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Updates in primary immunodeficiency

Jordan Orange, MD PhDProfessor of PediatricsColumbia University

DISCLOSURES• Consultant, Speaker; Honorarium

• Shire

• Consultant; Consulting fee• CSL Behring

• Advisory Board Member; Honorarium• ADMA

• Author; Royalty• UpToDate

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LEARNING OBJECTIVES

• Learn the current and updated classification for primary immunodeficiency

• Learn about advances in application of genetic diagnosis and precision medicine in primary immunodeficiency

• Evaluate recent experiences in the application of Quality of Life measurements for primary immunodeficiency patients

Primary Immunodeficiency

Genetic inability of the immune system to provide an advantage over the environment

• 2018: >350 diseases• Uniform newborn screening for SCID• Banner successes in gene therapy and

promise for genetic “surgery”• Mechanisms informing novel therapies for

cancer and autoimmunity (i.e. tofacitinib)• Insightful and unexpected biology• Opportunities for precision medicine

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Hallmarks of Primary Immunodeficiency

• Susceptibility to the external environment• Recurrent Infection• Severe Infection• Unusual Infection

• Susceptibility to the internal environment• Cancer • Autoinflammation• Autoimmunity

Utility of the 10 Warning Signs• Hendershot, RW et al. J All Clin Immunol 2003;111:S222

• At least one warning sign in 95%• At least 2 warning signs in 78%• At least 3 in 62%• 2 or more sinus infections in 1 yr – 68%• 2 + mos. on antibiotics – 54%• Need IV antibiotics to clear infections – 46%

• Reda, et. al, Allergy Asthma Immunol Res 2013 5:88-95• Sensitivity of any one sign 100%, Specificity of 26%

• PPV 53%, NPV 100%• Two signs: sensitivity 94%, Specificity 64%• Three signs: sensitivity 77% specificity 86%

www.info4pi.org

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Statistics, open arms and primary care practices• Statistically if a primary care

practice is 10,000 patients….• There should have 5 with primary

immunodeficiency!• Are they aware of their PIDD

patients?• GIVE US YOUR 5 SICKEST

CHILDREN…Only random digit dialing telephone survey of PIDD

US prevalence 1:1200 persons

Even without an index of suspicionSCID Newborn Screening

• Guthrie card punches• PCR measure of naïve T cells• Quantify TREC

• T Cell Receptor Excision Circles

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TREC assay (normal)

a

After Douek, et. al. Nature 1998 396:630

ad

d

TCRdTREC

TCR LocusThymic T cell

TT

T T

Periperal T cell (clonal expansion)

T

T

T

T

Isolate TRECs and enumerate per unit volume

NBS TREC for SCID – current experience

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True positive TRECPre-transplant management

• Refer to transplant center• Relative sequestration• Start PCP prophylaxis• Consider fungal prophylaxis (candida)• Start bacterial/infective prophylaxis (Ig therapy)• Consider specific viral propylaxis (acyclovir)• Breast feeding OK but consider maternal CMV status• Avoid vaccines• Irradiate blood products• Evaluate for and manage characteristic infections

J. Allergy and Clinical Immunology 2009 124:1152

Transplantation as the transformative standard of care in severe PID

Year of transplant Donor source

Gennery et. al. JACI 2010

Age at Transplant

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Transformative advances where transplant is sub par

Gene therapy for ADA-SCID (A. Aiuti)Survival

Correction of immune and metabolic defect

Reduction of severe infections

Aiuti et al., Science 2002; NEJM, 2009Cicalese, Ferrua et al, Blood 2016 and unpublished

0

200

400

600

800

1000

CD

3+T-

cell

coun

t (x1

06/L

)

Pre-treatment (n=15)

Year 1(n=15)

Year 3(n=14)

Year 5(n=10)

N=18

Ex vivo gene therapy for ADA-SCIDwas approved in the EU in 2016

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2018 IUIS update defines over 350 Primary Immunodeficiencies: an explosive field

The IUIS classificationIUIS table # PIDD classification # Genes/PIDDs

1 Immunodeficiencies affecting cellular and humoral immunity 49

2 Combined immunodeficiencies with associated or syndromicfeatures

67

3 Predominantly antibody deficiencies 40

4 Diseases of immune dysregulation 40

5 Congenital defects of phagocyte number, function or both 39

6 Defects in intrinsic and innate immunity 52

7 Autoinflammatory disorders 36

8 Complement deficiencies 30

9 Phenocopies of PID 12

Total = 365 (350 genes)

7245520198702

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The predominantly antibody deficienciesI: Monogenic

Primary humoral immunodeficiency category Gene defect Full gene name Inheritance

Severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells: Agammaglobulinemia

