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Treatment and prognosis of common variable immunodeciency

OfficialreprintfromUpToDate
www.uptodate.com2016UpToDate

Treatmentandprognosisofcommonvariableimmunodeficiency
Authors
SectionEditor
SamAhn,MD
ERichardStiehm,MD
CharlotteCunninghamRundles,MD,
PhD

DeputyEditor
AnnaMFeldweg,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:May2016.|Thistopiclastupdated:Mar30,2015.
INTRODUCTIONCommonvariableimmunodeficiency(CVID)isanimmunedisordercharacterizedbyimpaired
Bcelldifferentiationwithhypogammaglobulinemia.Thedisorderisassociatedwithabroadspectrumofclinical
manifestations,includingrecurrentinfections,chroniclungdisease,gastrointestinaldisease,andautoimmune
disorders.
Thecornerstoneoftherapyisimmuneglobulin(IG)replacement,whichhasdramaticallyalteredtheclinicalcourse
ofCVIDbyreducingtheburdenofrecurrentinfectionsandsubsequentcomplications.Managementalsoinvolves
vigilantmonitoringforassociatedproblems,suchaspulmonarydamage,gastrointestinal,autoimmuneand
granulomatousdiseases,andmalignancy[1].
ThetreatmentandhealthmaintenanceofpatientswithCVIDwillbediscussedhere,withanemphasisonadults.
Theclinicalmanifestations,diagnosis,andpathogenesisofthisdisorder,andissuesparticularlyrelevanttopediatric
patients,arepresentedseparately.(See"Clinicalmanifestations,epidemiology,anddiagnosisofcommonvariable
immunodeficiencyinadults"and"Commonvariableimmunodeficiencyinchildren"and"Pathogenesisofcommon
variableimmunodeficiency".)
IMMUNOGLOBULINREPLACEMENTTHERAPYThedefinitionofcommonvariableimmunodeficiency(CVID)
includesindividualswithvaryingdegreesoflossofantibody.Forthosewithsubstantialimpairmentsinantibody
productionandnonresponsetobothproteinandcarbohydratevaccines,immuneglobulin(IG)replacementis
necessary.ForsubjectswithhigherlevelsofserumimmunoglobulinG(IgG)andonlyminorimpairmentsin
responsetosomevaccines,IGtherapymaybepostponed,butthesepatientsshouldbefollowedclosely.(See
'Patientswithoutinfectionsorwithisolatedautoimmunedisease'below.)
ImpactoftherapyIGreplacementtherapyreducesthenumberofinfectionsanddecreasesantibioticuseand
hospitalizations[24].TheeffectivenessofIGreplacementinhypogammaglobulinemicpatientswasimmediately
apparentafterthistherapybecameavailable,andsorandomizedcontrolledtrialswereneverundertaken.Inone
retrospectiveseriesof50patientstreatedwithintravenousimmuneglobulin(IVIG),theannualincidenceof
pneumoniadecreasedfrom81percentbeforetreatment,to35percentontherapy,andtherateofhospitalization
decreasedfrom89to46percent[4].Inalargeseriesof2212patientswithCVIDenrolledinaEuropeanprimary
immunodeficiencyregistry,patientsreceivingIVIGatdosesyieldinghigherserumlevelshadfewerserious
infectionsanddaysofhospitalizationforprimaryimmunodeficiency,comparedwiththosewithlowerserumlevels
[5].However,treatmentwithIGdoesnotentirelyeliminateinfectionsinmostpatients,andthesinopulmonaryand
gastrointestinalsystems,inparticular,remainsusceptible.(See'Sinusitis'belowand'Gastrointestinalinfections'
below.)
ProgressionofchroniclungdiseaseIGreplacementmayslowtheprogressionofchroniclungdiseasein
patientswithCVID,althoughthishasnotbeenconclusivelyestablished.Aprospectivestudyof24patientsreceiving
standarddoseIVIGfoundasignificantimprovementinforcedexpiratoryvolumeinonesecond(FEV1)andhigh
resolutioncomputedtomography(HRCT)scoresinpatientswithchronicpulmonarydisease[6].However,another
studydocumentedprogressivelungchangesbyHRCTof21in22patientsfollowedoverthreeyears,despite
maintenanceoftroughIgGlevelsof500mg/dL,althoughsomeexpertsarguethatthistroughvaluewasnot
sufficient[7].
ChroniclungdiseaseisoneoftheindicationsforhigherIGdoses,whichmayprovideadditionalbenefitforsome
patients[810].Onestudyshowedradiographicimprovementofchroniclungdiseasein4of12CVIDpatients
receivingadoseof600mg/kgcomparedwithnoradiographicimprovementinanypatientreceivingadoseof200
mg/kg.Inaddition,allsixpatientsswitchedtohigherdoseIVIGinthisstudyshowedimprovementinforcedvital
capacity(FVC)andFEV1[8].Therearenostudiesdirectlycomparing600mg/kg(orotherdoses)with400mg/kgin
ordertodeterminetheoptimaldoseinsuchpatients.Untilmoredataareavailable,itisourpracticetoinitiateIG
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therapyatahigherdoseof600mg/kginpatientswhohaveevidenceofchroniclungdiseaseatdiagnosis.Thegoal
troughlevelisthesameasthatforstandarddosing.(See'Dosing'below.)
OtherdisordersinCVIDGastrointestinalinfectionsand/orcomplicationsarerelativelyunaffectedbyIG
replacement,forreasonsthatarenotwellunderstood.IGtherapymayexertaprotectiveeffectinthosewith
autoimmunedisease,althoughitisnotknowntoalterthedevelopmentofmalignancyortoimpactgranulomatous
disease[6,7].
