Current Allergy and Clinical Immunology - March 2008

with memory T-cell phenotypes. 18 These are yieldinggreater understanding in chronic viral infections, e.g.the demonstration of skewing of memory T-cell subsetsin HIV rapid progressors. 21 At the same time, thereare extremely rapid advances in the understanding ofthe regulation of immune responses by regulatory T-cells 22 and IL-23/IL-27 pathway, 23 among other pathwaysof immune regulation. Immune dysregulation dueto defective regulatory T-cell function in primaryimmune deficiencies has also recently beendescribed. 24 I anticipate that application of theseadvances in the future will yield new insights and be ofvalue in the evaluation of adult patients presenting withunusual infections, where currently available relativelycrude immune assays usually fail to demonstrate anyabnormality.Declaration of conflict of interestThe author declares no conflict of interest.REFERENCES1. Ozsahin H, Arredondo-Vega FX, Santisteban I, et al. Adenosinedeaminase deficiency in adults. Blood 1997; 89: 2849-2855.2. Russel MW, Kilian M. Biological activities of IgA. In: Mestecky J,Lamm ME, Strober W, Bienenstock J, McGhee JR, Mayer L, eds.Mucosal Immunology, 3rd ed. Elsevier Academic Press, 2005: 267-2903. Hattingh C, Green F, Bubb MD, Conradie JD. The incidence of IgAdeficiency amongst blood donors in Kwazulu-Natal. S Afr J Sci1996; 92: 206-209.4. Ross IN, Thompson RA. Severe selective IgM deficiency. J ClinPath 1976; 29: 773-777.5. Zaka-ur-Rab Z, Gupta P. Pseudomonas septicaemia in selectiveIgM deficiency. Indian Pediatrics 2005; 42: 961-962.6. Notarangelo LD, Lanzi G, Peron S, Durandy A. Defects of classswitchrecombination. J Allergy Clin Immunol 2006; 117: 855-864.7. Mansouri D, Adimi P, Mirsaedi M, et al. Primary immune deficienciespresenting in adults: seven years of experience from Iran.J Clin Immunol 2005; 25: 385-391.8. Boyle J. Characteristics of health outcomes of patients with primaryimmune deficiency diseases in the United States. J AllergyClin Immunol 2004;113: S43.9. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency:Clinical and immunological features of 248 patients. ClinImmunol 1999: 92: 34-48.10. Kampmann B, Hemingway C, Stephens A, et al. Acquired predispositionto mycobacterial disease due to autoantibodies to IFN-γ.J Clin Invest 2005; 115: 2480-2488.11. Lammas DA, Drysdale P, Ben-Smith A, et al. Diagnosis of defectsin the type 1 cytokine pathway. Microbes Infect 2000; 2: 1567-1578.12. Soderstrom T, Soderstrom R, Avanzi A, et al. Immunoglobulin Gsubclass deficiencies. Int Arch Allergy Appl Immunol 1987; 82:476.13. Lekstrom-Himes JA, Gallin JI. Immunodeficiency diseases causedby defects in phagocytes. N Engl J Med 2000, 343: 1703-1714.14. De Vries E. Patient-centred screening for primary immunodeficiency:a multi-stage diagnostic protocol designed for non-immunologists.Clin Exp Immunol 2006; 145: 204-214.15. Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP.Natural killer cells in antiviral defense: function and regulation byinnate cytokines, Annu Rev Immunol 1999; 17: 189-220.16. Orange JS. Human natural killer cell deficiencies and susceptibilityto infection. Microbes Infect 2002; 2: 1545-1558.17. Cunningham-Rundles C. Immune deficiency: office evaluation andtreatment. Allergy Asthma Proc 2003; 24: 409-415.18. Casazza JP, Betts MR, Price DA, et al. Acquisition of direct antiviraleffector functions by CMV-specific CD4+ T lymphocytes withcellular maturation. J Exp Med 2007; 203: 2865-2877.19. Hatam L, Schuval S, Bonagura VR. Flow cytometric analysis of naturalkiller cell function as a clinical assay. Cytometry 1994; 16: 59-68.20. Arkwright PD, Abinun M, Cant AJ. Autoimmunity in human primaryimmunodeficiency diseases. Blood 2002; 99: 2694-2702.21. Zhang JY, Zhang Z, Wang X, et al. PD-1 up-regulation is correlatedwith HIV-specific memory CD8+ T-cell exhaustion in typical progressorsbut not in long-term nonprogressors. Blood 2007; 109:4671-4678.22. Chess L, Jiang H. Regulation of immune responses by T cells.N Engl J Med 2006; 354: 1166-1176.23. Kastelein RA, Hunter CA, Cua DJ. Discovery and biology of IL-23and IL-27: related but functionally distinct regulators of inflammation.Annu Rev Immunol 2007; 25: 221–242.24. Torgerson, TR, Ochs HD. Regulatory T cells in primary immunodeficiencydiseases. Curr Opin Allergy Clin Immunol 2007; 7: 515-521.Clinical Immunology: Principles and Practice, 3/eExpert Consult with UpdatesEdited by RR Rich, TA Fleisher, WT Shearer, H W Schroeder II, A J Frew and CM WeyandApril 2008, hardcover, approx. 1616 pp, 700 illus., 203 x 254 mm, R3 800Written and edited by international leaders in the field, this book has, through two best-selling editions, beenthe place to turn for authoritative answers to your toughest challenges in clinical immunology. Now in full colorand one single volume, the 3rd edition brings you the very latest immunology knowledge - so you can offer yourpatients the best possible care. The user-friendly book and the fully searchable companion web site give youtwo ways to find the answers you need quickly...and regular online updates keep you absolutely current.Key features Leading international experts equip you with peerless advice and global best practices to enhance yourdiagnosis and management of a full range of immunologic problems. A highly clinical focus and an extremely practical organization expedite access to the answers you need inyour daily practice.New to this edition Cutting-edge coverage of the human genome project, immune-modifier drugs, and many other vital updateskeeps you at the forefront of your field. A new organization places scientific and clinical material side by side, to simplify your research and highlightthe clinical relevance of the topics covered. A multimedia format allows you to find information conveniently, both inside the exceptionally user-friendlybook and at the fully searchable companion web site. Regular updates online ensure that you'll always have the latest knowledge at your fingertips. Includes many new and improved illustrations and four colour design.Orders: Medical Book Seller, Tel Jackie: 083 303 8500, fax (021) 975-1970,E-mail: jackie@medbookseller.co.zaCurrent Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 7

APPROACH TO THE CHILD WITH RECURRENTINFECTIONS – PRESENTATION ANDINVESTIGATION OF PRIMARY IMMUNODEFICIENCYMonika Esser, MMed PaedClinical Immunology & Rheumatology Service,Immunology Unit, NHLS & Stellenbosch University,Department of Pathology, Tygerberg Academic HealthComplex, Tygerberg, South AfricaABSTRACTInfants and children, as part of normal developmentof immune competence, experience and survivemany infections – mostly subclinical – and a fairnumber of clinically apparent infectious illnesses.Mature immunity is generally achieved by the time achild reaches school age. An abnormal number andseverity of infections are the hallmarks of deficientimmunity.The commonest causes of immunodeficiencyworldwide are malnutrition, HIV and immunosuppressive-iatrogenicagents.Primary immunodeficiencies (PIDs), generally theresult of genetic defects, are rare conditions. Theseare suspected when a child or adult suffers fromrecurrent, prolonged, severe or unusual infectionswhich would not normally cause problems inotherwise healthy individuals.Early diagnosis of PID improves quality of life asmany PIDs are treatable. The related morbidity andmortality which inevitably accompanies a delayeddiagnosis can often be prevented. Unfortunatelydelayed diagnosis and its consequences are frequentlyseen in practice in South Africa.Algorithms for detecting PIDs exist for clinical andlaboratory investigations. Guidelines for patient managementare easily accessed via the Internet andantenatal diagnosis and genetic counselling arebecoming a reality. Gene transfer may offer hope forcures eventually.An overview of approach to history, clinical examinationand appropriate laboratory investigation forsuspected diagnosis of PID in children is presented.INTRODUCTIONWith the advent of the African AIDS pandemic the term‘immunodeficiency’ has gained new meaning. Some ofthe infection patterns seen as a result of HIV infectionare similar to those seen in the patient with PID.Cluster Differentiation – CD4 counts have becomecommon knowledge and medical staff are aware ofthe need for HIV testing in the patient with recurrentor unusual infections. But when HIV infection has beenexcluded, there is no evidence of malnutrition, allergieshave been addressed as possible causes, the child hasbeen taken out of the crèche, second-hand smokingCorrespondence: Dr M Esser, Immunology Unit, Department ofPathology, PO Box 19063, Tygerberg 7505, Cape Town, South Africa.Tel. 021-938-5228, fax 021-938-4005, e-mail monika@sun.ac.zahas been avoided and recurrent infections continue,the question of primary or inborn deficiencies as acause should arise. The majority of these present ininfancy with a 5:1 male over female predominancebecause of the X-linked inherited PIDs, but a largenumber are not recognised until adolescence or earlyadulthood.They may occur as frequently as 1/2 000 live births formilder defects 1 and even as frequently as 1/400 in thecase of IgA deficiencies which are asymptomatic in themajority of cases. There are currently more than 120PIDs with known genetic causes – the recent increasein classifications has been facilitated by the completionof the Human Genome Project in April of 2003.Accurate figures for prevalence in South Africa are notavailable but probably approach those quoted internationallyfor the well-recognised syndromes. Unusuallyhigh incidences of late complement deficiencies havehowever been reported by Orren et al. 2 for the Caperegion and other genetic immunodeficiencies particularto the Southern African region may yet be researched.Despite awareness about immunodeficiency related tothe HIV pandemic, the investigation of the child withrecurrent infections is still frequently delayed inSouth Africa, and if diagnosed correctly, is managed suboptimallyin many cases. Even in developed countriessuch as the UK diagnostic delays for antibody deficienciesof a median of 5.5 years in adults and 2.5 years inchildren have been shown. 3 Late diagnosis in this groupof patients is tragic as effective intravenous preparationsof gammaglobulin became available as early as 1980. 4Seamless monitoring is essential but follow-up is frequentlyinterrupted and suboptimal with transfer of theadolescent to the adult service – as happens to manyyoungsters with other chronic illnesses too.WHAT IS UNACCEPTABLE/ABNORMALFOR A CHILD IN TERMS OF RECURRENTINFECTIONS?Most doctors with some years of clinical experiencedevelop a good investigative threshold for this question.It is surprising therefore that the diagnosis of PID isoften equally if not more delayed in more affluentcommunities in South Africa. The easy access to broadspectrumantibiotics, nutritional support – even hyperalimentation,antireflux procedures and the practice ofchanging doctors if all else fails often mark the trail ofa late diagnosis in the face of good health care access.Neglect and lack of resources however may precipitatea more catastrophic course and paradoxically sometimesearlier investigation and diagnosis.Healthy young children may experience up to 6 upperrespiratory tract infections per year and even 10 ormore if exposed to day care, schoolgoing sibs or smoking.5 These infections should clear promptly and in thecase of bacterial infections they should respond rapidlyto antibiotics.While respiratory and gastrointestinal infections arecommon in immunodeficiency, skin infections such asulcerating BCG marks or with organisms such as8 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

Burkholderia cepacia may be serious warning signsof significant lack of cellular immunity or phagocytedysfunction respectively.Recurrent pneumococcal infections may signal lackof specific antibody or IRAK4 deficiency. The recurrenceof a pneumonia or pneumonia with anunusual/opportunistic organism such as Pneumocystiscarinii or infections with Giardia should beinvestigated.Recurrence of meningococcal meningitis should precipitateinvestigation for complement deficiencies.Deficient antibody responses especially to polysaccharideantigens may persist after infancy and result inrecurrent respiratory infections despite normal levelsof immunoglobulins.Recurrence of infection at one site obviously shouldalert to anatomical defects or obstructions.Recurrent fevers in an otherwise healthy child whereno pathogens can be documented and resolution isspontaneous may signify one of the periodic fever syndromeswhere maintenance treatment with colchicinein some variants may prevent onset of amyloidosis.More recently described defects of the interferongamma and interleukin 12, as well as the nuclear factorkappa B essential modulator (NEMO), pathways maypresent with disseminated mycobacterial andSalmonella infections. Patients with NEMO mutationsalso frequently have features of ectodermal dysplasiaof varying degrees such as conical teeth, sparse hairand decreased or absent sweat production.The Jeffrey Modell Foundation Medical AdvisoryBoard 6 has also developed a useful list of 10 warningsigns which include most of the above, as well as a relevantfamily history, and these should prompt immunologicalinvestigations.Contributing factors for recurrent infections in childhoodmust be excluded early on to prevent unnecessaryand costly investigation for PID:• Increased exposure including overcrowded housingand day care• Second-hand smoke• Atopy/asthma• Foreign body• Cystic fibrosis – incidence of about 1/2 500 in someCaucasian populations• Anatomical obstructions• Gastro-oesophageal reflux• Prematurity• Not having been breastfedMedical causes/associations for secondary oracquired immunodeficiency may mimic PID and mustbe investigated if appropriate:• Malnutrition• Infectious diseases – suspected HIV, Epstein Barrvirus, Mycobacterium tuberculosis, Cryptococcus• Malignancy• Immune suppressant treatment• Chronic inflammatory diseases such as systemiclupus erythematosus, rheumatoid arthritis• Protein loss• Chronic illness of organ systems• Asplenia, sickle cell diseaseHISTORYAfter review of the above factors and associations,specific questions are important which will guide theexamination and further investigation for PID:• History of age of onset of infections. These detailsare very important as severe combined deficienciesare likely to start in the first months of life, whereasantibody deficiencies may only become symptomaticin later childhood even in the virtual absence ofserum IgG. Passively transferred maternal antibodiesare detectable until 18 months of life in the infant'sserum and prolonged breastfeeding may protectagainst common pathogens. Although most patientswith PID will present in infancy or early childhoodbecause of the combined effects of immaturity andinborn deficiency of the immune system, deficienciesother than severe combined forms may even bediagnosed as late as mid-adulthood despite significantmorbidity.• Detailed perinatal history and history of the pregnancy• Pathogen history can point towards the broadgroup of defects in the immune defence: 7T cells – Pneumocystis carinii, mycobacteriae,Cryptococcus neoformans,herpes virusesB cells – Streptocccus pneumoniae, Haemophilusinfluenzae, Giardia lamblia,enteroviruses, staphylococci, CampylobactersppComplement – Neisseria sppPhagocytes – staphylococci, Aspergillus spp,Burkholderia cepaciaBecause of the close co-operation between differentcomponents of the immune defence system these categoriesand divisions are artificial and serve as guidelinesonly. Overlap of functions also termed immunologicalredundancy can further obscure a specific susceptibility.Comprehensive practice parameters, classificationsand algorithms are available for these specificdefects. 8-10• History for hallmark special features• Severe eczema and peticheae of Wiskott-Aldrichsyndrome• Delayed umbilical stump separation of leukocyteadhesion defect (although rarely observed in clinicalpractice) or poor wound healing• Postvaccination disseminated BCG or paralyticpolio in T-cell or B-cell disorders• Hypocalcaemic tetany of the neonate in DiGeorgeanomaly• Graft-versus-host disease caused by maternalengraftment or non-irradiated blood transfusion inT-cell defects• Arthritis which does not fit the defined categoriesof juvenile idiopathic arthritis (JIA) in agammaglobulinaemia(but also in aquired immunodeficiencysyndrome)• Autoimmunity of B-cell-related disorders or earlycomplement component deficiencies• Generalised molluscum contagiosum or extensivewarts of T-cell disorders• Dysplastic features (Fig. 1)• History of the family• Unexplained death in infancy or recurrent infectionhistory in maternal male relatives may be a clue toX-linked immunodeficiency where the mother isa carrier of the condition (Fig. 2).• A history of autoimmunity in family members maybe positive for the patient with common variableimmunodeficiency or IgA deficiency.• It is important to remember that a negative familyCurrent Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 9

the presence of chronic infections may alert toX-linked agammaglobulinaemia with inability to formimmunoglobulins due to absence of B cells.• Respiratory and ENT exams frequently reveal evidenceof scarred or perforated tympanic membraneswith purulent discharge and bronchiectasis mayalready be established• GIT examination may show hepatosplenomegalydue to chronic immune activation or hepatomegalywith or without jaundice as part of T-cell disordersand intrahepatic chronic infections.• Neurological exam should be evaluated particularlyin the presence of telangiectasia – although ataxiaand immunodeficiency can also occur without thehallmark ocular findings (Fig. 3).Fig. 1. Dysplasia and immunodeficiency – dysplasticteeth.history does not exclude PID which can also bedue to new mutations.• In South African practice adequacy and accuracyof the history must be evaluated critically in thecontext of multiple caretakers of the extendedfamily and language differences.EXAMINATIONA thorough physical examination of these childrenrequires additional time and a normal exam does notexclude significant immune defects. Exposure to thepathogen to which the patient is unduly susceptiblemay not have occurred yet, a protected environmentmay have limited exposure to pathogens and breastfeedingmay have aided in defence against infectionearly in life. The anxious and worried parents shouldnever be ignored, as they see their child for much moretime than the usual consultation and they are mostlyjustified in their concerns.• General appearance gives many clues to the alertmedical practitioner or nurse, especially with featuresof chronic illness such as pallor, wasting, clubbingand especially listlessness for which there is noother obvious explanation.• Detailed weight and height mapping and longitudinalanalysis give important information for onset ofillness and response to intervention.• Skin and mucosal features as mentioned abovemay be visible, and scarring from chronic infectionsor disseminated Varicella may alert to PID.• Dysmorphic features of DiGeorge anomaly withmicrognathia or those of trisomy 21 may be apparent.• Absence of lymphoid including tonsillar tissue inFig. 2. X-linked agammaglobulinaemia – family tree (SPienaar).Fig. 3. Ocular telangiectasia.LABORATORY EXAMINATIONSelective laboratory investigations are available atreferral centres of major hospitals in South Africa forassessment of a child who has been identified for furtherinvestigation after the above history and examinationapproach.The investigations where possible should be discussedwith the relevant immunology or general laboratories inconsultation with a pathologist/immunologist/infectiousdisease specialist to arrive at a correct diagnosisfor appropriate treatment.A modified approach of the guidelines as proposed bythe Jeffrey Modell Foundation 6 (© 2003 JeffreyModell Foundation) for PID investigation suitable forSouth Africa will result in sensible laboratory investigation.The adapted model of screening in bold also allowsfor the high prevalence of HIV/AIDS, tuberculosis andmalnutrition in South Africa.Stage 1Initial laboratory screen• Full blood count and differential count• IgG,M,A including IgE• HIV screenWhere indicated a sweat test for cystic fibrosis (Fig. 4),a Mantoux test and chest X-ray to exclude tuberculosisare performed. The Mantoux test and whereavailable trychophyton and Candida skin tests can beused to document presence of delayed-type hypersensitivity.Stage 2Where B-cell-related deficiencies are suspected a specificantibody response to universal vaccination withtetanus, diptheria and pertussis protein antigens is performed.10 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

Fig. 4. Sweat test.Stage 3Lymphocyte phenotyping is requested together withlymphocyte proliferation studies when not already testedin stage 2. Here one can further define lymphocytefunctional problems.The gold standard for lymphocyte proliferation measuresradioactive thymidine uptake of actively dividingcells upon stimulation with mitogens (or new flowmethod) phylo haemagglutinin A (PHA), Con A, proteinA and pokeweed and, where available, antigens(Candida).The patient’s clinical picture is taken into account whendeciding which further investigations to request, suchas neutrophil or other specialised lymphocyte investigations.Where chronic granulomatous disease is suspectedthe neutrophil burst test (flow cytometry) (Fig. 6) is indicated.Stage 4Access to highly specialised stage 4 investigationssuch as enzyme measurements, cytokine studies andgenetic investigations is limited in South Africa.Detailed complement fraction studies, Bruton’s tyrosinekinase (Btk) assays, neutrophil chemotactic/phagocytic assays, leukocyte adhesion studies andCD40 ligand screening are available at specialised laboratories.Following these steps of investigation the laboratoryguides the clinician to the early diagnosis of PID.Early screening in stages 1 and 2 is very cost-effectiveas it identifies most of the commoner antibody deficiencies.An algorithm for suspected antibody deficit is presentedin Figure 7.Fig 5. Complement C6 deficiency.A response to conjugate pneumococcal vaccine or topolyvalent pneumococcal (pure polysaccharide response)vaccine in older children may also be used as afurther screen of antibody production after vaccination.Haemophilus influenzae to b (Hib) vaccine responsecan also be used as a screen for conjugate vaccineresponse.Where appropriate, lymphocyte phenotyping isrequested in stage 2.CD3 (total T cells)CD4 (helper T cells)CD8 (suppressor T cells)CD19 (B cell)CD16 + 56 (NK cell)IgG subclass analysis can be used inselected patients to differentiate deficienciesand to delineate subclassdeficiencies if antibody responses aredefective. Practically these have beenRsuperseded by the antibody responseswhich yield better results for func-0 200 400 600 800 1000FSC-Htional and treatment implications.A total complement screen functionalFile: Data .004evaluation on ice is also included at anSample ID: monika ecoliearlier stage where patients are fromTube: Untitleddistant referral hospitals. More extensiveinvestigations at the initial visit aimX Parameter: FL1-H (Log)Acquisition Date: 21-Feb-06Gated Events: 12379to contain costs of repeat visits.Where certain indicator diseases arepresent (e.g. recurrent Neisserial10infections, indicative of C6 deficiency0 10 1 10 2 10 3 10 4FL1-H(Fig. 5)) complement fractions arerequested.Fig. 6. Neutrophil burst response flow cytometer.Counts SSC-410 40 80 120 160 200 0 200 400 600 800 1000SUMMARYThe above guidelines for history, examination and astructured approach to laboratory investigations shouldbe followed, including baseline:• full blood count and differential count• serum immunoglobulin isotypes• specific antibody studies and T- and B-cell phenotypesData .004 Data .004Counts0 30 60 90 120 150R510 0 10 1 10 2 10 3 10 4FL2-HHistogren StatisticsLog Date Units: Linear ValuesPatient ID: kontrolePanel: Untitled Acquisition Tube LisGate: G5Total Events: 15000Marker Left Right Events % Gated % Total Mean Geo MeanAll 1, 9910 12379 100.00 82.53 196.84 56.79M1 42, 9910 8021 64.80 53.47 299.98 220.11Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 11

