Abstract: Sublingual application of allergen extracts in specific immunotherapy is a modern approach aimed at improving patient treatment acceptance through reduced serious side effects. This therapeutic approach has proven to be efficacious and safe for the treatment of allergies caused by airborne allergens: 1) studies have shown a rapid onset of action, as early as seven days after beginning treatment; 2) a strong effect during treatment, superior to most forms of symptomatic treatment; 3) a lasting effect after cessation; 4) a preventive effect against new sensitizations and new-onset asthma; and 5) an unprecedented safety profile compared to the subcutaneous route. SLIT is an established treatment option for moderate to severe allergic rhinoconjunctivitis with or without asthma, which can be given to adults as well as to children above five. The complexity of the treatment of this condition mandates expert care by an experienced allergologist.
Specific Immunotherapy (SIT) is a form of treatment given to allergic individuals whose contact with certain substances provokes troubling allergic symptoms. Injections or oral preparations (tablets or drops) with gradually increasing doses of the allergen are given to patients. This lowers the body’s immune system’s reaction to these noxious substances by slowly familiarizing it to them. This seemingly tiring process poses in fact the only available cure option for allergic conditions that were previously considered inevitably chronic and debilitating, like the famous hay fever, or at times even fatal, as is the case with the insect venom allergies. Whereas other administration routes such as the subcutaneous, nasal, oral and bronchial exist, our review article here highlights important aspects of recent developments in sublingual immunotherapy (SLIT).
A Historical Perspective of Sublingual Immunotherapy
This approach was actually first discovered by Native Americans (Dakin, 1829), who would chew small bits of poison ivy every day until they became immune against its poisonous stings. In the early 1900s, studies in centers like St. Mary’s Hospital, the Hamburg Institute of Hygiene, and the Pasteur Institute Paris, led to the eventual publishing of the first papers on what became the basis of today’s specific immunotherapy (Noon, 1911). Much later in 1950s and 1960s, more advanced discoveries have been achieved in the area of immunology. A recent upstroke in the development curve of molecular biology has stirred interest in the topic of SLIT, making it possible to produce better, more specific preparations such as recombinant allergens that contain only the DNA of offensive biological particles enclosed in a tablet (Jutel et al., 2005).
Molecular Mechanism of Action
We will only touch briefly here on the immunological basis of the underlying concept of specific immunotherapy, which is very well documented in the literature (Novak et al., 2008). In specific immunotherapy, the immune response is modified to induce tolerance towards a specific antigen (Chen et al., 1994). SIT therapy heals the immune response of the atopic subject, by gradually steering it into a response similar to that in the normal non-atopic individual (Ling et al., 2004).
In an allergic subject, immunoglobulin E (IgE)-mediated T lymphocyte activation causes their differentiation into T helper 2 (Th2) cells. These cells cause the formation of B memory cells and produce various cytokines or immune transmitters, mainly IL-4, IL-5, and IL-13. These cytokines lead to the activation of eosinophils (Allam et al., 2008), basophils, and mast cells, evoking the classical allergic response.
In non-atopic individuals, contact with an allergen causes T cells to differentiate into another type of cells known as T helper 1 (Th1) cells, or regulatory T cells (Tregs) which play a central role in the immunosuppressive response (Allam et al., 2008; Novak et al., 2008) and produce again cytokines such as IL-10, IL-18, IFNγ, TGFβ, and SLAM. The next step in the cascade is B cell activation, which releases IgA (Schramm et al., 2003) and IgG4, leading to further decline in the IgE binding to cells (Wachholz et al., 2003).
The regulatory role of these transmitters was proved by various studies and their presence in patients receiving therapy is indicative of an improved, anti-allergenic profile. For instance, IL-10 suppresses further T cell clonal expansion and eosinophil activation (Bellinghausen et al., 2001), but increases IgG4 levels. The latter was found to play a highly significant role in the regulatory pathway as a major anti-allergenic mediator (Gafvelin et al., 2005).
