Primary Immunodeficiency
Introduction
In general, immunodeficiencies are divided into those of the specific immune system (e.g. T cells or B cells) or those of the innate or nonspecific immune system (e.g. complement and neutrophils). The age at which the patient presents gives good but not absolute clues as to the type of immune deficiency; for instance, severe combined immune deficiency (SCID) will present within the first 6 months of life. The type of infection also gives excellent clues as to the nature of the underlying immune defect. For example, recurrent meningococcal infection is a major feature of complement deficiency, while persistent respiratory syncytial virus infection in a small baby should raise the question of SCID. Other associated features also provide clues; for example, ataxia (unsteadiness on the feet) together with bacterial infections suggests ataxia telangiectasia.
Immunodeficiencies can also be divided into primary (usually genetic) and secondary, where the immune defect is caused by some other nonimmunological disease; for example, a glycogen storage disease that causes a neutrophil defect, or a drug (e.g. phenytoin). Sometimes the distinction is blurred; for example, the AIDS virus (HIV-1) infects CD4+ T lymphocytes and macrophages and alters their functional capacity. This is usually referred to as a secondary immunodeficiency, despite the ‘primary’ effect on T cells (see Chapter 2 for a further discussion of secondary immunodeficiencies). There may be some overlap between groupings (e.g. adenosine deaminase has its immunological effect through a metabolic abnormality that is genetically determined). Some host defence disorders are covered in Chapter 2 (e.g. cystic fibrosis).
All patients with primary immunodeficiencies should be under the care of an immunologist, who will be familiar with the range of complications.Classification of immunodeficiency
Genetic
Autosomal recessive.
Autosomal dominant.
X-linked.
Gene deletions, rearrangements.
Biochemical and metabolic
Adenosine deaminase deficiency.
Purine nucleoside phosphorylase (PNP) deficiency.
Biotin-dependent multiple carboxylase deficiency.
Deficient membrane glycoproteins.
Vitamin or mineral deficiency
Zinc deficiency.
B12 deficiency.
Biotin.
Undefined primary
Common variable immunodeficiency.
Specific antibody deficiency.
IgG subclass deficiency.
IgA deficiency.
Maturational
Transient hypogammaglobulinaemia of infancy.
Secondary (see Chapter 2)
Chronic infections (TB, leishmania).
Malignancy.
Lymphoma/leukaemia.
Extremes of age.
Transfusion therapy.
Drugs.
Plasmapheresis.
Radiation.
Nutrition.
Chronic renal disease (including dialysis).
Toxins (including alcohol, cigarettes).
Splenectomy.
Clinical features of immunodeficiency
Recurrent infections
There is no universally accepted definition of what constitutes ‘recurrent infection’ and therefore it is difficult to be categorical about who should be investigated for immunodeficiency. The following should be used as guidance.
Two major or one major and recurrent minor in 1 year.
Unusual organisms (Aspergillus, Pneumocystis).
Unusual sites (liver abscess, osteomyelitis).
Chronic infections (sinusitis).
Structural damage (e.g. bronchiectasis).
Other suspicious features.
A major infection is severe infection, usually requiring parenteral treatment in hospital, with objective evidence of infection (elevated CRP, positive culture). Minor infection is less severe and is usually treatable in the community with oral therapy, but has objective evidence of infection.
Other features raising suspicion of an underlying immunodeficiency
Skin rash (atypical eczema): Wiskott-Aldrich syndrome, hyper-IgE syndrome, Omenn’s syndrome.
Failure to thrive: any immune deficiency in childhood.
Hepatosplenomegaly: common variable immunodeficiency (CVID), Omenn’s syndrome.
Chronic osteomyelitis/deep-seated abscesses: chronic granulomatous disease.
Mouth ulceration (?cyclical): neutropenia.
Autoimmunity: CVID, hyper-IgM syndrome.
Family history.
Features associated with specific immunodeficiencies
Some features are diagnostic of particular immunodeficiencies.
Ataxia: ataxia telangiectasia; PNP deficiency.
Telangiectasia: ataxia telangiectasia.
Short-limbed dwarfism: X-linked immunodeficiency.
Skeletal abnormalities: ribs in ADA deficiency.
Cartilage-hair hypoplasia.
Ectodermal dysplasia.
Endocrinopathy (particularly with hypocalcaemia): chronic mucocutaneous candidiasis.
Partial albinism: Chediak-Higashi disease; Griscelli syndrome.
Thrombocytopenia (particularly with small platelets): X-linked thrombocytopenia; Wiskott-Aldrich syndrome.
Eczema: Wiskott-Aldrich syndrome; hyper-IgE syndrome; Omenn’s syndrome.
Neonatal tetany: 22q11 deletion syndromes (DiGeorge).
Severe bowel disease: IPEX
Abnormal facies (leonine, fish-shaped mouth, low-set ears): hyper-IgE (leonine); 22q11 deletion syndrome (fish-shaped mouth, low-set ears); ICF syndrome (see ‘Other chromosomal instability disorders’, p.50.
Mental retardation: 22q11 deletion syndromes, PNP deficiency; other genetic immunodeficiencies.
Investigation of immunodeficiency
History
Must include the following.
History of all infections: site, severity, need for antibiotics, hospitalizations.
Operations (grommets, lobectomies, etc.).
Immunization history.
Family history, especially for serious infections, unexplained sudden deaths, diagnosed immunodeficiencies, and autoimmune diseases.
Various organizations, including the Jeffrey Modell Foundation and the European Society for Immunodeficiencies have produced guidelines for non-specialists to encourage greater recognition of primary immunodeficiencies.
Examination
Particular features to pay attention to include the following.
Weight and height (failure to thrive).
Structural damage from infections (ears, sinuses, lungs).
Autoimmune features: vitiligo; alopecia; goitre.
Other suspicious/diagnostic features, as above.
Differential diagnosis
Formulate differential diagnoses in rank order and then investigate appropriately.
Laboratory investigation
Use laboratory facilities wisely.
Target investigations to differential diagnosis.