Recurrent URTI, OM+/– pneumonia orsystemic infections➞Ig levels normal ➞ B-cell number (N) and antibodies (N). Considerother immune defects and cystic fibrosis or ciliarydyskinesia➞ B-cell number (N) but antibodies deficient:selective/antibody deficiencydeficient ➞ B-cell number (N) common variableimmunodeficiency (CVID), CD40 ligand deficiencywith (N) or IgM➞ B cells absent (CD19–,CD20–): X-linkedagammaglobulinaemialow/normal ➞ B cells and specific antibody test normal:possible transient hypogammaglobulinaemia ofinfancy, malabsorption➞URTI – upper respiratory tract infection, OM – otitis mediaFig. 7. Algorithm for recurrent infections with serum immunoglobulin (SeIg) evaluation if antibody deficit is suspected.• when indicated a total complement screen and• neutrophil burst testwill diagnose the majority of the commoner immunodeficienciessuch as the antibody deficiencies, thecomplement disorders and chronic granulomatousdiseaseWhen this outline is followed, most children with PIDsshould be diagnosed adequately enough to decide on adysfunctional category and, very important, to decideon an appropriate treatment plan.Because of the diversity of immune defects and theclinical overlap with the immune competent host,where conditions which occur in immunodeficientpatients are also common in patients with normalimmune systems some clinicians use scoring systemsfor diagnosis of PID. 10Accurate diagnosis is crucial as an incorrect diagnosismay lead to high-risk interventions such as bone marrowtransplants or years of unnecessary and costlytreatment. 11For the diagnosed child the empowerment of theparent with information regarding their child'simmunodeficiency and follow-up is probably one of themost important predictors for better outcome in countrieswith low level of awareness for rare diseases.Support organisations such as PINSA (PrimaryImmunodeficiency Network South Africa) and nationalregistries further assist in creating awareness and supportstrategies with statistics.Other useful contacts include:For immunoglobulin replacement – NationalBioproducts Information Centre – www.nbi-kzn.org.zaFor immunology case histories – Immunopaedia –www.immunopaedia.org.zaDeclaration of conflict of interestThe author declares no conflict of interest.REFERENCES1. Verbsky JW, Grossman WJ. Cellular and genetic basis of primaryimmune deficiencies. Pediatr Clin N Am 2006; 53: 649-684.2. Orren A, Potter PC. Complement component C6 deficiency andsusceptibility to Neisseria meningitidis infections. S Afr Med J2004; 94: 345-346.3. Seymour B, Miles J, Haeney M. Primary antibody deficiency anddiagnostic delay. J Clin Pathol 2005; 58: 546-547.4. Ballow M. Primary immunodeficiency disorders: antibody deficiency.J Allergy Clin Immunol 2002; 109: 581-591.5. Woroniecka M, Ballow M. Office evaluation of children with recurrentinfection. Primary Immune Deficiencies: Presentation,Diagnosis and Management 2000; 47: 1211-1225.6. Jeffrey Modell Foundation Medical Advisory Board. 10 warningsigns of primary immunodeficiency diseases. 4 stages of primaryimmunodeficiency diseases. (Available at: http://www.info4pi.org.Accessed 24 January 2008.)7. Bonilla FA, Bernstein IL, Khan DA, et al. Practice parameter for thediagnosis and management of primary immunodeficiency. AnnAllergy Asthma Immunol 2005; 94: S1-S63.8. Notarangelo L, Casanova J-L, Fischer A, et al. Primary immunodeficiencydiseases: an update. J Allergy Clin Immunol 2004; 114:677-687.9. De Vries E. Patient-centred screening for primary immunodeficiency:a multi-stage diagnostic protocol designed for non-immunologists.Clin Exp Immunol 2006; 145: 204-214.10. Yarmohammadi H, Estrella L, Doucette J, Cunningham-Rundles C.Recognizing primary immune deficiency in clinical practice. ClinVaccine Immunol 2006; 13: 329-332.11. Buckley RH. Primary immunodeficiency or not? Making the correctdiagnosis. J Allergy Clin Immunol 2006; 117: 756-758.12 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

AN UPDATE OF THE PRIMARY ANTIBODYDISORDERSBrian Eley, MB ChB, FCPaed (SA), BSc Hons (MedBiochem)School of Child and Adolescent Health, University ofCape Town and Red Cross Children’s Hospital,Rondebosch, South AfricaABSTRACTMore than 200 primary immunodeficiency diseases(PIDs) have been described and the molecular basisof more than 120 characterised. Primary antibodydeficiencies are the most common group.Approximately 50% of patients with PIDs have aprimary antibody deficiency, and at least 80% of allprimary antibody deficiencies are due to four conditions,namely, transient hypogammaglobulinaemiaof infancy, IgG subclass deficiency, partial antibodydeficiency with impaired polysaccharide responsivenessand selective IgA deficiency (SIgAD). Many primaryantibody deficiencies either cause arrest duringearly B-lymphocyte development or impede theterminal differentiation of B lymphocytes. Severalgene mutations including Bruton’s tyrosine kinase(Btk) deficiency, µ heavy chain deficiency, λ5 deficiency,Igα deficiency and Igβ deficiency may causearrest in early development. The molecular analysisof common variable immunodeficiency (CVID) hasgained momentum. Mutations in genes encodinginducible T-cell costimulator, CD19, B-cell-activatingfactor receptor, transmembrane activator, calciummodulatingcyclophilin-ligand interactor, and thehomolog of Escherichia coli MutS have been associatedwith CVID. Genetic research has suggestedthat CVID and SIgAD are related conditions.However, significant immunological differencesbetween the two conditions exist. These observationsshould influence future CVID- and SIgAD-relatedresearch. The current classification of primaryantibody deficiencies is discussed, and recent publicationson clinical presentation and approach todiagnosis are reviewed.Correspondence: Prof B Eley, Red Cross Children's Hospital,Klipfontein Rd, Rondebosch, 7701. Tel 021-658-5111, fax 021-689-1287, e-mail Brian.Eley@uct.ac.zaINTRODUCTIONThe classic primary immunodeficiency diseases (PIDs)are relatively rare, occurring with a frequency of 1:500to 1:500 000 in the general population. 1 More than 200PIDs have been described and the molecular bases ofmore than 120 have been characterised. 2 Primary antibodydeficiencies as a group represent the most commontype of PIDs in humans. They are a heterogenousgroup of disorders in which the defining characteristicis the inability to produce an effective antibodyresponse to a pathogen. Most antibody deficiencieshave been associated with single gene mutations causingdefects in the development and function of B lymphocytes.However, some may result from environmentaltriggering in genetically predisposed individualsand a few are caused by delayed immunological maturation.3 More than 80% of confirmed antibody deficienciesthat are listed in national registries are due tofour antibody deficiencies, namely transient hypogammaglobulinaemiaof infancy, isolated IgG subclass deficiency,partial antibody deficiency with impaired polysaccharideresponsiveness and selective IgA deficiency.4 This paper reviews aspects of the primary antibodydeficiencies, particularly recent developments in thepublished literature with regard to their classification,pathogenesis, presentation and treatment.B-CELL DEVELOPMENTCharacterisation of the molecular events which directthe sequential development of lymphocytes has aidedthe elucidation of the pathogenesis of many primaryantibody deficiencies. Studies of naturally occurringmutations and molecularly engineered mouse modelshave benefited this work. 5 Haemapoeitic stem cellspass through several developmental stages beforemature B lymphocytes are produced. Development primarilyoccurs in the bone marrow compartment.Mutations in genes encoding proteins that are criticalfor the development of the B-lymphocyte lineage, particularlybetween the pro-B-cell and immature B-cellstages, may disrupt B-lymphocyte maturation leadingto partial or complete developmental arrest withdecreased B-lymphocyte number and profoundlyreduced immunoglobulin isotype (IgA, IgM, IgG, IgD,IgE) concentrations. By contrast, mutations in keygenes encoding proteins that regulate terminal differentiationand function of mature B lymphocytes mayresult in reduced immunoglobulin isotype concentrationsusually without a change in B-lymphocyte number(Fig. 1). 2,5,6PRIMARY ANTIBODY DISORDERSThe International Union of Immunological SocietiesPrimary Immunodeficiency Diseases ClassificationCommittee recently published an updated classificationof all known PIDs. The classification of the primary antibodydeficiencies has undergone several revisionssince 1990 as a result of the molecular advances. Sixcategories have been defined (Table I). 7Btk deficiency and related conditionsOne of the significant advances in recent times wasthe elucidation of deficiencies associated with thearrest of early B-lymphocyte development. Bruton'styrosine kinase (Btk) deficiency or X-linked or agammaglobulinaemia,an X-linked recessive condition, was thefirst antibody deficiency to be recognised in 1952. 8 Themolecular defect in Btk deficiency was described in1993. 9 Although Btk is expressed during all stages ofB-lymphocyte development except for plasma cells,deficiency causes arrest at the pre-B-cell stage. Thismay be detected on bone marrow analysis (Fig. 1). Btkdeficiency is fully penetrant, only males are affectedand the condition exhibits considerable clinical heterogeneity.However, the majority of patients are diagnosedbefore the age of 5 years. 10 Recently, the mutationof a large family with Btk deficiency in Cape Townwas characterised. 11 About 85% of patients with earlyonsetinfections, profound hypogammaglobulinaemiaand markedly reduced B-lymphocyte number, have BtkCurrent Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 13

IgαIgβIgµλ5BLNKBtkCD40LCD40AIDUNGIKK-γCVIDICOSCD19TACIMsh5BAFFRPlasma cellpro-B cellpre-B cellImmatureB cellMatureB cellMatureB cellIgM+IgM+ IgD+IgG, IgA or IgECommonlymphoidprecursorMemoryB cellHaematopoieticstem cellFig. 1. B-lymphocyte development and associated primary antibody deficiencies. Igα, Igβ, µ heavy chain (Igµ), λ5,B-cell linker protein (BLNK) and Bruton's tyrosine kinase (Btk) deficiencies affect early B-lymphocyte development.Deficiencies affecting terminal B-lymphocyte function include inhibitor-of-nuclear-factor-κB kinase (IKK-γ), conditionscausing hyper-IgM syndrome (CD40 and CD40 ligand (CD40L)), activation-induced cytidine deaminase (AID)and uracil-DNA glycosylase (UNG) deficiencies), and disorders associated with common variable immunodeficiency(CVID) including inducible costimulator (ICOS), CD19, transmembrane activator and calcium-modulatingcyclophilin-ligand interactor (TACI), homolog of Escherichia coli MutS (Msh5), and possibly B-cell-activating-factorreceptor (BAFFR).deficiency. Deficiencies of several components of thepre-B-cell receptor complex may also cause this phenotype,including mutations in the genes encoding µheavy chain, λ5 and Igα and Igβ . In addition, mutationsin the gene encoding the scaffold protein, B-cell linkerprotein (BLNK); may produce a similar phenotype.Unlike Btk deficiency all of these deficiencies are transmittedby autosomal recessive inheritance. 12-15Hyper-IgM syndromesDuring a primary infection, antigen binds to B lymphocytes,displaying cell-surface-bound IgM. Thereafter, BTable I. Current classification of primary antibody deficienciesI. Severe reduction in all serum immunoglobulin isotypes with profoundly reduced or absent B lymphocytes.Bruton’s tyrosine kinase (Btk) deficiencyµ heavy chain deficiencyλ5 deficiencyIgα deficiencyIgβ deficiencyB-cell linker protein (BLNK) deficiencyThymoma with immunodeficiencyMyelodysplasiaII.Severe reduction in serum IgG and IgA with normal, low or very low numbers of B cellsCommon variable immunodeficiency disorders (Mutations in transmembrane activator and calcium-modulatingcyclophilin – ligand interactor (TACI), B-cell-activating-factor receptor (BAFFR) and Msh5 may act as contributing polymorphisms)Inducible costimulator (ICOS) deficiencyCD19 deficiencyX-linked lymphoproliferative syndromeIII. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cellsCD40 ligand deficiencyCD40 deficiencyActivation-induced cytidine deaminase deficiencyUracil-DNA glycosylase (UNG) deficiencyIV. Isotype or light chain deficiencies with normal numbers of B cellsIg heavy chain deletionsκ chain deficiencyIsolated IgG subclass deficiencyIgA deficiency associated with IgG subclass deficiencySelective IgA deficiencyV. Specific antibody deficiency with normal immunoglobulin concentrations and normal numbers of B cellsVI. Transient hypogammaglobulinaemia of infancy with normal numbers of B cells14 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

lymphocytes refine the primary antibody repertoiregenerating a highly specific antibody response. Twomechanisms, class switching and somatic hypermutationare involved in antibody refinement. These mechanismsare T-lymphocyte dependent and take place inthe germinal centres of secondary lymphoid organs. 16Hyper-IgM (HIGM) syndromes are a group of conditionscharacterised by impaired immunoglobulin classswitching and somatic hypermutation. Patients withthese syndromes have an increased susceptibility tobacterial infection, normal numbers of peripheralB lymphocytes but low memory B lymphocytes(CD27+ B lymphocytes), normal or increased IgM, andlow or absent levels of IgA, IgG and IgE. In addition,there is increased susceptibility to Pneumocystisjeroveci pneumonia, and chronic diarrhoea and ascendingcholangitis caused by Cryptosporidium. 17The X-linked form of HIGM was characterised in 1993.It is due to mutations in the CD40 ligand (CD40L) gene.CD40L is expressed on T lymphocytes, and signallingvia CD40 triggers terminal B lymphocyte differentiationby class switching and somatic hypermutation. CD40Ldeficiency is responsible for approximately two-thirdsof cases of HIGM. 16 In 2003 the first South African kindredwith X-linked HIGM was fully characterised. 18Autosomal recessive forms of the HIGM, CD40L deficiency,activation-induced cytidine deaminase (AID)deficiency and uracil-DNA glycosylase (UNG) deficiencyhave been described. Another form of HIGM associatedwith anhydrotic ectodermal dysplasis is causedby mutations in the gene that encodes inhibitor-ofnuclear-factor-κBkinase-γ (IKK-γ). 19 Approximately 25%of patients with the HIGM phenotype have normalexpression of CD40L, CD40, AID and UNG. Researchtowards defining the molecular basis of this group ofpatients is ongoing. 16Common variable immunodeficiencyCommon variable immunodeficiency (CVID) is a heterogenousgroup of diseases associated withhypogammaglobulinaemia. In most cases inheritanceis sporadic. Males and females are equally affected.The peak incidence occurs during the second and thirddecades of life. 20 T-lymphocyte proliferation followingmitogen stimulation is impaired in 40% of patients withCVID and is directly associated with serum levels ofIgG. 21 Criteria for diagnosing CVID have been publishedby the European Society for Immunodeficiencies(ESID) (Table II). 22 During the last 10 years several genedefects have been identified in patients with the CVIDphenotype. Mutations in the Btk gene, and the X-linkedlymphoproliferative disease gene, SH2DIA may infrequentlybe associated with the CVID phenotype. 23-24More recently CVID has been associated with fouradditional monogenic defects: inducible T-cell costimulator(ICOS), CD19, transmembrane activator and calcium-modulatingcyclophilin-ligand interactor (TACI),and the homolog of Escherichia coli MutS (Msh5), amismatch repair protein. All four proteins are involvedwith terminal B-lymphocyte differentiation, includingthe regulation of class-switching and B-lymphocytememory generation. 25-29 A search for mutations in thegene encoding B-cell-activating-factor receptor(BAFFR) yielded a defect in one adult patient withhypogammaglobulinaemia. 30 These recent findingssuggest that the elucidation of the molecular eventsunderpinning terminal B-lymphocyte differentiationmay help to clarify CVID.Selective IgA deficiencySelective IgA deficiency (SIgAD) is the most commonPID, with a prevalence of 1:400 to 1:3 000 in healthyblood donors. 21 The condition is asymptomatic in mostindividuals. However, there is an association withrecurrent, mainly sinopulmonary infection, gastrointestinaldiseases, atopy, autoimmune disease andother diseases. Patients with severe infections are likelyto have an associated IgG subclass deficiency. 31 TheESID criteria for diagnosing SIgAD are listed in TableII. 22 The condition is probably caused by defective dif-Table II. Diagnostic criteria for common variable immunodeficiency (CVID) and selective IgA deficiency (SIgAD)I. CVIDProbableMale or female patient with marked decrease of IgG (at least 2 SD below the mean for age) and a marked decrease in atleast one of the isotypes IgM or IgA, and fulfills all of the following criteria:1. Onset of immunodeficiency at greater than 2 years of age2. Absent isohaemagglutinins and/or poor response to vaccines3. Defined causes of hypogammaglobulinaemia have been excludedPossibleMale or female patient with marked decrease (at least 2 SD below the mean for age) in at least one of the major isotypes(IgM, IgG and IgA) and fulfills all of the following criteria:1. Onset of immunodeficiency at greater than 2 years of age2. Absent isohaemagglutinins and/or poor response to vaccines3. Defined causes of hypogammaglobulinaemia have been excludedII. SIgADIgA deficiencyDefinitiveMale or female patient older than 4 years of age who has a serum IgA < 0.07 g/l but normal serum IgG and IgM, in whomother causes of hypogammaglobulinaemia have been excluded. These patients have a normal IgG antibody response tovaccination.ProbableMale or female patient older than 4 years of age who has a serum IgA at least 2 SD below normal for age but normalserum IgG and IgM, in whom other causes of hypogammaglobulinaemia have been excluded. These patients have a normalIgG antibody response to vaccination.Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 15

ferentiation of B lymphocytes to IgA-secreting plasmacells, as a result of disablement of isotype class switching.Familial studies suggest an allelic relationshipbetween SIgAD and CVID. 32 Mutations in the genesencoding TACI and Msh5 have been identified inpatients with SIgAD, further supporting the linkbetween SIgAD and CVID. 28,29 However, T- and B-lymphocytesubpopulations and activation/differentiationmarkers differ significantly between the two conditions.With the exception of abnormalities in the numbersof CD4+ and CD8+ lymphocytes, no major abnormalitieswere observed in patients with SIgAD. 33Despite the genetic overlap, these immunological differencesrequire molecular elucidation.Transient hypogammaglobulinaemia ofinfancyDuring intrauterine life maternal IgG is actively transferredto the fetus. At birth, the IgG concentration ofterm infants is equal to or greater than maternal IgGconcentration. Because most IgG is transferred duringthe second half of intrauterine life, preterm infants havea lower IgG concentration at birth. Maternal IgG in theinfant disappears after birth with a half-life of 25-30days, and intrinsic IgG production usually begins immediatelyafter birth. 34 In transient hypogammaglobulinaemiaof infancy, intrinsic immunoglobulin productionis delayed for up to 36 months, resulting in low IgG andIgA concentrations, but IgM concentration may be normalor low. Consequently, the physiological IgG nadirbetween 3 and 6 months of life is exaggerated and prolonged.35-37 Delayed production results in increasedsusceptibility to sinopulmonary infections. It is usually aself-limiting disease. In the majority of patientsimmunoglobulin concentrations normalise between 2and 4 years of age. 36,37 Long-term follow-up and re-evaluationof immunoglobulin responses are required toexclude other primary antibody disorders. 35Isolated IgG subclass deficiencyThis condition is characterised by decreased concentrationof one or more IgG subclass. The laboratorymethods for determining IgG subclass concentrationshave not been adequately standardised and age-relatedpopulation norms are not always available, creatingdiagnostic uncertainty. Low levels of IgG2 are frequentin children, particularly in association with poorresponses to polysaccharide antigens. IgG4 levels varywidely and many completely healthy people have nodemonstrable IgG4 on standard testing. Therefore isolatedIgG4 is difficult to interpret. Isolated IgG subclassdeficiency is usually asymptomatic but may be associatedwith recurrent viral/bacterial infections, frequentlyinvolving the respiratory tract. 7,34,35Specific antibody deficiency with normalimmunoglobulin concentrationFailure to respond to polysaccharide antigens, an IgG2subclass response, is a feature of specific antibodydeficiency. This results in recurrent or persistentsinopulmonary infections. Immunisation with conjugatepolysaccharide vaccines induces IgG1 and IgG3subclass responses thereby providing immunologicalprotection against recurrent infections. 7,34,35CLINICAL MANIFESTATIONSFailure to recognise PIDs early and to implementappropriate treatment can lead to serious morbidity andearly mortality. Because of the rarity of these conditions,awareness outside immunology circles is low,often resulting in a delay in diagnosis. A review of 93children diagnosed with PIDs at Red Cross Children'sHospital over a 14-year period showed that only 16%were diagnosed during the first year of life, 44% presentedbetween 1 and 5 years of age, 37% between 5and 16 years and 3% were more than 16 years old atthe time of diagnosis. 38 Primary antibody deficienciesbegin to manifest with recurrent bacterial infectionfrom 4-6 months of age, in parallel with the physiologicaldecline in maternally acquired IgG. Delayed recognitionleads to infective and non-infective complications.3History is the most important aspect of clinical evaluation.Patients at any age with recurrent infection, especiallyinvolving the upper and lower respiratory tracts,where the frequency and/or severity is atypical shouldbe considered for investigation for a primary antibodydeficiency. Children may in addition present with feverof unknown origin, failure to thrive and poor schoolattendance, related to recurrent infections. In SouthAfrica, socioeconomic factors such as overcrowding,malnutrition, aeropollutants including cigarette smokeand exposure to open fires, and HIV infection are morefrequently associated with recurrent infection. 39 Arecent systematic review provided clear insights intothe clinical manifestations and complications of the primaryantibody deficiencies. Recurrent respiratory andsinus infection occurred in as many as 90% and 98%of patients respectively in published cohorts (Table III).Primary antibody deficiencies are commonly associatedwith bacterial infection. However, infection due toenteroviruses, Cryptosporidium and Giardia speciesmay occur (Table IV). 3,35,40Patients may present with clinical manifestations otherthan recurrent infection. Many patients with CVIDdevelop autoimmune problems. Abnormal lymphoid tissueincluding nodular lymphoid hyperplasia of the gutwall or congenital absence of tonsils, hepatosplenomegaly,isolated splenomegaly, athropathy,atopic eczema, haematological complications or organspecificautoimmune diseases may be the initial presentation.3,40 Autoimmunity often results from theinability of the host to eradicate microbial pathogens.The resultant chronic inflammatory response damagesthe surrounding tissue. Thus autoimmunity is not associatedwith a breakdown of self-tolerance. Instead, tissuedamage occurs as the host tries to clear foreignimmunogens. Autoimmunity is associated with CVID,isolated IgA deficiency and HIGM syndromes. T-lymphocytedysregulation may contribute to the observedautoimmunity. 41The clinical presentation of conditions causing HIGMsyndrome is dependent on the underlying geneticabnormality. Patients with CD40L deficiency, usuallymanifest with severe bacterial infections during infancy.Respiratory infections are common and up to 40%of patients develop P. jeroveci pneumonia. Diarrhoeaoccurs in more than 50% of patients and the majorityfollow a chronic course. Cryptosporidium causeschronic diarrhoea and ascending cholangitis. A wideTable III. Presenting infections in patients with primaryantibody deficienciesRespiratory/chest infections 37-90%Recurrent sinus infections 19-98%Gastrointestinal infections 6-38%Cutaneous infections 1-13%CNS/meningitis 2-9%Septic arthritis/osteomyelitis 1-7%Opthalmic infections 1.4-10%16 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

