REVUE FRAN~AISE D ALLERGOLOGIE ET D'IMMUNOLOGIECLINIQUE
Oral and sublingual immunotherapy D. VERVLOET
KEY-WORDS: Specific immunotherapy - Oral specific immunotherapy- Sublingual specific immunotherapy Asthma.
sp6cifique MOTS-CLI~S: Immunoth6rapie Immunoth~rapie sublinguale - Asthme.
Local immunotherapy includes local nasal, local bronchial, oral and sublingual administration of allergens extracts. The purpose of this Local l m m u n o t h e r a p y (LIT) is the same that for subcutaneous desensitization i.e. reduction of symptoms score a n d treatments in patients suffering of rhinitis, asthma a n d / o r rhinitis and asthma. We do not talk about nasal immunotherapy which in 12 out of 14 placebo control double blind studies showed reduction in symptoms a n d / o r medication scores in patients suffering of rhinitis due to pollens allergy. Not enough studies can draw conclusions for rhinitis due to mites allergy, for asthma and for respiratory allergy in children. Bronchial immunotherapy has not be extensively evaluated and then this way of desensitization cannot be recommended at this time. Oral immunotherapy was evaluated in 9 studies [1-9] where conclusions can be drawn. Six studies were negative Three studies showed some positive
results, two with birch extracts [1,4], one with mite extracts . In this last study, only efficacy in eye symptoms was found. M1 studies but one focused on the effect of i m m u n o t h e r a p y on rhinitis. Only one study analyzed the effect of i m m u n o t h e r a p y on asthma. H i g h doses o f allergens extracts were given in some studies and side effects (urticaria, asthma, rhinitis, gastro intestinal symptoms) were occasionally reported. In the light of the data oral immunotherapy is not r e c o m m e n d e d either for the treatment of rhinitis a n d / o r asthma in adults and children. Sublingual immunotherapy has been investigated in 7 published or ~dn press,, studies with placebo control double blind protocol. In children two studies can be analyzed both using Dermatophagoides extracts. The first one from Tari et al.  studies 58 children (30 in the active group and 28 in the placebo group) aged from 5 to 12 suffering from asthma and rhinitis positive to mites according to prick, specific IgE and challenge tests. Patients took sublingually
UPRES 2050, Service de Pneumologie Allergologie, H6pital Sainte- Marguerite, MARSEILLE, (France). Correspondence • Pr. D. Vervloet, UPRES 2050, Service de Pneumologie Allergologie, H6pital Sainte Marguerite, 13009 MARSEILLE, (France). Interasma Marrakech' 98.
VERVLOET D. - Oral and sublingual immunotherapy. Rev. ft. Allergol., 1998, 38 (7S), $240-$242.
© Expansion Scientifique Publications, 1998
/ ORAL AND SUBLINGUAL 1MMUNOTHERAPY •
increasing doses of solution followed by maintenance therapy consisting of 15 drops 3 times of week. The results of the trial were assessed after 12 and 18 months according the following parameters : symptom scores, total and specific IgE levels, total IgG levels, nasal and bronchial challenge tests, side effects. Decrease of specific and non specific bronchial reactivity, increase of specific IgE and IgG, decrease of symptom score (nose and lung), decrease of drugs were shown in patients received the active treatment. However 32 episodes of systemic reactions were recorded in the active group with 3 urticaria, 8 mild asthma and 3 severe asthma. The second one from Hirsch et al.  studies 30 children (15 in the active group, 15 in the placebo group) aged from 6 to 16, suffering from asthma and rhinitis and allergic to mites. No difference was found for nasal symptom relief, and nasal symptoms scores were reduced in both placebo and active groups without significant difference. By contrast asthma symptoms decrease in the actively treated from a median of 0.36 to 0.07 (p<0.05). In contrast the placebo group increases from 0.07 to 0.25 (NS). It is however very difficult to i n t e r p r e t these data. As concerning rhinitis the n u m b e r of patients using nasal drugs was rather limited (3 out of 12 in the active group and 1 out of 10 in the placebo group). As concerning asthma score it should be noticed that the maximal theoretical score which could be found was 3. However the maximal score found before treatment was 0.36 in the active group and 0.07 in the placebo group. Three out of 10 patients from the placebo group did not have any a s t h m a s y m p t o m s score b e f o r e treatment. If before treatment the symptoms score is near 0 it is impossible to really compare this placebo group with the active one. A recent paper in press in Allergy  has studied the effect of sublingual immunotherapy in 66 children suffering of seasonal asthma, rhinitis and conjunctivitis due to olive tree pollen sensitization over a period of time of two years. This study showed discordant results with in the active treated group : - a lower score of dyspnea during both pollen seasons, - no difference in the peak flow rates, - a lower score of conjunctivitis only during the second year, - no difference for rhinitis, -no significant variation of specific IgE concentration, Rev.fr. Allergol.,
