IRT in PIDD’s - Indications & Applications 2019 presentations/irt-indictions...IRT in PIDD’s - Indications & Applications - André van Niekerk Paediatric Pulmonologist UP & Netcare

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


Introduction

IndicationsforIRT

IRTproducts&methods

Conclude


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



Diagnosticexample

I

−

−

−


II

↓

+

↓


III

N

+

↓


IV

↓

+

N




1.Quantifys-IgG:-  Age&platformappropriatereferenceranges-  ?CriticallevelforIRT



Diagnosticexample

I

−

−

−


II

↓

+

↓


III

N

+

↓


IV

↓

+

N




2.QuantifytheB-cells:-  Lymphocytephenotyping-  CD19



Diagnosticexample

I

−

−

−


II

↓

+

↓


III

N

+

↓


IV

↓

+

N




3.Specificresponsetovaccinesasdiagnostictoolforimmunodeficiency:•  Predictivevalueofdiminishedspecificantibodydeterminationpoorlydefined

•  Tetanus&diphtheriatoxoidpotentimmunogens-  Lowseroconversionpostvaccination

suggestsdeficit-  Healthyresponse20-30foldincrease



Diagnosticexample

I

−

−

−


II

↓

+

↓


III

N

+

↓


IV

↓

+

N




3.Specificresponsetovaccinesasdiagnostictoolforimmunodeficiency:•  PolysaccharideAg

-  PCV&PPSVstimulateimmuneresponsesdifferently

-  Responsesvaryaccordingtoage–after5yearsmoreconsistent

-  4-foldincreaseconsiderednormal-  Rapidwaningofresponsesacceptedas

indicationofimpairedquality



Diagnosticexample

I

−

−

−


II

↓

+

↓


III

N

+

↓


IV

↓

+

N




Definitelybeneficial

Probablybeneficial:furtherexpertreview&recommendationsMaybebeneficial


Introduction

IndicationsforIRT

IRTproducts&methods

Conclude


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



Individualisethedecisionontheroute&keeppatientpreference

inmind

IVIg&SCIgequallyeffective&equivalentlydosed

BaselineHIV,TB,FBC,biochemistrybeforeinitiation



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


Introduction

IndicationsforIRT

IRTproducts&methods

Conclude


•  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


Introduction

IndicationsforIRT

IRTproducts&methods

Conclude


ConcludePrescribermindfulness

•  Correctindications:-  Finitesupply-  Potentialadverseeffects&adverseconsequences-  Avoidfutileuse

•  IRTdelays,interruption&forcedproductswitchingharmpatients

•  Cost-effectivewhenadministeredpromptly&uninterrupted:-  Preventslife-threateninginfections-  Preventsend-organdamage-  Preventshospitaladmissions



Diagnosticexample

I

−

−

−


II

↓

+

↓


III

N

+

↓


IV

↓

+

N




Definitelybeneficial

Probablybeneficial:furtherexpertreview&recommendationsMaybebeneficial

•  ProfRobinGreen•  UPPulmonolgyteam

•  DrSylviavandenBerg•  DrCathyvanRooyen•  DrJanieKriel•  ProfMonikaEsser

•  ProfJonnyPeter•  ProfBrianEley•  DrSuvarnaBuldeo

THANKYOU

Documents

IRT in PIDD’s - Indications & Applications 2019 presentations/irt-indictions...IRT in PIDD’s - Indications & Applications - André van Niekerk Paediatric Pulmonologist UP & Netcare