Do not blanket screen.
Ensure basic tests are done before exotic tests.
Think whether tests will contribute to diagnosis or management. If they will not, then do not do them!
B-cell function
Full evaluation of the humoral immune system requires that all the parts are present and functioning. The latter usually requires in vivo test immunization, bearing in mind the caveat that no patient with suspected immunodeficiency should receive live vaccines. The following tests comprise a full screen of humoral function.
Serum immunoglobulins (be sure to use a low-level detection system for IgA to confirm absence).
Serum and urine electrophoresis (evidence for bands and urinary loss).
IgG subclasses.
IgE.
Antibacterial, antiviral antibodies (appropriate to immunization and exposure history).
Immunization responses (protein and polysaccharide antigens).
Isohaemagglutinins (IgM, dependent on blood group).
B-lymphocyte numbers (flow cytometry); class-switch memory B cells (CD27+/IgD–/IgM–).
Pokeweed mitogen (PWM) and antigen-stimulated antibody production in vitro (clinical indications limited).
T-cell function
Tests of T-cell function are less easy and less reliable than those for B cells, where antibody provides a convenient read-out. ‘Normal’ ranges for in vitro proliferation assays are quite wide: know your own laboratory ranges. Use absolute cell counts, not percentages.
Neutrophil function
Neutrophil function tests are not widely available, so if there is suspicion of a neutrophil defect, specialist help should be sought. Interpretation is difficult and tests may be influenced by intercurrent infection and drug therapy.
Neutrophil markers (CD11a, CD11b, CD11c, CD18, CD15).
Oxidative metabolism (quantitative and qualitative nitroblue tetrazolium reduction (NBT test); flow cytometric determination of oxidative burst).
Phagocytosis.
Bacterial killing (relevant organisms should be selected).
Chemotaxis (difficult to standardize, with wide normal range).
NK-cell function
This is an area of particular interest.
NK-cell numbers by flow cytometry (absolute counts).
K562 killing assay (radioimmunoassay, flow cytometry).
Cytokine-stimulated killing (lymphokine-activated killer cell (LAK) assay).
Perforin, granule-release assays.
Complement assays
Measurement of specific components.
Functional assays (haemolytic assays).
Toll receptor assays
Measurement of specific pathways.
Genetic studies
Genetic studies form an essential part of the investigation and management of primary immunodeficiencies.
Other investigations
The use of other investigative procedures depends very much on the clinical state of the patient.
Detection of autoimmunity:
anti-red cell, platelet, neutrophil antibodies
anti-endocrine autoimmunity (e.g. thyroid autoantibodies).
Exclusion of secondary causes:
renal disease, bowel disease (loss of immunoglobulins ± lymphocytes)
malignancy (lymph-node biopsy)
nutritional deficiencies (zinc, B12, iron)
drugs (cytotoxics, anticonvulsants).
Detection of nodular lymphoid hyperplasia (CT scanning, barium follow-through, endoscopy, biopsy).
Direct isolation of pathogens: bacteria, fungal, and viral (serology is usually unreliable—use PCR-based tests where culture is not possible).
Major B-lymphocyte disorders
Rare antibody deficiency syndromes
X-linked hyper-IgM syndrome (HIGM-1); CD40-ligand deficiency.
Autosomal hyper-IgM syndromes (HIGM-2-4):
HIGM-2; autosomal recessive activation-induced cytidine deaminase deficiency
HIGM-3; autosomal recessive CD40 deficiency
HIGM-4; similar to HIGM-2, molecularly undefined
X-linked hypogammaglobulinaemia with growth hormone deficiency.
Selective IgM deficiency.
X-linked lymphoproliferative syndrome (Duncan’s syndrome; XLPS).
Hyper-IgE syndrome (Job’s syndrome).
Selective IgE deficiency.
Transient hypogammaglobulinaemia of infancy.
Mu-chain deficiency.
Igα (CD79a) deficiency.
Igβ (CD79b) deficiency.
BLNK deficiency.
ICOS deficiency.
λ5/14.1 (surrogate light chain, IGLL1, CD179B) deficiency.
SWAP-70 deficiency.
κ and λ light-chain deficiency.
CD20 deficiency.
CD81 (TAPA1) deficiency.
LRRC8A (leucine-rich repeat-containing protein 8A) deficiency.
Thymoma with immunodeficiency (Good’s syndrome).
CD19 deficiency.
X-linked agammaglobulinaemia (Bruton’s disease)
This was the first immunodeficiency to be described (1952). It has an incidence of 1 in 100 000-200 000 and a prevalence of 1 in 10 000.
Cause
Genetic disorder due to a mutations on the X chromosome affecting the btk gene.
btk codes for a tyrosine kinase involved in B-cell maturation.
Defects in the gene prevent B-cell maturation from pro-B-cell to pre-B-cell.
Gene is located at Xq21.3-22. Mutations include deletions and point mutations, either conservative or leading to premature termination.X-
Phenotype correlates poorly with genotype.
Mild phenotypes occur with some limited B-cell development.
New mutations are common, so a family history may be absent.
The xid mutation in mice is similar, although some features differ.
Presentation
Usually early in childhood, after 6 months of age, when maternal antibody has largely disappeared.
Recurrent infections of lungs and ears (children of this age don’t have sinuses):
Haemophilus influenzae and pneumococci (upper and lower respiratory tract, meningitis)
meningococcus (meningitis)
staphylococci (septic arthritis)
Giardia, Salmonella, and Campylobacter infections of the gut
Rarely Pneumocystis.
Milder phenotypes may present later.
Diagnosis—key features
Early-onset bacterial infections in a male child with a family history.
Family history often absent.
Neutropenia very common at presentation but goes away with treatment and is probably due to chronic bacterial sepsis.
Failure to thrive and chronic diarrhoea common.
Distinction of milder forms, with some B cells and low but not absent IgG, from CVID is difficult and relies on the demonstration of abnormalities of the btk gene. Some patients previously classified as CVID will turn out to be XLA.
Specific antibody deficiency only reported with btk mutations.
