Diagnóstico Diagnóstico y y manejo manejo de de infecciones recurrentes infecciones recurrentes en en

pediatríapediatría

Ricardo Sorensen,MD

Chairman,Department of Pediatrics

LSUHSC••

Department of Pediatrics

LSUHSC

AFEBRILE

RECURRENT “PATHOLOGIC” INFECTIONS

Abnormality of infections defined by:• Age. Infections continuing after 3-5

years • Recurrence after antibiotic treatment• Severity and complications

• Lack of local or systemic predisposing factors

Distribution of Primary ImmunodeficienciesDiagnosed in 1,259 Patients

in 8 Latin American Countries in 1997

Defects of phagocytosis

7%Granulocyte

dysfunction with associated

abnormalities8%

Combined cellular & antibody IDs

5% Complement deficiencies

1%

Cellular & antibody IDs with

other abnormalities19%

Predominantly antibody IDs

60%

CLASSIFICATION OF PREDOMINANTLY ANTIBODY-DEFICIENCY SYNDROMES

Immunoglobulin deficiencies:• X-linked agammaglobulinemia• X-linked hyper IgM syndrome• Common variable immunodeficiency• Transient hypogammaglobulinemia of

infancy• IgM deficiency• IgA deficiencySorensen R, Moore C. Peds Clin NA 47:1225-1252, 2000

CLASSIFICATION OF PREDOMINANTLY ANTIBODY-DEFICIENCY SYNDROMES

IgG subclass deficiencies:• IgG 1 deficiency• IgG 2 deficiency

– selective deficiency– with IgA deficiency– with IgG4 deficiency

• IgG 3 deficiency• IgG 4 deficiency

ANTIBODY DEFICIENCIES

Clinical presentation (after 6 mo of age): • Recurrent upper and/or lower respiratory

infections• Severe or recurrent invasive infections

• Bronchiectasis• Chronic diarrhea

ANTIBODY DEFICIENCIES

Pathogens common to all deficiencies: • Streptococcus pneumoniae• Branhamella catarrhalis• Haemophilus influenzae (type b and

non typable)• Staphylococcus aureus

NEED FOR EVALUATION OF ANTIBODY MEDIATED

IMMUNITY

• Clinical manifestations common to many conditions

• Possible treatment of deficient specific immunity included in

evaluation

EVALUATION OF ANTIBODY-MEDIATED IMMUNITY

• IgM, IgG, IgA and IgE concentrations• IgG subclass concentrations

• Specific antibodies– Anti-protein antibodies– Anti-conjugate polysaccharide antibodies– Anti-polysaccharide antibodies

Patient 1Recurrent antibiotic use is abnormal

Importance of physical examination

Neutropenia may be part of some antibody deficiencies

Relationship between immunological phenotypes and molecular and gene abnormalities

CASE REPORT

Well-developed, well-nourished 14 month-old male at the 75th percentile for height and weight

Unremarkable family history

Recurrent URI and otitis media starting at age 3 months requiring 12 antibiotic treatments in the last 12 months

One severe febrile episode requiring hospitalization

Ear tubes were not placed

CASE REPORT (Continued)

Physical examination:

•Allergic shiners

•Purulent nasal secretion

•Cervical lymph nodes: not palpable

•Tonsils: absent

CASE REPORT (Continued)

WBC: 4.77 cells/ml

ANC 0.24 cells/ml

CASE REPORT (Continued)

Immunoglobulin concentrations: IgG mg/dl <7.9IgA mg/dl <6.0IgM mg/dl <5.0IgE IU/ml <7.0

Lymphocyte subpopulations: CD3/CD4 NormalCD19 <1CD 20 <1

CASE REPORT(Continued)

B cell tyrosine kinase (Btk):

Absent

Antibody DeficiencyPhenotypes-Genotypes

C V I DB cells IgM IgG IgA

H I G M

Agammaglobulinemia

IgM IgG IgA

B cells IgG IgA

SAP

CD40L

NEMO

B tk

, X linked& , AR

ICOS

CD40AIDUNG

Cµ IGHMIgα CD79Aλ Light chain

CD179BBLNK

IgM

B cells

Deficient Normal Elevated

CLASSIFICATION OF PREDOMINANTLY ANTIBODY-DEFICIENCY SYNDROMES

Continued

Specific antibody deficiencies with normal immunglobulin concentrations (SAD)

Patient 2

Normal immunoglobulinconcentrations do not rule out an

antibody deficiency

CASE REPORTWell developed 5-year-old boy.