PatientswithoutinfectionsorwithisolatedautoimmunediseaseAbout8to10percentofpatientswith
laboratoryconfirmedCVIDhavelittleornosignificantmedicalhistoryofinfections[11,12].Thesepatientsmayhave
lowserumIgGdiscoveredincidentally,ormorecommonly,inassociationwithautoimmunityorothercomplications
ofCVID.Studiestoconfirmtheabsenceofinfectionmayincludenormalsinusimaging,sedimentationrate,andC
reactiveprotein(CRP)level.
ForsubjectswithminordecrementsinserumIgGandonlymildimpairmentinvaccineresponseto
carbohydrateorproteinantigens,IGtherapymaybepostponed,butthepatientshouldbefollowedat
reasonableintervals(eg,6to12months).
PatientswithverylowlevelsofserumIgGwhohavelittleornovaccineresponseshaveclearCVIDandareat
riskforsevereinfections[13].WefeelthatwithholdingIGtherapyonthebasisoflackofpastinfectionswould
beunwise.
OverviewofadministrationIGreplacementtherapymaybeadministeredeitherintravenously(IVIG)or
subcutaneously(SCIG).AtypicalapproachistobegintherapywithIVIG.Iftheintravenous(IV)routeisusedto
initiatetherapy,thesubcutaneousroutemaybesubstitutedaftertwoormoremonthsonIVIG,ifthisispreferred.
WeoccasionallystartpatientswithverypoorvenousaccessonSCIGfromtheoutset.Amoredetaileddiscussionof
thecharacteristicsandsafetyofvariouspreparationsofIVIG,howtoinitiatetherapywithIVIGorSCIG,andhowto
convertfromIVIGtosubcutaneousIG,isfoundseparately.(See"Immuneglobulintherapyinprimary
immunodeficiency"and"Subcutaneousandintramuscularimmuneglobulintherapy".)
IntravenousrouteIVIGtherapycanbeadministeredintheoffice,infusioncenter,orhome.Selectedpatients
mayalsobecandidatesforselfinfusionofIVIG.Theplacementofindwellingcatheterssolelyfortheadministration
ofIVIGisnotrecommendedduetothepropensityofCVIDpatientstodevelopinfectiouscomplications[14].
DosingTheusualinitialdosingforIVIGinpatientswithCVIDis300to400mg/kgeverythreetofourweeks
withorwithoutpremedication.Patientswhoareactivelyinfectedatthetimeoftheinitialinfusionaremorelikelyto
experienceadversesymptomsduringinfusion,sowhenpossible,wetrytotreattheinfectionfirst,theninitiateIG.
PatientswithanydegreeofongoingsignificantinfectionshouldbetreatedwithantibioticsfirstandthengivenIG
therapy.Premedicationwithdiphenhydramineandacetaminopheniscommonlyusedforthosewhoareproneto
medicationsreactions,andinsomecases,aglucocorticoid(suchasIVhydrocortisone)isalsogiven.Onemayalso
repeattheinitialdose(ie,theentire300to400mg/kg)inafewdaysoraweeklaterifthepatientwasclearingan
infectionwhentheinitialdosewasgiven.Generally,afterthefirsttwoorthreeinfusions,premedicationisnolonger
needed.
ThehalflifeofIGisapproximately30days,althoughvariabilityamongindividualsexists.Steadystatelevelsare
usuallyachievedafterthreetosixmonthsoftherapy,andwemeasuretroughlevelsofIgGbeginningsixmonths
afterthefirstdose.ThelevelofIgGinthebloodontherapyshouldbeatleastnearthemiddleofthenormalrange,
andthepatientshouldexperienceasignificantdecreaseinmajorinfections[7,10].
IndicationsforhigherdosingIndicationsforhigherdosesofIGinapatientwithCVIDincludethefollowing
[10,1517]:
Continuedmajorinfections,suchasrefractorysinusitisatthestartingdoseof400mg/kg.Dosesof500to600
mg/kgpermontharerequiredinsomepatientstoattainsatisfactorytroughlevelsofIgGandtokeepthemfree
ofmajorinfections[10].
Chroniclungdisease.(See'Progressionofchroniclungdisease'above.)
VeryhighdosesofIVIG(ie,1gram/kg),eithergivenasasingledoseorrepeatedeverythreetofourweeksuntil
resolution,maybehelpfulinpatientsalreadyonstandardtherapywhodevelopautoimmunehematologicdisorders
[18].(See'Autoimmunedisorders'below.)
Weusuallyincreasethedosein5to10gramincrements,startingafterthefirstsixmonthsoftherapyifhigherdoses
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areneeded.Anotherwaytoincreasetheeffectivedoseistoshortenthedosingintervalfromeveryfourtoevery
threeweeks,whichincreasesthemonthlydoseby33percent.Tomonitortheneedforhigherdoses,reduced
infectionsand/orneedforantibioticsshouldbeobserved.
MonitoringTroughlevelsofIgGareusuallymeasuredeverysixmonths,evenaftersteadystatelevelis
achieved.Dosingmayneedtobeadjustedperiodically,aspatientweightandendogenousproductionorclearance
maychangeovertime.Additionalmonitoringissuesarediscussedseparately.(See"Overviewofintravenous
immuneglobulin(IVIG)therapy",sectionon'Monitoring'.)
SubcutaneousrouteAnalternativetoIVIGformaintenancetherapyissubcutaneousIG(SCIG).Thisisusually
administeredweeklyoreveryotherweek,dependingonbodyweightandIGrequirements.Thereisalsoa
subcutaneouspreparationthatisfacilitatedbyhyaluronidase,whichallowsforinfusionoflargerdosesandthuscan
beadministeredeverythreetofourweeks.Thisisdiscussedelsewhere.(See"Subcutaneousandintramuscular
immuneglobulintherapy",sectionon'Availableproducts'.)
