PRIMARY IMMUNODEFICIENCY Yackov Berkun. Recurrent infections nCommon –respiratory 6 - 8/y...

PRIMARY PRIMARY IMMUNODEFICIENCIMMUNODEFICIENC

YY

Yackov Berkun

Recurrent infectionsRecurrent infections

Common Common – respiratory 6 - 8/y respiratory 6 - 8/y – otitis 6/yotitis 6/y– gastroenteritis 2/ygastroenteritis 2/y

Day care moreDay care more

Respiratory infectionsRespiratory infections

AllergyAllergy AsthmaAsthma

– AtelectasisAtelectasis– Viral Viral

infectioninfection AspirationAspiration

Cystic fibrosisCystic fibrosis GastroesophageGastroesophage

al Refluxal Reflux TracheoesophagTracheoesophag

eal fistulaeal fistula

Recurrent otitisRecurrent otitis

0 - 3 year0 - 3 year 66% - one 66% - one 33% - three and 33% - three and

moremore Eustachian tubeEustachian tube

Secondary Immune Secondary Immune DeficiencyDeficiency

Severe malnutritionSevere malnutrition Nephrotic syndromeNephrotic syndrome Protein loosing enteropathyProtein loosing enteropathy Intestinal lymphangiectasiaIntestinal lymphangiectasia IrradiationIrradiation Drugs, toxinsDrugs, toxins

Secondary Immune Secondary Immune DeficiencyDeficiency

ChromosomalChromosomal– 21 trisomy21 trisomy– 8 trisomy8 trisomy

ViralViral– HIVHIV– CMV, EBVCMV, EBV– RubellaRubella– ToxoplasmaToxoplasma

Secondary Immune Secondary Immune deficiencydeficiency

MalignancyMalignancy Foreign bodyForeign body

Central lineCentral line Ventriculoperitoneal shuntVentriculoperitoneal shunt Heart valveHeart valve

BarrierBarrier BurnBurn

Secondary Secondary HypogammaglobulinemHypogammaglobulinem

iaia

DrugDrug antimalarialantimalarial corticosteroidscorticosteroids goldgold penicillaminepenicillamine sulfasulfa CaptoprilCaptopril carbamazepin, phenytoincarbamazepin, phenytoin

Primary Immune Primary Immune deficiencydeficiency

RareRare InheritedInherited GeneticGenetic Importance of early diagnosisImportance of early diagnosis None in current screeningNone in current screening

Primary immune Primary immune Deficiency IncidenceDeficiency Incidence

1:10,0001:10,000 IgA 1:400IgA 1:400 M/ F = 5M/ F = 5 100 syndromes100 syndromes

RBC plt

myeloid

PMN mφ

lymphoid

NK

thymus

CD8+

CD4+

CTL

TH2

TH1

Innate /acquired immunityInnate /acquired immunity

Pre-B

Components of the Immune System

Components of the Immune System

Humoral Cellular Humoral Cellular

SpecificNonspecific/innate

complement, interferon TNF etc.

macrophages, PMN, NK cell,

eosinophils

T cells; other effectors cells

antibodies

Innate Immunity Adaptive Immunity

CharacteristicsCharacteristics of Innate and of Innate and Adaptive ImmunityAdaptive Immunity

CharacteristicsCharacteristics of Innate and of Innate and Adaptive ImmunityAdaptive Immunity

No No ImmunologicImmunologic

memory memory

Antigen independent

No time lag

Not antigen specific

Antigen dependent

A lag period

Antigen specific

Development

of memory

Physical Barriers to ResistancePhysical Barriers to ResistancePhysical Barriers to ResistancePhysical Barriers to Resistance

NELSON 1 or more systemic bacterial

infections (sepsis, meningitis) 2 or more serious respiratory or

documented bacterial infections (cellulitis, abscesses, draining otitis media, pneumonia, lymphadenitis) within 1 yr

NELSON serious infections occurring at

unusual sites (liver, brain abscess) infections with unusual pathogens

(Pneumocystis jiroveci, Aspergillus, Serratia marcescens, Nocardia, Burkholderia cepacia)

infections with common childhood pathogens but of unusual severity

Additional clues

failure to thrive with or without chronic diarrhea

persistent infections after receiving live vaccines

chronic oral or cutaneous moniliasis

When? How? When? How? Cont.Cont.