BTK Bruton tyrosine kinase XL

IGHM Immunoglobulin heavy constant mu AR

CD79A CD79a molecule AR

CD79B CD79b molecule AR

BLNK B cell linker AR

IGLL1 Immunoglobulin lambda like polypeptide 1 AR

PIK3R1 Phosphoinositide-3-kinase regulatory subunit 1 AR

TCF3 Transcription factor 3 AD

Severe reduction in at least 2 serum immunoglobulin isotypes with normal or low number of B cells, CVID

ATP6AP1 ATPase H+ transporting accessory protein 1 XL

CD81 CD81 molecule AR

MOGS Mannosyl-oligosaccharide glucosidase AR

TTC37 Tetratricopeptide repeat domain 37 AR

CD19 CD19 molecule AR

MS4A1 Membrane spanning 4-domains A1 AR

CR2 Complement C3d receptor 2 AR

TRNT1 tRNA nucleotidyl transferase 1 AR

TNFRSF13C Tumor necrosis factor receptor superfamily member 13C AR

TNFRSF13B Tumor necrosis factor receptor superfamily member 13B AD or AR

PIK3CD Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta AD

PIK3R1 Phosphoinositide-3-kinase regulatory subunit 1 AD

PTEN Phosphatase and tensin homolog AD

TNFSF12 Tumor necrosis factor superfamily member 12 AD

IRF2BP2 Interferon regulatory factor 2 binding protein 2 AD

NFKB1 Nuclear factor kappa B subunit 1 AD

NFKB2 Nuclear factor kappa B subunit 2 AD

IKZF1 IKAROS family zinc finger 1 AD

Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells: Hyper IgM

AICDA Activation-induced cytidine deaminase AR

UNG Uracil DNA glycosylase AR

INO80 INO80 complex AR

MSH6 MutS homolog 6 AR

Antibody deficiency with elevated B cell numbers CARD11 Caspase recruitment domain family member 11 AD

UpToDate (modified)

The predominantly antibody deficienciesII: Non-monogenic/phenotypic from the IUIS

Diagnosis Ig phenotype Key features

Common Variable Immunodeficiency Severe reduction in at least 2 serum immunoglobulin isotypes with normal or low number of B cells

About half with autoimmune features

Specific antibody deficiency with normal Ig levels and normal B cells

Normal Reduced ability to produce antibodies to specific antigens

Transient hypogammaglobulinemia of infancy

IgG and IgA decreased Normal ability to produce antibodies to vaccine antigens, usually not associated with significant infections (JSO Disagree)

Selective IgA deficiency Very low to absent IgA with other isotypes normal, normal subclasses and specific antibodies

Mostly asymptomatic: Bacterial infections, autoimmunity mildly increased

IgG subclass deficiency with IgA deficiency

Reduced IgA with decrease in one or more IgG subclass

Recurrent bacterial infections

Isolated IgG subclass deficiency Reduction in one or more IgG subclass Usually asymptomatic, a minority may have poor antibody response to specific antigens and recurrent infections

What’s not here…?

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ControversiesGround to cover in diagnosis of antibody deficiency and application of therapy

Phenotype* PPV23 response, age >6 y PPV23 response, age <6 y Notes

Severe <2 protective titers (>1.3 µg/mL)

<2 protective titers (>1.3 µg/mL)

Protective titers present are low

Moderate <70% of serotypes are protective (>1.3 µg/mL)

<50% of serotypes are protective (>1.3 µg/mL)

Protective titers present to >3 serotypes

Mild Failure to generate protective titers to multiple serotypes or failure of a 2-fold increase in 70% of serotypes

Failure to generate protective titers tomultiple serotypes or failure of a 2-fold increase in 50% of serotypes

2-Fold increases assume a prevaccination titer of less than cutoff values in Summary Statement #26

Memory Loss of response within 6 mo

Loss of response within 6 mo Adequate initial response to >50% of serotypes in children <6 y of age and >70% in those >6 y of age

Controversies in antibody deficiency – Ground to cover in diagnosisDiagnostic vaccination work group report SS#32: The degree of polysaccharide non- responsiveness in selective antibody deficiency can be classified into 4 phenotypes.

Orange et al. J Allergy Clin Immunol. 2012

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Controversies in antibody deficiency -need more specific diagnosis

JACI 2018 142:1358

Still work to be done

JACI 2018 142:1358

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Genetic diagnosis of PIDD – does it matter?

• Applies a spectrum of natural history to patients• Important anticipatory medicine to practice• Age of atypical presentations of known diseases

• Is the atypical the typical?

