Immunotherapy: Evidence in atopy

Carla Irani, M.D

Allergy/Clinical Immunology

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)

Allergic Rhinitis and ComorbidAirway Diseases

Spector SL. J Allergy Clin Immunol. 1997;99:S773-S780

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

General Principles of Allergy Management

History of Allergen Immunotherapy

History of Allergen Immunotherapy

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

JACI 2005

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 hayfever

Varney va et al BMJ 1991;302:265-9

Immunotherapy for rhinitis (43 studies)

Malling HJ. Allergy 1998;53:461-472

Grass pollen immunotherapy for seasonal rhinitis/asthma

Walker SM et al., J Allergy Clin immunol 2001;107:87-93

Randomized placebo controlled studies with SLIT

Preventive Effects of immunotherapy:Novel sensitization

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.