Effect of Topical Intranasal Therapy on Epistaxis Frequency in Patients With Hereditary Hemorrhagic Telangiectasia: A Randomized Clinical Trial.

IMPORTANCE: Epistaxis is a major factor negatively affecting quality of life in patients with hereditary hemorrhagic telangiectasia (HHT; also known as Osler-Weber-Rendu disease). Optimal treatment for HHT-related epistaxis is uncertain. OBJECTIVE: To determine whether topical therapy with any of 3 drugs with differing mechanisms of action is effective in reducing HHT-related epistaxis. DESIGN, SETTING, AND PARTICIPANTS: The North American Study of Epistaxis in HHT was a double-blind, placebo-controlled randomized clinical trial performed at 6 HHT centers of excellence. From August 2011 through March 2014, there were 121 adult patients who met the clinical criteria for HHT and had experienced HHT-related epistaxis with an Epistaxis Severity Score of at least 3.0. Follow-up was completed in September 2014. INTERVENTIONS: Patients received twice-daily nose sprays for 12 weeks with either bevacizumab 1% (4 mg/d), estriol 0.1% (0.4 mg/d), tranexamic acid 10% (40 mg/d), or placebo (0.9% saline). MAIN OUTCOMES AND MEASURES: The primary outcome was median weekly epistaxis frequency during weeks 5 through 12. Secondary outcomes included median duration of epistaxis during weeks 5 through 12, Epistaxis Severity Score, level of hemoglobin, level of ferritin, need for transfusion, emergency department visits, and treatment failure. RESULTS: Among the 121 patients who were randomized (mean age, 52.8 years [SD, 12.9 years]; 44% women with a median of 7.0 weekly episodes of epistaxis [interquartile range {IQR}, 3.0-14.0]), 106 patients completed the study duration for the primary outcome measure (43 were women [41%]). Drug therapy did not significantly reduce epistaxis frequency (P = .97). After 12 weeks of treatment, the median weekly number of bleeding episodes was 7.0 (IQR, 4.5-10.5) for patients in the bevacizumab group, 8.0 (IQR, 4.0-12.0) for the estriol group, 7.5 (IQR, 3.0-11.0) for the tranexamic acid group, and 8.0 (IQR, 3.0-14.0) for the placebo group. No drug treatment was significantly different from placebo for epistaxis duration. All groups had a significant improvement in Epistaxis Severity Score at weeks 12 and 24. There were no significant differences between groups for hemoglobin level, ferritin level, treatment failure, need for transfusion, or emergency department visits. CONCLUSIONS AND RELEVANCE: Among patients with HHT, there were no significant between-group differences in the use of topical intranasal treatment with bevacizumab vs estriol vs tranexamic acid vs placebo and epistaxis frequency. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01408030.

Paranasal sinus mucoceles with skull-base and/or orbital erosion: is the endoscopic approach sufficient?

OBJECTIVE: The objective of this study was to review the management of paranasal sinus mucoceles with skull-base and/or orbital erosion in the endoscopic era. STUDY DESIGN: A retrospective data analysis. METHODS: A chart review was performed on 57 patients treated from January 2001 to March 2007. RESULTS: The average age at the time of presentation was 50.6 years with a 1:1 male: female ratio. The most common site was the frontal sinus (54.4%), followed by frontoethmoid (29.8%) and sphenoid (8.8%). Areas of erosion included skull base (40.4%), orbit (50.9%), and both orbit and skull base (8.8%). Endoscopic drainage using image guidance was used in all 57 patients without complications. Fifty-six cases (98.2%) had a functionally patent mucocele opening with a median follow-up of 15 months. CONCLUSIONS: The endoscopic approach can be safely used for the management of mucoceles with skull-base and/or orbital erosion. Open adjunct approaches can be avoided in most cases.

Endoscopic management of sphenoid sinus cerebrospinal fluid leaks.

