1. Primary Immunodeficiency
Nicola Wright, MD
Pediatric Resident Teaching
April 22, 2010

2. Overview Initial approach Phagocytic disorders Complement disorders
Humoral disorders
Cellular and Combined disorders
Cases

3. Primary Immunodeficiencies Rare Disorders?
Includes over 100 defined genetic disorders
Incidence of 1/ up to 1/500
“ Nothing is rare to the patient or the family of the patient that has it”

4. When should you be concerned?
C hronic
R ecurrent
U sual pathogens
I nvasive
S evere
E valuate!

5. 10 Warning Signs of PID 8+ AOM in 1 year 2+ sinus infections in 1 year
2+ months on Abx with little effect
2+ pneumonias in 1 year
FFT, chronic diarrhea
Recurrent, deep skin or organ abscesses
Persistent thrush after age 1
Need for IV Abx to clear infections
2+ deep seated infections
Positive family history
c/o Jeffrey Modell Foundation

6. Approach to the child with possible PID
History:
Infections – bacterial/viral/fungal
Autoimmune/allergy history
Umbilical cord separation
Evidence of lymph tissue/adenopathy/HSM
growth
Other congenital abnormalities
Vaccination history – how did they do with them?
FAMILY HISTORY
CONSANGUINITY

7. Approach to PID Physical Exam: Assess lymph tissue Signs of infection?
Signs of autoimmune/allergic disease – rashes
HSM
Clubbing
Other abnormalities – nail dystrophy, albinism, telangectasia, skeletal defects, heart defects, dysmorphism, etc
Rule out anatomical problems that may be the explanation for recurrent infections, eg cleft palate, abnormal airways, etc

8. Classification: Based on Immune Mechanism
Innate Immunity
Phagocytic system
Complement
Adaptive Immunity
Humoral Immunity
Cellular Immunity

9. Acquired Immunodeficiency
HIV
Drug induced: eg chemotherapy, immunosuppression in transplant patients, etc
Infection induced immunodeficiency: eg severe sepsis, viral suppression of the immune system
Others: eg protein losing enteropathy
DON’T FORGET ABOUT THEM in your differential!!!

10. You see a 9 month old girl with cervical adenitis. . .
the node develops into an abscess despite po antibiotics
Culture following I&D is positive for Serratia
What test do you want to do on this child?
CBC
Immunoglobulins
Lymphocyte numbers
Oxidative Burst

11. Phagocytic Disorders

12. Innate Immunity Phagocytic Disorders
The first line of defense
Present mainly with bacterial infections +/- fungal infections
Sepsis, Fever without source
Aphthous ulcers/gingivostomatitis
Perineal abscesses
Skin infections
Sinopulmonary infections

13. Phagocytic Disorders: Low Numbers (ie Neutropenia)
Kostmann syndrome, congenital neutropenia
Cyclic neutropenia: mutation of the elastase gene
Acquired causes of neutropenia: drugs, autoimmune, transient neutropenia of childhood, etc

14. Phagocyte Disorders: Abnormal Function

15. CGD Defective neutrophil oxidation Susceptible to catalase + bacteria
Soft tissue infections, adenitis, liver abscesses, osteomyelitis, pneumonia, sepsis,
Aspergillus infections
granulomas
Colitis in 17%
Most X-linked, also AR types
Diagnosed with NBT/DHR/oxidative burst
Confirm with protein flow cytometry and genetic sequencing

16. What diseases do you worry about with delayed separation of the umbilical cord?
How do you define delayed separation of the umbilical cord?

17. Leukocyte Adhesion Deficiency
Delayed umbilical cord separation
Persistent leukocytosis
Reduced pus formation
Impaired wound healing
Recurrent life-threatening bacterial and sometimes viral infections
Two types
I – defect of integrins CD11, CD18
II – defect of sialyl Lewis X, component of L-selectin

18. Hyper IgE Syndrome (Job syndrome)
Chronic eczematous rash
Recurrent skin and sinopulm infections
S. aureus infections
Mucocutaneous candidiasis
Skeletal and dental abnormalities
Pathologic fractures, shark teeth
Asymmetric facies
Lung cysts
IgE usually >2000
AD inheritance with incomplete penetrance
STAT3 mutation
Abnormal neutrophil chemotaxis

