Increased risk of hearing loss associated with macrolide use: a systematic review and meta-analysis.

The increased risk of hearing loss with macrolides remains controversial. We aimed to systematically review and meta-analyze data on the clinical risk of hearing loss, tinnitus, and ototoxicity following macrolide use. A systematic search was conducted across PubMed, MEDLINE, Cochrane, and Embase databases from database inception to May 2023. Medical Subject Heading (MeSH) terms and text keywords were utilized, without any language restrictions. In addition to the electronic databases, two authors manually and independently searched for relevant studies in the US and European clinical trial registries and Google Scholar. Studies that involved (1) patients who had hearing loss, tinnitus, or ototoxicity after macrolide use, (2) intervention of use of macrolides such as azithromycin, clarithromycin, erythromycin, fidaxomicin, roxithromycin, spiramycin, and/or telithromycin, (3) comparisons with specified placebos or other antibiotics, (4) outcomes measured as odds ratio (OR), relative risk (RR), hazard ratio (HR), and mean difference for ototoxicity symptoms using randomized control trial (RCT)s and observational studies (case-control, cross-section, and cohort studies) were included. Data extraction was performed independently by two extractors, and a crosscheck was performed to identify any errors. ORs along with their corresponding 95% confidence intervals (CIs) were estimated using random-effects models. The Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guidelines for RCTs and Meta-Analysis of Observational Studies in Epidemiology guidelines for observational studies were followed. We assessed the hearing loss risk after macrolide use versus controls (placebos and other antibiotics). Based on data from 13 studies including 1,142,021 patients (n = 267,546 for macrolide and n = 875,089 for controls), the overall pooled OR was 1.25 (95% CI 1.07-1.47). In subgroup analysis by study design, the ORs were 1.37 (95% CI 1.08-1.73) for RCTs and 1.33 (95% CI 1.24-1.43) for case-control studies, indicating that RCT and case-control study designs showed a statistically significant higher risk of hearing loss. The group with underlying diseases such as multiple infectious etiologies (OR, 1.16 [95% CI 0.96-1.41]) had a statistically significant lower risk than the group without (OR, 1.53 [95% CI 1.38-1.70] P = .013). The findings from this systematic review and meta-analysis suggest that macrolide antibiotics increase the risk of hearing loss and that healthcare professionals should carefully consider this factor while prescribing macrolides.

A Large Pleomorphic Adenoma in Nasal Cavity Misdiagnosed as Inverted Papilloma.

Pleomorphic adenoma (PA) is a benign tumor characterized by slow-growing mixed tumors in the craniofacial area. It is relatively common in salivary glands; however, PA of the nasal cavity, which arises in the minor salivary glands, is rare. We present the case of a large PA in the nasal cavity of an adult immunocompetent woman with nasal obstruction and intermittent epistaxis. Based on preoperative radiologic examinations, she was misdiagnosed with an inverted papilloma. Endoscopic resection was performed under general anesthesia. Pathologically, the patient was confirmed to have PA, which has great cellularity and few stromal components. No complications or recurrences during the 1-year follow-up period were observed.

Clinical Trial to Reconfirm the Efficacy and Safety of Cefetamet Pivoxil Treatment in Sinusitis Patients: A Double-Blind, Randomized, Parallel Designed, Multicenter, Active Comparator Study (CASIS Study).

OBJECTIVE: To evaluate the clinical efficacy and safety of cefetamet pivoxil for the treatment of acute bacterial rhinosinusitis in Korean patients compared to treatment with cefdinir. METHODS: A prospective, multicenter, randomized double-blind, comparative study was conducted by the Departments of Otorhinolaryngology-Head and Neck Surgery at 17 hospitals or universities in the Republic of Korea from March 2017 to April 2019. A total of 309 patients were screened and 249 patients participated in the study. RESULTS: Treatment with cefetamet pivoxil for 2 weeks showed 82.4% clinical cure and improvement rates in patients with acute bacterial rhinosinusitis compared to 84.68% in those taking cefdinir for 2 weeks, showing that cefetamet pivoxil administered twice a day for 2 weeks was as effective as cefdinir 3 times a day for 2 weeks for the treatment of acute bacterial rhinosinusitis. The overall adverse reaction rates of both drugs were 10.56% in the cefetamet pivoxil group and 15.49% in the cefdinir group, without serious adverse events or drug reactions. CONCLUSIONS: Cefetamet pivoxil twice a day was as efficacious and safe as cefdinir 3 times a day for the treatment of acute bacterial rhinosinusitis, which suggested that cefetamet pivoxil may be a suitable alternative to cefdinir.