XLA may rarely be associated with growth hormone deficiency (and short stature).
Occasional females will be identified with the immunological features of XLA.
Differential diagnosis will include coeliac disease and cystic fibrosis, although the laboratory tests will rapidly identify antibody deficiency.
Immunology
In the complete forms the immunology is fairly distinctive.
All immunoglobulins are absent or very low.
B cells are low or absent.
btk protein absent (confirm with genetic studies where there is a good history to exclude production of non-functional protein).
Lymph nodes show no germinal centres; no tonsils; pre-B cells in bone marrow (BM).
T-cell numbers and function are normal.
NK-cell numbers and function are normal.
Mild or incomplete variants may be difficult to distinguish from CVID.
Variable numbers of B cells including normal.
Variable immunoglobulins.
Poor/absent specific antibodies to polysaccharide antigens.
Complications
The major complications relate to delay in diagnosis.
Structural lung damage (bronchiectasis, sinusitis). Inadequate therapy will lead to progression of lung damage and the development of chronic sinus damage.
Chronic meningoencephalitis due to echoviruses and Coxsackieviruses may cause a progressive and fatal dementing illness; there is often muscle involvement, with a myositis and contractures. Diagnose by viral culture of CSF or by PCR-based techniques. Antiviral pleconaril is helpful (though not licensed by the US Food and Drug Administration). This disease appears less often since the introduction of intravenous immunoglobulin (IVIg) therapy as standard, but has not disappeared completely.
Ureaplasma/Mycoplasma septic arthritis. This is difficult to diagnose without special culture facilities. It is a highly destructive chronic infection and requires prolonged treatment (6 months) with tetracyclines ± erythromycin.
Haemophilus conjunctivitis.
Crohn’s-like disease of intestines. Possible increased risk of colonic cancer.
Possible increase in malignancies (colorectal, gastric, squamous cell lung).
Treatment
IVIg should be started at the earliest opportunity (see Chapter 16) at a dose of 200-600mg/kg/month given at intervals of 2-3 weeks. Longer intervals do not give satisfactory replacement.
Subcutaneous immunoglobulin given weekly (same total dose) is an alternative.
Trough IgG levels should be monitored regularly, with the aim of maintaining a level well within the normal range (6-9g/dl). Early institution of IVIg and adequate trough levels preclude the development of bronchiectasis.
Prompt antibiotic therapy (course of 10-14 days) for upper and lower respiratory tract infections together with physiotherapy and postural drainage if lung damage has already occurred. Ciprofloxacin is a valuable antibiotic (though not licensed for small children). Use cystic fibrosis approach of zero tolerance to cough.
Prophylactic azithromycin 3×/week ± carbocisteine is valuable where there is established bronchiectasis—teach postural drainage and effective cough.
As children get older and can comply, perform annual lung function testing, including transfer factor.
High resolution CT scanning (HR-CT) is useful for identifying subclinical bronchiectasis, but imposes a significant radiation burden and should not be overused.
Do not give oral poliovaccine as patients often fail to clear it, which increases the risk of reversion to wild type, with consequent paralytic disease.
Genetic counselling of the patient and family once the genetic basis is confirmed. Identify and counsel carriers.
Long-term immunological follow-up (plus additional specialist input as required).
XLA with growth hormone deficiency
This is a very rare disorder with immunological features identical to XLA in association with short stature (as opposed to failure to thrive). The disease maps the region of the X chromosome containing the btk gene, but not all cases appear to have mutations in the btk gene. Prognosis appears to be good. It is treated with IVIg and growth hormone.
Common variable immunodeficiency (CVID)
CVID is the most common symptomatic antibody deficiency with an estimated incidence of 1 in 25 000-66 000, based on Scandinavian data.
Cause
Cause of CVID is unknown: one hypothesis suggests that an environmental insult (virus infection?) in a genetically susceptible individual triggers the disease. No conclusive viral trigger has been identified.
Some evidence for a genetic background (linked to MHC A1B8DR3C4Q0 and to polymorphisms in the TNF-α gene).
May be a family history of other antibody deficiencies (especially IgA deficiency and IgG subclass deficiency) in up to 50% of cases, although other family members may be entirely asymptomatic.
Disease is heterogeneous in phenotype and immunological findings.
Diagnosis is now one of exclusion, once other genetic diseases have been ruled out.
Some CVID patients have been identified with mutations in TACI and BAFF-R. Significance is uncertain—may not be disease-causing.
SNPs in the gene for Msh5 have been reported, with increased frequency in patients with CVID and IgA deficiency.
Presentation
May present at any age from childhood through to old age, although the peak of presentation is in early childhood and early adulthood.
Usual presentation is with recurrent bacterial infections, as for XLA.
May present with autoimmune problems, especially thrombocytopenia, haemolytic anaemia, and organ-specific autoimmunity (e.g. thyroid, diabetes, vitiligo, and alopecia); these are common and may precede the development of recurrent infections.
Nodular lymphoid hyperplasia of bowel (polyclonal hyperplasia of Peyer’s patches) is unique to CVID. The cause is unknown, but it is possibly premalignant. This has characteristic features on small-bowel radiology.
Granulomatous disease with lymphadenopathy and (hepato-) splenomegaly, often involving the lung, is common in the severe form of CVID (about 25% of cases). Disease resembles sarcoidosis, but is Kveim-test negative (although this test is now rarely used). Specifically associated with complete absence of class-switch memory B cells.
More severe cases may develop opportunist infections (see late-onset combined immunodeficiency, p.43).
Diagnosis
History gives the clues. Clues are usually missed by general physicians and an average diagnostic delay of over 7 years is typical, by which time structural lung and sinus damage is severe and irretrievable.
Immunoglobulin levels are variably low: test immunization and exclusion of secondary loss (gut, urine) may be required.
Lymphopenia affecting predominantly the CD4+ T cells (CD45RA+ naive cells in particular) and B cells is common.
Immunology
Immunoglobulin levels are highly variable, and IgG may be only marginally reduced; specific antibodies are invariably low with poor/absent immunization responses.
