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.

Clinical example

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 PK_cs 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):