19. Phagocytic Disorders Lab Evaluation
First line: CBCD and smear
Second line:
Cyclic neutropenia workup if indicated
NBT/dihydrorhodamine/oxidative burst to rule out CGD
LAD workup if indicated (CD11/CD18 expression)
Neutrophil function and chemotaxis assays if indicated and available

20. Phagocytic Disorders Management
Infection prevention
Avoid hay, dirt, marijuana (aspergillus spores) for CGD
Prophylactic antibiotics if indicated
Septra for S. aureus in CGD, hyper IgE
Fungal prophylaxis for CGD, usually itraconazole
Aggressive treatment of infections
G-CSF if indicated/effective
Monitoring for complications
Eg malignancy in Kostmann, severe congenital neutropenia
Disease specific treatments
Eg interferon – gamma for CGD

21. A 5 month old baby is admitted to the PICU with Neisseria meningitis
What test should be done to rule out immune deficiency in this patient?
Immunoglobulins
CH50
C3, C4
Oxidative burst

22. Complement Deficiencies

23. Complement (C’) Deficiencies
Proteins required for inflammation, opsonization
Defects of all proteins have been described with the exception of factor B
Depending on the missing component, patients suffer either recurrent infections and/or immune-complex diseases like SLE
Patients are particularly susceptible to pyogenic bacteria and Neisseria sp

26. N. Meningitidis Infection
Though terminal C’ deficiencies are rare, they may constitute up to 1-5% of cases of first infection with N. meningitidis
The course of infection is clinically indistinguishable from patients with normal C’, but they are at risk for recurrent infections
Diagnosis: CH50
Properdin level (in males)
Most C’ components are acute phase reactants and are normally elevated during acute infection

27. Complement Deficiency Lab Evaluation
First line:
CH50*
properdin level in males
Second line:
AH50
Specific complement protein levels
*C’ proteins may be consumed with inflammation, eg SLE

28. Management of C’ Deficiency
Screen all patients with Neisseria sp. infections for C’ deficiency!
Vaccination against meningococcus
High index of suspicion for meningococcal infection if they present with fever
Standard therapy for meningococcal infections
Medicalert bracelet
Management of immune complex disease

29. Humoral Deficiencies

30. Adaptive Immunity Humoral Immune Deficiency
Hallmark is recurrent sinopulmonary infections with encapsulated bacteria such as Streptococcus sp, S. aureus and H. influenzae
Sepsis
Diarrhea: giardia, rotavirus
Chronic enteroviral infections, chronic enteroviral meningoencephalitis
Neutropenia
Autoimmune disease, especially cytopenias
Usually presents after 6 months of age when maternal Ab titers wane

31. Normal Immunoglobulin Levels for Age
Adult levels of IgG are reached during the 3rd trimester
Premature infants < 28 wks GA have low IgG
Healthy neonates have low/absent IgM and IgA

32. A 9 month old boy presents with RLL pneumonia
Hx is significant for:
2 prior episodes of OM
FTT with chronic diarrhea
Always has green purulent nasal D/C
No lymph nodes noted on PE
No significant thymic shadow on CXR
What tests would you do?
What is the most likely diagnosis?

33. Humoral Immunodeficiency
A defect of the antibody (Ab) producing B cells
Abnormalities include:
Abnormal B cell maturation resulting in low B cell numbers, eg Bruton agammaglobulinemia
A defect in the Ab making ability of B cells,
eg AR hyper IgM syndrome
A defect in the ability of B cells to respond to antigen (Ag) resulting in abnormal Ab production,
eg X-linked hyper IgM syndrome

34. Abnormal B cell Maturation Low B cell numbers with Agammaglobulinemia
85% due to X-linked agammaglobulinemia (XLA or Bruton agammaglobulinemia)
Mutation of Bruton protein tyrosine kinase (BTK) resulting in a block in B cell maturation Agammaglobulinemia results from an absence of mature B cells
Autosomal recessive defects cause the remaining forms of agammaglobulinemia eg m heavy chain defects, surrogate light chain defects, BLNK mutations, etc

35. Abnormal B cell Maturation Agammaglobulinemia
The clinical presentation of XLA and AR forms of agammaglobulinemia are similar
Paucity of lymph tissue
Profoundly decreased number of B cells and virtually undetectable serum Ig’s (all isotypes)
Normal T cell numbers and function
No risk for autoimmune complications
May present with neutropenia
Long term complications include chronic pulm disease and bronchiectasis

