Identifying Treatments for Taste and Smell Disorders: Gaps and Opportunities.

The chemical senses of taste and smell play a vital role in conveying information about ourselves and our environment. Tastes and smells can warn against danger and also contribute to the daily enjoyment of food, friends and family, and our surroundings. Over 12% of the US population is estimated to experience taste and smell (chemosensory) dysfunction. Yet, despite this high prevalence, long-term, effective treatments for these disorders have been largely elusive. Clinical successes in other sensory systems, including hearing and vision, have led to new hope for developments in the treatment of chemosensory disorders. To accelerate cures, we convened the "Identifying Treatments for Taste and Smell Disorders" conference, bringing together basic and translational sensory scientists, health care professionals, and patients to identify gaps in our current understanding of chemosensory dysfunction and next steps in a broad-based research strategy. Their suggestions for high-yield next steps were focused in 3 areas: increasing awareness and research capacity (e.g., patient advocacy), developing and enhancing clinical measures of taste and smell, and supporting new avenues of research into cellular and therapeutic approaches (e.g., developing human chemosensory cell lines, stem cells, and gene therapy approaches). These long-term strategies led to specific suggestions for immediate research priorities that focus on expanding our understanding of specific responses of chemosensory cells and developing valuable assays to identify and document cell development, regeneration, and function. Addressing these high-priority areas should accelerate the development of novel and effective treatments for taste and smell disorders.

NAVIGATE II: Randomized, double-blind trial of the exhalation delivery system with fluticasone for nasal polyposis.

BACKGROUND: Chronic rhinosinusitis is common and sometimes complicated by nasal polyps (NPs). Corticosteroid nasal sprays are often unsatisfactory because they are ineffective at delivering medication to high/deep sites of inflammation. OBJECTIVE: We sought to assess whether an exhalation delivery system with fluticasone (EDS-FLU) capable of high/deep drug deposition improves outcomes. METHODS: Patients (n = 323) 18 years and older with moderate-to-severe congestion and NPs were randomized to twice-daily EDS-FLU (93, 186, or 372 µg) or exhalation delivery system (EDS)-placebo for 24 weeks (16 double-blind plus 8 open-label when all received 372 µg). Coprimary end points were change in nasal congestion/obstruction at 4 weeks and summed bilateral polyp grade at 16 weeks. Secondary end points included symptoms, polyp elimination, and functioning. RESULTS: EDS-FLU was superior on both coprimary end points (P < .001 vs EDS-placebo, all doses). Mean polyp grade improved continuously through week 24 (P < .009, all comparisons), with polyps eliminated on at least 1 side in approximately 25% of patients at week 24 versus 8.7% with EDS-placebo (P ≤ .014, all comparisons). Sino-Nasal Outcomes Test scores also improved significantly versus those in patients receiving EDS-placebo (-21.1 to -21.4 vs -11.7 at week 16, P < .05 all doses). At the end of the double-blind period, EDS-FLU (all doses) significantly improved all 4 defining disease symptoms. In most patients (68%), those receiving EDS-FLU reported "much" or "very much" improvement. The number of patients eligible for surgery decreased by 62%-67%. The safety profile was similar to that reported in prior trials evaluating conventional corticosteroid nasal sprays in comparable populations. CONCLUSION: EDS-FLU produces clinically and statistically significant improvement in all 4 diagnostically defining disease symptoms, polyp grade, and quality of life in patients with chronic rhinosinusitis with NPs.

Advances in Understanding Parosmia: An fMRI Study.

INTRODUCTION: A number of patients with a diminished sense of smell also can suffer from parosmia. These patients with such a qualitative smell disorder are often more severely affected than patients exhibiting only a quantitative smell disorder. Qualitative smell disorders have heretofore been poorly investigated. The focus of the present study was, using functional MRI, to compare the central processing of olfactory stimulation in patients with qualitative smell disorders. MATERIAL AND METHODS: A total of 23 patients were investigated, 12 hyposmic patients without parosmia (HYP group) and 11 hyposmic patients with parosmia (PAR group). Both groups were matched with regard to sex and age. The olfactory smells used were peach and coffee odors. RESULTS: The two groups exhibited different patterns of activation. In HYP patients a stronger activation was observed in the medial orbitofrontal cortex, anterior cingulate cortex, and parahippocampal gyrus, whereas in the PAR group stronger activation in the thalamus and putamen was seen. DISCUSSION: These results are consistent with the hypothesis that there are specific patterns in the central processing of olfactory stimuli which differ in hyposmic patients with and without parosmia.

