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