36. Defects in Ab production
Hyper IgM Syndromes
Defects in Ab production
and
Response to Ag

37. Defects in Ab production
Generally comprise disorders with abnormal class switching from IgM to other isotypes
Eg AR hyper IgM syndrome, a defect of the AID enzyme expressed only in B cells and required for class switching and somatic hypermutation
Normal to high serum IgM with low IgG and IgA
Disrupted B cell maturation results in massive enlargment of lymph node germinal centers, including intestinal lymphoid hyperplasia
Risk for autoimmune hematologic diseases

38. Defects in B cell response to Ag
Due to abnormal ‘second signal’ molecules required by B cells for production of Ab
Eg; Defect of CD40 ligand on T cells in X-linked hyper IgM syndrome, or CD40 on B cells in AR hyperIgM syndrome
Normal to elevated IgM, low IgG, IgA
Lymphoid hyperplasia
Also at risk for opportunistic infections including PJP, CMV, cryptosporidium
Increased risk of malignancies
BMT is indicated for cure

40. Other Humoral Immune Deficiencies Common Variable Immune Deficiency
Heterogenous group of disorders
The defect is unknown in the majority
Most present in adulthood, but some present earlier (?different disease)
Definition:
decreased levels of at least 2 Ig isotypes
impaired specific Ab production
all other causes of immune deficiency ruled out
Risk of autoimmune disease
Increased risk of malignancy (x5)
Difficulty with chronic inflammatory diseases: lung, hepatitis, granulomas, IBD

41. CVID
Often have lymphoproliferation with adenopathy, splenomegaly (1/3)
Reactive follicular hyperplasia on bx
Non-caseating granulomas
May have lymphopenia and decreased T cell function
Family hx in 10-20%
Defects in T-B cell crosstalk

42. May develop anaphylaxis if given IVIG!!
IgA Deficiency
The most common form of PID
1/600 in Europeans and N. Americans
Increased susceptibility to sinopulmonary infections, though most are asymptomatic
Assoc with GI diseases (celiac, giardia), atopy, autoimmune disease
Can also have selective IgG subclass deficiency
Specific Ab production is usually normal
Definition: IgA < 0.7 g/L in a patient > 4 yo
Normal IgG and IgM
May develop anaphylaxis if given IVIG!!

43. IgG Subclass Deficiency
Usually low IgG2 and IgG4, or selective deficiency of IgG3
Mechanism is unknown
IgG4 reaches adult levels latest
Usually recurrent sinopulmonary infections and infections with encapsulated bacteria
May have specific Ab deficiency
Rule out concurrent IgA deficiency

44. Selective Antibody Deficiency
Normal Ig’s but abnormal response to Ag
Usually defect in response to polysaccharide Ag, eg pneumococcus
Poor response to pneumovax, though may have an adequate response to prevnar, the conjugated pneumococcal vaccination
Up to 25% of PID diagnoses!

45. Other Humoral Immune Deficiencies
Transient hypogammaglobulinemia of infancy
‘delayed’ maturation of the immune system
Rarely have difficulty with infections
Usually resolves by 3-5 yo
Rarely requires therapy
Do need to treat fevers, bacterial infections more aggressively

46. Investigation of Humoral Immune Deficiencies
Lymphocyte subsets to assess B cell numbers
IgG, IgA, IgM, IgE levels
Isohemagglutinin titers (IgM)
IgG subclasses
Titers to vaccinations
Especially titers to pneumovax (polysaccharide, unconjugated); pre and post titers
More specialized testing:
Btk flow, sequencing of Btk gene
CD40L/CD40 flow

47. Management of Humoral Deficiencies
Prophylactic IVIG is the mainstay of therapy ( mg/kg q3-4wks)
Only indicated for patients with significant difficulties with recurrent infections; continue therapy only if there is improvement!
SC Ig commonly used in Europe, now licensed in Canada
Weekly SC infusions of Ig
Can be done at home
Gives more steady state levels of IgG

48. Management of Humoral Deficiencies
Prophylactic Abx
Aggressive Abx therapy for infections
Monitoring for long term complications:
High index of suspicion for malignancy
Monitoring for chronic lung disease – YEARLY PFTs
Watch for autoimmune complications: CBCD, liver enzymes, screening for SLE, thyroid disease