SCIGisparticularlyhelpfulforpatientswithreactionstoIVIG,difficultintravenousaccess,orrapidIGloss(suchas
thosewithrapidcatabolism,nephroticsyndrome,orproteinlosingenteropathy).SCIGcanbeselfinfusedathome,
whichismoreconvenientformanypatientsandcanimprovequalityoflife.InitialdosingofSCIG,andconversionof
patientsfromIVIGtoSCIGarereviewedelsewhere.(See"Subcutaneousandintramuscularimmuneglobulin
therapy".)
ANTIMICROBIALTHERAPYAntibioticsmaybeadministeredprophylactically,aswellasforthetreatmentof
acuteinfectionsorexacerbationsofchronicinfections.
ProphylacticantimicrobialsTheefficacyofprophylacticantibioticsforpreventinginfectionsinpatientswith
commonvariableimmunodeficiency(CVID)hasnotbeenadequatelystudied.Wedonotroutinelyadminister
prophylacticantibioticstoallpatientswithCVID,althoughwedofindthisapproachhelpfulinCVIDpatientswith
ongoinglungdisease.Theuseofantibioticsinthismannerisreviewedseparately.(See"Medicalmanagementof
immunodeficiency",sectionon'Prophylacticantimicrobialtherapy'.)
Patientswithknownexposurestoinfluenzamaybetreatedwithantiviralmedications.Regimensarereviewedin
detailelsewhere.(See"Preventionofseasonalinfluenzawithantiviraldrugsinadults"and"Seasonalinfluenzain
children:Preventionandtreatmentwithantiviraldrugs",sectionon'Chemoprophylaxis'.)
PreventionofrecurrentsinusitisWedonotroutinelyrecommenddailyantibioticstopreventrecurrent
sinusitisinpatientswithCVIDwhoarereceivingIGtherapy,althoughtherearenopublishedstudiesexaminingthis
issue.Instead,weencouragepatientstomaintaingoodnasalhygienewithsalineirrigationsandwetreatinfections
astheyarise.Wealsotrytoavoidsurgicaltreatmentofchronicsinusitis,asdiseaseinvariablyreturns.Themedical
managementofchronicrhinosinusitisisreviewedseparately.(See"Chronicrhinosinusitis:Management"and
"Microbiologyandantibioticmanagementofchronicrhinosinusitis".)
ChronicbronchiectasisProphylacticantibiotictherapymaybehelpfulforpatientswithbronchiectasis,
frequentexacerbations,anddeclininglungfunctionandshouldtargetH.influenzaeandmycoplasma[16,19].(See
"Treatmentofbronchiectasisinadults",sectionon'Preventionofexacerbations'.)
GastrointestinalinfectionsThereisnoantibioticprophylaxisthatpreventsgastrointestinalinfectionsin
patientswithCVID,andtheimpactofIGtherapyonthegastrointestinaltractappearstobeminimal,asreviewed
previously.(See'Impactoftherapy'above.)
PatientswithlowCD4countsProphylacticantibioticstopreventinfectionwithPneumocystiscarinii(P.
jirovecii)maybegiventopatientswithCVIDandCD4counts<200cells/mcLhowever,itisnotstandardasitisin
patientswithhumanimmunodeficiencyvirus(HIV)infection.PatientswithCVIDaregenerallynotsusceptibleto
Pneumocystiscariniipneumoniaunlessgivenglucocorticoidsorotherimmunesuppressants(eg,
methotrexate/azathioprine)forprolongedperiods.(See"TreatmentandpreventionofPneumocystisinfectioninHIV
infectedpatients",sectionon'Treatment'.)
TreatmentofspecificinfectionsAntibioticsareessentialfortreatingacuteinfectionsinpatientswith
immunodeficiency.ItisourexperiencethatCVIDpatientstypicallydonotclearcommoninfectionswithouttheuseof
antibiotics.Asexamples,acutesinusitisorbronchitisisunlikelytoclearspontaneouslyinpatientswithCVID,unlike
inthegeneralpopulation,eveninpatientsreceivingimmuneglobulin(IG)replacement.Thus,promptidentification
andtreatmentwithantibioticscanhelppreventchronicinfectionsandinfectiouscomplications.Itisalsoimportantto
ensurethattheinfectionhasclearedcompletelyattheendofacourseofantibiotics,aspatientswith
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immunodeficiencysometimesrequirelongerdurationsoftherapy.
AntibioticresistancedoesnotseemtobeaprominentprobleminpatientswithCVID,forreasonswhicharenot
clear.Onestudyfoundthatthelungsofpatientswithprimaryantibodydeficiencywerepersistentlycolonizedwith
Haemophilusinfluenzae(identifiedinapproximatelytwothirdsofpatients)andthattheisolatesremainedsensitive
tocommonlyusedantibioticsandresistantstrainswerenotfounddespiterepeatedtreatment[20].Thisisconsistent
withourclinicalexperiencethatthesameantibioticscontinuetobeuseful,despiteprolongedorrepeatedexposure.
SinusitisAcutebacterialsinusinfectionsinpatientswithCVIDarecommonlycausedbyStreptococcus
pneumoniae,Haemophilusinfluenzae,andMoraxellacatarrhalis,similartointhegeneralpopulation[18].
ManagementofsinusitisinpatientswithCVIDissimilartothatinpatientswithoutimmunodeficiency,althoughthe
treatmentdurationmayneedtobelonger.Recommendationsforantibioticsforacutebacterialsinusitisarefound
separately.(See"Uncomplicatedacutesinusitisandrhinosinusitisinadults:Treatment",sectionon'Antibiotics'.)
