Research needs and search strategies
9.1. Introduction
The search strategies for all the (subchapters) include many pages. For that reason it was chosen to only have them online. You can find them at

While our understanding of CRS has increased considerably, this only serves to outline areas that will require further exploration and clinical trials for validation of observations and hypotheses.

9.2. Classification and Definitions
Much of the problems which have beset our understanding of rhinosinusitis, particularly chronic forms is the difficulty of defining populations for study. Thus there remains the need for clear and widely accepted guidelines on the design of clinical trials which indicate:
  • how to define the study population
  • choice of outcome measurements
  • choice of instruments to evaluate QoL.

It may also be advantageous to introduce some form of additional aetiological qualification to our classification systems which might be based on ICD coding.

There is also a need for the development of better objective staging systems that correlate with patient symptoms and QoL.
9.3. Acute rhinosinusitis
In acute rhinosinusitis, we need:

  • To know what factors determine whether ARS patients in the community consult with a doctor, pharmacist or self-manage without professional support
  • To demonstrate the prevalence of ARS in low, middle and high income countries and consider whether any predisposing factors differ dependant on income.
  • To develop a validated disease-specific QoL questionnaire specific to acute rhinosinusitis.
  • To establish if early use of therapies in viral URTI prevent bacterial ARS, particularly in those with recurrent ARS or at risk of complications.
  • To confirm if there are combinations of symptoms and signs that predict acute bacterial rhinosinusitis in Primary and Secondary Care.
  • To show if the relative frequency of different symptoms and signs in ARS predict a differential response to different therapies, such as topical steroids and antibiotics?
  • To determine what constitutes a clinically important response to antibiotics in ARS eg change in purulence of nasal discharge.
  • To determine biomarkers (eg CRP, procalcitonoin) that can predict acute bacterial rhinosinusitis or a clinically important response to antibiotics in ARS?
  • To confirm whether topical nasal steroids can be the first-line treatment for ARS in Primary Care and consider whether there are clinically important differences between different topical nasal steroid molecules and dosing regimes
  • To show whether the provision of educational and information materials for patients improve outcomes of ARS and reduce non-essential antibiotic use?
  • To demonstrate whether professional education and efficient dissemination of evidence-based guidelines to clinicians improve outcomes of ARS and reduce non-essential antibiotic use?
  • To show if the clinical and economic outcomes of ARS differ depending on which health professionals (e.g. rhinologists, ENT specialists, GPs, pharmacists?) manage patients.
  • Large epidemiological data collection on the true incidence of complications in ARS, determining the role of Primary Care physicians in the detection and/or prevention of complications and whether complications of ARS relate to access to medical care?
  • A large prospective study on the role of antibiotics in the prevention of acute complications.
  • A randomised trial of drainage versus intravenous antibiotics for small abscesses in young children (orbital and intracranial)
  • Large population studies characterizing co-morbidities in patients with ARS, compared to matched controls to identify significant co-morbidities or risk factors.
  • Studies to establish how allergic rhinitis increases the predisposition for rhinosinusitis and specifically if it increases the likelihood of S. pneumoniae sinus infection.
  • Assuming this is confirmed, studies to establish whether regular antihistamines and/or leukotriene receptor antagonists are effective in reducing ARS episodes in patients with allergic rhinitis.
  • To determine how exposure to cigarette smoke increases the predisposition for ARS, to establish whether exposure to cigarette smoke (active or passive) augments the predisposition for ARS in patients with allergic rhinitis and to show whether smoking cessation improves the frequency of ARS compared to active smokers.
  • To establish the prevalence of ARS in the Primary Ciliary Dyskinesia population, to determine whether aggressive treatment of ARS in patients with PCD prevents recurrence of ARS or development of CRS and to establish if aggressive treatment of ARS affects the progression of PCD-related bronchiectatic lung disease.
9.4. Chronic rhinosinusitis with or without NP
In chronic rhinosinusitis we need:

  • To consider if the prevalence of and predisposing factors for CRSsNP and CRSwNP differs in low, middle and high income countries
  • To determine the relative frequency and prognostic significance of different symptoms and signs in CRSsNP and CRSwNP in Primary Care.
  • To refine severity staging and its impact on QoL, using both subjective and objective measures
  • For endotyping and phenotyping, to define the minimal criteria for measuring sinus inflammation. eg sampling procedures and expression of data should be unified (ng of cytokine per ml, mg of tissue or protein content) so that a meta-analysis may be done.
  • To refine the inclusion criteria of non-ENT control groups.
  • To consider response to standard treatments for endotyping.
  • A long-term study on the natural history of osteitis.
  • A randomised trial comparing different treatment options for patients with CRS with significant osteitis.
  • A trial to show if the purulence of nasal discharge is truly an indicator of bacterial infection and can be used as a clinically important response to antibiotics in CRS?
  • To establish what, if any, childhood events increase chances of developing CRSwNP.
  • To establish how smoking increases the risk of CRS and whether the risk is reduced by smoking cessation.
  • To show if recognition of and appropriate treatment of allergic rhinitis reduce the incidence of CRSsNP and CRSwNP?
  • To investigate the impact of psychological problems such as depression, stress exposure and anxiety on subjective severity scores and to consider the impact of neurological co-morbidities like chronic fatigue, post-traumatic stress disorder, neurological hyposmia, and measures of other neural-based disorders that play a role in non-allergic rhinitis, which may have an impact on rhinosinusitis scores.
  • To consider neural aspects of facial pain, headache, smell disorders and hypersecretion.
  • To consider the role of gastro-oesophageal reflux.
With respect to inflammatory mechanisms in CRSwNP and CRSsNP, we should consider if it is possible to:
  • Develop a classification of CRS of phenotypes/endotypes based on "hypothesis-free" cluster analyses.
  • Understand the regulation of TGF-ß and related molecules in remodeling processes.
  • Understand the T regulatory cell deficit and the role of T effector cells in nasal polyp disease.
  • Understand the role of dendritic cells in CRS.
  • Understand the links between inflammation and remodeling.
  • Understand the impact of the microbiome on inflammation
  • Understand epigenetic regulation of upper airway disease.
  • Understand the pathogenesis of 'allergic' fungal rhinosinusitis and AERD.
  • Understand the link between CRSwNP and lower airway disease.
Nasal epithelial remodelling is a part of this natural defence mechanism, including migration, proliferation, and differentiation of epithelial cells, as well as the interactions between epithelial cells and stromal cells. To date, it is not possible to distinguish between a cause and an effect with regard to epithelium remodelling, nor are there clear roles for the many factors involved in nasal infectious and inflammatory diseases, due to a lack of intrinsic information about nasal epithelial cell responses. Most reported data are derived from lower airway studies or animal models. Therefore, research based on human nasal epithelial stem/progenitor cells can offer new light on pathophysiology of nasal airway disease from a different, more specific perspective. It will also allow molecular studies of human nasal epithelial cell interactions, differentiation, and repair, as well as responses to both environmental agents and to potential anti-inflammatory treatments.

