IMMUNOTHERAPY FOR ALLERGIES IS THERE A ROLE

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IMMUNOTHERAPY FOR ALLERGIES IS THERE A ROLE?

• Dr Gideon Lack
• Imperial College at
• St Marys Hospital
• London

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Background

• Allergy is a systemic disease starting in
  childhood
• Current treatment is directed at suppressing
  airway inflammation
• Current treatment is not curative
• Current treatment does not affect specific IgE or
  total IgE level
• Current treatment does not address the allergic
  causes of asthma
• Complete avoidance of allergens is not possible

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J. ALLERGY CLIN. IMMUNOL.DECEMBER 1988

• AGE OF THE PATIENTS (years)

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R.M.

• R.M is an 11 year old boy with horse allergy and
  asthma. His cousins raise horses and after horse
  exposure he would develop immediate urticaria,
  angioedema and wheeze followed 8 hours later by
  persistent cough and wheeze that lasted several
  days. Allergen avoidance and medical treatment
  were unsuccessful.

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Allergic Desensitisation

• R.M was treated with injections of horse dander
  extract in hospital over a 2 week period.

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Introduction immunotherapy

• There are few paediatric studies.
• Previous paediatric trials suffer from being too
  small, non-randomised, enrolling inappropriate
  subjects or using insufficient allergen.
• There is also concern about the potential for
  adverse effects in asthmatic children.
• Abramson M et al. Allergy 1999
  541022-1041

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Grass Pollen Immunotherapy as an Effective
Therapy for Childhood Seasonal Allergic Asthma 

• Roberts G, Hurley C and Lack GPaediatric
  Allergy, Asthma and Immunology, Imperial
  College at St Marys, London, UK.

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Aims of the study

• The primary aim of this study was to assess the
  efficacy of grass pollen immunotherapy in
  children with seasonal allergic asthma.
• Additionally we looked at cutaneous and bronchial
  allergen reactivity, airway inflammation and
  adverse effects.

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Methods - subjects

• Inclusion criteria
• 3-16 years
• seasonal allergic asthma and gt200mcg ICS daily
• positive SPT, specific IgE and conjunctiva
  provocation test to Phleum pratense
• written informed consent
• Exclusion criteria
• perennial asthma
• symptomatic allergy to other allergens

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Methods - design
1999/2000 2000
2000 2001
2001 AUTUMN WINTER SUMMER
AUTUMN SUMMER AUTUMN
ACTIVE SIT
Summer 2001 Diary, ExNO, induced sputum
Summer 2000 Diary, ExNO
Randomised
PLACEBO SIT
Allergen reactivity in skin and lungs
Allergen reactivity in skin
Allergen reactivity in skin and lungs
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Results - subjects
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Immunotherapy reduces asthma symptom-medication
score by 50
Summer 2001 results Median scores with p-values
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IT for childhood summer asthma

• Subjects 3-16 y with summer asthma but no
  perennial asthma, sensitized to grass pollen,
  n35
• Design RDBPC, 2y, cluster protocol
• Intervention Alutard SQ 100000SQU/ml vs placebo
• Results ? symptom-medication score in active
  group, no serious adverse effects

Roberts et al, manuscript submitted
Graham Roberts Immunotherapy How and Who?
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There was a 67 reduction in total steroid usage
with a trend towards significance
Summer 2001 results Median scores with p-values
p0.62 p0.16
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Despite using less steroids in the active group,
there was no difference in airway inflammation
Summer 2001 results Mean scores No significant
differences between groups
Standardised exhaled nitric oxide
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Immunotherapy reduces cutaneous allergen
reactivity
Ten fold reduction in cutaneous allergen
reactivity after immuno-therapy
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Immunotherapy reduces bronchial allergen
reactivity
Three fold reduction in bronchial allergen
reactivity after immuno-therapy
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Other results

• No significant difference in FEV1 variability or
  diurnal variability between the two groups
• Parents and subjects were no more likely to guess
  the correct group than that expected by chance
• There were no serious adverse events

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Conclusions

• Immunotherapy significantly reduced the asthma
  symptom-medication score by 50
• Despite using 67 less steroid medication, the
  immunotherapy group had similar levels of airway
  inflammation to the placebo group
• There was a large reduction in allergen
  reactivity in both the skin and lungs
• Immunotherapy was acceptable to families and was
  associated with minimal adverse effects

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Metanalysis of symptomatic deterioration from
placebo-controlled trials odds ratios (with 95
confidence intervals) for each study, paediatric
and adult studies and all studies combined
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Metanalysis of increased asthma medication
requirements from placebo-controlled trials odds
ratios (with 95 confidence intervals) for each
study and all studies combined
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Longterm efficacy of allergen immunotherapy

