During the last decades, the prevalence of allergy has dramatically increased. Allergen-specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease, but there are still many questions and unmet needs hindering its widespread use to fulfill its treatment potential and maximize its benefits for the society. To provide a comprehensive phenome-wide overview in sublingual immunotherapy, using ragweed allergy as a target, we planned and carried out a longitudinal, prospective, observational, open-label study (DesensIT). In this paper we present challenges of using deep and comprehensive phenotypes embracing biological, clinical and patient-reported outcomes in allergen-specific immunotherapy and show how we designed the DesensIT project to optimize data collection, processing and evaluation.