PRIMARY IMMUNODEFICIENCIES AND VACCINATIONS: where to …

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© 2010 Universitair Ziekenhuis Gent

PRIMARY IMMUNODEFICIENCIES AND

VACCINATIONS:

where to start?

Filomeen Haerynck

Department of Pediatric Pulmonology and Immunology

Centre for Primary Immune deficiencies

Ghent University Hospital

22© 2010 Universitair Ziekenhuis Gent

Immune system

Primary Immunodeficiencies

Cellular immunodeficiencies and immunization

Humoral immunodeficiencies and immunization

Complement disorders and immunization

Phagocytic disorders and immunization

PID and immunization: general remarks

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Immunization in immunocompromised children:general considerations

Risk to be infected with disease that could be prevented with immunization

Efficient protection? Optimal time for immunization?

Risk of the immunization itself ?


Immunization response

HUMORAL IMMUNE RESPONSE

- Production of neutralizing antibodies

CELLULAR IMMUNE RESPONSE

- >> live attenuated vaccines

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Immune response against bacteria

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Immune response against virus


Pathogeen → defect

Organism Ab defect CID Phagocyticdefect

Complementdefect

Virus Enterovirus All (>CMV,RSV,EBV,parainfl.)

No No

Bacterie Strept. Pneum.,H. Influenza,P.aeruginosa,St.Aureus,N. Mening, Mycoplasmapn

= Ab defectANDSalmonella spec, Listeria, enteric flora

S.AureusP.AeruginosaNocardiaasteroidesS. typhi

= Ab defect( > N. Mening )(MAC)

Mycobacteria No Nontuberculous Nontuberculous No

Fungi No Candida spec,Aspergillus spec,Cryptococcus, Histoplasmosis

Candida spec, Aspergillus spec

No

Protozoa Giardia Lamblia Pneumocystis jjiroveci,Toxoplasma gondii, Cryptosporidiul

No No

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Primary Immunodeficiencies• Incidence : 1 / 10 000 – 1/ 500 000 ( CF : 1 / 2500 )

PID Incidentie : 1/10 000 ( 1/ 500 000 )


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Huseyn, 6m

Consanguin parents3m: Chronic diarrhea (Rota), FTT5m: Respiratory distress with insufficiencyPCR CMV: positiveNFA: Moraxella Catharalis, Pneumocystis jjiroveci, ParainfluenzaeHIV Ab, HIV PCR: negative


Huseyn, 6m

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Huseyn, 6m

- WBC : 12 210 / mm3N: 9438 L: 1590 Mono: 1155 Eosino: 27 Baso: 0

- T- en B-cells:- T lympho (CD 3 +) : < 1%- Th-cell (CD4+): < 1%- Ts-cel (CD8 +): < 1%- B-lympho (CD19+): 92 % (1462/µl)- CD 56+ /CD 3 - (NK- cell): <1 %

- Total protein: normal gammaglob (0,9 %), alfa2 (19,3 %), alfa1 (7,8 %)

- IgG < 50 mg/dl - IgA < 4 mg/dl - IgM <20 mg/dl

DX : T – B + NK – SCID

(JAK3 defect (A.R.)

→ R/ Haplo- identical stamcellTx (mother) without conditioning


Severe Combined Immune deficiency (SCID)

Severe: without Tx: death within first year

Combined: T-cell AND B-cell disorder

Incidence: 1/50 000- 1/100 000 newborn

Symptoms: > 3 months

- Respiratory: severe bronchiolitis (viral), ILD (PCP)

- GE: chronic diarrhea (rota), FTT, candida

- chronic CMV, EBV infection

Diagnosis:

- Lymphopenia (< 6m: < 3000/ µl), absent lymphocytic

proliferation

- mostly associated hypogammaglobulinemia

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‘Bubble boy’ syndrome


Immunization and cellular immune deficienciesComplete T-cell disorder

SCID, CID, complete DiGeorge syndrome, Hyper-IgM syndrome

Live viral attenuated vaccines: CONTRAINDICATED

Oral Rota, MMR, Varicella, Yellow fever, (OPV, intranasal

influenza)

Live bacterial attenuated vaccines: CONTRAINDICATED

Oral thyphus, BCG

Inactivated vaccines

Standard vaccination (IPV,DTPa,Hib,Hep B, S.pn,

MenC, HPV): safe (immune response ?)

