Eric H. Holbrook

An updated review of clinical olfaction.

Purpose of reviewDisorders 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 developmentsResearch 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. SummaryCurrently, 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.

Immunohistochemical characterization of human olfactory tissue.

The pathophysiology underlying human olfactory disorders is poorly understood because biopsying the olfactory epithelium (OE) can be unrepresentative and extensive immunohistochemical analysis is lacking. Autopsy tissue enriches our grasp of normal and abnormal olfactory immunohistology and guides the sampling of the OE by biopsy. Furthermore, a comparison of the molecular phenotype of olfactory epithelial cells between rodents and humans will improve our ability to correlate human histopathology with olfactory dysfunction.

Lack of significant correlation between rhinosinusitis symptoms and specific regions of sinus computer tomography scans.

Background The sinonasal computer tomography (CT) scan is frequently used to help confirm the diagnosis of rhinosinusitis. However, little data exist correlating patient symptoms with CT findings. Methods Immediately preceding CT of the sinuses, 94 subjects without evidence of trauma, nasal tumors, or previous sinus surgery completed the Rhinosinusitis Outcome Measure 31 symptom questionnaire and were asked to locate areas of facial pain or pressure. CT scans were graded according to the Lund-MacKay system, and agger nasi and ethmoid bulla cells were measured. Data from CT scans and symptom/pain questionnaire responses were analyzed for significant correlations. Results No correlation was identified when comparing total Lund-MacKay scores, opacification of individual sinuses, and size of the agger nasi and ethmoid bulla cells with the Rhinosinusitis Outcome Measure 31 subset scores and areas of facial pain or pressure. Conclusion The sinus CT scan is a necessary tool for preoperative planning; however, it should not be used to predict symptoms or to localize areas responsible for facial pain or pressure.

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.

The EQ-5D: a new tool for studying clinical outcomes in chronic rhinosinusitis.

To describe the role and applicability of the EuroQol 5‐Dimension, 5‐Level (EQ‐5D‐5L) questionnaire for the assessment of general health‐related quality of life in patients with chronic rhinosinusitis.

Stem and progenitor cells of the mammalian olfactory epithelium: Taking poietic license.

The capacity of the olfactory epithelium (OE) for lifelong neurogenesis and regeneration depends on the persistence of neurocompetent stem cells, which self‐renew as well as generating all of the cell types found within the nasal epithelium. This Review focuses on the types of stem and progenitor cells in the epithelium and their regulation. Both horizontal basal cells (HBCs) and some among the population of globose basal cells (GBCs) are stem cells, but the two types plays vastly different roles. The GBC population includes the basal cells that proliferate in the uninjured OE and is heterogeneous with respect to transcription factor expression. From upstream in the hierarchy to downstream, GBCs encompass 1) Sox2+/Pax6+ stem‐like cells that are totipotent and self‐renew over the long term, 2) Ascl1+ transit‐amplifying progenitors with a limited capacity for expansive proliferation, and 3) Neurog1+/NeuroD1+ immediate precursor cells that make neurons directly. In contrast, the normally quiescent HBCs are activated to multipotency and proliferate when sustentacular cells are killed, but not when only OSNs die, indicating that HBCs are reserve stem cells that respond to severe epithelial injury. The master regulator of HBC activation is the ΔN isoform of the transcription factor p63; eliminating ΔNp63 unleashes HBC multipotency. Notch signaling, via Jagged1 ligand on Sus cells and Notch1 and Notch2 receptors on HBCs, is likely to play a major role in setting the level of p63 expression. Thus, ΔNp63 becomes a potential therapeutic target for reversing the neurogenic exhaustion characteristic of the aged OE. J. Comp. Neurol. 525:1034–1054, 2017.