OBJECTIVES: Cerebrospinal fluid (CSF) leaks that originate within the sphenoid sinus pose a unique surgical challenge due to difficulties with access and visualization The objective of this report is to illustrate concepts for the successful management of sphenoid sinus CSF leaks. METHODS: Retrospective data analysis was performed on 9 patients who presented to a tertiary care medical center for endoscopic repair of a sphenoid sinus CSF leak from January 2002 to January 2006. RESULTS: The patient cohort included 7 women and 2 men with a mean age of 51.7 years. In 5 cases the CSF leak was caused by a previous neurosurgical procedure; the other 4 cases were idiopathic. An endoscopic pterygomaxillary fossa approach was required in 4 cases. A layered reconstruction of the sphenoid sinus wall with collagen allografts (cadaveric acellular dermal allograft, 8 patients; bovine collagen membrane, 1 patient) and mucosa under endoscopic visualization with intraoperative surgical navigation was performed in all cases. The reconstruction was buttressed with autologous bone in 2 cases and with cartilage in 2 cases. Fibrin sealant was used in 7 cases. Two patients developed transient diabetes insipidus after the repair. Two patients developed a recurrent CSF leak necessitating revision repair 2 and 15 months, respectively, after the initial repair procedure. The average hospital stay was 6.5 days. The mean length of follow-up was 21.1 months. CONCLUSIONS: This series demonstrates that minimally invasive endoscopic repair of sphenoid sinus CSF leaks may be accomplished with an acceptable rate of morbidity and excellent outcomes. Extended endoscopic approaches, including the pterygomaxillary fossa approach, may be useful in selected instances.

New staging system for sinonasal inverted papilloma in the endoscopic era.

OBJECTIVES: Advanced endoscopic techniques have emerged as the preferred treatment modality for sinonasal inverted papilloma (IP); however, a staging system that provides prognostic information has not yet been developed. This study aims to develop a clinically relevant staging system for IP managed with the endoscopic approach as the primary surgical modality. DESIGN: A systematic review of the English-language literature (1985-2006) and a single institution's experience. METHODS: From the literature, 445 patients with IP treated by endoscopic resection were identified in 14 reports. Only patients with known IP sites and outcomes were included. RESULTS: Patients were categorized into three groups on the basis of recurrence rates (RR): group A (IP confined to the nasal cavity, ethmoid sinus, and medial maxillary sinus), 3.0% RR (n = 234); group B (IP with lateral maxillary sinus, sphenoid sinus, or frontal sinus involvement), 19.8% RR (n = 177); and group C (IP with extrasinus extension), 35.3% RR (n = 34). Pearson's chi-square test showed statistically significant differences for all pair-wise comparisons between groups (P < .05). Mean follow-up was 39.8 months. CONCLUSIONS: This new staging system for IP provides information about prognosis (as operationally defined by RR) for IP managed by advanced endoscopic techniques. In contrast, other staging systems for IP reflect surgeon's judgment rather than outcomes data. This new classification for IP provides important objective data for preoperative planning and patient counseling.

CC chemokine receptor 2 is protective against noise-induced hair cell death: studies in CX3CR1(+/GFP) mice.

Acoustic trauma was recently shown to induce an inflammatory response in the ear characterized by rapid entry of macrophages in the spiral ligament. The current study seeks to elucidate the mechanisms involved in summoning macrophages to the cochlear lateral wall and the role macrophages play in noise-induced injury or repair. CCL2 and its primary receptor, CCR2, are the most widely validated effectors of monocyte chemotaxis in vivo. CCL2-/- and CCR2-/- mice have been used extensively in studies of monocyte activation in neuronal injury. However, the function of CCL2 and CCR2 in the cochlea has not been studied. The present study examines the role of CCL2 and CCR2 in acoustic injury. CCL2-/- and CCR2-/- mice on a CX3CR1(+/GFP) background were exposed to octave band noise (8-16 kHz) for 2 h to determine the effect of CCL2 and CCR2 on monocyte migration into the cochlea, threshold shift, and cell survival. We found that threshold shift was unchanged in the two knockout mouse strains when compared to the background strain (CX3CR1(+/GFP)). Surprisingly, we found that monocyte migration was also unchanged, despite the absence of CCL2 or CCR2. However, there was a dramatic increase in noise-induced hair cell death in the CCR2-/- strain. This observation suggests that CCR2, independent of CCL2, plays a protective role in the cochlea after noise, and neither ligand nor receptor is necessary for monocyte migration. Possible mechanisms of neuroprotection by CCR2 are discussed.

Comparison of frontal pneumatization patterns between Koreans and Caucasians.