IgM may be normal, which contrasts with lymphoma, when the IgM is the first immunoglobulin to drop (Chapter 2).
B cells may be normal or low, but some cases in males may be latepresenting XLA.
CD4+ T cells are low, with specific depletion of CD45RA+ T cells. T-cell function to antigens and mitogens is poor in vivo and in vitro, and there is poor NK-cell function, with reduced NK-cell numbers.
Abnormalities of 5’-nucleotidase activity on the lymphocyte surface have been described but this is not a separate syndrome as is sometimes stated. The significance of the abnormality is not known.
Classification
Three groups are identified on the basis of B-cell responses to IL-2 + anti-IgM in vitro.
Group A: severe disease, with granulomata (hepatosplenomegaly); no IgG or IgM production in vitro.
Group B: rare; IgM production only in vitro (?cryptic hyper-IgM).
Group C: mild disease; IgG and IgM production in vitro.
This technique is unsuited to routine diagnosis; identification of classswitch memory B cells is more useful (group A patients lack class-switch memory B cells).
Clinical grouping by complications has been used as an alternative.
No complications.
Polyclonal lymphocytic infiltration.
Enteropathy.
Lymphoid malignancy.
83% of patients show a single clinical phenotype.
Phenotyping by flow cytometry has also been used (EUROclass trial).
Three patterns emerge.
Nearly absent B cells (<1%).
Severely reduced class-switched memory B cells (<2%)—may be seen in other PIDs (Wiskott-Aldrich syndrome, XLPS, idiopathic CD4 lymphopenia, and CGD).
Expansion of CD21low B cells (associated with lymphoproliferative disease and splenomegaly) >10%. CD24 may also be helpful in analysing this subset; calcium signalling is also abnormal.
Reduction of Treg is associated with an increase in autoimmune disease.
CVID 2: complications and treatment
Complications
Major complications of CVID relate to the delay in diagnosis with structural damage from infection: bronchiectasis and chronic sinusitis.
Patients may also have unusual infections, such as Campylobacter cholangitis, and Mycoplasma/Ureaplasma arthritis (see XLA, p.10). Rarely, opportunist infections such as Pneumocystis occur (but this should suggest hyper-IgM syndromes).
Malabsorption may occur due to a coeliac-like enteropathy, with villous atrophy.
Inflammatory bowel disease may occur with strictures.
Nodular regenerative hyperplasia of the liver is seen.
Granulomatous disease may affect any organ (brain, lungs, liver, spleen, lymph nodes, skin, eye).
In group A patients with splenomegaly, hypersplenism may occur with marked thrombocytopenia: splenectomy may be required.
40-fold increase in the risk of lymphoma, including intestinal lymphoma; any patient with lymphadenopathy should have a lymph node biopsy and BM examination to exclude the diagnosis. Lymphomas are often high grade and respond poorly to treatment.
Increase in gastric carcinoma, not related to Helicobacter pylori colonization.
Autoimmune disease is common, and patients should be monitored for the development of overt disease (hypothyroidism, pernicious anaemia, diabetes).
Treatment
The earlier the diagnosis is made, the better the prognosis.
Treatment is identical to that of XLA, with IVIg/SCIg, antibiotics, and physiotherapy for chest disease.
Prophylactic antibiotics should be considered if there is an inadequate response to optimal immunoglobulin therapy.
Patients with complete IgA deficiency may have a higher risk of developing anti-IgA antibodies to IVIg therapy, and a product low in IgA should be selected for them; most IVIg products now have reduced IgA content. The value of monitoring anti-IgA antibodies is questionable.
Patients with splenomegaly may catabolize IgG faster and may require larger doses or more frequent doses (weekly).
Regular lung function tests (volumes and transfer factor) and HR-CT scanning is required. Deteriorating lung function requires more aggressive therapy.
Chronic sinus disease requires ENT review, with endoscopic inspection.
Granulomatous disease responds well to steroids (alkaline phosphatase is a good marker); these are essential if there is interstitial lung disease (reduced transfer factor). They are not necessary for asymptomatic splenomegaly. Steroid use is associated with an increased risk of disseminated shingles. Splenectomy may be necessary for hypersplenism: such patients must have prophylactic penicillin, but immunizations are of little value. However, there is an additional risk of infection after splenectomy in CVID patients and caution is required.
Treat inflammatory bowel disease as for Crohn’s disease.
Liver disease may cause portal hypertension and hepatic encephalopathy—shunting may be required.
Gluten-free diet may help if there is coeliac-like disease.
Monitor for the development of malignant disease. Review frequency of cervical smears.
Consider need for bone mineral density monitoring (malabsorption).
Experimental therapy
PEG-IL-2 has been used successfully in a small cohort.
Retinoic acid has been shown to benefit some patients.
Cimetidine may also improve immunological function.
TNF anatagonists have been used with benefit for granulomatous disease in isolated cases.
IL-21 increase antibody production in CVID and may be a therapeutic option.
Selective IgA deficiency
Selective IgA deficiency is the most common primary immunodeficiency, but mostly passes unnoticed. Depending on the racial group, 1 in 400-800 individuals will be affected.
Cause
Cause is unknown, although it forms part of the spectrum of disease with CVID and shares the MHC type (A1, B8, DR3, C4Q0). It occurs in relatives of patients with CVID in 50% of cases.
Rarely due to a gene deletion, often including IgG2/IgG4.
Defects of class switching have been identified in a few patients.
Selective deficiencies of IgA1 or IgA2 have been reported (all due to gene deletions).
May be associated with other chromosomal abnormalities, usually involving chromosome 18 (18q syndrome and ring chromosome 18). Also with variant Turner’s syndrome (Xq), multibranched chromosomes, Klinefelter’s syndrome, and α1-antitrypsin deficiency.
Associated with drug therapy, particularly with phenytoin and penicillamine, although in many reports it is not clear whether the defect was present before drug therapy was introduced.
IgA-bearing B cells are present. IgA is synthesized but not secreted.