Chronic rhinitis, treated with antihistamines and nasalsteroids.

Recurrent wheezing treated with anti-leukotrienes andinhaled steroids.

History of recurrent upper respiratory infectionsincluding purulent otitis media and chronicsinusitis that improve transiently on antibiotics.

These infections persist despite ear tube placementand sinus surgery.

CASE REPORT continued

INITIAL EVALUATIONNo evidence of atopy,

low normal IgE concentration,

negative skin prick test withcommon inhalant and foodallergens.

CASE REPORT continued

Immunoglobulin Concentrations

ImmunoglobulinsIgG mg/dl 750IgA mg/dl 66IgM mg/dl 75IgE IU/ml 10

IgG Subclasses:IgG1 mg/dl 510IgG2 mg/dl 175IgG3 mg/dl 67IgG4 mg/dl 25

PNEUMOCOCCAL INFECTIONS

Importance in evaluation of antibody-mediated immunity

• Frequency of infections

• Multi-valent vaccines

PNEUMOCOCCAL CAPSULAR VACCINES

• POLYSACCHARIDE VACCINES

– 23 VALENT, PPV

• CONJUGATED VACCINES

– HEPTAVALENT, PCV-7

Number of Vaccines Neededfor Protection

Vaccines

4

1

1 2 >2Age in YearsIM

MU

NO

LOG

AIC

AL

MA

TUR

ATI

ON

3

2

Pneumococcal immunization depending on age of initiation

1 dose> 5 years

1 dose1 dose2-5 years

2 doses13-24 months

3 doses7-12 months

2,4,6,12-15 months

Normal infants

Polysaccharide (PPV)

Conjugate (PCV-7)

Vaccine

CASE REPORT continuedAntibody response to pneumococcal polysaccharide vaccine

Serotypes Vaccine Antibody response (IgG mg/ml)

Danish # US # PV Baseline Post- PV

1 1 X3 3 X4 4 X

6B 26 X9V 68 X14 14 X

18C 56 X19F 19 X23F 23 X

0.08 0.120.10 0.100.16 0.240.10 0.160.20 0.300.16 0.200.30 0.240.12 0.200.22 0.24

PV = Polysaccharide VaccineCV = heptavalent conjugate vaccine (Prevnar)

CASE REPORT continued

Specific tetanus, diphtheria and H. Influenzae antibodies:

Anti-proteinantibodies

Post-Immunization

Reference

Diphtheriatoxoid

2.69 >0.01 AU/ml

Tetanus toxoid 1.34 >0.1 IU/ml

H. Influenzae prp 2.400 >100 ng/ml

PATIENT DIAGNOSIS

Specific antibody deficiency to polysaccharide antigens with normal immunglobulins and normal specific antibodies to protein and conjugate polysaccharides

Specific Antibody Concentrations

0

20

40

60

80

100

-6 -3 -1 0 1 3 6 9 12 15 18 21 24

Ant

ibod

y C

once

ntra

tions

Months of age

ProteinAntigens

Conjugates

Normal Response

Years of Age

10y

PolysaccharidesAntigens

Abnormal Response

Specific Antibody Concentrations

0

20

40

60

80

100

-6 -3 -1 0 1 3 6 9 12 15 18 21 24

Ant

ibod

y C

once

ntra

tions

Months of age

ProteinAntigens

Conjugates

Normal Response

Years of Age

10y

PolysaccharidesAntigens

Abnormal Response

SPECIFIC ANTIBODY DEFICIENCIES

Associations• Atopic diseases

– Asthma– Atopic dermatitis

• Chromosomal abnormalities– Down syndrome– Pierre Robin– Ring chromosome 18– Other

• Any condition with recurrent infections

ANTIBODY DEFICIENCIESSUMMARY

• Variable immunological phenotypes• Recurrent or severe respiratory

infections• Frequent antibiotic use• May have mild clinical phenotypes with

late onset of infections• Patients usually do not appear ill

Recurrent Mucosal Infections

• Immunological evaluation after:

• Proper antibiotic treatment

• Reduction of inflammation

• Placement of ventilation tubes

Recurrent/Severe InfectionImmunization & EvaluationFully

ImmunizedIncomplete

Immunization

PathologicalRecurrent Infections

SevereInfection• Male• Absenttonsils

Mild InfectionNormal

Lymphoid Tissue

Evaluate* ImmunizeEvaluate if

infections continue

Evaluate*

* Immunuglobulin & specific antibodies

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