ChronicsinusitiscanbecomplicatedbyinfectionswithStaphylococcusaureus,Pseudomonasaeruginosaand
anaerobes[18].ChronicsinusitismaypersistdespiteIGreplacement,possiblybecauseofthemultifactorialnature
ofthiscondition(ie,chronicinfectionisjustonefactorinpathogenesis).TheimpactofhigherdoseIGhasnotbeen
reported.(See'Indicationsforhigherdosing'aboveand"Chronicrhinosinusitis:Clinicalmanifestations,
pathophysiology,anddiagnosis".)
PneumoniaManagementofpneumoniainpatientswithCVIDissimilartothatinpatientswithout
immunodeficiency,althoughthetreatmentdurationmayneedtobelonger.(See"Treatmentofcommunityacquired
pneumoniainadultsintheoutpatientsetting"and"Treatmentofcommunityacquiredpneumoniainadultswho
requirehospitalization".)
Pulmonaryinfectionsthatdonotclearandcontinuetocausefevershouldpromptevaluationformycoplasma.
Mycoplasmainfectionsareusuallyresponsivetomacrolideantibiotics.Thisorganismcanalsoinfectthebonesand
jointtissuesinpatientswithCVID.(See"Mycoplasmapneumoniaeinfectioninadults"and"Mycoplasma
pneumoniaeinfectioninchildren",sectionon'Treatment'.)
BronchiectasisThepathophysiologyofbronchiectasisisthoughttobedrivenbyacycleofchronicinfection
andscarringresultinginincreasingsusceptibilitytoinfection.Antibioticsplayanimportantroleinthetreatmentand
preventionofthiscondition.Inhaledglucocorticoidsmayreducecoughanddyspnea,althoughtheyshouldbeused
sparingly.(See"Treatmentofbronchiectasisinadults",sectionon'Antiinflammatorymedications'.)
Acuteexacerbationsofbronchiectasismaybeprecipitatedbybacterialinfection,suchasH.influenzae,S.
pneumoniae,andMycoplasmaspecies,acommonlymissedbutimportantorganisminCVID.Althoughprompt
sputumculturetodirecttherapyshouldbeperformedwhenpossible,empirictreatmentshouldincludecoveragefor
theseorganisms.Amoxicillinclavulanate,thirdgenerationcephalosporins,andfluoroquinolones(except
ciprofloxacin)foratleast14daysarefrequentlyused.(See"Treatmentofbronchiectasisinadults",sectionon
'Treatmentofacuteexacerbations'.)
Diseaseprogressionmaybeinsidiousandcanbemonitoredwithpulmonaryfunctiontestingandacomputed
tomography(CT)scanofthelungsatbaselineandpossiblyeveryonetotwoyearsthereafterifadditional
therapeuticinterventions(eg,achangeinantibiotictreatmentsoranincreaseinIGdose)arecontemplated[8].In
contrast,highresolutionCTexaminationsshouldprobablynotbeperformedatregularintervalsunlessthe
informationthesetestsprovideisessential.Radiationexposureshouldbelimitedtothatwhichisabsolutely
necessary,ascellularradiosensitivityhasbeendemonstratedinpatientswithCVID[21,22].
Inpatientswhoprogresstoseverebronchiectasis,surgicalinterventionhasbeenperformedinrarecasestoremove
thesignificantlydiseasedsegmentsoflungtissue.Thisshouldbereservedforpatientsinwhomintensiveantibiotic
andIGtherapy,overaperiodofmonthstoyears,hasfailed.
Finally,lungtransplantationhasbeenperformedwithvaryingsuccessinpatientswithantibodydeficiency,with
somewhatworseoutcomesthanthoseseeninpatientswithcysticfibrosis,althoughthereislittlepublisheddatafor
analysis[23,24].(See"Treatmentofbronchiectasisinadults".)
GastrointestinalinfectionsInpatientswithchronicorrecurrentdiarrhea,stoolculturesshouldbeexamined
forovaandparasites,becausegiardia,campylobacter,salmonella,andcryptosporidiaareseenwithgreater
frequencyinpatientswithCVID.Chronicnorovirusinfectioncanpresentasnonspecificenteropathy,butmay
respondtoribavirin[25].Acuteorchronicgiardiasisisgenerallyresponsivetometronidazole.(See"Epidemiology,
clinicalmanifestations,anddiagnosisofgiardiasis"and"Treatmentandpreventionofgiardiasis".)
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MEASURESTOAVOIDINFECTIONSSincetheintroductionofimmuneglobulin(IG)replacement,thequalityof
lifeformostpatientswithcommonvariableimmunodeficiency(CVID)hasdramaticallyimproved.
AdvicefortravelOnceonIGtherapy,manypatientsareabletotravelandparticipateinotheractivitiesthat
mightnothavebeenpossibleinthepastforpeoplewithimmunodeficiencies.Ingeneral,wedonotadvocate
restrictingforeigntravel,unlessthetravelistoaremoteareawithnoaccesstohealthcare.Patientsshouldbring
antibioticsthattheymightneedandconsumebottledwaterfromacleansource.Patientsshouldreceivethekilled
vaccinesapplicabletothatgeographicarea.
VaccinationsTheutilityofvaccinatingpatientswithcommonvariableimmunodeficiency(CVID)hasnotbeen
studiedextensively.Bydefinition,patientswithCVIDhaveimpairedresponsestovaccination,althoughvaccination
mightreinforceTcellimmunitytoviralagents,inadditiontoinducingtheformationofspecificantibodies.Theformer
mechanismmaybepreservedinsomepatientswithCVID,asthereisarangeofimmunologiccapacityinthis
disorder.