Tobacco Smoking Could Accentuate Epithelial-Mesenchymal Transition and Th2-Type Response in Patients With Chronic Rhinosinusitis With Nasal Polyps.

Tobacco smoking (TS) has been known as one of the most potent risk factors for airway inflammatory diseases. However, there has been a paucity of information regarding the immunologic alteration mediated by TS in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). To identify the effect of TS, we harvested human tissue samples (never smoker: n=41, current smoker: n=22, quitter: n=23) and analyzed the expression of epithelial-derived cytokines (EDCs) such as IL-25, IL-33, and thymic stromal lymphopoietin. The expressions of Th2 cytokines and total serum IgE showed a type-2 inflammatory alteration by TS. In addition, the epithelial marker E-cadherin and epithelial-mesenchymal transition (EMT)-associated markers (N-cadherin, α-SMA, and vimentin) were evaluated. Histological analysis showed that EDC expressions were upregulated in the current smoker group and downregulated in the quitter group. These expression patterns were consistent with mRNA and protein expression levels. We also found that the local Th2 cytokine expression and IgE class switching, as well as serum IgE levels, were elevated in the current smoker group and showed normal levels in the quitter group. Furthermore, the expressions of E-cadherin decreased while those of N-cadherin, α-SMA, and vimentin increased in the current smoker group compared those in the never smoker group. Taken together, these results indicate that TS contributes to the deterioration of pathogenesis by releasing local EDCs and Th2 cytokines, resulting in EMT in patients with CRSwNP. We verified that alterations of immunological response by TS in sinonasal epithelium can play a vital role in leading to CRSwNP.

Relationship between Chronic Rhinosinusitis and the Incidence of Head and Neck Cancer: A National Population-Based Study.

We analyzed the relationship between chronic rhinosinusitis (CRS) and the incidence of head and neck cancers (HNCs) in a Korean adult population. This retrospective cohort study included data from the Korean National Health Insurance Service database. Adjustments were made to minimize risk variables for sex, age, diabetes, hypertension, dyslipidemia, and rhinitis between the two groups. The primary endpoint was newly diagnosed HNC between January 2009 and December 2018. Among 1,337,120 subjects in the Korean National Health Insurance Service database, data from 324,774 diagnosed with CRS (CRS group) and 649,548 control subjects (control group) were selected. Patients with CRS exhibited a statistically significant greater risk for nasal cavity/paranasal sinus cancer, hypopharynx/larynx cancer, and thyroid cancer compared with the control group. In the CRS group, the adjusted hazard ratios for nasal cavity/paranasal sinus cancer were 1.809 (95% confidence interval (CI) 1.085-3.016), 1.343 (95% CI 1.031-1.748) for hypopharynx and larynx cancer, and 1.116 (95% CI 1.063-1.173) for thyroid cancer. CRS was associated with a higher incidence of HNCs. Therefore, physicians should carefully consider the possibility of HNC progression and implement therapeutic strategies to minimize the impact of these diseases.

Delta neutrophil index levels can be a good indicator to predict patients with chronic rhinosinusitis who need surgery.

