Upload
others
View
21
Download
0
Embed Size (px)
Citation preview
IRTinPIDD’s-Indications&Applications-
AndrévanNiekerk
PaediatricPulmonologistUP&NetcareClinton&AlberlitoHospitals
IRTinPIDD:indications&applicationsSynopsis
Introduction
IndicationsforIRT
IRTproducts&methods
Conclude
ManagingIRTcomplications
IntroductionInfectionsusceptibility
• Developmental/functionaldefectsoftheimmunesystem• Geneticorigin• Heterogeneousgroupofdisorders• Variablesigns&symptoms• Increasedsusceptibilitytoinfection
IntroductionSuspectingPIDD
• SPUR
• Growingnumbers• Now>350knownPIDD’s• USA:PIDDin1:1200livebirths• MostcommonSIgAd1:300–1:500
IntroductionPrevalenceofPIDD’s
McCuskeretal.AllergyAsthma&ClinicalImmunology2011,7(Suppl1):S11http://www.aacijournal.com/content/7/S1/S11
10
20
30
40
50
60
70
80
%
Malabsorptio
n
Sepsis
Sinu
sitis
Bron
chitis
Pneu
mon
ia
Otitismed
ia
Diarrhoe
a
Arthritis
Men
ingitis
Hepatitis
Cancer
n=2807
...........
IntroductionInfectionsbeforePIDDdiagnosis
IDF:PrimaryimmunedeficiencydiseasesinAmerica:thefirstnationalsurveyofpatientsandspecialist.1995,Availableat:http://209.251.35.238/publications/surveys/First_National_Survey_of_Patients_and_Specialists_(1995).
Commoninfectionsmaynotbetrivial
. .. . . . .n=2807
%
5
10
15
20
25
30
>65<1 1to5 6to11 12to17 18to39 40to64
Age(yr.)
IntroductionAgeatPIDDdiagnosis
IDF:PrimaryimmunedeficiencydiseasesinAmerica:thefirstnationalsurveyofpatientsandspecialist.1995,Availableat:http://209.251.35.238/publications/surveys/First_National_Survey_of_Patients_and_Specialists_(1995).
>40%notdiagnoseduntiladulthood
• Col.OgdenBruton• 8-year-oldboywithrecurrentPneumococcalsepsis,agammaglobulinaemia&noresponsetovaccination
• IgGfractionatedfromhumanplasma• SCIg• LaterdiagnosedwithBruton-typeagammaglobulinaemia(XLA)
IntroductionIRTinPIDD
Brutonetal.Pediatr.19529:722-228
• WHOacknowledgedneedforcontinuedIRTaccess:- ListofEssentialMedicines
- BonillaFA.JClinImmunol.2011;139:107–109- Oftenlife-long- Oftenlife-saving- Mustbeadministeredregularly
• Oftennoalternativetreatment
IntroductionListedasessentialmedicines
• Currentindications&prescribing• Limitedavailabilityoflicensedproducts• Perceptionofhighcost• Funderrelatedadministrativeburden• Restricted&delayedaccess• Supplychaininterruptions• IRTcomplications
IntroductionIRTdilemmas
IRTinPIDD:indications&applicationsSynopsis
Introduction
IndicationsforIRT
IRTproducts&methods
Conclude
ManagingIRTcomplications
Diagnosticgroup Listofspecificconditionsordrugs
Malignancies ChroniclymphocyticleukemiaMultiplemyelomaB-celllineagelymphoproliferativedisease
Drugs Anticonvulsants:carbamazepine,valproate,lamotrigine,phenytoinImmunosuppressive/immunomodulatoryagents:Corticosteroids(long-term,frequentuse),cyclophosphosphamide,mycophenolatemofitil(inorgantransplant),azathioprine,sulfasalazine,penicillamineB-celldepletion/suppressione.g.rituximaborCD19-targetedCART,atacicept,imatinib(TKI)Other:chlorpromazine,clozapine
Immunoglobulinlossorcatabolism
ProteinlosingenteropathyNephroticsyndromePlasmaexchange
Viralinfections HIV,parvovirusB19,congenitalrubella,EBV,CMV