$241 - - s i m i l a r evolution of IgG4 in both active and
placebo groups. Few minor adverse events were reported in the active group (8 buccal itching and oropharyngeal pruritus, one labial swelling and conjunctivitis symptoms). In conclusion as concerning children, there are n o t e n o u g h data to p r o p o s e sublingual immunotherapy either for rhinitis or asthma. In adults it is important to focus the point that at this time there is no published data evaluating the effect of sublingual i m m u n o t h e r a p y on asthma. As concerning rhinitis published studies can be analyzed. Three studies dealed with grass pollen allergy. The first one from Sabbah et al.  have shown in the actively treated patients fewer symptoms of rhinitis (sneezing a n d r h i n o r r h e a ) a n d o f conjunctivitis during the pollen season that in the placebo group. Consumption of nasal solution of sodium cromoglycate and of betamethasone and dexchlorpheniramine was significantly less in the desensitized group. Side effects were negligible. The second one from Feliziani et al.  studies 34 patients (18 in the active group and 16 in the placebo group) who received a rush preseasonal t r e a t m e n t schedule in o r d e r to reach the maintenance dose in 15 days with 2 administrations per day; the top dose reached was administrated 3 times a week until the end of the pollen season. Symptoms score and drug score were lower in the actively treated group. The third one from Clavel et al.  studies 136 patients with a history of pollen induced rhinoconjunctivitis and a positive skin prick test to a standardized grass pollen extract. The treatment started on January 1994 and the study ended in July 1994. The results showed no significant difference between the active and the placebo groups for nasal symptoms (sneezing rhinorrhoea, itching, total score rhinitis), no significant difference of ocular symptoms (redness, itching, total score conjunctivitis). By contrast, the medication score and the betamethasone intake were significantly reduced in the active group. Furthermore IgG4 levels increased significantly in the active group but without correlation with symptoms. Side effects were comparable in both groups. One study dealed with parietara allergy . A double-blind placebo-controlled study of immunotherapy was conducted in 31 patients with allergic rhinitis due to parietaria pollen. The actively treated patients had significantly lower medication scores than those on placebo when the maximum pollen count was recorded and at
• D. VERVLOET /
the end of the trial they showed a significant decrease in nasal reactivity. The last study was recently p u b l i s h e d  and assessed the symptoms score in 20 subjects with mite-induced rhinoconjunctivitis (6 of whom also had mild asthma). There were significantly lower symptom scores in the active group than in the placebo group. Furthermore, compared with the placebo group, inflammatory-cell infiltration after conjunctival challenge and ICAM-1 expression on conjunctival epithelium decreased significantly in the first year of treatment. Serum concentrations of e o s i n o p h i l cationic p r o t e i n d e c r e a s e d significantly in the active group. Imnmnotherapy was well tolerated. In conclusion, in adults, there are no proof at this time of the efficacy of sublingual
immunotherapy in asthma. However in rhinitis 4 studies with pollens extracts and 1 study with mite extracts showed positive results. To summarize before proposing sublingual immunotherapy in children more studies are needed for the evaluation of possible efficacy in rhinitis a n d / o r in asthma with pollen and with mite extracts. In adults, it is not known if sublingual immunotherapy is active in asthma and this way of treatment should not be used for this specific indication until more data are published. However in rhinitis several trials have shown efficacy in pollen allergy and one in mite allergy. Furthermore, recent unpublished study indicated that in 645 subjects sublingual immunotherapy was not responsible of severe adverse reactions .
