Primary Immune deficiencies : not only a disease for ...

© 2010 Universitair Ziekenhuis Gent

Primary Immune deficiencies :

not only a disease for pediatricians

Filomeen Haerynck Dienst Kinderlongziekten, infectieziekten en – immuunstoornissen Prinses Elisabeth Kinderziekenhuis UZ Gent BHS 8-11-2014


Immunodeficiency

Inflammation

Malignancy Autoimmunity

Infection


Bach JF. NEJM 2002; 347:911

The focus in clinical immunology has shifted


Immunity against virusses

NEJM 2000 :343,2


Immunity against bacteria

NEJM 2000 :343,2


Organism Ab defect CID Phagocytic defect Complement defect

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

No No

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

= Ab defect AND Salmonella spec, Listeria, enteric flora

S.Aureus P.Aeruginosa Nocardia asteroides S. 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

Pathogen → PID


PID prevalence : 1/2000- 1/10 000 - 500 000


www.bpidg.be


£


Huseyn, 6m - WBC : 12 210 / mm3 N: 9438 L: 1590 Mono: 1155 Eosino: 27 Baso: 0 - Lymphocytes: - T lympho ( CD 3 + ) : < 1% - Th cell ( CD4+ ): < 1% - Ts cell ( CD8 + ): < 1% - B lympho ( CD19 ): 92 % ( 1462/µl ) - CD 56+ /CD 3 - ( NK cel ): <1 % - Tot 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 → Common gamma chain defect !  Haplo- identical stemcellTx (mother) without conditioning


T cell deficiency !   WBC , differentiation !   Lymphocytes : < 6m: >3000/µl (cave : maternal engrafment) > 6 m: >2000/ µl •  Lymphocyte typing: T cells ( > 60% lymfo ) CD3+ CD3+/CD4+ CD3+/CD8+ T cell maturation : CD3+/CD4+/CD45RA CD3+/CD4+/CD45RO •  Lymphocytes profileration against mitogenes, Ag ( bv Tetanos,

Candida )


£


Ricardo, 16 years

!   6 m: rec RTI with monthly fever needing AB !   adenotomia, TTD !   2 – 4 y : rec. pneumoniae R/ IV AB !   Chronic cough

!   Familial : father: chronische sinusitis, mother : eczeem


Ricardo, 12 y

!   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/dl

IgA: < 23 mg/dl IgE:< 4 kU/l !   Pneumococcal antibodies ( after vaccin ):< 3 a.e !   Tetanos Antibody : < 0,01 IU/ml !   Lymphocyte proliferation test against mitogenes: normal


DIFFERENTIAL DIAGNOSIS ??


Ricardo, 16 y

!   Treatment : IVIG 1*/month (400 mg/kg/dose)

!   Persistent fever: IVIG 1*/3 weeks: improvement

!   Current: SCIG 1*/week (100-150 mg/kg/dosis)


Common Variabel Immune deficiency

!   - 1/ 25 000 – 1/ 100 000 - Hypogamma, IgA (subclasses), IgM - normal B en T cells, decreased B cell maturation - 6 -10 y and 26 – 40 y - lymphoid hyperplasia (DD: malignancy) - GE: colitis (Crohn like) – granulomata - auto-immune cytopenia, auto-immune hepatitis è Combined immune deficiency è stem cell transplantation


Lab tests !   WBC, differentation, Hb, Platelets !   Lymphocytes - subtyping : B ( CD 19+ ) cells T ( CD3+ ) cells Th ( CD3/CD4 )/ Ts ( CD3/CD8 ) Nk cells ( CD3-/CD56 + ) !   Tot IgG, IgA, IgM, IgE (age matched references!) !   IgG subclasses > 1 j !   Total protein, electroforesis !   Viral serology ( immune response VZV,MBR,… ) !   Viral PCR – HIV Al / PCR !   Viral en bacterial cultures

SSC

CD

14 (M

y4)-P

E

granulocytes

monocytes

lymphocytes

monocytes

granulo-cytes

T-lympho-cytes

CD

19 (L

eu-1

2)-P

E

CD

16 (L

eu-1

1b) e

n C

D56

(Leu

-19)

