This document discusses the classification, diagnosis, and management of primary immunodeficiency disorders. It defines primary immunodeficiencies as genetic defects that compromise the immune system. The document outlines various classifications of primary immunodeficiencies including antibody deficiencies, cell-mediated deficiencies, combined deficiencies, phagocytic defects, and complement system disorders. It provides details on specific primary immunodeficiency diseases, their genetic causes, clinical manifestations, diagnosis, and treatment approaches.

1. CLASSIFICATION, APPROACH TO DIAGNOSIS &
MANAGEMENT
OF
PRIMARY IMMUNODEFICIENCY DISORDERS
Presented by-: Dr.Gobinda Prasad Pradhan
Guide -: Dr. S.S.Mishra
Assoc.prof.

2. POINTS TO BE DISCUSSED
DEFINITION
EPIDEMIOLOGY
CLASSIFICATION
DESCRIPTION OF COMMON
ENTITY
CLINICAL APPROACH
INVESTIGATIONS
MANAGEMENT

4.  Deficiencies of defence mechanism may involve
specific immune functions-Humoral immunity, CMI
or both or Non specific mechanisms such as
phagocytosis, complement which augment & act in
conjunction with specific immune responses.

5. DEFINITION
 Immunodeficiency disorder are the conditions where the defence
mechanism of the body are impaired, leading to repeated microbial
infections of varying severity & sometimes enhanced susceptibility
to malignancies.
 TYPES –
1) PRIMARY ID
2) ACQUIRED or SECONDARY ID

6.  Primary ID-: Are compromised states that result from genetic
defect affecting 1 or more arms of the immune system.
 Secondary ID -: May result from infection, from malignancy or as
an adverse effect of immunomodulatory or immunosuppressive
medications( steroids, calcineurin inhibitors, TNF inhibitors, CT)

7. EPIDEMIOLOGY
 Because of lack of screening, the incidence & prevalence of primary
ID disease are unknown
 Although incidence has been estimated to be 1:10,000 birth
 Aprrox. 80% of the mutated genes causing more than 220 known
primary ID have been identified.

9. CLASSIFICATION OF PRIMARY ID
Antibody deficiency (B cell defect)
Cell mediated deficiency (T cell defect)
Combined B & T cell defect
Phagoccytic defect
Disorder of complement system

10. • X LINKED AGAMMAGLOBULINEMIA
• CVID
• SELECTIVE IgA DEF
• HYPER IgM SYNDROME
• TRANSIENT
HYPOGAMMAGLOBULINEMIA
OF INFANCY
ANTIBODY
DEFICIENCY
• THYMIC DYSPLASIA
• CHRONIC MUCOCUTANEOUS
CANDIDIASIS
• PNP DEFICIENCY
CELL MEDIATED
DEFICIENCY
• SCID
• HYPER IgE SYNDROME
• ATAXIA TELANGIECTASIA
• WISKOTT-ALDRICH SYNDROME
COMBINED
IMMUNODEFICIENCY

11. • LEUCOCYTE ADHESION
DEFICIENCY
• CHEDIAK-HIGASHI SYNDROME
• MPO DEFICIENCY
• CHRONIC GRANULOMATOUS
DISEASE
PHAGOCYTE
DEFECT
• COMPLEMENT COMPONENT
DEFICIENCY
• COMPLEMENT INHIBITOR
DEFICIENCY
COMPLEMENT
DEFECT

14. X-LINKED AGAMMAGLOBULINEMIA
 1st ID disease to have been recognised.
 Also known as Bruton agammaglobulinemia.
 gene maps to q22 on the long arm of the X chromosome and encodes the B-cell
protein tyrosine kinase Btk (Bruton tyrosine kinase) necessary for pre–B-cell
expansion and maturation into surface Ig-expressing B cells.
Clinical manifestations
 Remain well during the 1st 6-9 month of life by virtue of maternally transmitted IgG
antibodies.
 Thereafter, they acquire infections with extracellular pyogenic organisms, such as
Streptococcus pneumoniae and Haemophilus influenzae etc.
 Infections with Mycoplasma are also particularly problematic.
 Viral infections are usually handled normally with the exceptions of hepatitis viruses
and enteroviruses.