Unusual site Unusual site – Osteomyelitis, Osteomyelitis,

liver, brain liver, brain abscessabscess

When? How? When? How? Cont.Cont.

Unusual pathogen Unusual pathogen – PCP,PCP, Aspergillus, Serratia marcescens, Aspergillus, Serratia marcescens,

Nocardia,Nocardia, Burkholderia cepaciaBurkholderia cepacia Chronic infections Chronic infections Common pathogen - unusual Common pathogen - unusual

severityseverity

When? How? When? How? Cont.Cont.

Structural Structural damage damage (bronchiectasis)(bronchiectasis)

IncidenceIncidence Antibody deficiency 50%Antibody deficiency 50%

Combined 20%Combined 20%Phagocytic 18%Phagocytic 18%

T cell 10%T cell 10%

Complement 2%Complement 2%

Severe Combined IDSevere Combined ID

Diverse genetic mutationsDiverse genetic mutations Absence of all adaptive immune Absence of all adaptive immune

functionfunction Some - lack of natural killer (NK) Some - lack of natural killer (NK)

cellscells Most severe immunodeficiencyMost severe immunodeficiency

Severe Combined IDSevere Combined ID Early ( 4 - 5 mnt)Early ( 4 - 5 mnt) Diarrhea, pneumonia, Diarrhea, pneumonia,

otitis media, sepsis, otitis media, sepsis, cutaneous infectionscutaneous infections

Persistent Persistent Every pathogenEvery pathogen Opportunistic Opportunistic

– PCPPCP– BCG fatalBCG fatal– live vaccine live vaccine

SCID clinicalSCID clinical

Persistent CandidaPersistent Candida SeborrheaSeborrhea GVHDGVHD

– Maternal immunocompetent T cells crossing placenta

– T lymphocytes in nonirradiated blood products or allogeneic bone marrow

SCID clinicalSCID clinical

FTTFTT Chronic diarrheaChronic diarrhea

SCID featuresSCID features

No lymphoid tissue No lymphoid tissue – nodes, thymusnodes, thymus

HypogammaglobulinemiaHypogammaglobulinemia Impaired T cell functionImpaired T cell function Lymphocyte count <2800Lymphocyte count <2800 CD3<20%CD3<20%

SCIDSCID

MalignancyMalignancy Fatal < 2yFatal < 2y

SCID, X-linkedSCID, X-linked

Common Common γ-chain of IL-2 Receptor IL-4, -7, -9,-11,-15, -21

SCID, recessive SCID, recessive 11

ADA 15% ADA 15% – apoptosis, apoptosis, – <500 lymphocytes<500 lymphocytes– chondro-osseous chondro-osseous

dysplasiadysplasia Jak 3 deficiency 6% Jak 3 deficiency 6%

– B+,NK-B+,NK-– signalsignal

IL-7 receptor 10%IL-7 receptor 10%– B+,NK+B+,NK+

SCID, recessive SCID, recessive 22

ArtemisArtemis– V(D)J V(D)J

recombination/DNA recombination/DNA repair factor repair factor

RAG recombinase RAG recombinase activating genes activating genes – B-, NK+B-, NK+

CD45 Deficiency CD45 Deficiency – protein tyrosine protein tyrosine

phosphatase phosphatase – T- and B-cell antigen T- and B-cell antigen

receptor signal receptor signal transduction transduction

SCID management SCID management BMT is standard of care

– 3 mnt – 95%– HLA-identical or T-cell–depleted haploidentical

related bone marrow stem cells – without pretransplant chemoablation or post-

transplant GVHD prophylaxis Isolation PCP prophylaxis IVIG Suspected infections aggressive treatment

SCID management SCID management

Research Research Gene therapyGene therapy

– X-SCIDX-SCID PEG-ADA PEG-ADA

– ADA deficiency ADA deficiency

Screening for SCID (T-cell lymphopenia) has become incorporated as part of the newborn screening programs in a few states

Combined Combined Immunodeficiency (CID)Immunodeficiency (CID)

