Bibliographic updates

Claude MOLINA* & Jacques GAYRAUD**

1. Statins (S) and allergy
2. Natural history of infant cow milk allergy
3. Kiwi allergy in Europe
4. Proton pump inhibitors and asthma
5. Allergen tolerance mechanisms

1. Statins (S) and allergy

Theme: Anti-allergic therapeutics
Key words: Statins – Asthma – T CD4 lymphocytes – IL10 interleukin

Statins, well-known and widely-used cholesterol-lowering agents and inhibitors of the A-reductase coenzyme 3HMG, also have anti-inflammatory properties.
Moreover, as recently shown in a Taiwan study, they act as inhibitors to airway hyper-responsiveness in asthmatic mice sensitized to ovalbumin and treated per os with Pravastatine et Atorvastatine (Chin Fen Huang et al, Annals of Allergy, Asthma Immunol 2013 110 1 11-17 et Editorial de J.L.Rosenberg).
Closer to clinical considerations, a Thaï study analysed in vitro by flow cytometry the effect of an association of Simvastatine and Fluticasone on asthmatics’ T CD4 cells incubated with dentritic cells. They observed that the T regulators: Treg / Th 17 ratio was high and significantly more so than when each product was taken alone. A simultaneous increase in IL10, explains the reduction of airway inflammation. Conversely, high Th17 levels are apparently linked to severe and neutrophilic asthmas (K.Maneechotesuwan et al, Clin & Exp.Allergy 2013 43 212-222). Other statins, such as Fluvastatin and Lovastatin have similar properties, always observed in vitro.
On clinical point of view (JL.Rosenberg), the results are more limited and often contradictory. While the association of S and corticosteroids appears beneficial among the obese and hypercholesterolemic asthmatic, this needs to be confirmed by numerous therapeutic trials.
These studies nevertheless have drawn attention to the lipidic metabolism and its role in lung physiopathology.
However, there is drawback as concerns side-effects of S. since several of them have induced anaphylactic reactions. Thus, with the 37 year-old US patient suffering from family hypercholesterolemia (F.S Khan et al JACI 2013 131 1 234-236) a Rosuvastatine (Crestor®) desensitization protocol was
successfully performed in 72 h, the initial 0.01mg dose having enabled him to tolerate 9 months later the 20mg dose per os.

2. Natural history of infant cow milk allergy

Theme: Food allergy
Key words: Allergy prediction – Cow milk – Specific IgEs – Skin prick tests – Atopic dermatitis

In a multicenter study by US paediatricians (Baltimore, New-York, Denver, Little Rock, Chapel Hill (R.Wood JAC I 2013 1 in press) a cohort of 3-15 month-old infants was followed in two categories:
  • the first group was composed of infants with an obvious clinical history of milk allergy (as well as egg allergy for some of them) with a positive prick test to the trigger food;
  • the second was composed of children suffering from moderate to severe atopic dermatitis (AD), with positive prick test to milk or egg.

Only the children with a clinical history of milk allergy were enrolled and followed over a long period in order to assess the natural evolution of this allergy towards its resolution, the time taken to achieve it and hence the possibility of safely ingestion the food again.

Out of 293 infants, 244 milk-allergic were followed for over 5 years (66 months). Allergy resolved in 154 subjects (52,6%), i.e. a little over 1 in 2 and on average around the 63rd month.
Through statistics and a large number of biological parameters (mononuclear stimulation and PCR analysis), the authors tried to specify the predictive factors of allergy persistence, among which 3 emerged with a strong probability (P≤ 0.001):
  • Specific IgE levels at baseline
  • Skin test wheal size
  • Severity of AD
The chances of resolution are then associated with a low level of specific IgEs, a small size skin test wheal and a mild AD. They are generally higher in girls. It should also be noted that 20% of those children, still allergic, could tolerate cooked milk products.
However, no other biological criteria (IgG4 or IgE/IgG4 ratio, Fox P3, GATA 3, IL10, IL4, IFNγ) or mononuclear stimulation testing turned out to be resolution predictors.

This once again emphasizes the superiority of “good old” clinical practice over the most sophisticated biological tests, and this diagnosis triad constitutes a precious predictive tool for paediatricians and families with a view to a safe milk ingestion.

3. Kiwi fruit allergy (KA) in Europe

Theme: Food allergy
Key words: Kiwi – Skin prick tests – Specific IgEs –Molecular allergens – Iceland

A relatively frequent and not just anecdotal aetiology, KA was the theme of a European survey in the framework of the Prevall study, gathering 311 subjects in 12 different countries, among which France (Strasbourg), and 4 climatic regions throughout Europe.

They sought to elucidate European geographic differences, both in clinical terms and diagnostic methods, possible cross-allergies, prognosis and severity factors (Thuy-Le et al JACI 2013 131 164-171).
Two varieties of K are known. The most common, the object of the study, is the green variety, Actinidia deliciosa cultivar Hayward, whose extract includes several allergens, the 6 most representative of which were tested with ImmunoCap: Act d1, Act d 2, Act d 5, Act d8, Act d 9 et Act d 10, along with the total extract. The other variety, Actidinia Chinensis cultivar Hort 16 A, is less common.
Clinical signs were very varied, going from oral irritation (the mild form, 87% of cases) to moderate forms (digestive troubles) and to anaphylactic shock and occurring between 15 and 60 minutes after ingestion in 92% of cases. There were no challenge tests, the clinical and biological signs being evocative enough, whether it be mono-sensitization or association with sensitization to birch pollen or latex.
As for diagnosis, the comparison of skin prick-tests and I°cap with the 6 allergens shows a clear superiority of the biological test, sensitivity climbing from 20% for skin tests and the total extract I°cap, to 65% for the 6 molecular allergen I°cap.
As to sensitization, it varies according to region:
  • 32% of the patients living in Iceland were Act d1 (Actinide) sensitive.
  • Those from central and western Europe and eastern Europe were sensitized to Act d8 (a class 10 protein, 58% and 44% respectively)
  • Those from southern Europe, were mainly sensitized to Act d9 (profiline, 31%) and to Act d10 (a lipidic transfer protein, 22%).

