Administration regimens for sublingual immunotherapy to pollen allergens: What do we know?
Allergy and Respiratory Diseases
Department of Internal Medicine
L.go R. Benzi 10
The modalities of administration of sublingual immunotherapy (SLIT), including dosing, build-up phase, duration of the treatment, and frequency of the maintenance dose are largely variable. In the case of pollen (SLIT), the complexity increases, since preseasonal, coseasonal and pre-coseasonal regimens can be used. The administration regimens are of relevance from a practical point of view, but can also have economic implications. We review herein the available literature (randomized double blind controlled studies) on pollen SLIT, in order to derive experimentally-supported suggestions about the regimens of administration that should be preferred.
Nowadays, there is reliable evidence of the clinical efficacy of sublingual immunotherapy (SLIT) in respiratory allergies, as testified by more than 50 randomized controlled trials and meta-analyses, in adult and pediatric patients, with allergic rhinitis and/or bronchial asthma (1–5). In addition, as a distinctive characteristic, SLIT possesses a very favorable safety profile (1, 6). In fact, the most common side effects are local or gastrointestinal, but they are generally be mild and self-limiting, or manageable by temporary dose reduction. The safety profile seems not to be different in very young children (7, 8). Similarly to injection immunotherapy, the literature would suggest that SLIT is capable of preventing the onset of new sensitizations and of reducing the risk of asthma onset in pediatric patients with allergic rhinitis (9, 10). The most recent controlled trials (11–16), involving hundreds of subjects, have clearly demonstrated, at least for grass pollen, a clinical efficacy over placebo far greater than the recommended 20% (17), in addition to a dose-dependent effect.
One of the most important and debated aspects of SLIT is the regimen of administration. Usually, it involves an up-dosing phase with gradual increase of the doses, followed by a maintenance phase. This modality is directly derived by the injection route of immunotherapy. Concerning the maintenance phase, the extract can be given daily, on alternate days or once a week, based on personal experiences and empirical considerations. Also, the dose of allergen is largely variable and there are both positive and negative studies over a wide range of doses (from 2 to 375 times the doses used for injections). Another source of uncertainty is that for pollen allergens, SLIT can be given as preseasonal (start before and stop at the beginning of the pollen season), coseasonal (start and end with the pollen season), precoseasonal (start before the pollen season end continue until the end of it), or continuous (all year, independent of the pollen season). Thus, there is an urgent need for definition and uniformation of doses, regimens and administration schedules, especially for pollen allergens. The regimen of administration and the duration may have also economic implications.
Very recently, the regulatory authorities have started to afford the pharmaco-economic aspects of SLIT, with a special attention paid to the reimbursement modalities. For instance, in Italy the local council of Regione Lombardia has licensed a rule which restricts the reimbursement of pollen SLIT only to short precoseasonal courses of the duration of 3 months or less. (‘Concerning sublingual specific immunotherapy with seasona allergens (e.g. grass, birch, parietaria, compositae and ragweed), according to the numerous published studies, a pre-coseasonal treatment of three months is indicated’) (18).
These restrictions seems to be not justified or supported by the available literature, as detailed below, and could result in the risk of inappropriate treatment, with a consequent loss of the potential benefits of SLIT.
When making an objective evaluation of the clinical efficacy and dosing regimens of SLIT, only randomized, double blind and placebo-controlled trials must be taken into account, as recommended by the Evidence Based Medicine rules (19). The studies should include patients with ascertained respiratory allergy due to pollens only, and receiving well defined doses.
There are 41 studies of SLIT for pollen allergens (11–16, 20–54), as listed in Table 1. All the 41 studies included patients with seasonal allergic rhinitis, and in 15 trials the patients had also mild to moderate seasonal allergic asthma. The studies were conducted with different allergens: grasses in 25 trials, Parietaria in five, cypress-cedar in four, ragweed in two, birch in two, olive in one, trees plus birch in one, and grass plus olive in one. It is not possible to exactly determine or compare in all studies the dose of allergen in micrograms of major allergen, since extracts were quantified in various units, including BU, PNU, SQ-U, SE-U, Aueq, SU/ml, TU, wt/vol and HEP. Nevertheless one firm point is that the dose of extract for SLIT must be higher than for injection immunotherapy (high-dose SLIT). At least for grass pollen, the dose-ranging studies have shown that a monthly maintenance dose of about 600 mcg major allergen(s) achieves the best efficacy (12, 13).