Influenza vaccine: yearly recommended

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Wiskott-Aldrich syndrome, partial DiGeorge syndrome, Hyper-IgE, Ataxia-telangiëctasia

Live viral and bacterial attenuated vaccines:CONTRAINDICATED

BUT measure T-cell function:

- T-cell maturation and LTT

- if normal T-cell function: MMR recommended

Inactivated vaccines: safe and to be given

Immune response ~ T-cell defect

Immunization and cellular immune deficienciesPartial T-cell disorder


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Immunization and humoral immune deficiencies

3.5%

1.7%

1.8%

2.4%

3.4%

3.4%

3.7%

3.8%

3.8%

23.2%

24.5%

24.8%

0% 5% 10% 15% 20% 25% 30%

Other

Wiskott Aldrich

Hyper IgM

Ataxia Telangiectasia

DiGeorge

Complement def.

SCID

CGD

XLA

IgG subclass

Selective IgA Def.

CVI

Survey by IDF ( Immune Deficiency Foundation, USA )


Ricardo 12 y

6 m: rec URTI, LRTI with fever and monthly AB

2y-5y: recurrent bacterial pneumonia R/ IV AB

Chronic sinusitis

WBC : 7910 /µl ( N: 5140 L: 2057 mono: 601 eosino: 87)

CD3+: 70% (1440 / µl)

CD3+/CD4+: 49% (1008 / µl)

CD3+/CD8+: 19% (390 / µl)

CD19+: 20 % (411 / µl)

IgG: 200 mg/dl IgG2: 47 mg/dl IgG3:21 mg/dl IgM < 18 mg/dlIgA: < 23 mg/dl IgE:< 4 kU/l

Pneumococcal Ab:after PPS23V: no response

Tetanos Ab : < 0,01 IU/ml

Lymfocytic transformation test:normal

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Common Variable Immunodeficiency / hypogammaglobulinemia

Incidence: 1/ 25 000 – 1/ 100 000

↓↓ IgG, ↓ IgA (+ IgGsubclass), ↓IgM (50 %)

normal B- and T-cell

↓ memory B-cells

6 -10 j en 26 - 40 j

Lymphoid hyperplasia (malignancy)

Malabsorption, giardiasis

Auto-immune diseases


Treatment Ricardo, 12y

IVIG: monthly 400 mg/kg/dose

Persistent infections → IVIG/ 3 weeks

Currently: SCIG 1*/week

Follow-up: - blood analysis- 1*/2 year: LTT

Vaccination:- yearly Influenza vaccine

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Immunization and humoral immunodeficienciesSevere B-cell disorders

XLA, CVID, hypogammaglobulinemia

Live viral and bacterial attenuated vaccines:CONTRAINDICATED

BUT measure T-cell function:

- T-cell maturation and LTT

- if normal T-cell function: MMR recommended

Inactivated vaccines: safe

- standard vaccination to be given

- yearly Influenza vaccine: recommended

Immune response ~ severity of cellular defect


Immunization and humoral immunodeficienciesMild B-cell disorders

IgG subclass deficiency, SAD, transient hypogammaglobulinemia

NO CONTRAINDICATIONS

All standard (live attenuated and inactivated) vaccinations

Yearly Influenza vaccine: recommended (> 6m)

Time of vaccination: according to IVIG !!

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Immunization and IVIG/ SCIG

IVIG/SCIG may interfere with the immune response on

- Measles, Rubella

- Varicella

If live viral vaccines need to be administered:

- 6-8 m after stop of IVIG/SCIG

- If no interruption of IVIG/SCIG is possible:

- 4 w after last dose of IVIG/SCIG

Inactivated vaccines: no interference with the immune response


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Nicolas °8/2/1997

At term, 3th boy, non consanguinPost vaccination: abcedation (granuloma?)Uneventfull history4y9m: persistent fever, respiratory insufficiency

BAL: A.Fumigatus


Nicolas °8/2/1997Respiratory burst: 20 % (>70 %)Normal B- and T-cells, normal lymphocytic proliferation test, normal amount of neutrophils