Immunological effects of SLIT
Atopic patients have more helper-2 than helper-1 circulating T-lymphocytes; however, continuous exposure to the allergen in SLIT treatment reverses this ratio and causes the immune response to be turned back to the “normal” anti-allergic pathway (Romagnani et al., 2006). Specific research has illustrated the rise in pro-regulatory factors like IL-10, TGFβ, and IFNγ (Savolainen et al., 2007), activities of “blocking” IgG (Durham et al., 2006), and secretory IgA levels, as well as the Treg cell count (Novak et al. 2008). In contrast, during SLIT therapy, less IL-13 release from Th2 cells (Ippoliti et al., 2003), less IgE (Jutel et al., 2006), and less local adhesion molecule expression (Passalacqua et al., 1999) are observed, and fewer eosinophils and mediators are detected in nasal smears (Marogna et al., 2005).
Site of action in SLIT
Allergens are first picked up at the mucous membranes, rich with “antigen presenting cells” (APCs), which then activate the immune response early before any changes occur in the circulation (Cebra et al., 1984). Interestingly, the specific site of action for sublingual SIT is the lymphatic network running submucosally from the mouth to the gastrointestinal tract, commonly named mucosa-associated lymphoid tissue (MALT) or gut-associated lymphoid tissue (GALT). Its APCs are a type of cells called “dendritic cells” (Macatonia et al., 1995) and “islets of Langerhans cells” (Allam et al., 2008). Absorption of allergens occurs slowly in the mouth, where radio-labeled allergens were shown to persist for hours (Bagnasco et al., 2005).
Indications of SLIT
SLIT has established a stable position in the world literature as an “evidence level A treatment” for allergic conditions like rhinitis, which are not optimally controlled by drug therapy, and a viable alternative to the subcutaneous immunotherapy form (SCIT) (Bousquet et al., 2008). Review of new data suggests that SLIT is in fact overall superior to SCIT (Calderon and Mösges et al., 2010).
SLIT can be given to treat rhinoconjunctivitis, asthma, atopic dermatitis, latex allergy, and even food allergies. SLIT is also used to treat other various allergies like those to birch, grass, olive, parietaria, ragweed, house dust mites, and cat.
Most studies focused on SLIT for rhinoconjunctivitis with or without asthma; however, further studies have demonstrated its efficacy and safety profile in asthma alone (Calamita et al., 2006). Children with mild/moderate atopic dermatitis and house dust mite allergy have been shown to benefit from SLIT in blinded controlled studies (Pajno et al., 2007; Marogna et al., 2007). SLIT was also tested in cat allergy with positive preliminary safety and efficacy results (Alvarez-Cuesta et al., 2007). A new meta-analysis reported statistically significant symptom improvement with house dust mite tablets (Compalati et al., 2009). A positive response was recently reported when SLIT was investigated for latex allergy (Nettis et al., 2010).
Numerous contraindications such as active, acute, uncontrolled, or steroid dependant asthma, and cardiovascular, neoplastic, and degenerative conditions exist, limiting the proportion of allergic patients treatable with SLIT to one-tenth.
Before starting a patient on SLIT, doctors must establish the relation between a certain allergen and the allergy (Li et al., 2003). After careful assessment for “eligibility,” treatment administration is followed up by an expert team. The treatment concept, the importance of adherence to the regimen, and furthermore, the expected side effects, as well as the financial implications, must all be well explained to the treatment recipients.
SLIT and asthma
There is a link between nasal and bronchial epithelium; all atopic patients have some degree of non-specific airway hyper-responsiveness (Cirillo et al., 2009) which improves following SLIT (Caffarelli et al., 2000). Di Rienzo et al. (2003) demonstrated that in the 5th year of SLIT therapy, and again 5 years after stopping it, asthma persisted in only 4/35 and 3/35 of the children (respectively) versus 24/25 of those on symptomatic drug therapy.