15. DIAGNOSIS
 History
 suspected if lymphoid hypoplasia is found on physical examination (minimal
or no tonsillar tissue and no palpable lymph nodes)
 serum concentrations of IgG, IgA, IgM,and IgE are far below the 95%
confidence limits for appropriate age
 Levels of isohemagglutinins and antibodies to antigens given during routine
immunizations are abnormally low whereas they are normal in transient
hypogammaglobulinemia of infancy.
 Flow cytometry

16. COMMON VARIABLE IMMUNODEFICIENCY
 Sex distribution is equal (M=F)
 Syndrome characterized by hypogammaglobulinemia with phenotypically normal B
cells.
 also been called acquired hypogammaglobulinemia because of later age of onset
of infections.
 Most patients have no identified molecular diagnosis.
 Several different genetic defects with AD/AR inheritance.
 Environmental factors particularly drugs such as phenytoin, D-penicillamine, gold
& sulfasalazine are suspected to be triggers.

17. CLINICAL MANIFESTATIONS
 Normal-sized or enlarged tonsils and lymph nodes.
 ≈25% of patients have splenomegaly
 Increased risk of lymphomas among affected women in the 5th and 6th decades of life.
 CVID has been reported to resolve transiently or permanently in patients who acquire
HIV infection.
 Appears clinically similar to those of XLA in types of infection except that echovirus
meningoencephalitis is rare in pt. with CVID.

18. SELECTIVE
IgA
DEFICIENCY
M/C ID disorder
Phenotypically normal blood B cells are present.
CVID occurs in 1st degree relatives of patients with SELECTIVE IgA
DEFICIENCY & some patients IgA def. Later become pan
hypogammaglobulinemia.
Isolated absence or near absence (<10mg/dl) of serum &
secretory IgA.
IgA def. is assoc. with a celiac like syndrome which may or
mayn’t respond to a gluten free diet.

19. CLINICAL FEATURES
Recurrent infections same as that of
other ab deficiency syndrome
Administration of IVIG, which is >99% IgG, is
not indicated because most IgA deficient
patients make IgG antibodies normally.

20. HYPER IgM SYNDROME
 Characterized by normal or elevated serum IgM levels associated with low or absent
IgG, IgA, and IgE serum levels, indicating a defect in the class-switch recombination
(CSR) process.
 2 genes on the X chromosome- CD40 ligand & NEMO gene
 3 genes on autosome- AID gene, UNG gene, CD40 gene
 Patient shows enhanced susceptibility to infections & autoimmune processes such as
thrombocytopenia, neutropenia, haemolytic anaemia & renal lesions
 Elevated IgM levels with immunodeficiency sometimes seen in congenital rubella.

21. DIGEORGE SYNDROME (THYMIC HYPOPLASIA)
 Dysmorphogenesis of the 3rd and 4th pharyngeal pouches during early embryogenesis,
leading to hypoplasia or aplasia of the thymus and parathyroid glands.
 Microdeletions of specific DNA sequences from chromosome 22q11.2
 Syndromes assoc. :-
 CATCH 22 syndrome (cardiac, abnormal facies, thymic hypoplasia, cleft palate,
hypocalcaemia)
 Partial DiGeorge syndrome( Variable hypoplasia of the thymus and parathyroid
glands)
 complete DiGeorge syndrome (Complete aplasia)
 Approximately one-third of infants with complete DiGeorge syndrome have CHARGE
association (coloboma, heart defect, choanal atresia, growth or developmental
retardation, genital hypoplasia, and ear anomalies including deafness).

22. Source: Internet
DIGEORGE SYNDROME

23. CLINICAL FEATURES
 The diagnosis is often first suggested by hypocalcemic seizures during the neonatal
period.
 Partial thymic hypoplasia may have little trouble with infections and grow normally.
 Patients with complete DiGeorge syndrome resemble patients with severe combined
immunodeficiency in their susceptibility to infections.

24. SEVERE COMBINED IMMUNODEFICIENCY (SCID)
 Also known as Glanzman-Rinker syndrome/Bubble boy disease/Thymic
alymphoplasia.
 Impairment of both humoral & cellular response
 mutations in any 1 of at least 13 known genes that encode components of the
immune system crucial for lymphoid cell development.
 Lymph nodes, tonsils, adenoids, and Peyer’s patches are absent or extremely
underdeveloped.
 Screening in SCID is part of newborn screening programme in 21 states of the
United States now.

