Epidemiology
Epidemiologic studies of temporal and geographic variation in asthma morbidity have identified asthma as an important public health concern.
There is tremendous increase in the incidence of asthma and allergic rhinitis
Most recently, the NIH joined forces with the World Health Organization to find ways to lessen the global impact of asthma. (GARD)
Trends in estimated average annual rate of self-reported asthma during preceding 12 months by age group, United States, 1980 to 1993 and 1994.
(J Allergy Clin Immunol 1999;104:S1-9.)
Allergic Rhinitis
Epidemiologic Links between Allergic Rhinitis and AsthmaAllergic Rhinitis and Asthma Have Similar Prevalence Patterns
Study of worldwide prevalence of atopic diseases in 463,801 children 13–14 years of age. Children self-reported symptoms over 12 months using questionnaires.
Adapted from the International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee Lancet 1998;351:1225–1232.
UKAustralia
CanadaBrazil
USASouth Africa
GermanyFrance
ArgentinaAlgeria
ChinaRussia
0 5 10 15 20 25 30 35 40
% prevalence
UKAustralia
CanadaBrazil
USASouth Africa
GermanyFrance
ArgentinaAlgeria
ChinaRussia
0 5 10 15 20 25 30 35 40
% prevalence
Asthma
The Science of Allergen Immunotherapy
To paraphrase William Osler, the father of American medicine:
The practice of allergen immunotherapy is an art based on science.
Thirty years ago there was little science and today there is considerable science as to how allergen immunotherapy should be prescribed and administered
Most common allergens in Lebanon
1. Dust mites: farinae and pteronyssinus2. Grass: Phleum ,Dactylis and Lolium3. Olive (cross-reactive with ash)4. Pine, not very allergenic5. Parietaria6. Molds: Aspergillus and Altenaria7. Weeds: Ambrosia8. Coackroaches: Blatella germanica
Allergen Immunotherapy
Introduced by Leonard Noon in 1911, then Freeman
Historically: Weekly injections given before the season
1920: Perennial treatment
Indications
Presence of a demonstrated IgE-mediated disease (ST, RAST)
Documentation that specific sensitivity is involved in symptoms
Severity, duration of symptoms and incomplete response to pharmacotherapy
Venom immunotherapy: Hx of severe systemic allergic reaction
Contra-indications Inability of patients to comply
Auto-Immune diseases & immune deficiencies
Age: Chidren < 5 years
Uncontrolled severe asthma (FEV1 < 70 % predictive value)
Presence of other immunologic diseases
Treatment with -blockers
Malignancy
Chronic mouth lesions (sublingual immunotherapy)
Immunotherapy and pregnancy
Risk for a systemic reaction leading to abortion: one case report
No increase in prematurity, toxemia, abortion, neonatal death or congenital malformations
Fewer immediate skin tests in children whose mothers received IT while in utero (significant for grass pollen)
Dosage schedules There is a dose-response relationship Historically: coseasonal and preseasonal, not
recommended
Injections are started at 1:10,000W/V, or 1:100,000 for more sensitive patients
Injections are given weekly until patient reaches the maintenance dose of 0.6 to 0.8ml of 1:100, then interval of 4 to 6 weeks for 3 years
Sublingual immunotherapy is administered following a protocol for 3 years
Dosage schedule
Reduce volume administered (eg: 0.5 to 0.35) when a new vial of extract is given
Identify carefully at each time: patient’s dose schedule and patient’s vial
Observe for 20-30 min after injections for evidence of reactions in the case of subcutaneous immunotherapy
Sublingual immunotherapy is administered at home
Mechanisms
Complex, depends on the allergen and route of immunization
Diminution of TH2 response and enhancement of TH1
Decreased specific proliferation response to allergen
Increase of CD8+ lymphocytes
Mechanisms
Effect on specific IgE: Early rise in specific IgE Suppression of seasonal rise of specific IgE Later lowers specific IgE levels Decreased expression on FcRII on B cells Effect an specific IgG: Initial rise in specific IgG1 and IgG4 Specific IgG1 predominates early, IgG4 by end
of year 2
Mechanisms
Nonspecific loss of basophil histamine release following allergen challenge
Decreased cytokine release: IL4, PAF, HRF, TNF, MIF
Increased production of IFN-increased mRNA for IL-2 with a good correlation clinically
J Allergy Clin Immunol 97:1356-1365.1996
WHO position paper:Allergen immunotherapyBousquet J, Lockey RF, Malling HJ et al. Allergy 1998;53:suppl 44:1-42
Effective in IgE-mediated disease with a
limited spectrum (1 or 2) of allergies Effective in allergic rhinitis/conjunctivitis
allergic asthma and systemic reactions to
wasp/bee venom Should be combined with allergen
avoidance, pharmacotherapy and patient education
Grass pollen immunotherapy for seasonal rhinitis/asthma
Walker SM et al., J Allergy Clin immunol 2001;107:87-93