Low but not absent T-cell functionLow but not absent T-cell function Recurrent or chronic pulmonary infections, Recurrent or chronic pulmonary infections,

failure to thrive, oral or cutaneous failure to thrive, oral or cutaneous candidiasis, chronic diarrhea, recurrent candidiasis, chronic diarrhea, recurrent skin infections, gram-negative sepsis, skin infections, gram-negative sepsis, urinary tract infections, and severe urinary tract infections, and severe varicella in infancy varicella in infancy

Survive longer than SCIDSurvive longer than SCID Fail to thrive and die early in lifeFail to thrive and die early in life Neutropenia and eosinophilia are common Neutropenia and eosinophilia are common

CIDCID

Purine nucleoside phosphorylase Purine nucleoside phosphorylase deficiencydeficiency– serum and urinary uric acid lowserum and urinary uric acid low– neurologic abnormalitiesneurologic abnormalities– autoimmune diseasesautoimmune diseases

Interleukin 2 Receptor Interleukin 2 Receptor chain chain mutationmutation

Cartilage hair hypoplasia Cartilage hair hypoplasia – short-limbed dwarfism short-limbed dwarfism

CID, CID, bare lymphocyte syndrome

MHC class I (HLA-MHC class I (HLA-A, -B, and -C) A, -B, and -C) antigensantigens– CD8 -, CD4 + T

cells– chromosome 6 –

encode peptide transporter proteins TAP1 and TAP2

CID, MHC class II CID, MHC class II deficiencydeficiency

HLA-DR, -DQ, -DP 4 genes expression of MHC class II

molecules on the surface of B cells and macrophages

Low CD 4, high CD 8 hypogammaglobulinemic

Humoral BHumoral B Later (>7mnt)Later (>7mnt) Sinopulmonary infectionsSinopulmonary infections SepticemiaSepticemia Encapsulated bacteriaEncapsulated bacteria No fungal or viral – usuallyNo fungal or viral – usually No growth failure - usuallyNo growth failure - usually Replacement IVIG therapy- almost Replacement IVIG therapy- almost

normal life normal life

XLAXLA

Bruton, 1952Bruton, 1952 8 year boy8 year boy Recurrent infectionsRecurrent infections Protein electrophoresis: no Protein electrophoresis: no

globulinglobulin Replacement therapyReplacement therapy

ImmunoglobulinsImmunoglobulins

Glycoprotein molecules produced by Glycoprotein molecules produced by plasma cells in response to an plasma cells in response to an immunogen and function as antibodiesimmunogen and function as antibodies

Immune serum

Ag adsorbed serum

+ -

albumin

globulins

Mobility

Am

oun

t of

pro

tein

Molecular basisMolecular basis

1993: gene on Xq23.31993: gene on Xq23.3 Protein: 659 Protein: 659 aminoacids aminoacids

cytoplasmic Tyrosine Kinase, Brutoncytoplasmic Tyrosine Kinase, Bruton Signal transduction moleculeSignal transduction molecule Expressed in B until plasma cells, Expressed in B until plasma cells,

mono, myeloid, platelets, not T cellsmono, myeloid, platelets, not T cells

B-cell DifferentiationB-cell DifferentiationBone marrow Peripheral lymphoid tissue

Antigen-independent Antigen-dependent

Stem cell Pro-B Pre-B Immature Mature

B cells

+ IgM IgM + IgA IgA

IgEIgM + IgE

IgM + IgD IgG

IgM IgM

Germinalcenter cells

Plasmacells

Sell S, Max EE. Immunology, Immunopathology, and Immunity; 2001.

Molecular basis, cont. Molecular basis, cont.