Guidelines state that SIT is of benefit in intermittent, mild to moderate asthma but warn against its use in severe asthma (Bousquet et al., 2008). There are so far two meta-analyses of 25 studies on over 1,000 patients supporting these recommendations (Calamita et al., 2006).
SLIT in children
The administration of SLIT early in life through a “child-friendly” route not only provides a valuable therapeutic option for parents for treating symptoms but also stops the progress of this chronic condition early in life, and is so being increasingly used. Several very recent studies and meta-analyses testing grass pollen tablet mixtures in children concluded that SLIT has acceptable safety and efficacy profiles in children (Kleine-Tebbe et al., 2006; Penagos et al., 2006; Bufe et al., 2009; Wahn et al., 2009). SLIT was even tested in children below 5 years, with safety and efficacy results being similar to those seen with older children (Di Rienzo et al., 2005; Fiocchi et al., 2005).
Benefits of SLIT Therapy
In a study conducted last year, grass allergen tablets were found to act rapidly, within a week from the start of treatment (Horak et al., 2009). This relatively quick action and swift symptom relief has allowed a great deal of dosing modification so that the “co-seasonal” and “rush” dosing models (Ott et al., 2009), for example, could be employed (see below).
After a recent meta-analysis of 39 double-blinded placebo controlled studies (Radulovic et al., 2008), the efficacy of SLIT in the treatment of allergic rhinitis was established, and the most recently published meta-analysis with 2,971 patients concluded that a modest clinical effect has been achieved, although the effect is more pronounced in certain subgroups like adults (Di Bona et al., 2010).
Combining SLIT with antisymptomatic medication and treatment is naturally still needed, at least until the long term desired effect of the therapy sets in. Prevention through allergen avoidance still remains an indispensable measure, especially against dust mites and contact dermatitis. SLIT, on the other hand, may be considered as the safe option for therapeutic prevention.
SLIT vs. Other Medications. Of the few studies comparing subcutaneous and sublingual immunotherapy, in terms of efficacy and safety, only two had a strong design but the small patient number limited the strength of the evidence (Khinchi et al., 2004). Inter-comparison of various trials on SLIT tablets showed 15-35% improvement in symptom scores and 28-50% less use of symptomatic medication; these same measurements were much lower for symptomatic therapies like antihistamines or intranasal steroids (Durham et al., 2006).
Ease of Administration. There are no injections! Studies have shown that low compliance rate will inevitably affect the effectivity of SCIT (Wynn, 1995). Conversely, a high SLIT compliance rate is quoted in the literature (80-90% after 3 and 6 months) (Passalacqua et al., 2007). SLIT is a straightforward regimen for patients and doctors to use, and can be simply and conveniently home-administered by a well-educated patient. These factors explain why patients adhere better to a SLIT than a SCIT schedule.
Long term effects
SLIT not only provides effective symptomatic alleviation, but also has a long term disease modifying cumulative effect. For up to 5 years after a SLIT therapy is stopped, a patient still tolerates allergens better than before (Ott et al., 2009), the same as with SCIT therapy (Eng et al., 2002). The most recent and largest study (Durham et al., 2010) proves that the symptom and medication use scores remain lower at least one year after stopping a 3-year grass tablet course.
Protection against asthma
SLIT protects against new-onset asthma, for which rhinitis is a known risk factor (Bugiani et al., 2005). This protective effect has been established in various large studies over the years (Pradalier et al., 1999; Novembre et al., 2004; Niggeman et al., 2004).
Protection against new sensitizations
A patient receiving SLIT for treating allergy arising from exposure to certain allergens has less chances of developing new sensitizations (or allergies) to other allergens in the environment (Passalacqua et al., 2003; Marogna et al., 2008; Canonica, 2008).
Relative cost effectiveness
SIT has a positive cost-benefit profile. According to Ariano et al. (2006), the cost of SIT in the first 2 years of treatment may be similar to the conventional treatment, but is approximately 4 times less in the ensuing years. We must also not forget the unique long lasting effects of SLIT that other regular treatments do not have.
