REVIEW SCUAD and chronic rhinosinusitis. Reinforcing hypothesis driven research in difficult cases* Abstract Background: Our objective is to present recent research fndings on recalcitrant chronic rhinosinusitis (CRS) in relation to “Severe Chronic Upper Airway Disease” (SCUAD). Methodology: Literature review using Medline and Embase databases (search terms ‘chronic rhinosinusitis”, “chronic sinusitis” or “Severe Chronic Upper Airway Disease”) limited to articles published in the English language. Results: Complex pathophysiological mechanisms characterize various forms of chronic rhinitis and rhinosinusitis (CRS), where infammation persists in spite of adequate medical treatment. In these cases, a multifactorial etiology often underlies the deve- lopment of sino-nasal infammation. The interaction between chronic upper and lower airway infammation via neurogenic and systemic pathways may complicate the therapy of these patients, and lead to insufcient symptom control. Conclusion: The recently introduced defnition of “Severe Chronic Upper Airway Disease” (SCUAD) increases awareness of those patients with persistent infammation and symptoms despite guideline-driven pharmacologic treatment. The concept of SCUAD may prove helpful in directing research towards clarifying the defnition, diagnosis and pathophysiology of rhinitis and rhinosinu- sitis, their limits and overlap. In this review, a hypothesis on SCUAD immunopathology is also presented. Key words: chronic rhinosinusitis, severe chronic upper airways disease, defnitions, pathophysiology Emmanuel P. Prokopakis 1 , Ioannis M. Vlastos 1 , Berrylin J. Ferguson 2 , Glenis Scadding 3 , Hideyuki Kawauchi 4 , Christos Georgalas 5 , Nikolaos Papadopoulos 6 , Peter W. Hellings 5,7 1 Department of Otorhinolaryngology, University of Crete School of Medicine, Heraklio, Crete, Greece 2 Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, USA 3 Department of Allergy and Medical Rhinology, Royal National TNE Hospital, London WC1X8DA, United Kingdom 4 Department of Otorhinolaryngology, Shimane University, Faculty of Medicine, Izumo, Japan 5 Department of Otorhinolaryngology, Academic Medical Centre, Amsterdam 6 Department of Pedo-Allergiollogy, University of Athens, Greece 7 Department of Otorhinolaryngology, University Hospitals Leuven, Leuven, Belgium Rhinology 52: 3-8, 2014 DOI:10.4193/Rhino13.049 *Received for publication: April 29, 2013 Accepted: September 12, 2013 3 Introduction Severe Chronic Upper Airway Disease (SCUAD) is a term recently introduced by Bousquet et al. (1) defning those patients with al- lergic (AR), non-allergic (NAR), and occupational rhinitis (OR) and chronic rhinosinusitis (CRS) with and without nasal polyposis, whose symptoms are inadequately controlled despite pharma- cological treatment following international validated guidelines, such as ARIA (2,3) and EPOS2012 (4) . Chronic infammatory disor- ders of the upper airways are extremely prevalent and have a major impact on public health and the socioeconomic state (2,3) . It is estimated that up to one third of rhinitis and rhinosinusitis patients present with persistent infammation and/or symptoms despite adequate treatment (3,4) . In other words, a great number of these patients fail to respond to treatment options suggested by guidelines such as antibiotics, steroids or surgery. Moreover, these disorders commonly complicate diagnosis and manage- ment of diseases of the lower airways. The group of SCUAD patients is a subgroup of patients that challenge the currently