25. Source: Internet
BUBBLE BOY DISEASE

26. CLINICAL FEATURES
 Present within the 1st few months of life with recurrent or persistent
diarrhea, pneumonia, otitis media, sepsis, and cutaneous infections.
 Growth may appear normal initially, but extreme wasting usually ensues after
diarrhea and infections begin.
 Persistent infections with opportunistic organisms.
 Affected infants also lack the ability to reject foreign tissue and are therefore
at risk for severe or fatal graft-versus host disease (GVHD).
TYPES -: XR (T-/ B+/NK- cells) – M/C form of SCID
AR (-ve B & T cells) – M/C due to ADA deficiency

27. WISKOTT-ALDRICH SYNDROME
 X linked recessive syndrome.
 Ch. by atopic dermatitis, thrombocytopenic purpura with normal appearing
megakaryocytes but small defective platelets and undue susceptibility to
infections.
 Clinical manifestations :-
 prolonged bleeding from the circumcision site or bloody diarrhea during
infancy
 Atopic dermatitis & recurrent infection usually develop during 1st yr of life.
 Survivals beyond teenage is rare.
 Infections, bleeding and EBV assoc. malignancy are the major causes of
death.
 Predominant Ig pattern is a low serum level of IgM, elevated IgA & IgE and
normally or slightly low IgG concentration.

28. ATAXIA TELANGIECTASIA
 It is a complex syndrome with immunologic, neurologic, endocrinologic, hepatic, and
cutaneous abnormalities.
 Long arm of chromosome 11
 The gene product is a DNA-dependent protein kinase localized predominantly to the
nucleus and involved in cell-cycle control.
 Clinical features:-
 Progressive cerebellar ataxia
 Oculocutaneous telangiectasia
 Chronic sinopulmonary disease
 High incidence of malignancy
 Ataxia typically becomes evident soon after these children begin to walk and
progresses until they are confined to a wheelchair.
 The telangiectasias begin to develop at 3-6 yr of age.
 Recurrent sinopulmonary infections occur in approximately 80% of these patients.

29. TELANGIECTASIA

30. HYPER IgE SYNDROME
 Relatively rare primary immunodeficiency syndrome ch. By recurrent
staphylococcal abscesses of skin,lungs and other sites.
 Markedly elevated IgE levels.
 Occur in two forms. Autosomal dominant & autosomal recessive

31. AUTOSOMAL DOMINANT HYPER IgE SYNDROME
 Characteristic clinical features of the autosomal dominant form of the hyper-IgE
syndrome are staphylococcal abscesses, pneumatoceles, osteopenia, and unusual
Coarse facial features.
 history from infancy of recurrent staphylococcal abscesses involving the skin, lungs,
joints, viscera and other sites.
 Often have histories of sinusitis and mastoiditis.
 In neonates and infants with the pruritic pustular dermatosis, IgE levels will be
elevated for age and are usually in the 100s.
 C. albicans is the second most common pathogen.
 Allergic respiratory symptoms are usually absent.
 Delay in shedding primary teeth, recurrent fractures are seen.
 IgE levels >2000 IU/mL confirm the diagnosis.

32. Autosomal Recessive Hyper-IgE
Syndrome
 Unlike those with the autosomal dominant form of this syndrome, a large
majority of patients with autosomal recessive hyper-IgE have severe atopic
dermatitis, asthma, food allergies, and anaphylaxis.
 Neurologic problems, Malignancies are also more common than in the
autosomal dominant form.
 Do not have pneumatoceles, a history of fractures, unusual facial features, or
delayed shedding of the baby teeth, as seen with the autosomal dominant
form of the hyper-IgE syndrome

34. TREATMENT
 Long-term administration of therapeutic doses of a penicillinase-resistant
antistaphylococcal antibiotic.(Most effective therapy)
 IVIG
 appropriate thoracic surgery
 Bone marrow transplantation
 Treatment of choice for the autosomal recessive form is allogeneic bone
marrow transplantation.

35. LEUKOCYTE ADHESION DEFICIENCY
 Rare autosomal recessive disorders of leukocyte function.
 Delayed separation of the umbilical cord is seen
 Characterized by recurrent bacterial and fungal infections and depressed
inflammatory responses despite striking blood neutrophilia.
 The neutrophils have significant defects in adhesion, motility, and ability to
phagocytose bacteria.
 Children with LAD-2 share the clinical features of LAD-1 but have normal
CD11/CD18 integrins
 Features unique to LAD-2 include neurologic defects, cranial facial dysmorphism,
and absence of the erythrocyte ABO blood group antigen (Bombay phenotype).