>500 mutation>500 mutation New mutations are commonNew mutations are common Pro+, pre- BPro+, pre- B No genotype- phenotype No genotype- phenotype

correlationcorrelation In same family different severityIn same family different severity 1:200.0001:200.000

XLAXLA

Presentation after 6 monthPresentation after 6 month Milder phenotypes laterMilder phenotypes later 1.5 year- 90% symptomatic1.5 year- 90% symptomatic Encapsulated pyogenic bacteriaEncapsulated pyogenic bacteria

– Hemophylus influenza type b Hemophylus influenza type b – Streptococcus pneumoniaeStreptococcus pneumoniae

MycoplasmaMycoplasma

XLAXLA

Lungs, ears (sinuses not Lungs, ears (sinuses not developed)developed)

Chronic diarrhea, FTTChronic diarrhea, FTT NeutropeniaNeutropenia

XLAXLA

MeningitisMeningitis MeningoencephaliMeningoencephali

is (echo, is (echo, coxackie)coxackie)

XLAXLA

Skin infectionsSkin infections MyositisMyositis ArthritisArthritis

– Septic staph, Septic staph, mycoplasma, mycoplasma, ureaplasmaureaplasma

XLA, late clinical XLA, late clinical

BronchiectasisBronchiectasis SinusitisSinusitis

DiagnosisDiagnosis

MaleMale History, familyHistory, family Absent Ig (all)Absent Ig (all) Hypoplastic lymph nodes without Hypoplastic lymph nodes without

germinal centersgerminal centers No tonsils and adenoidsNo tonsils and adenoids

DiagnosisDiagnosis

B cell low-absentB cell low-absent Normal T, NKNormal T, NK Normal pro B cell (CD 34+19+)Normal pro B cell (CD 34+19+) No pre B cell (CD 34-19+)No pre B cell (CD 34-19+)

TreatmentTreatment

EarlyEarly IVIG 0.4 - 0.6 gr/kg/3-4 weekIVIG 0.4 - 0.6 gr/kg/3-4 week Aim- normal levels > 600 mg/dlAim- normal levels > 600 mg/dl Prompt, early, effective antibioticsPrompt, early, effective antibiotics No live vaccine (esp polio)No live vaccine (esp polio)

B cellB cell

B cell disordersB cell disorders

X Linked Agammaglobulinemia X Linked Agammaglobulinemia (Bruton’s)(Bruton’s)

Common Variable ImmunodeficiencyCommon Variable Immunodeficiency IgA deficiencyIgA deficiency IgG subclassesIgG subclasses Transient Hypogammaglobulinemia Transient Hypogammaglobulinemia

of infancyof infancy

B cell disorders, rareB cell disorders, rare

X Linked HyperIgMX Linked HyperIgM Mu chain deficiencyMu chain deficiency chainchain Ig Ig

– CD 79, BCR receptor signalCD 79, BCR receptor signal

Common Variable IDCommon Variable ID

A group of undifferentiated A group of undifferentiated disorders with defective antibody disorders with defective antibody formationformation

Incidence 1:25,000Incidence 1:25,000 Normal number of defective B Normal number of defective B

cellscells Low serum IgG and IgALow serum IgG and IgA

Common Variable IDCommon Variable ID

Females=males Females=males Later onsetLater onset Autoimmune disorders Autoimmune disorders Lymphoreticular and Lymphoreticular and

gastrointestinal malignanciesgastrointestinal malignancies

Hyper-IgM syndromeHyper-IgM syndrome

Recurrent infectionsRecurrent infections Low IgA, IgG, IgE, normal-elevated Low IgA, IgG, IgE, normal-elevated

IgMIgM 1960- dysgammaglobulinemia1960- dysgammaglobulinemia 1980- intrinsic B defect in Ig 1980- intrinsic B defect in Ig

isotype switchisotype switch 1993- CD40 ligand 1993- CD40 ligand

HIGM, clinicalHIGM, clinical

Upper and lower respiratory tract Upper and lower respiratory tract pyogenic infectionspyogenic infections

Second yearSecond year Pneumocystis carini pneumoniaPneumocystis carini pneumonia Protracted diarrhea Protracted diarrhea

– Cyptosporidum parrumCyptosporidum parrum

HIGM, clinical, HIGM, clinical, cont.cont.

Sclerosing cholangitisSclerosing cholangitis Liver disease Liver disease

– later tumorslater tumors Chronic neutropenia in 50%Chronic neutropenia in 50% Thrombocytopenia- someThrombocytopenia- some

HIGM, clinical, HIGM, clinical, cont.cont.