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

e-evaluation of serum immunoglobulin concentrationssince hypogammaglobulinaemia may be transient andresolve spontaneously. 45,46IVIG is not indicated in IgA deficiency. In patients withIgA deficiency, transient hypogammaglobulinaemia ofinfancy or isolated IgG subclass deficiency plus recurrentinfections, prophylactic antibiotics may be administered,using amoxicillin (twice daily) or azithromycin(weekly). In transient hypogammaglobulinaemia ofinfancy IVIG replacement may be used in children withsevere, recurrent infections until immunoglobulin productionnormalises. Patients with isolated IgG subclassdeficiencies account for the greatest misuse of IVIG.Immunoglobulin therapy should be used for a minorityof patients who are unable to produce specific antibodyand continue to experience recurrent infectionsdespite prophylactic antibiotics. 35,39,40The treatment of HIGM syndromes includes theadministration of IVIG. In patients with X-linked HIGM,IVIG does not prevent the development of sclerosingcholangitis and malignancy. 17 Alternative therapieshave been employed successfully including granulocyte-colony-stimulatingfactor for neutropenia, allogenicbone marrow transplantation (BMT) or cord blood celltransplantation to cure X-linked HIGM, and combinedBMT and liver transplantation to addressX-linked HIGM complicated by end-stage liver failure.17,47-50 Similarly, X-linked lymphoproliferative syndromehas been treated with IVIG and BMT. 43OUTCOMEInadequate diagnosis or suboptimal treatment placesthe patient at risk of recurrent infections, organ-specificcomplications and early mortality. Recurrent respiratoryinfections may lead to bronchiectasis and end-stagelung disease with cor pulmonale and respiratory failure.Abnormal lung functions, usually an obstructive pattern,have been reported to be more common in CVIDthan in Btk deficiency. Lung functions should be monitoredregularly to ensure that IVIG replacement is optimisedto prevent these complications. 3,40Gastrointestinal disorders occur in 20-47% of patientswith primary antibody deficiencies. 3 Hepatic complicationsmay occur as a result of specific viral infectionssuch as hepatitis C and primary biliary cirrhosis, oftenassociated with Cryptosporidium parvum infection. InX-linked HIGM this invariably leads to end-stage liverfailure. 50 Primary antibody deficiencies are associatedwith an increased risk for malignancy, varying from 1.8-to 13-fold. Lymphoreticular malignancies, particularlynon-Hodgkin's lymphomas are most frequent. Othercomplications include disability arising from meningitis,neurodegeneration and autoimmune phenomena. 3,40Despite these problems many well-managed patientsrespond to appropriate treatment resulting in improvedlife expectancy and decreased infectious complications.In conclusion, many primary antibody deficiencies havebeen comprehensively characterised. The increasedknowledge has impacted favourably on treatment andlong-term prognosis.Declaration of conflict of interestThe author declares no conflict of interest.REFERENCES1. De Vries E, for the Clinical Working Party of the European Societyfor Immunodeficiencies (ESID). Patient-centred screening for primaryimmunodeficiency: a multi-stage diagnostic protocol for nonimmunologists.Clin Exp Immunol 2006; 145: 204-214.2. Maródi L, Notarangelo LD. Immunological and genetic bases ofnew primary immunodeficiencies. Nat Rev Immunol 2007; 7: 851-861.3. Wood P, Stanworth S, Burton J, et al. Recognition, clinical diagnosisand management of patients with primary antibody deficiencies:a systematic review. Clin Exp Immunol 2007; 149; 410-423.4. Stiehm RE. The four most common pediatric immunodeficiencies.Adv Exp Med Biol 2007; 601: 15-26.5. Fischer A, Malissen B. Natural and engineered disorders of lymphocytedevelopment. Science 1998; 280: 237-243.6. Cunningham-Rundles C, Ponda PP. Molecular defects in T- and B-cell primary immunodeficiency diseases. Nat Rev Immunol 2005;5: 880-892.7. Geha RS, Notarangelo LD, Casanova J, et al. Workshp summary.Primary immunodeficiency diseases: an update from theInternational Union of Immunological Societies Primary ImmunodeficiencyDiseases Classification Committee. J Allergy ClinImmunol 2007; 120: 776-794.8. Bruton OC. Agammaglobulinaemia. Pediatrics 1952; 9: 722-728.9. Vetrie D, Vorechovsky I, Sideras P, et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosinekinases. Nature 1993; 361: 226-233.10. Conley ME, Broides A, Hernandez-Trujillo V, et al. Genetic analysisof patients with defects in early B-cell development. Immunol Rev2005; 203: 216-234.11. Pienaar S, Eley B, Beatty D, Henderson HE. X-linked agammaglobulinaemiaand the underlying genetics in two kindreds. J PaediatrChild Health 2000; 36: 453-456.12. Conley ME. Early defects in B cell development. Curr Opin AllergyClin Immunol 2002; 2: 517-522.13. Ferrari S, Lougaris V, Caraffi S, et al. Mutations of the Igbeta genecause agammaglobulinemia in man. J Exp Med 2007; 204: 2047-2051.14. Dobbs AK, Yang T, Farmer D, Kager L, Parolini O, Conley ME.Cutting edge: a hypomorphic mutation in Igbeta (CD79b) in apatient with immunodeficiency and a leaky defect in B cell development.J Immunol 2007; 179: 2055-2059.15. Minegishi Y, Rohrer J, Coustan-Smith E, et al. An essential role forBLNK in human B cell development. Science 1999; 286: 1954-1957.16. Etzioni A, Ochs HD. The hyper-IgM syndrome – an evolving story.Pediatr Res 2004; 56: 519-525.17. Levy J, Espanol-Boren T, Thomas C, et al. Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr 1997; 131: 47-54.18. Pienaar S, Eley BS, Hughes J, Henderson HE. X-linked hyper IgM(HIGM1) in an African kindred: the first report from South Africa.BMC Pediatr 2003; 3: 12. http//:www.biomedcentral.com/1471-2431/3/12.19. Jain A, Ma CA, Liu S, Brown M, Cohen J, Strober W. Specific missensemutations in NEMO result in hyper-IgM syndrome withhypohydrotic ectodermal dysplasia. Nat Immunol 2001; 2: 223-228.20. Salzar U, Grimbacher B. Update on common variable immunodeficiency(CVID). ESID Newsletter 2004; 3: 17-23.21. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency:clinical and immunological features of 284 patients. ClinImmunol 1999; 92: 34-48.22. European Society for Immunodeficiency. Diagnostic criteria forPID. http//:www.esid.org (last accessed: 14 November 2007.)23. Weston SA, Prasad ML, Mulligghan CG, Chapel H, Benson EM.Assessment of male CVID patients for mutations in the Btk gene:how many have been misdiagnosed? Clin Exp Immunol 2001; 124:465-469.24. Eastwood D, Gilmour KC, Nistala K, et al. Prevalence of SAP genedefects in male patients diagnosed with common variable immunodeficiency.Clin Exp Immunol 2004; 137: 584-588.25. Grimbacher B, Hutloff A, Schlesier M, et al. Homozygous loss ofICOS is associated with adult-onset common variable immunodeficiency.Nat Immunol 2003; 4: 261-268.26. Van Zelm MC, Reisli I, van der Burg M, et al. An antibody-deficiencysyndrome due to mutations in the CD19 gene. N Engl J Med2006; 354: 1901-1912.27. Salzar U, Chapel HM, Webster ADB, et al. Mutations inTNFRSF13B encoding TACI are associated with common variableimmunodeficiency in humans. Nat Genet 2005; 37: 820-828.28. Castigli E, Wilson SA, Garibyan L, et al. TACI is mutant in commonvariable immunodeficiency and IgA deficiency. Nat Genet 2005; 37:829-834.29. Sekine H, Ferreira RC, Pan-Hammarström Q, et al. Role for Msh5in the regulation of Ig class switch recombination. Proc Natl AcadSci USA 2007; 104: 7193-7198.18 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

SEVERE COMBINED IMMUNODEFICIENCY(SCID) – ADVANCES IN MOLECULARDIAGNOSIS, NEONATAL SCREENING ANDLONG-TERM MANAGEMENTHeather Finlayson, MB ChB, DCH, FC PaedsPaediatric Infectious Diseases Unit, Red CrossChildren's Hospital, School of Child and AdolescentHealth, University of Cape Town, South AfricaABSTRACTSevere combined immunodeficiency (SCID) is a rarebut important disorder. A true paediatric emergency,patients who are diagnosed early and referredappropriately have an excellent prognosis. AlthoughSCID was first diagnosed only approximately 50years ago, there has been a wealth of new knowledgegained in this relatively short period of time.Much has been learnt about the genetic basis of thedisease, early diagnosis soon after birth and finallydefinitive treatment through immune reconstitution.An early haematopoietic stem cell transplant with anHLA-identical donor has a survival approaching 95%and there have been encouraging results using genetherapy in adenosine deaminase (ADA)-SCID and X-linked SCID.INTRODUCTIONSevere combined immunodeficiency (SCID) is a groupof rare single gene disorders with an incidence thoughtto be around 1:75 000 births. 1 This, however, may bean underestimate as some children with the disorderdie from overwhelming infection prior to a diagnosisbeing confirmed. To date 10 different SCID phenotypeshave been identified. 2 All types of SCID have a block inT-cell development with either direct or indirect impairmentof B-cell immunity, making patients susceptibleto infection by multiple pathogens. Patients with SCIDwho do not receive treatment in the form of immunereconstitution rarely survive beyond one year of life. 1,3,4CLASSIFICATION AND CLINICAL PRESEN-TATIONThe various forms of SCID are classified according totheir lymphocyte phenotype 5 (Table I). Knowledge ofthis immunological profile can be suggestive of theunderlying genetic defect. Most cases of SCID havevery low or absent T cells. Patients are then classifiedaccording to the presence (T – B + SCID) or absence(T – B – SCID) of B lymphocytes and can be further classifiedby the presence or absence of natural killer (NK)cells.Four different mechanisms have been identified as acause of SCID:1. Premature cell death of lymphocyte precursors dueto accumulation of purine metabolites. This occursin the autosomal recessive condition, adenosinedeaminase (ADA) deficiency, which accounts forapproximately 10-20% of all SCID cases. 2,6-8 Celldeath occurs by apoptosis and all cell lines (T, B andNK cells) are affected. ADA is expressed in all tissuesand thus also has effects on other organs suchas the lungs, liver and brain. 92. Defective signalling through the common γ-chaindependentcytokine receptors. This is the mostcommon form of SCID and accounts for >50% of allcases. 1,2,6 Interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15,IL-21R all share a common subunit, the commonγ-chain. A deficiency in either the function or expressionof this chain results in the X-linked form of SCID(SCID-X1). Both mature T lymphocytes and NK cellsTable I. Classification of severe combined immunodeficiencyLymphocytephenotype Inheritance Chromosome1. T – B – SCID• NK + RAG 1/2 deficiency AR 11p13DCLRE1C (Artemis deficiency) AR 10p13• NK – Adenosine deaminase deficiency AR 20q13.11Reticular dysgenesisAR2. T – B + SCID• NK + IL7α deficiency AR 5p13CD45 deficiencyARCD3δ/CD3ε/CD3ζ deficiencyAR• NK – Common gamma-chain deficiency X-linked Xq13.1JAK3 deficiency AR 19p13.1Correspondence: Dr H Finlayson, Paediatric Infectious Diseases Unit, Red Cross Children's Hospital, Klipfontein Rd, Rondebosch 7700.Tel 021-658-5111, e-mail Heather.Finlayson@uct.ac.za20 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

are absent. IL-7Rα gene mutationresults in pureT-cell deficiency. B-cell developmentis normal in boththese groups of SCID, despitethe known role of IL-7 in B-cellsurvival and differentiation. 3,4Janus-Kinase 3 (JAK-3) is atyrosine kinase which binds tothe γ-chain cytoplasmic regionthereby mediating γ-chain signallingupon cytokine binding.A deficiency of JAK-3 resultsin a SCID phenotype identicalto SCID-X1.3. Defective V(D)J (variable,domain, joining) gene rearrangementof T-cell receptors(TCR) and B-cell receptors(BCR). Approximately 30% ofall SCID patients fall into thisgroup. 2 Clonal diversity of Tand B cells is generated by thesomatic rearrangement of TCR and BCR. This is initiatedby two recombination activating gene (RAG-1and RAG-2) proteins. Mutations in the genes encodingthese proteins result in faulty development of Tand B cells, with sparing of NK cells (T – B – NK + ).Artemis is a protein involved in DNA repair after double-strandedcuts have been made by RAG-1 andRAG-2. A deficiency of this protein also results inimpaired V(D)J arrangement and thus a T – B – NK +phenotype. Patients with artemesis deficiency alsoshow increased sensitivity to ionising radiation.4. Defective pre-TCR and TCR signalling. This rareform of SCID accounts for only 1-2% of all cases. 2These pure T-cell deficiencies (T – B – NK + ) are a resultof defects in key proteins involved in pre-TCR orTCR signalling such as CD45 phosphatase or a CD3subunit (CD3δ and CD3ε).Although we now know that SCID has many underlyinggenetic defects, all forms of SCID manifest with asimilar clinical presentation, typically with severe infectionsearly in life. The average age of presentation is 6months, when maternal antibodies are declining. 3Infections usually involve the respiratory tract or thegut and patients often present with persistent diarrhoeaand failure to thrive. Opportunistic infectionssuch as Pneumocystis jerovici, Candida albicans, andcytomegalovirus, as well as infections with adenovirus,respiratory syncytial virus and parainfluenza-3 alsooccur. Children who received BCG vaccination at birthare at risk of dissemination. 3,4 Maternal T-cell engraftmentmay occur in as many as 40% of children withSCID. 10 The maternal placenta is an incomplete barrierand maternal cells often occur in healthy neonates. Inimmunocompetent newborns these cells are cleared;however, as SCID infants lack T cells, maternal cellsmay persist. Clinical findings vary, with up to 60%asymptomatic and symptomatic graft-versus-host diseasemost commonly presenting with skin manifestationssuch as chronic eczematous skin rash or generalisedexfoliative erythrodermia. 10Because of the severity of the clinical presentation,SCID should be regarded as a clinical emergency.Diagnosis should be confirmed as early as possible, asearly diagnosis and management significantly improvethe outcome.PROSPECTS FOR NEONATAL DIAGNOSISChildren who are diagnosed early and receive appropriatemanagement and definitive treatment in the formTable II. Suggested screening test methods for SCIDTest method Dried blood spot Anticipated problemsFBC and absolute No High false-positives andlymphocyte count-negativesLabour intensiveAbsent TREC Yes 1.5% indeterminateresultsMay need repeat testIL-7 immunoassay Yes 2-tier testingpreliminary stagesLow CD3 immunoassay Yes Preliminary stagesMicroarray mutation Yes Many gene mutationsdetectionthus high falsenegativesFBC – full blood count, TREC – T-cell receptor excision circleof a haematopoetic stem-cell transplant (HSCT) have afar better prognosis than those children in whom thediagnosis has been delayed. 11 Prenatal diagnosis isnow available for those parents who have a positivefamily history. However, many children with SCID areborn to parents with no family history of the disease.Children with SCID are healthy at birth and have noexternal characteristics of the condition. The infectiouscomplications which bring them to medical care maynot initially be distinguishable from routine childhoodinfections. Thus diagnosis may be delayed.Newborn screening would identify these children early,before infectious complications set in, thus giving thema better outcome after HSCT. In the USA a SCIDNewborn Screening Working Group was convened inMay 2007 with the goal of pursuing integratedapproaches to SCID screening. SCID is thought tomeet many of the accepted criteria for neonatalscreening 12 in that it is fatal in infancy without definitivetreatment, there is a short asymptomatic period afterbirth, effective treatment is available in the form ofHSCT and more recently gene therapy, 13,14 early treatmentimproves outcome and the cellular and humoraldeficiencies may be detectable through screeningtests.A simple and effective test still needs to be identified.Currently a number of screening test methods havebeen suggested for SCID (Table II), some of which arebeing implemented in pilot studies. SCID is a rare diseaseand therefore any screening test needs to have ahigh positive predictive value for it to be accepted fornewborn screening. The main problem with currentlyproposed tests is the rate of false-positive or indeterminateresults. 15 All proposed tests are based on thefact that all patients with SCID are unable to make normalnumbers of T cells. However the test must alsotake into account that maternal T-cell engraftment mayoccur and patients with a T – B + phenotype may have anormal number of B cells.All children with SCID are lymphopenic at birth, 3,11,12thus routine blood counts with manual differentialscould diagnose nearly all cases of SCID at birth. 6However there is a high number of both false-positivesand -negatives, as not all children who are lymphopenichave SCID and some patients with SCID may have alow-normal absolute lymphocyte count because of thepresence of B cells (IL2RG, JAK3 and IL7R genedefects) or maternal lymphocytes. Furthermore thistest is potentially labour-intensive since it does notmake use of the dried blood spots (DBS) collected rou-Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 21

tinely from all neonates at birth in the USA. The UKPrimary Immunodeficiency Network also uses a lowlymphocyte count as an entry into their protocol forscreening for SCID. 16 However a recent audit fromBirmingham, UK, 17 found that although only 1 out of the56 cases of lymphopenia was documented by the clinician,there were no clear missed cases of SCID. Theytherefore thought it would be more cost-effective todiscuss cases of lymphopenia with an immunologistbefore doing further investigations for SCID.T-cell receptor excision circles (TREC) are formed duringnormal thymic maturation of T cells. Chan andPuck 18 showed that children with SCID (and thereforea low number of mature T cells) have low or undetectablelevels of TRECs, whereas normal healthy newbornshave high levels. Furthermore adult T cells havearound five times fewer TRECs; thus the TRECs foundin neonatal DBS are unlikely to be derived from transferredmaternal T cells and maternal T- cell engraftmentis unlikely to interfere with the test. The TREC can beperformed using real time PCR on DNA obtained fromDBS on routinely obtained Guthrie cards. However,approximately 1.5% of anonymous Guthrie cards yieldedindeterminate results because of failure to amplifyTRECs. Further screening and possibly further diagnostictests would be required in these cases. In 12states in the USA a second Guthrie card is routinelyrequested for all infants in the first month of life. Inthese states a second test done on previous indeterminatesamples would lead to a reduction of persistentlyindeterminate results in the range of 0.1% orless. 15 Pilot SCID screening using the TREC test will beimplemented in Wisconsin within the next year. 15,19Immunoassays for IL-7 and T-cell-specific proteins arebeing evaluated as possible first-line or second-linenewborn screening tests. 15,20 High IL-7 levels are associatedwith T-cell lymphopenic states and may possiblybe useful in a two-tier system together with TREC testingas these tests combined give a specificity of100%. 20 CD3 testing alone or in combination withCD45 or other T-cell proteins is another neonatalscreening option with good sensitivity. 19 These twomethods, however, are in preliminary stages of exploration.Finally, direct detection of gene mutations using resequencingmicroarray chips is also an option. Althoughthis potentially will have a high number of false-negatives,it would also give one an immediate specificgene diagnosis.There is growing momentum for neonatal screening inthe USA. However, in South Africa even if a suitabletest is found, this is unlikely to be implemented in thenear future. There is currently no universal neonatalscreening for any disorder in South Africa. Perhaps asnational prevention of mother-to-child transmission(PMTCT) screening of 6-week HIV-exposed infantsimproves, the infrastructure created by this screeningwill help with implementation of other important preventableconditions. Within the current constraints doctorsseeing young infants should be aware of the possibilityof the diagnosis in infants who present withsevere opportunistic infections early on in life andinvestigate and refer timeously. Parents with a familyhistory of SCID should also be offered early screeningof subsequent offspring.MANAGEMENTThere are three long-term management options forchildren with SCID. Firstly HSCT either through amatched sibling, a haploidentical parent or a matchedunrelated donor. Children suffering from ADA-SCIDhave the further option of enzyme replacement therapywith pegylated ADA enzyme. Finally gene therapyhas been an exciting new option although somecaveats still seem pertinent.Enzyme replacement therapy (ERT) forADA-SCIDThis has been used for ADA deficiency since 1987.PEG-ADA is given by intramuscular injection once ortwice a week. This maintains a high ADA activity in theplasma (> 100 times normal) as there is no significantcellular uptake of PEG-ADA. Extracellular toxic metabolitesdeoxydenosine and adenosine are eliminated leadingto normalisation of intracellular dATP levels. Over a2-4-month period cellular and humoral immunity isreconstituted. Although many children recover fullimmunity in the short term, approximately half willrequire ongoing immunoglobulin replacement. In thelong term some patients show a decline in T-cell numbersand become lymphopenic. Despite this, childrenseem to remain clinically well with normal growthparameters and free from infection. 8Haematopoietic stem cell transplantHSCT from an HLA-identical sibling, if available, is thebest option for a child diagnosed with SCID. Data fromEurope between 1963 and 1999 showed a 3-year survivalof 77%. 21 However, children receiving transplantsafter 1996 had a survival rate of over 90%, possiblybecause of improved severe infection management.What makes SCID such an attractive option for HSCTis the fact that because children with SCID have noT-cell function, they are unable to reject the graft andtherefore do not need myeloablative therapy beforetransplant. The toxicity of the procedure is thusreduced, including problems such as neutropenia andmucositis, the need for platelet and red blood cell(RBC) transfusion, veno-occlusive disease and longtermimpaired growth and sterility. 22 Graft-versus-hostdisease (GVHD) is also rare in these children. 21,22 AnHLA-identical donor is available only in a minority ofcases. Therefore most children will receive an HSCTfrom an HLA-mismatched related donor, made possibleby new techniques which allow for T-cell depletion ofthe donor graft. However the prognosis for these childrenis significantly less than for their HLA-identicalcounterparts. Data from Europe looking at 294 patientsshowed a 3-year survival of only 54%; again thisimproved over time with children transplantedbetween 1996 and 1999 having a survival of 75%. 21Data from Duke University in the USA also showed a77% survival. 22 Improved survival is most likely due tobetter prevention of GVHD by more efficient methodsof T-cell depletion and prevention and treatment ofinfection. 21There are three factors which play a role in the differentsurvival rates between identical and haploidenticalHSCT: 1• Although patients receive T-cell-depleted haploidenticalHSCT some still experience GVHD which impactson long-term survival. 21• Graft rejection is more common in patients with anNK + SCID phenotype. These children have a poorerprognosis as haploidentical HSCT is associated withan increased rate of failure of engraftment. This evidencesuggests that NK cells have a role in allogeneicreactions in humans. 1• Kinetics of T-cell development is the major factoraffecting different outcomes. In children receiving anHSCT from a related identical donor (RID) mature22 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