Olfactory cocainization is not an effective long-term treatment for phantosmia.

Phantosmia, the perception of an odor when there are no odorants in the environment, can be a very debilitating symptom. In the 1960s, Zilstorff reported olfactory distortions could be treated by the topical application of a cocaine solution to the olfactory epithelium. In evaluating this treatment, we observed no long-term benefit using cocaine on 6 patients with phantosmia. Based on our observations, the patient's olfactory ability was not a determining factor in the initiation or quality of their phantosmia. Following topical cocainization, we observed a remarkable delay of hours to days in the return of olfactory ability, and when cocaine was applied to only 1 nostril, there was a decreased olfactory ability on the noncocainized side. These results may suggest the possibility that phantosmia is related to a central processing problem.

Efficacy of the exhalation delivery system with fluticasone in patients with chronic rhinosinusitis with nasal polyps whose symptoms recur after sinus surgery.

BACKGROUND: Sinus surgery removes inflamed tissue, restores airflow, and improves delivery of medication into surgically opened spaces. The exhalation delivery system with fluticasone (EDS-FLU; XHANCE® ) uses a novel delivery system to create closed-palate, positive-pressure, bidirectional mechanics that significantly alter the deposition of the topically acting anti-inflammatory medication. We ask whether EDS-FLU efficacy differs for patients with recurrent symptoms after sinus surgery versus patients without surgery. OBJECTIVE: We aimed to compare EDS-FLU treatment responses in patients with recurrent symptoms after endoscopic sinus surgery (ESS) and patients who have never had sinus surgery. METHODS: Data were pooled from two large, controlled trials (NAVIGATE I and II) for exploratory analyses. Chronic rhinosinusitis symptoms, polyp grade, and quality-of-life measures were compared between patients with prior ESS and those without prior ESS. RESULTS: Patients with prior ESS (exhalation delivery system-placebo [n = 53], EDS-FLU 186 µg [n = 52], and EDS-FLU 372 µg [n = 49]) and unoperated patients (exhalation delivery system-placebo [n = 108], EDS-FLU 186 µg [n = 108], and EDS-FLU 372 µg [n = 111]) treated with EDS-FLU reported similar and substantial benefits as measured by multiple symptom and quality-of-life/functioning outcomes (congestion score, 22-Item Sinonasal Outcomes Test [SNOT-22], Rhinosinusitis Disability Index [RSDI], Patient Global Impression of Change) and by nasal polyp grade. In previously operated patients, unlike surgery-naive patients, multiple outcomes (SNOT-22, RSDI, polyp grade) consistently showed numerically but not statistically greater responses to the higher dose. CONCLUSIONS: Patients with recurrent symptoms after sinus surgery who were treated with EDS-FLU demonstrated significant symptom and quality-of-life improvement. Unlike unoperated patients, patients with prior ESS had a numerically but not statistically greater response to the higher dose of EDS-FLU (two sprays per nostril twice a day).

International consensus statement on allergy and rhinology: Olfaction.

BACKGROUND: The literature regarding clinical olfaction, olfactory loss, and olfactory dysfunction has expanded rapidly over the past two decades, with an exponential rise in the past year. There is substantial variability in the quality of this literature and a need to consolidate and critically review the evidence. It is with that aim that we have gathered experts from around the world to produce this International Consensus on Allergy and Rhinology: Olfaction (ICAR:O). METHODS: Using previously described methodology, specific topics were developed relating to olfaction. Each topic was assigned a literature review, evidence-based review, or evidence-based review with recommendations format as dictated by available evidence and scope within the ICAR:O document. Following iterative reviews of each topic, the ICAR:O document was integrated and reviewed by all authors for final consensus. RESULTS: The ICAR:O document reviews nearly 100 separate topics within the realm of olfaction, including diagnosis, epidemiology, disease burden, diagnosis, testing, etiology, treatment, and associated pathologies. CONCLUSION: This critical review of the existing clinical olfaction literature provides much needed insight and clarity into the evaluation, diagnosis, and treatment of patients with olfactory dysfunction, while also clearly delineating gaps in our knowledge and evidence base that we should investigate further.