Lymphoid hyperplasiaLymphoid hyperplasia– hepatosplenomegalyhepatosplenomegaly– lymphadenopathylymphadenopathy– enlarged tonsilsenlarged tonsils

HIGM, laboratory HIGM, laboratory

Normal circulating B cellsNormal circulating B cells IgM levels increase with ageIgM levels increase with age Normal specific IgMNormal specific IgM No specific IgGNo specific IgG T cells number and subsets normalT cells number and subsets normal Proliferation:Proliferation:

– normal to mitogensnormal to mitogens– reduced to antigens reduced to antigens

HIGM, prognosisHIGM, prognosis

IVIGIVIG Worse prognosisWorse prognosis <30% alive at 25 year<30% alive at 25 year

– PCP earlyPCP early– liver disease and malignancy laterliver disease and malignancy later

Transplantation bone marrow Transplantation bone marrow – liverliver

HIGM, molecularHIGM, molecular

T cell signal for B activationT cell signal for B activation

PhagocytesPhagocytes

GingivitisGingivitis Skin (furunculosis)Skin (furunculosis)

PhagocytesPhagocytes

Visceral Visceral abscessesabscesses

LymphadenitisLymphadenitis Low virulenceLow virulence

– S. AureusS. Aureus– gram –gram –– AspergillusAspergillus

PhagocytesPhagocytes

Killing defectKilling defect– Persistent Persistent

abscessabscess– GranulomaGranuloma

PhagocytesPhagocytes

Adhesion, chemotaxisAdhesion, chemotaxis– HealingHealing– Cold abscess – no pusCold abscess – no pus– Delayed umbilicusDelayed umbilicus

Chronic granulomatous Chronic granulomatous disease (CGD)disease (CGD)

Primary immunodeficiency phagocytic Primary immunodeficiency phagocytic cellscells

PMN, eosinophils, monocytes, PMN, eosinophils, monocytes, macrophagesmacrophages

mutation in one of 4 subunits of the mutation in one of 4 subunits of the NADPH oxidase complexNADPH oxidase complex

Defective superoxide generation Defective superoxide generation Catalase + bacteria and fungi Catalase + bacteria and fungi

Chronic granulomatous Chronic granulomatous disease (CGD)disease (CGD)

Recurrent life-threatening bacterial Recurrent life-threatening bacterial and fungal and fungal infections

Exuberant inflammatory responses-Exuberant inflammatory responses-granuloma formationgranuloma formation

AutoimmuneAutoimmune Poor wound healing and dehiscence Poor wound healing and dehiscence 1 in 200,000 persons1 in 200,000 persons

CGDCGD 400 Mutations400 Mutations

– membrane-bound membrane-bound – gp91 gp91 phox phox

((phphagocyte agocyte oxoxidase) idase) and p22 and p22 phoxphox

– cytoplasmic p47 cytoplasmic p47 phox phox and p67 and p67 phoxphox

CGD clinical featuresCGD clinical features < 5 y (75%)< 5 y (75%) soft tissues infections

– cellulitis and subcutaneous abscess

Recurrent pneumonia, Recurrent pneumonia, lung abscess, sinusitis, lung abscess, sinusitis, otitisotitis

CGD clinical featuresCGD clinical features SSuppurative lymphadenitis Abscesses Abscesses

– skin, lymph node, liver, CNS, perianalskin, lymph node, liver, CNS, perianal

CGD clinical featuresCGD clinical features

Severe, resistant facial Severe, resistant facial acneacne

painful inflammation of painful inflammation of the naresthe nares

severe gingivitissevere gingivitis aphthous ulcersaphthous ulcers

CGD clinical featuresCGD clinical features

Catalase-producing pathogens Catalase-producing pathogens degrade ambient hydrogen degrade ambient hydrogen

peroxideperoxide– Staph Aureus Staph Aureus – BurkholderiaBurkholderia– gram-negative enteric bacilli Serratia

marcescens, Klebsiella, Proteus, Salmonella, Aerobacter

– AspergillusAspergillus

CGD Inflammatory CGD Inflammatory ComplicationsComplications

GranulomaGranuloma– gastrointestinal and genitourinary gastrointestinal and genitourinary

obstruction obstruction Autoimmune diseases Autoimmune diseases

– SLE, discoid lupus, pneumonitis, IBDSLE, discoid lupus, pneumonitis, IBD– systemic steroid therapy, systemic steroid therapy,

