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Approach to ChildrenApproach to Children with Suspected Primary
fImmunodeficiency
Akaluck (Ben) Thatayatikom, MDDivision of Allergy/Immunology/RheumatologyDivision of Allergy/Immunology/Rheumatology
Department of Pediatrics, University of Kentucky04/23/2009
Primary Immunodeficiencies (PID)y ( )
Articles published
Orange JS. Immunol Allergy Clin N Am 2008
Primary Immunodeficienciesy
2.5% Complement
8 4% Combined T and B cell
2.7% Genetic disorders of immune regulation
pdeficiencies
0.4% Autoinflammatory disorders
8.4% Combined T and B cell immunodeficiencies 0.4% Defects in innate immunity:
receptors &B signaling components11.2% Phagocytic defectsdefects
56% Antibody deficiencies18.3% Other well-defined immunodeficienies
Rezaei N et al. Primary Immunodeficiency Diseases 2008
Primary Immunodeficiencies (PID)y ( )
Symptomatic recognition Diagnosis
Clinical interventions
Natural history of disease
Clinical interventions
SymptomaticAsymptomatic
Bi h E l l D h
Disability
Birth Earlyclinicaldisease
Late sequelae Death
Modifed from MMWR 2004
Objectives
f
j
• Physiology of immunity• Clinical features of primary immunodeficiency (PID)
– Age onsetg– Systemic or organ manifestation– Specific organisms– Family historyFamily history
• Whom to test• How to test PID before referral• Transient Hypogammaglobulinemia in Infancy (THI)
Immune Systemy
Doan et al. Immunology
Innate Immunityy
Rich. Clinical Immunology 2007
Adaptive Immunityp y
Doan et al. Immunology
Adaptive Immunityp y
Stiehm et al. Immunology disorders in Infants & Children 2004
Features of Immune System Failurey
Self VS Non-self RecognitionSelf VS Non self RecognitionInfection
AllergyAutoimmunity
MalignancyAutoinflammatory disorders
Gennery AR, Cant AJ. Adv Exp Med Biol. 2009
Non-Immunologic Causesg
Recurrent infectionsRecurrent infections• Abnormal mucous membranes and integuments:
– Burns, severe eczema, bullous diseases, ectodermal d l i t th tdysplasia, percutaneous catheters.
• Obstruction of hollow viscus: – Allergic rhinitis, adenoid hypertropy with Eustachian tube
dysfunction, asthma, cystic fibrosis, inhaled foreign body, posterior urethral valves, ureteropelvic junction obstruction.
• Foreign body: – Ventriculoperitoneal shunt, prosthetic cardiac valves,
orthopedic devices, catheters.• Vascular abnormalities:
– Large left to right intracardiac shunt, diabetes mellitus.
Non-Immunologic Causes
Recurrent infections
g
Recurrent infections• Congenital:
– Cysts and sinus tracts, tracheoesophageal fistula, abnormal ciliary functionabnormal ciliary function.
• Neurologic: – Incoordinate swallowing, recurrent aspiration, poor
i t ff trespiratory effort.• Metabolic disorders:
– Galactosemia, certain amino acid and organic acid disorders.
• Unusual microbiologic factors: – Antibiotic overgrowth, resistant organism, continuous g g
reinfection.
Secondary Immunodeficiencyy y
• Premature and Newborn• Premature and Newborn• Hereditary & Metabolic Diseases:
– Chromosal abnomalities (Down syndrome, etc)– Uremia, DM, NS, myotonic dystrophy– Malnutrition,vitamine & mineral deficiency– Protein-losing enteropathies,
• Immunosuppressive agents & Radiation• Infectious diseases:
– Congenital rubella viral examthem (measles varicella etc)– Congenital rubella, viral examthem (measles, varicella, etc)– HIV, CMV, EBV– Bacterial infections, mycobacterial, fungal, parasite.