Surgeon radiation exposure in ESS with balloon catheters.

OBJECTIVE: Less invasive instruments such as balloon catheters are available for sino-ostial dilation during endoscopic sinus surgery (ESS). Currently, balloon catheter position is confirmed under fluoroscopic visualization. Radiation exposure has been an area of concern. This study was initiated to determine surgeon radiation exposure when fluoroscopy is used during ESS with balloon catheters. STUDY DESIGN: A multi-center, prospective evaluation of surgeon radiation exposure was conducted. SUBJECTS AND METHODS: For three months, 14 sinus surgeons wore dosimeters to record radiation exposure while using C-arm fluoroscopy during balloon catheter-aided sinus surgery. One dosimeter was placed at collar level (chest), outside the lead apron and another dosimeter was placed on a finger (extremity). These dosimeters were sent for readings. Deep, eye, and shallow radiation dose for each surgeon was calculated. RESULTS: Thirteen chest badges recorded annualized averages of 191.08, 193.54, and 187.69 mrems for deep, eye, and shallow exposure respectively. Eleven ring badges recorded 584.00 mrems. CONCLUSIONS: A recent publication reported low levels of surgeon radiation exposure during ESS with balloon catheters. This study validates radiation exposure among experienced surgeons is well below the annual occupational radiation exposure limit of 50,000 mrem. With vigilant technique and education, fluoroscopy reliance can be minimized.

The changing face of paranasal sinus fungus balls.

OBJECTIVES: We describe the clinical, radiographic, and histopathologic characteristics of fungus balls. METHODS: We performed a retrospective review of 24 consecutive patients with the diagnosis of a paranasal sinus fungus ball (mycetoma) from 2001 to 2008. RESULTS: We found that 18 of the 24 primarily involved sinuses had bony thickening, and 13 of the 24 had notable dilatation of the ostium. Eleven of the 24 patients were found to have some degree of immunocompromise (from organ transplantation, diabetes, etc). The patient's immune status correlated with the type of fungus involved. (Mucor-like fungi were more common in immunocompetent patients, and aspergillus-like fungi were more common in immunocompromised patients.) Also, there was a predilection for immunocompetent patients to have dilatated ostia, whereas immunocompromised patients were more likely to have a nondilatated ostium (p = 0.019). CONCLUSIONS: Our series of paranasal sinus fungus balls defines a group of patients heretofore poorly described in the literature. Our data reveal an increased incidence in immunocompromised patients. We also found consistent radiographic patterns, correlations between immune status and the fungal pathogen, correlations between ostial enlargement and immune status, and the presence of cranial nerve pareses. These represent new findings that merit further study.

Congenital familial bilateral branchial tracts: a rare case.

The embryologic development of the head and neck is directed by an ensemble ofnumero us genes. Embryologic malformations of the head and neck are rare. When they do occur, the most common are thyroglossal duct cysts and branchial anomalies. Most malformations are apparent at birth. Complete excision at an early stage is recommended to prevent complications such as infection. We describe an extremely rare case of bilateral branchial tracts in which there was evidence of a genetic etiology. To the best of our knowledge, this is the first case of familial bilateral branchial tracts to be described in the literature.

Treatment of acute and chronic rhinosinusitis in the United States, 1999-2002.

OBJECTIVE: To generalize the prescribing trends of a statistically defined sample of patient visits because of acute or chronic rhinosinusitis in the United States, using reported diagnostic codes from the International Classification of Diseases, Ninth Revision, Clinical Modification. DESIGN: Four-year prospective study. SETTING: Public use data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey collected by the National Center for Health Statistics. RESULTS: The most frequently recommended medications for treatment of both acute and chronic rhinosinusitis are antibiotic agents, followed by antihistamines; nasal decongestants; corticosteroids; and antitussive, expectorant, and mucolytic agents, respectively. In addition, corticosteroids are used for the treatment of chronic rhinosinusitis. CONCLUSIONS: The use of prescription antibiotics far outweighs the predicted incidence of bacterial causes of acute and chronic rhinosinusitis. Frequency of antibiotic class used was not congruent with reported antimicrobial efficacy of the respective classes. Despite contradictory efficacies reported in the literature, inhaled corticosteroids were frequently used to treat acute rhinosinusitis. Antibiotics and inhaled nasal corticosteroids are being used more often than their published efficacies would encourage.