T-cells become detectable 10-15 days post transplant.1,23 These cells have a memory phenotype.T-cell counts reach normal values at 1-2 months postHSCT. These T cells are fully functional and providesufficient immunity to protect patients. This howeverdoes not occur in haploidentical HSCT.Approximately 3-4 months post HSCT naïve T-cellTRECs appear in both groups suggesting neothymopoeisis.1,23 Why this takes 3 months to develop isunknown. The thymus in patients with SCID developsabnormally, in the absence of T-cell precursors,and therefore may be unable to support thymopoeisis.However SCID patients receiving HSCT in theneonatal period have TREC-positive naïve T cellswithin 15-30 days and counts increase far morequickly, thus thymi of very young patients may nothave been damaged by toxic metabolites (ADA-SCID) or prolonged absence of T-cell precursors(SCID-X1) or infections. Finding a way to speed upthis immune reconstitution in haploidentical HSCTcould potentially improve outcome.Following most HSCTs, B cells remain those of therecipients, 1,23 indicating poor B-cell engraftment. B-cellfunction does not develop to the same extent as T-cellfunction and most patients require immunoglobulininfusions to prevent infections. 23 SCID-X1 and JAK-3deficiency patients who lack donor B cells continue tohave poor B-cell function while those with ADA-SCIDand IL-7Rα deficiency have good host B-cell function.Pretransplant chemotherapy improves the B-cellengraftment in SCID-X1 and JAK-3 deficiency; howeverthis does not guarantee B-cell engraftment andthe risks associated with chemotherapy can outweighthe potential benefits. 23The final potential source for HSCT is HLA-matchedunrelated donors (MUDs). A recent study comparedoutcomes of the three groups of HSCT, 24 They showed80.5% survival in MUD HSCT. Patients receiving MUDHSCTs showed complete donor engraftment in 88.5%and only one patient still required intravenousimmunoglobulin, suggesting good long-term immunereconstitution. With expanding donor bases worldwideMUD HSCTs may be an attractive alternative forpatients without an HLA-identical sibling. Patients inthis study all received transplants within 4 months ofdiagnosis and delay in finding a donor did not increasemortality prior to the HSCT. In fact, the authors felt thatthis provided time to stabilise the patient and improvenutritional status.Much is known about the long-term survival of childrenwho receive HSCT. However, not much is known aboutthe long-term quality of life these patients experienceafter transplant. A recent study from Italy looked at clinicaloutcome 5 years after transplant. 25 They found thatmost children had attained satisfactory growth withonly 17.5% below the 3rd centile for weight and 12.5%below the 3rd centile for height. All patients wereattending school, although 3 patients required individualisedsupport. Ten per cent of children had severeneurological problems. One of these children has ADA-SCID which is known to have a high incidence of neurologicalproblems during long-term follow-up 9 becauseof the generalised metabolic abnormality associatedwith the condition. Viral infection around the time ofHSCT may also influence clinical outcome. Most importantlythe majority of patients from this study live athome and 60% do not require any treatment. This supportsHSCT as an effective treatment for SCID providingnot only long-term survival but also a good qualityof life in most patients.Gene therapyThis has been successful in treating ADA-SCID 26 andSCID-X1. 13,14 This was achieved by using retroviral vectorscontaining therapeutic genes to transduce patientCD34 + cells. Patients with ADA-SCID receive a mildnon-myeloablative chemotherapy prior to receiving thecorrected stem cells to improve engraftment of thecells. 8 PEG-ADA, if started prior to gene therapy, isstopped in order to improve the selective advantage ofthe new cells 8,27 and has been associated withimproved immunity following therapy. Follow-up ofthese patients has been short when compared withERT and HSCT. Initial results are encouraging withgood immune recovery and normal growth and development;26 however long-term effects will have to bemonitored.Two groups in France 14 and the UK 13 have shown successusing gene therapy in SCID-X1. This has beencomplicated by lymphoproliferative disorders in 4 childrenfrom the French group. 28,29 These seem to berelated to retroviral vector integration close to theLMO2 proto-oncogene promoter, which was shown inthe first 2 patients. 28 LMO2 induction by chromosomaltranslocations is known to be associated with a form ofacute lymphoblastic lymphoma. Furthermore the initial2 cases were 1 and 3 months of age respectively whenthey received gene therapy, suggesting that age mayplay a role in insertional mutagenesis. These patientsreceived a higher dose of transformed cells and hadrapid T-cell development early after gene therapy, 28supporting a higher proliferative capacity of neonatalhaematopoietic stem cells. 2 Both these factors mayalso have played a role in inducing mutagenesis.No cases of insertional mutagenesis have been identifiedin the UK group. This may be due to slight differencesin protocol. They did not add fetal calf serum tothe cell culture medium, used a three times lower IL-3concentration and used a different viral envelope 13,29which may target a slightly different T-cell subset thatis less prone to transformation. 29 However, follow-up inthis group has been shorter.The occurrence of insertional mutagenesis has uncoveredthe need to make gene therapy safer in thefuture. A number of methods are currently being investigated.Current retroviruses used in gene therapy havestrong enhancer and promoter regions within the longterminal repeats (LTRs), 29 lentiviruses still have a preferencefor inserting near active genes but do not insertnear the promoter or 5’ regions of the gene. 30 The useof self-inactivating lentiviruses which lack LTR promoteractivity after proviral integration may be a safer vector.The expression of the therapeutic gene wouldoccur via an internal promoter with little enhancer activity;furthermore further safety may be achieved byusing tissue-specific or gene-specific promoters to providemore tightly regulated gene expression. 2,27,29,30Insulators are small DNA elements which act as barriersand therefore prevent promoter-enhancer elementsand/or chromatin modifications from influencing theexpression of neighbouring genes. These may alsoimprove safety by limiting the activation of genesaround the insertion site. 2,29,30 While this may decreaseenhancer activity it will not eliminate it entirely. Theinsertion of a second transgene that encodes a prosuicideproduct such as herpes thymidine kinase wouldenable transduced cells to be killed by gancyclovir. 2,29,30However there are unresolved problems using thisapproach such as expression and function of the suicidegene, the induction of in vivo resistance, theimmunogenicity of the thymidine kinase and the limita-Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 23

tions to the use of antiviral drugs once the transducedcells have been injected. 29 Advances are expected fromsite-specific integration by targeting gene integrationinto neutral regions or sites that are known to be safe.This can be achieved by transferring integrases withrare integration sites into the human genome or byhomologous recombination of small DNA fragmentsthat can modify genomic DNA, thus simply repairingthe mutation in situ. 2,29,30 This work is still in the preliminarystages.Gene therapy has not been as successful in older children31 despite effective gene transfer to CD34 + cells.This suggests an age constraint to the efficacy of genetherapy, possibly because thymopoeisis may be influencedby infection, GVHD and physiological ageing. 31Therefore, as in HSCT, immune reconstitution withgene therapy should be considered as early as possible.CONCLUSIONAlthough first diagnosed only 50 years ago there hasbeen remarkable advancement in the understanding ofSCID resulting in improved survival and quality of life.SCID is a rare disease. It now has an excellent prognosisif treated early before the onset of severe infections.Implementation of neonatal screening mayincrease early diagnosis. Currently paediatriciansshould consider this diagnosis in any child who presentswith severe opportunistic infections early in lifeand investigate appropriately.Declaration of conflict of interestThe author declares no conflict of interest.REFERENCES1. Fischer A, Le Deist F, Hacein-Bey-Abina S, et al. Severe combinedimmunodeficiency. A model disease for molecular immunology andtherapy. Immunol Rev 2005; 203: 98-109.2. Cavazzana-Calvo M, Lagresle C, Hacein-Bey-Abina S, Fischer A.Gene therapy for severe combined immunodeficiency. Annu RevMed 2005; 56: 585-602.3. Buckley RH, Schiff RI, Schiff SE, et al. Human severe combinedimmunodeficiency: genetic, phenotypic, and functional diversity inone hundred eight infants. J Pediatr 1997; 130: 378-387.4. Stephan JL, Vlekova V, Le Deist F, et al. Severe combined immunodeficiency:a retrospective single-center study of clinical presentationand outcome in 117 patients. J Pediatr 1993; 123: 564-572.5. Geha RS, Notarangelo LD, Casanova JL, et al. Primary immunodeficiencydiseases: an update from the International Union ofImmunological Societies Primary Immunodeficiency DiseasesClassification Committee. J Allergy Clin Immunol 2007; 120: 776-794.6. Buckley RH. Primary immunodeficiency diseases: dissectors of theimmune system. Immunol Rev 2002; 185: 206-219.7. Gaspar HB, Gilmour KC, Jones AM. Severe combined immunodeficiency– molecular pathogenesis and diagnosis. Arch Dis Child2001; 84: 169-173.8. Booth C, Hershfield M, Notarangelo L, et al. Management optionsfor adenosine deaminase deficiency; proceedings of the EBMTsatellite workshop (Hamburg, March 2006). Clin Immunol 2007;123: 139-147.9. Rogers MH, Lwin R, Fairbanks L, Gerritsen B, Gaspar HB.Cognitive and behavioral abnormalities in adenosine deaminasedeficient severe combined immunodeficiency. J Pediatr 2001; 139:44-50.10. Muller SM, Ege M, Pottharst A, Schulz AS, Schwarz K, Friedrich W.Transplacentally acquired maternal T lymphocytes in severe combinedimmunodeficiency: a study of 121 patients. Blood 2001; 98:1847-1851.11. Myers LA, Patel DD, Puck JM, Buckley RH. Hematopoietic stemcell transplantation for severe combined immunodeficiency in theneonatal period leads to superior thymic output and improved survival.Blood 2002; 99: 872-878.12. Lindegren ML, Kobrynski L, Rasmussen SA, et al. Applying publichealth strategies to primary immunodeficiency diseases: a potentialapproach to genetic disorders. MMWR Recomm Rep 2004;53(RR-1): 1-29.13. Gaspar HB, Parsley KL, Howe S, et al. Gene therapy of X-linkedsevere combined immunodeficiency by use of a pseudotypedgammaretroviral vector. Lancet 2004; 364: 2181-2187.14. Hacein-Bey-Abina S, Le Deist F, Carlier F, et al. Sustained correctionof X-linked severe combined immunodeficiency by ex vivogene therapy. N Engl J Med 2002; 346: 1185-1193.15. Puck JM. Neonatal screening for severe combined immune deficiency.Curr Opin Allergy Clin Immunol 2007; 7: 522-527.16. UK primary immunodeficiency network guideline, Severe combinedimmunodeficiency – initial diagnosis and management.Available at: http://www.ukpin.org.uk/Guidelines/11.01-SCID.pdf.Accessed 10/03 2007.17. Krishna MT, Tarrant JL, Cheadle EA, Noorani S, Hackett S,Huissoon AP. An audit of lymphopenia infants under 3 months ofage. Arch Dis Child 2008; 93: 90-91.18. Chan K, Puck JM. Development of population-based newbornscreening for severe combined immunodeficiency. J Allergy ClinImmunol 2005; 115: 391-398.19. Puck JM, SCID Newborn Screening Working Group. Populationbasednewborn screening for severe combined immunodeficiency:steps toward implementation. J Allergy Clin Immunol 2007;120: 760-768.20. McGhee SA, Stiehm ER, Cowan M, Krogstad P, McCabe ER. Twotiereduniversal newborn screening strategy for severe combinedimmunodeficiency. Mol Genet Metab 2005; 86: 427-430.21. Antoine C, Muller S, Cant A, et al. Long-term survival and transplantationof haemopoietic stem cells for immunodeficiencies:report of the European experience 1968-99. Lancet 2003; 361:553-560.22. Buckley RH, Schiff SE, Schiff RI, et al. Hematopoietic stem-celltransplantation for the treatment of severe combined immunodeficiency.N Engl J Med 1999; 340: 508-516.23. Buckley RH. Molecular defects in human severe combined immunodeficiencyand approaches to immune reconstitution. Annu RevImmunol 2004; 22: 625-655.24. Grunebaum E, Mazzolari E, Porta F, et al. Bone marrow transplantationfor severe combined immune deficiency. JAMA 2006; 295:508-518.25. Mazzolari E, Forino C, Guerci S, et al. Long-term immune reconstitutionand clinical outcome after stem cell transplantation forsevere T-cell immunodeficiency. J Allergy Clin Immunol 2007; 120:892-899.26. Aiuti A, Slavin S, Aker M, et al. Correction of ADA-SCID by stemcell gene therapy combined with nonmyeloablative conditioning.Science 2002; 296: 2410-2413.27. Qasim W, Gaspar HB, Thrasher AJ. Update on clinical gene therapyin childhood. Arch Dis Child 2007; 92: 1028-1031.28. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, et al. LMO2-associatedclonal T cell proliferation in two patients after gene therapyfor SCID-X1. Science 2003; 302: 415-419.29. Cavazzana-Calvo M, Fischer A. Gene therapy for severe combinedimmunodeficiency: are we there yet? J Clin Invest 2007; 117:1456-1465.30. Puck JM, Malech HL. Gene therapy for immune disorders: goodnews tempered by bad news. J Allergy Clin Immunol 2006; 117:865-869.31. Thrasher AJ, Hacein-Bey-Abina S, Gaspar HB, et al. Failure ofSCID-X1 gene therapy in older patients. Blood 2005; 105: 4255-4257.24 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

INTRAVENOUS IMMUNOGLOBULINEA Goddard, MSc, MB ChB, PhD, MMed (Paed)School of Child and Adolescent Health, University ofCape Town and Red Cross Children's Hospital,Rondebosch, Cape Town, South AfricaABSTRACTThere has been a rapid expansion of the use of intravenousimmunoglobulin (IVIG) for an ever-growingnumber of conditions. IVIG is used at a ‘replacementdose’ (400-600 mg/kg/month) in antibody deficiencies.In contrast it is used at a high dose (2 g/kg/month) as an ‘immunomodulatory’ agent in anincreasing number of immune and inflammatory disorders.The limitations for IVIG are the cost of thepreparation and the need for intravenous infusions.Due to the cost, shortages and growing use of IVIGthere have been attempts to develop evidencebasedguidelines for the use of IVIG in a wide varietyof haematological, autoimmune and neurologicalconditions. This commentary provides the recommendationsand recent publication regarding theuse of IVIG in various conditions. Although IVIG is asafe treatment option when compared with otherimmunosuppressive agents there needs to be anunderstanding of the potential adverse reactionsand their management. It is important for the physicianto carefully assess and monitor patients on IVIGso that treatment can be optimised.INTRODUCTIONIntravenous immunoglobulin (IVIG) replacement therapyhas greatly reduced the morbidity due to bacterialinfections associated with major forms of antibody deficiency.IVIG has a few proven indications and manypotential ones. There has been a rapid expansion in theuse of IVIG. It has had a major impact in the treatmentof conditions in the fields of neurology, haematology,rheumatology and dermatology. In a recent study inCanada the leading indications for IVIG use were idiopathicthrombocytopenic purpura (17.3%), primaryimmune deficiency conditions (14.9%) and chronicdemyelinating polyneuropathy (11.8%). The leadingprescribing specialists were neurologists (32.2%) andhaematologists (26.1%). 1 It is safe and does not havethe side-effects of steroids or other immunosuppressiveagents.BACKGROUNDImmunoglobulin replacement has been standard therapyfor patients with primary immune deficiency diseasessince its use by Bruton in 1952. 2 For many years,these preparations could only be given intramuscularly.Administration of intramuscular immune serum globulinresulted in a decrease in the incidence of infectionsof patients with agammaglobulinaemia. However injectionswere painful, the IgG was absorbed slowly and itCorrespondence: Dr EA Goddard, Red Cross Children's Hospital,Klipfontein Rd, Rondebosch, 7701. Tel 021- 658-5111, fax 021-689-1287, e-mail liz.goddard@uct.ac.zawas difficult to maintain IgG levels above 2 g/l.Intravenous administration of immune serum globulincaused shock-like episodes, chills and hyperpyrexia.Although attempts were made to modify immuneserum globulin for intravenous use, intramuscular useremained the sole form of replacement therapy until1981 (29 years later) when intravenous preparationsbecame commercially available. This reduced the painof administration and allowed larger volumes to beinfused. Over 25 IVIG preparations are available worldwidewhich have been approved by various regulatorybodies. 3 All are tolerated and effective. The variousIVIG products differ in a number of ways includingimmunoglobulin and IgG subclass distribution, antibodycontent, approved maximum infusion rate and sideeffects.The characteristics of the various productsmay result in differences in efficacy and safety whichmay have a significant impact on the choice of productfor some patients.PRODUCTIONAn ideal IVIG preparation would contain structurally andfunctionally intact immunoglobulin molecules with anormal biological half-life and a normal proportion ofIgG subclasses. The preparation should contain highlevels of antibody or antibodies relevant to its proposeduse. There should be no contamination and vasomotorpeptides, endotoxin or infectious agents.Nearly all IVIG preparations are isolated from pooledhuman plasma (1 000 to 10 000 donors) by the Cohnalcohol fractionation method which results in five plasmafractions. The Cohn fraction II contains the bulk ofthe antibodies and is appropriate for intramuscular andsubcutaneous use. This fraction is further purified forthe production of IVIG. The WHO has established thefollowing production criteria for IVIG (1982): 41. Each lot should be derived from plasma pooled fromat least 1 000 donors.2. It should contain at least 90% intact IgG with thesubclasses present in ratios similar to normal pooledplasma.3. IgG molecules should maintain biological activitysuch as complement fixation.4. It should be free from contaminants of prekallikreinactivator kinins, plasma proteases and preservatives.5. It should be free from infectious agents.As for all blood products donors are screened forhepatitis B surface antigen, HIV -p24 antigen, and antibodiesto syphilis, HIV-1, HIV-2 and hepatitis C.Commercial lots are produced from plasma pooledfrom 1 000 to 10 000 donors so contain a broad spectrumof antibodies. Differences in the manufacturingprocesses of different IVIG preparations affect opsonicactivity, Fc-receptor function and complement fixation.Thus different IVIG preparations should not be consideredas a generic productMECHANISM OF ACTION OF IVIGIVIG acts via a variety of mechanisms in different diseasestates and these have been reviewed in detail byBallow 5 and Jolles et al. 6 The mechanisms of action of26 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

therapeutic IVIG are complex. In many conditionsadvances in the understanding of its actions have beenmade. The predominant mechanisms depend on boththe IVIG dose and on the pathogenesis of the underlyingdisease and can be divided into four broad groups: 61. Actions mediated via the variable regions F (ab'). 22. Actions of Fc region on a range of receptors.3. Actions mediated by complement binding within theFc fragment.4. Immunomodulatory substances other than antibodyin the IVIG preparationsUSES OF IVIGIVIG has many uses and is an important treatment inmany diseases. The original use was as replacementtherapy (400-600 mg/kg/month) in primary and secondaryantibody deficiencies. However, IVIG has manyimmunomodulatory and anti-inflammatory effects athigher doses (2 g/kg/d) and now more than 100 inflammatoryand autoimmune disorders are treated withIVIG. Several IVIG preparations are available and aresupplied in either a lyophilised form or as ready-to-usesolutions.IVIG therapy has a few proven indications and manypotential ones. There are currently six clinical indicationsin the USA with Food and Drug Administration(FDA) approval 7 (Table I):1. Treatment of primary immunodeficiencies.2. Prevention of bacterial infections in patients withhypogammaglobulinaemia and recurrent infectioncaused by B-cell chronic lymphocytic leukaemia.3. Prevention of coronary artery aneurysms inKawasaki disease.4. Prevention of infections, pneumonia and acute graftversus-hostdisease (GVHD) after bone marrowtransplantation.5. Reduction of serious bacterial infection in childrenwith HIV.6. Increase of platelet count in idiopathic thrombocytopenicpurpura to prevent or control bleeding.There are many disorders for which IVIG is used as atreatment (Table II) and there are several excellentrecent reviews on the topic which detail the evidencefor the use of IVIG treatment in a wide variety ofhaematological, autoimmune and neurological conditions.6-10Primary and secondary immunodeficiencyThe clearest indication for immune globulin replacementis antibody deficiency. Such deficiencies rangefrom virtually complete absence of all majorimmunoglobulin classes to more selective deficiencies.The use of IVIG in primary and secondary antibody deficiencieshas been thoroughly reviewed by Stiehm. 11Patients with primary antibody deficiencies are susceptibleto bacterial infections and require lifelongimmunoglobulin replacement therapy. In primary orsecondary hypogammaglobulinaemia IVIG protectsagainst infection by providing an adequate concentrationof IgG (Table II). 7,11Dosage of IVIG in primary antibodydeficienciesThe usual dose of IVIG for antibody replacement isbetween 400-600 mg/kg every 2-4 weeks. The dose isadjusted so that the trough level just before the nextinfusion is at least 500 mg/dl. For other uses the dosesrange between 400 mg/kg/day for 5 days or a morerapid course of 1-2 g/kg given over 1-2 days. 7Infusions are given every 3 to 4 weeks at an initial doseof 400-600 mg/kg titrating the dose and interval toachieve a rough level greater than 500 mg/dl in agammaglobulinaemicpatients. 7 The dose of IVIG needed tokeep the patient symptom-free depends on the severityof the antibody defect and the catabolic rate ofinfused IVIG. Doses of 400 mg/kg or greater haveimproved efficacy over lower doses in reducing theincidence of infection. 12 After the sixth infusion asteady state will have been achieved and the dose ordosing interval should be altered to achieve the optimalclinical result. When IgG production is deficient but notcompletely absent, such as in CVID, dosing is morecomplex. IgG trough levels can be unreliable andshould not be used as a primary endpoint for guidingTable I. FDA-approved indications for IVIGDisease statePrimary immunodeficiency disease orprimary humoral immunodeficiencyIdiopathic thrombocytopenic purpura(ITP)Kawasaki disease (syndrome)B-cell chronic lymphocytic leukaemiaHIV infectionBone marrow transplantationAdapted from Orange et al. 7IndicationIndicated for the treatment of primary immunodeficiency states orfor increase of circulating antibody levels in primary immunodeficiencydiseases or for replacement therapy of primary immunodeficiency states inwhich severe impairment of antibody-forming capacity has been shownIndicated when a rapid increase in platelet count is needed to preventbleeding. control bleeding, or both in ITP or to allow a patient with ITP toundergo surgeryIndication for the prevention of coronary artery aneurysms associated withKawasaki diseaseIndicated for the prevention of bacterial infections in patients withhypogammaglobulinaemia, recurrent bacterial infections, or both, associatedwith B-cell chronic lymphocytic leukaemiaIndicated for paediatric patients with HIV infection to decrease the frequencyof serious and minor bacterial infections and the frequency ofhospitalisation and increase time free of serious bacterial infectionIndicated for bone marrow transplant recipients ≥ 20 years of age todecrease the risk of septicaemia and other infections, interstitial pneumoniaof infections or idiopathic causes, and acute GVHD in the first 100days after transplantationCurrent Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 27

Table II. Major uses of IVIGNeurologyHaematologyImmunologyDermatologyOtherGuillain BarresyndromeMultifocal motorneuropathyChronic inflammatorydemyelinatingpolyneuropathyDermatomyositis andinflammatorymyopathiesMyasthenia gravisLambert-EatonsyndromeStiff person syndromeImmunethrombocytopeniaPost bone marrowtransplantMyeloma andchroniclymphocyticleukaemiaParvovirusB19-associatedaplasiaImmuneneutropeniaImmune haemolyticanaemiaPrimary antibodydeficiencies(XLA, CVID, HIGMWAS and others)Secondary antibodydeficiencies(myeloma, CLL,drugs andother causes)KawasakisyndromeDermatomyositisToxic epidermalnecrolysisBlistering diseasesImmune urticariaAtopic dermatitisScleromyxoedemaPyodermagangrenosumVasculitisSysytemiclupuserythematosisStreptococcaltoxic shocksyndromeBirdshotretinochoroidopathyAutoimmuneuveitisMucousmembranepemphigoidIVIG is used mainly at high dose (2 g/kg) for the indications listed in neurology, haematology, rheumatology, dermatology and others while inimmunology replacement doses (0.4 g/kg) are given. XLA – X-linked agammaglobulinaemia, CVID – common variable immunodeficiency, HIGMimmunodeficiencywith hyper-IgM, WAS – Wiskott Aldrich syndrome, CLL – chronic lymphocytic leukaemia.Adapted from Jolles et al. 6therapy. A target trough level of a serum IgG equal tothe pretreatment level plus 300 mg/dl has been used.A dose must be individualised and titrated to achieveclinical effect for each patient. The issue of IgG dosefor patients with normal IgG levels but impaired specificantibody production is more difficult because IgGtrough levels are not particularly useful. Dose adjustmentswill be needed with children's growth or in protein-losingconditions. Despite the number of studiescomparing different IgG doses of primary immunodeficiency,none has directly compared different dosingintervals. At present the dosing interval should beselected according to the ability of a given regimen tomaintain an adequate IgG trough level, an acceptableclinical effect, or both. If patients who are receivingIVIG every 28 days experience malaise or upper respiratorytract symptoms in the week before infusion, amore frequent dosing schedule should be considered.Monitoring IVIG in primary antibodydeficienciesThe therapeutic guidelines for the monitoring of theuse of IVIG in primary antibody deficiencies are summarisedin Table III.Monitoring IVIG therapyIVIG therapy can take up to 6 months to achieve maximalbenefits. Trough levels increase gradually withoptimal dosing (400-600 mg/kg/month) until a steadystate is achieved after 4-8 months of regular IVIG infusions.Because of individual variation in IgG distributionand catabolism, serum IgG trough levels (i.e. prior toinfusion level) should be checked every 2 months forthe first 8 months of therapy to ensure that targettrough levels of > 500 mg/dl are met or exceeded.Once the dose has been optimised, trough levels needonly be monitored every 6 months. 11Monitoring liver functionLiver function including serum transaminase levelsshould be monitored regularly (every 3 months) toexclude subclinical, passively transmitted hepatitis.Batch numbers of the IVIG infused must be recorded inthe patient notes.Monitoring infectionsWhile patients are on IVIG therapy it is advised that thenumber, duration, site and severity of all infections, allantibiotic use and other relevant clinical details berecorded to document the benefit of the IVIG therapy.Monitoring disease progressionChest damage may progress insidiously despite optimalIVIG therapy so regular review of pulmonary functionis recommended.Autoimmune diseasesHigh dose IVIG has immunosuppressive and antiinflammatoryeffects and has been used with variableresults in several systemic autoimmune diseases(Table II). 6,7 In contrast to the 'replacement' dose of 400mg/kg/month, the 'high' dose IVIG is given at2 g/kg/month when it is used as an immunomodulatoryagent in immune or inflammatory disorders.Idiopathic thrombocytopenic purpura(ITP)ITP is an FDA-approved indication for IVIG. It is animportant treatment option of acute ITP in childrenwith the severe presentation (platelet count < 20 x10 9 /l) of this disorder. 8 It is used to treat patients atgreatest risk of bleeding complications or those withchronic refractory disease. The mechanism of action isthought to be blockade of the Fc receptors in the reticuloendothelialsystem leading to inhibition of bindingand destruction of antibody-coated platelets.Haematological disordersIVIG has been used in numerous haematological conditions(Table II). 6,7Treatment for haemolytic disease of the newborn(HDN) includes phototherapy and exchange transfu-28 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