-PE

T-lympho-cytes

NK-cells

gated on lymphocytesgated on lymphocytes

CD3 (Leu-4)-FITCCD3 (Leu-4)-FITC

FSC CD15 (CLBCD15)-FITC

B-lymphocytes


Humoral deficiency !   Cellular : - B cells ( CD19 + ) - B memory cells ( CD19+/CD27+/IgD- ) !   - Polysaccharide Ab response - Pneumococcal Antibody response - basal Ab – pneumo 23 vaccinations - 1 month later: Ab response

- protein Ab response: immune response against tetanos

Patient 1 Patient 2

Before Serotype 8 Serotype 9N

9 0,5 11 0,8

12 0,6 6 0,5

U/ml mg/l U/ml mg/l

After Serotype 8 Serotype 9N

133 6,9 41 3,2

12 0,6 7 0,6

U/ml mg/l U/ml mg/l


I. Primary Immune deficiencies Ø Agamma, Hypogamma, IgG subclass deficiencies,

congenital antipolysacharide antibody deficiency

Ø AND recurrent infections!

Ø Approval of BPIDG member

II. Secundary Immune deficiencies (protein loosing, drugs (not steroids!) )

Ø Hypogamma (adults < 7,5 g/l)

Ø  AND recurrent infections!

Indication for IVIG/ SCIG


SCIG I.  Hizentra 20% liquid preparation 5 ml= 1 g 10ml= 2g 20 ml= 4g 50ml=10g II. Gammanorm 16%


SCIG

Adapted from CSL Behring


Selective IgA deficiency

!   1/300-1/500 !   B cells → IgA – secreting plasma cells → ↓ serum IgA !   Normal IgG and IgM !   Gastrointestinal disease and sIgA def < CVID (IgM compensation) !   >> asymptomatic


£


Auto-immune lymphoproliferative syndrome ( ALPS )

!   Canale-Smith syndrome !   ↑↑ nonmalignant lymphoid cells, ↑ CD3+/CD4-/CD8- T CR αβ

cells !   ↓ lymphocyte apoptosis ( Fas- FasL ) splenomegalie/adenopathie !   Auto-immune cytopenia !   Auto-immune hepatitis


Daan, 9 m Ø  recurrent infections, failure to thrive and chronic diarrhea Ø  Admission: irritability, fever, hepatosplenomegaly and

ascites Patient References

-  Haemoglobin

-  Thrombocytes

-  Ferritin

-  Fibrinogen -  Soluble CD25

-  HLA DR expression on CD3+/CD8+

-  Bone marrow

6,9 g/dl

14 000 /µL

1228 µg/L

86 mg/dL

24271 pg/mL

63%

normal

11-14

217-497 * 10“

7-142

200-400

857- 2916


Differential diagnosis????


Daan, 9 m Patient References

-  Haemoglobin

-  Thrombocytes

-  Ferritin

-  Fibrinogen -  Soluble CD25

-  HLA DR expression on CD3+/CD8+

-  Bone marrow

-  CD107a expression on NK cells

- non stimulated - stimulated - Perforin expression

6,9 g/dl

14 000 /µL

1228 µg/L

86 mg/dL

24271 pg/mL

63%

normal

3,34% 4,31%

99%

11-14

217-497 * 10“

7-142

200-400

857- 2916


!   1. Familial disease/known genetic defect !   2. Clinical and laboratory criteria (5/8 criteria)

!   Fever !   Splenomegaly !   Cytopenia =>2 cell lines

!  Hemoglobin <90 g/l (below 4 weeks <120 g/l) !  Platelets <100×109/l !  Neutrophils <1×109/l

!   Hypertriglyceridemia and/or hypofibrinogenemia !   Fasting triglycerides => !   Fibrinogen <1.5 g/l !   Ferritin =>500 µg/l !   sCD 25=>2,400 U/ml§ !   Decreased or absent NK-cell activity !   Hemophagocytosis in bone marrow, CSF, or lymph nodes: not

necesarry for the diagnosis

Clinical criteria HLH


Familial hemophagocytic lymphohistiocytosis


Ø  Treatment: HLH-2004 protocol (dexamethason, cyclosporin and etoposide Ø  HSCT

Ravelli et al. Genes and immunity 2012


Genetic HLH

Gene Protein Chromosome

Familial Hemophagocytic lymphohistiocytic syndrome (FHL)