In terms of mucosal protection, there is evidence that IgG and IgM may substitute as secretory immunoglobulins.
Presentation
Most cases are asymptomatic.
There is an increased incidence of allergic disease, including food allergies and intolerances.
Connective tissue diseases (SLE, rheumatoid arthritis, and juvenile chronic arthritis), coeliac disease, inflammatory bowel disease, pernicious anaemia, and other organ-specific autoimmune diseases.
Nodular lymphoid hyperplasia.
Increased presence of a range of autoantibodies.
False-positive pregnancy tests due to heterophile antibodies.
Infections are rarely a problem unless additional humoral defects are present.
Occasional cases will come to light as a result of adverse reactions to blood products. This is deemed to be very rare (incidence 1 in 15 million transfusions).
Diagnosis
Requires the demonstration of undetectable IgA, not just a low IgA. Automated analysers do not read low enough to ascertain this beyond doubt. Check with low-level radial immunodiffusion or Ouchterlony double-diffusion assays.
Beware of the presence of anti-animal antibodies in IgA deficiency which give false readings in immunoassays using antisera derived from sheep, goats, and horses.
Patients should be screened for evidence of other humoral defects: IgG subclasses and specific antibodies if there is a history of infections. If there is doubt, then test immunization should be undertaken.
IgA antibodies can be measured but current assays detect IgG and IgM antibodies and therefore do not identify risk of anaphylaxis. The significance of IgG and IgM anti-IgA antibodies is uncertain. High levels may be seen in the absence of reactions. There is only one report of detection of IgE anti-IgA antibodies.
Immunology
The IgA will be undetectable (< 0.05g/L), but total IgG and IgM will be normal. IgG subclasses may be reduced (G2 and G4). Secreted IgA will be absent (secretory piece deficiency is vanishingly rare), but testing for this is of little clinical value.
T-cell function is normal (PHA and antigens).
Auto-antibodies may be present (NB anti-IgA antibodies). There will be an increased IgE in the presence of atopic disease.
In the absence of IgA, IgM and IgG appear on mucosal surfaces.
Complications
A major problem with IgA deficiency is the possibility of transfusion reactions thought to be due to anti-IgA antibodies. These are extremely rare (1 in 15 million). The Blood Transfusion Service in Sheffield (UK) will carry out confirmatory tests and issue a blood transfusion warning card.
Malignancy may be increased, although this may depend on other diseases present in association with IgA deficiency, especially lymphoma and gastric adenocarcinoma.
It is possible that there may be progression to more significant humoral immunodeficiency with time.
Treatment
Treatment is directed at the presenting disease.
Avoid IgA-containing products if possible: The National Blood Authority no longer routinely provides blood products from IgAdeficient donors. Use an IVIg/SCIg (if required) with a low IgA content.
Where immunoglobulin replacement therapy is required for recurrent infections, this has been shown to be safe.
In view of the low risk of reactions, the wearing or carrying of an alert card is of doubtful value.
Selective IgA2 deficiency
Cases have been reported with selective IgA2 deficiency, with normal IgA1. This does not appear to be due to heavy-chain gene deletions affecting the α2 gene in all cases.
IgG subclass deficiency
Cause
The cause of IgG subclass deficiency is unknown, but it forms part of the spectrum with CVID and IgA deficiency. It is possible that some cases represent CVID in evolution. Rarely, cases may be due to gene deletions, but these individuals may be entirely healthy.
IgG subclass levels are related to allotypes of IgG (Gm allotypes); therefore different racial groups may have different ‘normal’ ranges,
depending on the prevalence of different allotypes. This should be taken into account when diagnosing IgG subclass deficiency.
Presentation
As for CVID, presentation can be at any age. Recurrent infections may be a feature, particularly for IgG2 ± IgG4 deficiency. IgG4 deficiency occurring alone has also been associated with bronchiectasis.
Other conditions associated with subclass deficiency include asthma (IgG3 deficiency), sinusitis (IgG3 deficiency), intractable epilepsy of childhood (although this may be due to anticonvulsants), and autoimmune disease (SLE).
Diagnosis
Measurement of IgG subclasses on more than one occasion is required and it is important to check that appropriate age-specific normal ranges are used (preferably related to the racial background).
Detection of low levels of IgG4 may require more sensitive assays to detect true absence; earlier normal ranges using less sensitive assays found a significant number of individuals with undetectable IgG4. Most of these have detectable IgG4 on sensitive assays.
There is a poor correlation of specific anti-pathogen responses and IgG subclass levels. All patients should have specific antibodies measured and be test immunized.
Detection of low or absent subclasses does not necessarily correlate with clinical disease.
Immunology
A normal total IgG is entirely compatible with subclass deficiency, although low IgG1 usually reduces the total IgG (this also behaves like CVID for practical purposes). The IgA is normal or low; IgM is normal.
B- and T-cell numbers are usually normal.
Poor specific antibody responses to bacterial and viral antigens may be present in some patients.
Complications
Long-term progression to CVID is a possibility.
Bronchiectasis may occur in IgG4 deficiency.
Treatment
Treatment is controversial: only symptomatic patients should be treated. If recurrent infections are a problem, the first step might be to use continuous antibiotics, followed by IVIg if infections are not controlled.
IVIg has been shown to be of benefit in asthma due to IgG3 deficiency (and, interestingly, a low IgG3 preparation worked), and in chronic sinusitis.
It is theoretically possible to bypass IgG2 deficiency using proteinconjugated polysaccharide vaccines to generate a protective IgG1 response.
Specific antibody deficiency with normal serum immunoglobulins
This syndrome is probably much more common than hitherto realized.
Cause
The cause is unknown. It is unrelated to IgG subclass deficiencies. There is usually a failure to respond to polysaccharide antigens (T-independent) and possibly other protein antigens (HBsAg?).
In small children, it may be due to a maturational delay that resolves spontaneously.
Presentation
Recurrent bacterial infection of upper and lower respiratory tract (Haemophilus, Pneumococcus, Moraxella) is the usual presentation.