Cyclosporine, sulfasalazine Cyclosporine, sulfasalazine

CGD, clinical CGD, clinical manifestationsmanifestations

Lymphadenopathy (75.6%)Lymphadenopathy (75.6%) Pulmonary infections (65.9%)Pulmonary infections (65.9%) Skin involvement (63.4%)Skin involvement (63.4%) Gastrointestinal (56.1%)Gastrointestinal (56.1%) Skeletal (29.3%)Skeletal (29.3%) Central nervous system (2.4%)Central nervous system (2.4%)

CGD X-linkedCGD X-linked

onset is earlier onset is earlier – 81% vs 19%<10y81% vs 19%<10y

obstructive granulomas and obstructive granulomas and infections are more frequentinfections are more frequent

mortality rate is highermortality rate is higher

DiagnosisDiagnosis

Dyes - reactive oxygen productionDyes - reactive oxygen production Nitroblue tetrazolium, rhodamine, Nitroblue tetrazolium, rhodamine,

dichlorofluoresceindichlorofluorescein Chemiluscency (single oxigen- light Chemiluscency (single oxigen- light

emissionemission))

ManagementManagement

Fever and leukocytosis rare even Fever and leukocytosis rare even in severe infections- only ESRin severe infections- only ESR

Discovery on CXR or brain CTDiscovery on CXR or brain CT Aggressive management with Aggressive management with

surgical debridement of infectionsurgical debridement of infection

ManagementManagement

Prophylactic Prophylactic – co-trimoxazoleco-trimoxazole– itraconazole some benefit itraconazole some benefit interferon interferon

BMTBMT

Immunocompetence Evaluation

thorough history, physical examination, and family history

Most immunologic defects can be excluded at minimal cost with the proper choice of screening tests, which should be broadly informative, reliable, and cost-effective

Evaluation, historyEvaluation, history

Age Age – 4-5 month SCID4-5 month SCID– 7-9 month B cell7-9 month B cell

Recurrent pneumonia- asthma?Recurrent pneumonia- asthma? WhereWhere

– Foreign bodyForeign body– AspirationAspiration

Growth?Growth? Diarrhea?Diarrhea?

Evaluation, historyEvaluation, history

Thrush?Thrush? MedicationsMedications Blood transfusionBlood transfusion PastPast

– neonatal hypocalcemianeonatal hypocalcemia– TEFTEF

Immunisation - live Immunisation - live

Evaluation, historyEvaluation, history

FamilyFamily– consanquinityconsanquinity– deathdeath– infectioninfection– addictaddict

Evaluation, Evaluation, examinationexamination

IllIll GrowthGrowth Mucosal- thrushMucosal- thrush HairHair

Evaluation, Evaluation, examinationexamination

Skin– rash– eczema

Evaluation, Evaluation, examinationexamination

Skin– telangiectasia

Evaluation, Evaluation, examinationexamination

Lymph nodes Lymph nodes – Peripheral, Peripheral,

tonsilstonsils– Hepatomegaly Hepatomegaly

(CVID, Omenn)(CVID, Omenn)

Evaluation, siteEvaluation, site

SkinSkin LymphadenitisLymphadenitis GingivitisGingivitis AbscessAbscess

– phagocytephagocyte

Evaluation, siteEvaluation, site

OtitisOtitis SinusSinus PulmonaryPulmonary MeningitisMeningitis

– B cellB cell

PathogenPathogen

VirusVirus– T cellT cell– Enterovirus- B Enterovirus- B

cellcell FungiFungi

– T cellT cell– Aspergillus- Aspergillus-

phagocytephagocyte

PathogenPathogen ParasiteParasite

– T cellT cell– Giardia- B cellGiardia- B cell

BacteriaBacteria– encapsulated- B cell, complementencapsulated- B cell, complement– mycobacterial- T cellmycobacterial- T cell– Pneumocystis Carini – T cellPneumocystis Carini – T cell– low virulence- phagocytelow virulence- phagocyte

Workup 1: CBCWorkup 1: CBC

Normal lymphocyte counts are higher in Normal lymphocyte counts are higher in infancy and early childhood than later in infancy and early childhood than later in lifelife

