Current Allergy and Clinical Immunology - March 2008

ange of haematological problems occur. Neutropeniais present in two-thirds of patients. Patients withCD40L deficiency commonly develop autoimmunemanifestations including neutropenia, thrombocytopenia,seronegative arthritis and inflammatory bowel disease.16,17,35 Patients with CD40 deficiency tend to havea pattern of severe recurrent infection and failure tothrive. However, P. jeroveci infection is unusual andautoimmune haematological complications do notoccur. A characteristic feature is lymphoid hyperplasiawith lymphadenopathy. In contrast to the lymph nodesin CD40L deficiency that lack germinal centres, in CD40deficiency lymph nodes have large germinal centres.16,42 Patients with AID deficiency or UNG deficiencyhave a milder clinical presentation of recurrent infection,lack opportunistic infection and their diagnosismay occasionally go unrecognised until the second orthird decade of life. 16X-linked lymphoproliferative syndrome (XLP) has beenclassified as a primary antibody deficiency. It is causedby mutations in the SH2DIA gene which encodes theprotein, SLAM-associated protein (SAP). This proteinregulates signal transduction of the SLAM-familyreceptors and therefore contributes to crosstalkbetween B- and T-lymphocytes. The main clinical phenotypesin patients with XLP include fatal infectiousmononucleosis due to Epstein-Barr virus (EBV) in 50%of cases, and in surviving patients recurrent infectionsdue to hypogammaglobulinaemia (30%) and lymphoma(25%). 43,44INVESTIGATIONSA detailed clinical evaluation should direct the laboratoryinvestigation of recurrent infection. Several patternsof infection occur which clinicians should learn torecognise. 1 Primary antibody conditions commonlymanifest with recurrent upper and lower respiratorytract infection, due mainly to a spectrum of extra-cellularbacteria (Table IV). Special features include unexplainedbronchiectasis, autoimmune phenomena(CVID, SIgAD, X-linked HIGM), enteroviral meningoencephalitis(Btk deficiency), P. jeroveci pneumonia (XlinkedHIGM), Epstein Barr virus infection (XLP) andgastrointestinal disorders (CVID). The differential diagnosisincludes other causes of recurrent infectionssuch as socioeconomic factors, HIV infection, gastrooesophagealreflux, allergies and cystic fibrosis. 1,34,39If primary antibody deficiency is suspected thenscreening investigations should include full blood countand differential count, peripheral smear for granulocyteTable IV. Micro-organisms causing common infectionsInfectionCommon organismsSinopulmonarySeptic arthritisGenitourinaryMeningitisGastrointestinalMeningoencephalitis(Btk deficiency)Streptococcus pneumoniaeHaemophilus influenzaeMoroxella catarrhalisStaphylococcus aureusMycoplasma spp.Staphylococcus aureusUreaplasma spp.Streptococcus pneumoniaeHaemophilus influenzaeCryptosporidium spp.Giardia spp.Enterovirusesmorphology, platelet volume, IgA, IgG, IgM and a complementscreen (CH50). In addition, granulocyte disordersand combined immune deficiency may be excludedwith additional tests, nitro-blue tetrazolium test andlymphocyte subset quantification (CD3+ [total] lymphocytes,CD4+ [helper] cells, CD8+ [suppressor] cells,CD19+ or CD20+ [B] lymphocytes and CD16+ and/orCD56+ [natural killer] cells). From these investigationsit may be established if an antibody deficiency is presentand the major deficiency type (Table V).Immunoglobulin concentrations in children should becompared against age-related norms. 1,34Normal immunoglobulin levels do not exclude a specificantibody deficiency. Specific antibody productionshould be investigated. Isohaemagglutinins are naturallyoccurring IgM antibodies to the ABO blood groupsubstances. By 1 year of age, 70% of infants have positiveisohaemagglutinin titres. Isohaemaemagglutinintitres may be measured at local blood banks. Titres ≥ 1in 8 to A 1 and B cells are usually present in normal individuals.Responses to protein antigens fall within theIgG1 subclass. Titres to protein antigens, e.g. tetanustoxoid, may be determined in vaccinated children. Theresponse to polysaccharide vaccines, e.g. 23-valentpnuemococcal polysaccharide vaccine, reside withinthe IgG2 subclass. Conjugate polysaccharide vaccinesare not helpful in the functional evaluation of an IgG2subclass deficiency or a selective polysaccharide antibodydeficiency because the responses to conjugatevaccines fall within the IgG1 and IgG3 subclasses.34,35,39 Advanced immunological testing requires specialisedassays such as the detection of CD40L expressionby flow cytometry in patients with animmunoglobulin pattern consistent with HIGM syndromeand assays to screen for and characterisegenetic mutations. Few specialised investigations arecurrently available in South Africa.TREATMENTFor many primary antibody deficiencies intravenousimmunoglobulin G (IVIG) replacement therapy is thetreatment of choice. The intravenous route is preferredbecause it avoids painful intramuscular injections.Generally 300-600 mg per kg every 3-4 weeks is recommended.Life-long replacement is indicated forsevere, genetically confirmed disorders including Btkdeficiency, related conditions and CVID. In CVID withouta molecular genetic diagnosis, IVIG should initiallybe administered for a period of 1-5 years followed byTable V. Major types of primary antibody deficienciesDisease B cells ImmunoglobulinsBtk deficiency Absent/low Low IgG, IgA, IgMCVID > 1% Low IgG, IgANormal/low IgMHIGM Normal Raised IgMsyndromesLow IgG, IgAIsolated IgG Normal NormalsubclassdeficiencySelective IgA Normal Low IgAdeficiencyNormal IgG, IgMSpecific Normal NormalantibodydeficiencyCVID – common variable immunodeficiency, HIGM syndromes –hyper-IgM syndromes.Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 17