New targets in prevention of allergy

1. Prevention of allergy
Where are we in 2015 ?
Dr Masy Nadine
European Exam in Allergology
UEMS Examination EAACI
Certificate of excellence in Allergology and Clinical
Immunology
Berlin, 17th of november 2015
Allergy Course
“Targets for Prevention”

2. The gut microbiota :
in the early development of both local and systemic immune maturation and programming
Studies on prevention :
1. The gut microbiota its localisation
Microbial Activities and Intestinal Homeostasis: A Delicate Balance Between Health and DiseaseChristina L. Ohland1 and Christian Jobin1,2
(Cell Mol Gastroenterol Hepatol 2015;1:28–40

3. Microbial Activities and Intestinal Homeostasis: A Delicate Balance Between Health and DiseaseChristina L. Ohland1 and Christian Jobin1,2
(Cell Mol Gastroenterol Hepatol 2015;1:28–40
Studies on prevention :
2. The gut microbiota and intestinal
homeostasis

4. The gut microbiota :
in the early development of both local and systemic immune maturation and programming
Studies on prevention :
3. The gut microbiota and fiber diet
Increase in dietary fiber dampens allergic responses in the lung. Gary B Huffnagle. Nature Medicine 20, 120–121
(2014

5. The immune system and the
gut microbiota: friends or
foes? N. Cerf-Bensussan,
V.Gaboriau-Routhiau.
Nature Reviews Immunology
10, 735-744 (October 2010)
Studies on prevention :
4. The gut microbiota and altered host system

6. Studies on prevention :
5. The gut microbiota of the pregnant woman
Gut microbiota and allergy: the importance of the pregnancy period
Thomas R. Abrahamsson, Richard You Wu, Maria C. Jenmalm
Pediatric Research (2015) 77, 214–219 doi:10.1038/pr.2014.165
A possible route for bacteria originating from the gut to reach the placental tissue during pregnancy.
Dendritic cells (DCs) actively penetrate the epithelium, sample the microbes within the gut lumen, and
transport them to the placenta…

7. Studies on prevention :
6. The gut microbiota of the pregnant woman
Epigenetic changes of the promoter region of immunoregulatory genes important for allergy development could explain how
the effect of microbial exposure to the mother during or even before pregnancy is transferred to the next generation…
Gut microbiota and allergy: the importance of the pregnancy period
Thomas R. Abrahamsson, Richard You Wu, Maria C. Jenmalm
Pediatric Research (2015) 77, 214–219 doi:10.1038/pr.2014.165

8. Studies on prevention :
7. The gut microbiota of the pregnant woman
There is a temporal dissociation between the major changes in microbial exposure to children in westernized
countries, which occurred during the first half of the century, and the onset of the accelerating increase in allergic
diseases…
Gut microbiota and allergy: the importance of the pregnancy period
Thomas R. Abrahamsson, Richard You Wu, Maria C. Jenmalm
Pediatric Research (2015) 77, 214–219 doi:10.1038/pr.2014.165

9. Seventeen studies, reporting data from 4755 children
(2381 in the probiotic group and 2374 in the control group)
Infants treated with probiotics had a significantly lower RR for eczema compared to controls.
No significant dif- ference in terms of prevention of asthma or rhinoconjunctivitis
The results of the meta-analysis show that probiotic supplementation prevents infantile eczema, thus
suggesting a new potential indication for probiotic use in pregnancy and infancy.
Studies on prevention :
8. Probiotics started prenatally and in combination with
breastfeeding
and it is mainly probiotics started prenatally and in combination with breastfeeding,
showing the best effectiveness
Gut microbiota and allergy: the importance of the pregnancy period
Zuccotti G, Meneghin F, Aceti A, Barone G, et al. Probiotics for prevention of atopic diseases in infants: systemic review and meta-analysis. Allergy
2015: 70: 1356–71.

10. In a recent large meta-analysis performed on 25 trials,
the authors concluded that a prenatal and/or early-life probi-
otic
Lactobacillus, Bifidobacterium, and Saccharomyces
administration reduces the risk of atopic sensitization
but may not reduce the risk of asthma/wheezing.
Studies on prevention :
9. Probiotics started prenatally and in combination with
breastfeeding
Dugoua J-J, Machado M, Zhu X, Chen X, Koren G, Einarson TR. Probiotic safety in pregnancy: a systematic review and meta- analysis of
randomized controlled trials of Lactobacillus, Bifidobacterium, and Saccharomyces spp. J Obstet Gynaecol Can 2009;31:542–552.