Other
Intestinallymphangiectasia&chylothoraxMyotonicdystrophy
IndicationsforIRTGuidelineindicationsinSID’s
• InterimuseforPIDD’sunderinvestigation:- Workupofdiagnosisdelayed/complex- Individualrecommendation
IndicationsforIRTPIDD’sunderinvestigation
• EssentialinPIDD’saffectingthehumoralimmunesystem:- Mostlyforantibody(quantity)deficiencies
- AlsoinPIDD’swithantibodyfunction(quality)deficiencies
• Betterunderstandingofunderlyingdefectswillbroadenindications
• IndividualIRTguidelinesforeachspecificdiagnosisimpractical
IndicationsforIRTPIDDindications
Category s-IgGquantity
B-cells s-IgGquality
Diagnosticexample
I
−
−
−
SCID;Agammaglobulinaemia
II
↓
+
↓
CID;CVID;HyperIgM;NEMO(subset)
III
N
+
↓
CID;NEMOsubset;Specificantibodydeficiency;IgGsubclassdeficiencywithspecificantibodydeficiency
IV
↓
+
N
THI;Primaryhypogammaglobulinaemia
IndicationsforIRTPhenotype-groupingapproachforPIDD
AdaptedfromStiehm,Orange,Ballow,et.al.Adv.Pediatr.201057:185-218
Category s-IgGquantity
B-cells s-IgGquality
Diagnosticexample
I
−
−
−
SCID;Agammaglobulinaemia
II
↓
+
↓
CID;CVID;HyperIgM;NEMO(subset)
III
N
+
↓
CID;NEMOsubset;Specificantibodydeficiency;IgGsubclassdeficiencywithspecificantibodydeficiency
IV
↓
+
N
THI;Primaryhypogammaglobulinaemia
IndicationsforIRTPhenotype-groupingapproachforPIDD
AdaptedfromStiehm,Orange,Ballow,et.al.Adv.Pediatr.201057:185-218
1.Quantifys-IgG:- Age&platformappropriatereferenceranges- ?CriticallevelforIRT
Category s-IgGquantity
B-cells s-IgGquality
Diagnosticexample
I
−
−
−
SCID;Agammaglobulinaemia
II
↓
+
↓
CID;CVID;HyperIgM;NEMO(subset)
III
N
+
↓
CID;NEMOsubset;Specificantibodydeficiency;IgGsubclassdeficiencywithspecificantibodydeficiency
IV
↓
+
N
THI;Primaryhypogammaglobulinaemia
IndicationsforIRTPhenotype-groupingapproachforPIDD
AdaptedfromStiehm,Orange,Ballow,et.al.Adv.Pediatr.201057:185-218
2.QuantifytheB-cells:- Lymphocytephenotyping- CD19
Category s-IgGquantity
B-cells s-IgGquality
Diagnosticexample
I
−
−
−
SCID;Agammaglobulinaemia
II
↓
+
↓
CID;CVID;HyperIgM;NEMO(subset)
III
N
+
↓
CID;NEMOsubset;Specificantibodydeficiency;IgGsubclassdeficiencywithspecificantibodydeficiency
IV
↓
+
N
THI;Primaryhypogammaglobulinaemia
IndicationsforIRTPhenotype-groupingapproachforPIDD
AdaptedfromStiehm,Orange,Ballow,et.al.Adv.Pediatr.201057:185-218
3.Specificresponsetovaccinesasdiagnostictoolforimmunodeficiency:• Predictivevalueofdiminishedspecificantibodydeterminationpoorlydefined
• Tetanus&diphtheriatoxoidpotentimmunogens- Lowseroconversionpostvaccination
suggestsdeficit- Healthyresponse20-30foldincrease
Category s-IgGquantity
B-cells s-IgGquality
Diagnosticexample
I
−
−
−
SCID;Agammaglobulinaemia
II
↓
+
↓
CID;CVID;HyperIgM;NEMO(subset)
III
N
+
↓
CID;NEMOsubset;Specificantibodydeficiency;IgGsubclassdeficiencywithspecificantibodydeficiency
IV
↓
+
N
THI;Primaryhypogammaglobulinaemia
IndicationsforIRTPhenotype-groupingapproachforPIDD
AdaptedfromStiehm,Orange,Ballow,et.al.Adv.Pediatr.201057:185-218
3.Specificresponsetovaccinesasdiagnostictoolforimmunodeficiency:• PolysaccharideAg
