Recognition of Primary Immunodeficiency

1. Recognition of Primary Immunodeficiency Dr. Andy Gennery Clinical Reader/Honorary Consultant Paediatric Immunology + HSCT Sept 2010

2. Joseph Priestly: The more elaborate our means of communication, the less we communicate.

3. Immunodeficiency ‘a failure to achieve immune function to provide efficient, self-limited host defence against the biotic and abiotic environment while preserving tolerance to self.’ Casanova et al. J Allergy Clin Immunol 2005

5. The Problem • Infancy + early childhood - immune system encounters antigens for first time, mounting immune responses and acquiring memory.

6. The Problem • Infancy + early childhood - immune system encounters antigens for first time, mounting immune responses and acquiring memory. • Young children mix with other children in families or nursery

7. The Problem • Infancy + early childhood - immune system encounters antigens for first time, mounting immune responses and acquiring memory. • Young children mix with other children in families or nursery • Exposed to many pathogens.

8. The Problem • Infancy + early childhood - immune system encounters antigens for first time, mounting immune responses and acquiring memory. • Young children mix with other children in families or nursery • Exposed to many pathogens. • Young children vulnerable to infection - recurrent infection is common.

9. The Problem • Recurrent or persistent infection is major manifestation of primary immunodeficiency (PID).

10. The Problem • Significant treatment advances make it important to recognize children with PID early, before significant end organ damage occurs to maximize opportunity for successful treatment.

11. Physiological immunodeficiency of immaturity • Maternal IgG transferred to fetus during 3rd trimester via the placenta • As maternal IgG decays intrinsic IgG responses develop • As maternal IgG decays there is a physiological nadir between 3 - 6 months, which may be prolonged

12. Maternal IgG passed to foetus in last trimester

13. Physiological immunodeficiency of immaturity • Production of IgG2 (anti-polysaccharide responses) delayed in young children, explaining infant susceptibility to polysaccharide encapsulated organisms such as pneumococcus

14. Physiological immunodeficiency of immaturity • Production of IgG2 (anti-polysaccharide responses) delayed in young children, explaining infant susceptibility to polysaccharide encapsulated organisms such as pneumococcus • These responses mature between about 2–5 years of age, (may be delayed beyond this).

15. Age

16. Organism

17. Warning Signs

18. RC., dob 03/2001 Referred Nov 2006 (prev. phone/advice): 2 episodes of Pneumococcal sepsis Little response to single dose Prevenar Good response to Pneumovax ? Falling HiB specific antibody levels For further investigation

19. Local hospital notes review • Dec 2001 • ? Meningitis • CRP <1; ESR 21 mm/h • WCC 22x10e9/l (Ne 14.6); PLT 424x10e9/l • B/C; CSF; urine: -ve cultures • Urine: +ve Pneumococcal Ag • March, May, Nov 2002 - fitting episodes • Dec 2003 • Lethargic, fever • CRP 212 • WCC 32x10e9/l (Ne 29) • B/C – Strep. Pneumoniae (strain 18C)

20. Jan 2004 Normal IgG, A, M; IgG subclasses Tet 0.05 (>0.1 IU/ml) HiB <0.1 (>1 mg/l) Pneumo 23 (>20 mg/l) Aug 2004 (after Tet/HiB boost) Tet 0.24 HiB >9 Pneumo 10 Oct 2004 – Prevenar (conj. Pneumococcal vacc.) July 2005 Tet 0.19 HiB 1.1 Pneumo 13 Measles, Rubella +ve Mumps equivocal July 2006 - Pneumovax (polysaccharide-only Pn. vacc.) Oct 2006 Tet 0.27 HiB 0.2 Pneumo 100 Abdominal US – present spleen Complement function (C+A) normal Serum sample before Prevenar sent to Manchester for Pneumococcal strain-specific antibody responses ? Serum to Manchester post-Prevenar Lakshman R et al. ADC, 2003 Investigations(on Penicillin prophylaxis => Trimethoprim)

21. Strain IgG (mcg/l) – ‘putative protective level >/= 0.35’ pre-PV post-Prevenar post-Pneumovax (Oct 04) (Jul 05) (Oct 06) 1 0.05 0.07 1.06 4 0.06 0.4 6.3 5 1.49 0.32 1.54 6B 0.04 0.23 3.69 9V 0.04 0.48 5.57 14 0.07 3.47 135.5 18C 0.37 0.63 0.41 19F 0.18 0.63 17.19 23F 0.07 0.08 3.21 3 n/a 0.38 0.38 7F n/a 0.07 0.82 19A n/a 0.04 0.1