49. Cellular Immune Deficiencies

50. Cellular Immune Deficiencies
Very few abnormalities ONLY affect the cellular system, most are combined
Defects of the interferon-g and IL-12 axis
Both required for the TH1 pathway, which activates cytotoxic T and NK cells
Susceptible to intracellular organisms: atypical mycobacteria, salmonella
Includes chronic mucocutaneous candidiasis

51. Chronic Mucocutaneous Candidiasis
Persistent or recurrent infections of the skin, nails, mucous membranes by Candida
Rarely develop Candida sepsis or organ infection
7 defined subgroups
Responds to antifungals but recurs once stopped

52. Combined Immune Deficiencies
The most profound immune defects
Recurrent bacterial, viral and fungal infections
Opportunistic infections, eg PJP
Diarrhea, FTT
Autoimmune/atopic phenomena
Risk of maternal engraftment and assoc GVHD
Usually present in the first few months of life
SCID: documented abN of humoral and cellular immune system coupled with life-threatening complications
The earlier the diagnosis the better!!!

53. Combined Immune Deficiency Multiple Genetic Defects
T cell development totally blocked
Common gamma chain (XSCID), Jak3
Defects of VDJ recombination (abnormal TCR and Ig formation)
RAG ½, Omenn’s, Artemis
Enzyme defects toxic to lymphocytes
ADA, PNP deficiencies
Defective signaling in immune cells
ZAP 70

54. Combined Immune Deficiency
Classified based on lymphocyte phenotype
T- B+ NK –
common g chain defect
JAK3 deficiency
T- B+ NK+
IL-7R a defect
T- B- NK-
ADA deficiency
PNP deficiency
T- B- NK+
RAG1 or RAG2 defect
Omenn’s syndrome
Artemis mutations
T-B+
CD45 deficiency
CD3 deficiency
T+B+
ZAP-70 defect
IL-2 defect
CD25 defect
MHC type I deficiency
MHC type II deficiency

55. Combined Immune Deficiencies X-linked SCID
The most common type is X-linked SCID due to a defect of the common g chain receptor (44% of SCID)
Protein required for the cytokine receptors of IL-2, IL-4, IL-7, IL-9, IL-21
Results in arrest of T and NK cell development and a B cell maturation defect
Lymphoid hypoplasia and recurrent infections
Risk for autoimmune complications
BMT is required for cure, the earlier the better!!

56. SCID Adenosine Deaminase Deficiency
The most common type of SCID with AR inheritance (16%)
Defective enzyme in the purine salvage pathway results in progressive lymphopenia due to metabolic poisoning of the cells
Skeletal abnormalities in 50%
PEG-ADA can partially correct
BMT is the only cure
Similar phenotype in PNP deficiency

57. Approach to Combined/Cellular Defects Laboratory Investigations
CBC and Differential
Peripheral Smear

58. Labs 3 mo girl with the following CBCD: Hgb 92 Hct 0.28
Platelets WBC 4.8
Neutrophils 2.5
Lymphocytes 0.6
monos 0.9
eos 0.7

59. Labs The CBC
DON’T NEGLECT THE LYMPHOCYTE COUNT!
Look at the differential – the WBC may be normal despite lymphopenia
Lymphocyte counts are much higher in infants than adults and decrease with age; a normal adult ALC of 1.5 is NOT NORMAL in an infant
ALC = absolute lymphocyte count
(normal at 3 mo ; normal WBC 6-18)

60. Labs Cellular Immune System
First: Lymphocyte count!
Lymphocyte subsets (T, B, and NK cell numbers)
Delayed type hypersensitivity skin test
Second: Lymphocyte proliferation assays
Antigen stimulation assay (if available)
Third: ADA/PNP levels
Protein or mutational analysis for specific types of SCID as indicated

61. Lymphocyte Proliferation Assays
Mitogens:
Patient lymphocytes are stimulated with mitogens, or chemicals that are strong activators of T cells
A normal response is proliferation of the lymphocytes, measured by 3H thymidine incorporation into the cells
Phytohemagglutinin, concanavalin A and pokeweed mitogen are standard
Likely SCID if PHA is < 10% of normal

62. Lymphocyte Proliferation Assays
Antigen Stimulation:
Same concept as mitogens, but common protein antigens are used instead of mitogens to stimulate the T cells
A sort of ‘in vitro’ DTH test
The patient must have prior sensitization to the antigen
Tetanus and candida commonly used, sometimes PPD
More sensitive test of lymphocyte function than mitogen assays

