Application Of a Standardized Titrated Nasal Provocation Test With HDM and Birch Pollen Extract In Multicentre Clinical Studies In Allergic Rhinitis

Background: Titrated nasal provocation tests (TNPT) can be used in the diagnosis of allergic rhinitis (AR) and as a disease model in clinical trials evaluating the efficacy of treatment. However, the techniques for provocation and readouts vary, requiring standardization to enable the use of TNPT as a tool in multi-centre trials. We performed a standardized TNPT with HDM and birch pollen extracts in two separate clinical trials investigating the dose response curve of allergen immunotherapy products. The upper airway response by symptom scores and peak nasal inspiratory flow (PNIF) measurements was documented. In addition, we compared the upper airway responses across the different allergen concentrations and investigated a possible correlation.

Methods: Patients with suspected HDM or birch pollen induced AR were screened prior to enrollment into two multicentre efficacy studies with allergen immunotherapy. Patients with a positive medical history and a positive skin prick test to either HDM or birch pollen underwent a standardized TNPT starting with the diluent and up to 3 serial concentrations of a standardized allergen extract (D. Pter or Betula verrucosa 100, 1,000 and 10,000 AU/ml, 1 puff per nostril) at 20 minutes intervals. The upper airway response was quantified by a composite symptom score according to Lebel (0-11) and a PNIF measurement 15 minutes after each administration. TNPT was considered positive once a score ≥6 was reached. Symptom scores and PNIF were repeated 1 hour after the provocative allergen concentration.

Results: In the HDM study 150 patients were screened. For 103 patients (54M/49F) a positive TNPT with both symptom scores and PNIF results were available. In the birch study a total of 317 patients was screened and for 245 patients (120M/125F) a positive PNIF with both symptom scores and PNIF results were available. In both TNPTs the most prominent symptom was nasal blockage followed by rhinorrhoea in the HDM patients and pruritus in the birch pollen patients. A consistent dose-response relationship was found between serial allergen concentrations and increasing symptom scores, matching a gradual decrease in PNIF. One hour after the provocative allergen concentration, both measurements had not returned to baseline values. There was a moderate though highly significant correlation between symptom scores and PNIF (r=0.54 for HDM; r=-0.51 for Birch pollen; p<0.01).

Conclusions: When applied in a multi-centre setting in patients with suspected HDM or birch pollen induced AR, a standardized TNPT with an allergen extract  induces a consistent gradual increase in allergic symptoms and signs that can be reliably quantified by well-defined composite symptom scores and PNIF. These results indicate that the TNPT can be used with both seasonal and perennial allergens in dose response studies with immunotherapy products.