The fact that chronic rhinosinusitis (CRS) appears to be increasing in both prevalence and incidence is an observation that is commonly cited.1,2 This disease is estimated to affect at least 20 million people in the United States annually, as measured by office visits.3 In addition to the symptoms commonly associated with CRS, sufferers are further affected in their daily function, as measured by quality of life. This translates into an impact of this disease that is roughly equivalent to that of other serious chronic medical conditions, such as diabetes and congestive heart failure.4 Unfortunately, despite what appears to be the size of this problem, health care professionals continue to struggle with a clear understanding of the condition, and are further hampered by a lack of consistently effective management algorithms.
Some Reasons for the Current Paucity of Outcomes Data
In order to understand the disconnect that exists between the impact of this disease process and the current lack of consistent medical options, it is important to understand the state of the current knowledge base as it relates to CRS. At present, a clear understanding of this disease remains elusive. Historically, CRS has been treated in a fashion that suggests that it represents an end-stage manifestation of unsuccessfully managed acute bacterial rhinosinusitis.5 This assumes that the disease represents a smoldering form of bacterial infection. To the contrary, studies focusing on the use of antibiotics in a variety of fashions have collectively yielded varied and inconsistent results, challenging the universal application of this modality of therapy and the validity of bacterial infection as a universal cause of CRS. This, in turn, has given rise to the consideration of a number of alternative etiologies and mechanisms that have been proposed as possible instigators of CRS. Fungus, bacterial superantigens, biofilms, aberrations in innate immunity, and genetic factors related to cystic fibrosis are among some of the subjects that are currently under consideration, some of which may hold potential for treatment options.
Looking beyond the present-day uncertainties that underlie the cause of CRS, consistent management strategies have also been challenged by an overall inconsistency in the methodology used to assess treatment outcomes. The issues that affect collective assessment of the current body of literature related to CRS are numerous, and include such problems as variances in study design and outcome measures, use of nonvalidated symptom questionnaires, and inconsistent subject entry criteria. The ultimate effect of this inconsistency is an inability to collate and decipher the literature in a systematic and reliable fashion. A simple query of the Cochrane Database of Systematic Reviews (www.cochrane.org ) illustrates this point. A search of the keywords chronic sinusitis yields only two completed reviews, only one of which addresses medical management. In comparison, a similar search performed for the keyword diabetes results in 135 separated systematic reviews or meta-analyses.
Trends reflected in the current literature reveal a true step toward better understanding of CRS, as well as an effort to raise the bar as it pertains to the quality of research being dedicated to all aspects of this disease. And although it is encouraging to witness the diversity of interest in CRS that has emerged over the past decade, real improvement at the point of patient service remains relatively unchanged. Patients continue to suffer and practitioners continue to struggle with a lack of reasonably consistent management options.
Where Does That Leave the Physician and Patient?
One of the real-world issues that influences physicians’ ability to treat CRS is the lack of medications that are indicated by the FDA for the treatment of CRS (or chronic sinusitis). Health care providers are forced to choose from a number of available nonindicated medications that are selected based on currently available information via a wide range of sources. Given the state of the current literature regarding this disease, it is not surprising that dogma and anecdote frequently assume a significant role in the selection of treatment choices. Having long used this approach, some consistencies emerge when specialty-specific groups are queried, but variances remain large. In a questionnaire survey mailed to the nonresident members of the American Rhinologic Society, medical management of CRS was addressed.6 This group of specialists indicated that the mainstay of therapy was the combination of long-term antibiotic therapy and intranasal corticosteroid sprays. On the other hand, nasal saline, oral corticosteroids, and allergy immunotherapy were employed less consistently by respondents. It is reasonable to think that even more variance may exist among less specialized physicians.
This practice of varied use of medications based on an individual physician’s experience is currently the only approach available and most certainly reflects the standard of care, but it is also laden with a number of potential pitfalls and is not consistent with current principles of evidence-based medicine. At the very basis of the problem at hand is the lack of basic efficacy and safety data as they relate to medical therapies for CRS. Inconsistent and unpredictable treatment outcomes resulting in patient frustration, frequent call-backs, and doctor shopping by patients are all too often encountered in patients with CRS. These problems are compounded by the expense of a nonsystematic approach to medical care. Failed therapy results in direct treatment-related costs, as well as the indirect costs associated with loss of productivity. To make matters worse, in some cases medications used to treat CRS are not covered by third-party payers because of their non-FDA indicated status.
Fortunately, some efficacy and safety data are available for medical treatment of CRS. The solitary Cochrane systematic review related to medical management of CRS supports the role of nasal saline for symptom relief. In a similar fashion, data exist that support the role of several intranasal corticosteroids in the treatment of nasal polyposis.7 At present, these intranasal corticosteroid trials are the only studies that have been subjected to the regulatory oversight of the FDA, thus raising the validity of the resultant data and its interpretation to that of the standard for medical treatment of other disease processes.