FHL-1 FHL-2 FHL-3 FHL-4 FHL-5

Unknown PFR1

UNC13D STX11

STXBP2(UNC18B)

Unknown Perforin

Munc13-4 Syntaxin11 Munc18-2

9q21.3-q22 10q21-22

17q25 6q24

19p13.2-3

Immunodeficiency syndromes Chediak-Higashi syndrome Griscelli syndrome 2 X-linked proliferative syndrome type-1 X-linked proliferative syndrome type-2

LYST RAB27A SH2D1A BIRC4

Lyst Rab27a

SAP XIAP

1q42.1-q42.2 15q21 Xq25 xq25

Other immune defects and HLH Hermansky- Pudlak syndrome 2 SCID ITK deficiency CD27 deficiency

Acquired HLH Infectious agents Autoinflammatory and autoimmune disease (MAS) Malignant disease Immunosuppression Metabolic disease



£


!   Early childhood: recurrent URTI (otitis, sinusitis) !   5 y: unilateral pneumonia !   6 y: Pneumococcal meningo-encephalitis + pneumonia,

general seizures, mydriasis !   6,5 y: Pneumococcal meningitis

Maxim, 7 years History

Normal immune system ?

Investigations?


!   WBC: 9140/µl (neutro: 4530/µl - lymfo: 3330/µl) !   Cellular adaptive immune system

!  CD3+: 2100/µl !  CD3+/CD4+: 1170/µl !  CD3+/CD8+: 566/µl

!   Humoral adaptive immune system !  CD19+: 866/µl !  Total IgG: 6,9 g/l IgG2: 1,54 g/l IgG3: 0,59 g/l !  IgA: 0,9 g/l ! IgM: 0,5 g/l !  Good response to Pneumo 23 vaccin (polysaccharide Ab) !  Immune for tetanus

Maxim, 7 years Investigations

Ab: antibodies


! Opsonisation by - complement factors - IgG2 - specific pneumococcal Ab !   Phagocytosis by macrophages/neutrophils !   Spleen: clearing of opsonized bacteria

?? normal

normal

Spleen = present and functional

??

Streptococcus Pneumoniae Defense

FcR: Fc receptor; CR: complement receptor; MAC: membrane attack complex; Ab: antibodies


Complement system – Investigation

First tests C3 C4 CH50 AP50 MBL

CH50 MBL AP50

C3

C4

COMMON TERMINAL PATHWAY

Ab-Ag, virus, CRP Carbohydrates LPS, Zymosan

MBL: mannose binding lectin


Maxim, 7 years Investigations

COMPLEMENT SYSTEM C3 (0,9 – 1,8 g/l) 1,4 g/l C4 (0,1 – 0,4 g/l) 0,2 g/l CH50 (23 – 46 U/ml) 2 U/ml AP50 (30 – 113 %) 78 % MBL (750 – 2750 ng/ml) 2614 ng/ml C2 concentration (1,4 – 2,5 mg/dl) <0,17 mg/dl C2 functional test (16-91%) pending C1q pending


Maxim, 7 years

!   Congenital complement factor C2 deficiency

Diagnosis


Maxim, 7 years

Clinical implications

!   Increased susceptibility to acute fulminant bacterial infections !   >> Encapsulated bacteria (S. pneumoniae, N. meningitidis, H.

influenzae type 2, …)

!   R/ chronic AB prophylaxis, vaccinations

!   Increased susceptibility to auto-immune diseases !   >> SLE ! Nephrologic disease


Conclusion

!   Onset: children – first symptons: ADULTS

!   Suspect PID when: - frequent / chronic infections - severe presentation - hematological abnormalities after exclusion of malignancy


https://clinicalimmunology.ugent.be www.uzgent.be/nl/zorgaanbod/mdteams/primaire-immuunstoornissen

Primary Immune deficiencies : not only a disease for ...

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