OBJECTIVES: Predicting the need for surgical treatment among patients with chronic rhinosinusitis (CRS) is challenging. The delta neutrophil index (DNI) has been proposed as a useful laboratory marker of immature granulocytes, which indicates infection or severe inflammation in several diseases. This study evaluated DNI as an early predictor of the need for surgery in patients with CRS. METHODS: A total of 117 patients diagnosed with CRS were enrolled in this retrospective and observational study. Medical records, including symptoms data, WBC count, ESR level, LUC count, Lund-Mackay scores, and DNI, were reviewed. The receiver operating characteristic (ROC) curves were analyzed to determine the optimal cut-off values for predicting surgery. RESULTS: Among 117 patients, 49 patients (41.9%) needed surgical intervention. The areas under the WBC, ESR, LUC, and DNI ROC curves were .571, .600, .592, and .782, respectively. The optimal cut-off value of DNI to predict surgery was .9%. The prognostic precision of DNI showed that the sensitivity was 59.2% and the specificity was 98.5%. In the analysis of risk factors, DNI levels were significantly associated with surgical intervention (odds ratio, 2.22; 95% confidence interval, 1.48-3.34; P < .01). CONCLUSIONS: The level of DNI, which reflects the severity of the disease, may be a useful predictor for determining the need for surgical intervention in patients with CRS. This is the first literature to verify the role of DNI in upper airway disease.

Association of nasal septal deviation with the incidence of anxiety, depression, and migraine: A national population-based study.

BACKGROUND & AIMS: Nasal obstruction caused by nasal septal deviation is very bothersome and, therefore, can affect the patient's emotional state. However, little is known about the effect of nasal septal deviation (NSD) on the neuropsychiatric aspects of patients. Therefore, this study aims to verify the higher incidence of anxiety, depression, and migraine in patients diagnosed with NSD compared to general populations using big data. METHODS: This retrospective cohort study collected subjects from the Korean National Health Insurance Service (NHIS) database. Adjustments were made to minimize the confounding of variables for age, sex, residence type, income levels, hypertension, diabetes, dyslipidemia, rhinitis, and chronic rhinosinusitis between the two groups. The primary endpoint of this study was newly diagnosed anxiety, depression, and migraine between January 2009 and December 2018. Kaplan-Meier survival curves, logarithmic rank test, and Cox proportional regression test were used for statistical analysis. RESULTS: Among a total of 135,769 subjects in the NHIS database, 48,495 patients with NSD (NSD group) and 54,475 control subjects (control group) were selected. Patients with NSD had an increased risk of anxiety, depression, and migraine compared to the control group. In the NSD group, the adjusted hazard ratios (HR) were 1.236 (95% CI, 1.198-1.276) for anxiety, 1.289 (95% CI, 1.238-1.343) for depression, and 1.251 (95% CI, 1.214-1.290) for migraine. CONCLUSION: NSD is associated with a higher incidence of anxiety, depression, and migraine. Therefore, it is suggested that physicians carefully consider psychoneurological distress and employ therapeutic strategies to minimize these conditions.

Tolosa-Hunt Syndrome Misdiagnosed as Surgical Complication After Frontal Balloon Sinuplasty.

ABSTRACT: Tolosa-Hunt syndrome (THS) is a rare benign disease caused by granulomatous inflammation in the craniofacial region. It is mostly idiopathic and generally presents with painful ophthalmoplegia, ipsilateral oculomotor paresis, and steroid responsiveness. There are few reports of THS after sinus surgery. Here, we present a case of THS in an adult immunocompetent patient with severe ophthalmic pain and diplopia after frontal balloon sinuplasty. The patient was initially misdiagnosed as having a surgical complication. The patient was treated with massive corticosteroid pulse therapy, and the symptoms resolved dramatically. There were no complications or recurrence in the 7-month follow-up period.

The effects of intermittent hypoxia on human nasal mucosa.

PURPOSE: Intermittent hypoxia (IH) is characterized by hypoxia-reoxygenation, reported to be a critical risk factor for obstructive sleep apnea (OSA). This experiment aimed to evaluate the direct effects of IH on the human nasal mucosa. METHODS: The direct effects of IH on the human nasal mucosa was evaluated by measuring the ciliary beat frequency (CBF) and expression levels of inflammatory cytokines (granulocyte-macrophage colony-stimulating factor, transforming growth factor-ß, interleukin-6, and tumor necrosis factor-α). The normoxia group was exposed to a normoxic condition for 72 h. The IH group was exposed to 288 cycles of IH (1 cycle: hypoxia, 5 min; subsequent normoxia, 10 min) for 72 h. CBF was measured using an automated computer-based video image processing technique. Changes in the expression of cytokines were assessed by real-time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The normoxia group revealed a persistent CBF pattern and a physiological range of inflammatory cytokines. However, the IH group showed a cyclic decrease in CBF and increased expression of inflammatory cytokines. Cytotoxicity assay indicated no difference in the survival rates between the two groups. CONCLUSIONS: IH results in increased expression of inflammatory cytokines that adversely affects the mucociliary transport in the upper airway and, consequently, may result in airway inflammation.