TABLE III. Recommendations for the use of IVIG in primary antibody immunodeficiencies1. Record brand, lot number, dose, infusion rate, and side reactions2. Maintain the IgG trough levels > 500 mg/dl3. IgG trough levels gradually increase for 4-8 months on high dose IVIG therapy4. For every 100 mg/kg of IVIG given, IgG peak levels increase 200-250 mg/dl and trough levels increase 100 ml/dl (after28 days)5. Usual maintenance dose is 400-500 mg/kg every 4 weeks6. Check IgG trough level every 2 months until stable, then every 6 months7. Check blood count and liver function tests twice yearly8. IgG half-life varies in different patients so dosage must be individualised9. Consider extra doses with infection, stress and gastrointestinal or genitourinary loss10. Home infusions, slow subcutaneous infusions and rapid infusion of 10-12% IVIG can be used for convenience, economyand shortened administration time in some patientsAdapted from Stiehm. 11sion. In the last few years IVIG has been shown to significantlyreduce the overall use of exchange transfusion.13,14 IVIG is recommended for the treatment ofHDN with severe hyperbilirubinaemia. The AmericanAcademy of Pediatrics (2004) 15 recommends IVIG treatment(0.5-1.0 g/kg over 2 hours) if the bilirubin is risingdespite intensive phototherapy or if it is within 2-3mg/dl (34-51 µmol/l) of the threshold for exchangetransfusion. 8,15 The mechanism of action is uncertainbut IVIG is thought to inhibit haemolysis by blockingantibody receptors on red blood cells.Neurological disordersIVIG is licensed for use in Guillain Barre syndrome(GBS) but is used in many other neurological conditions(Table II). 7,9,10,16 A Cochrane systematic review hasshown that IVIG is as efficacious as plasma exchangein GBS. 17 There are no randomised trials of IVIG in childrenwith GBS but the evidence from the adult trialshas been sufficient for IVIG to be recommended in childrenwith GBS. IVIG (2 g/kg over 2-5 days for adults, 2days for children) is recommended as a treatment forGBS within 2 weeks of symptom onset for: (i) patientswith grade 3 symptoms (able to walk with aid) orgreater; or (ii) patients with symptoms that are progressing.ROUTE OF ADMINISTRATIONImmunoglobulin replacement therapy can be given viathe intramuscular, subcutaneous and intravenousroutes. Preparations intended for the intramuscular andsubcutaneous routes must not be given intravenously.Intravenous administration pooled human immunoglobulinhas been available from 1981 and has becomean important therapy in clinical medicine. IVIG hasallowed infusion of higher doses over a short time, andhas remained the standard route of administration.However IVIG therapy is not ideal for all patients. Thelimitations of IVIG are:• Difficulty for those with poor venous access• Patients with recurrent systemic reactions• Requires hospitalisation or a good home-care programme.Subcutaneous immunoglobulin (SCIg)Subcutaneous administration of immunoglobulin byslow infusion was tried in the late 1970s. 18 It was abandonedbecause of the length of time of administrationand the occurrence of sterile abscesses.However more recently reports have shown that rapidsubcutaneous immunoglobulin (SCIg) therapy is a safe,effective and well-tolerated alternative to IVIG. 19,20,21SCIg treatment does not require venous access and isassociated with the slow release of IgG into the bloodwhich enables trough IgG levels to remain high and stablebetween infusions. 22,23 The growing availability ofSCIg therapy for home administration has offeredincreased flexibility to both children and adults. 21,24There are no significant differences in efficacy oradverse reaction results between immunoglobulinreplacement therapy given subcutaneously and intravenously.21,25 There has been an increase in use of thesubcutaneous route in Europe. The immunoglobulindose used for subcutaneous replacement therapy isusually 0.1 g/kg/week.Subcutaneous infusions are only indicated in primaryimmunodeficiency disorders. It is unclear whether subcutaneousinfusions will be effective for disordersdepending on the immunomodulatory action of IVIGand it is not recommended for this use.SAFETY OF IVIGSystemic reactions to IVIG infusion range from 3% to15%. They are usually self-limiting and can be avoidedby decreasing the rate of the infusion. Infusion ratesare usually started at 0.01-0.02 ml/kg/min andincreased up to 0.1 ml/kg/min. Fortunately most IVIGreactions are mild and non-anaphylactoid. Typically theyinclude backache, abdominal pain, nausea, chills, rhinitis,asthma, low-grade fever, myalgia and headaches(Table IV). Slowing or stopping the infusion for 15-30minutes will reverse many reactions. Pretreatment prophylaxiswith diphenhydramine (1 mg/kg/dose), acetaminophen(15 mg/kg/dose), aspirin (15 mg/kg/dose) oribuprofen (5 mg/kg/dose) is also helpful. More seriousreactions can be treated with hydrocortisone (6mg/kg/dose; maximum 100 mg). 11More serious adverse events can occur during or soonafter infusion: anaphylaxis, renal, cardiovascular, centralnervous system and haematological events havebeen reported. 26 Anaphylaxis is very rare and is associatedwith anti-IgA antibodies in some patients withtotal IgA deficiency (IgA < 0.05 g/l). Acute renal failureand neurodegeneration have been associated withIVIG but not temporally related to the infusion. 7 It hasbeen suggested that the sucrose-based products areCurrent Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 29

Table IV. Adverse effects of IVIG therapyImmediate infusion-related* Transmission of infective agents* Consequences of increasingserum IgG †Mild to moderate reactions – Hepatitis C – several outbreaks to Renal – reversible renal impairmentheadaches, backache, chills, date; additional anti-viral step (majority of cases), acute renal failurenausea, muscle pain – occur introduced by most manufacturers in mixed cryoglobulinaemiain approximately 1% of following last outbreak in 1994infusions and are largelyHaematological – cerebal and coronaryrate-related ? Prions – potential risk; no thromboses, acute haemolysis,documented cases to dateneutropeniaSevere – anaphylaxis mayNeurological – acute aseptic meningitisoccur very rarely in IVIGDermatological – eczema, urticaria,recipients who have higherythema multiforme cutaneoustitres of anti-IgA antibodiesvasculitis*May occur with either low or high-dose IVIG; † predominantly associated with high-dose IVIG.Adapted from Jolles et al. 6 Table V. Costs of IVIG in South Africa (December 2007)more commonly associated withacute renal failure. The more importantand commonly seen IVIGinducedadverse effects are summarisedin Table IV.The risk of infectious complicationsis low. There are stringent requirementsfor donor screening andtransmissible disease testing. Themanufacturing process includessteps of viral inactivation orremoval to protect against infectiousagents that might be presentdespite screening procedures.Hepatitis B and HIV have neverbeen transmitted through IVIG and there is no knowncase of transmission of Creutzfeldt-Jakob disease.Since 1984 transmission of hepatitis C has been reported10 times and is estimated to have involved 4 000patients worldwide. 3 Further antiviral steps of pasteurisation,nanofiltration or solvent detergent treatmenthave been added to the manufacturing procedures todecrease this risk.IVIG is a product made from large pools of humanplasma and thus infectious disease transmissionalways remains a possibility. The risk of infection fromhuman plasma preparations can never be completelyruled out.The effect of live vaccines may be inhibited if IVIG isused. It is recommended that these vaccines be given3 months after the last dose of IVIG.COST OF IVIGIn 1997 there was a worldwide shortage of IVIG due todisruption of production caused by the need for USbasedplasma fractionators to comply with more stringentUS FDA requirements. Intravenous immuneglobulin costs between R220 and R350 per gram(depending on quantity bottled) (Table V). These costsdo not include the costs associated with administrationof IVIG.CONSIDERATIONS IN THE USE OF IVIGBecause of the cost, shortages and growing use ofIVIG there have been attempts in many countries todevelop guidelines for monitoring of and indications forthe use of IVIG. 1,7,10,27 Clinicians should limit their prescriptionof IVIG to conditions for which efficacy isPatient Schedule Cost of IVIG0.5 g/kg 2.0 g/kg20 kg child 1 dose R 2 853 R 9 0981x monthly/yr R 37 089 R 118 2741x 3-weekly/yr R 48 501 R 154 66670 kg adult 1 dose R 8 000 R 31 0001x monthly/yr R 104 000 R 403 0001x 3-weekly/yr R 136 000 R 527 000supported by evidence-based studies. In South Africa itmust be ensured that that the patients who will benefitmost from IVIG (determined from evidence-basedguidelines) will have access to this treatment. It isimportant to recognise that IVIG products vary in theircomposition and these differences have clinical implicationsparticularly when used for immunomodulation.28Although there is statutory documentation for the useof blood, there are no guidelines for the use or monitoringof IVIG in South Africa although it has beenrecognised that this would be valuable. It is advisedthat clinicians:• Document product, lot number and dose ofimmunoglobulin used in patients• Document the indication for the IVIG• Monitor liver function tests and viral screens, pretherapyand serially throughout IVIG therapy• Record any side-effects.Declaration of conflict of interestThe author declares no conflict of interest.REFERENCES1. Constantine MM, Thomas W, Whitman L, et al. Intravenousimmunoglobulin utilization in the Canadian Atlantic provinces: areport of the Atlantic Collaborative Intravenous Immune GlobulinUtilization Working Group. Transfusion 2007; 47: 2072-2080.2. Bruton OC. Agammaglobulinaemia. Pediatrics 1952; 9: 722-728.3. Chapel HM. Safety and availability of immunoglobulin replacementtherapy in relation to potentially transmissable agents. Clin ExpImmunol 1999; 118: S29-S34.4. World Health Organization. Appropriate uses of humanimmunoglobulin in clinical practice: Memorandum from anIUIS/WHO meeting. WHO Bulletin 1982: 60; 43-47.30 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

5. Ballow M. Mechanisms of action of intravenous immune serumglobulin therapy. Pediatr Infect Dis J 1994; 13: 806-811.6. Jolles S, Sewell WAC, Misbah SA. Clinical uses of intravenousimmunoglobulin. Clin Exp Immunol 2005; 142: 1-11.7. Orange JS, Hossny EM, Weiler CR, et al. Use of intravenousimmunoglobulin in human disease: A review of evidence by membersof the primary Immunodeficiency committee of the AmericanAcademy of Allergy, Asthma and Immunology. J Allergy ClinImmunol 2006; 117: S525-S553.8. Anderson D, Ali K, Blanchette V, et al. Guidelines on the use ofintravenous immune globulin for hematologic conditions. TransfusMed Rev 2007; 21: S9-S56.9. Feasby T, Banwell B, Benstead T, et al. Guidelines on the use ofintravenous immune lobulin for neurologic conditions. TransfusMed Rev 2007; 21: S57-S107.10. Robinson P, Andersen D, Brouwers M, et al. Evidence-based guidelineson the use of intravenous immune globulin for hematologicand neurologic conditions. Transfus Med Rev 2007; 21: S3-S8.11. Stiehm ER. Human intravenous immunoglobulin in primary andsecondary antibody deficiencies. Paediatr Infect Dis 1997; 16: 696-707.12. Roifman CM, Gelfand EW. Replacement therapy with high doseintravenous gamma-globulin improves chronic sinopulmonary diseasein patients with hypogammaglobulinaemia. Pediatr Infect DisJ 1988; 7: S92-S96.13. Alcock GS, Liley H. Systematic review: immunoglobulin infusionfor isoimmune haemolytic jaundice in neonates. CochraneDatabase Syst Rev 2002; CD00331314. Gottstein R, Cooke RW. Systemic review of intravenousimmunoglobulin in haemolytic disease of the newborn. Arch DisChild Fetal Neonatal Ed 2003; 88: F6-F10.15. Management of hyperbilirubinaemia in the newborn infant 35 ormore weeks of gestation. Pediatrics 2004; 114: 297.16. Ferguddon D, Hutton B, Sharma M. et al. Use of intravenousimmunoglobulin for treatment of neurologic conditions: a systematicreview. Transfusion 2005; 45: 1640-1657.17. Hughes RA, Raphael JC, Swan AV, et al. Intravenous immunoglobulinfor Guillain-Barre syndrome. Cochrane Database SystematicRev 2004: CD 00206318. Berger M, Cupps T, Fauci A. Immunoglobulin replacement therapyby slow subcutaneous infusion. Ann Intern Med 1980; 93: 55-56.19. Thomas M, Brennan VM, Chap, et al. Rapid subcutaneousimmunoglobulin in children. Lancet 1993; 342: 1432-1433.20. Gardulf A, Andersen V, Bjorkander, et al. Subcutaneousimmunoglobulin replacement in patients with primary antibodydeficiencies: safety and costs. Lancet 1995; 345: 365-369.21. Fasth A, Nyström J. Safety and efficacy of subcutaneous humanimmunoglobulin in children with primary immunodeficiency. ActaPaediatr 2007; 96: 1474-1478.22. Waniewski J, Gardul A, Hammarstom L, Bioavailability of gammagobulinafter subcutaneous infusion in patients with common variableimmunodeficiency. J Clin Immunol 1994; 14: 90-97.23. Berger M. Subcutaneous immunoglobulin replacement in primaryimmunoglobulin replacement in primary immunodeficiency. ClinImmunol 2004; 112: 1-7.24. Ochs HD, Gupta S, Kiessling P, et al. Safety and efficacy of selfadministeredsubcutaneous immunoglobulin in patients with primaryimmunodeficiency diseases. J Clin Immunol 2006; 26:265-273.25. Chapel HM, Spickett GP, Ericson D. et al. The comparison of theefficacy and safety of intravenous versus subcutaneousimmunoglobulin replacement therapy. J Clin Immunol 2000; 20: 94-100.26. Pierce LR, Jain N. Risks associated with the use of intravenousimmunoglobulin. Transfus Med Rev 2003; 17: 241-251.27. Australian Health Ministers Advisory Council. Review of the useand supply of intravenous immunoglobulin in Australia. A report bythe Blood and Blood Products Committee. June 2000.htpp://www.nba.gov.au/pubs/_pdf.ivig.pdf (last accessed: 15February 2008).28. Vo AA, Cam Vi, Toyada M, et al. Safety and adverse events profilesof intravenous gammaglobulin products used for immunomodulation:a single center experience. Clin J Am Soc Nephrol 2006; 1:844-852.Allergy and Immunology Secrets 2/ewith STUDENT CONSULT Online AccessM. Eric Gershwin, MD and Stanley M. Naguwa, MD2005, softcover, 352 pp, 19 illus., Mosby, R490As the number of asthma and immunodeficiency cases continues to rise, thoroughknowledge of immunologic processes is becoming increasingly important. Despitethe seemingly small number of chapters, each chapter provides comprehensivecoverage of all the topics necessary to pass the allergy-clinical immunology boardsin the easy-to-use Secrets format. Chapters include epidemiology, pathophysiology,asthma, sinusitis, urticaria/angioedema, atopic dermatitis, anaphylaxis, food allergy/intolerance, insect allergy, drug hypersensitivity, immunodeficiency, and systemicmast cell disease. The smart way to study! Elsevier titles with STUDENT CONSULTwill help you master difficult concepts and study more efficiently in print and online!Perform rapid searches. Integrate bonus content from other disciplines. Downloadtext to your handheld device. And a lot more. Each STUDENT CONSULT title comeswith full text online, a unique image library, case studies, USMLE style questions,and online note-taking to enhance your learning experience.Key features Excellent preparation for allergy-clinical immunology boards. Includes a chapter on alternative medicine treatments for allergy. All the most important “need-to-know”, questions-and-answers in the proven format of the highlyacclaimed Secrets Series® Concise answers that include the author’s pearls, tips, memory aids, and “secrets” Bulleted lists, algorithms, and illustrations for quick review Thorough, highly detailed index Thought-provoking questions that provide succinct answers Presentation of a vast amount of information, but not overly simplistic.Orders: Medical Book Seller, Tel Jackie: 083 303 8500, fax (021) 975-1970,E-mail: jackie@medbookseller.co.zaCurrent Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 31

CASE OF THE MONTHAhmed Ismail Manjra, MB ChB, FC Paed (SA), DipAllergology (SA), M Clin Pharm, FAAAAIWestville, Durban, South AfricaC Motala, MB ChB, DCH (SA), FC Paed (SA), FACAAI,FAAAAIAllergy Clinic, Red Cross Children’s Hospital, CapeTown, South AfricaMASTOCYTOMA IN A 3-MONTH-OLDINFANTMastocytosis is a heterogeneous group of diseasescharacterised by the abnormal infiltration of mast cells(MC) in the skin and, sometimes, other organs.Symptoms in mastocytosis are caused by biologicalmediators released from MC and/or the infiltration ofneoplastic MC in various organs, the skin and the bonemarrow being predominantly involved. A WHO consensusclassification for mastocytosis 1 exists, which iswidely accepted and includes three major categories:1. Cutaneous mastocytosis (CM), a benign disease inwhich MC infiltration is confined to the skin, is preferentiallyseen in young children and exhibits amarked tendency to regress spontaneously.2. Systemic mastocytosis (SM), a rather rare disorder,it is commonly diagnosed in adults and includesfour major subtypes:(i) indolent SM (ISM, the most common forminvolving mainly skin and bone marrow);(ii) a unique subcategory termed SM with an associatednon-mast-cell clonal haematological disease(SM-AHNMD);(iii) aggressive SM, usually presenting without skinlesions, and(iv) MC leukaemia (MCL), probably representingthe rarest variant of human leukaemias.The diagnosis of SM, SM-AHNMD, and MCL might beconfused with a variety of endocrinological, vascular, orimmunological disorders. It is therefore of particularimportance to be aware of the possibility of an underlying(malignant) MC disease in patients with unexplainedvascular instability, unexplained (anaphylactoid)shock, idiopathic flushing, diarrhoea, headache, andother symptoms that might be mediator related. Animportant diagnostic clue in such cases is an increasedserum tryptase level.Systemic manifestations dependent on whether thereis multiorgan/specific organ involvement, e.g. recurrentflushing with multiorgan involvement; gastrointestinaltract involvement: increase in gastric and colonicmucosal mast cells, gastroduodenitis, bonemarrow:anaemia, thrombocytopenia, hepatosplenomegaly. 23. The extremely rare localised extracutaneous MCneoplasms, either presenting as malignancy (MCsarcoma) or as benign tumour termed extracutaneousmastocytoma.Diagnostic criteria for mastocytosis 1 are available andare widely accepted. SM criteria include one major criterion(multifocal compact tissue infiltration by MC) andfour minor criteria:(i) prominent spindling of MC;(ii) atypical immunophenotype of MC with coexpressionof CD2 and/or CD25 (antigens whichhave not been found to be expressed on normal/reactiveMC);(iii) activating (somatic) point mutations of the c-kitproto-oncogene usually involving exon 17, withthe imatinib-resistant type D816V being mostfrequent, and(iv) persistently elevated serum tryptase level(>20 ng/ml).To establish the diagnosis of SM, at least one majorand one minor criterion, or at least three minor criteria,have to be fulfilled.Case reportA 3-month-old child presented with a solitary, progressivelyenlarging lesion on the abdomen. There were noassociated systemic manifestations. There was nofamily history of mastocytosis. On examination thechild was well-looking and had a brownish-red lesion, 5cm in diameter on the abdominal wall. It was firm,shiny, nodular, non-tender with a typical peau d’ orangeappearance. (Fig 1). Stroking of the lesion with a tongueblade elicited a typical urticarial lesion (Darier’s sign).Abdominal examination was otherwise normal. Therewere no other cutaneous lesions. A punch biopsy wasperformed after application of an emla patch. Histologyrevealed dense infiltration of mast cells, typical featuresof a mastocytoma (Figs 2-4). The child was notgiven any treatment. The follow-up visit a month laterThis is a new feature aimed at highlighting instructivecase studies that clinicians encounter. If youhave an interesting case that you would like to sharewith our readiers, please submit your case report tothe Section Editor, Prof Cas Motala, e-mailcassim.motala@uct.ac.zaCorrespondence: Dr AI Manjra, PO Box 1085, Westville 3630, tel 031-265-1024, fax 031-265-1029, e-mail manjra@mweb.co.zaFig. 1. Mastocytoma on abdomenCurrent Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 33

Fig. 2. Surface epidermis with underlying infiltrate ofsmall mononuclear cellsFig. 3. High power view of infiltrate in dermis showingeosinophilic granules in the cytoplasm of the cells aswell as interspersed eosinophils.DiscussionSeveral recent studies 3-7 have reported distinct epidemiological,clinical and prognostic differences inpaediatric mastocytosis as compared with the adultform. The most common cutaneous lesions in childreninclude urticaria pigmentosa, mastocytoma (one-thirdof cases) and diffuse cutaneous mastocytosis. 3,4Mastocytomas are present at birth in over 40% ofcases. The disease occurs before the age of 2 years in50% of children, with a peak incidence of 60% in thefirst year of life. 5-7 Most cases of paediatric mastocytosisare sporadic and the majority of lesions are distributedover the trunk and limbs. Treatment of mastocytosisis usually symptomatic (H1 and H2 antihistaminesto control itching). A particularly important aspect ofmanagement is the avoidance of triggering factorssuch as hot weather/bath. In contrast to adults, mastocytosisin children usually has a benign course.Systemic, mast cell disease in adults is a long-lastingdisorder with recurrent and varying symptoms with thepotential for malignant transformation, albeit rare.AcknowledgementDr Anil Bramlev’s assistance is acknowledged for thepathology slides and reports.Fig. 4. Giemsa stain confirming granules in the cytoplasmtypical of mast cells.revealed that the lesion had almost completelyresolved. The patient has remained well and asymptomaticsince.Declaration of conflict of interestThe author declares no conflict of interest.REFERENCES1. Horny HP, Sotlark, Valent P. Mastocytosis: state of the art.Pathobiology 2007; 74: 121-132.2. Tebbe B, Stavropoulos PG, Krasagakis K, Orfanos CE. Cutaneousmastocytosis in adults. Evaluation of 14 patients with respect tosystemic disease manifestations. Dermatology 1998; 197: 101-108.3. Ben-Amitai D, Metzker A, Cohen HA.Pediatric cutaneous mastocytosis:a review of 180 patients. Isr Med Assoc J 2005; 7: 320-322.4. Kiszewski AE, Durán-Mckinster C, Orozco-Covarrubias L, Gutiérrez-Castrellón P, Ruiz-Maldonado R. Cutaneous mastocytosis in children:a clinical analysis of 71 cases. J Eur Acad Dermatol Venereol2004; 18: 285-290.5. Middelkamp Hup MA, Heide R, Tank B, Mulder PG, Oranje AP.Comparision of mastocytosis with onset in children and adults.J Eur Acad Dermatol Venereol 2002; 16: 115-120.6. Hannaford R, Rogers M. Presentation of cutaneous mastocytosisin 173 children. Australas J Dermatol 2001; 42: 15-21.7. Tay YK, Giam YC. Cutaneous mastocytosis in Singapore. SingaporeMed J 1993; 34: 425-429.34 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