OBJECTIVE: To evaluate the prevalence of specific frontal recess cells in Korean and Caucasian populations; to evaluate and compare the relationship between anterior skull base length and frontal recess pneumatization in these two populations. MATERIALS AND METHODS: Frontal recess anatomy was studied with high resolution sinus CT scans obtained in 60 Korean adults and 41 Caucasian adults. None of the subjects had a history of frontal sinus disease or trauma. The anterior cranial base length (ACBL, distance between the nasion and center of the pituitary fossa) and anterior ethmoid length (AEL, distance between the nasion and upper attachment of basal lamella) was also measured on each side. RESULTS: Supraorbital ethmoid cells were more common in Caucasians whereas suprabullar cells and recessus terminalis were more common in Koreans. The prevalence of some frontal recess pneumatization patterns (specifically supraorbital ethmoid cell, suprabullar cell, and recessus terminalis) were more commonly associated with race rather than with ACBL or AEL. CONCLUSION: Frontal recess pneumatization patterns differ in the Korean and Caucasian adult populations. Because corresponding differences in skull base length were not identified, these differences seem likely to reflect other factors. Such information has clinical significance for frontal recess surgery in these patient populations.

Closure of persistent tracheocutaneous fistula following "starplasty" tracheostomy in children.

OBJECTIVE: The "starplasty" technique of pediatric tracheostomy was introduced in 1990 as an alternative pediatric tracheostomy technique associated with several advantages. The only apparent drawback of this technique is the higher incidence of persistent tracheocutaneous fistula following decannulation. Several methods have been proposed for closure of persistent tracheocutaneous fistula in children, including fistulectomy with primary closure and fistulectomy with healing by secondary intent. Some authors advocate placement of a drain at the time of primary closure. We present our experience with closure of persistent tracheocutaneous fistula following starplasty in children over the past 15 years. METHODS: Ninety-six starplasty procedures were performed on 96 children from 1990 to present, all by the senior author or under the guidance of the senior author. Twenty-eight of these children have been decannulated. Three fistulas closed spontaneously following decannulation. Of the remaining 25 children, 13 have undergone surgical closure of the tracheocutaneous fistula by the senior author. All tracheocutaneous fistula closures were performed as a fistulectomy with primary closure in three layers. Drains were not used in any of the patients. RESULTS: There were three minor complications in the postoperative period (wound infection and airway granuloma) and no major complications. None of the patients have experienced any degree of airway stenosis and there was no need for a repeat tracheotomy in any of the tracheocutaneous fistula closure patients. The cosmetic results were deemed to be good. CONCLUSIONS: "Starplasty" is a safe, reliable pediatric tracheostomy technique that has been shown to decrease the incidence of perioperative morbidity and mortality. The only drawback appears to be a high incidence of postoperative tracheocutaneous fistula. Our method of persistent tracheocutaneous fistula closure following starplasty is safe and effective, with no major complications and no incidence of postoperative airway narrowing.

Treatment of Hereditary Hemorrhagic Telangiectasia-Related Epistaxis.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an incidence of 1:5000. Recurrent, spontaneous epistaxis is the most common presenting symptom. Severity of epistaxis varies widely, from mild, self-limited nosebleeds to severe, life-threatening nasal hemorrhage. Treatment of HHT-related epistaxis presents a challenge to the otolaryngologist due to the recurrent, persistent nature of epistaxis often requiring multiple treatments. Treatment modalities range from conservative topical therapies to more aggressive surgical treatments.

Randomized controlled trial of a bioabsorbable steroid-releasing implant in the frontal sinus opening.

