Jayant M. Pinto

A randomized, double-blind, placebo-controlled trial of anti-IgE for chronic rhinosinusitis

Evidence suggests IgE may play a role in chronic rhinosinusitis (CRS). We sought to determine if treatment with a monoclonal antibody against IgE (omalizumab) is effective in reducing CRS inflammation. We performed a randomized, double blind, placebo controlled clinical trial in subjects with CRS despite treatment (including surgery). Subjects were randomized to receive omalizumab or placebo for 6 months. The primary outcome was quantitative measurement of sinus inflammation on imaging. Secondary outcome measures included quality of life, symptoms, and cellular inflammation, nasal airflow (NPIF) and olfactory testing (UPSIT). Subjects on omalizumab showed reduced inflammation on imaging after treatment, whereas those on placebo showed no change. The net difference, however, was not different between treatments. Treatment with omalizumab was associated with improvement in the Sino-Nasal Outcome Test (SNOT-20) at 3, 5, and 6 months compared to baseline with no significant changes in the control group. Remaining measures showed no significant differences across treatments. We conclude that IgE plays, at most, a small role in the mucosal inflammation of CRS and the symptoms. Placebo controlled, blinded studies with larger enrollment are needed to determine the clinical significance of any potential change.

Olfactory Dysfunction Predicts 5-Year Mortality in Older Adults

Prediction of mortality has focused on disease and frailty, although antecedent biomarkers may herald broad physiological decline. Olfaction, an ancestral chemical system, is a strong candidate biomarker because it is linked to diverse physiological processes. We sought to determine if olfactory dysfunction is a harbinger of 5-year mortality in the National Social Life, Health and Aging Project [NSHAP], a nationally representative sample of older U.S. adults. 3,005 community-dwelling adults aged 57–85 were studied in 2005–6 (Wave 1) and their mortality determined in 2010–11 (Wave 2). Olfactory dysfunction, determined objectively at Wave 1, was used to estimate the odds of 5-year, all cause mortality via logistic regression, controlling for demographics and health factors. Mortality for anosmic older adults was four times that of normosmic individuals while hyposmic individuals had intermediate mortality (p<0.001), a “dose-dependent” effect present across the age range. In a comprehensive model that included potential confounding factors, anosmic older adults had over three times the odds of death compared to normosmic individuals (OR, 3.37 [95%CI 2.04, 5.57]), higher than and independent of known leading causes of death, and did not result from the following mechanisms: nutrition, cognitive function, mental health, smoking and alcohol abuse or frailty. Olfactory function is thus one of the strongest predictors of 5-year mortality and may serve as a bellwether for slowed cellular regeneration or as a marker of cumulative toxic environmental exposures. This finding provides clues for pinpointing an underlying mechanism related to a fundamental component of the aging process.

Genetics of chronic rhinosinusitis: state of the field and directions forward.

The cause of chronic rhinosinusitis (CRS) remains unclear. Study of the genetic susceptibility to CRS might be a valuable strategy to understand the pathogenesis of this burdensome disorder. The purpose of this review is to critically evaluate the current literature regarding the genetics of CRS in a comprehensive fashion. The most promising findings from candidate gene studies include the cystic fibrosis transmembrane conductance regulator gene (CFTR), as well as genes involved in antigen presentation, innate and adaptive immune responses, tissue remodeling, and arachidonic acid metabolism. We also review the few hypothesis-independent genetic studies of CRS (ie, linkage analysis and pooling-based genome-wide association studies). Interpretation of the current literature is limited by challenges with study design, sparse replication, few functional correlates of associated polymorphisms, and inadequate examination of linkage disequilibrium or expression quantitative trait loci for reported associations. Given the relationship of CRS to other airway disorders with well-characterized genetic components (eg, asthma), study of the genetics of CRS deserves increased attention and investment, including the organization of large, detailed, and collaborative studies to advance knowledge of the mechanisms that underlie this disorder.