Table 1. Characteristics (allergen, duration, regimen, dose/preparation) of SLIT in 41 randomized controlled studies with pollens extracts 1994–2009
|(20)||Grass||4 months||Precoseasonal||Daily, then 3/week||40 days||210 μg Dac g 5 Glycerosaline|
|(21)||Grass||4 months||Precoseasonal||3/week||15 days||19 mcg grass per month. glycerol-phenol|
|(22)||Parietaria||6 months||Precoseasonal||3/week||50 days||1 μg Par j 1 per month glycerophenol|
|(25)||Olive||6 months per 2 seasons||Precoseasonal||Daily||2 months||1.215 μg Ole e 1/month. Glycerophenol|
|(23)||Grass||6 months||Precoseasonal||Daily||25 days||288 mcg Phl p 5/month. Aqueous|
|(24)||Birch||4 months||Precoseasonal||3/week||28 days||62 μg Bet v 1/month. Glycerophenol|
|(26)||Grasses||6 months||Precoseasonal||2/week||21 days||4.250 BU/month Glycerinated|
|(27)||Parietaria||5 months||Preseasonal||Daily||15 days||3.6 μg Par j 1/mo. Cumulative: 16 mcg Par j 1 Glycerophenol|
|(29)||Grass||4 months||Precoseasonal||Daily||15 days||255 μg Phl p5/month. Cumulat 935 μg Glycerophenol/tablets|
|(30)||Parietaria||6 months per 2 seasons||Continuous||3/week||40 days||2 730 μg Par j 1/mo; cumulat : 52.5 mg|
|(28)||Parietaria||8 months||Precoseasonal||3/week||2 weeks||1.5 μg Par j 1/mo; cumulat 12 mcg Par j 1 Glycerophenol|
|(32)||Grass (monoid)||14 weeks||Preseasonal||3/week||2 months||12 000 AU/mo. Cumulative 37 000 AU|
|(31)||Grass||4 months||Precoseasonal||3/week||28 days||Cumul 210 μg Dac g 5; Glycerosaline|
|(33)||Cypress||8 months||Precoseasonal||3/week||50 days||30 000 RU/mo, Cumulat 300 000 Glycerine-Acque|
|(34) (second year open)||Birch||24 months per 2 seasons||Precoseasonal||3/week||18 days||90 μg Bet v 1/mo Glycerophenol|
|(35)||Grass||18 months||Continuous||Daily||6 weeks||0.9 mg Phl p 5 per month Glycerinate|
|(36)||Ragweed three doses||7 months||Precoseasonal||3/week||28 days updos + 30 days transition ||1.4–4.0 mg Amb a 1/month Solution/tablets|
|(37) (vs plac/control)||Parietaria||13 months||Precoseasonal||3/week||25 days||1.56 μg Par j 1/month; Cumul: 23 μg. Glycerosaline|
|(38)||Grass||2 years 2 seasons||Continuous||Daily||30 days||6 μg/month glycero-phenol|
|(39)||Grass||1 year + 2 open||Continuous||Daily||3 weeks||273 μg Phl p 5/month; Cumul: 9.6 mg. Solution|
|(40)||Grass||1 year or 2 years||Precoseasonal||3/week||2 months||329 μg Dac g 5/month Solution-tablets|
|(41)||Grass||3 years||Continuous||3/week||4 weeks||6 μg major/month. Glycerophenol|
|(42)||Ragweed three doses||4 months||Coseasonal||Daily||17-days||3.1–9.4 mg Amb a 1/month.|
|(12)||Grass three doses||6 months||Precoseasonal||Daily||No||15 μg (136 pts); 150 μg (139 pts); 450 μg (294 pts) Phl p 5/month tablets|
|(11)||Grass||5 months||Precoseasonal||Daily||No||450 μg Phl p 5/month. Cumulat. 2.7 mg tablets|
|(43)||Hazelnut, birch, elm (2 doses)||18 months two seasons||Continuous||Daily||5 weeks||Group 1 3.6 mcg and Group 2 30 mcg per week|
|(45)||Grass||6 months||Precoseasonal||Daily||NO||450 μg Phl p 5/month. Cumulat. 2.7 mg Tablets|
|(44)||Grass (monoid)||2 years two seasons||Preseasonal||2/week||14 weeks||8000 AU/month Tablets|
|(47)||Juniper||4 months per two season||Coseasonal||Daily|| 1 day||6 mg Jun a 1/month Glycerol-aqueous|
|(46)||Grass||2 years two seasons||Continuous||2/week||20 days||168 μg Lol p 5/month; cumul 4.5 mg. Solution|
|(13)||Grass three doses||6 months||Precoseasonal||Daily||5 days||240 μg (157 pts); 750 μg (155 pts); 1.2 mg (160 pts)/month. Tablets|
|(48)||Jap cedar||7 months||Precoseasonal||1/week||1 month||6 μg Cry j 1/month Solution. Spit|
|(49)||Grass||10 months||Precoseasonal||3/week||5 weeks||250 μg group 5/month; cumul: 2.5 mg. Solution|
|(50)||Olive + Grass||10 months||Precoseasonal||Daily||NO||60 μg group 5 and 90 μg Ole e 1/month. Solution|
|(51)||Grass||9 months||Precoseasonal||Daily||2 months||Cumulative 3.5 mg Phl p 5|
|(52)||Grass||1 year||Precoseasonal||Daily||50 days||38 μg Lol p 5/month; Cumul 456. Solution; SLIT or supralingual|