• Des Roches A et al Allergy 199651430-33
  (HDM)
• Hedlin G et al JACI 199596879-85
  (cat)
• Naclerio RM et al JACI 1997100293-300
  (ragweed)
• Mosbech H et al Allergy 198843523-29
  (grass)
• Durham SR et al NEJM 1999324468-475
  (grass)
• Walker SM et al JACI 2003 AAAAI Abs 799
  (grass)
• Jacobsen L et al Allergy 199752914-20
  (tree)
• Golden DBK et al JACI 199697579-87 (venom)

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Durham SR et al New Engl J Med 1999341468-75
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Moller C Dreborg S Ferdousi HA Halken S Host
A Jacobsen L Koivikko A Koller D Niggemann B
Norberg LA Urbanek R Valovirta
E Wahn U
J Allergy Clin Immunol 2002109251-6
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PAT Study Period
Follow up
Follow up
SIT
JACI, in press
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Patient flow
Patients included 205
SIT group 103
Control group 102
Drop out 8
Drop out 6
Continued for 3 years as controls 94
Continued for 3 years on SIT 97
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RHINITIS CHANGE FROM BASELINE (VISUAL ANALOGUE
SCORES)
P0.080
Plt0.05
Plt0.01
1
2
3
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CONJUNCTIVITIS CHANGE FROM BASELINE (VISUAL
ANALOGUE SCORES)
Plt0.001
Plt0.05
Plt0.001
1
2
3
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Definition of clinical asthma

• Two out of the following symptoms (repeated)
• Coughing
• Wheezing
• Shortness of breath
• Not triggered by infections
• Effect of beta2-agonist

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DEVELOPMENT OF ASTHMA AT 3 YEARS N151 (patients
without asthma in season one)
Odds-ratio 2.52 (1.3 5.1)
N60
N40
N32
N19
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DEVELOPMENT OF ASTHMA AT 5 YEARS N142 (patients
without asthma in season one)

Odds-ratio 2.68
(1.3 5.7)
100
N
60
80
N
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60
No asthma
of ptt.
N
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Asthma
40
N
15
20
0

SIT
Control
Moller C et al, J Allergy Clin Immunol
2002109251-6 (follow up results)
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Conclusion

• In allergic children suffering from hay fever
  caused by allergy to grass and/or birch pollen
  and no diagnosed asthma, there is a high
  frequency of bronchial hyperresponsiveness and
  undiagnosed asthma.
• Allergy vaccinations reduces the risk for
  development of asthma in children suffering from
  hay fever.

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Immunotherapy with a standardized
Dermatophagoides pteronyssinus extract Specific
Immunotherapy prevents the onset of new
sensitizations in children

• A. Des Roches, Bousquet et al
• J Allergy Clin Immunol 1997
• Vol 99, no 4, pp 450-453

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Prevention of new sensitivities after HDM
immunotherapy in children
Des Roches A. et al. JACI 199799450-53
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Prevention of the onset of new sensitivities in
monosensitive patients (Der. pt.) treated for 3
years.
(n44)
Roches et al, JACI, Vol. 99, No 4
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ANTI-IgE TREATMENT FOR ALLERGY
Circulating IgE
IgER
Allergen cross-bridging
Histamine
IgE
Secretory granule
Anchored IgE
Anti-IgE
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Effect of Anti-IgE Therapy in Patients with
Peanut Allergy
Donald Y.M. Leung, M.D., Ph.D., Hugh A. Sampson,
M.D., John W. Yunginger, M.D., A. Wesley Burks,
Jr., M.D., Lynda C. Schneider, M.D., Cornelis H.
Wortel, M.D., Ph.D., Frances M. Davis, Ph.D.,
John D. Hyun, B.S., William R. Shanahan, Jr.,
M.D., for the TNX-901 Peanut Allergy Study Group
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Leung D. NEJM 2003 348986-993
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The co-seasonal application of anti-IgE after
preseasonal specific immunotherapy decreases
ocular and nasal symptom scores and rescue
medication use in grass pollen allergic
children Objective A randomised,
double-blind, placebo-controlled trial was
conducted to compare the efficacy of single and
combined treatment with SIT and anti-IgE
(Omalizumab) in reducing symptom severity and
rescue medication use Conclusions Co-seasonal
Omalizumab therapy showed considerable effects in
children with seasonal allergic rhinitis. The
combination of Sit plus Omalizumab was clinically
superior to each treatment alone during the first
year of observation C Rolinck Werninghaus et
al, Allergy 2004 59 973-979
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Summary

• SIT seems to be even more effective in children
  than in adults
• SIT decreases symptoms and medication usage in
  childhood asthma and rhinitis
• SIT modifies the natural history of allergic
  disease and has long term benefits
• SIT prevents the development of asthma in
  children with hayfever

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Summary (cont.)

• SIT prevents the development of new allergic
  sensitisations in children
• SIT has a very good safety profile in children
• SIT is very well tolerated by children
• Can SIT be used in the primary prevention of
  allergic disease and asthma in high risk
  children?
• Can SIT be used together with other forms of
  immunomodulation to treat polyallergic decline?

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Acknowledgements

• Graham Roberts
• Catriona Hurley
• Victor Turcanu
• Kevin Babb
• ALK-Abello