Olfaction: Anatomy, physiology, and disease

The olfactory system is an essential part of human physiology, with a rich evolutionary history. Although humans are less dependent on chemosensory input than are other mammals (Niimura 2009, Hum. Genomics 4:107–118), olfactory function still plays a critical role in health and behavior. The detection of hazards in the environment, generating feelings of pleasure, promoting adequate nutrition, influencing sexuality, and maintenance of mood are described roles of the olfactory system, while other novel functions are being elucidated. A growing body of evidence has implicated a role for olfaction in such diverse physiologic processes as kin recognition and mating (Jacob et al. 2002a, Nat. Genet. 30:175–179; Horth 2007, Genomics 90:159–175; Havlicek and Roberts 2009, Psychoneuroendocrinology 34:497–512), pheromone detection (Jacob et al. 200b, Horm. Behav. 42:274–283; Wyart et al. 2007, J. Neurosci. 27:1261–1265), mother–infant bonding (Doucet et al. 2009, PLoS One 4:e7579), food preferences (Mennella et al. 2001, Pediatrics 107:E88), central nervous system physiology (Welge‐Lüssen 2009, B‐ENT 5:129–132), and even longevity (Murphy 2009, JAMA 288:2307–2312). The olfactory system, although phylogenetically ancient, has historically received less attention than other special senses, perhaps due to challenges related to its study in humans. In this article, we review the anatomic pathways of olfaction, from peripheral nasal airflow leading to odorant detection, to epithelial recognition of these odorants and related signal transduction, and finally to central processing. Olfactory dysfunction, which can be defined as conductive, sensorineural, or central (typically related to neurodegenerative disorders), is a clinically significant problem, with a high burden on quality of life that is likely to grow in prevalence due to demographic shifts and increased environmental exposures. Clin. Anat. 27:54–60, 2014.

Cutting edge: polymorphisms in the ICOS promoter region are associated with allergic sensitization and Th2 cytokine production.

The establishment of ICOS as an important regulator of Th2 development and effector function makes the ICOS locus an attractive candidate for Th2-mediated diseases, such as asthma and allergy. In evaluation of this candidate locus in humans, we identified 11 variants and determined that two in the putative promoter region are significantly associated with allergic sensitization and serum IgE levels. In addition, cultures of activated PBMCs from individuals homozygous for the associated polymorphisms produced increased levels of the Th2 cytokines, IL-4, IL-5, and IL-13, as well as TNF-α compared with controls. One of the polymorphisms, −1413G/A, demonstrated differential NF-κB binding in mobility shift analysis, suggesting that this polymorphism has functional consequences. Overall, these data demonstrate that ICOS is a susceptibility gene for allergic sensitization, perhaps through the promotion of Th2 differentiation.

Racial Disparities in Olfactory Loss Among Older Adults in the United States

BACKGROUND Age-related olfactory loss (presbyosmia) substantially decreases quality of life, presages neurodegenerative disease, impairs nutrition, and predicts mortality. We sought to determine how race is associated with olfactory loss in older American adults in order to inform both health care and policy. METHODS The National Social Life, Health and Aging Project interviewed a cross-sectional nationally representative probability sample of older adults in the United States. African Americans and Hispanics were oversampled, providing power to detect disparities for these subgroups. As part of an omnibus survey of demographic, social, psychological, and biological measures, National Social Life, Health and Aging Project assessed the ability to verbally identify odors by presenting five odor pens. Multivariate ordinal logistic regression quantified racial differences in odor identification, and then tested potential confounders. RESULTS African Americans and Hispanics had markedly worse olfactory function (controlling for gender and age) compared with whites (p < .001), twice the magnitude of gender differences, and comparable to aging 9 years. Cognition, household assets, and education accounted for the disparity found among Hispanics but not among African Americans. Moreover, other potential confounders, such as physical or mental health, including tobacco and alcohol use, did not account for the African American health disparity, which remained significant (p = .001) after including these factors. CONCLUSIONS African Americans are more likely to suffer from presbyosmia, a health disparity not explained by gender, education, cognition, physical or mental health, and health behaviors. This novel health disparity may result from lifetime environmental exposures, diet, or genetic susceptibility. Dissecting the interactions among these putative mechanisms will provide insight into ameliorating this decline in critical human sensory function.

General olfactory sensitivity database (GOSdb): candidate genes and their genomic variations.

