SPECIFIC ANTIBODY

DEFICIENCY (SAD)

Jaichat Mekaroonkamol, MD.

OUTLINES

Definition and Terminology

Indication for evaluation

Epidermiology

Clinical syndromes

Pathogenesis

Evaluation and diagnosis

Treatment

Prognosis

DEFINITION

“Specific antibody deficiency with

normal serum immunoglobulin only

deficient specific antibody

response to polysaccharide

antigens”

Notarangelo L. et al. JACI 010

TERMINOLOGY

Specific antibody deficiency

Selective antibody deficiency with

normal immunoglobulin

Impaired polysaccharide

responsiveness

Polysaccharide nonresponse

INDICATIONS FOR EVALUATION

Recurrent or severe sinopulmonary

infections

Streptococcus pneumoniae,

Haemophilus influenzae, Moraxella

catarrhalis or Staphylococcus aureus

Otitis media, Bronchitis, acute and

chronic rhinosinusitis, pneumonia,

bronchiectasis

Pediatr Allergy Immunol 2008: 19: 505–512

Pediatr Allergy Immunol 2008: 19: 505–512

RECURRENT INFECTIONS

Middleton’s Allergy, 8th ed

Pediatr Allergy Immunol 2008: 19: 505–512

Infancy

11 Pre-school

8

School age

4

10 WARNING SIGNS

10

10 WARNING SIGNS: ADULT (>18 YEAR OLD)

11

Suspect Immunodeficiency

Middleton’s Allergy, 8th ed

RECURRENT INFECTIONS

Middleton’s Allergy, 8th ed

RECURRENT INFECTIONS

Middleton’s Allergy, 8th ed

RECURRENT INFECTIONS

NATURE REVIEWS | IMMUNOLOGY , 2013

J Clin Immunol, 2009

52.2%

25.4%

10.4% 12%

J Clin Immunol, 2009

30%

Prevalence 7-19%

BolyeRJ. et al. ClinExp Immunol. 2006 Dec;146(3):486-92

Royal Children’s Hospital, Melbourne

between 1 January 2004 and 30 June 2005

Age 2–18 years at the time of evaluation

Suspected antibody deficiency: 10 warning

signs : 74 patients

An adequate IgG antibody response

post-immunization antibody >/= 1·3 µg/ml

fourfold increase over the preimmunization value

SAD : response to less than 50% of the

serotypes tested (11 patients: 14.9%)

Exclusion criteria

• An identified primary or secondary immune

disorder

including isolated IgG, IgG2 or IgA deficiency

• Immunosuppressive medication

• Anatomical abnormalities

BolyeRJ. et al. ClinExp Immunol. 2006 Dec;146(3):486-92

BolyeRJ. et al. ClinExp Immunol. 2006 Dec;146(3):486-92

RR of chronic otorrhoea in those with allergic rhinitis 0·85 (P = 0·28)

Independent

NATURE REVIEWS | IMMUNOLOGY , 2013

HUMORAL IMMUNE RESPONSE

T dependent responses

T independent responses

Abbas. Cellular and Molecular immunology. Seventh Edition

T

Dependent

Antigens

TI-1

Antigens

TI-2

Antigens

Induces response in babies Yes Yes No

Induces response in athymia No Yes Yes

Primes T cells Yes No No

Polyclonally activates B cells No Yes No

Requires repeating epitopes No No Yes

T Dependent & Independent Antigens

Examples TD: Diptheria toxin, influenza heamagglutinin, Mycobacterium tuberculosis