Columellar Wound Immediately After Open Rhinoseptoplasty Treated With Application of DuoDERM Extra Thin.

ABSTRACT: Most patients who undergo open rhinoseptoplasty do not develop any wound at the transcolumellar incision site. However, some patients require wound care immediately post-operation. Dressing is difficult to perform in the columellar region because of the location. Here, we report 2 cases of columellar wound as a complication of open rhinoseptoplasty. A patient developed mild wound dehiscence immediately after primary rhinoseptoplasty, whereas another developed partial columellar skin necrosis after the revision operation. We applied DuoDERM Extra Thin dressing (ConvaTec Group, Deeside, UK) for columellar wound and achieved healing. DuoDERM Extra Thin can be a simple and easy dressing material for immediate care of transcolumellar wounds.

Upregulation of FZD5 in Eosinophilic Chronic Rhinosinusitis with Nasal Polyps by Epigenetic Modification.

Eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP) is one of the most challenging problems in clinical rhinology. FZD5 is a receptor for Wnt5A, and its complex with Wnt5A contributes to activating inflammation and tissue modification. Nasal polyps and eosinophil/non-eosinophil counts are reported to be directly correlated. This study investigated the expression and distribution of FZD5, and the role of eosinophil infiltration and FZD5 in eosinophilic CRSwNP pathogenesis. The prognostic role of eosinophil levels was evaluated in seven patients with CRSwNP. Fifteen patients with CRS were classified based on the percentage of eosinophils in nasal polyp tissue. Methylated genes were detected using methyl-CpG-binding domain sequencing, and qRT-PCR and immunohistochemistry were used to detect FZD5 expression in nasal polyp tissue samples. The results showed that mRNA expression of FZD5 was upregulated in nasal polyps. FZD5 expression was significantly higher in nasal polyp samples from patients with eosinophilic CRSwNP than in those from patients with non-eosinophilic CRSwNP, as indicated by immunohistochemistry. Furthermore, inflammatory cytokine levels were higher in eosinophilic CRSwNP-derived epithelial cells than in normal tissues. In conclusion, FZD5 expression in nasal mucosal epithelial cells is correlated with inflammatory cells and might play a role in the pathogenesis of eosinophilic CRSwNP.

Intratympanic dexamethasone injection for refractory tinnitus: prospective placebo-controlled study.

OBJECTIVES/HYPOTHESIS: The purpose of this study is to investigate the effectiveness of intratympanic dexamethasone injections (ITDI) for refractory tinnitus. STUDY DESIGN: A prospective, placebo-controlled, randomized, double-blind study. METHODS: Thirty patients with refractory tinnitus who were diagnosed in the Department of Otolaryngology, Ajou University Hospital, Suwon, Republic of Korea, between 2006 and 2007 were enrolled and then were assigned into two groups of ITDI (15 patients) or saline (15 patients) by permuted block randomization. Intratympanic injections were double-blind performed four times within 2 weeks. After 4 weeks, we analyzed the improvement and aggravation rates of tinnitus using the following parameters: questionnaires, tinnitus handicap index (THI), loudness matching test, frequency, and duration of tinnitus. RESULTS: The effectiveness rates of ITDI for refractory tinnitus reported in the tinnitus questionnaires, in the THI, and in the loudness matching test were all 33.3% in the steroid group, and 26.7%, 40.0%, and 26.7% in the saline group, respectively. However, there were no statistically significant differences in both groups. To analyze the therapeutic effect of ITDI on tinnitus under 6 months of its development, the improvement rates reported in the tinnitus questionnaires, in the THI, and in the loudness matching test were all 28.5% in the steroid group, and 40.0%, 40.0%, and 30.0% in the saline group, respectively. There were also no statistically significant differences in both groups. CONCLUSIONS: ITDI may not be effective for refractory tinnitus. The indication of ITDI for tinnitus needs to be limited to specific cases.