Adverse Events and Safety Aspects
The issue of the possibility of severe and life threatening events following SCIT was first addressed by English authorities in 1986, who decided that all dosing should only be carried out in highly qualified centers with resuscitation equipment at hand. This led to the sharpened focus of research on the sublingual route as an alternative for the subcutaneous route (Scadding et al., 1986). The favorable safety profile of SLIT is recorded by the observations of Cox et al. (2006) among 14 other studies, which show no reports of any severe adverse effects with the SLIT experience.
Local side effects
Although there may be no injection pricks, there are still mild oral side effects, ranging from generally tolerated itching, burning, and mucosal swelling to typical nausea and diarrhea. Reports of their incidence rates vary from 7% (Lombardi et al., 2001) to up to 86% (Dahl et al., 2006). These side effects can be addressed by dose modification/reduction, and antihistamine administration. Some grass allergen tablets, however, seem to have a higher local side effect ratio, being experienced by 50-80% of patients (Dahl et al., 2006; Didier et al., 2007). A management approach for this reaction was to place the tablets between the teeth and lips, the so-called specific vestibular immunotherapy (SVIT) (Allam et al., 2008).
Systemic side effects
Systemic side effects of SLIT, such as asthma or urticaria, are usually moderate and are reported as rare, versus the 5% rate in the injection form therapy (Tabar et al., 1993).
It was documented that the most feared event of anaphylaxis had never been reported in the literature, except as a result of incautious dosing or human error (Gidaro et al., 2005). There are to date only 4 events of anaphylaxis recorded for the one million doses taken by 4,378 patients reported in the literature. In all cases, successful intervention prevented further disability. Allergen mixtures generally have the disadvantage that adverse reactions cannot be traced back to a single perpetrator. As a result, modern protocols address distinct monoallergen treatments individually, e.g., grass tablets or house dust mite tablets.
How SLIT Is Given
There are 2 phases in a classical immunotherapy schedule: a build-up (induction or up-dosing) phase, where the dose is gradually increased, and a phase of maintenance on the highest dose.
The dosing is usually to be started in the symptom remission phase, months before the pollen season, stopped before the season (”pre-seasonal” schedule) or continued throughout the season (”pre-co-seasonal” schedules). For perennial allergies, the SLIT can be started essentially at any time of the year. In order to attain the desired effect, the best time to start is always 4 months before the expected allergy onset (e.g., pollen season) (Dahl et al., 2006; Didier et al., 2007).
The ultra rush schedule with a buildup of less than 2 hours was first introduced in both adults (Rossi et al., 2005) and children (Tripodi et al., 2005). Recent large-scale trials demonstrated that up-dosing is not needed (Durham et al., 2006; Dahl et al., 2006; Rodriguez et al., 2006).
The efficacy, safety, and tolerability of such administration is ensured in the course of these studies, and the rapid onset can make this form of therapy an option equal to the standard antihistamine/inhaled corticosteroids (ICS) option (Vervloet et al., 2003).
Doses are pre-manufactured and are ready for patient use. In America, SIT is defined as a parenteral administration of an allergen; consequently, SLIT is not FDA approved and its prescription could incur medical liability. Although aqueous extracts were used earlier, tablets have recently been formulated, as the grass pollen tablet, and their efficacy has been evaluated in recent studies (Durham et al., 2006; Didier et al., 2007). They are easy to be administrated and could possibly reach a larger absorptive area and sites of action. Tablets cannot be divided to control the dose; however, there are standardized mixtures of one or a few allergens available.