Secondary Immunodeficiency
• Infiltrative & Hematologic diseases
y y
• Infiltrative & Hematologic diseases– Histiocytosis, lymphoma, leukemia, myeloma– Agranulocytosis, aplastic anemia, cyclic neutropenia
T l t i i– Transplant recipiens• Surgery & Trauma
– Burns, head injury, hypothemia– Splenectomy, anesthesia
• Miscellaneous – SLE, alcoholic hepatitis, chronic active hepatitis, etc., p , p ,– Aging
Clinical Features of PID
Age at presentation PIDAge at presentation PID
Neonatal period •Omenn syndrome•Severe congenital neutropenia•DiGeorge syndrome•LAD•Reticular dysgenesisy g
First 6 months •SCID•Other T cell deficiency•CD40 ligand deficiency•CD40 ligand deficiency
Omenn’s Syndromey
Generalized scaly exudative erythroderma, enlarged lymphoid tissuesGeneralized scaly exudative erythroderma, enlarged lymphoid tissuesProtracted diarrhea, FTT, eosinophilia, hypogammaglobulinemiaGenetic defects: RAG1, ARG2, Artemis, ADA deficiency, IL7Ra
Abundant lymphocytic infiltrate in superficial dermis with keratinocytes damage and eosinophil infiltrate
Netherton Syndromey
Mutations of SPINK5 gene encoding LEKTI (Lymphoepithelial Kazal-type related inhibitor), a serine protease
Pathognormonic:gTrichorrhexis invaginata
(Ball-in-socket hair shaft deformity)
Leukocyte Adhesion Defect (LAD)y ( )
Delves PJ. N Engl J Med 2000
Leukocyte Adhesion Defect (LAD)y ( )
Hallmarks: Gingivitis, severe periodontitis, failure to form pus, limited inability to demarcate the fibrotic skin debris, and limited inflammation.
Clinical Immunology, Principles and Practice 3rd, 2007
When an umbilical cord separatesp
Cord care regimen and days to umbilical cord separation
JoDee M, et al. NeoReviews 2004
SCID
Fischer A, Immunological Reviews 2005
SCID
Wang HC, et al. Allergy Asthma Proc 2006
Clinical Features of PID
Age at presentation PIDg p
After 6 months- 5 years •Hypogammaglobulinemia•Wiskott-Aldrich syndrome•Phagocytic defects•DiGeorge syndrome•Chronic mucocutaneous candidiasis
After 5 years •Late presentation of the above•AT, other DNA repair disorder•CVID•CVID•Specific antibody deficiency•Complement disorder
Wiskott-Aldrich syndrome (WAS)y ( )
Puck JM. N Engl J Med 2006
Chronic Granulomatous Disease (CGD)( )
Painful inflammation of the nares
Severe gingivitis
Aspergillus pneumonia
Large granuloma Esophageal stricture Wound dehiscence & impaired would healing Large granuloma
in the neckp g
caused by granulomaimpaired would healing at the surgical incision sites
Lekstrom-Himes. N Engl J Med 2000
Chronic Granulomatous Disease (CGD)( )
Dihydrorhodamine-123 (DHR) assay
Normal
XL-CGD carrier
Normal
XL-CGDNitroblue tetrazolium (NBT) testRich Clinical Immunology, 2007Lekstrom-Himes. N Engl J Med 2000
Clinical Features of PID
Organism Candidate immune defectgPneumococcus, HIB • B cell/ Antibody
• ComplementSt h l N t hilStaphylococcus • Neutrophil
Meningococcus • Complement (Late C5-C9)
Gram negative bacteria • Neutrophil
Salmonella • Cell–mediated1 f• Type 1 cytokine defects
Giardia lamblia • B cell/antibody• Cell mediated
Crytosporidium • Cell mediated
Adapted from Slatter MA. Clin Exp Immunol 2008
Clinical Features of PID
Organism Candidate immune defectgMycoplasma • B cell/ Antibody
Candida albicans • Cell mediated• Neutrophil• Monocyte
Aspergillus spp • NeutrophilAspergillus spp • Neutrophil
Herpes viruses (eg CMV) • Cell-mediated
Enteroviruses • Antibody• Cell–mediated
Other viruses (eg measles) • Cell mediated( g )
Adapted from Slatter MA. Clin Exp Immunol 2008
Clinical Features of PID
Organism Candidate immune defectgBCG • Cell-mediated
