Primary immuno deficiency pid Heath newborn

1. Approach
to PID
-P.T.Nanmaaran
Junior Resident
Pediatrics

2. Scope of this session
Background
01
Classification
02
Clinical markers
03
Case scenarios
04

3. Background
How common?
Introduction to Immunity
01

4. History
● The first PID was discovered 70 years ago —> CGD (around 1950)
● Then SCID—> WAS and Bruton’s agammaglobulinemia
● The introduction of immunoglobulin replacement (1952) and bone marrow
transplantation (1957
● Around 2010, PID discovered was around 150
● Now its more than 350 diseases described—> expansion in understanding immune basis
and genetic etiology.

5. Background- “Inborn Errors of Immunity”
 Primary immunodeficiency diseases (PIDs) are inherited disorders that
impair the immune response, leading to increased risk of infections,
immune dysregulation, autoimmune phenomena, inflammation, and
malignancy.
 >1 million cases in India; 6 million people —> PIDs worldwide, of which only
27,000–60,000 have been diagnosed
 Approximate incidence : 1 in 2000 to 1: 10,000
 For now more than 344 gene defects and 354 disease identified and it is
increasing….
Primary Immunodeficiency Disorders in India—A Situational ReviewAnkur Kumar Jindal, Rakesh Kumar Pilania, Amit Rawat and Surjit Singh*Allergy
Immunology Unit, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India

6. Primary Immunodeficiency Disorders in India—A Situational ReviewAnkur Kumar Jindal, Rakesh Kumar Pilania, Amit Rawat and Surjit Singh*Allergy
Immunology Unit, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India

7. Basics –Immunity
Innate Immunity Adaptive Immunity
Lag time Short Long
Active Always active Activated after antigen exposure
Specificity Non-specific Specific
Eg., Skin epithelium,GI and
Respiratory mucosa
Cells Neutrophils,Eosinophils,Basoph
ils,Monocytes and NK cells
Pattern recognition receptors
B and T lymphocytes,
Plasma cells—>antibody

8. Cells of adaptive immunity
B cells T cells
Produced in Bone Marrow Bone Marrow
Mature in Bone Marrow Thymus
Lymph node Follicles Para-follicular
Spleen Follicles Per—arteriolar region
Immune system Humoral —> antibody
mediated
Cell mediated—>
CD4/CD8 T cells

9. Cell mediated immunity

10. Humoral immunity

12. Jeffrey Model
foundation-10
warning signs
2000’s
 Unusual site
 Unusual organism
 Unusual severity
 Unusual response after
live vaccine
 Recurrence
 Failure to thrive
When to suspect PID?

13. 10 warning signs…
● The overall significance of having any of the 10 warning signs to suspect
PID showed that
● When at least one warning sign was exhibited, the sensitivity was 100,
specificity was 26%.
● Meeting at least two criteria of the 10 warning signs led to a sensitivity
of 94% specificity of 64%.
● When at least three criteria of the 10 warning signs were fulfilled, the
sensitivity was 77% ,the specificity was 86%
The most common asymptomatic PID –
Selective IgA deficiency (1:223 to 1:1000)
The most common symptomatic PID –
Antibody deficiency

14. PID ontogeny
Cellular immune defect Humoral immune defect
12 months

15. General understanding
02
Classification

16. Based on component of immune system involved
1. Combined T-cell and B-cell immunodeficiencies- SCID
2. Predominantly antibody deficiencies –CVID, X-linked
agammaglobulinemia
3. Other well defined immunodeficiency syndromes- DiGeorge, Ataxia
telengiectasia, WAS
4. Diseases of immune dysregulation-HLH
5. Congenital defects of phagocyte number and function – LAD, CGD
6. Defects in innate immunity- MSMD, CMC
7. Auto-inflammatory disorders- FMF
8. Complement deficiencies( C1 inhibitor deficiency- hereditory
angioedema)