11. Studies on prevention :
10. Microbial exposure and colonization
Promising candidates for allergy preventionJames E. Gern, MD, FAAAAIMadison, Wis J Allergy Clin Immunol 2015;136:23-8.)

12. Studies on prevention :
11. Epigenetics and farm exposure in childhood
Michel S, Busato F, Genuneit J, et al. Farm exposure and time trends in early childhood may influence DNA
methylation in genes related to asthma and allergy. Allergy 2013;68:355–64.
Farming seems to influence methylation in a
number of the genes and gene families.
It suggests the feasibility of such studies in
asthma, and it highlights that a strong
protective environmental factor, such as
growing up on a farm, which is associated with
disease development influences methylation
and that timing of DNA collection for analysis is
crucial

13. Studies on prevention :
12. Early moisturizing in infants at risk for
atopic dermatitis
Simpson EL, Chalmers JR, Hanifin JM, et al. Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention. J Allergy Clin
Immunol 2014: 134: 818–23.DU TEXTE DE

14. Horimukai K, Morita K, Narita M, Kondo M, et al. Application of moisturizer to neonates prevents development of atopic dermatitis. J Allergy Clin Immunol 2014: 134: 824–
30.
Studies on prevention :
13. Early moisturizing in infants at risk for
atopic dermatitis

15. Gueniche A, Knaudt B, Schuck E, et al. Effects of non-pathogenic gram-negative bacterium Vitreoscilla filiformis lysate on atopic
dermatitis: a prospective, randomized, double-blind, placebo- controlled clinical study. Br J Dermatol 2008: 159: 1357–63.
Effects of Vitreoscilla filiformis treatment on atopic
dermatitis lesions. (Gram-negative aerobic bacterium)
Patients treated
(a)with placebo
(b) with V. filiformis lysate
before and on day 29 of treatment.
Studies on prevention :
14. Early moisturizing with
bacterial products

16. Gueniche A, Knaudt B, Schuck E, et al. Effects of non-pathogenic gram-negative bacterium Vitreoscilla filiformis lysate on atopic
dermatitis: a prospective, randomized, double-blind, placebo- controlled clinical study. Br J Dermatol 2008: 159: 1357–63.
Effects of Vitreoscilla filiformis treatment on pruritus.
The mean visual analogue scale (VAS) score for
pruritus by visit and treatment group with its 95%
confidence interval.
Compared with baseline a significant decrease was
observed only in the V. filiformis group (verum),
already by day 15 (P < 0·0002) and on day 29
(P < 0·0001).
The between-group difference concerning pruritus
VAS endpoint was also significant on day 29
(P = 0·017) as well as the course of pruritus
development (the time by treatment interaction;
P = 0·008).
Studies on prevention :
15. Early moisturizing with bacterial products

17. Gueniche A, Knaudt B, Schuck E, et al. Effects of non-pathogenic gram-negative bacterium Vitreoscilla filiformis lysate on atopic
dermatitis: a prospective, randomized, double-blind, placebo- controlled clinical study. Br J Dermatol 2008: 159: 1357–63.
Effects of Vitreoscilla filiformis
treatment on SCORing of
Atopic Dermatitis (SCORAD).
Compared with baseline a
significant decrease was
observed only in the
V. filiformis group (verum),
Studies on prevention :
16. Early moisturizing with bacterial products

18. Studies on prevention :
17. Studies on weaning
Du Toit G, Katz Y, Sasieni P, et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin
Immunol 2008: 122: 984–91.
In one study, it was found
that the risk of peanut
allergy was 10 times higher
among Jewish children in UK,
compared to Israeli children
of similar ancestry, which
was attributed to the early
introduction of peanuts in
the Israeli children

19. Studies on prevention :
18. Studies on weaning : peanut
Du Toit G, Katz Y, Sasieni P, et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin
Immunol 2008: 122: 984–91.
UK UK ISRAEL

20. Studies on prevention :
19. Studies on weaning : Israelic children
Du Toit G, Katz Y, Sasieni P, et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin
Immunol 2008: 122: 984–91.