The actual dose differs according to manufacturers in terms of schedule, amount, and units. For example, the allergen content of some grass tablets is up to 50 times greater than some others (Sander et al., 2009). However, the optimum effective dose recommended is always on the larger side, being 300 IR (Didier et al., 2007) or 75,000 SQ-T (Durham et al., 2006) for grass tablets. This variation has limited comparative studies (Mösges et al., 2006) until recently. Overall, the dose used in SLIT is very high, up to 100 times that used in SCIT (Bousquet et al., 2008). Recent grass allergen studies performed in adults and children tablets (Bufe et al., 2004; Durham et al., 2006) demonstrated superior efficacy at a high dose compared to a lower one.
Gidaro et al. (2005) observed that small doses more commonly led to systemic effects, meanwhile higher doses caused more gastrointestinal side effects. However, the opposite was reported in a larger study with hundreds of patients, that adverse events are dose dependant (Durham et al., 2006).
Practically, the dose is given once daily in the early morning after fasting, and is allowed to dissolve (and be absorbed) sublingually.
Optimal maintenance duration
The optimal maintenance duration that has been carried out in most studies is approximately 4-5 years (Di Rienzo et al., 2003; Marogna et al., 2007) as is the case with SCIT therapy (Bousquet et al., 2008).
Follow-up evaluation parameters
Clinical assessment is reported on a patient clinical diary, in the form of “symptom scores” and the frequency of symptomatic medication use. Clinical examination (of the nose, conjunctivae, and skin of subjects) and allergen exposure challenges are evaluation methods that can demonstrate to the patient measurable improvement, thereby yielding satisfaction and fostering increased compliance. Functional tests like nasal peak inspiratory flow and, for asthmatics, pulmonary function tests and spirometry (Ciprandi et al., 2004) are all sensitive measurements of the treatment effects for SLIT.
The authors report no conflicts of interest.
Calamita Z, Saconato H, Pela AB, Atallah AN. Efficacy of sublingual immunotherapy in asthma: systematic review of randomized-clinical trials using the Cochrane Collaboration method. Allergy 61(10):1162-1172, 2006.
Calderon M, Mösges R, Hellmich M, Demoly P. Towards evidence-based medicine in specific grass pollen immunotherapy. Allergy 65(4):420-434, 2010.
Canonica GW. SLIT Impact in Europe. Symposium 2304. AAAAI Annual Meeting, Philadelphia, Pennsylvania, USA, Mar. 15, 2008.
Cebra JJ, Fuhrmann JA, Griffin P, Rose FV, Schweitzer PA, Zimmerman D. Changes in specific B-cells and the dissemination of the primed state in vivo following antigenic stimulation by different mucosal routes. Ann Allergy 53:541-549, 1984.
Ciprandi G, Cirillo I, Tosca MA, Vizzaccaro A. Bronchial hyperreactivity and spirometric impairment in patients with seasonal allergic rhinitis. Respir Med 98(9):826-831, 2004.
Cirillo I, Pistorio A, Tosca M, Ciprandi G. Impact of allergic rhinitis on asthma: effects on bronchial hyperreactivity. Allergy 64(3):439-444, 2009.
Compalati E, Passalacqua G, Bonini M, Canonica GW. The efficacy of sublingual immunotherapy for house dust mites respiratory allergy: results of a GA2LEN meta-analysis. Allergy 64(11):1570-1579, 2009.
Cox LS, Larenas Linnemann D, Nolte H, Weldon D, Finegold I, Nelson HS. Sublingual immunotherapy: a comprehensive review. J Allergy Clin Immunol 117(5):1021-1035, 2006.
Dahl R, Kapp A, Colombo G, De Monchy JG, Rak S, Emminger W, Rivas MF, Ribel M, Durham SR. Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 118:434-440, 2006.
Di Bona D, Plaia A, Scafidi V, Leto-Barone MS, Di Lorenzo G. Efficacy of sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: A systematic review and meta-analysis. J Allergy Clin Immunol 126(3):558-566, 2010.
Di Rienzo V, Canonica GW, Passalacqua G. Long-lasting effect of sublingual immunotherapy in children with asthma due to house dust mite: a 10 year prospective study. Clin Exp Allergy 33:206-210, 2003.