TI-1: Bacterial lipopolysaccharides, Brucella abortis

TI-2: Pneumococcal polysaccharides, Salmonella polymerised flagellin

TD: Activate B-1 and B-2 B cells

TI-1: Activate B-1 and B-2 B cells

TI-2: Activate only B-1 B cells

B LYMPHOCYTE SUBSETS

Abbas. Cellular and Molecular immunology. Seventh Edition

Abbas. Cellular and Molecular immunology. Seventh Edition

BACTERIAL POLYSACCHARIDES

NATURE REVIEWS | IMMUNOLOGY , 2013

J. Clin. Invest. 120:214–222 (2010)

IMMUNOLOGY OF BACTERIAL

POLYSACCHARIDE ANTIGENS

Innate immunity

Complement activation Alternative: covalent attachment of C3b

Lectin: MBL bind to mannose residues

Common pathway

Activation of phagocytes and inflammation Phagocytes use surface receptors to recognize: C-type

lectin like, scarvenger receptor

Toll-like receptors

Adaptive immunity

PATHOGENESIS

Not fully understood

Different defects may result in the

same problem

Delayed maturation of the immune

system

Rijkers GT immunodeficiency. 1993;5(1):1-21.

Middleton’s Allergy, 8th ed

EVALUATIONS

Immunoglobuline levels: IgG, IgA

and IgM

IgG subclass levels

Response to protein vaccines

“Only identifiable abnormality is the

response to polysaccharide

vaccines”

Rijkers GT immunodeficiency. 1993;5(1):1-21.

PNEUMOCOCCAL VACCINATION

Number of serotypes used varies

from 4 to 23, 12 to 14 are most

commonly used

At least 4 weeks after vaccination

Same laboratory perform

Children with recurrent respiratory infections

between 1995 and 1997

Without immunoglobulin, IgG subclass, or other

known primary or secondary

Immunodeficiency

A total of 113 patients

J ALLERGY CLIN IMMUNOL, AUGUST 1998

J ALLERGY CLIN IMMUNOL, AUGUST 1998

Adequate IgG

antibody response

• Post titer >/= 1.3

µg/ml

• Minimum fourfold

increase over the

baseline

J ALLERGY CLIN IMMUNOL, AUGUST 1998

J ALLERGY CLIN IMMUNOL, AUGUST 1998

J ALLERGY CLIN IMMUNOL, AUGUST 1998

J ALLERGY CLIN IMMUNOL, AUGUST 1998

Normal response 24 mo – 5 yr

“protective’’ antibodies to 50% or more of the serotypes tested, with at least a 2-fold increase in the titers

6-65 yr “protective’’ antibodies to 70% or more of the

serotypes tested, with at least a 2-fold increase in the titers

Protective level ≥ 1.3 mcg/ml

Pneumococcal IgG antibody

responses

J Allergy Clin Immunol 2012

PROTECTIVE TITER

“antibody titers ≥ 200 ng of AbN/ml :

decreased nasopharyngeal colonization

with specific pneumococcal serotypes”

in children

the conversion factor is 160 ng of antibody N/ml to 1 microgram/mL.

DECREASED NASOPHARYNGEAL COLONIZATION

Lancet Infect Dis 2004; 4: 144–54

A cohort study

95 immunocompetent children and 22

HIV-infected children

Ages 2 to 15 years

PPV

J Allergy Clin Immunol, 2006;118:1336-41

J Allergy Clin Immunol, 2006;118:1336-41

Pre-PPV titer, microgram/ml +/- SD

HIV: 1.5 +/- 1.2

Control: 1.3 +/- 0.7

J Allergy Clin Immunol, 2006;118:1336-41

J Allergy Clin Immunol. 2009 January ; 123(1): 195–200

“Although no definitive data are

available, the recommendation of an

expert panel is that an adequate

response to 50% or 70% of

serotypes tested is a normal

response for children or adults, respectively”

J Allergy Clin Immunol, 2006;118:1336-41

Bonilla FA. et al. Ann Allergy Asthma Immunol. 2005

J Allergy Clin Immunol 2012

Retrospective chart analysis between 2001 and 2007

Patients had to have received the unconjugated 23-

valent pneumococcal vaccine

There were 40 children (≤16 years old) and 539 adults

Ages ranged from 4 to 87 years

J Allergy Clin Immunol. 2009 January ; 123(1): 195–200

J Allergy Clin Immunol. 2009 January ; 123(1): 195–200

J Allergy Clin Immunol. 2009 January ; 123(1): 195–200

10-40 %

J Allergy Clin Immunol. 2009 January ; 123(1): 195–200

Normal response 24 mo – 5 yr

“protective’’ antibodies to 50% or more of the serotypes tested, with at least a 2-fold increase in the titers