• Type 1 cytokine defectsIFN R1IFN-gR1IFN-gR2STAT1, IL-12RB1IL-12B
Mycobacteria (typical & atypical) • Type 1 cytokine defectsMycobacteria (typical & atypical) Type 1 cytokine defects• NFkBsignalling pathway defects (NEMO)
Adapted from Slatter MA. Clin Exp Immunol 2008
Clinical Features of PID
Features Primary Immunodeficiency
Respiratory tract infectionsPersistent sinopulmonary
• SCID• Hypogammaglobulinemia
S ifi tib d d finfections • Specific antibody def• Complement deficiency• Cyclic neutropenia• NEMO• IRAK4 deficiency
Recurrent skin infection • CGDRecurrent skin infection, periodontitis, gingivostomatitis
CGD• HIE• LAD
XLA• XLA• Neutropenia
Clinical Features of PID
Features Primary Immunodeficiency
Eczema • HIE• WAS
O ’ d• Omenn’s syndrome• Netherton syndrome• CGD• IPEX• Hypogammaglobulinemia(CVID, HIM, IGAD, XLA)(CVID, HIM, IGAD, XLA)
Recurrent mucosal candidiasis
• SCID• Chronic mucocutaneous
didi icandidiasis• HIE
Clinical Features of PID
Features Primary Immunodeficiency
Respiratory tract infectionsPersistent sinopulmonary
• SCID• Hypogammaglobulinemia
S ifi tib d d finfections • Specific antibody def• Complement deficiency• Cyclic neutropenia• NEMO• IRAK4 deficiency
Recurrent skin infection • CGDRecurrent skin infection, periodontitis, gingivostomatitis
CGD• HIE• LAD
XLA• XLA• Neutropenia
Clinical Features of PID
Features Primary Immunodeficiency
Neutropenia • XLA• CVID
HIM• HIM• IGAD• WHIM• Cartilage-hair hypoplasia• Reticular dysgenesis• Dubowitz syndromeDubowitz syndrome• Griscelli syndrome
Thrombocytopenia • WASDiG d• DiGeorge syndrome
• CVID• CGD
Clinical Features of PID
Features Primary Immunodeficiency
Telangiectasia • Ataxia telangiectasia
Absence or scanty • XLAbse ce o sca tylymphoid tissues • SCID
• Complete DiGeorge anomaly
Delayed cord separation • LADDelayed cord separation • LAD
Lymphoma • AT• WASWAS• XLP• CVID
Hepatoma • HIM (CD40 ligand def)
Warning Signsg g
2 or more of the warning
sings
History of respiratory infections in the first 12 yr among children from a birth cohortamong children from a birth cohort
1314 German children born in 1990 tracked until age 12 yr (760 children)
Age Normal number of respiratory t t i f ti i d
1314 German children born in 1990 tracked until age 12 yr (760 children)
tract infection episodes per yearInfant
(0 2 Yr)11
(0-2 Yr)Pre-school age
(3-5 Yr)8
(3 5 Yr)School age
(6-12 Yr)4
( )
Gruber C, et al. Pediatr Allergy Immunol 2008
Warning Signsg g
2 or more of the warning
sings
Underlying causes of recurrent pneumonia in childrenpneumonia in children
238 children (2.5 mo-15.6yr) 220 (92%) i h d l i 18 (8%) i h k
Underlying illness
Mean age
Dx prior to pneumonia
Dx after 1st
pneumonia Dx after recur
pneumoniaTotal
220 (92%) with underlying causes,18 (8%) with unknown cause
Aspiration syndrome
6.3yr 109 1 4 114
Immune 3.8yr 26 7 1 34disorder
Cong heart disease
1.8yr 22 0 0 22
Asthma 4.5yr 12 0 7 19Anomalies respiratory
4mo 9 7 2 18
GE reflux 1.4yr 0 10 3 13Total 178 (80.9%) 25(11.4%) 17 (7.7%) 220
Owayed AF, et al. Arch Pediatr Adolesc Med 2000
Warning Signs
Unexplainted bronchiectasis
g g
• Unexplainted bronchiectasis.• Unusual presentation of the infection.• Dysmorphic features associated with recurrent y p
infection.• Infections worsening chronic disorders (asthma or
seizure)seizure).• Development of vaccine pathogen after vaccination
(e.g., HiB infection despite previous HiB vaccine).C li ti i t d ith li i ti• Complication associated with live vaccination.
• Delayed umbilical cord separtation• Unexplained autoimmune disease.Unexplained autoimmune disease.