63. Labs Other tests CXR, U/S or CT – assess thymus
DNA testing to rule out maternal engraftment
FISH for XX/XY in boys, VNTR’s in girls
Specific testing for other immune deficiencies:
DiGeorge syndrome – FISH for 22q11.2 hemizygosity
Testing of cytokine pathways
NK cell function testing, perforins
Etc, etc, etc

64. SCID Management High index of suspicion for infection!!!!
Treat early and aggressively
Prophylaxis: isolation precautions **
PJP prophylaxis
IVIG
fungal prophylaxis
Supportive care is EXTREMELY important
Need aggressive nutritional support
BMT as early as possible
NO LIVE VACCINATIONS
CMV negative, irradiated blood products only

65. Labs Testing for Infections
Aggressively look for infections!!!
Patients usually do not come in with the classic presentation of an infection
Blood – bacterial cx +/- fungal cx, viral cx, viral PCR’s
Stool – bacterial cx, O+P for giardia, C.diff, rota, adeno PCR, EBV PCR
If you can culture it, then culture it!
Don’t ever forget to rule out HIV (by NA method)
Don’t forget about PJP even if the patient is on prophylaxis

66. Therapy Aggressive management of complications, eg autoimmune
Watch for long term complications – chronic pulm disease, malignancy
Treat them with VZIg, acyclovir for VZ exposures
Specific therapies as indicated, eg PEG-ADA
Carrier testing and genetic counseling

67. Case 1

68. An 8 mo boy : Born at term, admitted at birth for R/O sepsis, mom GBS+
CBC day 1 showed plts 80
Tx for ? Sepsis, plts 120 at D/C
Rash on trunk, hands, face, feet at a few months; dx as eczema, tx with topical steroids with minimal improvement
Nails noted to be dystrophic
One URTI
3-4 episodes of OM tx with po Abx
Diaper rash tx with po Abx
Red spots on head at 7 mo
Referred to heme for dystrophic nails

69. PE: Normal vitals and growth
Eczema like rash on face, trunk, limbs, hands, feet
Dystrophic nails
Shotty cervical and inguinal adenopathy
No HSM

70. Labs: Hgb 108 Plt 17 WBC 17.2 Neuts 9.1 Lymphs 4.1
Smear: slightly microcytic, hypochromic
What else would you look at on the smear?

71. Other labs: IgG normal; subclasses normal IgM normal IgA normal
IgE elevated
Diphtheria, tetanus titers protective
VZ titer positive

72. Lymphocytes: CD3 (T cells) low 1.5 CD4 (T helper) normal 1.2
CD8 (T cytotoxic) low 0.177
Elevated CD4:CD8 ratio
CD19/CD20 (B cells) low 0.42
CD16/56 (NK cells) low 0.177
Mitogens normal
Antigen stimulation normal

73. The diagnostic test. . .
Flow cytometry for the Wiskott Aldrich protein showed decreased expression
Genetic sequencing of the WASP protein confirmed Wiskott Aldrich syndrome

74. Wiskott Aldrich Syndrome
X-linked defect of WASP
Intracellular signaling protein important for actin cytoskeletal organization
Triad of eczema, thrombocytopenia and recurrent infections
Usually present in first year of life
Small, defective platelets, bleeding a cause of significant morbidity and mortality
Variable combined immune defect
Progressive lymphopenia
Poor specific antibody production
Low IgM, IgG, high IgA, high IgE
Prone to autoimmunity
High risk of malignancy, especially EBV-induced RE cancers
BMT curative

75. Outcome alloBMT, sister was a 6/6 match Graft rejection
Supportive care
IVIG, antifungals, PJP prophylaxis, close monitoring
Developed colitis
C. diff, EBV+
Awaiting 2nd BMT

76. Case 2

77. A 39 wk GA girl presented day one of life with:
Resp distress and desats, requiring O2
Septic W/U done, started Abx
Pneumonia on CXR
Interrupted aortic arch, VSD, bicuspid aortic valve on echo; started prostaglandin
Dysmorphic with short palpebral fissures, bulbous nasal tip, micronathia, sacral dimple
Cervical ribs on CXR

78. Labs
Hgb 105 Hct 32.9
Plt 167
WBC 20.3
Neut 15.3
Lymphs 2.6

79. Immune labs IgG, IgM, IgA low CD3 0.6 low CD19 0.432 low
CD4:CD8 elevated
Mitogens: PHA low, ConA, PWM normal
Antigen stimulation: tetanus, candida, PPD low

80. Summary Dysmorphic Heart defect Pneumonia +/- sepsis
Panlymphopenia with poor T cell function
Low immunoglobulins
The diagnostic test is. . .