LymphopeniaLymphopenia– <1000, infant<1,5 - 2000<1000, infant<1,5 - 2000

T cell, combinedT cell, combined LeucocytosisLeucocytosis

LAD, HyperIgELAD, HyperIgE

OmmenOmmen

Workup 1: CBCWorkup 1: CBC

NeutropeniaNeutropenia Congenital, acquiredCongenital, acquired

Lysosomal inclusionLysosomal inclusion– Chediac Higashi Chediac Higashi

SyndromeSyndrome

Workup 1: CBCWorkup 1: CBC

RBC Howell-Jolly RBC Howell-Jolly bodiesbodies– Congenital Congenital

aspleniaasplenia

Small plateletsSmall platelets– Wiskott-Aldrich Wiskott-Aldrich

syndromesyndrome

ESR is normal, chronic bacterial or fungal infection is unlikely

Workup 2: IgWorkup 2: Ig

Normal- no humoralNormal- no humoral IgG - 6 yearIgG - 6 year IgA - adolescentIgA - adolescent IgM IgM - - HyperIgMHyperIgM IgE IgE - -

– HyperIgE JobHyperIgE Job IgE IgE - T cell - T cell

– DiGeorge, Ommen, WASDiGeorge, Ommen, WAS

Workup 3: T cellWorkup 3: T cell

CXR ( Thymus, lung)CXR ( Thymus, lung) Delayed hypersensitivityDelayed hypersensitivity

– Candida- Candida- most cost-effective test of T-cell function most cost-effective test of T-cell function

– TrychophytonTrychophyton– MumpsMumps– PPDPPD

Workup 4: specialWorkup 4: special

CD 19, 20 (- XLA, + CVID)CD 19, 20 (- XLA, + CVID) CD 2,3,4,8,CD40L,TCRCD 2,3,4,8,CD40L,TCR Proliferation to mytogen:Proliferation to mytogen:

– T: PHA, con A, Candida, TetanusT: PHA, con A, Candida, Tetanus– B T dep: fungi, RWMB T dep: fungi, RWM– B T indep: LPS, Staph, EBVB T indep: LPS, Staph, EBV

Workup 4: special, Workup 4: special, contcont

SubclassesSubclasses IsohemagglutininIsohemagglutinin

– antibodies to type A and B red blood antibodies to type A and B red blood cell polysaccharide antigens cell polysaccharide antigens

– IgM antibodiesIgM antibodies– may be normally absent < 2 yr may be normally absent < 2 yr – always absent if blood type AB always absent if blood type AB

Workup 4: special, Workup 4: special, contcont

Special response Special response – diphtheria, tetanus, diphtheria, tetanus, H. influenzaeH. influenzae

polyribose phosphate, polyribose phosphate, pneumococcal antigens pneumococcal antigens

Pre and 2-3 wk post vaccinePre and 2-3 wk post vaccine– DT- protein (T dependent)DT- protein (T dependent)– Pneumococcal- polysaccharide (T Pneumococcal- polysaccharide (T

independ.) independ.)

Workup 5: phagocyteWorkup 5: phagocyte

CD11,18CD11,18 CD15 (LAD2)CD15 (LAD2) Chemotaxis (LAD, CHS, HyperIgE)Chemotaxis (LAD, CHS, HyperIgE) Nitrobluetetrazoline (NADPH)Nitrobluetetrazoline (NADPH)

Workup 5: phagocyteWorkup 5: phagocyte, , contcont

Intracellular Intracellular killingkilling

Chemiluscency Chemiluscency (single oxigen- (single oxigen- light emission)light emission)

Peroxidase Peroxidase stainingstaining

Workup 6: ComplementWorkup 6: Complement

CH50CH50 Sheep Sheep

RBC+anti RBC+anti sheep RBC sheep RBC antibodyantibody

Recurrent infectionsRecurrent infections

Most recurrent infections - no Most recurrent infections - no identifiable immunodeficiency identifiable immunodeficiency disorderdisorder

Major reason - excessive exposure Major reason - excessive exposure of infants to infectious agentsof infants to infectious agents

Excessive use of antibiotics Excessive use of antibiotics masked classic presentationmasked classic presentation