  • Further research is needed on the impact of bacterial, fungal or other microbial colonization/infection, with clear definition of such impact and we need some standardized methodology for research. For example should measures of minimal undetectable colonization, like PCR, or molecular cultivating techniques or hardly detectable immune response to colonizer be taken into account and if so, when?
  • If infection is characterized by invasion, as well as by immune response to the micro-organism, we need to define how this invasion is established at both a local and systemic level.
  • Nearly all of the currently conducted human research is performed in patients who already have established disease or controls who do not. While this is useful in identifying unique contributors to the pathophysiology of CRS and subsequent treatments, it does not identify the actual cause of the disease. Currently available animal models are either allergic models or genetically manipulated animals that artificially generate an inflammatory response and again, do not answer the cause of the disease. There is thus a need for innovative experimental models in CRS.
  • We should also focus on the differences between CRSwNP in western patients and elsewhere in the world. We need to identify key cytokines which mediate Th2 skewing across the epithelial barrier: TSLP vs. IL-25 vs. IL-33 vs.? The second key issue is the identity of the key effector cell(s): mast cells vs. esoinophils vs. neutrophils vs. ?
  • There are variations in local anatomic immune response that are not related to airflow and environmental exposures. Research is needed into variations in immune response of the ethmoid/middle meatus for example, as this is different from the mucosal response of the septum or inferior turbinate.
  • In the assessment of rhinosinusitis symptoms and examination in chronic rhinosinusitis, we need better tools for the diagnosis and differential diagnosis of facial pain.
  • We need to understand the environmental factors that alter gene expression which may predispose to CRS. This may allow us to begin recognizing disease-causing agents versus disease-modifiers or exacerbating agents and in turn may allow us to alter behavior or implement therapies that can counteract any genetic predispositions and reverse/ moderate epigenetic pre-disposition.
9.5. CRSwNP and CRSsNP in relation to the lower airways
To better understand the relationship of the upper and lower airways, we need:

  • To conduct research on the basic physiology of the nose, including humidification and heat exchange and its effect on pulmonary function.
  • To establish whether treatment of CRS affects outcomes of co-morbid lower airways disease (eg asthma, COPD).
  • To undertake further RCTs studying the effects of surgery and medical treatment on the lower airways (lung function/ QoL/symptoms) in CRSwNP and concomittant asthma.
9.6. Paediatric Chronic Rhinosinusitis
There is an urgent need to:

  • Develop tools/tests in the context of clinical trials to differentiate the role of chronic adenoiditis from that of chronic rhinosinusitis in children with chronic nasal complaints.
  • Establish the relevance of CT abnormalities in children with chronic nasal symptoms.
  • Investigate immune mechanisms by better evaluating tissues obtained at the time of surgery for CRS through well organized, multi-centre collaborations.
  • Undertake a multicentre randomized, placebo controlled, double- blind study evaluating the effect of oral antibiotics in paediatric CRS.
  • Elucidate best surgical interventions by designing and executing prospective, randomized, multi-centre, controlled clinical trials. Severity of disease on CT scans and symptom questionnaire should ideally be matched pre-operatively and the following interventions could be compared: adenoidectomy alone, adenoidectomy with a wash-out, adenoidectomy with a wash-out and balloon maxillary sinuplasty, and endoscopic sinus surgery. An additional arm that includes medical therapy should also be included.
9.7. Management of CRSwNP and CRSsNP
We need to:
  • Improve professional education and efficient dissemination of evidence-based guidelines to optimise outcomes and reduce referral rates to secondary care.
  • Develop therapeutic approaches based on endotypes of disease such as IL-5 and SE-IgE positive polyps.
  • Demonstrate whether the relative frequency of different symptoms and signs in CRSwNP and CRSsNP predict a differential response to different therapies, such as topical steroids and antibiotics.
  • Conduct multicentre trials on endoscopic versus open management of complications of CRS, both intracranial and orbital.
  • Conduct a large prospective placebo controlled study of long-term antibiotic treatment in a well-defined CRS population, exploring effects on the patient's quality of life, immune system, microbiota of the airway as well as the health economic impact.
  • Seek better local therapies for immunomodulation.
  • Conduct an RCT on oral steroids versus surgery on the long term outcomes of CRSwNP.
  • Conduct an RCT studying the effects of oral corticosteroids on olfactory function in CRSwNP.
  • Conduct multicentre RCTs on surgery versus no treatment for patients with CRSwNP to establish the natural course of disease.
  • Conduct RCTs on minimal versus more extensive endoscopic sinus surgery.
  • Investigate the effect of early surgical intervention on CRSwNP to see if it alters the course of the disease.