21. Studies on prevention :
20. Studies on weaning : peanut consumption
Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N
Engl J Med 2015: 372: 803–13.
The British LEAP study (Learning Early About Peanut Allergy),
640 ‘high-risk’ babies (defined as those with egg allergy, severe eczema or both)
The infants were assigned to two groups: those whose parents were to regularly
feed them peanut and those whose parents were told to have their children avoid
peanut altogether.
The children, enrolled between the ages of 4 and 11 months, were given a
conclusive peanut food challenge at age 5.
At that age, on average, only 3.2% of the ‘consumption’ group had developed a
peanut allergy, compared to more than 17.2% in the ‘avoidance’ group. They
reported that in the peanut consumption group, at a high risk of developing
allergy, showed a reduction of the odds that a peanut allergy will develop by a
remarkable 70–80%.
The results of the study have huge implications on the early
introduction of allergic foods to prevent food allergy.
YES NO

22. Studies on prevention :
21. Guidelines of the AAAAI
early peanut introduction
J Allergy Clin Immunol 2015;136:258-61
The American Academy of Allergy, Asthma
and Immunology (AAAAI) implemented the
study in their new guidelines on allergy
prevention

23. Studies on prevention :
22. Early exposure to cow’s milk protein
Katz Y, Rajuan N, Goldberg MR, et al. Early exposure to cow’s milk protein is protective against IgE-mediated cow’s milk protein
allergy. J Allergy Clin Immunol 2010: 126: 77–82.
Supplementation at birth with CMP (cow’s milk protein) should be
recommended to promote its tolerance. For those patients with IgE-
mediated CMP allergy, soy is a reasonable feeding alternative.

24. Studies on prevention :
23. Studies on weaning : early egg introduction
Palmer DJ, Metcalfe J, Makrides M, et al. Early regular egg exposure in infants with eczema: a randomized
controlled trial. J Allergy Clin Immunol 2013: 132: 387–92.

25. Studies on prevention :
24. Studies on weaning : early egg introduction
Palmer DJ, Metcalfe J, Makrides M, et al. Early regular egg exposure in infants with eczema: a randomized
controlled trial. J Allergy Clin Immunol 2013: 132: 387–92.
Induction of immune tolerance pathways and reduction in the egg allergy rate can
be achieved by early regular oral exposure to egg
• from 4 months of age
• in infants with moderate-to-severe eczema.
The earlier introduction of egg in solid foods does not appear to increase the risk
of egg allergy in this high-risk group.
However, caution needs to be taken when these high-risk infants are first exposed
to egg because many have sensitization already and clinical reactivity by 4 months
of age. This points to much earlier events in the initiation of food sensitization, well
before the introduction of complementary feeding.
Clinical implications: Caution needs to be taken when infants with moderate-to-
severe eczema are first exposed to egg because many have sensitization already
and clinical reactivity by 4 months of age.

26. Studies on prevention :
25. Studies on weaning :
early egg introduction (Melbourne, Australia)
Koplin JJ, Osborne NJ, Wake M, Martin PE, Gurrin LC, Robinson MN, et al. Can early introduction of egg
prevent egg allergy in infants? A population-based study. J Allergy Clin Immunol 2010;126:807-13.
the observational Australian HealthNuts study suggested that first exposure to more
allergenic (unbaked) egg was more likely to reduce the egg allergy risk

27. Studies on prevention :
26. Studies on weaning :
early egg introduction (Melbourne, Australia)
Koplin JJ, Osborne NJ, Wake M, Martin PE, Gurrin LC, Robinson MN, et al. Can early introduction of egg
prevent egg allergy in infants? A population-based study. J Allergy Clin Immunol 2010;126:807-13.

28. Studies on prevention :
27. Studies on weaning : early egg introduction
(Melbourne, Australia)
Koplin JJ, Osborne NJ, Wake M, Martin PE, Gurrin LC, Robinson MN, et al. Can early introduction of egg
prevent egg allergy in infants? A population-based study. J Allergy Clin Immunol 2010;126:807-13.
The observational Australian HealthNuts study suggested that
first exposure to more allergenic (unbaked) egg was more likely to reduce the egg allergy
risk
In low-allergy risk infants Baked eggs : cake and biscuits Cooked eggs = hard-boiled,soft-boiled, fried or poached eggs

29. Studies on prevention :
28. Studies on breastfeeding:
Peroni DG, Pescollderungg L, PiacentiniGL, et al. Immune regulatory cytokines in the milk of lactating women
from farming and urban environments. Pediatr Allergy Immunol 2010: 21: 977–82.