22. Clinics Dec 2006/Feb 2007 • Well grown • No infections • Big tonsils, peripheral LN • Specific Pneumococcal Ab Deficiency • Talked to parents • Penicillin prophylaxis FOR LIFE • ? Further Ix for underlying PID

23. Local hospital notes review • Dec 2001 • ? Meningitis • CRP <1; ESR 21 mm/h • WCC 22x10e9/l (Ne 14.6); PLT 424x10e9/l • B/C; CSF; urine: -ve cultures • Urine: +ve Pneumococcal Ag • March, May, Nov 2002 - fitting episodes • Dec 2003 • Lethargic, fever • CRP 212 • WCC 32x10e9/l (Ne 29) • B/C – Strep. Pneumoniae (strain 18C)

24. RC., dob 03/2001 2 episodes of Pneumococcal sepsis For further investigation

25. AG 06/2008 • 39/52, No problems • Swelling L face + ear 5/52 - mastoiditis • WCC 71, N 54, L 5, plt 651 • CT brain normal • No growth • Oral candida since 4/52

26. AG 06/2008 • Lymph subsets normal • Neutrophil oxidative burst normal

27. AG 06/2008 • Leukocyte Adhesion Deficiency

28. AG 06/2008 • Swelling L face + ear 5/52 - mastoiditis • Oral candida since 4/52 • WCC 71,N 54 • Careful history – delay in loss of umbilical stump

29. JT 04/2003 • Normal birth • Well until 6/52 • Staph aureus septicaemia 6/52 • ‘icthyotic erythroderma’ • lymphadenopathy

30. JT 04/2003 • Pseudomonas ear infection • Pneumococcal meningitis • Rotavirus enteritis • 10/12 O/E fine hair • Thickened eczema • LN++ • 3 cm liver

31. JT 04/2003 • Mainly OK!! • IgG 4, IgM 0.3 • Low tet/Hib - responded to vaccine boost • ??? Some sort of immunodeficiency??? • Start IVIG

32. JT 04/2003 • Defect in NEMO - NF kappa B essential modulator

33. JT 04/2003 • Normal birth • Well until 6/52 • Staph aureus septicaemia 6/52 • ‘icthyotic erythroderma’ • lymphadenopathy

34. JT 04/2003 • Pseudomonas ear infection • Pneumococcal meningitis • Sometimes diagnosis becomes clear over time!!

35. AD 09/2008 • 2nd child, unrelated parents • Well until 3 months - bronchiolitis (hMPV) • Admitted - no symptom resolution • Cough continued

36. AD 09/2008 • Re-admission 2 months later - pneumonia - hMPV • Continued chestiness, O2 requirement • Weight loss • Referred age 7/12 • Hypogammaglobulinaemia, lymphopenia

37. AD 09/2008 • 2nd child, unrelated parents • Well until 3 months - bronchiolitis (hMPV) • Lymphopenic • Admitted - no symptom resolution • Cough continued

38. AD 09/2008 • Re-admission 2 months later - pneumonia - hMPV • Continued chestiness, O2 requirement • Weight loss • Referred age 7/12 • Hypogammaglobulinaemia, lymphopenia

39. DC 02/2010 • 3 yr boy, 2nd of 3 boys • No FH of note • Neonatal history unremarkable

40. DC 02/2010 • 48hr h/o L neck swelling, fever, rash, red tongue, cracked lips. • ? Kawasaki disease • Rx antibiotics, IVIG

41. DC 02/2010 • Fever settled • X 3 episodes fever @ night, sweats • Odd gait • ? Kawasaki disease/JIA overlap

42. DC 02/2010 • M/P x 3 - better • Symptoms recurred - fever, limp, sweats • L Cx LN swelling - pointing

43. DC 02/2010 • I+D • home • Burkholderia cepacia grown from LN

46. DC 02/2010 • 3 yr boy, 2nd of 3 boys • No FH of note • Neonatal history unremarkable

47. DC 02/2010 • 48hr h/o L neck swelling, fever, rash, red tongue, cracked lips. • ? Kawasaki disease • Rx antibiotics, IVIG

48. DC 02/2010 • Fever settled • X 3 episodes fever @ night, sweats • Odd gait • ? Kawasaki disease/JIA overlap

49. DC 02/2010 • M/P x 3 - better • Symptoms recurred - fever, limp, sweats • L Cx LN swelling - pointing

50. DC 02/2010 • I+D • home • Burkholderia cepacia grown from LN