OBJECTIVES/HYPOTHESIS: To assess safety and efficacy of a steroid-releasing implant in improving surgical outcomes when placed in the frontal sinus opening (FSO) following endoscopic sinus surgery (ESS) in patients with chronic rhinosinusitis (CRS). STUDY DESIGN: Prospective, multicenter, randomized, blinded trial using an intrapatient control design. METHODS: Eighty adult (≥ 18 years) CRS patients who underwent successful bilateral frontal sinusotomy were randomized to receive a steroid-releasing implant in one FSO, whereas the contralateral control side received no implant. All patients received standard postoperative care. Endoscopic evaluations recorded at 30-days postendoscopic sinus surgery (ESS) were graded real time by clinical investigators and by an independent, blinded sinus surgeon to assess the need for postoperative interventions in the FSO. RESULTS: Implants were successfully placed in all 80 frontal sinuses, resulting in 100% implant delivery success. At 30-days post-ESS, steroid-releasing implants provided a statistically significant (P = 0.0070) reduction in the need for postoperative interventions compared to surgery alone by an independent reviewer, representing 38% relative reduction. Clinical investigators reported statistically significant reduction in this measure at 30 days (P < 0.0001) and 90 days (P = 0.0129). Clinical investigators also reported a 55.6% reduction in the need for oral steroid interventions (P = 0.0015), 75% reduction in the need for surgical interventions (P = 0.0225), 16.7% reduction in inflammation score, 54.3% reduction in restenosis rate (P = 0.0002), and 32.2% greater diameter of FSO (P < 0.0001) on treated sides compared to control at 30 days. No implant-related adverse events were reported. CONCLUSION: This study demonstrates the efficacy of steroid-releasing implants in improving outcomes of frontal sinus surgery. LEVEL OF EVIDENCE: 1b. Laryngoscope, 126:2659-2664, 2016.

Qualitative development of the sinus control test: a survey evaluating sinus symptom control.

BACKGROUND: Ideal management of chronic rhinosinusitis (CRS) requires ongoing monitoring of disease and its control. Existing control instruments are limited in their correlation to patient reported outcomes, the need for endoscopy, or lack of validation from a multidisciplinary group. The goal of this study was to develop a patient-based Sinus Control Test (SCT) for determining CRS control. METHODS: A systematic literature review and focus groups consisting of 20 patients and 11 medical experts in CRS from various medical specialties were used to generate items. A draft 13-item questionnaire was administered to 50 patients with CRS in a prospective fashion. Patients were evaluated using the 22-item Sino-Nasal Outcome Test (SNOT-22) instrument, Lund-Mackay computed tomography (CT) score, and Lund-Kennedy endoscopy score. A rhinologist blinded to the questionnaire results also provided an overall control of the disease for each patient. A regression model was generated to identify which subset of items showed the greatest discriminate ability in relation to specialist's and patient's global rating of disease control. RESULTS: Four questions were included in the final questionnaire (p < 0.05), each with a scale of 0 to 4, with an overall total score ranging from 0 to 16. Optimal classification resulted in patients with a score from 1 to 3 (well controlled), 4 to 11 (partially controlled), and 12 to 16 (uncontrolled). SCT scores correctly classified control levels 72% of the time when compared to physician's assessment. CONCLUSION: The SCT is a simple, patient generated questionnaire that can measure the control of CRS without requirement of endoscopy or CT evaluation.

Vitamin D3 as a novel regulator of basic fibroblast growth factor in chronic rhinosinusitis with nasal polyposis.

BACKGROUND: The immunopathogenesis of chronic rhinosinusitis (CRS) is largely unknown, but it is thought that different inflammatory profiles are responsible for the different CRS subtypes. 25-Hydroxyvitamin-D (25-VD3) has been shown to alter inflammatory mediators in other disease processes and 25-VD3 deficiency is associated with CRS with nasal polyps (CRSwNP), but it is unknown if 25-VD3 levels impact local inflammation in CRS. This study investigated the correlation between plasma 25-VD3 and sinonasal mucus monocyte chemoattractant protein-1 (MCP-1), regulated upon activation normal T cell expressed and secreted (RANTES), and basic fibroblast growth factor (bFGF) levels in patients with CRS. METHODS: Study subjects undergoing endoscopic sinus surgery (ESS) for CRS were prospectively enrolled from January 2012 to August 2014. Control subjects included patients undergoing ESS for noninflammatory pathology. Blood and sinonasal mucus were collected at the time of ESS. Plasma 25-VD3 was measured by enzyme-linked immunosorbent assay (ELISA) and mucus levels of MCP-1, RANTES, and bFGF by cytometric bead array (CBA). RESULTS: A total of 57 patients were enrolled and categorized as CRS without nasal polyps (CRSsNP) (n = 31), CRSwNP (n = 14), and controls (n = 12). No significant correlation was found between MCP-1 and 25-VD3. There was a significant negative correlation between 25-VD3 and RANTES (r = -0.612; p = 0.026) and bFGF (r = -0.578; p = 0.039) in CRSwNP patients; however, there was no significant correlation in CRSsNP patients. CONCLUSION: This data suggests that 25-VD3 may play a role in regulation of RANTES and bFGF expression in CRSwNP. This may occur through regulation of NP fibroblasts or other immune cells. Further investigation is warranted to better elucidate the role of RANTES, bFGF, and 25-VD3 in CRSwNP.