LivevaccinesshouldnotbegiventopatientswithCVID[26].ThesafetyoflivevaccinesinapatientwithCVIDand
significantlyimpairedTcellfunctionhasnotbeenexamined,althoughwearenotawareofanyreportsofCVID
patientsbeingaffectedadverselybyvaccinationwitheitherliveorothertypesofvaccines,incontrasttopatients
withseverecellularimmunedefects.Otherissuesrelatedtovaccinationincludethefollowing:
FamilymembersandhouseholdcontactsofpatientswithCVIDmayreceivelivevaccines.
PatientswithCVIDwhoareplanningtotravelshouldreceivetheappropriatekilledvaccinestoprevent
infectiousdiseasesendemictothatarea.
WeroutinelyadministerinactivatedinfluenzavaccinetopatientswithCVID,althoughatleastonestudy
showedthatsomeCVIDpatientsrespondonlypartially[27].Vaccinationguidelinessupportthispractice
[28,29].Inaddition,wetreatpatientswithaknownexposuretoinfluenzawithantiviralagents.Patients
receivingimmuneglobulin(IG)replacementmaybepartiallyprotectedfrominfluenzaduetothepresenceof
antiinfluenzaantibodiesintheimmunoglobulin(Ig)preparation,althoughthishasnotbeenformally
documented.
THERAPYFORNONINFECTIOUSDISORDERSNoninfectiousdisordersinpatientswithcommonvariable
immunodeficiency(CVID)includeautoimmuneconditions,enteropathyresemblinginflammatoryboweldisease,
splenomegalyandlymphoproliferation,andgranulomatousorlymphoidinfiltrationsofthelungsorotherorgan
systems.
Severaloftheseconditionsnecessitatetheadministrationofchronicimmunosuppressivetherapy,andahigher
incidenceofcomplications(includingoverwhelminginfection)hasbeenreportedinpatientswithCVID[30].
Therefore,patientsshouldbecarefullymonitoredforthespecificcomplicationsassociatedwiththetherapyin
question.
PulmonarydiseasePulmonarycomplicationsarecommoninpatientswithCVID.Bronchiectasis,
bronchospasm,restrictiveandobstructivepulmonarydisease,andnonsarcoidgranulomatousdiseaseareamong
themostcommon.Althoughtheliteratureisinconclusive,someimprovementorstabilizationofdiseasemaybe
achievedwithhigherdosesofintravenousimmuneglobulin(IVIG),asmentionedpreviously[31].(See'Indications
forhigherdosing'aboveand"Clinicalmanifestationsanddiagnosisofbronchiectasisinadults".)
Theuseofimmunosuppressantsandimmunomodulatorstotreatgranulomatousandlymphocyticinterstitiallung
disease(GLILD)inpatientswithCVIDisdiscussedelsewhere.(See"Pulmonarycomplicationsofprimary
immunodeficiencies",sectionon'Commonvariableimmunodeficiency'.)
GastrointestinaldiseaseMostchronicdiarrhealillnessesinCVIDpatientsarenoninfectiousinetiology[32].
CVIDpatientswithrecurrentorchronicdiarrheashouldbereferredtoagastrointestinalspecialist.
Prolongeddiarrheacanleadtomalabsorptionofallfatsolublevitamins,ironandcalcium,andvitaminsB12andE,
andpatientsshouldbemonitoredforthesedeficiencies.VitaminEdeficiencyhasbeendescribedinaCVIDpatient
withsevereenteropathypresentingassensoryloss,ataxia,andretinitispigmentosa[33].Intakeandoutputshould
bemonitoredandsupplements,includingprotein,vitamins,andminerals(iron,zinc),suppliedasrequired.(See
"Overviewofthetreatmentofmalabsorption".)
PatientswhodevelopsignificantenteropathiesorCrohn'slikecolitis,mayrequireantiinflammatory(eg,
mesalamine)orimmunosuppressivetherapy,suchaschronicoralbudesonide,orshortcoursesofother
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glucocorticoids,azathioprineor6mercaptopurine.Infliximabhasbeenusedwithsignificantclinicalimprovementin
afewpatientswithsevereenteropathy,althoughthisagentmaybeassociatedwithanincreasedriskoffungallung
infections[34].Patientswithsevereenteropathyandcolitisleadingtomalnutritionmayrequiresupplementationwith
totalparenteralnutrition(TPN).(See"Nutritionanddietaryinterventionsinadultswithinflammatoryboweldisease",
sectionon'Totalparenteralnutrition'.)
AutoimmunedisordersHematologicdisordersarethemostcommonformofautoimmunediseaseinCVID
patients.Areviewof326patientsfoundthat11percenthadahistoryofimmunethrombocytopenia(ITP),Coombs'
positiveautoimmunehemolyticanemia(AIHA),orEvanssyndrome[18].Mostofthesedevelopedhematologic
autoimmunediseasebeforeorconcurrentwiththediagnosisofCVIDandinitiationofIVIG,ratherthanafter[18,35].
ItispossiblethatIVIGmayprovidesomeprotectionagainstthesedisordersorrecurrencesofthem,althoughthis
hasnotbeendemonstrated.
ForbothITPandAIHA,glucocorticoidshavetraditionallybeenthefirstlinetreatment.IfITPoccurswhileon
immuneglobulin(IG)replacement,higherdosesofIGtherapy(eg,1to2grams/kilogram)canbeadministered[18]
withorwithoutintravenoussolumedrol.Thetreatmentoftheseconditionsisreviewedelsewhere.(See"Immune
thrombocytopenia(ITP)inadults:Initialtreatmentandprognosis"and"Immunethrombocytopenia(ITP)inchildren:
Initialmanagement"and"Warmautoimmunehemolyticanemia:Treatment"and"Autoimmunehemolyticanemiain
children:Classification,clinicalfeatures,anddiagnosis".)