• Can help justify/advocate for patient benefits• Implications for undiagnosed family members• Genetic counselling • PGD

Types of genetic analyses available

• Sanger “direct” sequencing - individual genes• “next gen” - massively parallel sequencing panels• Whole exome sequencing

• Varying coverage, varying analysis,

• Whole genome sequencing • RNA seqencing• Copy number variation (also important)

• Karyotype, FISH, Chromosomal microarray (CMA, SNPchip)

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Question from Orange

The best genetic test to apply for a patient you suspect of having a diagnosable PID isa) Whole exome sequencingb) Next generation sequencing panelc) The one approved by the patient’s insuranced) Whole genome sequencing with copy number variation

quantificatione) Targeted gene tests

Recent genomic diagnostic discovery = pretest probability Modality Reference(s) Details Diagnostic rate

NGS Panel Moens - 2014 Plos OneNijman – 2014 JACIAl-Mousa – 2016 JACIYu – 2016 JACIErman – 2017 Scand J ImmAbolhassani – 2018 JACIBisgin – 2018 Biomed ResRae – 2018 Clin Genet

179 gene panel – High PPV 161 gene panel 162 gene panel (unsolved pts)47 Gene panel (SCID/CID)356 gene SCID onlyVaried – CIDs high PPV62 Gene panel424 Gene panel

60%15%29%70% NBS+33%78%46%48%

WES Maffucci – 2016 Front ImunolChinn – 2018 Blood

50 CVID 48 HLH 2004+

30%54%

WES + CNV Stray-Pedersen – 2017 JACI

De Valles-Ibanez – 2018 Front Imm

Difficult to diagnose patientsPI category rates from 10-100%CVID

40%

24%WGS Mousallem - 2015 JACI

Belkadi – 2015 PNASApplication in 6 patientsWGS greater accuracy for CNV

WGS + RNAseq Van Schouwenburg – 2015 ClinImmunol

Limited cases Potential additive value

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CIS recommendations for genetic testing

• Clinical immunologists should be able to use genetic testing• Genetic testing provides a definitive diagnosis and should be offered

to at risk family members• Genetic counseling should be provided by an immunologist or GC• Choice of genetic test should be made by immunologist – there is no

best “first test”• Choice of test need by case-by-case• Follow up genetic or functional tests may be needed• Genetic testing is not prerequisite to initiate therapy

The Houston Project in primary immunodeficiency (2012-2018+):An unbiased WES approach to otherwise difficult to diagnose PIDD

Stage 1: 485 individuals 280 families8 new diseases

Stage 2: 1000+ individualsnew approach to “HLH”

Overarching message about utility

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Unbiased WES results for the first 280 families with PIDDThe Houston Project for PIDD…

5% have more than one confirmed disease causing gene “blended” phenotype

X-linked Recessive (19%)

AutosomalRecessive

(43%)Parental (73%)

De novo (27%)

Autosomal Dominant

(38%)…

Getting an answer: Diagnostic Implications

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HLH Diagnostic Guidelines

• Molecular diagnosis consistent with HLH, or…• 5/8 of the following

• Fever• Splenomegaly• Cyopenias affecting 2/3 lineages• Triglycerides ≥265mg/dl and/or Fibrinogen ≤150mg/dl• Ferritin ≥500µg/l• Soluble CD25 ≥2400 U/ml• Low or absent NK cell activity• Hemophagocytosis• No evidence of malignancy

Pediatr. Blood Cancer 2007;48:125-31

Revisiting hematophagocytic lymphohistiocytosis (HLH) in the precision genomic era

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NK cell antiviral killing

Orangelab

Historical molecular defects leading to HLH

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Why does HLH occur?

Infected monocyte

VirusImmunologic infection

NK cell/CTL

DC

Monocyte

Lymphocyte

IL-12+

TNF+

TNF+IFN-a

IFN-g

IL-12

TNFxIFN-g

IFN-g

IL-12+

TNF+

xxx

xx

xx x

xxx

IFN-g

IL-12

TNF

• 122 subjects (1999 – 2016) met HLH-2004 criteria for HLH

• Median age at diagnosis: 6.1 years [2 weeks – 18.5 years]• 51% male / 49% female• 101 subjects received clinical or research-based genetic testing

HLH in the genomic era – precision diagnosis of PID

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Disease-causing familial HLH gene mutations were present in less than 20% of subjects tested

Note: no potential digenic or polygenic single heterozygous variant combinations were statistically likely to be disease-causing

Overall Genetic Findings(n = 101)

Genetic explanations in 45% of families, 69% excluding cases not tested by WES

More families with PIDD and/or DIAP than fHLH

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PIDD Genes IdentifiedCARMIL2 CASP10 CYBB DOCK8