- PCV&PPSVstimulateimmuneresponsesdifferently
- Responsesvaryaccordingtoage–after5yearsmoreconsistent
- 4-foldincreaseconsiderednormal- Rapidwaningofresponsesacceptedas
indicationofimpairedquality
Category s-IgGquantity
B-cells s-IgGquality
Diagnosticexample
I
−
−
−
SCID;Agammaglobulinaemia
II
↓
+
↓
CID;CVID;HyperIgM;NEMO(subset)
III
N
+
↓
CID;NEMOsubset;Specificantibodydeficiency;IgGsubclassdeficiencywithspecificantibodydeficiency
IV
↓
+
N
THI;Primaryhypogammaglobulinaemia
IndicationsforIRTPhenotype-groupingapproachforPIDD
AdaptedfromStiehm,Orange,Ballow,et.al.Adv.Pediatr.201057:185-218
Definitelybeneficial
Probablybeneficial:furtherexpertreview&recommendationsMaybebeneficial
IRTinPIDD:indications&applicationsSynopsis
Introduction
IndicationsforIRT
IRTproducts&methods
Conclude
ManagingIRTcomplications
IRTproducts&methodsNogenericalternatives
• IRTtherapiesarenotgenericmedicine:- Uniquebiologicalproducts- Processingdifferences- Variabletolerability,risk,infusionrates&efficacy
- Notinterchangeable• AspecificIRTproductshouldbeallowed:- Equalaccess&- Continuousbasis- Notaffectedbyfiscalregulation&supplychaininterruptions
IRTproducts&methodsMethods
• IVIg• SCIg• fSCIg
• Consider:- Venousaccess- Side-effects- Monitoringrequirements- Equipmentrequirements- Patientchoice,socialcircumstance&training- Possibilityofhometreatment- Funderallowance
IRTproducts&methodsMethods
• IVIg• SCIg• fSCIg
Individualisethedecisionontheroute&keeppatientpreference
inmind
IVIg&SCIgequallyeffective&equivalentlydosed
BaselineHIV,TB,FBC,biochemistrybeforeinitiation
IRTproducts&methodsMethods
• IVIg• SCIg• fSCIg
IMIgnotrecommendedforIRT
MucosalimmunityIgAmediated:IRTdoesnotrestoremucosal
immunity
• Dose:- Initiate@400-600mg/kg/month- Titrateaccordingtotroughlevel&infectionburden
• Initialinfusionsinresourcedfacility:- Observe&managecomplications
• FollowPIdirectedinfusionrate
IRTproducts&methodsIVIg
Donotconsiderindwellingcathetersforthesolepurposeof
IRT
0 7 14 21 0 7 14 214
6
8
10
12
14
days days
s-IgG(g/l)
IgG30gIVI IgG12gweeklysubcutaneousx3
XLApatient
IRTproducts&methodsTroughlevelsIVIgvsSCIg
·
······ · ·
·· · · ·
IRTproducts&methodsSCIg
• Createsubcutaneousdepot• Slowabsorptionfromdepot:
- Avoidpeakrelatedsystemicside-effects
- Avoidtroughrelatedinfectionrisk- Verylowriskofanaphylaxis
• Idealforhome-basedIRT
• Startingdose100-200mg/kg/week• Definiteindications:
- SystemicadverseeffectstoIVIg- DifficultaccesstoanIVtransfusioncentre
- Problematicvenousaccess- UndetectableIgAwithanaphylaxisrisk
• Meritoriousindications:- Personalpreference- Patientswhoareindependent,compliant&enjoyssupporttodoso
- Socialtime-constraints
IRTproducts&methodsSCIg
Age(yr.) ml/week Weight@100mg/w Vol/site(ml) Sites
<2 5 8 5 1
3-5 10 16 10 1
7-8 15 24 15 1
9-11 20 32 10-20 1-2
12-13 25 40 12.5-25 1-2
Adult 40 60 20-40 1-2
Adult 50 80 25 2
IRTproducts&methodsSCIg:160mg/ml@100mg/kg/week
IRTproducts&methodsSCIg:subcutaneousinfusionsites
IRTproducts&methodsSCIg:Pumpvspush
IRTinPIDD:indications&applicationsSynopsis
Introduction
IndicationsforIRT
IRTproducts&methods
Conclude