Comparison of electrosurgical plasma coagulation and potassium-titanyl-phosphate laser photocoagulation for treatment of hereditary hemorrhagic telangiectasia-related epistaxis.

BACKGROUND: Potassium-titanyl-phosphate (KTP) laser photocoagulation is commonly used for treatment of hereditary hemorrhagic telangiectasia-related epistaxis (HHT-RE). Electrosurgical plasma coagulation (EPC), also known as coblation, has not been rigorously evaluated for HHT-RE. METHODS: Patients seeking treatment for HHT-RE between September 2010 and September 2012 were prospectively randomized (1:1) to KTP or EPC in a single blind prospective cohort study. Length of surgery and estimated blood loss (EBL) were recorded. Epistaxis severity scores (ESSs) and 10-cm visual analogue scale (VAS) scores for HHT-RE-related symptoms were administered at enrollment and at 3, 6, 12 months following surgery. Statistical analysis used Friedman's and Pearson's chi-square tests. RESULTS: Eleven HHT patients were prospectively enrolled and followed. Six patients underwent EPC treatment while 5 underwent KTP. Three patients in the KTP subgroup and 2 patients in the EPC subgroup requested additional surgical treatment within 12 months (p > 0.999). There were no significant differences in terms of EBL (p = 0.126) and length of surgery (p = 0.429) between treatment groups. Mean ESSs were not significantly different between groups at any follow-up point (KTP, p = 0.896; EPC, p = 0.159). Compared to KTP, mean ESSs were higher in the EPC subgroup at baseline and lower at all other time points. Mean nasal obstruction VAS scores were significantly lower in the EPC subgroup at all follow-up points. CONCLUSION: EPC is a viable alternative to KTP laser photocoagulation for epistaxis control in patients with HHT. Subjectively, patients experience less nasal obstruction following EPC as compared to KTP treatment. A multicentered, well-powered study is warranted to better determine treatment outcomes.

Antisomnogenic cytokines, quality of life, and chronic rhinosinusitis: a pilot study.

OBJECTIVES/HYPOTHESIS: Sleep disturbance, reduced quality of life (QOL), and other components of "sickness behavior" in patients with chronic rhinosinusitis (CRS) are poorly understood. These complex changes in central behavior are due to the effects of immune mediators acting in the brain. We hypothesized that immune mediators that have been associated with CRS are also associated with sickness behavior, somnifacient complaints, and CRS disease-specific QOL. STUDY DESIGN: Pilot study. METHODS: Twenty patients with CRS were prospectively enrolled and completed the Pittsburgh Sleep Quality Index (PSQI), disease-specific QOL, and olfactory instruments. Ethmoid mucosa was obtained and reverse transcription-polymerase chain reaction was performed for the cytokines interleukin (IL)-4, -13, and transforming growth factor-ß (TGF-ß). Average change in crossover threshold was calculated, and differences in gene expression were correlated with sleep quality, CRS-specific QOL, and disease severity. RESULTS: Patients with CRS reported overall poor sleep quality and poor CRS-specific QOL with significant correlations between them. Increased expression of TGF-ß (r = -0.443; P = .050) and IL-4 (r = -0.548; P = .012) correlated with sleep dysfunction, whereas IL-13 expression was linearly associated with worse sleep quality (PSQI scores r = -0.417; P = .075). IL-4 and TGF-ß expression was not associated with CRS disease severity or QOL, whereas significantly higher levels of IL-13 expression correlated with worse CRS disease severity and QOL. CONCLUSIONS: Patients with CRS exhibited behavioral changes commonly referred to as sickness behavior, which include poor sleep quality and reduced QOL. The upregulation of IL-4 and TGF-ß may contribute to inflammatory brain-mediated effects on sleep quality, whereas IL-13 may be a pleiotropic signaling molecule influencing sleep, QOL, and CRS disease severity. LEVEL OF EVIDENCE: 2b.