LRBA MCM3AP NCF1 PIK3CDRAG1 RAG2 STAT1 (GOF) STAT2

STAT3 (GOF) TTC7A WAS

Dysregulated Immune Activation or Proliferation (DIAP)

Viral Triggering and FHL more likely under age 1

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The new details matter – precise prognostics

HLH algorithm in the genomic age

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Beyond Simple GeneticsMultilocus Variation – a frontier in PID

Gonzaga-Jauregui C, Harel T, et al. (2015) Cell Rep 12:1169-83. Lemmers RJLF, et al. (2012) Nat Genet 44:1370-6. Posey JE, Harel T, et al. (2017) N Engl J Med 376:21-31. Timberlake AT, et al. (2016) eLife e20125. Yang Y, et al. (2013) N Engl J Med 369:1502-11. Yang Y, et al. (2014) JAMA 312:1870-9. Figure courtesy of Dr. Jennifer Posey - BCM

Parent A:unaffected

Parent B:unaffected

Offspring: Affected, 2 conditions

(AD de novo + AR)

Parent A:unaffected

Parent B:unaffected

Offspring: Affected + Modifiers = Variable expressivity

Parent A:unaffected

Parent B:unaffected

Offspring:Affected

One condition

Multiple Molecular Diagnoses Digenic Inheritance Mutational Burden

Multiple diagnoses - The blend…• Severe HPV (3) Repeated pneumonia (7), severe VZV (10), cryptococal

meningitis (11)• Age 21

• CD4=604, CD8=84, NK=119, CD19=134• Colony survival=8% (37-63%)

Chinn, et. al. Front Immunol 2017

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An age of rational specific immunological therapies

An age of rational specific immunological therapiesmade possible through molecular diagnosis

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Replacement therapy is an outcome altering intervention for patients with PIDD

Chapel and Cunningham-Rundles, BJH 2009

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Qol matters and tells us something

• Quality of life physical function social function relate to outcome in PIDD

• Tabolli, et. al 2014

QoL in US PIDD patients receiving Ig therapy

• Immune Globulin (IG) users identified in IDF database, 4,000 randomly selected as potential respondents

• Un-incentivized, 10 page IDF Treatment Survey, Medical Outcomes Study SF -12 (version 2)

• Two mailings conducted between December 2013 and February 2014 resulted in 40% response rate

• 1,266 completed both IDF and SF-12 questionnaires

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US Patients with CVID receiving Ig therapy have lower QoL

Just treating CVID does not create normalcy

While treatment with Ig can be life alteringthere is there still work to do• Does the treatment itself present opportunity?• What is the “burden” of treatment

• Different from the impact of the disease itself• The “work” of being a patient on a prescribed treatment

• Examples of burdens from treatment• Financial• New physical maladies • Quality of life impairment

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Patient Perceptions Convenience of Treatment

89%

11%

83%

17%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Little to no bother Moderate to extremebother

IGSC (n=489)

IGIV (n=644)

Perc

ent o

f Sub

ject

s

*

*

Rider, et. al. 2017 J. Clin Immunol 37:461-475

74%

26%

79%

21%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Little to no bother Moderate to extremebother

IGSC (n=489)

IGIV (n=637)

* P<0.01

*

*

Number of Needle Sticks

Patient Perceptions Local adverse events systemic adverse events

75%

25%

95%

5%0%

10%20%30%40%50%60%70%80%90%

100%

Little to no bother Moderate to extremebother

IGSC (n=490)

IGIV (n=643)

Perc

ent o

f Sub

ject

s

*

*

Rider, et. al. 2017 J. Clin Immunol 37:461-475

81%

19%

75%

25%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Little to no bother Moderate to extremebother

IGSC (n=490)

IGIV (n=643)

*

*

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Patient Perceptions Time to Infuse Interrupts Life

76%

24%

71%

29%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Little to no bother Moderate to extremebother

IGSC (n=490)

IGIV (n=643)

Perc

ent o

f Sub

ject

s

Rider, et. al. 2017 J. Clin Immunol 37:461-475

63%

37%

60%

40%

0%10%20%30%40%50%60%70%80%90%

100%

Little to no bother Moderate toextreme bother

IGSC (n=491)

IGIV (n=639)

Patient Perceptions Cost of Infusions Overall Bother

49% 51%46%

54%

0%10%20%30%40%50%60%70%80%90%

100%

Little to no bother Moderate toextreme bother

IGSC (n=484)IGIV (n=640)

Perc

ent o

f Sub

ject

s

Rider, et. al. 2017 J. Clin Immunol 37:461-475

76%

24%

78%

22%

0%10%20%30%40%50%60%70%80%90%

100%

Little to no bother Moderate to extremebother

IGSC (n=493)IGIV (n=657)

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Jolles, Orange, et. al. CEI, 2015

The present: Choices in Ig Therapy – can we get it right to improve outcomes?

