To the EditorIs the potential clinical benefit of allergen immunotherapy underestimated in multicentre studies?The clinical efficacy of allergen immunotherapy (AIT) is documented by clinical studies. The standards for clinical trials study design, patient’s selection, appropriate outcomes and statistical treatment have been described by World Allergy Organization (1). As the primary outcome in patients with allergic rhinoconjunctivitis a combined symptom and medication score are recommended as a simple and standardized method that balances both symptoms and the need for antiallergic medication in an equally weighted manner (2). The latest EAACI Guidelines on Allergen Immunotherapy for allergic rhinoconjunctivitis state the indication for AIT to patients experience moderate-to-severe symptoms which interfere with usual daily activities or sleep despite regular and appropriate pharmacotherapy and/or avoidance strategies (3). A problem in recent AIT studies is that in order to include sufficient numbers of patients, they need to be multicentre trials often involving several countries. A fundamental requirement for being able to documenting a beneficial effect of the intervention (AIT), patients included should have a minimum of rhinoconjunctivitis symptoms.A recent published study of tree-pollen sublingual immunotherapy (4) needs some comments. The severity of the disease in the included patients are reflected in the symptom and medication score of placebo-treated patients. The mean daily symptom score (DSS) in the placebo-group during the birch pollen season was 2.75 (on a scale 0-18). The daily mean medication score in the placebo-group was 2.42 (on a scale 0-20) (Figure 1). The implications of these disease scores are that for symptoms the placebo (or untreated) patients have a mean daily symptom score ≈ 0.5 on a scale 0-3 for 6 individual symptoms and for medication the placebo (untreated) patients have a mean intake of < ½ antihistamine per day. The disease severity in the placebo group shows that: either patients have not been selected as having moderate-to-severe rhinitis or pollen exposure at some centres have been so low that correctly included patients have virtually had no clinical symptoms. A suspicion that the latter is the most likely comes from data on “Severe days” (defined as DSS ≥ 6 and ≥2 moderate symptoms or 1 symptom assessed as severe). The proportion of severe days during the birch season was for the placebo group 0.23 [95% CI: 0.17, 0.29]. The proportion of symptom-free days (no symptoms and no use of rescue medication) was 0.24 [95% CI: 0.23, 0.25] in the placebo group. The implications are that untreated patients (placebo) have 23% of days with severe symptoms (although the definition does not imply disabling symptoms) and 24% symptom-free days.In seasonal allergy trials, the observed treatment effect is highly dependent on pollen exposure with the magnitude of efficacy being greater with higher pollen exposure (5). The treatment effects are therefore diluted by including patients with minimal symptoms. A possible method to circumvent this problem is to group study centres into tertiles according to symptom observed in the placebo patients in each centre (low, middle and high tertiles) (6). This allows an estimation of the efficacy that could be achieved in patients from sites where symptoms were severe during the pollen season.ConclusionThe use of a tertile approach to analyse efficacy of AIT in seasonal allergic rhinitis clinical studies can give a more accurate assessment of the potential maximal clinical benefit. By giving information of efficacy based on tertiles in the key secondary endpoints allow for evaluating the potential benefit of AIT in centres with a low, middle and high symptom-medication score in placebo patients. When only presenting average data using the full analysis set of all subjects the full capacity of the treatment will be diluted due to inclusion of virtually asymptomatic patients.Hans-Jørgen Malling, MD, DMSchttps://orcid.org/0000-0003-4868-6307Allergy Clinic, Copenhagen University Hospital Gentofte, Gentofte Hospitalsvej 8, DK 2900 Hellerup, DenmarkCorresponding author contact: hjmalling@dadlnet.dkNo fundingThe author declare no conflict of interests in relation to this workWord counts 598ReferencesG. W. Canonica, C. E. Baena-Cagnani, J. Bousquet et al. Recommendations for standardization of clinical trials with Allergen Specific Immunotherapy for respiratory allergy. A statement of a World Allergy Organization (WAO) taskforce. 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