ABC OF ALLERGOLOGYATOPIC ECZEMA – THE ITCH THATERUPTSAdrian Morris, MB ChB, DCH, MFPG, Dip Allergy(SA)Atopic eczema, otherwise known as atopic dermatitisor infantile eczema is a chronic relapsing itchy skin disease.Atopic eczema is usually the first clinical manifestationof allergy in atopic families. It usuallycommences about the third month of life as a weepyrash on the face and outer surfaces of arms and legsand then progresses in later childhood as a dry scalyand itchy rash commonly in the inner creases of theelbows and knees. Some children may not outgrowtheir eczema and the condition can persist or recurs inadulthood.Preventing eczemaDietInstitute general allergy prevention measures in highallergy-risk newborns. These include avoidance ofparental smoking during pregnancy and after birth, andbreastfeeding until at least 6 months of age. Commonallergy-provoking foods such as cow’s milk, eggs, fish,peanuts, wheat and soya should be avoided in thebreastfeeding mother's daily diet. Avoidance of solidfoods in babies up to 6 months of age can be followedby the careful introduction of the potential allergy-provokingfoods such as cow’s milk, wheat and egg after12 months, with nuts and fish only being introducedafter 24 months. Up to 25% of infantile eczema isaggravated by food allergy and food additives or colouringscan also aggravate eczema in older children. Skinirritation from pseudo-allergens in acidic citrus fruits,tomatoes, pineapples, berry fruits, cheese, chocolateand Marmite, occurs in patients with eczema. Thesefoods may also cause peri-oral and contact facial irritation.Discourage hit-and-miss elimination diets in childrenwith their potential for malnutrition.ClothingChildren should avoid hot, humid and cold, dry weather,sweating, woollen or synthetic clothing close to theskin and perfumed soaps. Cotton underwear, clothingand bed linen are recommended. Dry winter air anddust mites also aggravate eczema.Detergents and chemicalsNon-biological washing powders should be usedinstead of enzyme-enriched products. Use an additionalrinse cycle to remove all washing powder. Bubblebaths, household antiseptics and medicated soaps arebest avoided. Swimming pool chlorine may also irritateand dry out the skin. Local household skin irritantsinclude detergents, wool, mohair, nylon and feathers.House-dust mites and dog and cat dander may aggravateeczema.BathBath water should be lukewarm and moisturising emollientsmust be applied to the skin within 3 minutes ofCorrespondence: Dr A Morris, 303 Library Square, Wilderness Road,Claremont 7708. Tel 021- 674-3637, e-mail adrianm1@telkomsa.netpatting the skindry (never rub theskin dry). Avoidall soap, shampooand bubblebath; rather useplain aqueouscream as a soapsubstitute. AddOilatum Plus, colloidaloatmealand/or liquidparaffin to bathwater.Flexural eczema of child’s legs.In bedCover as much skin as possible with non-allergeniclightweight cotton clothing, taking care not to overdressor overheat the child. Cotton night mittens aswell as neatly clipped fingernails will reduce scratching.Sometimes elbow splints need to be applied to stopintractable scratching at night. Avoid all woollen andsynthetic garments.CareersYoung adults should decide on a career that is less likelyto expose them to irritant chemicals and avoid nursing,hairdressing, catering, motor mechanics, or thebuilding industry. Protective gloves with cotton innerliningswill help prevent irritant contact dermatitis thatis so very common in eczema sufferers.Treating eczemaEmollientsOintment is better than cream, use as much and oftenas possible.These moisturising creams and ointments (the greasierthe better) are the mainstay of eczema treatment. Theyare completely safe and should be applied liberally tothe whole body frequently (every 4 hours if necessary)to hydrate and protect the skin. Some people may findthat some of these preparations irritate their skinbecause of preservative or fragrance content; if thisoccurs, try another product. Suitable emollients includeemulsifying ointment, petroleum jelly, Epi-max,cetomacrogol, etc. Sometimes coal tar is applied totreat thickened skin. Aqueous cream is a good soapsubstitute but a poor emollient. Apply plenty of emollienta few minutes before applying the steroid creams.Prescribe at least 250 g per week for children and 600 gper week for adults.Steroid creamsDo not be afraid to use to clear eczema.Topical steroids provide rapid relief and when used nomore than twice daily for short periods (5-7 days) willsettle eczema flare-ups. They may also be used forlonger periods by diluting in any emollient (50:50) inwhich case treatment can be tapered off more slowly.Long-term steroid use may lead to thinning of the skinand colour changes; however the newer preparationsseem to be less problematic (mometasone and flutica-36 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

sone). Unfounded steroidophobia is a major problemand always leads to suboptimal eczema control.Treating the eczema aggressively in early life mayreduce further eczema exacerbations by ‘disciplining’the eczema. Hydrocortisone 1% is suitable to use onthe face but is too weak to treat eczema on the body.Alternate-day cortisone tablets may occasionally benecessary in very severe eczema.AntibioticsThese may be needed if eczema suddenly deteriorates.Eczema sufferers are more prone to skin infections(bacterial, fungal and viral, including the common wart).Antibiotic skin creams (fucidic acid and mupirocin) orchlorhexidine 5% in the bath and occasionally oralantibiotics (flucloxacillin) are prescribed to treat infectedeczema. Suspect an infection if there is suddendeterioration in the eczema with crusting, oozing anddiffuse skin redness. Swab the skin for bacterial cultureto identify staphylococcal and streptococcal colonisation,and remember to treat nasal carrier-status.AntihistaminesThese are essential to stop itch, sleep disturbance and‘allergic march’.The older sedating-type antihistamine tablets or syrupsuch as chlorphenamine and hydroxyzine will reduceitching especially at night. Antihistamine creams maysensitise the skin and should be avoided. Newer nonsedatingantihistamines have both anti-itch and antiinflammatoryproperties (cetirizine, loratidine,fexofenadine and their isomers) and should be usedcontinuously for a few months. Clinical studies suggestthat continuous use of cetirizine in early life slows the‘allergic march’ from eczema to asthma and urticaria(ETAC study)Wet wraps (if all else fails)Application of damp tubular elasticised bandages andocclusive dressings to the limbs at night promotes skinhydration and the absorption of emollients and steroidcreams. This is very effective in severe childhoodeczema on limbs with exudates. First apply steroidointment with plenty of moisturising emollients. Twolayers of elastic tubular bandages are applied over theaffected limbs. The inner layer is applied wet to aidabsorption of emollients and the outer layer applieddry.Other therapies (mostly ineffective)Be wary of unsubstantiated alternative eczema therapies.Miraculous natural cures for eczema are veryoften laced with crushed prednisone. Evening primroseoil (or gamolenic acid), flaxseed and omega 3 oilsoffer no additional benefit to eczema sufferers.Extracts of Chinese herbal tea have been evaluated buttaste awful and may cause liver toxicity. Difficult-totreateczema especially on the face may respond tonon-steroidal immune-modulator creams such astacrolimus (Protopic) and pimecrolimus (Elidel) but skinredness may be a side-effect. Ultra-violet light therapytreatment may be helpful. There is growing evidencethat lactobacillus supplements if given early mayreduce eczema in infants by altering the gut immuneresponses.Declaration of conflict of interestThe author declares no conflict of interest.REFERENCES1. Primary Care Dermatology Society & British Association ofDermatologists, Guidelines for the management of atopic eczema2006, http://www.bad.org.uk/healthcare/guidelines/BCDSBAD-Eczema.pdf (last accesssed 30 January 2008.)2. Lowe AJ, Hosking CS, Bennett CM, et al. Skin prick test can identifyeczematous infants at risk of asthma and allergic rhinitis. ClinExp Allergy 2007; 37: 1624-1631.3. Warner JO. A double-blinded, randomized, placebo-controlled trialof cetirizine in preventing the onset of asthma in children withatopic dermatitis: 18 months' treatment and 18 months' post treatmentfollow-up. J Allergy Clin Immunol 2001; 108: 929-937.(Query: Is this the ETAC study mentioned above? If not, pleasesupply ref for ETAC study.)Basic Immunology, 3/eFunctions and Disorders of the Immune System With STUDENT CONSULT Online AccessAbul K. Abbas, MBBS and Andrew H. Lichtman, MD, PhD2008, softcover, 320 pp, 250 illus, R720Here’s a readable and concise introduction to the workings of the human immune system, with emphasis onclinical relevance. The format makes learning easy with short, easy-to-read chapters, color tables, key pointsummaries, and review questions in every chapter.Key features Relates basic science to clinical disorders through clinical cases for better application in a real-worldsetting. Includes a full Glossary to keep you on the cutting edge of immunologic terminology. Includes appendices summarizing the features of CD Molecules, a handy Glossary, and Clinical Casesthat test your understanding of how the immune system functions in health and disease. Illustrated with beautiful full-color artwork for enhanced visual learning.New to this edition Provides the most up-to-date immunology information including coverage of regulatory T cells, and biologyof the Th17 subset of CD4+ T cells to keep you completely current. Access integration links through included STUDENT CONSULT access for more in-depth study.Orders: Medical Book Seller, Tel Jackie: 083 303 8500, fax (021) 975-1970,E-mail: jackie@medbookseller.co.zaCurrent Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 37

ALLERGIES IN THE WORKPLACEEPOXY RESIN EXPOSURE AND DERMATITIS– A CASE STUDYAnna Fourie, MScMedNational Institute for Occupational Health,Johannesburg, South AfricaHilary Carman, MB BCh, FFDerm (SA)NIOH Dermatology Clinic & private practice,Johannesburg, South AfricaTanusha Singh, MScMedNational Institute for Occupational Health,Johannesburg, South AfricaABSTRACTEpoxy resins are a well-known cause of occupationalcontact dermatitis (OCD). A high index of suspicionfor allergic or irritant contact dermatitis inworkers dealing with these agents should be maintained.The cases presented below highlight someof the complexities of assessing skin reactions toepoxy resins.INTRODUCTIONEpoxy resins are important raw materials with applicationsin practically every major industry. They are foundin adhesives and glues, laminates, surface coatings,paints and inks, product finishes, vinyl gloves, dentalbonding agents, floor coverings and microscopyimmersion oil. They are used primarily as two-componentadhesive systems comprising an epoxy resin anda curing agent (also called a hardener or catalyst). Someepoxy products also contain additives which may beirritants such as organic solvents, fillers such as fibreglassor sand, and pigments. Epoxy resin monomerspolymerise by cross-linking with the curing agents, orhardeners, to form the final product which is solid. Thehardening agents are usually amines or acid anhydrides.These solids have a three-dimensional network.The most commonly used monomer is made by combiningbisphenol A and epichlorohydrin to form diglycidylethers that vary in chain length. Some epoxiescure in a few minutes at room temperature. Othersneed additional time or heat to harden.The cured epoxy resin is non-sensitising. Allergic contactdermatitis (ACD) results from exposure to theuncured resin or to hardeners. Approximately 90% ofcases result from sensitisation to the epoxy monomer.The curing agents are responsible for the remainder ofcases. 1 Epoxy resins cause more cases of OCD thanany other chemical introduced in recent years. 2,3Therefore skin exposure to these substances in theworkplace should be avoided. Patch testing is used todetermine sensitivity to contact allergens, and specifictests to diagnose allergy to epoxy resin chemicals areavailable at the National Institute of OccupationalHealth (NIOH).Correspondence: Ms Tanusha Singh, National Institute forOccupational Health, PO Box 4788, Johannesburg, 2000. E-mailTanusha.singh@nioh.nhls.ac.zaContact dermatitis from epoxy resin exposure.CASES REPORTEDTen workers who presented with possible work-relatedskin disease and who had been exposed to epoxy resinwere referred to the NIOH for assessment betweenJanuary and August 2005. Eight workers came fromthe same company. This company used both quick-settingepoxy and heat-requiring epoxy. These processesresult in epoxy vapours which would be present in thefactory environment.MethodsThe workers were clinically assessed by means of aclinical and work history, and skin examination. Patchtesting was performed on all of the workers. TheEuropean standard (ESS) and/or plastic/glue (PG) serieswere used for testing. The ESS consists of 25 differentallergens which are the most frequently encounteredcauses of allergic contact dermatitis. Among these isepoxy resin which would pick up sensitisation in workersexposed to the chemical. In the plastics, glues andepoxy series in use at the time there were 7 other possibleallergens found in epoxy resins; the newer seriesavailable at NIOH now has 9 other allergens.Patch testingWorkers were referred for patch testing by occupationalhealth practitioners at the companies where theywork and by dermatologists. Patch tests were notdone on workers with acute widespread dermatitis orthose on oral steroids. The allergens used wereobtained from Chemotechnique Diagnostics (Malmö,Sweden) and Trolab Hermal (Reinbeck, Germany) andincluded the European standard and plastic, glues andepoxy series of patches as well as substances obtainedfrom the workers’ respective workplaces. Patch testingwas performed with IQ chambers from Chemotechniqueand left in place for 3 days. They were readbetween 15 and 30 minutes after removing the patches.Ideally patches should be left in place for 48 hours,removed, the results read and the reading repeatedafter another 24 or 48 hours. This allows for differentiationbetween allergic and irritant reactions since an irri-Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 39

tant reaction fades by 72 hours. For practical reasonsthe patches were read only once, after 3 days.Patients were instructed to remove the patches if theydeveloped a severe reaction before the second visitand to note exactly where the patches had beenplaced. The reactions are graded as shown in Table I.Table I. Interpretation of patch test reactionsGrade Reaction Appearance– Negative Normal? Questionable Erythema1+ Weak Non vesicular witherythema and papules2+ Strong Vesicular or oedematous3+ Extreme Spreading, bullous orulcerativeIR Irritant Glazed, ‘burned appearance’,pustular, edge effectResultsResults are shown in Table II.Clinical presentationA careful work history confirmed that all workers wereemployed in factories in which epoxy resins were used.All the workers complained of itch and/or a burningsensation of the skin. Eight workers presented withdermatitis (redness, swelling, blistering, weeping, scalingand thickening of the skin). One worker presentedwith swelling and redness of his eyes and lips whichwas typical of urticaria. The tenth worker presentedwith patchy loss of pigmentation known as leucoderma.The distribution of the rash, namely on the hands,arms, neck, body and face suggested that the workerswere exposed to dusts and vapours containing the sensitisingagents, as well as known direct skin contact.Patch testing• Four of the workers had definite reactions (1-2+) toepoxy resin included in the European standard series.This confirmed true allergy.• A further 3 workers had questionable reactions (?) tothe same allergen, indicating possible allergic reactions.Workers were also tested with relevant allergensfrom the plastic and glues series but thesewere negative.• Four of the workers reacted to epoxy-based substancesfrom the workplace.• One of the workers developed mild irritant reactionsto workplace substances.• Worker No. 7 complained of swelling of the eyes andlips immediately after entering the workplace areawhich is consistent with an acute urticaria.• Worker No. 9 presented with leucoderma (resemblingvitiligo) around the eyes and on the neck.DISCUSSIONFrom the results it can be seen that exposure to epoxyin these workers caused occupational contact irritantand allergic dermatitis, urticaria and leucoderma.Symptomatic workers who are exposed to epoxyresins should be assessed by means of a detailed medicalwork and exposure history, a medical examinationand comprehensive allergy testing. The most commonskin reaction in these workers was contact dermatitiswhich is known to be the most common form of occupationalskin disease (OSD). 4,5 In the cases consideredin this study half of those tested had definite reactionsto epoxy resins while three others had equivocal reactions.This corresponds with other studies that indicatethat epoxy resin is a common cause of ACD. 6-8The questionable reactions indicated possible sensitisationand these workers should be monitored andretested if indicated.In addition to the ESS the appropriate allergens fromthe plastic, glues and epoxy series were applied butthese were negative. In the newer epoxy series(Chemotechnique) additional allergens have recentlybecome available. These are important as it has beenshown that polyamine hardeners such as diethylenetriamine,triethylenetetramine and dimethyloaminopropylamine, as well as reactive diluents can alsocause allergic reactions. 7-9Therefore potential reactions in patients who may havebeen allergic to these epoxy chemicals were notdetected. It is hoped that the NIOH will shortly acquirethese allergens. In addition positive reactions may havebeen missed since reactions occasionally occur up to 6to 7 days after application of the patch test. 10This case study highlights the importance of testingwith workplace agents and confirms the findings ofother studies. 11 In one case the worker tested negativeto the epoxy allergens in the commercial series butpositive to the workplace substance. In another caseepoxy resin allergy was confirmed by a positive reactionto the allergen supplied by the workplace.The composition of workplace agents may not be identicalto the commercially available allergens because ofmanufacturing variations and different formulations.Tests with workplace substances, however, are problematicas false-negative and false-positive reactionsmay occur. The substance may be inappropriately dilutedor may contain other irritating constituents.Epoxy resins and many other chemicals used in theworkplace (e.g. thinners, mica, and solvents) maycause irritant reactions in workers. Since patch testsidentify allergic reactions and are not useful in thedetection of irritant reactions the possibility of irritantreactions should be considered in all cases. In thecases described above many workers used thinners toremove cured epoxy from their hands. In an attempt toremove cured epoxy one worker resorted to usingsandpaper.Worker No. 7 complained of an almost immediateswelling of the eyes and lips when entering the workarea. This is typical of an urticarial type of response(probably IgE-mediated hypersensitivity reaction).Urticarial reactions are rare but do occur in epoxy-resinexposedsubjects, normally in conjunction with ACD. 8This IgE type of reaction is important since it can leadto other occupational disorders such as rhinitis, conjunctivitisand asthma. 12An unexpected finding was a case of leucoderma(resembling vitiligo) around the eyes and on the neck ofworker No. 9. Several such cases following allergiccontact dermatitis to epoxy resin have been documented.3,8 Occupational health workers in companieswhere epoxy resins are used should be aware of thiscondition.Since epoxy resin exposure is a common cause ofOCD, it is important that the work environment is wellcontrolled and the workers properly protected. Thereactions on the face and neck seen in some of theworkers demonstrate the importance of vapours andpossibly dusts in causing OCD.40 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

Table II. Summary of exposure, clinical findings and patch test reactions for individual casesJob description Occupational exposure Clinical findings Patch testAllergenReaction1. Encapsulating Epoxy resin, thinners, mica Itchy, vesicular rash Epoxy resin (ESS) ?on arms, neck & Potassium dichromate (ESS) ?around eyes Clioquinol (ESS) 2+Fragrance mix (ESS) ?Epoxy resin (W) 1+2. Crane driver Epoxy resin, mica sheets Itchy rash on feet, Epoxy resin (ESS) 2+upper body & arms, Fragrance mix (ESS) 2+hyperpigmented areas Epoxy resin (W) 2+seen3. Process worker Epoxy resin, thinners, mica Itchy rash on dorsum Cobalt Chloride (ESS) 1–2+of hands, arms & neck Epoxy resin (ESS) ?Nickel sulphate (ESS) 1+4. Process worker Epoxy resin, thinners, Itchy rash on neck, ESS Negmica & greaseface & forearms,swelling of eyes & face5. Armature winder Epoxy resins, thinners, Itchy, red rash & dry, ESS Negvarnish, Bostik putty, scaly skin on inner Epoxylite (W) ?IRthermosetting tape forearm Hot potting resin (Part A) (W) ?IR6. Encapsulating Epoxy resin, thinners, mica, Itchy rash on dorsum Epoxy resin (ESS) 1+heavy-duty hand cleaner of hands, forearms, Epoxylite (W) 1+neck & eyelids,swelling of eyes7. Encapsulating Epoxy resin, thinners, Red, swollen eyes & Epoxy resin (ESS) 1+mica & greaseswollen lips, no visiblecontact dermatitis8. Core making Epoxy resins; powder coating, Itchy vesicular rash on Epoxy resin (ESS) ?Heavy-duty hand cleaner palmar & dorsal surfaceof hands, & web spaces9. Coil taping Epoxy resin, thinners, mica Depigmented areas Epoxy resin (ESS) 2+around eyes & neck Nickel sulphate (ESS) 2+(Contact leucoderma)10. Apprentice Epoxy resin, cold glue, Dry, scaly, cracked skin Wool alcohols (ESS) ?pattern maker wood, thinners on hands, starts as Paratertiary phenolitchy, vesicular rash formaldehyde resin (ESS) ?Reactions: Neg = negative; ? = questionable; 1+ = weak; 2+ = strong; 3+ = extreme; IR = irritant.Allergens: ESS = European Standard Series; W = substances from the workplace.Airborne contamination must be controlled through theintroduction of adequate ventilation such as localexhaust ventilation. 13 In addition personal protectiveequipment should include safety glasses, face shield,and full face respirators depending on the extent ofexposure.Appropriate hand and body protection is required. Theglove material should be appropriate for the type ofchemical exposure. Latex gloves give good protectionagainst epoxy resins but only fair protection against thehardeners and solvents encountered. Ethyl vinyl alcohollaminate gloves on the other hand provide excellentprotection if used within the limits of the breakthroughtime. They should be replaced if damaged. 14 Chemicalresistantclothing, including disposable aprons, coveralls,lab coats and sleeves, should also be used. 13SUMMARYEpoxy resins cause dermatitis, both true allergic andirritant, leucoderma and urticaria. Health care workersshould be alert to the problems caused by these chemicalsand should ensure that all possible cases are fullyassessed. It is important that optimum protectivemeasures should be instituted to protect all workersfrom these potentially dangerous substances.Declaration of conflict of interestThe authors declare no conflict of interest.REFERENCES1. Marks J, Elsner P, DeLeo V, eds. Contact & OccupationalDermatology. 3rd ed. Chapter 5 (Standard Allergens). St Louis:Mosby Inc, 2002.2. Rietschel R, Fowler J, eds. Fisher’s Contact Dermatitis. 4th ed.Chapter 29 [Plastic (Synthetic Resin) Dermatitis]. Baltimore:Williams & Wilkins, 1995.3. Bray PG. Epoxy resins. Occup Med 1999; 14: 743-758.4. Gawkrodger DJ. Patch testing in occupational dermatology. OccupEnviron Med 2001; 58: 823-828.5. Chew AL, Maibach HI. Occupational issues of irritant contact dermatitis.Int Arch Occup Environ Health 2003; 76: 339-346.6. Jappe U, Geier J, Hausen BM. Contact vitiligo following a strongpatch test reaction to triglycidyl-p-aminophenol in an aircraft indus-Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 41

try worker: case report and review of the literature. ContactDermatitis 2005; 53: 89-92.7. Geier J, Lessmann H, Hillen U, et al. An attempt to improve diagnosticsof contact allergy due to epoxy resin systems. First resultsof the multicentre study EPOX 2002. Contact Dermatitis 2004; 51:263-272.8. Kanerva L, Pelttari M, Jolanki R, Alanko K, Estlander T, Suhonen R.Occupational contact urticaria from diglycidyl ether of bisphenol Aepoxy resin. Allergy 2002; 57: 1205-1207.9. Jolanki R, Kanerva L, Estlander T, Tarvainen K, Keskinen H, Henriks-Eckerman ML. Occupational dermatoses from epoxy resin compounds.Contact Dermatitis 1990; 23: 172-83.10. Jonker MJ, Bruynzeel DP. The outcome of an additional patch-testreading on days 6 or 7. Contact Dermatitis 2000; 42: 330-335.11. Ormond P, Hazelwood E, Bourke B, Lyons JP, Bourke JF. Theimportance of a dedicated patch test clinic. Br J Dermatol 2002;146: 304-307.12. Kanerva L, Jolanki R, Tupasela O, et al. Immediate and delayedallergy from epoxy resins based on diglycidyl ether of bisphenol A.Scand J Work Environ Health 1991; 17: 208-215.13. Epoxy Resin Systems Safe Handling Guide 1997 [cited 2007/05/25]; Available from: http://www.plasticsindustry.org/about/epoxy/epoxy_guide.htm.14. Health and Safety Executive. An Assessment of Skin Sensitisationby the Use of Epoxy Resin in the Construction Industry. ResearchReport 079, 2003. Granta Park, Cambridge [cited 2007/05/25];Available from: http://www.hse.gov.uk/research/rrpdf/rr079.pdfManaging the Allergic PatientJohn H. Krouse, MD, PhD, M. Jennifer Derebery, MD and Stephen J. Chadwick, MD2008, hardcover, 400 pp, 300 illus., 265 x 195 mm, R1 800This new reference provides up-to-date, disease-specific diagnostic and treatmentprotocols in a new, full-colour, heavily illustrated reference. This is the most currentallergy management information at your fingertips – regardless of your medicalspecialty.Key Features Get the most up-to-date guidance from the most trusted experts in the field. Quickly locate key anatomy, tests, and management protocols in the clinicalsetting. Find everything you need in one place with diagnosis and managementincluded in each chapter. Compare common presentations and quickly reference the latest in diagnosisand treatment options with over 300 clinical and diagnostic algorithms, photographs,charts, and tables.Contents1 – Introduction to Allergy. 2 – Principles of Allergy Management. 3 – Management of the Patient withRhinitis. 4 – Management of the Patient with Rhinosinusitis. 5 – Management of the Patient with Asthma.6 – Management of the patient with Ocular Allergy. 7 – Otitis Media: Background and Science. 8 – Managementof the Child with Otitis Media. 9 – Management of the Patient with Inner Ear Allergy. 10 – Managementof the Patient withLaryngitis. 11 – Management of the Patient with Drug Allergy. 12 – Management of thePatient with Occupational Allergy. 13 – Management of the Patient with Atopic Skin Disease. 14 – Managingthe Allergic Child.15 – Management of the Patient with Anaphylaxis.Allergy 3/eStephen T. Holgate and Lawrence M. LichtensteinAugust 2006, hardback, 448 pp, 450 illustrations, Mosby, R1 700This comprehensive, clinically oriented full-colour resource offers you a wealth ofdetailed information on the diagnosis, treatment, and management of allergic diseases—fromasthma to urticaria. Thoroughly updated to reflect today’s knowledge,this edition features all of the latest developments in allergy and immunology. Plus, aconsistent, logical organization puts vital information at your fingertips.Features Features abundant algorithms that provide at-a-glance assistance in identifyingthe allergic conditions. Offers in-depth information in a chapter dedicated entirely to asthma. Valuable treatment protocols assist in prescribing appropriate therapies andeffective management Includes extensive references that point the way to the key works in the literature. Features a new detailed chapter on pediatric allergy, an increasingly common condition. Includes a CD-ROM containing all of the illustrations from the book downloadable into PowerPoint.Orders: Medical Book Seller, PO Box 3784, Tygervalley 7536Tel Jackie: 083 303 8500, fax (021) 975-1970,E-mail: jackie@medbookseller.co.za42 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