So, why do no FDA-approved medications indicated for the treatment of CRS exist? The answer is simple. Until recently, the FDA did not endorse a definition for CRS. Given the extensive costs related to drug development, this absence of a simple working definition for chronic rhinosinusitis essentially removed all incentive to the pharmaceutical industry for investment in a drug that could never receive an indication for its targeted disease process. In fact, the current indications for intranasal corticosteroid sprays exist for nasal polyposis and not for chronic rhinosinusitis, representing a fortunate loophole of sorts. So, what appears to be crucial to the development of improved treatment modalities for CRS is the collaborative cooperation of physician groups, industry, and regulatory agencies.
Collaborations among academic researchers, regulatory agencies, and pharmaceutical manufacturers have long existed, and have served an important role in the process of preclinical and clinical drug development programs. The relationships and motivations of each of the bodies are, by their very nature, adversarial at times. Nevertheless, it is this very collaboration that appears to be necessary to move forward. During product development, conflicts of interest arise, which are impossible to avoid and instead must be acknowledged and managed. The innate conflicts that present within these collaborations must be balanced with the potential to develop new products for patient care.8
Steps in the Right Direction
Reflecting on the course of events that have lead to recent regulatory changes, it is clear that efforts by members of the medical community set the stage to move forward. In 2002, Michael Benninger, MD, under the direction of the Sinus and Allergy Health Partnership, convened a task force to define chronic rhinosinusitis. The results of that meeting resulted in the first published definition for chronic rhinosinusitis. In its most simplified form, chronic rhinosinusitis was defined as an inflammatory process involving the mucosa of the nose and paranasal sinuses lasting for more than 12 weeks.2 This definition served as a catalyst for further discussion and codification of a definition for the disease. Opposition to certain nuances of the definition was voiced. Two areas of continued difference relate to the use of the term rhinosinusitis as opposed to sinusitis, and to temporal aspects of the disease, but the fundamentals of the definition arguably remained largely intact.
The FDA responded, in turn, with the announcement of a proposed draft guidance in November 2006, titled Sinusitis: Designing Clinical Development Programs of Nonantimicrobial Drugs for Treatment. In this document, chronic sinusitis is defined as an inflammation of the sinuses …when duration is longer than 8 weeks.9 As with many of the opposing points of view that were earlier argued, the main points of difference were those of nomenclature and duration of therapy. Rebuttals were submitted by several sources, the draft guidance, however, was posted with no changes made in the definition.10
Although the definition offered by the FDA for chronic sinusitis differs somewhat from that originally developed by the Task Force on Chronic Rhinosinusitis, the issue that is most relevant to the standardized drug development is the endorsement of a definition by the FDA that is based on the inflammatory response that is common to the disease. This constitutes the next step in establishing the collaborations necessary for medical treatment development, and will hopefully usher in a new era of concept development, testing, and implementation of therapies for CRS that are held to the same efficacy and safety standards common to FDA-approved interventions.
- Meltzer EO, Hamilos DL, Hadley JA, et al. Establishing definitions for clinical research and patient care. Otolaryngol Head Neck Surg 2004;131(6)Suppl 1:S1-S62.
- Benninger MS, Ferguson BJ, Hadley JA, et al. Adult chronic rhinosinusitis: definitions, diagnosis, epidemiology, and pathophysiology. Otolaryngol Head Neck Surg 2003;129(3)Suppl 1:S1-S32.
- Benninger MS, Holzer SE, Lau J. Diagnosis and treatment of uncomplicated acute bacterial rhinosinusitis: Summary of the Agency for Health Care Policy and Research evidence-based report. Otolaryngol Head Neck Surg 2000;122:1-7.
- Gliklich RE, Metson R. The health impact of chronic sinusitis in patients seeking otolaryngologic care. Otolaryngol Head Neck Surg 1995;113:104-9.
- Subramanian HN, Schectman KB, Hamilos DL. A retrospective analysis of treatment outcomes and time to relapse after intensive medical treatment for chronic sinusitis. Am J Rhinol 2002;16:303-12.
- Dubin MG, Liu C, Lin SY, Senior BA. American Rhinologic Society member survey on maximal medical therapy for chronic rhinosinusitis. Am J Rhinol 2007;21(4):483-8.
- Valera FC, Anselmo-Lima WT. Evaluation of efficacy of topical corticosteroid for the clinical treatment of nasal polyposis: searching for clinical events that may predict response to treatment. Rhinology 2007;45(1):59-62.
- Orlandi RR, Marple BF. Development and evaluation of new technologies in otolaryngology-head and neck surgery. Otolaryngol Head Neck Surg 2007;137(4):529-31.
©2008 The Triological Society