81. Chromosome 22q11.2 deletion syndrome (DiGeorge)
Classic triad of thymic hypoplasia, parathyroid hypoplasia, congenital heart defects
Incidence of up to 1/4000 live births
Other etiologies: del10p, diabetic embryopathy, FAS
Variable immune defect with increased incidence of opportunistic infections, recurrent sinopulm and viral infections
Mainly a cellular defect
Wide range of severity – SCID-like to apparently normal
Increased risk of autoimmunity in later life – 10%

82. Case 3

83. A 15 yo girl with:
Recurrent OM, bilat, starting at ~ 18 mo, nearly 1/mo
Myringotomy tubes x 3, cultured for S. pneumo and Staph aureus
Recurrent tonsillitis, strep throats. T+A at 5 yo, OM improved
Recurrent sinusitis starting at 7 yo; ENT sx x 2
2 documented pneumonias, 1 requiring admit and O2
PE normal

84. Labs
Hgb 123
Plt 202
WBC 3.83
ANC 1.55
ALC 1.99

85. Immune labs IgG 0.585 low IgM normal IgA 0.17 low IgE < 1.5
IgG1 low IgG2 low
IgG3 normal IgG4 low
Tetanus and diptheria titers nonprotective postvaccination
Hib nonprotective VZ nonprotective
Prepneumovax – positive to serotype 19
Postpneumovax – positive to serotypes 14 and 19

86. Immune labs CD3 normal CD19 slightly low CD4 normal CD16/56 low
CD4:CD8 normal

87. Diagnosed with CVID Also found to be a CF carrier
Started on IVIG at 8 yo with improvement
Severe H/A post IVIG starting at 12 yo
IVIG stopped, return of infections, feeling unwell, missing school
Tried prophylactic Abx without success
Started SCIg with improvement

88. Case 4

89. A 7 mo Hispanic baby with:
Hx disseminated CMV
pneumonitis, hepatitis, pancytopenia
Blood CMV PCR’s positive
Treated with IV gancyclovir x 3 wks with resolution of hepatitis and pancytopenia, improvement of viremia
CMV PCR’s positive increasing 1 month later, continued gancyclovir another 3 months
Increasing viremia despite gancylcovir – ruled out compliance issues with meds, CMV resistance
Neutropenia presumed to be secondary to gancyclovir +/- CMV
Responded to G-CSF

90. Case Report, cont’d
Hx of urinary tract infections with renal tract abnormality (hydronephrosis/hyrdroureter)
On prophylactic antibiotics for UTI (keflex then nitrofurantoin)
Hypogammaglobulinemia
On intermittent IVIG; levels followed, IVIG given only if trough levels were low
On pentamidine IV for PJP prophylaxis
? Given monthly

91. Case Report, cont’d CMV viremia worsened despite gancyclovir
Treated with cidofavir, IVIG q2wks
Worsening respiratory status while in hospital requiring intubation and ventilation, PICU
Bronchioalveolar lavage revealed CMV pneumonitis and PCP
Antivirals continued
Started high dose Septra IV for PCP, also given glucocorticoids
Respiratory status continued to deteriorate, he died at 10 mo

92. Labs
WBC 1.9 – 25.7, ANC 0 – 12.9;
Hgb 69 – 131
Platelets –
Elevated liver enzymes initially with CMV
Blood CMV PCR > copies initially, dropped to 3750, back up to

93. Immune work-up T cells 1757 - 3624 (normal) CD4: 466 – 1660 (normal)
CD8: 1078 – 1920 (elevated)
CD4:CD8 ratio reversed
B cells: 249 – 4754 (elevated)
NK cells: 48 – 279 (normal)
Mitogens normal

94. Immune work-up IgG 84 (very low) – 672 (on IVIG) IgM <10 (very low)
IgA <10 (very low)
ADA, PNP normal
HIV RNA PCR negative

95. Other labs Antineutrophil Ab negative CANCA negative
ANA <40, C3 normal
Negative sweat Cl for CF
Bone marrow aspirate – decreased granulopoiesis, many histiocytes, ? Hemophagocytosis, no malignancy
Repeat BMA – decreased granulopoiesis, no hemophagocytosis, no malignancy
A diagnosic test was done. . .