RituximabhasbeenusedsuccessfullyandshouldbeconsideredforpatientswithCVIDandITPorAIHArefractory
toglucocorticoids[3638].Inmostcases,glucocorticoidsarecontinueduntiltheeffectsofrituximabcanbe
assessed.Inaretrospectiveanalysisof33adultsandchildrenwithITP,AIHA,orboth,overallresponserateto
rituximabwas85percent[36].Tenpatientsrelapsed,ofwhomsevenofninerespondedtorepeattreatment.The
incidenceofseriousinfectionswasnotincreasedinpatientswhowerereceivingadequateIGreplacement.Thus,
rituximabwouldbepreferredoversplenectomy.IGshouldbecontinuedduringrituximabtherapy.Rituximabdosing
forITPandAIHAisreviewedelsewhere.(See"Immunethrombocytopenia(ITP)inadults:Secondlineand
subsequenttherapies",sectionon'Rituximab'and"Warmautoimmunehemolyticanemia:Treatment",sectionon
'Rituximab'and"Autoimmunehemolyticanemiainchildren:Treatmentandoutcome",sectionon'Treatment'.)
SplenectomycanbeusedasalastresorttreatmentofsevererefractoryITPandAIHAinpatientswithCVID.Earlier
seriesreportedsignificantratesofseriousinfections[35],althoughlaterstudiesaresomewhatmoreencouraging.
Thelargestseriesavailableanalyzedoutcomesin45patientswithCVIDfrommultiplecenterswhounderwent
splenectomy,24ofwhomhadautoimmunecytopenias[39].Ofthese,19hadfailedglucocorticoids,IGtherapy,or
both,andtwohadfailedrituximab.Seventyfivepercentexperiencedaclinicalresponsetosplenectomy(definedas
needingnofurthertherapybeyondlowdosemaintenanceglucocorticoids),whiletheremaining25percenteither
respondedinitiallybutsufferedmultiplerelapsesordidnotrespondandrequiredsubsequentalternativetherapy.
Therewerenineepisodesofbacterialmeningitisorsepticemiain40patients(infectionsbelievedtobedirectly
relatedtosplenectomy),althoughsixofthesewereinpatientsnotreceivingIGtherapy.Nodeathsresultedfrom
theseinfections.However,therewere16otherepisodesofviralreactivations,fungalinfections,andotherserious
bacterialinfections,atleastfourofwhichwerefatal.Overall,themortalityrateinthesplenectomizedpatientswas
1.6percentperpatientyear,comparedwithanestimatedrateof2.3percentinallpatientswithCVIDand
autoimmunecytopenias[40].Thus,splenectomyisareasonableoptionforpatientswithrefractorydiseaseanddoes
notappeartoincreasemortality.However,werecommendthatIGtherapyshouldbeinplacepriortosurgery.
GranulomatousdisordersAntiinflammatoryorimmunomodulatorytherapymayalsobeneededforthe
granulomatousdiseaseassociatedwithCVIDhowever,therearenostandardtreatmentprotocolsandresponses
arevariable[31,41].
Inaretrospectiveanalysisof59patientswithgranulomatousinfiltrationofvariousorgans,32patientswere
treatedmostcommonlywithglucocorticoids(initialdose,30to60mgdailyforamedianof18months)[41].
Overall,58percentofthosereceivingglucocorticoidsshowedacompleteorpartialresponse.Granulomasof
thelymphnodesseemedmoreresponsivethangranulomasinotherorgans,althoughnoneofthefourpatients
withgastrointestinalgranulomaresponded.Otherdrugsthatwerehelpfulinsomepatientsincluded
cyclophosphamide,hydroxychloroquine,rituximab,azathioprine,andmethotrexate.Thecombinationof
rituximabandazathioprinehasbeenusedsuccessfullyinafewpatientswhohavepulmonarygranuloma
associatedwithinterstitiallungdisease(GLILD)onbiopsy[42].
ThesuggestionthatasmallsubgroupofpatientswithCVIDmayhaveelevatedproductionoftumornecrosis
factoralpha(TNFalpha)hasledtouseofTNFinhibitorsinsomepatientswithgranulomatousconditions.
Casereportshavedocumentedthefollowing:
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CutaneousgranulomasrefractorytoothertherapiesrespondedtothesolubleTNFalphareceptorfusion
protein,etanercept[43].
Pulmonarygranulomatousdiseaseandseveresystemicgranulomatousdiseasehavereportedly
respondedtoinfliximab,achimericmonoclonalantibodytoTNFalpha[4446].
OtherchronicdisordersOnestudyreportedelevatedratesofsensorineuralhearinglossinchildrenwithCVID,
possiblysecondarytorepeatedepisodesofotitismedia[47].Completeaudiologicalexaminationsshouldbe
consideredinpatientswhodisplaysignsofimpairedhearingorperformpoorlyinschool.
DETECTIONOFMALIGNANCYPatientswithcommonvariableimmunodeficiency(CVID)mustbemonitoredfor
lymphoma,gastriccancer,andothermalignancies[30,48,49].
EarlydetectionWesuggestthefollowing:
PatientswithCVIDshouldreceiveallageappropriatecancerscreeningproceduresthatarerecommendedfor
thegeneralpopulation.(See"Preventivecareinadults:Recommendations",sectionon'Cancer'.)