6-65 yr “protective’’ antibodies to 70% or more of the

serotypes tested, with at least a 2-fold increase in the titers

Protective level ≥ 1.3 mcg/ml

Pneumococcal IgG antibody

responses

J Allergy Clin Immunol 2012

Pneumococcal IgG antibody

responses

J Allergy Clin Immunol 2012

TREATMENT

1. Immunization with conjugate vaccines

2. Aggressive management of conditions

predisposing to recurrent

sinopulmonary infections

3. Increased vigilance and appropriate

antibiotic therapy for infections

4. Prophylactic antibiotics

5. Immunoglobulin replacement

IMMUNIZATION WITH CONJUGATE VACCINES

13-valent pneumococcal conjugate

vaccine should be used

80 to 90 percent respond to one dose of

the conjugate vaccine

patients who respond to the conjugate vaccine also improve clinically

Sorensen RU et al. PediatrInfect DisJ. 1998 Aug;17(8):685-91

Referred for evaluation of recurrent respiratory

infections

All enrolled patients were immunized with the

experimental 7-valent PCV within 6 months of

their immunization with PPV

3 groups

I: PCVPPVPCV 17: 2-13 yr(5.3)

II: PCVPPV(≥3/9 serotypes)PPV 11: 2-8 yr (4.6)

III: PCVPPV single dose 67: 2-13 Yr (5.6)

Sorensen RU et al. PediatrInfect DisJ. 1998 Aug;17(8):685-91

Sorensen RU et al. PediatrInfect DisJ. 1998 Aug;17(8):685-91

Sorensen RU et al. PediatrInfect DisJ. 1998 Aug;17(8):685-91

MMWR / June 28, 2013 / Vol. 62 / No. 25

MMWR / June 28, 2013 / Vol. 62 / No. 25

M. Ballow / Ann Allergy Asthma Immunol 111 (2013)

MMWR / October 12, 2012 / Vol. 61 / No. 40

MMWR / October 12, 2012 / Vol. 61 / No. 40

Clinical Infectious Diseases 2009; 48:S65–74

Clinical Infectious Diseases 2009; 48:S65–74

TREATMENT

1. Immunization with conjugate vaccines

2. Aggressive management of conditions

predisposing to recurrent

sinopulmonary infections

3. Increased vigilance and appropriate

antibiotic therapy for infections

4. Prophylactic antibiotics

5. Immunoglobulin replacement

MANAGEMENT OF SINOPULMONARY DISEASE

Aggressive management of other

conditions predisposing to recurrent

sinopulmonary infections

Allergic rhinitis and asthma

Prompt recognition and treatment of

sinopulmonary bacterial infections

TREATMENT

1. Immunization with conjugate vaccines

2. Aggressive management of conditions

predisposing to recurrent

sinopulmonaryinfections

3. Increased vigilance and appropriate

antibiotic therapy for infections

4. Prophylactic antibiotics

5. Immunoglobulin replacement

ANTIBIOTIC PROPHYLAXIS

Frequency and severity of infections

remain high after immunization with

conjugate vaccine and management of

atopic disease

One of the largest studies examined 120

children aged 2 to 15 years of age

72 % were successfully managed with

prophylactic antibiotics

WolpertJ. PediatrAsthma Allergy Immunol. 1998; 12:183

No published controlled studies

Regimens were initially derived from a

series of immunocompetent patients

with recurrent otitis media

Amoxicillin(20 mg/kg per day as a single

dose or divided BID)

Trimethoprim-sulfamethoxazole(5 mg/kg per

day as trimethoprimas a single dose)

Azithromycin(10 mg/kg per week)

Liston TE et al. Pediatrics 1983; 71:524.

Principi N, et al. Am J Dis Child 1989; 143:1414.

De Diego JI et al. Int J Pediatr Otorhinolaryngol 2001; 58:47.