Di Rienzo V, Minelli M, Musarra A, Sambugaro R, Pecora S, Canonica WG, Passalacqua G.Post-marketing survey on the safety of sublingual immunotherapy in children below the age of 5 years. Clin Exp Allergy 35(5):560-564, 2005.
Didier A, Malling HJ, Worm M, Horak F, Jager S, Montagut A, Andre C, De Beaumont O, Melac M. Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. J Allergy Clin Immunol 120(6):1338-1345, 2007.
Durham SR, Yang WH, Pedersen MR, Johansen N, Rak S. Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 117(4):802-809, 2006.
Durham SR, Emminger W, Kapp A, Colombo G, De Monchy JG, Rak S, Scadding GK, Andersen JS, Riis B, Dahl R. Long-term clinical efficacy in grass pollen-induced rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet. J Allergy Clin Immunol 125(1):131-138, 2010.
Eng PA, Reinhold M, Gnehm HP. Long-term efficacy of preseasonal grass pollen immunotherapy in children. Allergy 57(4):306-312, 2002.
Fiocchi A, Pajno G, La Grutta S, Pezzuto F, Incorvaia C, Sensi L, Marcucci F, Frati F. Safety of sublingual-swallow immunotherapy in children aged 3 to 7 years. Ann Allergy Asthma Immunol 95(3):254-258, 2005.
Gafvelin G, Thunberg S, Kronqvist M, Grönlund H, Grönneberg R, Troye-Blomberg M, Akdis M, Fiebig H, Purohit A, Horak F, Reisinger J, Niederberger V, Akdis CA, Cromwell O, Pauli G, Valenta R, van Hage M. Cytokine and antibody responses in birch-pollen-allergic patients treated with genetically modified derivatives of the major birch pollen allergen Bet v 1. Int Arch Allergy Immunol 138(1):59-66, 2005.
Gidaro GB, Frati F, Sensi L, Incorvaia C, Frati F, Ciprandi G. The safety of sublingual-swallow immunotherapy: an analysis of published studies. Clin Exp Allergy 35: 565-571, 2005.
Horak F, Jaeger S, Worm M, Melac M, Didier A. Implementation of pre-seasonal sublingual immunotherapy with a five-grass pollen tablet during optimal dosage assessment. Clin Exp Allergy 39(3):394-400, 2009.
Ippoliti F, De Santis W, Volterrani A, Lenti L, Canitano N, Lucarelli S, Frediani T. Immunomodulation during sublingual therapy in allergic children. Pediatr Allergy Immunol 14:216-221, 2003.
Jutel M, Jaeger L, Suck R, Meyer H, Fiebig H, Cromwell O. Allergen-specific immunotherapy with recombinant grass pollen allergens. J Allergy Clin Immunol 116(3):608-613, 2005.
Khinchi MS, Poulsen LK, Carat F, André C, Hansen AB, Malling HJ. Clinical efficacy of sublingual and subcutaneous birch pollen allergen-specific immunotherapy: a randomized, placebo-controlled, double-blind, double-dummy study. Allergy 59(1):45-53, 2004.
Kleine-Tebbe J, Ribel M, Herold DA. Safety of a SQ-standardised grass allergen tablet for sublingual immunotherapy: a randomized, placebo-controlled trial. Allergy 61(2):181-184, 2006.
Li JT, Lockey RF, Bernstein IL, Portnoy JM, Nicklas RA. Allergen immunotherapy: a practice parameter. Ann Allergy Asthma Immunol 90(1):1-40, 2003.
Ling EM, Smith T, Nguyen XD, Pridgeon C, Dallman M, Arbery J, Carr VA, Robinson DS. Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet 363(9409):608-615, 2004.
Lombardi C, Gargioni S, Melchiorre A, Tiri A, Falagiani P, Canonica GW, Passalacqua G. Safety of sublingual immunotherapy with monomeric allergoid in adults: multicenter post-marketing surveillance study. Allergy 56(10):989-992, 2001.