Manypatientshavelymphadenopathyandsplenomegaly,althoughthedevelopmentofconstitutional
symptoms,solitarynodules,expandinglymphnodes,orothermassesshouldpromptconsiderationof
lymphoma.Peripheralbloodstudies,orlymphnodeorbonemarrowbiopsymaybeindicatedtoassess
clonality.(See"ClinicalpresentationanddiagnosisofnonHodgkinlymphoma".)
Bronchoscopywithbiopsymaybeindicatedforfocalpulmonaryfindingsthatfailtoresolvewithtreatment.
Inolderstudies,gastriccancerwasfoundmorecommonlyinCVIDpatients,althoughithasnotbeenseenwith
thesamehigherincidenceinmorerecentstudies[5].Althoughitisnotuniversallyagreedthatallpatients
requirescreeningforgastriccancer,asurveillanceprotocolhasbeensuggested[50].Thisapproachcallsfor
screeningallpatients(atdiagnosis)forH.pyloriinfectionwithureabreathtesting,eradicationtherapyif
infectionisdetected,andrepeatbreathtestingtodemonstrateclearance.Inaddition,serumB12andiron
concentrationaremeasuredannuallyforallpatients.Patientswhodevelopdyspepsiaorunexplainedweight
lossduringtheirfollowupperiod,thosewithpositiveureabreathtesting,andthosewithlowserumB12level
shouldundergouppergastrointestinalendoscopy,includingbiopsiesoftheantrumandfundus.Amore
conservativeapproachwouldbetoperformendoscopyandbiopsyforH.pyloriinpatientsonlyiftheydevelop
symptomsofgastritisorgastroesophagealrefluxdisease.(See"AssociationbetweenHelicobacterpylori
infectionandgastrointestinalmalignancy".)
CautioususeofradiationbasedtestsUseofradiationbasedimagingstudiesinpatientswithCVIDshouldbe
conservativeandthoughtful,sincetheyareathigherbaselineriskformalignancies[5154].Cliniciansshould
attempttominimizecumulativeradiationexposurebychoosingcomputedtomography(CT)protocolsthatuse
reducedradiationdoseintensitywheneverpossible,ormagneticresonanceimaging(MRI).Inacohortstudyof21
patientswithCVID,findingsofMRIandchestCTscansareanalyzed.Theconcordancebetweenthetwo
techniqueswasgoodindetectingbronchiectasisseverityandextensioninpatientswithsevereandmoderate
degreesofbronchialpathology.However,MRIwaslesssensitiveindetectingmilddefects,mainlyduetothelow
MRIsensitivityintheassessmentofprebronchialalterations.Therefore,CTscanisstillthegoldstandardfor
diagnosinginitialbronchialalterations[55].
INVESTIGATIONALTREATMENTSInterleukin2(IL2)treatmenthasundergoneevaluationinpatientswith
commonvariableimmunodeficiency(CVID)becauseofdatademonstratingdeficiencyofIL2productioninsome
patientsandobservedTcelldefectsthatmightbeexplainedbyadeficiencyinIL2.Investigationalstudiesoflow
doseIL2treatmentresultedinimprovedTcellfunctionaswellasnovelantibodyproductioninresponseto
neoantigenvaccination[56,57].However,therewereonlymodestimprovementsofclinicalparameters.Thistherapy
mightbeconsideredinthetreatmentofrefractoryinfectionsinsubjectswithCVIDwhohavedemonstrateddefects
inTcellfunction.
Allogeneicstemcelltransplant(ASCT)hasbeenperformedinasmallnumberofpatientswithCVID,eitherforthe
treatmentofhematologicmalignanciesorforseveremanifestationsofCVIDthatwerenotrespondingtoother
interventions[58,59].Inareviewof25patients,overallsurvivalwas48percent,withgraftversushostdiseasethe
leadingcauseofdeath.Amongthosewhosurvived,onehalfwereabletodiscontinueimmuneglobulinandthe
conditionpromptingASCTresolvedin92percent[59].Thus,ASCTcouldbeconsideredinindividualswith
malignanciesorseverediseaserefractorytootheroptionsafteracarefulriskbenefitanalysis.
PROGNOSISTheincidenceofdeathassociatedwithacutebacterialinfectionincommonvariable
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immunodeficiency(CVID)decreaseddramaticallywiththeadventofimmunoglobulin(Ig)treatment.Thereafter,the
majorcausesofdeathhavebeencomplicationsofchroniclungdiseaseandmalignancies[11,12,49,60,61]:
Thelargestseriesof473patientsreportedlongtermdatafor411individuals,followedoveraperiodof40
years[11].Duringthistime,19.6percentdied,withamedianageatdeathof44and42forfemalesandmales,
respectively.Theleadingcausesofdeathwererespiratoryfailureduetochroniclungdisease(36percent),
lymphoidandothermalignancies(29percent),andliverdisease(9percent).Reducedsurvivalwasseenin
patientswithgastrointestinaldisease,chroniclungdisease,hepaticdisease,andlymphoma,althoughnotin
thosewithothercomplications,suchasautoimmunedisorders,granuloma,orbronchiectasiswithoutother
lungdisease.Longtermsurvivalwasexcellentinpatientswithonlyinfectiouscomplications,butsignificantly
lowerinthosewithoneormorenoninfectiouscomplications(95versus42percentat40years,respectively).
ImmunologicparametersassociatedwithhighermortalitywerelowerlevelsofserumimmunoglobulinG(IgG),
increasedserumimmunoglobulinM(IgM),andlowerpercentagesofcirculatingBcells.
Anothercenterreportedonthe353patientsdiagnosedasadultsalsofollowedovera40yearperiod[61].