|(53)||Cedar||5 months||Precoseasonal||1/week||6 weeks||2000 JAU|
|(54)||Grass||2 years 2 seasons||Continuous||Daily||1 day||1.2 mg/month Solution|
|(14)||Grass||8 months||Precoseasonal||Daily||NO||600 μg major allergen/month. Tablets|
|(15)||Grass||3 months per 4 years||Coseasonal||Daily||1 day||750 μg major allergen/month tablets|
|(16)||Grass||6 months||Precoseasonal||Daily||NO||450 mcg Phl p 5/month tablets|
Due to the favorable safety profile, it has become progressively clear that the build-up phase could be not necessary, and that starting with the maintenance dose does not increase the risk of side effects (55, 56). This was confirmed in some of the recent large trials where the no-updosing protocol was used. Moreover, in 21 of the studies an once-daily regimen, instead of each-other-day (13 studies) or less, was used. Of note, the once-daily administration was applied in six studies, including the largest trials (11–16). The no build-up and the once daily administration schedule are more patient-friendly and are expected to improve the compliance and would avoid dosing mistakes. For this reason, they should be probably preferred.
The duration of treatment, the dosing regimen and the period of follow-up varied considerably among studies. The duration of SLIT courses varied from 3 months (minimum duration) to 3 years (maximum duration). The administration regimen was preseasonal in three studies (27, 32, 44), co-seasonal in three (15, 42, 47), and continuous in eight trials (30, 35, 38, 39, 41, 43, 46, 54), despite the allergen was seasonal. In the remaining 27 trials the adopted regimen was precoseasonal. All the ‘big trials’ with grass extracts were conducted with a precoseasonal schedule of administration, with the exception of one study which used a co-seasonal regimen (15). This latter study, involving a 3-month SLIT was conducted in Germany, where the grass pollen season is usually shorter than in the Mediterranean area. In this area, the grass pollen season is often longer than 1 month, and for other plants, such as Parietaria, the pollen season always exceeds 6 months in duration. Moreover, the results of that study with grass pollen cannot be immediately transferred to all the remaining allergens. In addition, it has been clearly demonstrated that a preseason period of at least 8 weeks is required to achieve an optimal effect with grass pollen (57). Concerning the preventative effects of SLIT, in one of the two studies (9) the treatment was given coseasonally for 4 months, and in the other one (10) the SLIT was given continuously. One randomized open trial with birch pollen SLIT given continuously achieved a significant benefit in rhinitis and asthma, and the benefit progressively increased over the considered 5-year period (58). Finally, for pollen allergens, there is no study directly comparing the various alternatives (preseasonal, precoseasonal, coseasonal or continuous). Nonetheless, the large majority of the trials utilized the precoseasonal regimen, and therefore this should be considered the optimal choice.
The overall evaluation of the available literature on SLIT would suggest that a precoseasonal regimen, starting at least 8 weeks before the pollen season would be the best choice for pollen SLIT. Of course a continuous regimen (all year round) for pollen allergens is associated with higher expenditures, although the pharmaco-economy data suggest that also in this case, in the long periods, SLIT is dominant over pharmacotherapy alone (58). The once-a-day administration of the maintenance dose would improve the convenience for the patient, as well as the omission of the induction phase. Policymakers and health authorities should carefully evaluate the evidence from the literature, as well as the characteristics of the local pollen seasons before imposing unjustified restrictions to reimbursement.