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Purpose of ReviewOlfactory dysfunction is a prevalent condition affecting 5–15% of the general population, with significant impact on quality of life. This review summarizes the most recent and relevant literature in the treatment of olfactory dysfunction.Recent FindingsCurrent evidence supports the short-term use of topical corticosteroids and systemic therapy. These treatments may occur in conjunction with olfactory training, which is well supported by the literature. While there are several additional treatments currently under investigation, meaningful conclusions are not yet able to be made regarding their efficacy.SummaryThe treatment of olfactory dysfunction is targeted at the suspected etiology when possible. After normal aging, chronic rhinosinusitis, post-infectious sequelae including as a result SARS-CoV-2 infection (COVID-19), and head trauma are the most common causes. Current evidence supports the short-term use of topical corticosteroids and systemic therapy. Several additional treatments are under investigation but recommendations for their use cannot currently be made.

The mechanisms by which any upper respiratory virus, including SARS-CoV-2, impairs chemosensory function are not known. COVID-19 is frequently associated with olfactory dysfunction after viral infection, which provides a research opportunity to evaluate the natural course of this neurological finding. Clinical trials and prospective and histological studies of new-onset post-viral olfactory dysfunction have been limited by small sample sizes and a paucity of advanced neuroimaging data and neuropathological samples. Although data from neuropathological specimens are now available, neuroimaging of the olfactory system during the acute phase of infection is still rare due to infection control concerns and critical illness and represents a substantial gap in knowledge. The active replication of SARS-CoV-2 within the brain parenchyma (ie, in neurons and glia) has not been proven. Nevertheless, post-viral olfactory dysfunction can be viewed as a focal neurological deficit in patients with COVID-19. Evidence is also sparse for a direct causal relation between SARS-CoV-2 infection and abnormal brain findings at autopsy, and for trans-synaptic spread of the virus from the olfactory epithelium to the olfactory bulb. Taken together, clinical, radiological, histological, ultrastructural, and molecular data implicate inflammation, with or without infection, in either the olfactory epithelium, the olfactory bulb, or both. This inflammation leads to persistent olfactory deficits in a subset of people who have recovered from COVID-19. Neuroimaging has revealed localised inflammation in intracranial olfactory structures. To date, histopathological, ultrastructural, and molecular evidence does not suggest that SARS-CoV-2 is an obligate neuropathogen. The prevalence of CNS and olfactory bulb pathosis in patients with COVID-19 is not known. We postulate that, in people who have recovered from COVID-19, a chronic, recrudescent, or permanent olfactory deficit could be prognostic for an increased likelihood of neurological sequelae or neurodegenerative disorders in the long term. An inflammatory stimulus from the nasal olfactory epithelium to the olfactory bulbs and connected brain regions might accelerate pathological processes and symptomatic progression of neurodegenerative disease. Persistent olfactory impairment with or without perceptual distortions (ie, parosmias or phantosmias) after SARS-CoV-2 infection could, therefore, serve as a marker to identify people with an increased long-term risk of neurological disease.

The extent to which medical management of chronic rhinosinusitis (CRS) may improve health utility value (HUV) remains unknown. We conducted a prospective pilot study to longitudinally assess HUV via the EQ-5D-5L questionnaire in patients with CRS who were receiving medical therapy but did not undergo sinus surgery. The primary study outcome was HUV at 12-month follow-up; secondary end points included HUV at baseline and 3- and 24-month follow-up. Our study enrolled 115 patients who received the following medical treatments: saline irrigations (n = 83, 72.2%), steroid sprays (n = 93, 80.9%), antihistamines (n = 64, 55.7%), steroid irrigations (n = 29, 25.2%), and oral antibiotics (n = 58, 50.4%). There was a statistically significant improvement (mean, +0.073; P = .003) in HUV at 12 months (minimum clinically important difference, 0.055) as compared with baseline. However, there was no statistically significant trend in HUV over time between baseline and 24-month follow-up (P = .3033). These findings can inform cost-effectiveness research as new medical therapies for CRS emerge.

Objective Repair of cerebrospinal fluid (CSF) leaks of the lateral recess of the sphenoid (LRS) sinus can be challenging to accomplish via an endoscopic transphenoidal approach. The endoscopic transpterygoid approach can improve surgical access to the lateral recess but requires more extensive surgical dissection. We review our experience with LRS CSF leak repair via both techniques to determine whether preoperative radiologic data can help predict the most appropriate surgical approach. Methods Electronic medical records of patients with LRS CSF leaks were retrospectively reviewed at a single tertiary referral center. Radiographic measurements from preoperative computed tomography images were reviewed. Results Twenty‐two LRS CSF leaks were identified. The transphenoidal and transpterygoid approach were used in 6 (27.3%) and 16 (72.7%) cases, respectively. The mean vidian canal to foramen rotundum angle of the repairs accessed transphenoidally as compared to the transptyergoid approach were not significantly different (41.93° ±10.91, 40.72° ±19.49, respectively; P = .63). However, the mean volume of the LRS accessed by the transpterygoid approach was significantly greater compared to those accessed through the transphenoidal approach (0.97 cm3 ± 0.48, 0.39 cm3 ± 0.40, respectively; P = .04). A LRS volume of 0.400 cm3 or greater predicted the use of the transpterygoid approach with 93.3% sensitivity and 60.0% specificity. Conclusion This study demonstrated that LRS CSF leaks that necessitated repair by the transpterygoid approach, rather than transphenoidal approach, were in the context of significantly larger lateral recess. Assessment of the LRS volume is a quantifiable parameter to aid in preoperative surgical planning. Level of Evidence Level 4. The endoscopic endonasal surgical approach is the gold standard in these repairs, however, the LRS sinus is particularly challenging due to anatomical constraints. Another method, known as the endoscopic endonasal transpterygoid (ETTP) approach has been used, but requires a more invasive process. Depending on the location of the CSF leak, maneuverability limitations and risks are important to consider. Our goal is to define a quantifiable parameter that will be useful in preoperative surgical planning to determine the safest, most effective approach on a case‐by‐case basis.