Immunotherapy and Asthma
N Engl J Med 1997;336:324-31 Adkinson et al: No benefit in children sensitized to many
allergens, but decrease in use of inhaled steroids
N Engl J Med 1999;341:468-475 Durham et al: Immunotherapy for grass-pollen allergy for 3 to 4
years induces prolonged clinical remission accompanied by a persistent alteration in immunologic reactivity
Immunotherapy and Asthma
Cochrane collaboration: Fifty-four randomized controlled trials were
analyzed: 25 for house mite allergy 13 pollen 8 animal dander 2 Cladosporium 6 with multiple allergens
Immunotherapy and Asthma
Allergy 1999 Abramson et al: The Cochrane collaboration:
Immunotherapy may reduce asthma symptoms and use of medications
But the size of the benefit compared to other therapies is not known
The possibility of adverse effects (anaphylaxis) must be considered
Immunotherapy and Asthma
NHLBI recommendations:1. If avoidance is not possible2. Appropriate treatment fails to control allergic
asthma3. Greater efficacy in children and young
adults4. Greater likelihood of success if single
sensitivity5. FEV1 at least 70% of predicted
The Origins and Prevention of Atopy and Asthma . Immunotherapy as a preventative asthma therapy: The PAT trial
In a large multicenter trial 205 children aged 6 to 14 years with grass and/or birch pollen allergy but without any other allergy, were randomized either to receive specific immunotherapy for 3 years or to an open controlled group
Möller et al, Pollen immunotherapy reduces the development of asthma Möller et al, Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis 8the PAT-Study. J in children with seasonal rhinoconjunctivitis 8the PAT-Study. J Allergy Clin Immunol 2002; 109:251-6 Allergy Clin Immunol 2002; 109:251-6
PAT Trial
Subjects had moderate to severe hay fever symptoms At inclusion none reported asthma with need of daily
treatment. Symptomatic treatment was limited to loratadine,
levocabastine, sodium cromoglycate, and nasal budesonide.
Asthma was evaluated clinically and by peak flow. Methacholine bronchial provocation tests were carried out
during the season(s) and during the winter. Before the start of immunotherapy, 20% of the children
had mild asthma symptoms during the pollen season(s).
Allergen immunotherapy : the future
Conventional subcutaneous immunotherapy Alternative routes: mainly sublingual Recombinant allergens Modified allergens Peptides DNA vaccines Adjuvants (ISS, IL-12, mycobacteria) Anti-IgE
Immunotherapy for the 21st century
T cell strategies of allergy vaccination
Overlapping peptides of Fel d 1 : Allervax
Cat
Genetic immunization
CpG motifs or immunostimulatory sequence
T cell strategies
B Kay (AAAAI 2001):multiple, short, overlapping peptides containing T cell epitopes can induce both peptide and whole allergen-specific hyporesponsiveness
Norman et al Am J Resp Crit Care Med 1996
Allervax: 2 reactive peptide for chain 1, safe and efficacious
Pene et al JACI 1997 Significant decrease in IL4 secretion after 6 wks of high dose Allervax Cat
DNA-based immunotherapeutics of allergic disease
Immunization with plasmid gene vaccines: Induction of Th1-biased immune response and prevention of development of Th2
Allergen mixed with immunostimulatory aligodeoxynucleotide (ISS-ODN or CpG motifs): Cryptic immunostimulatory DNA sequences which provide Th1 adjuvant activity for the immune responses
DNA-based immunotherapeutics of allergic disease
Physical allergen-ISS-ODN conjugates (AIC): More immunogenic than native antigens and antigens/ISS-ODN cocktails, and more effective in the prevention of allergic hypersensitivity responses
Immunomodulation with ISS-ODN alone: Effective allergen-independent immunomodulator, in early and late phase(short lived, proven in mice only)
Specific immunotherapy in perennial rhinitis
Mild rhinitis Moderate rhinitis+/- conjunctivitis
Severe rhinitis+/- conjunctivitis
Allergen avoidance (when possible)
Pharmacotherapy
Consider immunotherapy
WHO Position Paper 1997
Specific Immunotherapy and Asthma
Intermittent asthma Mild persistent asthma
ModeratePersistent asthma
Severe persistentasthma
Pharmacotherapy
Consider immunotherapy
WHO Position Paper 1997
Immunotherapy in Atopic Dermatitis (AD)
No evidence in large studies May be useful when done for allergic
rhinitis in a patient suffering as well from atopic dermatitis
Atopic dermatitis is an atopic state not always caused by allergens
But!! Dust mites have been shown to exacerbate AD
Toward Allergy and Asthma Prevention
There is justifiable hope that some chronic and debilitating diseases, such as asthma and allergic rhinitis, that markedly affect the lives of the young and the old equally can be prevented before they start or can be stopped before resulting in irreversible harm.