Macatonia SE, Hosken NA, Litton M, Vieira P, Hsieh CS, Culpepper JA, Wysocka M, Trinchieri G, Murphy KM, O’Garra A. Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J Immunol 154(10):5071-5079, 1995.
Marogna M, Bruno M, Massolo A, Falagiani P. Long-lasting effects of sublingual immunotherapy for house dust mites in allergic rhinitis with bronchial hyperreactivity: A long-term (13-year) retrospective study in real life. Int Arch Allergy Immunol 142(1):70-78, 2007.
Marogna M, Tomassetti D, Bernasconi A, Colombo F, Massolo A, Businco AD, Canonica GW, Passalacqua G, Tripodi S. Preventive effects of sublingual immunotherapy in childhood: an open randomized controlled study. Ann Allergy Asthma Immunol 101(2):206-211, 2008.
Mösges R, Pasch N, Schlierenkämper U, Lehmacher W. Comparison of the biological activity of the most common sublingual allergen solutions made by two European manufacturers. Int Arch Allergy Immunol 139(4):325-329, 2006.
Marogna M, Spadolini I, Massolo A, Canonica Gw, Passalacqua G. Clinical, functional, and immunologic effects of sublingual immunotherapy in birch pollinosis: A 3-year randomized controlled study. J Allergy Clin Immunol 115(6):1184-1188, 2005.
Nettis E, Di Leo E, Calogiuri G, Milani M, Donne P, Ferrannini A, Vacca A. The safety of a novel sublingual rush induction phase for latex desensitization. Curr Med Res Opin 26(8):1855-1859, 2010.
Niggemann B, Jacobsen L, Dreborg S, Ferdousi Ha, Halken S, Host A, Koivikko A, Koller D, Norberg La, Urbanek R, Valovirta E, Wahn U, Moller C. Five-year follow up on the PAT study: specific immunotherapy and long-term prevention of asthma in children. Allergy 61:855-859, 2006.
Noon L. Prophylactic inoculation against hay fever. Lancet 1:1572-1573, 1911.
Novak N, Haberstok J, Bieber T, Allam JP. The immune privilege of the oral mucosa. Trends Mol Med 14(5):191-198, 2008.
Novembre E, Galli E, Landi F, Caffarelli C, Pifferi M, De Marco E, Burastero SE, Calori G, Benetti L, Bonazza P, Puccinelli P, Parmiani S, Bernardini R, Vierucci A. Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol 114(4):851-857, 2004.
Ott H, Sieber J, Brehler R, Fölster-Holst R, Kapp A, Klimek L., Pfaar O, Merk, H. Efficacy of grass pollen sublingual immunotherapy for three consecutive seasons and after cessation of treatment: the ECRIT study. Allergy 64(1):179-186, 2009.
Pajno GB, Caminiti L, Vita D, Barberio G, Salzano G, Lombardo F, Canonica GW, Passalacqua G. Sublingual immunotherapy in mite-sensitized children with atopic dermatitis: a randomized, double-blind, placebo-controlled study. J Allergy Clin Immunol 120(1):164-170, 2007.
Passalacqua G, Albano M, Riccio AM, Fregonese L, Puccinelli P, Parmiani S, Canonica GW. Clinical and immunological effects of a rush sublingual immunotherapy to parietaria species: a double blind placebo controlled trial. J Allergy Clin Immunol 104:964-968, 1999.
Passalacqua G, Di Rienzo V, Marcucci F, Puccinelli P, Parmiani S, Frati E, Sensi L, Canonica G. Long-lasting efficacy of sublingual immunotherapy in children. J Allergy Clin Immunol 111: S72, 2003.
Passalacqua G, Musarra A, Pecora S, Amoroso S, Antonicelli L, Cadario G, Di Gioacchino M, Lombardi C, Ridolo E, Sacerdoti G, Schiavino D, Senna G. Quantitative assessment of the compliance with once-daily sublingual immunotherapy in children (EASY project: evaluation of a novel SLIT formulation during a year). Pediatr Allergy Immunol 18(1):58-62, 2007.