An updated review of clinical olfaction.

PURPOSE OF REVIEW: Disorders of the sense of smell can result through hundreds of different processes, but most commonly occur from upper-respiratory-tract infections, trauma, and chronic rhinosinusitis. RECENT DEVELOPMENTS: Research in the basic science of olfaction has progressed rapidly with powerful new molecular discoveries; however, our ability to treat these disorders remains limited. In clinical olfaction we are just realizing the broader existence of the sensory dysfunction in our population. We are discovering associations between neurodegenerative disorders and smell function that may allow us to identify these disorders earlier in the disease process. We are also challenging our previous categorization schemes and realizing that many etiologies cross the traditional conductive and neuro-sensory divisions. SUMMARY: Currently, aside from the possible therapeutic potential of systemic steroids, we have no effective treatment for the most common causes of olfactory loss. Recent advances in the basic science of olfaction provides us with an opportunity to develop new and novel clinical studies in an attempt at improving the quality of life for many of these patients.

Abnormalities of axon growth in human olfactory mucosa.

OBJECTIVES/HYPOTHESIS: Random biopsies of the human adult olfactory mucosa often demonstrate degenerative changes in the olfactory epithelium (OE) in both dysosmic and normosmic patients and, consequently, have limited diagnostic usefulness. However, detailed analysis of the subepithelial tissue with specific attention to the fascicles of the olfactory nerve and abnormalities of axonal growth may improve the correlation of histopathology with sensory function. STUDY DESIGN: Retrospective review of human OE biopsies. METHODS: Mucosal biopsies from the olfactory area obtained from 27 subjects were examined by light and electron microscopy, with particular attention to the olfactory nerve fascicles; results were correlated with clinical status. Immunohistochemical analysis was used to characterize the extent of axonal depletion, relative maturity of the parent population, and aberrant axonal growth. RESULTS: As expected, there are areas of respiratory metaplasia and neuronal depletion in normosmic as well as dysosmic patients. The degree of axon degeneration within the fascicles correlates better with individual olfactory status. Immature neurons predominate, and re-entrant neuromas develop in patients with olfactory loss caused by disconnection from the olfactory bulb. Individuals with olfactory loss caused by epithelial damage as with chronic rhinosinusitis display evidence of nerve fascicle degeneration and intraepithelial neuromas. CONCLUSION: The status of olfactory axons provides useful information on the overall condition of the olfactory periphery and improves the diagnostic usefulness of mucosal biopsies. In addition to an assessment of the epithelium per se, the fascicles of the olfactory nerve need to be characterized for a complete analysis of the olfactory mucosa.

Olfactory and sensory attributes of the nose.

The human nasal cavity contains multiple sensory and olfactory structures. The nasal mucosa with its complex innervation detects the danger substances in the air and stimulates the protective reflexes. Healthy olfactory mucosa allows for appreciation of pleasant aromas and food flavors. The olfactory nerve, in concert with the trigeminal nerve, serves as a main interpreter and modulator of chemosensory information. The anatomy of the olfactory neuroepithelium, which occupies only a small portion of the nasal mucosa, is generally well understood, while the presence and distribution of the sensory/tactile receptors in the mucosa of the nasal cavity is still a subject of controversy. The nasal vestibule, lined with skin, contains receptors that can sense noxious stimuli and air-flow. The sensitivity of the nasal mucosa to air-flow still needs further research. Understanding the distribution of the air-flow receptors could help to guide nasal surgery for obstruction.

Altered olfactory acuity in the morbidly obese.