The effects of a 1.8 GHz continuous electromagnetic fields on mucociliary transport of human nasal mucosa.

OBJECTIVES/HYPOTHESIS: The aim of this study was to investigate the effects of a 1.8 GHz continuous electromagnetic fields (EMF) on human nasal mucociliary transport, and to determine the pathophysiology of ciliary beat frequency (CBF) during an EMF-induced change. METHODS: Human nasal mucosa cells were exposed to a 1.8 GHz EMF (SAR=1.0 W/kg), and CBF was analyzed using an optical flow technique with the peak detection method. RESULTS: The 1.8 GHz-exposed group showed a decreased CBF when compared to the control group. In the cytotoxicity assay, difference in survival rates was not found between the two groups. In the EMF-exposed group, protein kinase C (PKC) activity was increased during a PKC activity assay. The broad PKC inhibitor, Calphostin C abolished the EMF-induced decrease of CBF. The EMF-induced decrease of CBF was abolished by GF 109203X, a novel PKC (nPKC) isoform inhibitor, whereas the decrease was not attenuated by Gö-6976, a specific inhibitor of conventional PKC (cPKC) isoform. CONCLUSIONS: EMF may inhibit CBF via an nPKC-dependent mechanism. Therefore, we have confirmed that EMF could decrease CBF by increasing PKC activity.

Clinical features of recurrent or persistent benign paroxysmal positional vertigo.

OBJECTIVES: To identify clinical features and causes of recurrent or persistent benign paroxysmal positional vertigo (BPPV) and to analyze the effectiveness of frequently repeated canalith repositioning procedures (CRPs). STUDY DESIGN: Case series with chart review. SETTING: Academic university hospital. METHODS: The authors retrospectively reviewed the clinical records of 120 patients who were diagnosed with BPPV at the Dizziness Clinic in Ajou University Hospital, Korea, between 2004 and 2008. "Persistent" and "recurrent" BPPV were respectively defined as BPPV continuing more than 2 weeks and recurring BPPV in the same canals after at least 2 weeks of a symptom-free interval following previous successful treatments. The authors treated patients with frequently repeated CRPs such as the modified Epley maneuver or a barbecue rotation every 2 or 3 days in the outpatient clinic. RESULTS: Among 120 patients with BPPV, 93 (77.5%) were typical, 15 (12.5%) were persistent, and 12 (10.0%) were recurrent. Although the most common cause was idiopathic in both recurrent and persistent BPPV, secondary causes, including trauma, were much more common in recurrent and persistent BPPV than in typical BPPV. Typical and recurrent BPPV developed most commonly in the posterior semicircular canals. Persistent BPPV was most commonly detected in the lateral semicircular canals. After frequently repeated CRPs, 91.7% and 86.7% of the patients with recurrent or persistent BPPV, respectively, had resolution of nystagmus and vertigo. CONCLUSION: Recurrent and persistent BPPV are not rare diseases and occur with a higher incidence than expected, especially in patients with secondary causes. However, they can be successfully treated with frequently repeated CRPs.

Lipoteichoic acid from Staphylococcus aureus induced expression of MMP-9 in human middle ear epithelial cells.

OBJECTIVE: Change in matrix metalloproteinases (MMPs) and regulation of their tissue inhibitors of metalloproteinases (TIMPs) could play certain role in the pathogenesis of otitis media. This study was designed to evaluate the modulation of MMPs and TIMPs in middle ear epithelium by lipoteichoic acid (LTA) isolated from Staphylococcus aureus. METHODS: Human middle ear epithelial (HMEE) cells were treated with LTA. MMP activities were examined by PCR, ELISA and zymography, and levels of TIMPs were measured by PCR and ELISA. RESULTS: LTA isolated from S. aureus increased MMP-9 mRNA expression and secretion in HMEE cells, whereas no effect on the expressions of MMP-1, -2, -3, -7 and TIMP-1, -2 was observed. CONCLUSIONS: LTA increased the activity of MMP-9, not TIMPs in middle ear epithelia, suggesting that disturbed balance between MMP-9 and TIMPs could play an active role in LTA-induced otitis media.