Debate re diagnostic criteriaDebate re diagnostic criteria

Please email your comments to:Please email your comments to:

helen.chapel@ndm.ox.ac.ukhelen.chapel@ndm.ox.ac.uk

Validation of criteria for CVID Validation of criteria for CVID diagnosisdiagnosis

In relation to ESID / PAGID criteria In relation to ESID / PAGID criteria in in Conley et al 1999Conley et al 1999

Data from the pan-European Data from the pan-European registry 1992 - 2004registry 1992 - 2004

1294 “CVI” patients entered into 1294 “CVI” patients entered into the registry in Stockholm the registry in Stockholm

(Hammarstrom)(Hammarstrom)

QLQ1-CT-2001-01395 4

Ig isotypes at presentation Ig isotypes at presentation - red circle shows 40 - red circle shows 40 patients with normal IgA & IgM levels but low IgG levels - so IgG patients with normal IgA & IgM levels but low IgG levels - so IgG subclass deficiency patients [0.03%] subclass deficiency patients [0.03%] - what to do with slightly low - what to do with slightly low

IgM (dotted line)?IgM (dotted line)?

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New proposals for partial New proposals for partial antibody deficienciesantibody deficiencies

Helen Chapel, Janne Bjorkander, Mary-Ellen Conley, Helen Chapel, Janne Bjorkander, Mary-Ellen Conley, Teresa Espanol, Amos Etzioni, Bodo Grimacher, Lennart Teresa Espanol, Amos Etzioni, Bodo Grimacher, Lennart

Hammarstrom, Maria Kanariou, Luigi Notarangelo, Hammarstrom, Maria Kanariou, Luigi Notarangelo, David Webster on behalf of ESID and the EUROPID David Webster on behalf of ESID and the EUROPID

groupgroup

Funded by a grant from the EU - QLQ1-CT-2001-01395

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Criteria - Criteria - General points:General points:

• Criteria for diagnosis: studies/registers etcCriteria for diagnosis: studies/registers etc

• agreed by ESID & PAGIDagreed by ESID & PAGID

• Definite Definite = 98% probability that same = 98% probability that same diagnosis in 20 years;diagnosis in 20 years;gene mutation & gene mutation & clinical featuresclinical features

• ProbableProbable = 85% probability that same = 85% probability that same diagnosis in 20 years; diagnosis in 20 years; clinical & lab clinical & lab features as no known single gene defect features as no known single gene defect

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Common Variable Immune Common Variable Immune Deficiency Disorders [CVIDs]Deficiency Disorders [CVIDs]

ProbableProbable:: male/female patient with male/female patient with allall of: of:• Aged > 4 years Aged > 4 years • Serum IgG and IgA more than 2 SD below Serum IgG and IgA more than 2 SD below

mean for age mean for age • Poor response to all vaccinesPoor response to all vaccines• Causes of secondary antibody deficiencies Causes of secondary antibody deficiencies

excluded (eg lymphoma, medications)excluded (eg lymphoma, medications)

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IgA with IgG subclass IgA with IgG subclass deficiencies deficiencies DRAFTDRAFT

Male or female patient with recurrent/ severe Male or female patient with recurrent/ severe infections and infections and allall the following: the following:

• Aged > 7 yearsAged > 7 years• Marked decrease in IgA [ie <0.05g/l] and Marked decrease in IgA [ie <0.05g/l] and at at

leastleast one of IgG one of IgG 1-31-3 subclasses less than the subclasses less than the 55thth centile for age centile for age

• Poor responses to some vaccinesPoor responses to some vaccines

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Male or female patient with recurrent/ severe Male or female patient with recurrent/ severe infections and infections and allall the following: the following:

• Aged > 7 yearsAged > 7 years• Normal levels of IgM & IgA and Normal levels of IgM & IgA and at leastat least

twotwo of IgG of IgG 1-31-3 subclasses less than the 5 subclasses less than the 5 thth centile for agecentile for age

• Poor responses to some vaccinesPoor responses to some vaccines

IgG subclass deficiencies IgG subclass deficiencies DRAFTDRAFT

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Does this patient have an IgG subclass Does this patient have an IgG subclass deficiency ?deficiency ?