Cigarette smoke combined with Toll-like receptor 3 signaling triggers exaggerated epithelial regulated upon activation, normal T-cell expressed and secreted/CCL5 expression in chronic rhinosinusitis

BACKGROUND Chronic rhinosinusitis (CRS) is characterized by persistent mucosal inflammation and frequent exacerbations. OBJECTIVE To determine whether innate epithelial responses to cigarette smoke or bacterial or viral pathogens may be abnormal in CRS leading to an inappropriate inflammatory response. METHODS Primary nasal epithelial cells (PNECs) were grown from middle turbinate biopsies of 9 healthy controls and 11 patients with CRS. After reaching 80% to 90% confluence, PNECs were exposed to medium or cigarette smoke extract (CSE) 5% (vol/vol) for 1 hour, washed, then stimulated with staphylococcal lipoteichoic acid, LPS, or double-stranded RNA (dsRNA). After 24 hours, gene expression was quantified by QRT-PCR. RESULTS At baseline, PNECs revealed elevated TNF-alpha and growth-related oncogene-alpha (a C-X-C chemokine)/CXCL1 (GRO-alpha) (4-fold increase, P = .02; and 16-fold increase, P = .004, respectively) in subjects with CRS compared with controls with normal levels of IL-1beta, IL-6, IL-8/CXCL8, human beta-defensin-2, monocyte chemoattractant protein 2/CCL8, monocyte chemoattractant protein 3/CCL7, and regulated upon activation, normal T-cell expressed and secreted (RANTES)/CCL5. Immunostaining of nasal biopsies, however, revealed comparable epithelial staining for TNF-alpha, GRO-alpha, and RANTES. There were no differences in mRNA induction by CSE, TNF-alpha, lipoteichoic acid, LPS, or dsRNA alone. The combination of CSE+dsRNA induced exaggerated RANTES (12,115-fold vs 1500-fold; P = .03) and human beta-defensin-2 (1120-fold vs 12.5-fold; P = .05) in subjects with CRS. No other genes were differentially induced. Furthermore, CSE+dsRNA induced normal levels of IFN-beta, IFN-lambda1, and IFN-lambda2/3 mRNA in subjects with CRS. CONCLUSION Cigarette smoke extract plus dsRNA induces exaggerated epithelial RANTES expression in patients with CRS. We propose that an analogous response to cigarette smoke plus viral infection may contribute to acute exacerbations and eosinophilic mucosal inflammation in CRS.

Decreased nasal mucosal sensitivity in older subjects

Background The sensitivity of the human nasal cavity mucosa to touch is not well understood. The site of receptors and mode of action responsible for the sensation of the nasal airflow is a topic of controversy. Previous studies have suggested that the skin-lined nasal vestibule is more sensitive to airflow than the mucosa of the nasal cavity. A possible decline in nasal sensitivity to airflow in older subjects has not been studied. Methods The threshold of the mucosal sensitivity to jets of air was assessed in 76 subjects with healthy nasal cavities. A total of 141 nostrils were tested, 67 in younger patients and 74 in older patients. Results Statistically significant (p < 0.001) increases in thresholds were found for all points tested for older patients compared with the younger patients. In general, the more sensitive locations were in the nasal vestibule. The nasal cavity mucosa in the inferior meatus was slightly more sensitive than the middle meatus. Conclusion We have measured the threshold to touch (air jet sensitivity) in nine places in each of 141 nasal cavities and determined that the variability and sensitivity of these measurements among people varies by age and the distance from the nostril. Older subjects were found to have a higher threshold for the sensation of air flow, and the nasal vestibule was found to be more sensitive than the rest of the nasal cavity mucosa with the inferior meatus slightly more sensitive then the middle meatus.

Distorted olfactory perception: A systematic review

Abstract The sense of smell provides people with valuable input from the chemical environment around them. The human sense of smell generally fails in three ways; one is an intensity reduction and the other two are the quality of changes. Smell disorders can be classified into central or peripheral depending on their origin. Central causes can be related to an area of hyper-functioning brain cells generating this odor perception, thus olfactory distortions have also been observed with epilepsy and migraine. In this paper, we present a review of the current clinical understanding of olfactory distortions and discuss how they can be evaluated and therapies to treat this debilitating condition.

EQ-5D-derived health utility values in patients undergoing surgery for chronic rhinosinusitis.

Health utility value (HUV) is an index used to measure health‐related quality of life for the valuation and comparison of treatments. The Euroqol 5‐Dimension (EQ‐5D) questionnaire is a widely used method for determining HUV, but it has not been applied for this purpose in patients with chronic rhinosinusitis (CRS) who undergo sinus surgery.