30. Studies on prevention :
29. Studies on breastfeeding:
Peroni DG, Pescollderungg L, PiacentiniGL, et al. Immune regulatory cytokines in the milk of lactating women
from farming and urban environments. Pediatr Allergy Immunol 2010: 21: 977–82.

31. Studies on prevention :
30. Studies on hypo-allergenic milks :
• von Berg A, Filipiak-Pittroff B, Kramer U, Link E, et al. Preventive effect of hydrolyzed infant formulas persists
until age 6 years: long-term results from the German Infant Nutritional Intervention Study (GINI). J Allergy Clin
Immunol 2008: 121: 1442–7.

32. Studies on prevention :
31. Studies on hypo-allergenic milks :
• Nieto A, Wahn U, Bufe A, Eigenmann P, et al. Allergy and asthma prevention 2014. Pediatr Allergy Immunol
2014: 25: 516–33.

33. Studies on prevention :
32. Studies on hypo-allergenic milks :
Nieto A, Wahn U, Bufe A, Eigenmann P, et al. Allergy and asthma prevention 2014. Pediatr Allergy Immunol
2014: 25: 516–33.

34. Studies on prevention :
33. Studies on the gut microbiome in pregnancy:
Koren O, Goodrich JK, Cullender TC, Spor A, et al. Host remodeling of the gut microbiome and metabolic
changes during pregnancy. Cell 2012: 150: 470–80.
T1 Trimester 1
T3 Trimester 3

35. Studies on prevention :
34. Studies on the gut microbiome in pregnancy:
Koren O, Goodrich JK, Cullender TC, Spor A, et al. Host remodeling of the gut microbiome and metabolic
changes during pregnancy. Cell 2012: 150: 470–80.
Actinobacteria (which includes Bifidobacteria) and Proteobacteria
seem to undergo a significant distributive change in the last
trimester of pregnancy, and it could be that focussing on
Bifidobacteria is a better way to go
Perhaps probiotics need to be started earlier in pregnancy (from the
onset?), as the dynamics of the own microbiota, changing from the
beginning of pregnancy, have been shown.
Unfortunately, there are no comparative studies of microbiota
during pregnancy between allergic and non-allergic women.

36. Studies on prevention :
35. Studies on immunotherapy :
Bae JM, Choi YY, Park CO, Chung KY, Lee KH. Efficacy of allergen-specific immunotherapy for atopic dermatitis:
a systematic review and meta-analysis of randomized control trials. J Allergy Clin Immunol 2013: 132: 110–7.

37. Studies on prevention :
36. Studies on immunotherapy :
Prevention of New Sensitizations by Specific Immunotherapy in Children With Rhinitis and/or Asthma
Monosensitized to House Dust Mite. J Investig Allergol Clin Immunol 2007; Vol. 17(2): 85-91
Effect on
SIT on the
medication
score

38. Studies on prevention :
37. Studies on food immunotherapy :
OIT for
peanut
OIT can result in desensitisation in children, and that this is
associated with evidence of underlying immune-modulation.
However, this treatment approach was associated with a
substantial risk of adverse events, although the majority of
these were mild.
In view of the risk of adverse events and the lack of evidence of
long-term benefits, allergen-specific peanut OIT cannot currently
be recommended as a treatment for the management of
patients with IgE-mediated peanut allergy.
Larger RCTs are needed to investigate the acceptability, long-
term effectiveness and cost-effectiveness of safer treatment
regimens, particularly in relation to the induction of clinical and
immunological tolerance.
Nurmatov U, Venderbosch I, Devereux G, Simons FE, Sheikh A. Allergen-specific oral immunotherapy for
peanut allergy. Cochrane Database Syst Rev 2012: 9: CD009014.

39. Studies on prevention :
38. Studies on food immunotherapy :
Tang ML, Ponsonby AL, Orsini F, et al. Administration of a probiotic with peanut oral immunotherapy: a
randomized trial. J Allergy Clin Immunol 2015: 135: 737–44.
OIT for
peanut
and
probiotics
This is the first randomized placebo-controlled trial
evaluating the novel co-administration of probiotic and
peanut OIT and assessing for sustained unresponsiveness
in children with peanut allergy.
PPOIT was effective in inducing two-week sustained
unresponsiveness, and immune changes that likely reflect
reprogramming of the peanut- specific immune response.
Further work is required to confirm sustained
unresponsiveness after a longer period of secondary
peanut elimination and to clarify the relative contributions
of probiotic vs OIT.