• Originally investigated in Originally investigated in 1983 for boils 1983 for boils Staphylococcal Staphylococcal

phagocytosis & killing phagocytosis & killing defect defect ? significant? significant

discharged in 1989 without discharged in 1989 without treatmenttreatment

• 1991 - more boils 1991 - more boils ?linked to ?linked to stress stress

• Family history:Family history: Sister (bronchiectatic) had Sister (bronchiectatic) had

pneumoniapneumonia Half-brother died - Half-brother died -

bronchiectasis with CVIDbronchiectasis with CVID

• Serum IgG 5.3 g/l; IgA none, Serum IgG 5.3 g/l; IgA none, IgM normalIgM normal

• 1992 -1999 trial of 1992 -1999 trial of immunoglobulin therapy immunoglobulin therapy - reduced the boils- reduced the boils

• Diagnosis soughtDiagnosis sought normal IgE & CXR -unlikely normal IgE & CXR -unlikely

Job’s syndrome Job’s syndrome low IgG 3 “ antibody low IgG 3 “ antibody

deficiency”deficiency” worsening of asthma “APBA” worsening of asthma “APBA”

+ve aspergillus precipitins (1 +ve aspergillus precipitins (1 line); mild eosinophilia onlyline); mild eosinophilia only

• No more boils after 1995No more boils after 1995

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IgG subclass deficiency IgG subclass deficiency (contd 3)(contd 3)

Transferred in 2000:Transferred in 2000:• Normal numbers of B cellsNormal numbers of B cells• Specific antibodies - present, even to encapsulated pathogens Specific antibodies - present, even to encapsulated pathogens • Stopped IVIg & no infections (not even boils) for 5 yearsStopped IVIg & no infections (not even boils) for 5 years• Reviewed every 3 months; IgG Reviewed every 3 months; IgG and espand esp. IgG 3 reached stable, . IgG 3 reached stable,

normal levels within 6 monthsnormal levels within 6 months• Aspergillus precipitins now negative Aspergillus precipitins now negative (moved to new house)(moved to new house)

Diagnosis: ? transient IgG3 defectDiagnosis: ? transient IgG3 defect

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We need more data…….We need more data…….

Mininum data set for ESID online registry:Mininum data set for ESID online registry:• Demographs Demographs - age, gender, family Hx- age, gender, family Hx

• Serum Ig levels Serum Ig levels - IgM, IgA, IgG - IgM, IgA, IgG

• B cell numbers B cell numbers including B memory markersincluding B memory markers

• T cell numbers T cell numbers including CD4, CD8 etc for inter-current complicationsincluding CD4, CD8 etc for inter-current complications

• Clinical complications Clinical complications - granuloma, autoimmunity, lymphoproliferation, none- granuloma, autoimmunity, lymphoproliferation, none

• Antibody responses to test Imx. Antibody responses to test Imx. • ? Which and to be done where ?? Which and to be done where ?

• IgG subclass levels - ? in a single laboratoryIgG subclass levels - ? in a single laboratory

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Conclusions re testingConclusions re testing

Currently we need to:Currently we need to:

• Do test Imx responses to Do test Imx responses to standardstandard protein / carbohydrate protein / carbohydrate antigens for all new patients antigens for all new patients to distinguish CVIDs from partial to distinguish CVIDs from partial

antibody failures antibody failures

• Role for new vaccines/assaysRole for new vaccines/assays

• Add neoantigen test Imx for existing/ treated patients Add neoantigen test Imx for existing/ treated patients in in

order to categorise them more preciselyorder to categorise them more precisely

• Quality assurance and reference preparationsQuality assurance and reference preparations

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Extra essential dataExtra essential data

• Antibody [ IgG] responses to which test Imx. Antibody [ IgG] responses to which test Imx. Proteins Proteins - tetanus, diphtheria, Hib, rabies,- tetanus, diphtheria, Hib, rabies, Carbohydrates Carbohydrates - Pneumovax, Typhim Vi, new vaccine?- Pneumovax, Typhim Vi, new vaccine? Neoantigens Neoantigens - Tick-borne encephalitis vaccine- Tick-borne encephalitis vaccine Reference preparations from ….. Whom?Reference preparations from ….. Whom? Reference assays for Consensus to be done……. where ?Reference assays for Consensus to be done……. where ?

• IgG subclass levels IgG subclass levels ? in a single laboratory ? in Sweden ? in a single laboratory ? in Sweden

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Should we add plasmablasts to memory Should we add plasmablasts to memory B cell immunophenotyping ?B cell immunophenotyping ?

Plasmablasts on days 0,4,7 and 14 following Imx Plasmablasts on days 0,4,7 and 14 following Imx with influenza vaccine in a normal individualwith influenza vaccine in a normal individual

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IUIS 2006 IUIS 2006 (J All. & Clin.Imm.in press)(J All. & Clin.Imm.in press)

•This is a diagnosis of exclusion of other known primary antibody deficiencies. There are several different clinical phenotypes, probably representing distinguishable diseases with differing immunopathogeneses.It is not clear currently whether the mutations associated with some of these patients involve disease causing genes, disease modifying genes or polymorphisms.

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IUIS 2005IUIS 2005