IgG therapy

Yes No

Patient education• Educate about disease (what)

and treatment (how)

• Educate about the necessity of regular treatment (why)

• Confirm diagnosis• Monitor clinical outcomes and reassess

therapy if necessary

SCIG

No Issues• Monitor clinical outcomes and patient/family-

satisfaction/quality of life

• Reassess regimen if necessary

IVIG• Patient preference/requirements

(e.g. for a long infusion interval)• Good tolerability• Good venous access

Graphic algorithm for selection of treatment regiment. The proposed algorithm is based on individual clinical outcomes and patient-related factors and relates to immunoglobulin (Ig)G therapy only. Adjunct antibiotic prophylaxis is not included, but can be considered as concomitant treatment.

Dose• Increase dose (efficacy)•Monitor clinical outcomes

1Infusion Interval

•Shorten/adjust (efficacy)•Monitor clinical outcome•Consider SCIG

2Patient education

•Check understanding of treatment and technique

3Management of AEs

•Use premedication•Change product

4Infusion rate

•Reduce•Monitor tolerability over time and increase again when/if possible

5Administration route

•Switch to SCIG therapy

6Site of care

•Switch to home therapy

•Train in self-administration

•Transition to officebased infusions

•Transition to hospitalbased infusions

7

Wear-off effect

1 2

Insufficient efficacy• High infection rate• Inadequate IgG levels

1 2 3Poor tolerability

4 5 6Poor compliance

3 4 7

Poor venous access

6Inconvenience

2 6 7

Jolles, Orange, et. al. CEI, 2015

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Site of care• Transition to office-based infusions• Transition to hospital-based infusions

7

IgG therapy

Yes No

Patient education• Educate about disease (what)

and treatment (how)

• Educate about the necessity of regular treatment (why)

• Confirm diagnosis• Monitor clinical outcomes and reassess

therapy if necessary

SCIG• Patient preference/ requirements

(life style and/or logistics)• Need for stable IgG levels• Poor venous access• Poor tolerability with IVIG

IVIG

Dose• Increase dose (efficacy)• Monitor clinical outcomes• Changing dose and infusion interval at

the same time is not recommended

1 Infusion Interval• Shorten (efficacy)• Monitor clinical outcome• Increase (convenience)

2 Patient education• Check understanding

of treatment and technique

3 Management of AEs• Check infusion technique and equipment (needle length)• Do not rotate infusion sites• Change product• Use antihistamines and analgesics if local AEs persist• Local/topical measures

4 Infusion rate• Reduce (tolerability)• Monitor AE’s over time and

increase again when/if possible

5 Administration route• Switch to IVIG therapy6

Insufficient efficacy• High infection rate• Inadequate IgG levels

1 2 3

Inability to self-administer

6 7

No Issues• Monitor clinical outcomes and patient/family-

satisfaction/quality of life

• Reassess regimen if necessary

Poor compliance

3 6 7

Infusion technique• Inform that local reactions are to be expected and

will reduce/disappear• Support patient over the first 8-10 weeks• Educate about treatment

8 Equipment• Change needle• Use sufficiently long needles• Use pump or push• Use branched tubing sets• Increase needle gauge

9 Infusion volume• Reduce (tolerability)• Increase (fewer sites)• Use a more concentrated product

10 Number of sites• Increase to shorten infusion duration

(convenience)• Increase to reduce volume

per site (tolerability)

11

Infusion-related local reactions4 5 8 9 10 11

Inconvenience

42 6 11

Graphic algorithm for selection of treatment regiment. The proposed algorithm is based on individual clinical outcomes and patient-related factors and relates to immunoglobulin (Ig)G therapy only. Adjunct antibiotic prophylaxis is not included, but can be considered as concomitant treatment.

Jolles, Orange, et. al. CEI, 2015

Conclusions

• NBS is highly effective for SCID diagnosis• Rapid and new treatment options

• Innovation in the genetic era of immune disease• Precision diagnosis can be of value• Justification for your pretest probabilbity

• Think about HLH in critically ill children and rethink the approach to diagnosis getting to correct treatment

• Complex genetics require an openness to new paradigms in the future• Precision and personalized diagnosis can equate with specific therapeutics in PID• There are challenges in diagnosing antibody deficiency – clinical judgment

matters!• Consider options in treatment to reduce burden on patients with a focus on QoL