36.  Infections in LAD-2 are milder than that in LAD-1.
 LAD-3 is characterized by a Glanzmann thrombasthenia-like bleeding disorder,
delayed separation of the umbilical cord, and serious skin and soft-tissue
infections similar to that seen in LAD-1
 Children with severe forms of LAD present in infancy with recurrent, indolent
bacterial infections of the skin, mouth, respiratory tract, lower intestinal tract,
and genital mucosa.

37.  Early allogeneic hematopoietic stem cell transplantation (HSCT) is the TOC
for severe LAD-1 (and LAD-3).
 Some LAD-2 patients have responded to fucose supplementation,
 Prophylactic trimethoprim-sulfamethoxazole

38. CHEDIAK-HIGASHI SYNDROME
 rare autosomal recessive disorder.
 characterized by increased susceptibility to infection caused by defective
degranulation of neutrophils,
 a mild bleeding diathesis, partial oculocutaneous albinism, progressive
peripheral neuropathy, and
 a tendency to develop a life-threatening form of HLH.
 LYST (for lysosomal traffic regulator), the gene mutated in CHS.
 located at chromosome 1

39. Clinical Manifestations
 Light skin and silvery hair
 Frequently complain of solar sensitivity and photophobia.
 Frequent infections and neuropathy are common.
 Susceptible to Gram-positive bacteria, Gram-negative bacteria, and fungi,
with S. aureus being the most common.
 The most life-threatening complication Is ch. by pancytopenia, high fever, &
lymphohistiocytic infiltration of liver, spleen, and lymph nodes.
 Diagnosis of CHS is established by finding large inclusions in all nucleated
blood cells.

40. Treatment
 High-dose ascorbic acid (200 mg/day for infants, 2,000 mg/day for adults).
 The only curative therapy to prevent the accelerated phase is HSCT.

41. CHRONIC GRANULOMATOUS DISEASE
 CGD is a rare disease.
 It is caused by 4 genes, 1 X-linked and 3 autosomal recessive in inheritance.
 Any patient with recurrent pneumonia, lymphadenitis, hepatic or subcutaneous or
other abscesses, osteomyelitis at multiple sites.
 a family history of recurrent infections, or any infection with an unusual catalase
positive organism requires evaluation.
 The most common pathogen is S. aureus, although any catalase-positive
microorganism may be involved.
 More than 80% of CGD patients have positive serology for Crohn disease.
 The diagnosis is most often made by performing flow cytometry using
dihydrorhodamine 123 (DHR).
 The nitroblue tetrazolium dye test is frequently cited in the literature but is now
only rarely used clinically

42. Treatment
 HSCT is the only known cure for CGD.
 oral trimethoprim sulfamethoxazole
 interferon-γ 50 μg/m2 3 times/wk
 Itraconazole
 Granulocyte transfusions have been used but it is not clear that they are very
helpful.
 Corticosteroids may be useful

43. A
L
G
O
R
I
T
H
M

47. WHAT WE NEED
SUSPECT SCREENING INVESTIGATIONS

48.  Evaluation of immune function should be initiated in those rare infants or
children who do have c/f of specific immune disorder & in all who have
+ve family h/o early infant death or known ID disorder, unusual, chronic
or recurrent infections such as
a) 1 or more systemic bacterial infection( sepsis, meningitis)
b) 2 or more serious respiratory or documented bacterial infection(cellulitis,
abscess, pneumonia, draining OM)
c) Serious infection at unusual sites(Liver, brain abscess)
d) Infections with unusual pathogen( P. jiroveci, Aspergillus, Nocardia)
e) Infections with common childhood pathogens but of unusual severity.

49. TAKE HOME MESSAGE
 Primary care physician must have high index of suspicion.
 R/O ID in any child having recurrent infection.
 No benefits of IVIG in selective IgA deficiency.
 A simple routine investigation may detect a ID.

50. references
 Ananthanarayan R, Paniker CKJ, Textbook of microbiology, 10th ed. Hyderabad: University press; 2017
 Burckley RH. Evaluation of suspected immunodeficiency. In:Kliegman,Stanton,Geme S,Schor(Eds). Nelson
Textbook of paediatrics. 1st southeast asia ed.Elsevier; 2017. p999-1006
 Burckley RH. Primary defect in antibody production. In:Kliegman,Stanton,Geme S,Schor(Eds). Nelson Textbook of
paediatrics. 1st southeast asia ed.Elsevier; 2017. p1012-18
 Coates TD. Disorders of phagocytic function. In:Kliegman,Stanton,Geme S,Schor(Eds). Nelson Textbook of
paediatrics. 1st southeast asia ed.Elsevier; 2017. p1040-47