In immunization programmes for hepatitis B, about 5% of individuals fail to respond to the standard three-dose schedule; a fourth dose still leaves 1-2% who fail to make a serological response. These patients clearly have some form of specific immune deficit (see Chapter 2 for the approach to management of these individuals).
Diagnosis
There is a history of recurrent typical infections with normal immunoglobulins and IgG subclasses.
Proof requires demonstration of failure to respond to specific antigens (test immunization).
Immunology
Immunoglobulins and IgG subclasses are normal, but there are low specific antibodies, especially to capsulated organisms, and poor responses to test immunization, especially to polysaccharide antigens (Pneumovax II®).
The use of serotype-specific responses may add confidence to the diagnosis.
Salmonella typhi Vi antigen has also been evaluated as a test antigen.
Meningococcal polysaccharide vaccines may be used but the serological responses are less well established.
For all vaccines, a normal response is a rise in titre into the protective range and a 4× increase over the pre-immunization level. Ideally, pre-and post-vaccine samples should be run on the same assays as the inter-assay coefficient of variation (CV) of specific antibody assays is high.
Children under the age of 2 years do not respond to Pneumovax II®. However, the inability to respond to polysaccharide antigens in infants may be bypassed by conjugation of the polysaccharide to a protein, for example, the Hib-conjugate vaccines and Prevenar®, the heptavalent pneumococcal polysaccharide vaccine.
T- and B-lymphocyte numbers and T-cell function are normal.
Complications
Long delay in diagnosis leads to structural lung damage. Delay may be of the order of 15-20 years because clinicians fail to recognize immunodeficiency in the presence of normal total immunoglobulins.Treatment
Treatment is still controversial. Conjugate vaccines should be tried to bypass defect if this is ineffective.
First step should be prophylactic antibiotics (azithromycin 250-500mg od 3×/week, adult dose); tetracycline 500mg bd is an alternative, but is less effective.
Continuous antibiotics are inadequate for patients with established lung disease; these should be managed on IVIg/SCIg as for XLA. No randomized placebo-controlled trials.
In small children, spontaneous improvement may occur, and continuous prophylactic antibiotics and close supervision may be sufficient.
Remember. Normal serum immunoglobulins and IgG subclasses do not exclude humoral immune deficiency!X-linked hyper-IgM syndrome (HIGM-1)
Originally this was thought to be a B-cell disorder, but the demonstration in the X-linked form of a primary T-cell defect means that this form should be reclassified as a T-cell defect. However, the predominant effect is of a humoral immune deficiency.
Cause
the X-linked form has now been shown to be due to a deficiency of the CD40-ligand (CD154) on T cells (gene located at Xq26-27) required for B-cell immunoglobulin class switch.
CD40 is also expressed on monocyte-macrophages, and the interaction with CD40L is integral to antigen presentation.
Presentation
Presentation is with recurrent bacterial infections; this may include Pneumocystis carinii pneumonia.
There is often neutropenia and thrombocytopenia. Autoimmune disease of all types is common.
Diagnosis
There is usually an early onset; the diagnosis should always be considered when Pneumocystis pneumonia is the presenting illness. The differential diagnosis includes SCID and HIV infection.
There will be a normal or high IgM, with low IgG and IgA.
Most cases can be identified by failure to upregulate expression of CD154 on activation of T cells; this does not identify cases where point mutations permit expression of non-functional CD154.
Genetic identification is possible.
Immunology
IgM (and IgD) are normally raised with a low IgG and IgA. However, the IgM may be normal in the absence of infection. There will be high isohaemagglutinins. Specific IgM responses are present but may be short-lived. IgM+ and IgD+ B cells are present.
T-cell function may be normal or poor. Some patients have reduced cell-mediated immunity, as evidenced by the occurrence of Pneumocystis infection. The expression of CD40-ligand on activated T cells may be defective (use PMA + ionophore).
Mild variants exist compatible with minimal disease and survival into adult life.
Complications
Opportunist pneumonias; there appears to be a particular risk of cryptosporidial infection of the biliary tree, leading to a severe cholangitis and liver failure.
Autoimmune diseases including haemolytic anaemic, thrombocytopenia, and neutropenia; parvovirus-induced anaemia.
Increased risk of lymphomas (IgM+, due to chronic overstimulation) and hepatocellular, bile duct, and neuroendocrine carcinomas.
Long-term prognosis without transplantation is poor (infections and liver disease) in X-linked hyper-IgM syndrome (HIGM-1).
Treatment
IVIg/SCIg should be started at the earliest opportunity: the IgM returns to the normal range with adequate therapy. Doses should be in the range 0.4-0.6g/kg every 2-3 weeks.
Prompt antibiotics are required for infections, as for other antibody deficiencies.
Consideration should be given to the use of PCP prophylaxis (co-trimoxazole 480mg bd, 960mg od, or 960mg 3×/week; azithromycin and atovaquone are alternatives where co-trimoxazole cannot be tolerated).
All drinking water, even if bottled, should be boiled, as domestic supplies cannot be guaranteed to be free of Cryptosporidium.
Bone marrow/stem cell transplantation (BMT/SCT) is the treatment of choice, where the diagnosis is made early in life and compatible donors are available.
Liver transplantation may be required for liver disease secondary to Cryptosporidium infection.
Autosomal hyper-IgM syndromes
Four rare types of autosomal hyper-IgM have now been identified.
HIGM-2
Caused by defects in the activation-induced cytidine deaminase gene (AID gene, 12p13).
Intrinsic B-cell defect with failure to class-switch. B cells express CD19, sIgM, and sIgD.
T-cell function is normal: opportunistic infections such as Pneumocystis do not occur.
T-cell expression of CD154 is normal.
Lymphoid histology is abnormal, with hyperplasia and giant germinal centres.
Presentation is with recurrent bacterial and gastrointestinal infections from early in childhood.
HIGM-3
Caused by deficiency of CD40 expression on B cells owing to a genetic defect (20q12-13.2).
Clinical features are identical to those of HIGM-1, and opportunist infections can occur.