96. Summary
This patient has SCID despite normal lymphocyte numbers and normal mitogens
Documented humoral defect, clinically documented cellular defect with CMV and PJP, life-threatening infection
T+B+NK+ phenotype

97. Combined Immune Deficiency
Classified based on lymphocyte phenotype
T- B+ NK –
common g chain defect
JAK3 deficiency
T- B+ NK+
IL-7R a defect
T- B- NK-
ADA deficiency
PNP deficiency
T- B- NK+
RAG1 or RAG2 defect
Omenn’s syndrome
Artemis mutations
T-B+
CD45 deficiency
CD3 deficiency
T+B+
ZAP-70 defect
IL-2 defect
CD25 defect
MHC type I deficiency
MHC type II deficiency

98. The diagnostic test: HLA-DR expression (MHC class II) absent
Normal HLA-A,B,C expression (MHC class I)
“Bare lymphocyte syndrome”

99. Bare Lymphocyte Syndrome
Type I – defect of TAP, MHC class I deficiency
Type II – MHC class II deficiency
Type III – MHC class I and II deficiency

100. MHC class II Deficiency
Rare cause of SCID
Autosomal recessive, usually a hx of consanguinity
Defective thymic education and T cell help
Absence of normal antigen processing and presentation via MHC class II molecules
Suffer recurrent viral, bacterial, fungal and protozoan infections
Most die in early childhood of malabsorption, failure to thrive, infections
Prone to sclerosing cholangitis

101. Labs Normal B and T cell numbers Reduced CD4 cells
Reduced CD8 cells in 1/3
Panhypogammaglobulinemia
Absent delayed type hypersensitivity
Management:
For SCID-like phenotypes – BMT
Milder forms: IVIG
Rapid, aggressive treatment of infections

102. Other immune deficiencies

103. NK cell defects Hemophagocytic Lymphohistiocytosis (HLH)
Defect in perforin or granzyme B
PRF1, UNC13D or MUNc13-4 genes
Present with fever, adenopathy, HSM, pancytopenia, hepatitis, neuro abnormalities
Hemophagocytosis on BMA or in other tissues
Poor NK cell function, high sIL-2R, may have low perforin expression
New markers are coming soon. . .
Can be rapidly progressive if not treated
Steroids, CSA, etoposide the mainstays of therapy
50% mortality
BMT indicated for suspected familial cases

104. Lymphoproliferative Disorders
X-linked Lymphoproliferative Disorder
Defect of the SAP protein
SH2D1A gene defects
Susceptible to EBV infections
Fulminant EBV infection +/- HLH
Progressive immune deficiency
EBV malignancies - lymphoma
BMT is indicated

105. Lymphoproliferative Disorders
Autoimmune Lymphoproliferative Syndrome (ALPS)
Defect of apoptosis
Defects found in Fas, FasL, caspases
Lymphocytes fail to apoptose as appropriate
Develop lymphadenopathy, HSM
Autoimmune cytopenias
Many patients with Evan’s syndrome may be variants of ALPS
Managed with immune suppressants

106. Defects of regulatory T cells
Immune Dysfunction, Polyendocrinopathy, Enterocolitis, X-linked (IPEX)
Defect of FOXP3 protein, required for CD4+CD25+ regulatory T cells
Develop multiple autoantibodies
Neonatal DM
Autoimmune thyroiditis
Autoimmune cytopenias
Enterocolitis
Managed with immune suppression
Some patients transplanted, tend not to do well

107. Chromosomal Breakage Syndromes
Ataxia-telangiectasia
Progressive cerebellar ataxia, fine telangiectasia, recurrent sinopulm infections
Raised AFP
Variable immune defect, progressive
Usually combined defect
Risk of autoantibodies
Increased susceptibility to malignancy
Lymporeticular and other, eg breast ca

108. Important points: LOOK AT YOUR CBCD
Think about PID in kids with autoimmunity, especially if at a young age
DON’T FORGET HIV
Think about chromosome 22q11.2 deletion syndrome, it has a wide variety of presentations
Look for infections, they often don’t present with typical symptoms

109. Useful resources for parents and providers:
Immune Deficiency Foundation
The Jeffrey Modell Foundation for Primary Immune Deficiency