Genetic variations in olfactory receptors likely contribute to the diversity of odorant‐specific sensitivity phenotypes. Our working hypothesis is that genetic variations in auxiliary olfactory genes, including those mediating transduction and sensory neuronal development, may constitute the genetic basis for general olfactory sensitivity (GOS) and congenital general anosmia (CGA). We thus performed a systematic exploration for auxiliary olfactory genes and their documented variation. This included a literature survey, seeking relevant functional in vitro studies, mouse gene knockouts and human disorders with olfactory phenotypes, as well as data mining in published transcriptome and proteome data for genes expressed in olfactory tissues. In addition, we performed next‐generation transcriptome sequencing (RNA‐seq) of human olfactory epithelium and mouse olfactory epithelium and bulb, so as to identify sensory‐enriched transcripts. Employing a global score system based on attributes of the 11 data sources utilized, we identified a list of 1,680 candidate auxiliary olfactory genes, of which 450 are shortlisted as having higher probability of a functional role. For the top‐scoring 136 genes, we identified genomic variants (probably damaging single nucleotide polymorphisms, indels, and copy number deletions) gleaned from public variation repositories. This database of genes and their variants should assist in rationalizing the great interindividual variation in human overall olfactory sensitivity (http://genome.weizmann.ac.il/GOSdb).

Effects of saline sprays on symptoms after endoscopic sinus surgery

Background Topical saline is commonly recommended after endoscopic sinus surgery. The efficacy in this situation has never been shown. Methods We performed a controlled clinical trial to determine the effect of saline sprays on symptoms after endoscopic sinus surgery. Patients were randomized to receive normal saline (NS; n = 20), buffered hypertonic saline (HS; n = 20), or no spray (n = 20). A questionnaire measured symptoms of nasal obstruction, discharge, pain, headache, and trouble sleeping. Daily pain medication usage was recorded. Results Symptom scores over the first 5 postoperative days showed higher nasal discharge scores in the HS group. Day-by-day comparisons showed that the HS group reported significantly higher pain scores during some postoperative days. The NS group showed similar scores to control. Conclusion NS and HS sprays do not have a beneficial effect on symptoms compared with no treatment. HS sprays enhanced nasal drainage and pain. Our results do not support prescribing saline sprays early after sinus surgery but do not exclude the use of topical saline in other forms or for other uses, although they may be used for other intentions.

Olfactory cleft inflammation is present in seasonal allergic rhinitis and is reduced with intranasal steroids.

Background Allergic rhinitis (AR) is commonly associated with olfactory loss, although the mechanism is not well studied. This study was designed to determine the effect of mometasone furoate (MF) on olfactory loss in seasonal AR (SAR) and study its effect on inflammation in the olfactory region. Methods We performed a randomized, double-blind, placebo-controlled, parallel clinical trial in 17 patients with SAR who had symptoms of impaired olfaction. Subjects received MF or placebo for 2 weeks during their allergy season. Before and after treatment, we measured nasal peak inspiratory flow (NPIF), chemosensory quality of life, and objective olfactory function (the University of Pennsylvania Smell Identification Test). Additionally, nasal cytology samples were obtained from each visit, and a unilateral endoscopic biopsy specimen of the olfactory epithelium was obtained at the end of the study and scored for inflammation. Results Treatment with MF was associated with improved nasal symptoms (p < 0.015), NPIF (p < 0.04), reduced nasal inflammation (p < 0.05), and chemosensory-specific quality of life (p < 0.03). Histological analysis of the olfactory region reveals fewer eosinophils in the MF group when compared with placebo (p < 0.012). We found no improvement in objective olfactory function (p > 0.05). Conclusion The use of MF in SAR is associated with reduced eosinophilic inflammation in the olfactory region and improved symptoms of AR. The presence of eosinophils in the olfactory area in SAR may indicate a direct, deleterious effect of inflammation on olfactory epithelium in this disease. In this study we show that inflammation in SAR can affect the olfactory cleft, implicating a direct role for allergic inflammation in smell loss. Treatment with intranasal steroids is associated with decreased inflammation in the olfactory region in humans. This treatment is also associated with improved olfactory quality of life.

Rhinitis in the geriatric population

The current geriatric population in the United States accounts for approximately 12% of the total population and is projected to reach nearly 20% (71.5 million people) by 2030[1]. With this expansion of the number of older adults, physicians will face the common complaint of rhinitis with increasing frequency. Nasal symptoms pose a significant burden on the health of older people and require attention to improve quality of life. Several mechanisms likely underlie the pathogenesis of rhinitis in these patients, including inflammatory conditions and the influence of aging on nasal physiology, with the potential for interaction between the two. Various treatments have been proposed to manage this condition; however, more work is needed to enhance our understanding of the pathophysiology of the various forms of geriatric rhinitis and to develop more effective therapies for this important patient population.