Current Allergy and Clinical Immunology - March 2008

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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
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