Differential expression of innate immunity genes in chronic rhinosinusitis.

BACKGROUND: Prior research has identified several components of the innate immune system that may play a significant role in chronic rhinosinusitis (CRS), but the role of innate immunity in patients with CRS is poorly understood. The objective of this study was to determine differential expression of innate immunity genes in the mucosa of patients with CRS with nasal polyposis (CRSwNP) and CRS without nasal polyposis (CRSsNP) when compared with controls. METHODS: Control patients (n = 9) and patients with CRS (n = 36) who failed medical management were prospectively enrolled. Ethmoid mucosa samples were harvested during surgery and quantitative real-time polymerase chain reaction was used to determine levels of mRNA expression of Toll-like receptor (TLR) 2 and TLR9 and interleukin-22 receptor (IL-22R). The average change in crossover threshold and fold change were calculated and differences between controls, CRSwNP, and CRSsNP were compared. Statistical analysis was performed using the Kruskall-Wallis and adjusted Mann-Whitney U tests. RESULTS: Patients with CRSwNP (n = 16) and CRSsNP (n = 20) showed lower mean expression of TLR2 (p < 0.05) compared with controls. Patients with CRSsNP showed significantly higher mean expression of IL-22R (p < 0.05) than controls. CONCLUSION: The sinonasal innate immune system may have a significant role in the development of CRS. We found differential expression of innate immune mediators between patients with and without nasal polyposis. These results provide further evidence of disruption of innate immunity at the mucosal level in CRS and highlight differences between polyp- and non-polyp-forming CRS phenotypes at the molecular level. In addition to our knowledge, this is the first report of altered IL-22R expression in CRSsNP patients. This study was a part of the clinical trial NCT01332136 registered in www.clinicaltrials.gov.

Steroid-independent upregulation of matrix metalloproteinase 9 in chronic rhinosinusitis patients with radiographic evidence of osteitis.

BACKGROUND: Chronic sinonasal inflammation is associated with tissue remodeling, such as osteitis, which may be a marker of refractory disease; however, the pathophysiology of osteitis in chronic rhinosinusitis (CRS) is insufficiently understood. METHODS: Ethmoid mucosa and bone samples were obtained from 35 medically refractory CRS patients and 9 control subjects. Quantitative real-time polymerase chain reaction (RT-PCR) was performed separately on bone and mucosa for matrix metalloproteinase 2 and 9 (MMP2, MMP9) and tissue inhibitor of matrix metalloproteinase 1 (TIMP1). Osteitis was classified as mild, moderate, or severe by measuring bone thickness of the maxillary, sphenoid, and ethmoid sinuses on multiplanar computed tomography (CT). Patients were classified based on severity of osteitis and compared to controls. RESULTS: Nine patients demonstrated radiographic evidence of osteitis (mild = 3, moderate/severe = 6). Bone PCR revealed biologically significant upregulation of MMP9 in all patients with CRS, but the magnitude of the upregulation decreased with severity of osteitis. Mucosa PCR showed upregulation of MMP9 in moderate/severe osteitis only. No significant changes were seen in MMP2 or TIMP1 regulation. CONCLUSION: This is the first study to evaluate the role of MMP in the bone and mucosa of patients with sinonasal osteitis. The pattern of expression suggests there may be a time- and tissue-dependent role for MMP9 in the pathophysiology of osteitis. In addition, MMP9 overexpression is seen despite preoperative oral and intranasal steroid use, suggesting that if MMP9 is an important factor in the development of osteitis then steroids may not be the best treatment in prevention of osteitis.

Osteitis in chronic rhinosinusitis: a review of the literature.