Penagos M, Compalati E, Tarantini F, Baena-Cagnani R, Huerta J, Passalacqua G, Canonica GW. Efficacy of sublingual immunotherapy in the treatment of allergic rhinitis in pediatric patients 3 to 18 years of age: a meta-analysis of randomized, placebo-controlled, double-blind trials. Ann Allergy Asthma Immunol 97(2):141-148, 2006.
Pradalier A, Basset D, Claudel A, Couturier P, Wessel F, Galvain S, Andre C. Sublingual-swallow immunotherapy (Slit) with a standardized five-grass-pollen extract (drops and sublingual tablets) vs. placebo in seasonal rhinitis. Allergy 54:819-828, 1999.
Radulovic S, Calderon M, Wilson D, Durham SR. Cochrane systematic review: Safety profile of sublingual immunotherapy (SLIT) for allergic rhinitis (AR). J Allergy Clin Immunol 121(2):142-142, 2008.
Rodriguez F, Boquete M, Ibanez MD, De La Torre-Martinez F, Tabar AI. Once daily sublingual immunotherapy without updosing - A new treatment schedule. Int Arch Allergy Immunol 140(4):321-326, 2006.
Romagnani S. Regulatory T cells: which role in the pathogenesis and treatment of allergic disorders? Allergy 61(1):3-14, 2006.
Rossi RE, Monasterolo G. A pilot study of feasibility of ultra-rush (20-25 minutes) sublingual-swallow immunotherapy in 679 patients (699 sessions) with allergic rhinitis and/or asthma. Int J Immunopathol Pharmacol 18(2):277-285, 2005.
Sander I, Fleischer C, Meurer U, Bruning T, Raulf-Heimsoth M. Allergen content of grass pollen preparations for skin prick testing and sublingual immunotherapy. Allergy 64(10):1486-1492, 2009.
Savolainen J, Jacobsen L, Valovirta E. Sublingual immunotherapy in children modulates allergen-induced in vitro expression of cytokine mRNA in PBMC. Allergy 61:1184-1190, 2006.
Scadding K, Brostoff J. Low dose sublingual therapy in patients with allergic rhinitis due to dust mite. Clin Allergy 16:483-491, 1986.
Schramm C, Herz U, Podlech J, Protschka M, Finotto S, Reddehase MJ, Köhler H, Galle PR, Lohse AW, Blessing M. TGF-beta regulates airway responses via T cells. J Immunol 170:1313-1319, 2003.
Tabar AL, Garcia BE, Rodriquez A, Olaguibel JM, Muro MD, Quirce S. A prospective safety monitoring study of immunotherapy with biologically standardized extracts. Allergy 48:450-453, 1993.
Tripodi S, Di Rienzo Businco A, Benincori N, Scala G, Pingitore G. Safety and tolerability of ultra-rush induction, less than one hour, of sublingual immunotherapy in children. Int Arch Allergy Immunol 139(2):149-152, 2005.
Vervloet D, Birnbaum J. Safety and clinical efficacy of rush sublingual Juniperus Ashei immunotherapy. Proceedings of EAACI 228, 2003.
Wachholz PA, Soni NK, Till SJ, Durham SR. Inhibition of allergen-IgE binding to B cells by IgG antibodies after grass pollen immunotherapy. J Allergy Clin Immunol 112(5):915-922, 2003.
Wahn U, Tabar A, Kuna P, Halken S, Montagut A, De Beaumont O, Le Gall M. Efficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis. J Allergy Clin Immunol 123:160-166, 2009.
Wynn SR. Immunotherapy compliance-a shot in the dark? Ann Allergy Asthma Immunol 74:195-197, 1995.
[Discovery Medicine; ISSN: 1539-6509; Discov Med 10(53):348-354, October 2010.]