Specific antibody deficiency
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Transcript of Specific antibody deficiency
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
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!