ManagingIRTcomplications
• Generallysafe• Mostlymild&reversible• Canbesevere• IVIg:
- Systemic(20-40%)- Especiallywithinitiatingtransfusions&- Switchingbetweenproducts
• SCIg:- Localreactions(75%)- Lesssystemic(0.43%)
ManagingIRTcomplicationsAdverseevents
• Onset30min-6hours• Non-anaphylactic:
- Fever,flushing,chills- Nausea,vomiting,diarrhoea- Bloodpressurefluctuations,dizziness- Arthralgia,myalgia- Maculopapularskineruptions,urticaria- Shortnessofbreath- Fatigue- Headache
• Anaphylactic:- MoreinCVID&SIgAD
ManagingIRTcomplicationsImmediatesystemicadversereactions
• Onset6hours–1weekafterIRT:- Headache- Asepticmeningitis- Thromboembolic,haemolitic
ManagingIRTcomplicationsDelayedsystemicadversereactions
• >1weekposttransfusions• Viraltransmissions
- HepatitisC- ParvoB19
• Veryrarereportsonneurodegeneration
ManagingIRTcomplicationsLatesystemicadverseevents
NoreportsofHIVtransmission
• Pre-hydrate• Infusionrates:
- Slowinitialinfusionrate&titraterateaccordingtoPI- Interruptinfusion&restartslowly
• Medicaltreatment:- Ibuprofen&glucocorticosteroidsformoderateorseverereactions- +/-oralpromethazine+/-IVIhydrocortisone- Ibuprofenpre-treatmentwithpreviousmoderatetoseverereactions
• Anaphylaxis:- Beprepared- Stopinfusion- Adrenaline&anaphylaxisprotocol
ManagingIRTcomplicationsPrevent&manageimmediateadversereactions
• UncommonwithIVIg:- Pain- Bleeding- Bruising
• CommonwithSCIg:- Discomfort- Pruritis- Redness&swelling- Lesswithfollow-upinfusions&correctprimingoftheneedle
• Managewithwarm/coldcompresses
ManagingIRTcomplicationsInfusionsitereactions
• PatientsshouldnotbewithoutIRT• Significantadversereactionsinupto18%whenswitchingproduct• Carefulconsiderationbeforeswitching:
- Notforminoradverseeffects- Nounnecessaryswitchingforpatientinconvenience
• Alternatives:- Changetoalternativemethod/product- Lowerdoseinrange(200-400mg/kg/month)- Increasedosinginterval- Prophylacticantibiotics
ManagingIRTcomplicationsStock-outs&shortages
IRTinPIDD:indications&applicationsSynopsis
Introduction
IndicationsforIRT
IRTproducts&methods
Conclude
ManagingIRTcomplications
ConcludePrescribermindfulness
• Correctindications:- Finitesupply- Potentialadverseeffects&adverseconsequences- Avoidfutileuse
• IRTdelays,interruption&forcedproductswitchingharmpatients
• Cost-effectivewhenadministeredpromptly&uninterrupted:- Preventslife-threateninginfections- Preventsend-organdamage- Preventshospitaladmissions
Category s-IgGquantity
B-cells s-IgGquality
Diagnosticexample
I
−
−
−
SCID;Agammaglobulinaemia
II
↓
+
↓
CID;CVID;HyperIgM;NEMO(subset)
III
N
+
↓
CID;NEMOsubset;Specificantibodydeficiency;IgGsubclassdeficiencywithspecificantibodydeficiency
IV
↓
+
N
THI;Primaryhypogammaglobulinaemia
IndicationsforIRTPhenotype-groupingapproachforPIDD
AdaptedfromStiehm,Orange,Ballow,et.al.Adv.Pediatr.201057:185-218
Definitelybeneficial
Probablybeneficial:furtherexpertreview&recommendationsMaybebeneficial
• ProfRobinGreen• UPPulmonolgyteam
• DrSylviavandenBerg• DrCathyvanRooyen• DrJanieKriel• ProfMonikaEsser
• ProfJonnyPeter• ProfBrianEley• DrSuvarnaBuldeo
THANKYOU