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. 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. 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. 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.

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. 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. 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. 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 airflow, 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.

The lack of accuracy in the current prostate specific antigen (PSA) test for prostate cancer (PCa) screening causes around 60–75% of unnecessary prostate biopsies. Therefore, alternative diagnostic methods that have better accuracy and can prevent over-diagnosis of PCa are needed. Researchers have examined various potential biomarkers for PCa, and of those fatty acids (FAs) markers have received special attention due to their role in cancer metabolomics. It has been noted that PCa metabolism prefers FAs over glucose substrates for continued rapid proliferation. Hence, we proposed using a urinary FAs based model as a non-invasive alternative for PCa detection. Urine samples collected from 334 biopsy-designated PCa positive and 232 biopsy-designated PCa negative subjects were analyzed for FAs and lipid related compounds by stir bar sorptive extraction coupled with gas chromatography/mass spectrometry (SBSE-GC/MS). The dataset was split into the training (70%) and testing (30%) sets to develop and validate logit models and repeated for 100 runs of random data partitioning. Over the 100 runs, we confirmed the stability of the models and obtained optimal tuning parameters for developing the final FA based model. A PSA model using the values of the patients’ PSA test results was constructed with the same cohort for the purpose of comparing the performances of the FA model against PSA test. The FA final model selected 20 FAs and rendered an AUC of 0.71 (95% CI = 0.67–0.75, sensitivity = 0.48, and specificity = 0.83). In comparison, the PSA model performed with an AUC of 0.51 (95% CI = 0.46–0.66, sensitivity = 0.44, and specificity = 0.71). The study supports the potential use of urinary FAs as a stable and non-invasive alternative test for PCa diagnosis.

In order to establish infections within the mammalian host, pathogens must protect themselves against toxic reactive oxygen species produced by phagocytes of the immune system. The fungal pathogen Histoplasma capsulatum infects both neutrophils and macrophages but the mechanisms enabling Histoplasma yeasts to survive in these phagocytes have not been fully elucidated. We show that Histoplasma yeasts produce a superoxide dismutase (Sod3) and direct it to the extracellular environment via N-terminal and C-terminal signals which promote its secretion and association with the yeast cell surface. This localization permits Sod3 to protect yeasts specifically from exogenous superoxide whereas amelioration of endogenous reactive oxygen depends on intracellular dismutases such as Sod1. While infection of resting macrophages by Histoplasma does not stimulate the phagocyte oxidative burst, interaction with polymorphonuclear leukocytes (PMNs) and cytokine-activated macrophages triggers production of reactive oxygen species (ROS). Histoplasma yeasts producing Sod3 survive co-incubation with these phagocytes but yeasts lacking Sod3 are rapidly eliminated through oxidative killing similar to the effect of phagocytes on Candida albicans yeasts. The protection provided by Sod3 against host-derived ROS extends in vivo. Without Sod3, Histoplasma yeasts are attenuated in their ability to establish respiratory infections and are rapidly cleared with the onset of adaptive immunity. The virulence of Sod3-deficient yeasts is restored in murine hosts unable to produce superoxide due to loss of the NADPH-oxidase function. These results demonstrate that phagocyte-produced ROS contributes to the immune response to Histoplasma and that Sod3 facilitates Histoplasma pathogenesis by detoxifying host-derived reactive oxygen thereby enabling Histoplasma survival.

Synergistic cancer therapies SMAC mimetic compounds synergize with oncolytic viruses and other innate immune stimuli to promote tumor cell death. Smac mimetic compounds (SMC), a class of drugs that sensitize cells to apoptosis by counteracting the activity of inhibitor of apoptosis (IAP) proteins, have proven safe in phase 1 clinical trials in cancer patients. However, because SMCs act by enabling transduction of pro-apoptotic signals, SMC monotherapy may be efficacious only in the subset of patients whose tumors produce large quantities of death-inducing proteins such as inflammatory cytokines. Therefore, we reasoned that SMCs would synergize with agents that stimulate a potent yet safe “cytokine storm.” Here we show that oncolytic viruses and adjuvants such as poly(I:C) and CpG induce bystander death of cancer cells treated with SMCs that is mediated by interferon beta (IFN-β), tumor necrosis factor alpha (TNF-α) and/or TNF-related apoptosis-inducing ligand (TRAIL). This combinatorial treatment resulted in tumor regression and extended survival in two mouse models of cancer. As these and other adjuvants have been proven safe in clinical trials, it may be worthwhile to explore their clinical efficacy in combination with SMCs.