Class-switch memory B cells are markedly reduced or absent.
Monocyte function is also defective (CD40 is expressed on monocytes). CD40 is also expressed on endothelial cells.
Neutropenia may occur.
Increased risk of lymphomas and hepatocellular, bile duct, and neuroendocrine carcinomas.
HIGM-4
Clinically a mild variant of HIGM-2, but with normal AID levels.
The molecular defect is unknown.
Some IgG production may occur.
X-linked ectodermal dysplasia with HIGM (NEMO deficiency; IκBα deficiency)
Cases have been reported of X-linked ectodermal dysplasia with HIGM due to loss-of-function mutations in the NEMO gene (Xq28), coding for IKK-γ, which block the release of NFκB on cellular activation.
Not all patients with NEMO mutations have extodermal dysplasia.
Gain-of-function mutations in IκBα, with which IKK-γ interacts, have been reported to produce an autosomal dominant ectodermal dysplasia similar to NEMO deficiency.
IL-10 production is lacking.
Patients with NEMO mutations have impaired polysaccharide responses.
IgA levels may be increased more than IgM.
Patients with IκBα mutations have hypogammaglobulinaemia, reduced CD4+ and CD8+ T cells, and absent T-cell proliferation to anti-CD3.
Clinical features include early-onset severe bacterial and viral infections, atypical mycobacterial infections, chronic diarrhoea, bronchiectasis, and failure to thrive.
Hypomorphic NEMO mutations have also been associated with ectodermal dysplasia associated with osteopetrosis and lymphoedema, and incontinentia pigmenti.
Prophylactic antibiotics are required.
Anti-herpes prophylaxis may be required.
Treatment with IVIg is helpful.
HSCT has been used in both NEMO and IκBα mutations, with successful outcomes.
X-linked lymphoproliferative disease type 1, SAP deficiency (Duncan’s syndrome, XLP-1)
This is a very rare genetic disorder, leading to failure to handle EBV correctly.
Cause
The genetic defect has been localized to Xq26, and the gene has now been cloned.
The gene product SAP (SLAM-associated protein, SH2D1A) controls the activation of T and B cells via SLAM (signalling lymphocyte activation molecule), a surface protein. SLAM is involved in γ-IFN production and the switch from Th2 to Th1.
The reason for the failure to handle EBV appropriately is not yet known.
Presentation
Patients are fit and well until EBV is encountered. Upon infection with EBV, five outcomes are possible.
Fulminant EBV infection (58%); mortality is 96%!
Haemophagocytic lymphohistiocytosis (HLH).
EBV+ non-Hodgkin’s lymphoma (30%); risk of lymphoma is 200-fold greater than in the normal population.
Immunodeficiency, usually profound hypogammaglobulinaemia (30%). Some cases have been misdiagnosed as CVID.
Aplastic anaemia, often associated with hepatitis (3%).
Vasculitis, lymphomatoid granulomatosis (3%).
Overall mortality was 85% by the age of 10 years but is now improving, especially for patients with HLH and lymphoma.
Survival is only 18.6% for untransplanted patients with HLH.
Overall survival is now 62.5% for untransplanted patients on Ig replacement.
Mild cases are recognized.
Diagnosis
Diagnosis is difficult, especially if there is fulminant EBV infection.
Flow cytometric tests for intracellular proteins can demonstrate the presence of protein, but this does not exclude mutations causing the production of non-functional proteins.
Immunology
Immunology is usually normal before infection, but it is rarely checked unless there is a family history. Carriers may have subtle immunological abnormalities, such as unusually high anti-EBV VCA antibodies.
After infection, in those who survive, there are reduced immunoglobulins (all three classes). T-cell proliferation to mitogens and antigens is poor, and there is reduced γ-IFN production. NK-cell function is also poor. CD8+ T cells may be persistently elevated.
Antibodies to EBV may be poor or even absent.
Treatment
IVIG/SCIg should be used for the hypogammaglobulinaemia.
HSCT may be an option as part of the treatment of lymphoma. Survival after HSCT with good immune reconstitution is 81%.
Prophylactic use of aciclovir in at-risk family members is of unproven value.
During acute fulminant EBV, therapy directed against the abnormal CD8+ T cells (Campath®) and transformed B cells (rituximab, anti-CD20) may be valuable.
X-linked lymphoproliferative disease Type 2, XIAP deficiency (XLP-2)
XIAP is an (X-linked) inhibitor of apoptosis, also known as BIRC4, and stops cell death triggered by viral infection or excess caspase production.
Cause
Genetic defect has been localized to Xq24-25.
XIAP binds to and inhibits caspases 3, 7, and 9.
Presentation
Mutations in XIAP have been associated with severe inflammatory bowel disease.
Similar presentations to XLP-1 may occur.
Asymptomatic cases are described.
Diagnosis
Based on clinical suspicion followed up by genetic testing.
Flow cytometric tests for intracellular proteins can demonstrate the presence of protein, but this does not exclude mutations causing the production of non-functional proteins.
Immunology
XLP-2 patients have increased lymphocyte apoptosis in response to CD95.
iNKT cells are normal and NK-mediated cytotoxicity is normal.
Transient hypogammaglobulinaemia of infancy (THI)
Cause
THI is thought to be due to a delay in immune development, leading to a prolongation of the physiological trough of antibody after the age of 6 months when maternal antibody has largely disappeared.
Common in families of patients with other antibody deficiencies.
Diagnosis excludes hypogammaglobulinaemia by reasons of prematurity.
Presentation
Usual presentation is with recurrent bacterial infections, typically of the upper and lower respiratory tract, occurring after 6 months of age. It may last up to 36 months before spontaneous recovery takes place.
Transient neutropenia and thrombocytopenia have been reported.
Diagnosis
There will be an early onset.
Presence of normal B-cell numbers differentiates THI from XLA. IgM is frequently normal, and there may be evidence of specific antibody responsiveness.
Check for btk expression to exclude XLA.
No specific diagnostic features, and the diagnosis can only be made for certain after full recovery of immune function has taken place.