SNIPPETS FROM THE JOURNALSAllan S Puterman, MB ChB, FCP, FAAAAIThe November 2007 edition of the Journal of Allergyand Clinical Immunology contains the long-awaitedreport of the National Asthma Education andPrevention Program – Expert Panel Report 3.This report entitled Guidelines for the Diagnosis andManagement of Asthma is also supported by the USADepartment of Health and Human Science NationalInstitutes of Health and the National Heart, Lung andBlood Institute.This is one of the most comprehensive guidelines onasthma management currently published. The guidelinesopen with a detailed disclosure of financial interestsby all participants. The guidelines define asthma,explore the diagnosis and expand on long-term management.Management consists of four components including:• assessing and monitoring asthma severity and control• education for a partnership of care• control of environment and comorbid conditions• medication.The panel emphasises the importance of control buttakes into account both the degree that manifestationsof asthma are minimised by therapeutic intervention(control) as well as the intrinsic intensity (severity) ofthe disease process in a particular patient. The panelrecommends that for managing asthma, one should‘assess severity to initiate therapy and assess controlto adjust therapy’.New concepts introduced include ‘Current impairment’which refers to frequency and intensity of symptoms,low lung function and limitations of daily function.Further ‘Future risk’ refers to a likelihood of exacerbations,progressive loss of lung function and adverseeffects of medication. The guidelines stress that somepatients may be at high risk for exacerbations eventhough they have few day-to-day symptoms.The educational aspect confirms the importance ofteaching patients skills to self-monitor and manageasthma. A written asthma action plan is key. New recommendationsencourage expanding education intoschools and also deal with clinician education.The stepwise approach is emphasised with theincrease to 6 steps from the original 4. I have taken theliberty of reproducing Figure 13 ‘Stepwise approach formanaging asthma long-term in children 0 to 4 and 5 to11’, firstly, to show how this guideline is both comprehensiveyet simple, and secondly because it covers theage group that is often the most problematic.This guideline supplement is a timely addition as it mayprovide the answer to a pertinent question asked byHans Bisgaard in the Letters to the Editor section ofthe JACI October 2007 edition, namely ‘What drivesprescription patterns in pediatric asthma management?’He has analysed data from the Danish Asthma Registerof Medicinal Products Statistics which containsrecords from all prescriptions for medicinal productsprescribed in Denmark. His analysis shows anincreased prescription in children of combinationICS/LABA products as well as an increased use ofthese products as first-line treatment in previouslysteroid-naïve children. Both trends are contrary toDanish guidelines. His discussion includes possiblereasons, such as real-life experience may be betterthan clinical trials, and disease severity may be increasing.Pharmacuetical industry pressure and inefficientguideline dissemination are also mentioned.The answer to Bisgaard’s question may lie in a verysimple line that is repeated often in the new Americanguidelines. ‘The stepwise approach is meant toassist, not replace, the clinical decision-makingrequired to meet individual patient needs.’Correspondence: Dr A Puterman, e-mail: putall@global.co.za44 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

➞Step up if needed (first check inhaler technique, adherence, environmental control, andcomorbid conditions)Assist controlStep down if possible (and asthma is well controlled at least 3 months)Step 6➞Step 5Step 4Step 3Step 2Step 1NotesChildren 0-4 Years of AgePreferredAlternativeQuick-ReliefMedicationIntermittentAsthmaPersistent Asthma: Daily MedicationConsult with asthma specialist if step 3 care or higher is required. Consider consultation at step 2.SABA PRN Low-dose ICS Medium-dose ICS Medium-dose ICS+LABA ormontelukastCromolyn ormontelukastEach Step: Patient Education and Environment ControlHigh-dose ICS+LABA ormontelukastHigh-dose ICS+LABA ormontelukast• SABA as needed for symptoms: Intensity of treatment depends on severity of symptems• With viral respiratory symptoms: SABA q 4-6 hours (longer with physician consult).Consider short course of oral systemic corticosteroids if exacerbation is severe or patient hashistory of previous sever exacerbations.Caution: Frequent use of SABA may indicate the need to step up treatment. See text* forrecommendations on initiating daily long-term-control therapy.+oral corticosteroids• The stepwise approach is meant to assist, not replace, theclinical decision-making required to meet individual patientneeds.• If an alternative treatment is used and response isinadequate, discontinue it and use the preferred treatmentbefore stepping up.• If clear benefit is not observed within 4-6 weeks, andpatient’s/family’s medication technique and adherence aresatisfactory, consider adjusting therapy or an alternativediagnosis.• Studies on children 0-4 years of age are limited. Step 2preferred therapy is based on Evidence A.* All otherrecommendations are based on expert opinion andextrapolation from studies in older children.• Clinicians who administer immunotherapy should beprepared and equipped to identify and treat anaphylaxis thatmay occur.Key: Alphabetical listing is used when more than one treatmentoption is listed within either preferred or alternative therapy.ICS, inhaled corticosteroid; LABA, inhaled long-actingß 2 -agonist; LTRA, leukotriene receptor antagonist; oral corticosteroids,oral systemic corticosteroids ; SABA, inhaled shortactingß 2 -agonist.Children 5-11 Years of AgePreferredAlternativeQuick-ReliefMedicationIntermittentAsthmaPersistent Asthma: Daily MedicationConsult with asthma specialist if step 4 care or higher is required. Consider consultation at step 3.SABA PRN Low-dose ICS Low-dose ICS+Cromolyn,LTRA,nedocromil ortheophylineLABA , LTRA ortheophylineORMedium-dose ICSMedium-dose ICS High-dose ICS++LABALABAMedium-dose ICS+LTRA ortheophylineHigh-dose ICS+LTRA ortheophylineHigh-dose ICS+LABA+oral corticosteroidsHigh-dose ICS+LTRA ortheophyline+oral corticosteroidsEach Step: Patient Education, Environment Control, and Management ofComorbiditiesSteps 2-4: Consider subcutaneous allergen immunotherapy for patitentswho have persistent, allergic asthma• SABA as needed for symptoms: Intensity of treatment depends on severity of symptoms up to3 treatments at 20-minute intervals as needed. Short course of oral systemic corticosteroidsmay be needed.Caution: Increasing use of SABA or use >2 days a week for symptom relief (not prevention of EIB)generally indicates inadequate control and the need to step up treatment.• The stepwise approach is meant to assist, not replace, theclinical decision-making required to meet individual patientneeds.• If an alternative treatment is used and response isinadequate, discontinue it and use the preferred treatmentbefore stepping up.• Theophyline is a less desirable alternative due to the needto monitor serum concentration levels.• Step 1 and step 2 medications are based on Evidence A.*Step 3 ICS and ICS plus adjunctive therapy are based onEvidence B* for efficacy of each treatment and extrapolationfrom comparator trials in older children and adults –comparator trials are not available for this age group; steps4-6 are based on expert opinion and extrapolation fromstudies in older children and adults.• Immunotherapy for steps 2-4 is based on Evidence B* forhouse-dust mites, animal danders, and pollens; evidence isweak or lacking for moulds and coclroaches. Evidence isstrongest for immunotherapy with single allergens. The roleof allergy in asthma is greater in children than adults.• Clinicians who administer immunotherapy should beprepared and equipped to identify and treat anaphylaxis thatmay occur.Key: Alphabetical listing is used when more than one treatmentoption is listed within either preferred or alternative therapy.EIB, exercise-induced bronchospasm; ICS, inhaled corticosteroid;LABA, inhaled long-acting ß 2 -agonist; LTRA, leukotrienereceptor antagonist; SABA, inhaled short-acting ß 2 -agonist.*See original article for detailsCurrent Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 45

SECRETARY’S REPORTA brief update of ALLSA Excomactivities during the past fewmonths:A considerable amount of time hasbeen spent on updating the membershipdatabase so as to ensureeffective communication withmembers.Preparations for the congress to beheld between 29 May and 1 June2008 at Sun City are at anadvanced stage. ALLSA is honoured to have threeinternational faculty who will be delivering state-of-theartpresentations this year – Prof T Platts-Mills (USA),Prof S Prescott (Australia) and Prof N Papadopoulos(Greece).On the research front, a total of four ALLSA researchawards to the value of R125 000 were announced atthe end of last year. The successful applicants were DrAnita van der Walt, Dr Didintle Motsepe, Dr BarbaraNurse and Ms Gina Stear. It is anticipated that a similaramount of funding will be made this year too, thanks toour sponsors, GlaxoSmithKline, AHR Pharma (formerlyUCB Pharma), MSD and Cipla Medpro.ALLSA hosted a successful symposium on ‘Allergy andasthma to seafood: A paradigm model for developingcountries’ at the WAO Congress in Thailand inDecember last year (see report elsewhere in thisissue). A number of South African researchers also presentedtheir scientific communications in various othersessions of the congress.On the advocacy front, ALLSA has written a letter tothe SAMJ on its position with regard to ALCAT/IgGtesting, which will be published in March 2008. ALLSAExcom continues its work on developing the ALLSAgovernance charter.We would like to extend special thanks to RuwaydaAdams, Anne Hahn and Jean Aprill for their supportwork in the Cape Town office and production of theALLSA journal.Mohamed JeebhayHonorary SecretaryALLSA INTER-CITY MEETINGS 2008GAUTENGVENUE: MSD offices MidrandDate: Wednesday evening 19h00 for 19h3012 MARCH Dr Omolemo Kitchin/Dr Teshni MoodleySome fascinating cases in allergy practice7 MAY World Asthma Day Speaker to be confirmed16 JULY Dr Sharon Kling Ethics of Allergy Practice22 OCTOBER Dr Mike Levin New Thoughts on Allergy Diagnostic TestingEach meeting also includes local speakers who will prepare case studiesDr T MoodleyDr R MasekelaDr O KitchinDr H LewisDr A Halkas48 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

NEWSALLSA hosts a symposium at the WorldAllergy Congress in BangkokThe XX World Allergy Organisation Congress was heldfrom 2-6 December 2007 in Bangkok, Thailand. TheAllergy Society of South Africa (ALLSA) hosted a symposiumon ‘Allergy and asthma to seafood: a paradigmmodel for developing countries’. The symposium wasco-chaired by Prof. Mohamed Jeebhay from the Schoolof Occupational and Environmental Medicine at theUniversity of Cape Town and Dr Andreas Lopata fromthe Royal Melbourne Institute of Technology inAustralia. Seminars in the session presented aspectsof ongoing research on seafood allergy at theUniversity of Cape Town, which covered‘Epidemiological studies of allergy and asthma amongseafood processing workers in South Africa’ and‘Molecular characterisation of fish and crustaceansallergens causing allergy’, presented by Prof. Jeebhayand Dr Lopata, respectively. Dr Natalie Nieuwenhuizen,a postdoctoral fellow in the Division of Immunology atthe University of Cape Town, sponsored by MSD SouthAfrica to attend the conference, delivered a paper on‘Immunological mechanisms of seafood allergy’. Thefinal presentation, ‘Allergen microarray technology fordiagnosis and surveillance of seafood allergy’described the results of allergen microarray studiesperformed in collaboration with the Centre forProteomics and Genomics Research, directed by DrReinhard Hiller. The symposium highlighted the issuethat seafood allergens are important in causing allergiesand asthma in the occupational setting. The majordifference between consumer-related seafood allergyand occupational seafood allergy is that sensitisationprimarily occurs through inhalation of allergens presentin aerosols produced during processing of seafood. Thesymposium highlighted the need for characterisation ofthese airborne seafood allergens for further applicationin diagnosis, workplace environmental control andimmunotherapy in domestic and occupational settings.Prof Jeebhay addressing the symposium.Left to right:Drs AndreasLopata and NatalieNiewenhuizen withProf MohamedJeebhay enjoyingthe marvellouscultural heritage ofThailand at theGrand Palace.Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 49

PATIENT INFORMATION SHEETS –ANOTHER ALLSA MEMBERSHIP BENEFITDid you know that membership of ALLSA entitles you to receive copies of ourPatient Information Sheets which provide information on various aspects of allergyin an easy-to-understand format for your patients?Topics covered include:Allergen ImmunotherapyAllergic Reactions to Honey Bee and Wasp StingsAllergic RhinitisBedding Protectors and Allergy ControlCockroach AllergyCoeliac DiseaseContact DermatitisDrug AllergyEgg AllergyFish AllergyFood Additives and PreservativesFood AllergyHouse-Dust Mite AllergyLatex AllergyMilk Allergy/IntoleranceMould AllergyPeanut AllergyPet AllergySeafood AllergySoya AllergyTreatment of Allergic EczemaUrticaria and AngioedemaVacuuming and Allergy ControlWheat AllergyPatient information sheets can be ordered in batches of 50 from the ALLSA office,tel 021-447-9019, email mail@allergysa.orgThere is no charge for the leaflets, but we do charge for postage.50 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

PRODUCT NEWSNEW DESIGN FOR SYMBICORDAstraZeneca is proud to introduce a new design forSymbicord boxes and packaging. The purpose of thepackaging change is to standardise the colours anddesign globally, so that wherever in the world youmay be, the Symbicord packaging will look the same.In line with these changes, we are also keeping thesecolours for our promotional and educational material,so that the design is standardised throughout. Thenew look is bold, positive, professional and modern,with an emphasis on clinically relevant and clear information.The approach is future-focused, to reflect theconstant innovation and challenging of conventionsthat is the basis of our approach to medicine atAstraZeneca.Please note that the ingredients and doses ofSymbicord will remain the same.In conjunction with the new look, AstraZenecaintends to introduce user-friendly educational andsupport material to assist and support people withasthma.The new material is aimed at providing the busyphysician and his/her patients with the tools that theyneed so that people with asthma can take responsibilityfor their own asthma control.S 3Symbicord® Turbuhaler® 80:4,5 µg/dose (Inhaler), Reg No.35/21.5.1/0404. Each delivered dose contains as active constituents:Budesonide 80 micrograms and formoterol fumaratedihydrate 4,5 micrograms.S 3S 3Symbicord® Turbuhaler® 160:4,5 µg/dose (Inhaler), RegNo. 35/21.5.1/0405. Each delivered dose contains as activeconstituents: 160 micrograms and formoterol fumarate dihydrate4,5 micrograms.Symbicord® Turbuhaler® 320:9 µg/dose (Inhaler), Reg No.38/21.5.1/0187. Each delivered dose contains as active constituents:Budesonide 320 micrograms and formoterolfumarate dihydrate 9 microgramsNAME AND BUSINESS ADDRESS OF THE HOLDEROF THE CERTIFICATE OF REGISTRATION:AstraZeneca Pharmaceuticals (Pty) Limited, 5 Leeuwkop Road,Sunninghill, 2157, South Africa. Reg No. 92/05854/07.Tel: +27 11 797 6000. Fax: +27 11 797 6001. www.astrazeneca.co.zaHEALTHWAY EMF AIR PURIFIERWorld’s most advanced medical grade airpurifiersStudies have shown that indoor pollution is five timesmore dangerous than outdoor pollution and we spend90% of our time indoors. It seems we live in an environmenttailored to creating allergy sufferers.One of the best ways to combat allergies is to removeairborne allergens in the first place. Until recently, thiswas not possible for the average man on the street as itrequired expensive, advanced equipment.Healthway has pioneered the quest for smaller air purificationunits that are packed with all the required technologybut packaged into an affordable product.The Healthway EMF Air Purifier is one of the mostadvanced air purification systems in the world. It is certifiedby FDA as a class 2 medical device and defined as amedical air purification system.Independent laboratory testing certified that bacteriawere reduced by 98-100%, virus by 99-100% and mouldand fungi by 94-100%.The system includes dual cleanable pre-filters for largerparticulate collection. It also includes 4 pounds of granulecarbon and zeolite filter for high-capacity multiplegas/chemical scrubbing.The EMF system is 99.97% efficient at collecting 0.3microns size particulate. The 12 inch diameter EMF filteris 100% sealed so no air can bypass around the filter, toensure 100% of the air passing through the system istreated by the EMF germ-killing zone.H2O International is proud to be the exclusive distributorof this product. With a 13-year history of great service,over 70 branches nationwide and a central warehousestocked with maintenance staff and parts, you can restassured that you are buying from a well-established companythat can back you up on any after-sales service youmay need.Call H2O toll free on 0800 492 837 and receive a freeindoor quality test valued at R495.00.52 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

PRODUCT NEWSMSD (Pty) Ltd is proud to announce the introduction ofSINGULAIR 4 mg. Studies have shown that asthma in childrenunder the age of six is on the increase worldwide. 1SINGULAIR 4 mg is the first asthma controller therapy, thatis not a steroid, to be approved in South Africa for childrenas young as 2 years old. 2Studies have shown improvements in symptom and activityscores from as early as day one, affirming the efficacy ofSINGULAIR 4 mg in this age group. 3 The current guidelinesfor treatment of asthma in children, as compiled by theAllergy Society of South Africa (ALLSA), call for the introductionof a leukotriene antagonist as a controller agent inthis age group at step 2, after the use of short-acting relievermedication has proven to be inadequate in controllingasthma symptoms. In other words using leukotriene antagonistas a first line controller agent. 4 At present, of theleukotriene receptor antagonists, only SINGULAIR is indicatedfor use in children under the age of 12. 2SINGULAIR 4 mg is indicated for the prophylactic treatmentof mild to moderate asthma in the 2-5 year old age group.SINGULAIR 4 mg is presented in a 28-day pack and onetablet should be taken once daily at bedtime. 2 To date worldwideuse is more than 2.2 million children in more than 90countries. This puts SINGULAIR in the unique position ofbeing the only controller therapy to be registered and indicatedfor asthmatic patients from 2 years old and up. 2TheFREEDOMtobe a Child!REFERENCES:1 Ehrlich, R. The Prevalence of Asthma in South Africa. CurrentAllergy and Clinical Immunology March 2002; Vol 15: 4-8.2 Data on File.3 Knorr B, Franchi LM, Bisgaard H, et al. Montelukast, a leukotrienereceptor antagonist, for the treatment of persistent asthma inchildren aged 2 to 5 years. Pediatrics 2001;108(3):1-10.4 Motala C, Kling S, Gie R, et al. Guidline for the management ofChronic Asthma in Children – 2000 Update. SAMJ. 2000; 90:524-539.MSD (Pty) Ltd (Reg. No. 1996/003791/07), Private Bag 3, HalfwayHouse 1685.Copyright © MERCK & CO., INC., Whitehouse Station, N.J., U.S.A.1999. ® Registered Trademark of MERCK & CO., INC., WhitehouseStation, N.J., U.S.A. Before prescribing, please refer to the full packageinsert. 06-2004-SGA-03-ZA-230-OReg. No: 35/10.2.2/0397, SINGULAIR 4 mg S3Cipla’s Dry Powder RangeStill the most cost-effective 1 combinations available!Feb 2008For Mr. Moderate AsthmaticRx: with DP-Haler l Revolizer1. Budeflam DP 400µg daily2. Foratec DP 12µg daily3. Asthavent 200µg DP PRNDr Make It- BetterREFERENCE1. PCD Feb 2008.S3 Reg. No. 36/21.5.1/0258S2 Reg. No. 37/10.2.1/0084S2 Reg. No. 30/10.2.1/0345Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 53

PRODUCT NEWSBOEHRINGER INGELHEIM LAUNCHESTHE NEW INFLAMMIDE ® 200 NOVOLIZER ®The prevalence of asthma is continuing to rise throughoutthe world and South Africa. Guidelines still recommendinhaled corticosteroids as the cornerstone ofasthma therapy. 1 Despite the availability of numeroustreatments the disease remains poorly controlled. 2Inappropriate and incorrect use of inhaler devices contributeto the lack of adequate asthma control; 71% ofpatients misuse their MDIs and up to 47% of patientscannot co- ordinate on activation and inspiration. 3 It isnow well recognised that improvement in drug deliverywill continue to be paramount in improving asthma management.4Boehringer Ingelheim has launched the newInflammide ® 200 Novolizer ® . This product combinesthe proven efficacy of Inflammide ® 200 with the innovativetechnology of the Novolizer ® delivery system.The Inflammide ® 200 Novolizer ® is designed in such away that it is virtually impossible to use incorrectly,closely meeting the characteristics sought in an ‘ideal’inhaler. 5The Inflammide ® 200 Novolizer ® is breath actuated andcan only be successfully activated once the thresholdPIFR of 35-50 litres/min is generated. At this level thecomplete dose is delivered to the patient. The Novolizer ®has a triple feedback that tells the patient when eachdose has been successfully inhaled, 5 thus optimisingdosing.In healthy volunteers the median lung deposition ofbudesonide administered via the Novolizer ® was 19.9 -32.1% at mean PIFR of 45 - 90 litres/min. 6The Inflammide ® 200 Novolizer ® contains 200 µg ofbudesonide per inhalation in a 200-dose cartridge. Theproduct will be available in 2 forms:• The Inflammide ® 200 Novolizer ® Complete whichcontains the Novolizer device and a cartridge.• The Inflammide ® 200 Novolizer ® refill which containsthe cartridge only.In line with the Montreal Protocol manufacturers werecompelled to switch their asthma inhalers, which containCFC propellants, to more environmentally friendly productsby December 2005. The Inflammide ® 200 Novolizer ®is a multidose dry powder inhaler (MDPI) and does notcontain any propellants, making it not only patient-friendlybut environmentally friendly too.The Inflammide ® 200 Novolizer ® offers substantial advantagesover metered dose inhalers making it an idealreplacement product for patients using budesonideMDIs.For further information please contact Greg Zurnamer(Inflammide ® 200 Novolizer ® product manager) at 011-886-1075 or e-mail: zurnamer@jnb.boehringer-ingelheim.comREFERENCES1. Lalloo UG et al. Guidelines for the management of chronic asthmain adults - 2000 update. S Afr Med J 2000;, 90: 540-552.2. Barnes PJ. Editorial Overview. Asthma management: can we furtherimprove compliance and outcomes? Respir Med 2004; supplementA, S8-S9.3. Giraud V, Roche N. Misuse of corticosteroid metered-doseinhaler is associated with decreased asthma stability. Eur RespirJ 2002; 19: 246 251.4. Barnes PJ. Asthma guidelines: recommendations versus reality.Respir Med 2004; Supplement A S1-S7.5. O’Conner BJ. The ideal inhaler: design and characteristics toimprove outcomes. Respir Med 2004; Supplement A S10-S16.6. Newman SP, Hirst PH, Pitcairn GR. Scintigraphic evaluation oflung deposition with a novel inhaler device. Curr Opin Pulm Med2001; 7(suppl 1): S12- S14.ONLINE CPD ACCREDITATION NOWAVAILABLE FOR CURRENT ALLERGY& CLINICAL IMMUNOLOGYCurrent Allergy & Clinical Immunology has beenaccredited for CPD points in the Clinical category,so you can now earn 2 CPD points for IndividualLearning. CPD accreditation is only availablethrough the online service; no faxed or mailedresponses will receive CPD credits. To obtainCPD credits:1. Read the journal2. Answer the questionnaire on p.59 byaccessing the online CPD accreditation on theALLSA website at www.allergysa.org/cpdor follow the links from the home pagewww.allergysa.org.3. To register, you will need to enter your name,personal details, HPCSA number and a password.4. Once you have registered, you will receive anemail confirming your registration. You caneither answer the questionnaire immediatelyor log on at a later date to answer the questionnaire.Please note that each questionnairehas a closing date – the closing date for submissionof the November 2008 questionnaireis 31 March 2008 and for the March 2008questionnaire it is 30 June 2008.5. Follow the instructions given on the questionnairepage and online.6. After you have submitted your answers, theywill be marked immediately, and you will beinformed of the results and the number ofpoints earned.7. At any time you will be able to see your currentCPD credits from the journal by logging on.54 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

