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.