BACKGROUND: Obese individuals have been reported to have a heightened desire for and ability to identify sweets when compared with leaner persons. Smell, like taste, may also be altered in obese persons compared with leaner subjects. This study was designed to determine if the sense of smell is different between morbidly obese and moderately obese individuals. METHODS: 101 adult volunteers undergoing preoperative evaluation completed the 12-item Cross-Cultural Smell Identification Test (CC-SIT) before surgical intervention. Age, BMI, and smoking history were also obtained. RESULTS: 101 subjects completed the preoperative CC-SIT (87 female, 14 male). Mean age of the subjects was 40 +/- 12 years. Mean BMI was 42.5 +/- 12.5 kg/m(2). 46 subjects (46%) had a BMI >45. 21 were smokers (21%). 9 subjects (9%), all female non-smokers, had a CC-SIT score representing olfactory dysfunction. Subjects with BMI >45 were more likely to have olfactory dysfunction than subjects with BMI <45 (16% vs 4%, P <0.05). CONCLUSION: Morbidly obese individuals are more likely than moderately obese individuals to demonstrate CC-SIT scores consistent with olfactory dysfunction. The reason for this is unclear but is probably related to metabolic changes occurring in morbidly obese individuals.

Long-term follow-up of surgically treated phantosmia.

OBJECTIVES: To determine whether transnasal excision of olfactory epithelium is a safe, effective therapy and to learn more of the pathogenesis of phantosmia by studying the histological features of the excised mucosa. DESIGN: A retrospective study consisting of a medical record review and telephone survey. Follow-up ranged from 1 to 11 years (average, 5.4 years). Excised tissues were histologically processed and descriptively compared with normal and other abnormal olfactory tissues. SETTING: Tertiary university medical referral centers. PATIENTS: All patients who presented to the primary author (D.A.L.) from 1988 to 1999 with unremitting phantosmia lasting longer than 4 years. INTERVENTION: Olfactory testing and transnasal endoscopic excision of olfactory mucosa. MAIN OUTCOME MEASURES: Tested olfactory function, patients' perception of phantom odor resolution, and histological findings. RESULTS: Of 8 patients, 7 have complete and permanent resolution of their phantosmia. Postoperatively, the single nostril olfactory ability in the operated-on nostril is decreased in 2 nostrils, remains unchanged in 7, and is improved in 1. The excised olfactory mucosa generally shows a decreased number of neurons, a greater ratio of immature to mature neurons, and disordered growth of axons with some intraepithelial neuromas. CONCLUSIONS: Surgical excision of olfactory epithelium is an effective and safe method to relieve phantosmia while potentially preserving olfactory ability. The abnormal histological features of the excised olfactory tissue suggest at least some pathological condition in the peripheral olfactory system. This nasal surgery requires intensive olfactory evaluation and follow-up. It is also extremely difficult with significant risks, and therefore should be limited to specialized centers.

Anosmia: diagnosis and management.

Disorders of the sense of smell can be frustrating for both the patient and physician. Ongoing research in this field has provided insight into the possible mechanisms for smell loss; however, therapy is still limited. Commercially distributed smell testing kits and newer screening tests using material available in all clinical settings have made diagnosis and measurement of the degree of impairment available to all physicians. A detailed history and physical examination are the most powerful tools in the evaluation of smell disorders, whereas imaging studies are reserved for preoperative planning or detailed assessment of positive physical findings.

Techniques of intranasal steroid use.

OBJECTIVE: The effectiveness of topical intranasal steroids (INS) sprays for the treatment of allergic and nonallergic rhinitis may be limited by lack of instruction in the optimal spray technique. To determine whether the technique used affects the efficacy and safety of the product, this review of evidence had the goal of identifying and establishing a preferred method of applying INS sprays. STUDY DESIGN: A MEDLINE search of pertinent literature on 7 INS and 1 intranasal antihistamine spray preparations conducted with the use of appropriate search terms, yielded an initial 121 articles, 29 of which were identified as appropriate for review and grading for quality of evidence. RESULTS: The analysis provided no definitive evidence regarding how best to instruct patients to use INS or antihistamine spray devices. CONCLUSIONS: On the basis of a lack of clear evidence regarding instructions to maximize efficacy and safety of these drugs, the panel recommended a 7-step standard technique.