BACKGROUND: The role of osteitis, or inflammation involving bone, is 1 potential reason for disease recalcitrance in chronic rhinosinusitis (CRS) and is not extensively studied. This review article will discuss osteitis in CRS, including pathophysiology, diagnostic methods, clinical significance, and treatment modalities. METHODS: A systematic review of the literature was performed using PubMed search terms osteitis, osteomyelitis, bone involvement, hyperostosis, neo-osteogenesis, osteoneogenesis, remodeling, single positron emission computed tomography (SPECT), and nuclear scintigraphy, with each term cross-referenced with chronic rhinosinusitis. This search was then narrowed to English language articles, which were reviewed for relevance. Cited references of relevant articles were also examined. RESULTS: The PubMed search identified 231 articles, which after reviewing for inclusion criteria resulted in 26 articles that were included in the current review. Pathophysiology, including current understanding of molecular mechanisms contributing to osteitis, is discussed. Histology, computed tomography (CT), and SPECT have been used to establish a diagnosis. Radiographic staging systems exist but are not standardized. Osteitis has been treated both with intravenous antibiotics and surgery. Five articles involved assessment of outcomes in patients with osteitis. CONCLUSION: Osteitis involves inflammatory changes in the underlying bone that may lead to recalcitrant CRS. Osteitis is associated with worsened measures of disease severity such as CT, endoscopy, and olfactory scores, and affects the degree of improvement in quality-of-life measures after both medical and surgical treatment. Future studies directed at characterizing the underlying molecular mechanisms including earlier and precise identification may improve our ability to treat this significant aspect of CRS.

Hereditary hemorrhagic telangiectasia-related epistaxis: innovations in understanding and management.

BACKGROUND: Epistaxis is the most common manifestation of hereditary hemorrhagic telangiectasia (HHT), affecting approximately 90% of patients at some point during their lifetime. Bleeding is chronic and varies from mild, self-limited episodes to severe, transfusion-dependent or life-threatening epistaxis. Treatment options vary from conservative, nonsurgical management to more aggressive surgical approaches. A number of treatment options have been introduced in recent years. There is little consensus in the literature regarding treatment algorithms. The objective of this investigation was to provide a contemporary review of HHT-related epistaxis, including pathophysiology, disease manifestations, and state-of-the-art treatment modalities. METHODS: A systematic review of the literature for HHT-related epistaxis was performed using the search terms "hereditary hemorrhagic telangiectasia" and "epistaxis." Additional literature search regarding current recommendations for HHT evaluation and recent developments in genetic mechanisms, pathophysiology, and treatment of HHT was also performed. RESULTS: A total of 308 articles were identified and reviewed for appropriateness of inclusion whereas 64 articles met inclusion criteria. Treatment options range from topical and hormonal therapy to more aggressive surgical modalities. Most treatment descriptions are case series, with few randomized controlled trials. A number of new and novel therapies have been introduced in recent years. CONCLUSION: HHT is a heterogeneous disease requiring multidisciplinary evaluation and treatment. Therapeutic options for HHT-related epistaxis vary from conservative, nonsurgical measures to more aggressive surgical treatments. A graduated treatment plan is recommended. Patients present with a wide degree in variation of severity of epistaxis, and treatment is best tailored to the individual patient.

Tissue remodeling gene expression in a murine model of chronic rhinosinusitis.

OBJECTIVE/HYPOTHESIS: The matrix metalloproteinase (MMP), fibroblast growth factor (FGF), and bone morphogenetic protein (BMP) families regulate tissue remodeling in many normal and pathophysiologic processes. We hypothesize that induction of chronic sinonasal inflammation will be associated with changes in regulation of these tissue remodeling cytokines. METHODS: Balb/c mice aged 8 to 12 weeks were sensitized and treated with intranasal Aspergillus fumigatis (AF) three times per week for 1 week, 3 weeks, 2 months, and 3 months (n = 8 each time point). Sinonasal tissues were evaluated for changes in MMP, FGF, and BMP regulation using standard RT-PCR techniques. Additional snouts were processed for histology and immunohistochemistry. Untreated mouse snouts of identical age were used as controls. RESULTS: Significant upregulation of MMP8 was observed at 2 months, and MMP1a, MMP7, MMP8, and MMP12 were all significantly upregulated at 3 months. FGF3 was significantly upregulated at 3 weeks and 3 months, and FGF5, FGF6, and FGF8 were all significantly upregulated at 3 months. BMP8b and BMP9 were significantly upregulated at 3 months. Histologic analysis revealed mucosal, stromal, and mucin gland hypertrophy, increased mucin production, and metaplasia with loss of cilia. Antibody staining was strongly positive in the AF-treated group. CONCLUSIONS: Induction of CRS is associated with time-dependent changes in tissue remodeling cytokine expression occurring in conjuction with inflammatory tissue changes. Antibody staining for upregulated cytokines suggests local production within the sinonasal mucosa. Further study is required to better understand the association between BMP, FGF, and MMP regulation and tissue remodeling changes resulting from chronic inflammation.