Immunodeficiency Related (IDR) Scores
Scores of diagnoses and conditions d f th li i l dassessed from the clinical record
N(#237)
Median of IDR scores
(I t til )(Interquartile)PID
(113)8
(5-13)
Non PID
(124)
6 (3-10)
Positive predictive value of IDR 8 or more
= 59%
Yarmohammadi H, et al. Clin Vaccine Immunol 2006
Immunological evaluation of allergic respiratory children with recurrent sinusitisrespiratory children with recurrent sinusitis
27children with mild-mod asthma, ARChronic ( last 3 8 weeks) sinusitis and recurrent (3 or more per year) sinusitisChronic ( last 3-8 weeks) sinusitis and recurrent (3 or more per year) sinusitis
IgA IgG2
IgG1 IgG3
Carvahol, et al. Pediatr Allergy Immunol 2005
PScreening for PID
Recurrent sinopulmonary tract infections
g
Recurrent sinopulmonary tract infectionsEncapsulated bacteria
Diagnosis consideration: B cell/ antibody def, Complement, phagocytic def, WAS, HIV
Initial tests: CBC with differential count, IgG, IGA, IgM, Specific antibody titers (Tetanus, HIB, Pneumococcal), CH50
Referring: if abnormal, or normal but problems persist
Screening for PID
Recurrent skin infections
g
Recurrent skin infectionsRecurrent pyogenic infections
Diagnosis consideration: B cell/ antibody def, Complement, phagocytic def, LAD, HIE
Initial tests: CBC with differential count, IgG, IGA, IgM, IgE CH50, nasal swab culture
Referring: if abnormal, or normal but problems persist
Screening for PID
Failure to thrive opportunistic/ fungal infections
g
Failure to thrive, opportunistic/ fungal infectionsUnusual or severe infections
Diagnosis consideration: B cell/ antibody def, T cells defects & SCID, STAT1 deficiency, XLP, NEMOIRAK4 def
Initial tests: CBC with differential count, IgG, IGA, IgM, IgE
Referring: All casesReferring: All cases
Screening for PID
Autoimmune or chronic inflammatory disease
g
Autoimmune or chronic inflammatory diseaseLymphoproliferative diseases
Diagnosis consideration: ALPS, XLP, IPEX, APECED, CVID, complement def
Initial tests: CBC with differential count, IgG, IGA, IgM, CH50Autoantibodies, ESR, CRP
Referring: All cases, especially with infections
Transient Hypogammaglobulinemia in Infancy (THI)in Infancy (THI)
• A prolongation of physiologicA prolongation of physiologic hypogammaglobulinemia
• Low IgG with or without low IgALow IgG with or without low IgA and/or IgM beyond 6 months of age
• Most infants are able to respond• Most infants are able to respond normally to vaccine antigens
As mptomatic VS s mptomatic• Asymptomatic VS symptomatic
• Hypogammaglobulinemia may i t t th f 5persist up to the age of 5 years.
Transient Hypogammaglobulinemia in Infancy (THI)in Infancy (THI)
Clinical FeaturesClinical Features• Recurrent sinopulmonary tract
infections, recurrent diarrhea, prolonged oral candidiasis.
• Eczema, AR, food allergyT il d l h d• Tonsils and lymph nodes are present.
• Mild neutropenia or d eut ope a othrombocytopenia
Transient Hypogammaglobulinemia in Infancy (THI)in Infancy (THI)
Lab FeaturesLab Features
• Low IgG beyond 6 months of age
N l l I A (1/2 f )• Normal or low IgA (1/2 of cases)
• Normal or low IgM (1/5 of cases)
• Normal protective antibody titers
or non-protective or antibody titersor non protective or antibody titers
(15% of cases) including low tetanus
HIB l titHIB, pneumococcal titers
Dorsey MJ, Ann Allergy Asthma Immunol 2006
Transient Hypogammaglobulinemia in Infancy (THI)in Infancy (THI)
Lab FeaturesLab Features• Normal or elevated B (CD19) cells• Normal T, NK (CD3/4/8, CD56) cells, ( , )
Dorsey MJ, Ann Allergy Asthma Immunol 2006
Transient Hypogammaglobulinemia in Infancy (THI)in Infancy (THI)
DiagnosisDiagnosisRequire follow up and retesting with normal results.
• Typical case
Low IgG, not profound hypogammaglobulinemia except premature
Normal antibody titers
N l B (CD19) T (CD3/4/8) NK (CD3/4/8 CD 6) llNormal B (CD19), T (CD3/4/8), NK (CD3/4/8, CD56) cells
• May have low IgG + Low IgA +/- Low IgM, +/- Low antibody titers and elevated B (CD19) cellsantibody titers and elevated B (CD19) cells
Transient Hypogammaglobulinemia in Infancy (THI)in Infancy (THI)
TreatmentTreatment• Observation, F/U Immunoglobulin level yearly
• Most THI will spontaneously resolve by age 4.
• Antibiotic prophylaxis
• IVIG is not indicated. A period of IVIG replacement may be considered.
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