Mortalityinthisgroupwasverysimilarat19.5percent,withamedianageatdeathof54and53fromfemales
andmales,respectively.Theleadingcauseofdeathwaschroniclungdisease(30percent).Asimilar
percentageofpatientssuccumbedtolymphoma,whileahigherpercentagediedfromothertypesof
malignancies.
Inathirdseriesof334patients,mortalitywashighestinpatientswithbronchiectasis,enteropathy,polyclonal
lymphocyticinfiltration,andautoimmunity[12].Inthisseries,therewerenoassociationsbetweensurvivaland
genderorinitialserumIgG,immunoglobulinA(IgA),orIgMlevels.
SubsequentresearchhasdemonstratedthatthepercentageofcirculatingclassswitchedmemoryBcellscanbe
usefulinpredictingapatient'sriskforthedevelopmentofcertaincomplicationsofCVID,suchaslymphoid
hyperplasia,granulomatousdisease,orautoimmunedisorders.Thisisdiscussedelsewhere.(See"Pathogenesisof
commonvariableimmunodeficiency".)
SUMMARYANDRECOMMENDATIONSThemanagementofcommonvariableimmunodeficiency(CVID)
involvessufficientimmuneglobulin(IG)replacementtherapyandmonitoringforandtreatmentofassociated
inflammatorydisordersandmalignancies.
IGreplacementIGreplacementtherapyreducesthefrequencyofmosttypesofinfectionsinpatientswithCVID.
Itmayalsoslowtheprogressionofchroniclungdiseaseandoffersomeprotectionagainstautoimmunedisorders.
However,thereislittleevidencethatIGtherapyprotectsagainstthedevelopmentofmalignancyorgranulomatous
disease.(See'Impactoftherapy'above.)
WerecommendthatpatientswithCVIDreceiveIGreplacementtherapy(Grade1A).Theusualinitialdosing
forintravenousimmuneglobulin(IVIG)is300to400mg/kg,giveneverythreetofourweeks,withthegoalof
maintainingatroughimmunoglobulinG(IgG)levelinthemiddleofthenormalrangeandreducingthe
incidenceofsignificantinfections.SomepatientsrequiremoreIGthanotherstoattainthesegoals.(See
'Immunoglobulinreplacementtherapy'above.)
WesuggesthigherdosesofIGreplacementforCVIDpatientswithpersistentinfections(eg,sinusitis),chronic
pulmonarydiseaseorautoimmunehematologicdisorders(Grade2C).(See'Indicationsforhigherdosing'
above.)
PatientsmayprefersubcutaneousIGtherapy,asthiscanbeselfadministeredathomeandismore
convenientformany.SubcutaneousadministrationismedicallyindicatedforpatientswithreactionstoIVIG,
thosewithrapidIGloss,andthosewithpoorintravenousaccess.(See"Subcutaneousandintramuscular
immuneglobulintherapy".)
ApproachtoinfectionsTreatmentwithIGreplacementdoesnotentirelyeliminateinfectionsinmostpatients
withCVID,andantibiotictherapyisalsoessential.
WesuggestprophylacticantibioticstopreventinfectionsinCVIDpatientswithongoinglungdiseasedespite
immunoglobulin(Ig)replacementtherapy,andinthoserequiringchronicglucocorticoidsorother
immunosuppressivemedications(Grade2C).WedonotroutinelygiveprophylacticantibioticstoallCVID
patientsandtheutilityofthisinterventionhasnotbeenadequatelystudied.(See"Medicalmanagementof
immunodeficiency",sectionon'Prophylacticantimicrobialtherapy'.)
PatientswithCVIDdonotusuallyclearcommoninfectionswithoutantibiotics,andantibiotictherapyshouldbe
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institutedearlyforcommoninfections,suchasbronchitisandacutesinusitis.Inaddition,longercoursesof
therapyaresometimesrequiredtoeradicateinfectionscompletely.(See'Treatmentofspecificinfections'
above.)
WesuggestthatpatientswithCVIDwhoplantotravelreceivetheappropriateinactivatedvaccinations(Grade
2C).Livevaccinationsshouldbeavoided.Somepatientsmayonlymountapartialresponse.(See
'Vaccinations'above.)
Approachtononinfectiousdisorders
PatientswithCVIDmayrequireimmunosuppressivetherapiesforautoimmune,inflammatory,and
granulomatousdisorders,althoughtheyappeartosufferfromhigherratesofinfectiousadverseeffects.
Patientsrequiringsuchtherapiesshouldbecarefullymonitoredforthespecificcomplicationsassociatedwith
theagentinquestion.(See'Therapyfornoninfectiousdisorders'above.)
PatientswithCVIDshouldundergoallageappropriatecancerscreeningandadditionallybemonitoredfor
signsandsymptomsoflymphoma.Theseincludeconstitutionalsymptoms,solitarynodules,expandinglymph
nodes,othermasses,andfocalpulmonaryfindingsthatfailtoresolvewithtreatment.(See'Detectionof
malignancy'above.)
ACKNOWLEDGMENTWearesaddenedbytheuntimelydeathofLloydMayer,MD,whopassedawayin
September2013.UpToDatewishestoacknowledgehisdedicatedworkonthisandothertopicreviews.
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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Topic3952Version19.0

ContributorDisclosures
SamAhn,MDNothingtodisclose.CharlotteCunninghamRundles,MD,PhDNothingtodisclose.ERichard
Stiehm,MDConsultant/AdvisoryBoards:ADMABiologics[Infectionsofrespiratorysyncytialvirusinorgan
transplants(Respiratorysyncytialvirusimmuneglobulin)].AnnaMFeldweg,MDNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseare
addressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovided
tosupportthecontent.AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDate
standardsofevidence.
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