ALLSA MEMBERSHIP 2008Support your society, it supports allergology in South AfricaALLSA remains one of the world’s most pro-active and innovative allergy societies. Our pioneering website andpatient information resources have spurred other national societies to follow suit.ALLSA relies on an active membership base to continue to provide excellent resources to healthcare workers inSouthern Africa. We welcome new members from all over Southern Africa and membership is open to all healthcareworkers with an interest in allergology. Our current membership includes medical practitioners (general practitioners,physicians, pulmonologists, ENT specialists, dermatologists, ophthalmologists, paediatricians andanaesthetists), nurses, dieticians, medical technologists, pharmaceutical industry staff and medical students .Membership currently costs only R200 annually; this is a tax-deductible expense.Members enjoy a number of privileges which include:• The highly rated ALLSA journal – Current Allergy & Clinical Immunology, which is edited by Profs Weinberg andZar, and published quarterly. This journal is available on-line.• Access to ALLSA’s comprehensive allergy website at www.allergysa.org.• On-line CPD accreditation.• Patient information guides and leaflets on common allergic disorders.• Discounted ALLSA congress registration fees for our annual congress.• Regional allergy courses, meetings and journal clubs.• Support with examination preparation for the Diploma in Allergology of the Colleges of Medicine of SA.• Access to allergy research funding and annual ALLSA research awards of up to R50 000 per research study.For more details on membership and privileges please contact Ruwayda Adams on tel 021-447-9019,fax 021-448-0846, or e-mail enquiries to mail@allergysa.orgPlease cut out the membership application form and post together with your payment.ALLSA Membership ApplicationR200 annual subscription✃Dr/Sr/Mr/Mrs/Ms: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Address: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .E-mail address:. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Phone: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fax: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Speciality: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Special Interests: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Comments: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Post to: Allergy Society of South Africa, PO Box 88, Observatory 7935Direct debit details:Standard Bank: RondeboschSort Code: 02-50-09Account Number: 07 149 1821Cheques payable to Allergy Society of South AfricaFor direct deposits: Kindly fax your bank deposit slip as proof of payment (Fax No. 021-448-0846)Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 55

PRODUCT NEWSNASONEX IS NOW INDICATED FROMTHE AGE OF 2 YEARS!Nasonex Aqueous Nasal Spray is indicated for use inadults, adolescents and children between the agesof 2 and 11 years to treat the symptoms of seasonalallergic or perennial allergic rhinitis.In patients who have a history of moderate to severesymptoms of seasonal allergic rhinitis, prophylactictreatment with Nasonex Aqueous Nasal Spray is recommendedprior to the anticipated start of the pollenseason.Dosage and directions for useAdults and adolescents: The usual recommendeddose for prophylaxis and treatment is two sprays (50µg/spray) into each nostril once daily (total dose200 µg). Once symptoms are controlled, dose reductionto one spray into each nostril (total dose 100 µg)may be effective in some patients for maintenance.Children between the ages of 2 and 11 years: Theusual recommended dose is one spray (50 µg/spray)in each nostril once daily (total dose 100 µg).For more information contactGary Vine,Schering-Plough (Pty) Ltd,011-922-3300.PIMECROLIMUS CREAM 1% IN ATOPICDERMATITIS: A 6-MONTH, OPEN-LABELTRIAL IN PAEDIATRIC PATIENTSPimecrolimus, a new, non-steroid, inflammatorycytokineinhibitor, has been shown to prevent progressionto flare in atopic dermatitis (AD) and toimprove long-term disease control when applied as a1% cream. In this 6-month, open-label, multinationalstudy, 177 infants aged 3-23 months and 489 childrenaged 2-17 years, with mild to severe AD, were included.The study was designed to evaluate the efficacyand safety of pimecrolimus cream 1% used as a firstlinetreatment. Treatment consisted of an initial bidregimen, for as long as signs and symptoms of diseasepersisted; this was followed by treatment asrequired at the first signs and symptoms of AD.Emollients were allowed as per the physician's normalpractice, and topical corticosteroids could be used totreat severe flares at the discretion of the physician.Efficacy was assessed by evaluations of pruritus, andtotal-body and facial Investigators' GlobalAssessment (IGA). Results from the first return visit(day 7) showed an improvement from baseline of 1in total-body and facial IGA for infants (59.1% and72.8% of patients, respectively) and children (59.3%and 62.2%, respectively). Pruritus was absent or mildin 67.8% and 65.4% of infants and children, respectively.This level of improvement in the patient populationwas maintained throughout the 6-month study.Adverse events occurred in 75.7% of infants and71.1% of children. Most adverse events were commonchildhood illnesses that would be expected inthis population (e.g. nasopharyngitis (infants 22.0%,children 12.8%), upper respiratory tract infection(infants 18.6%, children 11.9%) and cough (infants8.5%, children 10.1%)). Concerning pimecrolimus'slocal tolerability, application-site burning occurred in2.3% of infants and 7.0% of children, and local pruritusoccurred in 0.6% infants and 1.0% children.Application-site reactions were most frequentlyreported during the first 6 weeks of treatment andwere mild to moderate in intensity. In conclusion,pimecrolimus cream 1% was effective in the treatmentof the early signs and symptoms of AD (including pruritus)in infants and children, and demonstrated agood safety profile.Reference available on request. Contact Thoko Nzama, 011-929-911156 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

PRODUCT NEWSTHE VISUALISATION OF HYGENIC CLEANLINESSThe most impressive inventions have always been the simplest.The vacuum cleaner itself is a good example. NowMiele has gone one step further: a vacuum cleaner with anintegrated Allergotec hygiene sensor is the icing on the cake.The quality of the air we breathe fluctuates permanently onaccount of all kinds of outside influences. The higher theconcentration of micro-organisms in the air, the poorer thequality. They can trigger off respiratory problems and allergicresponses. These tiny particles settle on carpets, upholstery,curtains and bedding and ride piggy-back on ubiquitousdomestic dust.Now the time has come to welcome another world-first tothe Medicair range of products. The floorhead provided withthe S5280 Medicair vacuum cleaner now features theAllergotec hygiene sensor, a device which automaticallydetects particulate contamination levels. During vacuuming,a microprocessor monitors the particle count in the air intakeas an indication of the potential allergy burden. This informationis relayed to the user in the form of a ‘traffic-light’indicator using the colours red, amber and green. ‘Red’ –keep cleaning, ‘amber’ – almost clean and ‘green’ – you canmove on, the area vacuumed is now ‘hygienically cleaned’.In addition, the model also sports an Active HEPA filterwhich ensures that even the smallest particles stay in thedustbag and are not re-released into the room. As well asensuring superb levels of hygiene, the Active HEPA filteralso guarantees odour-free room air, thanks to its layer ofactivated charcoal. As the collar on Miele dustbags is selfclosingon removal from the dust compartment, personswho react highly sensitively to dust can rest assured that thedust stays where it belongs – in the dustbag!Automatic suction control allows the vacuum cleaner toadapt with ease to different floor coverings. The Allergotecfloorhead adapts to both carpeting and smooth floors bymeans of a footswitch at the transition from the one floortype to the other.Miele (Pty) Ltd South Africa, PO Box 69434,Bryanston 2021, tel 011-548-1900,Cape Town, tel 021 946 3148/9,E-mail: info@miele.co.za, www.miele.co.zaGlaxoSmithKlineFURTHER ACCEPTANCE FOLLOWSGLAXOSMITHKLINE’S SERETIDE PRICEREDUCTIONGlaxoSmithKline’s decision to reduce the price of itsflagship asthma medication, Seretide, is showingencouraging signs of success. Seretide is used in thetreatment of chronic asthma and was already one ofthe most prescribed chronic medications in SouthAfrica at the time of the 20% price reduction. Medicalschemes, as well as medical practitioners and healthcareprofessionals, are also starting to adopt Seretideas the medication of choice, now that it is moreaffordable. Medical institutions are following suit andthe cumulative effect is that more and more chronicasthma sufferers in South Africa are gaining accessto the medication.Following the price reduction, one of South Africa'sleading medical aid schemes, Medscheme, includedSeretide in its Restrictive Formulary from 1 February2006. The result is that all Medscheme-administeredasthma patients now have access to Seretide.Restrictive formularies are primarily used to determineprescriptive needs of the lower to middleincome groups, which means that the use of Seretideis likely to be extended to asthma sufferers who previouslywould have had no means of gaining accessto the medication. In the light of the Department ofHealth’s drive towards creating lower income medicalschemes, the inclusion of Seretide in a major healthscheme's Restrictive Formulary gains extra significance.It is still too early to ascertain the extent towhich chronic asthma sufferers in previously disadvantagedcommunities are now able to acquireSeretide, but as time elapses this should becomeeasier to determine.S3 SERETIDE® 50/100 ACCUHALER® - 33/21.5.4/0413SERETIDE® 50/250 ACCUHALER® - 33/21.5.4/0414SERETIDE® 50/500 ACCUHALER® - 33/21.5.4/0415SERETIDE® 25/50 INHALER - 35/21.5.4/0411SERETIDE® 25/125 INHALER - 35/21.5.4/0412SERETIDE® 25/250 INHALER - 35/21.5.4/0413.Composition: ACCUHALER® - Each blister contains a mixture of salmeterolxinafoate equivalent to 50 µg of salmeterol and microfine fluticasonepropionate (100 µg, 250 µg or 500 µg). Contains lactose asexcipient.INHALER- Each single actuation provides salmeterol xinafoate equivalentto 25 µg of salmeterol and 50, 125 or 250µg of fluticasone propionate.GlaxoSmithKline South Africa (Pty) Ltd; (Co. reg. no.1948/030135/07)Private Bag X173, Bryanston. 2021 Tel +27 11 745 6000. Fax +27 11745 7000. September 2005. For full prescribing information, pleasesee package insertFor more information, please visit www.gsk.com orcontact: Dudu Ndlovu, Head: Corporate Affairs, tel011-745-6101, Fax 011-388-6101,e-mail dudu.d.ndlovu@gsk.comCurrent Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 57

PRODUCT NEWSNew Nestlé NAN H.A. 1 with PROTECTSTART TM and Nestlé NAN H.A. 2 withPROTECT PLUS TMNestlé Nutrition proudly presents the introduction of two new advanced premiuminfant formulas, that not only provide all the essential nutrients for babies' optimalphysical and mental development but also train and modulate their natural immunedefences to reduce the risk of allergies in those crucial first years of life.The alarming increases in recent decades of allergic diseases in children in bothWestern and developing countries, is a concern. This trend has also been reported inSouth Africa.Exclusive breastfeeding during the first six months is the simplest and most effective prevention of allergies caused by foreignfood proteins. Mother's milk, with its immunogenicity and natural bifidogenic effect, actively promotes the simultaneousdevelopment of oral tolerance. For the infant at risk of developing allergies, where breastfeeding is not possible, an alternativeis the unique hypoallergenic infant formula, developed by the leaders in infant nutrition, Nestlé Nutrition.New Nestlé NAN H.A. 1 with PROTECT START TM is the only hypoallergenic starter formula with a unique nutrient combination,to meet the needs of infants from birth. It is designed primarily to support the establishment of a balanced immune systemand it is clinically proven to reduce the risk of developing allergies.PROTECT START TM is made up of:• OPTI PRO HA• Bifidogenic nutrient combinations• LCPUFA's long-chain polyunsaturated fatty acids such as DHA and ARAFor the infant older than 6 months, as a follow-up to New NAN H.A. 1, Nestlé introduces New NAN H.A.2 with PROTECT PLUS TM. Nestlé NAN H.A. 2 with PROTECT PLUS TM is a state-of-the-art hypoallergenic follow-upformula with BL-active cultures, to meet the needs of older infants.PROTECT PLUS TM is made up of:• OPTI PRO HA• BL active cultures• LCPUFA's long-chain polyunsaturated fatty acids such as DHA and ARAThese products are improved formulations, which replace the current NAN H.A. that you know and trust.For more information please contact Nestlé Consumer Services on 0860 09 6789 www.nnia.orgIgE testing in persistent coughIgE testing is helpful for GPs in determining those youngchildren with persistent cough who will and will not developasthma at age of 6 years.Cough is the main complaint in at least 13% of general practiceconsultations for children from birth to 4 years of age.Clinical parameters alone cannot identify the subgroup ofchildren for whom the risk of developing asthma is high, andtherefore if a special investigation could be found to have ahigh predictive effect, this would be of great benefit to theclinician.A study in The Netherlands of 752 children visiting 72 GPs,found that IgE testing was helpful for GPs in determiningthose young children with persistent cough who will and willnot develop asthma at age of 6 years.The aim of the study was to investigate the diagnostic addedvalue of allergen-specific IgE measurements to predictdevelopment of asthma at the age of 6 in young childrenwith persistent cough. A structured questionnaire and ablood sample at inclusion were used to construct a simplescoring formula including age at inclusion (3-4 years), wheezing,and family history of pollen allergy. A follow-up examinationwith lung function tests and questionnaires wasperformed at the age of 6 years.Serum total IgE and specific IgE for cat, dog, and house-dustmites were determined. The children with an IgE-positivestatus were matched to those with a negative status definedby age, sex, region (rural versus urban) and IgE antibody testing,and using the baseline criteria the researchers could categorisethe children into 16 groups. The range of predictivevalues for asthma development in these groups increasedfrom 6- 75% to 1-95% when IgE antibody testing wasincluded. Almost 13% of the group (all less than 4 years ofage) had an IgE-positive status for cat, dog, and/or housedustmites. In 3-year-old wheezing children without familyhistory of pollen allergy the probability of developing asthmaat the age of 6 was 48.1%. After testing for allergen-specificIgE the children could be categorised into an IgE-positivegroup with high risk (88.1%) and an IgE-negative group withlow risk (28.3%). The predictive values were below 5% innon-wheezing children with negative test results butincreased to 20-50%> if the tests were positive.The study concluded that the assessment of specific IgE toinhalants may be helpful in determining those children withpersistent cough (≥ 5 days) who will and who will not developasthma at the age of 6 years. In particular, IgE testing wasable to categorise children who wheeze into low- and highriskgroups.Eysink PED, ter Riet G, Aalberse RC, et al. Accuracy of specific IgE inthe prediction of asthma: development of a scoring formula for generalpractice. Br J Gen Pract 2005; 55: 125-3158 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1

CPD QUESTIONNAIREEarn 2 CPD points after you have read the journal by completingthe following questionnaire online on the ALLSAwebsite at www.allergysa.org/cpd or follow the links fromthe home page. To earn points, you will need to registerand fill in personal details (make sure you have yourHPCSA number handy and decide on a password beforehand).Once you have registered, you can answer thequestionnaire. If you have registered for a previous questionnaire,you'll need your HPCSA number and passwordto logon. Please note that there is only one correct answerper question, and you will have only one opportunity tosubmit the questionnaire, so please check answers carefully.You will be able to change anwers if you click thewrong one by mistake, but once you click 'SubmitAnswers' the test will be submitted and marked.Points will be submitted electronically to the HPCSA.The closing date for submission of this questionnaire is 30June 2008.IMMUNODEFICIENCY DISEASES PRESENTING INADULTS – DIAGNOSIS AND MANAGEMENT1. True or false: Primary immune deficiency is alwaysdiagnosed in childhood and never presents for the firsttime in adults.a) Trueb) False2. True or false: Recurrent localised infections are astrong indication of underlying systemic immunedefect.a) Trueb) False3. True or false: Antibody deficiency is more common inadults than primary cellular immune defects.4. True or false: The commonest diagnosis for immunedeficiency in adult patients is common variablehypogammaglobulinaemia (CVH) which can involveboth humeral and cellular immunity.APPROACH TO THE CHILD WITH RECURRENT INFEC-TIONS – PRESENTATION AND INVESTIGATION OFPRIMARY IMMUNODEFICIENCY1. Choose ONE incorrect answer: Contributing factorsfor recurrent infections in childhood include:a) Exposure to smoke in the homeb) Day care attendance of the childc) Schoolgoing siblings in the homed) Breastfeeding (HIV-negative mother)e) Gastro-oesophageal refluxf) Anatomical obstructions2. Choose ONE incorrect answer: Cost-effective firststage initial laboratory or side room investigations inSouth Africa for a child with recurrent respiratory infectionsincludesa) Full blood count and differentialb) Immunoglobulin isotypes G, M, A, and Ec) HIV testingd) Mantoux skin teste) Lymphocyte proliferationsf) Sweat test3. Choose ONE incorrect answer:a) Deficient antibody response can occur despite normallevels of serum IgG.b) Recurrent meningococcal infections point towardsphagocyte defects.c) Absence of tonsillar tissue in the presence of recurrentbacterial infections may give a clue to defectiveB-lymphocyte development.d) X-linked agammaglobulinaemia is clinically expressedin males.e) An ulcerating BCG can be a warning sign of lack ofcellular immunity.SEVERE COMBINED IMMUNODEFICIENCY (SCID)1. True or false: All children who have SCID can be diagnosedby an absolute lymphocyte count after birth.a) Trueb) False2. True or false: The most common type of SCID isX-linked and is due to a deficiency of the commongamma chain.a) Trueb) False3. True or false: SCID should be suspected in any childwho presents early in life with severe or opportunisticinfections.a) Trueb) FalseAN UPDATE OF THE PRIMARY ANTIBODY DISORDERS1. True or false: True or false: Arrest in early B-cell developmentresults in decreasing B-lymphocyte numbersand profoundly reduced immunoglobulin isotypeconcentrations.a) Trueb) False2. True or false: Common variable immunodeficiency is aheterogenous group of diseases associated with complementdeficiencies.a) Trueb) False3. True or false: Patients with X-linked Hyper-IgMsyndrome may present with serious Pneumocystisjeroveci or Cryptosporidium infections.a) Trueb) False4. True or false: For many primary antibody deficienciesintravenous immunoglobulin G replacement therapy isthe treatment of choice.a) Trueb) FalseINTRAVENOUS IMMUNOGLOBULIN1. True or false: All IVIG preparations are equally efficacious.a) Trueb) False2. True or false: IVIG is a recommended treatment optionfor haemolytic disease of the newborn.a) Trueb) False3. True or false: The usual dose of IVIG for antibodyreplacement therapy is between 400 and 600 mg/kgevery 2-4 weeks.a) Trueb) FalseEPOXY RESIN EXPOSURE AND DERMATITIS – A CASESTUDY1. True or false: In rare cases depigmentation can resultfrom exposure to epoxy resins and is referred to as‘leucoderma’.a) Trueb) False2. True or false: Exposure to the organic solvents that areadded to some epoxy products can cause allergic contactdermatitis.a) Trueb) False3. True or false: ACD, ICD, CU, leucoderma, but not respiratoryreactions may result from exposure to epoxyresins.a) Trueb) FalseAccredited by the Colleges of Medicine of South AfricaCurrent Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 59

INSTRUCTIONS FOR AUTHORSCurrent Allergy & Clinical Immunology publishesarticles concerned with the understanding andpractice of allergic diseases or clinical immunology.Material submitted for publication to CurrentAllergy & Clinical Immunology is accepted oncondition that it has not been published elsewhere.The management reserves the copyrightof the material published. All named authorsmust give consent to publication. Current Allergy& Clinical Immunology does not hold itselfresponsible for statements made by contributors.Original research, review articles, case reports,brief research reports or photographs may be submitted.Letters to the editor are welcome and ifsuitable will be published in a correspondence section.All articles will be subject to peer review.Electronic submission is preferable. However, ifauthors are unable to submit electronically then thearticle may be posted to the correspondenceaddress listed at the end of these instructions.Manuscript preparation1. Articles may be submitted electronically onlineat www.allergysa.org/articles or follow thelinks from the homepage www.allergysa.org.To register, you need to enter your name, personaldetails, HPCSA number and a password.Once you have registered, you will receive anemail confirming your registration. You caneither submit your article immediately or logon at a later date. Authors should state theirfull name, qualifications, institutional affiliationand provide a corresponding address andemail on the title page. Articles should be amaximum of 3500 words with no more than 3figures and 3 tables. Short reports should be amaximum of 1000 words with a maximum of2 tables or illustrations. Case reports shouldnot exceed 2000 words, with a maximum of 3figures, 3 tables and 10 references, and shouldconform to the usual structure: abstract (notmore than 50 words), introduction, methods,results, discussion.2. Each article should be accompanied by a summaryof not more than 200 words (50 words forshort reports). A structured abstract is requiredfor original research papers.3. Authors are requested to declare conflict ofinterest and source of funding relating to thearticle. Authors should disclose any relationshipwithin the last 2 years with pharmaceuticalcompanies in the following categories ifpertinent to the article: research grants, educationalsupport (sponsorship at conference),advisory boards, speaker, consultant or sharesin companies. This must be stated at the endof the manuscript before the references.Details of ethical approval obtained must beincluded in all original research articles.4. All abbreviations should be spelt out when firstused in the text and thereafter used consistently.5. Scientific measurements should be expressed inSI units.6. Tables should be labelled with Roman numerals,thus: I, II, III, etc. and illustrations withArabic numerals, thus: 1, 2, 3, etc. Tables andfigures should be submitted as part of the manuscriptfile. Please do not submit photographsin Powerpoint and MS Word format – a highresolutionjpg is required. Photographs shouldbe submitted separately from the manuscriptfile and clearly labelled.7. Where identification of a patient is possible froma photograph the author must submit a consentto publication signed by the patient, or by theparent or guardian in the case of a minor.8. If any tables or illustrations submitted have beenpublished elsewhere, written consent to republicationshould be obtained by the author fromthe copyright holder and the author(s).References1. References should be inserted in the text assuperior numbers, and should be listed at theend of the article in numerical order.2. References should be set out in the Vancouverstyle, and only approved abbreviations of journaltitles should be used; consult the January issueof Index Medicus (No. 1 Part 1) for these details.Names and initials of all authors should be givenunless there are more than six, in which case thefirst three names should be given followed by ‘etal.’ First and last page numbers should be given.Example:1. Khakoo G, Lack G. Recommendations forusing MMR vaccine in children allergic toeggs. BMJ 2000; 320: 929-932.3. References for books should include author,title, town, publisher and date.Example:1. Abbas AK, Lichtman AH. Basic Immunology.Philadelphia: WB Saunders, 2001.4. ‘Unpublished observations’ and ‘personal communications’may be cited in the text, but not inthe reference list. Articles accepted but not yetpublished can be included as references followedby ‘(in press)’.All correspondence should be addressed to:The Editors, Current Allergy & Clinical Immunology,Allergy Society of South Africa, PO Box 88,Observatory 7935, South Africa.E-mail: allsa@mweb.co.za60 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1