Primary Immunodeficiency

Nicola Wright, MDPediatric Resident

Teaching

April 22, 2010

Overview

• Initial approach

• Phagocytic disorders

• Complement disorders

• Humoral disorders

• Cellular and Combined disorders

• Cases

Primary ImmunodeficienciesRare Disorders?

• Includes over 100 defined genetic disorders

• Incidence of 1/10 000 up to 1/500

“ “ Nothing is rare to the patient or the family Nothing is rare to the patient or the family of the patient that has it”of the patient that has it”

When should you be concerned?

• C hronic• R ecurrent• U sual pathogens• I nvasive• S evere• E valuate!

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

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

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

Classification: Based on Immune Mechanism

Innate Immunity

• Phagocytic system

• Complement

Adaptive Immunity

• Humoral Immunity

• Cellular Immunity

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!!!

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?A. CBCB. ImmunoglobulinsC. Lymphocyte numbersD. Oxidative Burst

Phagocytic Disorders

Innate ImmunityPhagocytic 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

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

Phagocyte Disorders:Abnormal Function

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

What diseases do you worry about with delayed separation of the umbilical cord?

How do you define delayed separation of the umbilical cord?

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

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

Phagocytic DisordersLab 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

Phagocytic DisordersManagement

• 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

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?

A. ImmunoglobulinsB. CH50C. C3, C4D. Oxidative burst

Complement Deficiencies

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

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: CH50Properdin level (in males)

• Most C’ components are acute phase reactants and are normally elevated during acute infection

Complement DeficiencyLab Evaluation

First line:• CH50*• properdin level in males

Second line:• AH50• Specific complement protein levels

*C’ proteins may be consumed with inflammation, eg SLE

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

Humoral Deficiencies

Adaptive ImmunityHumoral 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

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

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?

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

Abnormal B cell MaturationLow 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 heavy chain defects, surrogate light chain defects, BLNK mutations, etc

Abnormal B cell MaturationAgammaglobulinemia

• 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

Hyper IgM Syndromes

Defects in Ab production

and

Response to Ag

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

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

Other Humoral Immune DeficienciesCommon 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

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

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!!

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

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!

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

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

Management of Humoral Deficiencies

• Prophylactic IVIG is the mainstay of therapy (400-500 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

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

Cellular Immune Deficiencies

Cellular Immune Deficiencies

• Very few abnormalities ONLY affect the cellular system, most are combined

• Defects of the interferon- 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

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

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!!!

Combined Immune DeficiencyMultiple 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

Combined Immune Deficiency

T- B+ NK –• common chain defect• JAK3 deficiency

T- B+ NK+• IL-7R 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

Classified based on lymphocyte phenotype

Combined Immune DeficienciesX-linked SCID

• The most common type is X-linked SCID due to a defect of the common 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!!

SCIDAdenosine 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

Approach to Combined/Cellular DefectsLaboratory Investigations

CBC and Differential

Peripheral Smear

Labs

Hgb 92 Hct 0.28

Platelets 354 000 WBC 4.8

Neutrophils 2.5

Lymphocytes 0.6

monos 0.9

eos 0.7

3 mo girl with the following CBCD:

LabsThe 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 2.8-14.4; normal WBC 6-18)

LabsCellular 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

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

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

LabsOther 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

SCIDManagement

• High index of suspicion for infection!!!!• Treat early and aggressively• Prophylaxis: isolation precautions **

PJP prophylaxisIVIGfungal prophylaxis

• Supportive care is EXTREMELY important• Need aggressive nutritional support• BMT as early as possible

• NO LIVE VACCINATIONS• CMV negative, irradiated blood products only

LabsTesting 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

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

Case 1

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

PE:

• Normal vitals and growth• Eczema like rash on face, trunk, limbs,

hands, feet• Dystrophic nails• Shotty cervical and inguinal adenopathy• No HSM

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?

Other labs:

• IgG normal; subclasses normal• IgM normal• IgA normal• IgE elevated

• Diphtheria, tetanus titers protective• VZ titer positive

Lymphocytes:

CD3 (T cells) low 1.5CD4 (T helper) normal 1.2CD8 (T cytotoxic) low 0.177Elevated CD4:CD8 ratio

CD19/CD20 (B cells) low 0.42

CD16/56 (NK cells) low 0.177

Mitogens normalAntigen stimulation normal

The diagnostic test. . .

• Flow cytometry for the Wiskott Aldrich protein showed decreased expression

• Genetic sequencing of the WASP protein confirmed Wiskott Aldrich syndrome

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

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

Case 2

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

Labs

• Hgb 105 Hct 32.9• Plt 167• WBC 20.3• Neut 15.3• Lymphs 2.6

Immune labs

• IgG, IgM, IgA low

• CD3 0.6 low CD19 0.432 low• CD4 0.468 low CD 16/56 0.120 low• CD8 0.132 low• CD4:CD8 elevated

• Mitogens: PHA low, ConA, PWM normal• Antigen stimulation: tetanus, candida, PPD low

Summary

• Dysmorphic• Heart defect• Pneumonia +/- sepsis• Panlymphopenia with poor T cell function• Low immunoglobulins

• The diagnostic test is. . .

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%

Case 3

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

Labs

• Hgb 123• Plt 202• WBC 3.83• ANC 1.55• ALC 1.99

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

Immune labs

• CD3 normal CD19 slightly low• CD4 normal CD16/56 low• CD8 normal• CD4:CD8 normal

Diagnosed with CVIDAlso 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

Case 4

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

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

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

Labs

• WBC 1.9 – 25.7, ANC 0 – 12.9; • Hgb 69 – 131• Platelets 29 000 – 442 000• Elevated liver enzymes initially with CMV • Blood CMV PCR > 100 000 copies initially, dropped to

3750, back up to 31 500

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

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

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. . .

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

Combined Immune Deficiency

T- B+ NK –• common chain defect• JAK3 deficiency

T- B+ NK+• IL-7R 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

Classified based on lymphocyte phenotype

The diagnostic test:

• HLA-DR expression (MHC class II) absent• Normal HLA-A,B,C expression (MHC class I)• “Bare lymphocyte syndrome”

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

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

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: IVIGRapid, aggressive treatment of infections

Other immune deficiencies

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

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

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

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

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

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

Useful resources for parents and providers:

• Immune Deficiency Foundationwww.primaryimmune.org

• The Jeffrey Modell Foundation for Primary Immune Deficiency

www.jmfworld.com