Severity factors are independently represented, by residence in Iceland and by Act d1 sensitization. Although independent (P=0.003), their association is even more significant (P≤ 0 .001).
Finally, the treatment, obviously only by eviction, is not always straightforward, due to cross-sensitizations and risks of “hidden” foodstuffs.

4. Proton-pump inhibitors (PPIs) and asthma

Theme: Asthma treatment
Key words: Proton-pump inhibitors – asthma – gastroesophageal reflux – pneumonia

Commenting on a recent publication by J.G.Mastronarde et al (NEJM 2009 9 April 360 1487-1499) which reported that Esomeprazole lacked efficacy over poorly-controlled asthma, several specialists are now contesting some of these conclusions (C-S Hsu et J-H Kao, NEJM 31 January 2013) and are looking again at the issue of PPIs and asthma.
Recalling the high prevalence of asymptomatic gastroesophageal reflux in these patients, they state that acid reflux by pH monitoring as observed in the quoted study, only represents a sub-group of subjects and is not representative of the patients at large. This only means that acid reflux is not a likely cause of these poorly controlled asthmas.
However other factors such as Body-mass index, age, sex, smoking status, have not been explored sufficiently to justify the authors’ conclusions.
Similarly, J.Lenglinger from Vienna believes that only endoscopy with biopsy can reveal an asymptomatic reflux requiring PPI treatment.
Besides, M.P.Wise et al (from Cardiff) state that, if PPIs reduce both the volume and acidity of gastric contents, they do not prevent a more or less bacteria-enriched pulmonary microaspiration and are then often associated with pulmonary complications and at the least an inflammation which may explain the lack of efficacy of treatment

In his response, R.A.Wise from Baltimore (USA), one of the leaders of the initial survey, confirms the frequency in these refractory asthmas of asymptomatic reflux, actually also found in other respiratory affections (cystic fibrosis or interstitial fibrosis) and interpreted as a consequence of alterations in pulmonary mechanics. Is it really necessary, in such cases, to perform an endoscopy with biopsy given the risks and cost involved?
The author does not think so and suggests looking firstly for other possible causes of failure of the asthma treatment (obesity, age, drugs). As for the risk of infectious complications or pneumonia, due to PPIs and aggravating asthma, he had no confirmation of it despite a wide-ranging random survey of 412 patients.
He nevertheless admits the possibility of harmful as well as beneficial effects of gastroesophageal acid suppression.
On the whole, it appears that unless there is a strong suspicion of reflux, PPIs do not improve these poorly-controlled asthma and could even worsen their evolution.

5. Mechanisms of tolerance (T) to allergens

Theme: Immunology
Key words: Tolerance – Allergens – TH2 lymphocytes – T regulators - TGFβ - Ig G1 – IgG4 – Specific immunotherapy – Epitopes – Recombinant allergens – Toll-like receptors

In the framework of the immunology topics planned for our BUAs, this one is analyzed in several recent papers that we shall briefly summarize, within the strict limits of a usual item.
  • a European paper, by the C.M.Akdis group (O.U Soyer et al: Allergy 2013 68 2 16- 170), a supplement to his excellent contribution in Nature Medicine (2012 18 5 736-746);
  • and an American one, by the Woodfolk group (J.Wisniewski et al Clin.Exp.Allergy 2013 43 164-176).
Tolerance can be defined with Medawar as the state of indifference or non-reactivity towards a substance (here, the allergen) which should normally induce a response.
Recent advances in immunology and molecular biology have identified the mechanisms that in allergic diseases do away with or reduce the inflammation initiated by the differentiation of T cells, particularly Th2, following the presentation of the allergen to dendritic cells. Regulatory cells (T.reg) play a pivotal role in inhibiting Th2-mediated inflammation through cytokines (IL 10 and TGFβ) or antibodies (IgG1, IgG4) targeted by introduction in the body (injection, ingestion or inhalation) of allergens during specific immunotherapy (SI) and inhibiting the IgE-allergen binding.
But other cells (Th1, Th17, even Th9 or Th22), pro-inflammatory with their cytokines, mediators, transcription factors (Fox p3), surface molecules (CD), can also modulate the immune response. Incidentally, for about ten years, biological drugs (e.g. monoclonal antibodies) have replaced chemical ones.
The efficacy and safety of this Tolerance can be improved in 6 ways (Akdis):
  1. By short-circuiting the IgE-allergen link through fragmentation of the allergen and use of linear peptide epitopes of T cells;
  2. By using recombinant allergens;
  3. By associating allergens with innate immunity stimulators such as Toll-like receptors (TRL 4);
  4. By varying allergen administration: subcutaneous, sublingual, epicutaneous, intra-lymphatic (lymph-node);
  5. By merging allergens with immunity modifiers such as FcγRIIb which inhibits basophil and mastocyte degranulation;
  6. By associating SI with monoclonal antibodies (e.g. Omalizumab) to avoid the anaphylactic risks of rush-treatment;
  7. Finally, we should emphasize the possible role of the intestinal microbiome and the discovery of tolerance markers which open up new therapeutic targets.

Comments and questions welcome:

*Pr. Claude Molina
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**Dr Jacques Gayraud
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Last updated 25 July 2014