→ CHRONIC GRANULOMATOUS DISEASE

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Immunization and phagocytic disorders

CGD, Shwachman-Diamond syndrome, severe congenital neutropenia

Standard vaccination including live VIRAL attenuated vaccines

Live BACTERIAL attenuated vaccines:CONTRAINDICATED

Recommended:

Yearly Influenza vaccine


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Complement system

Ram et al.Clin Microbiol Rev 2010


Complement and diseases>> bacterial infections

>> auto-immune diseases

Atypical HUS

Membrano-proliferative glomerulonephritis

Leucocytic adhesion defect

Paroxysmal noctural haemoglobulinuria

> Hereditary angioedema

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Willem, 7 yearsHistory

Childhood: recurrent URTI ( otitis, sinusitis )

3 y: Pneumococcal meningo-encephalitis, general seizures

Deafness left, hearing loss right

WBC: 6660 / µl (N: 2260/µl L: 3470 /µl)

CD3+:2570 /µl CD3+/CD4+: 1870 /µl CD3+/CD8+: 486/µl

CD19+: 763/µl

Total IgG: 8,2 g/l IgG2: 0,66 g/l IgG3: 0,21 g/l IgA: 0,15 g/l IgM: 0,9 g/l

Basal Ps Ab: 4 a.e

Postvaccination Ps Ab: 23 a.e

Investigations :

→ Normal immune system ??


COMPLEMENT

C3 (0,9 – 1,8 g/l) 1,3 g/l

C4 (0,1 – 0,4 g/l) 0,2 g/l

CH 50 ( 80 – 120 % ) 3 %

AP 50 ( 17 – 45 % ) 29 %

MBL (750 – 2750ng/ml) 66 ng/ml

WillemInvestigations

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COMPLEMENT

C3 (0,9 – 1,8 g/l) 1,3 g/l

C4 (0,1 – 0,4 g/l) 0,2 g/l

CH 50 ( 80 – 120 % ) 3 %

AP 50 ( 17 – 45 % ) 29 %

MBL (750 – 2750ng/ml) 66 ng/ml

C2 concentration (1,4-2,5 mg/dl)

C2 functional test ( 16-91%)

< 0,16 mg/dl

1 %

WillemInvestigations

C2 concentration (1,4-2,5 mg/dl)

C2 functional test ( 16-91%)

< 0,16 mg/dl

1 %

3838© 2010 Universitair Ziekenhuis GentWalport M. NEJM 2001

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Treatment

QUESTIONS ??????

Prophylaxis : Penicilline orally until at least 18 years

Yearly rheumatologic and nephrologic screening

Awareness: fever:

- clinical examination

- AB orally /IV AB ( 3 rd generation cephalosporines)

Vaccination


Immunization and complement disorders

No contraindications for standard vaccination (live attenuated and inactivated vaccines)

Recommended:

- Yearly Influenza vaccine (> 6m)

- Pt > 2y < 8y: - unconjugated PPS23V every 3-5 y

- Pt > 8y: - conjugated PCV

- unconjugated PPS23V every 3-5 y

- if no MenC or Hib: recommended

- (men ACWY© > 12y)

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Immunization of close family members and healthworkers:s herd immunity

RECOMMENDED Varicella (if seronegative)

- No contact with PID pt if rash in vaccinated personMMR (if seronegative)InfluenzaPertussisRota vaccine: may be given

- Avoid contact with stool 14 d after Rota vaccine• Other Live vaccines??

OPV: NO!!Intranasal influenza : NO

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Immunization and PID

No live attenuated vaccines in severe cellular ID

All PID: inactivated vaccines safe BUT immune response suboptimal

Recommended vaccines in PID:

- Influenza vaccine

- Complement disorders: pneumococcal,

meningococcal, Hib vaccineImmunize close contacts and health workers


Studies in pediatric PID patients are needed !!

Think about PID in children with recurrent and/or atypical and/or severe infectious diseases !!

Risks of avoiding vaccination in PID may be greater thanthe benefits of vaccination

Distinguish the response as measured by antibody titer from the overall clinical effect of vaccination

Some remarks…

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