Altered expression of tissue remodeling genes in a mouse model of acute allergic rhinitis.

BACKGROUND: Osteogenesis, fibrosis, and scarring are prominent pathologic changes resulting from chronic sinonasal inflammation, and these tissue changes may increase the degree of disease symptomatology and the level of surgical difficulty. Members of the bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) families of cytokines and the matrix metalloproteinase (MMP) family of endopeptidases are known to regulate tissue remodeling in other disease processes, but their role in acute and chronic sinonasal inflammation remains undefined. METHODS: A previously described mouse model of acute allergic rhinitis secondary to Aspergillus fumigatis exposure in BALB/C mice was used. Intranasal challenge was performed 1 week following intraperitoneal sensitization with A. fumigatis extract and mice were sacrificed 6 hours (n = 8) and 24 hours (n = 8) later. Additional mice were intranasally challenged 3 times per week and sacrificed at the end of 7 days (n = 8) and 21 days (n = 8). The snouts were processed for quantitative reverse-transcription polymerase chain reaction (RT-PCR) and compared to untreated controls for messenger ribonucleic acid (mRNA) expression of BMP1, 2, 3, 4, 5, 6, 7, 8a, 8b, 9, 10, FGF1, 2, 3, 4, 5, 6, 7, 8, 10, and MMP1a, 2, 3, 7, 8, 9, 12, and 14. Additional 21-day-old mice were prepared for sinonasal histopathology. Control mice were treated with the same protocol, with intraperitoneal phosphate-buffered saline (PBS) and intranasal PBS substituted for A. fumigatis extract. Untreated mice were used for additional comparison. RESULTS: Compared to both the PBS-treated and untreated control groups, statistically significant (p < 0.05) upregulation of MMP8 was observed in the 6-hour time point. Significant downregulation of MMP8 was observed at 1 week. Significant upregulation of FGF3 was observed at 1 week (p < 0.05). BMP3 and BMP5 were significantly downregulated in the 1-week group (p < 0.05). The mice exhibited histologic sinonasal changes consistent with allergic inflammation. CONCLUSION: Intranasal exposure to A. fumigatis results in altered expression of several tissue remodeling cytokines at varying time points in the acute allergic rhinitis mouse model. These changes in cytokine regulation may subsequently contribute to sinonasal osteogenesis, scarring, and fibrosis as seen in chronic rhinosinusitis.

Tissue remodeling in the acute otitis media mouse model.

OBJECTIVES: Otitis media is an infectious, inflammatory process involving the middle ear space. Chronic inflammation is associated with fibrosis, scarring and osteogenesis within the middle ear, which may contribute to subsequent hearing loss and increase the difficulty of treatment. METHODS: Heat-killed Streptococcus pneumoniae was injected into the middle ears of 8-12 week old Balb/c mice. Control mice were treated with PBS middle ear injections. Middle ears were harvested at 1, 3, 5 and 7 days following injection (n=8 for each time point). The middle ears were processed using standard RT-PCR techniques. Up- and down-regulation of mRNA expression of various members of the Bone Morphogenetic Protein (BMP), Fibroblast Growth Factor (FGF) and Matrix Metalloproteinase (MMP) families was quantified and compared to PBS treated controls (n=8 for each time point). RESULTS: Significant upregulation of MMP2, MMP3 and MMP9 was observed at varying time points (p<0.05). Significant downregulation of BMP3, BMP4, BMP5 BMP6 and BMP8a was seen at varying time points (p<0.05). Significant downregulation of FGF3, FGF6, FGF10 and FGFr1 was observed at varying time points (p<0.05). No significant expression of BMP8b, BMP9, BMP10, FGF5, FGF8, MMP1a, MMP7 and MMP14 was detected within the middle ear. CONCLUSIONS: Inflammation within the middle ear following injection of bacterial products results in changes in the regulation of several tissue remodeling cytokines and proteinases in the mouse model. Further understanding of these molecular processes may allow for the development of treatment modalities aimed at preventing middle ear tissue remodeling.