17. Approach to PID

18. Age of presentation
1. SCID
2. SCN
3. DiGeorge
4. LAD
First few weeks First 6 months
1. SCID
2. T-cell deficiency
3. LAD
4. CGD
1. Hypogammaglobulinemia
2. WAS
3. Phagocytic defects
4. Di-george syndrome
5. CMC
6 months – 5years After 5years
1. CVID
2. Specific-Ab deficiency
3. Complement defects

19. Type of organism
Primary pathogen Site involved Example
Cellular defects Intracellular fungus
Protozoa
Viruses
Bacteria like
salmonella
Non-specific SCID,Digeorge
B cells/Humoral
defects
Encapsulated bacteria
like Pneumococcus,
Hemophilus ,
Enteroviral .
Sino-pulmonary,
CNS
IgG and IgM
deficiency
Phagocytes Staphylococcus,
Pseudomonas
Candida,Aspergillus
Lung,skin,lymph
nodes
CGD, LAD
Complement Neisseria,
Encapsulated
organisms
CNS,Lung and skin Lupus like
syndrome,Hereditory
angioedema

20. Specific diseases
03
Clinical markers

21. Skin
● Wiskott Aldrich syndrome
● IPEX
● Hyper IgE syndrome
● Omenn syndrome
● Ig A deficiency
● CVID
1.Eczema

22. Skin
● CGD
● LAD
● Hyper Ig E syndrome
Recurrent skin infection, Periodontitis and
Gingivitis

23. Skin
● SCID
● CMC
● Hyper IgE syndrome
Recurrent mucosal candidiasis

24. Hair
● Chediak Higashi syndrome
● Griscelli syndrome
● Hermansky pudlack syndrome
Hypopigmented hair

25. Other markers
● AtaxiaTelengiectasia ● Di-George syndrome
● SCID
● X-linked Agammaglobulinemia
● WAS
● LAD

26. Specific diseases
04
Case Scenarios

27. Case scenario 1
● Karuppasamy, 3 months old male child presented with fever , respiratory distress for 3
days; worsened very rapidly ; expired due to septic shock within a day.
● ALC-3000; previous 3 sibling death at similar age; consanguinity present
● Previous child workup for complement and Ig profile was normal.

28. Severe Combined
Immunodeficiency
ZAP 70 mutation positive

29. SCID
● Usually present within first six months of life with failure to thrive, chronic
diarrhea, persistent oral thrush, skin rash, pneumonia, and sepsis
● Disseminated BCG infection is commonly seen in patients with SCID
● Lymphopenia is commonly seen with patients with SCID
● >22 groups of SCID is present. ADA deficiency, X-Linked SCID , Artemis
deficiency , PNP deficiency etc.,
● Less than 2 years + Less than 20% CD3 T cells/ALC<3000/mm3/one
defined mutation Diagnose SCID

30. SCID

32. Case scenario 2
● Kavish, 7 months old male child presented with increase in head size and umbilical
discharge.
● Consanguinity present; delayed umbilical cord fall present.
● Recurrent hospital admissions for non-healing omphalitis / required more than 2 months
of iv antibiotics
● His total count at admission was 85000
● He had brain abscess too which was evacuated and craniectomy was done.

33. LAD-1
Mutation proven positive

34. LAD

35. Leukocyte adhesion deficiency
● Recurrent infection + neutrophilia
● Delayed seperation of umbilical cord
● No pus formation
● No signs of inflammation
● LAD-1 : CD11/CD18 low
● LAD-2 : CD 15 /Normal CD11 and CD18
● LAD-2  associated with Bombay blood group
● LAD-3  Associated with Glanzman thrombasthenia like bleeding disorder
● HSCT can be tried in LAD 1 and LAD 3

36. Chronic granulomatous disease
Boy
Persistent
pneumonia
Persistent
lymphnode
swellling
Lung/Liver
abscess
Osteomyelitis

37. CGD
● Inflammatory granuloma present
● NBT/DHR

38. Case 3
● 18 months old boy; Recurrent otitis media and pneumonia since 8 months of
age
● Absent tonsils and Lymph node
● Consanguinity present
● IgA-16 mg/dL (40-200)
● IgG-184 mg/dL (490-1610)
● IgM- 9 mg/dL (50-299)