40. Studies on prevention :
39. Studies on immunotherapy :
Determinants of efficacy and safety in epicutaneous allergen immunotherapy: summary of three clinical trials.
Allergy, Volume 70, Issue 6, June 2015, Pages: 707–710, G. Senti, S. von Moos, F. Tay, N. Graf, P. Johansen and
T. M. Kündig
Epicutaneous
immunotherapy
Prior to the pollen season 2009,
patients received six patches (allergen extract: n = 48;
placebo: n = 50) with
weekly intervals, administered onto tape-stripped skin.
Allergen EPIT produced a
median symptom improvement of 48% in 2009 and 40% in
the treatment-free follow-up year 2010 as compared to
10% and 15% improvement after placebo
EPIT (P = 0.003).
After allergen EPIT but not placebo EPIT, conjunctival
allergen reactivity was significantly decreased and allergen-
specific IgG4 responses
were significantly elevated (P < 0.001).

41. Studies on prevention :
40. Studies on immunotherapy :
Prevention of oral food allergy sensitization via skin application of food allergen in a mouse model. Allergy,
Volume 67, Issue 5, May 2012, Pages: 622–629, W. Li, Z. Zhang, A. Saxon and K. Zhang
Epicutaneous
immunotherapy
with food in a
mouse model Treg

42. Mondoulet L, Dioszeghy V, Puteaux E, et al. Specific epicutaneous immunotherapy prevents sensitization to
new allergens in a murine model. J Allergy Clin Immunol 2015: 135: 1546–57.
Epicutaneous
immunotherapy
with food in a
mouse model
(EPIT)
Treg
Studies on prevention :
41. Studies on immunotherapy :

43. Studies on prevention :
42. Studies on immunotherapy :
Chang YC, Chow YH, Sun HL, et al. Alleviation of respiratory syncytial virus replication and inflammation by
fungal immunomodulatory protein from Flammulina velutipes. Antiviral Res 2014: 110: 124–31.
• Non-specific IT, using Th1 or Treg cell stimulants, such as
bacterial antigens, should also become a subject of research
in primary prevention.
• One example is the anti-inflammatory and inhibitory
effect on RSV replication of the golden needle mushroom
(Flammulina velutipes)
Non-specific
immunotherapy
using Th1 or Treg
cell stimulants
Non-specific
immunotherapy
FIP-fve proteinFlammulina velutipes

44. Studies on prevention :
43. Studies on immunotherapy :
Mpairwe H, Webb EL, Muhangi L, et al. Antihelminthic treatment during pregnancy is associated with
increased risk of infantile eczema: randomized-controlled trial results. Pediatr Allergy Immunol 2011: 22: 305–
12.
Non-specific immunotherapy ,
using immunomodulating
agents like helminths during
pregnancy
Schistosoma
mansoni
Decreased
risk of
eczema in
infants

45. Studies on prevention :
44. Studies on immunotherapy :
Mpairwe H, Webb EL, Muhangi L, et al. Antihelminthic treatment during pregnancy is associated with
increased risk of infantile eczema: randomized-controlled trial results. Pediatr Allergy Immunol 2011: 22: 305–
12.
Antihelminthic treatment
of pregnant African mothers with
Schistosoma mansoni
Schistosoma
mansoni
Praziquantel
Increased
risk of
eczema in
infants
Albendazole

46. Studies on prevention :
45. Studies on immunotherapy :
In utero priming by worms protects against respiratory allergies. Hermelijn H. Smits, Cezmi A. Akdis. Journal
of Allergy and Clinical Immunology, Vol. 134, Issue 6, p 1280–1281
In utero
priming by
Schistosoma
mansoni

47. They are three types of primary prevention strategies
- early administration of bacterial products (most studies are on probiotics)
- early moisturizing in infants at risk for atopic dermatitis
- early exposure to allergenic foods (studies are on milk,peanut and egg)
- the use of immunotherapy
- the use of immunomodulatory treatments (mushrooms proteins, worms
products...)
 much more research needs to be carried out
 we have to define what advice can really be given in clinical practice
Take home messages
on prevention in allergy
Berlin, 17th of november 2015
Allergy Course
“Targets for Prevention”

48. Thank you
Dr Masy Nadine
European Exam in Allergology
UEMS Examination EAACI
Certificate of excellence in Allergology and Clinical
Immunology
Berlin, 17th of november 2015
Allergy Course
“Targets for Prevention”