Giovane A.L., Bardare M., Passalacqua G., Ruffoni S., Scordamaglia A., Chezzi E., Canonica G.W. - A three-year doubleblind placebo-controlled study with specific oral immunotherapy to Dermatophagoides: evidence of safety and efficacy in paediatric patients. Clin. Exp. Allergy, 1994, 24, 53-9.
Cooper PJ., DarbyshireJ., NunnAJ., WarnerJ.O.-Acontrolled trial of oral hyposensitization in pollen asthma and rhinitis in children. Clin. Allogy, 1984, 14, 541-550.
TaudorfE., Laursen L.C., Djurup R., Kappelgaard E., Pedersen C.T., S0borg M., Wilkinson R, Weeke B. - Oral administration of grass pollen to hay fever patients. An efficacy study in oral hyposensitization. Allergy, 1985, 40, 321-335.
M611er C., Dreborg S., Lanner A., Bj6rkst~n B. - Oral immunotherapy of children with rhinoconjunctivitis due to birch pollen allergy'. A double blind study. Allergy, 1986, 41, 271-279.
Mosbech H., Dreborg S., Madsen E, Ohlsson H., Stahl Skov P., Taudorf E., Weeke B. - High dose grass pollen tablets used for hyposensitization in hay fever patients. A one-year double blind placebo controlled study. Allergy, 1987, 42, 451-455.
Taudorf E., Laursen LC,, Lanner A., Bj6rkst~n B., Dreborg S., S0borg M., Weeke B. - Oral immunotheraW in birch pollen hay fever.j~ Allergy Clin, Immunol., 1987, 80, 153-161.
OppenheimerJ., AresonJ.G., Nelson H.S. - Safety and efficacy of oral immunotherapy with standardized cat extract. J. Alle~D~ Clin. Immunol., 1994, 93, 61-67.
Van Deusen M.A., Angelini B.L., Cordoro K.M., Seiler B.A., Wood L., Skoner D.E - Efficacy and safety of oral immunotherapy with short ragveeed extract. Ann. Allergy Asthma. Immunol., 1997, 78, 573-580.
Litwin A., Flanagan M., Entis G., Gottschilich G., Esch R., Gartside R, MichaelJ.G. - Oral immunotherapy with short ragweed extract in a novel encapsulated preparation : a double-blind study.~ Allergy Clin. Immunol., 1997, 100, 30-38.
10. Tari M.G., Mancino M., Monti G. - Efficacy of sublingual immunotherapy in patients with rhinitis and asthma due to house dust mite. A double blind study. Alle~gol. fmmunopathol., 1990, 18, 277-284. 11. Hirsch T., Sahn M., Leupold W. - Double-blind placebo-controlled study of sublingual irnmunotherapy with house dust mite extract (D.pt.) in children. Pediat~:Allergy ):mmunoL, 1997, 8, 21-27. 12. VourdasD., SyrigouE., PotmnianouR, CaratE, BatardT., Anclrfi C., Papageorgiou ES. - Double-blind placebo-controlled evaluation of sublingual immunotherapy with standardized olive tree pollen extract in pediatric patients with allergic rhinoconjunctivitis and mild asthma due to olive tree pollen sensitization. Allergy, 1998, in press. 13. Sabbah A., Hassoun S., Le Sellin J., Andre C., Sicard H. - A double blind placebo controlled trial by the sublingual route of immunotherapy with a standardized grass pollen extract. Allergy, 1994, 49, 309-313. 14. Feliziani V., Latmada G., Parmiani S., Dall'Aglio RE - Safety"and efficacy of sublingual rush immunotherapy with grass allergen extracts. A double blind study. AllergoL Immunopathol., 1995, 23, 224-230. 15. Clavel R., BousquetJ., Andr6 C.-Clinical efficacy of sublingualswallow immunotherapy: a double-blind placebo-controlled trial of a standardized five grass pollen extract in rhinitis. Allergy, 1998, in press. 16. Troise C., Voltolini S., Canessa A., Pecora S., Negrini A.C. Sublingual immunotherapy in parietaria pollen induced rhinifis: a double blind study.J. Invest. Allergol. Clin. Immunol., 1995, 5, 25-30.
Rev. f~ Allergol., 1998, 38, 7S