Immunology
IgG and IgA are low for age; IgM is usually normal. B cells are present; T-cell numbers and function are normal. IgG must be reduced on more than one occasion. A reduction to <2 SD below the lower end of the normal range has been suggested by some authorities.
Vaccine responses may be normal or reduced.
Treatment
Mild cases may be managed with prophylactic antibiotics.
IVIg/SCIg treatment may be required in more severe cases; it can be used for a fixed period and withdrawn at intervals to check for spontaneous recovery.
By definition all recover! If there is no recovery, the patient has an alternative diagnosis.
Hyper-IgE syndrome (Job’s syndrome)
Frequently classified with neutrophil defects, but these are secondary to the dysregulation of T- and B-cell function and the very raised IgE.
Cause
Autosomal dominant form is associated with dominant negative mutations in the DNA-binding domain of signal transducer and activator transcription (STAT3).
Autosomal recessive inheritance has also been described and is due to mutations in tyrosine kinase 2 (TYK2); similar clinical features may be seen in dedicator of cytokinesis 8 (DOCK8) deficiency, which is also autosomal recessive.
Presentation
Patients present with atypical eczema and recurrent invasive bacterial infections. Staphylococci and Haemophilus are the usual pathogens. Invasive candidiasis may occur.
Pneumatocoeles due to staphylococcal infection are a diagnostic feature. These may become colonized with Aspergillus or Pseudomonas.
Non-tuberculous mycobacterial infection may occur in STAT3 deficient patients.
The dominant form may be associated with invasive fungal infections and Pneumocystis jirovecii.
Osteopenia, probably due to abnormal osteoclast function, is a feature and may lead to recurrent fractures.
Coarse ‘leonine’ facies, but not all patients have red hair as originally described.
There is an increased risk of lymphoma.
Diagnosis
The clinical history is typical, especially the occurrence of pneumatocoeles.
IgE levels are massively elevated and are usually much higher than in atopic eczema.
Occurrence of invasive as opposed to cutaneous infections distinguish HIGE from atopic eczema.
Immunology
IgE is massively elevated (>50 000kU/L) and there may be IgG subclass and specific antibody deficiencies, with poor/absent immunization responses.
Eosinophilia may be present, especially during infection
Variable abnormalities of neutrophil function, affecting chemotaxis, phagocytosis, and microbicidal activity, have been reported, but are likely to be due to inhibition by the high IgE or defects in cytokine production.
Both STAT3 and TYK2 mutations lead to defective Th17 function. There may be defects in the production of γ-IFN, IL-12, IL-17, and IL-18
Absent CD45RO on T cells has been reported.
Treatment
Cimetidine (as an immunoregulatory agent) has been recommended, although the value appears to be limited.
γ-IFN is used in severe fungal infections (no randomized trials).
Omalizumab has been tried, but may not be appropriate where there is very high IgE (unlicensed indication).
Surgery for pneumatocoeles and deep-seated abscesses may be required.
Stem cell transplantation has been tried in some cases, with benefit.
Rare antibody deficiency syndromes
Antibody deficiency, presenting as ‘common variable immunodeficiency’, has been associated with the following extremely rare genetically identified disorders.
Mu-chain deficiency.
Igα (CD79a) deficiency.
Igβ (CD79b) deficiency
BLNK deficiency.
ICOS deficiency.
λ5/14.1 (surrogate light-chain, IGLL1, CD179B) deficiency.
SWAP-70 deficiency.
κ and λ light chain-deficiency.
CD20 deficiency.
CD81 (TAPA1) deficiency.
LRRC8A (leucine-rich repeat-containing protein 8A) deficiency.
Routine genetic tests for these are not yet available; screenings of large cohorts of CVID patients have shown that these disorders account for very few cases currently diagnosed as CVID. Flow cytometry will be able to identify the lack of some surface proteins, where there is a high index of suspicion.
Severe combined immunodeficiency (SCID)
Severe combined immunodeficiency involves both the T-cell arm and the B-cell arm. Often the major defect is on the T-cell side; B cells may be present but, in the absence of T cells, fail to respond or develop appropriately. The diagnosis is frequently missed at first, which reduces the chance of a successful outcome from treatment. It is estimated that the incidence is 1 in 50 000 births. Almost all cases are now accounted for by identified genetic defects.
Successful management of SCID requires a multidisciplinary team used to dealing with very sick small infants. Management should be restricted to centres experienced in the diagnosis and care of SCID. It should not be undertaken in haematology-oncology bone marrow transplant units as the requirements are very different from those of leukaemic patients.
Presentation
Most cases of SCID present with common clinical features, no matter what the underlying defect.
Typical features include:
early-onset infections (bacterial, viral, fungal, opportunist)
persistent candidiasis
chronic enteric virus excretion
failure to clear vaccines (BCG, oral polio)
failure to thrive
Lymphopenia: an absolute lymphocyte count of <2×109/L in a baby less than 6 months old is pathological and indicates SCID until proven otherwise. Therefore it is mandatory to looking at the differential white count in all babies with recurrent infections.
If SCID is suspected, investigation is URGENT—seek advice at once from a paediatric immunologist.
Infections in SCID
There is onset of infections soon after birth.
These include:
recurrent bacterial infections (pneumonia, otitis media, sepsis)
persistent thrush
persistent viral infections (RSV, enteroviruses, parainfluenza, CMV, other herpesviruses, rotavirus, small round structured virus (SRSV))
opportunist infections (PCP; fungal infections, including Aspergillus).
There are very significant risks from the administration of live vaccines especially BCG and polio.
Other features of SCID
Failure to thrive.
Diarrhoea (consider chronic enteroviral infection, rotavirus, SRSV).
Skin rash (Omenn’s syndrome, MFE).
Bone abnormalities (flared ribs—ADA deficiency; malabsorption—rickets).
Short-limbed skeletal dysplasia.
Hepatosplenomegaly (BCGosis, graft-versus-host disease (GvHD) from MFE or blood transfusions, Omenn’s syndrome).
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