain weight or grow normally
6. Recurrent, deep skin or organ abscesses
7. Persistent thrush in the mouth or on the skin, after age 1 year
8. Need for intravenous antibiotics to clear infections
9. Two or more deep-seated infections such as meningitis, osteomyelitis, cellulitis or sepsis

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