39. Agammaglobulinemia
● Absent B cells and Reduced Ig levels are
suggestive of Agammaglobulinemia
● X-Linked or AR inheritance
● 1952  Colonel Ogden Bruton found reduced
immunoglobulin levels in a boy with recurrent
infections .He was the first to give Ig (im)
● Basic defect: Pro B cell to mature B cell –
Btk gene expression defective
● More than 50% will have serious infection by 2
years of age
● Marked reduction in all types of
Immunoglobulin

40. X-LA vs CVID

41. B cell defects
● Reduced Ig with normal to low B cells with abnormal specific antibody responses 
common variable immunodeficiency (CVID)
● Markedly low IgG and IgA with normal to elevated IgM levels s/o Hyper IgM syndrome
● Antibody deficiency- best approach to diagnosis Serum specific antibody titers
(usually IgG) in response to vaccine antigens (tetanus toxoid and pneumococcus)
● Pre and post immunization levels will be diminished or absent
● In many PIDs, antibody responses to these antigens are absent.

42. Case 4
● 1 1/2 year old boy was admitted from Feb,12 to March
8,2021–> Presented with fever for 20 days; Multiple
swellings for 20 days;Not responding to oral antibiotics for 2
months—> worked up for Primary Immunodeficiency Ig
profile-Normal;Bone marrow-Paucity of myeloid series of
cells/No blasts;TBNK profile was normal.
● The child had issues 1.Left cervical abscess 2.Right
Otomycosis 3.Oral Candidiasis
● His ANC counts never raised >1000

43. Severe Congenital
Neutropenia

44. Severe congenital neutropenia
● Mutation in ELANE, HAX 1 and G6PC3
● More prone for Staphylococcus, E.coli and
Pseudomonal infections
● Cyclical neutropenia – once in 21 days
● Monocytosis is common during Neutropenic phase
● Treatment –G-CSF
● Defintite management HSCT

45. Some well known immunodeficiency syndromes
1. Wiscott Aldrich Syndrome
2. Ataxia Talengectasia
3. Di-george anomaly
4. Hyper IgE Syndromes(HIES)/AD (Jobs Syndrome)

46. ● 4 year old boy Recurrent pneumonia and Otitis media ; eczema over
trunk and Thrombocytopenia
● PS was s/o Microplatelets
● Triad of Atopic dermatitis; Infections and Thrombocytopenia
● X-linked
● No autoimmunity
● WAS gene
Case 5

47. DiGeorge syndrome
● Hypocalcemic seizures
● Dysmorphic facies
● Decreased CD3 +T cells
● Diagnose by FISH

48. CBC in PID:
Neutrophil Normal Rules out LAD/
Neutropenia
Lymphocyte Normal Rules out T-cell defect
Platelet Normal Rules out WAS
Howel Jolly bodies Present Asplenia

49. CBC in PID:
Hypereosinophilia Present Omenn syndrome, Hyper
IgE syndrome,WAS

50. Rule of 2/3 rd’s
● For a child less than 3 years
o 2/3 of WBC should be lymphocytes
o 2/3 of lymphocytes should be T cells
o 2/3 of T cells should be CD4 cells
• For a child more than 3 years
o 2/3 of WBC should be neutrophils
o 2/3 of lymphocytes should be T cells

51. Screening tests for PID
B Cell defect Antibody levels(Ig)
Antibody titres to vaccination
(Protein and Polysaccharide)
T cell defect ALC
Flow cytometry (for naïve T cells)
Phagocytic defect ANC
Respiratory burst assay
Complement deficiency CH50
AH50

52. Approach

53. Disorders treated with HSCT
● Bone Marrow Transplant
● Prophylactic Antibiotics and anti-fungals
● Lifelong IVIg Replacement 0.4 - 0.6 gm/kg every 3 weeks
Management

54. Disorders treated with IVIG

55. Summary

56. Thank you…!