ANTIBIOTIC PROPHYLAXIS

Prophylactic antibiotics are not necessary

Prolonged courses (eg, one to three months for

chronic sinusitis) to clear infections completely

Administer antibiotics only when there are

clinical or laboratory signs of active infection,

and to assure that the infection is fully resolved before discontinuation

TREATMENT

1. Immunization with conjugate vaccines

2. Aggressive management of conditions

predisposing to recurrent

sinopulmonaryinfections

3. Increased vigilance and appropriate

antibiotic therapy for infections

4. Prophylactic antibiotics

5. Immunoglobulin replacement

IMMUNOGLOBULIN REPLACEMENT THERAPY

Recurrent infections that persist after

immunizing with conjugate vaccines and

appropriate antibiotic

Uncontrollable recurrent otitis media,

bronchiectasis

Multiple antibiotic hypersensitivities

Zora JA. Ann Allergy. 1993;70(4):283

OrtigasAP. Ann Allergy Asthma Immunol. 1999; 82:71

Patients with well-documented severe

or moderate polysaccharide

nonresponsiveness and evidence of

recurrent infections, with a proven

requirement of antibiotic therapy for improvement

Clinical and Experimental Immunology, 169: 57–69

IMMUNOGLOBULIN REPLACEMENT THERAPY

Retrospective uncontrolled series of pediatric

patients ; significant decreases in infections

Based on clinical response, serum trough

levels of IgG are NOT helpful

Responses to polysaccharide sometimes

improve after treatment for 6 to 24 months and

have to be reevaluated

Zora JA. Ann Allergy. 1993;70(4):283

OrtigasAP. Ann Allergy Asthma Immunol. 1999; 82:71

Pediatrics 2014;133:e154–e162

Patients received 7 consecutive IVIG infusions

6 serotypes, peak values reached a

level > 1.3 mg/mL in 87% to 100% of

the patients.

Pediatrics 2014;133:e154–e162

PROGNOSIS

Usually benign if they are identified and

properly managed

Repeat immune studies after a mean

interval of 3.1 years showed 50% of

patients developed normal responses

Normalize antibody responses to

bacterial polysaccharides by age 5 to 6 years

WolpertJ. PediatrAsthma Allergy Immunol. 1998; 12:183

99 children, mean age 5·9 (range 2–16) years, with

recurrent or severe infections

Acute otitis media ≥ 5

Sinusitis ≥ 3

Pneumonia ≥ 2

History of severe invasive infection

89 healthy children matched for age and gender

No children had received previous PCV or PPV

Adequate response respond to 50% or more of the serotypes, with at least a fourfold

increase in titre and protective levels ≥ 1·3 mg/ml

Post titer at 2 week of vaccination

Clinical and Experimental Immunology, 2012

Clinical and Experimental Immunology, 2012

Ten of 91 (11%) children had SAD.

Three children (3%) in control group responded inadequately to PPV

10 SAD

8 PPV

5 responded adequately

3 responded inadequately

2 PCV 1 responded adequately

0.5-5 years

Clinical and Experimental Immunology, 2012

Ten of 91 (11%) children had SAD.

Three children (3%) in control group responded inadequately to PPV

4 inadequate

3 PPV

PPV

PCV

Hypo

responsiveness

1 PCV IVIG

Interval??

10 months

Clinical and Experimental Immunology, 2012

Ten of 91 (11%) children had SAD.

Three children (3%) in control group responded inadequately to PPV

3 Healthy

Inadequate

1 PPV Responded adequately

2 None

recurrent

infection

6 years

3.6 years

SAD is often transient and resolves

itself within a few years without specific treatment

Clinical and Experimental Immunology, 2012

CONCLUSIONS

SAD = inability to respond to polysaccharide

antigens in children over the age of two years

Recurrent sinopulmonary infections with

polysacccharide organism: Chronic otorhea

23vPPV is most valuable nonprotein, polysaccharide

vaccine for the evaluation of a T-cell independent

response

Adequate response depend on age and immunogenic

potential of various serotypes

often transient and resolves itself within a few years without specific treatment

L/O/G/O

Thank You!