Allergic Fungal Rhinosinusitis Linked to Other Hyper-IgE Syndromes Through Defective Th17 Responses.

BACKGROUND: In a gene expression analysis comparing sinus mucosa from allergic fungal rhinosinusitis (AFRS) to that from non-AFRS chronic rhinosinusitis with nasal polyp (CRSwNP) subjects, the antimicrobial peptide (AMP), histatin 1 (HTN1), was found to be the most differentially down-regulated gene in AFRS. OBJECTIVE: To identify the molecular etiology of the down regulated expression of HTN1 METHODS: We used RT-PCR to compare the expression of AMPs and utilized a fungistasis assay to evaluate the anti-fungal activity of sinus secretions. Using flow cytometry, we characterized the presence of Th17/22 cells and STAT signaling from AFRS, non-AFRS CRSwNP patients, and healthy controls. RESULTS: We confirm the decreased expression of AMPs in AFRS sinus mucosa with concordant decrease in antifungal activity in sinus secretions. We show that IL-22 and IL-22-producing T cells are deficient within sinus mucosa of AFRS subjects. In vitro studies demonstrated a defect in IL-6/STAT3 signaling critical for TH17/TH22 differentiation. Epithelial cells from AFRS patients could express AMPs when stimulated with exogenous IL-22/IL-17 and circulating Th17 cell abundance was normal. CONCLUSION: Similar to other hyper-IgE syndromes, but distinct from CRSwNP, AFRS patients express a defect in STAT3 activation limited to IL-6-dependent STAT3 phosphorylation that is critical for Th17/TH22 differentiation. This defect leads to a local deficiency of IL-17/IL-22 cytokines and deficient AMP expression within diseased sinus mucosa of AFRS patients. Our findings support evaluation of therapeutic approaches that enhance airway AMP production in AFRS.

Analgesic Effects of Intravenous Acetaminophen vs Placebo for Endoscopic Sinus Surgery and Postoperative Pain: A Randomized Clinical Trial.

Importance: Intravenous acetaminophen is a commonly prescribed analgesic for the prevention and treatment of postsurgical pain. Its efficacy in the context of endoscopic sinus surgery (ESS) has yielded mixed results. Objective: To compare the efficacy of perioperative intravenous acetaminophen (IVAPAP) with that of placebo in improving early postoperative pain after endoscopic sinus surgery (ESS). Design, Setting, and Participants: A prospective, randomized clinical trial including 62 patients undergoing ESS for chronic rhinosinusitis in a single tertiary referral hospital. Interventions: Participants were randomized to receive 1 g of IVAPAP or 100 mL of placebo consisting of saline infusions immediately before the start of surgery and 4 hours after the initial dose. Main Outcomes and Measures: The primary outcome was postoperative pain measured by visual analog scale (VAS) scores up to 24 hours after surgery by blinded observers. Secondary endpoints included postoperative opioid (intravenous and oral) use and adverse events in the 24-hour postoperative period. Results: Of the 62 enrolled adult participants, 60 were randomized (31 to IVAPAP intervention and 29 to placebo). The mean (SD) age of participants was 53.7 (14.7) years and 35 (58%) of the participants were men and 25 (42%) were women. Within the first hour, mean pain scores were reduced in the IVAPAP group compared with the control group, reaching a maximum difference of 7.7 mm on a VAS scale favoring the treatment group with a true difference possibly as high as 22 mm, and the data are compatible with a clinically meaningful difference. At 12- and 24-hours, average pain scores were less in the placebo group and the data are compatible with a clinically meaningful difference of 5.8 (-5.2 to 16.8) and 8.2 (-1.9 to 18.4), respectively, favoring the placebo group. However, at all time points the CIs included the null value and were wide, thus preventing definitive conclusions. Inspection of the secondary outcomes favored IVAPAP, but the wide range of the CIs and inclusion of the null value prevent definitive conclusions. Conclusions and Relevance: The results of this study are inconclusive. The data suggest that perioperative intravenous acetaminophen may reduce immediate postoperative pain and opioid requirements compared with placebo and these differences could be clinically meaningful. Unfortunately, the imprecision of the estimates prevents definitive conclusion. Use of IVAPAP does not seem to increase adverse events. Trial Registration: clinicaltrials.gov Identifier: NCT01608308.

Increased percentage of mast cells within sinonasal mucosa of chronic rhinosinusitis with nasal polyp patients independent of atopy.

BACKGROUND: Initial attention on the pathophysiology of chronic rhinosinusitis (CRS) has focused on eosinophils. Other immune cells such as mast cells (MCs) have been identified and appear to be elevated in CRS with nasal polyp (NP) patients. MCs are commonly linked to immunoglobulin E (IgE)-mediated inflammatory changes characterized by elevated T helper 2 cytokines. Although atopy is a common comorbid condition with CRS, the objective of this study was to determine if elevated MCs are linked primarily to atopic status in CRS patients and to understand the significance of MCs in the pathophysiology of CRS. METHODS: Ethmoid sinonasal mucosa from patients undergoing endoscopic sinus surgery was harvested from 3 groups: healthy control (HC), CRS without NP (CRSsNP), and CRS with NP (CRSwNP) and analyzed by flow cytometry to quantify CD117(+) /CD203c(+) MCs and CRTH2(+) CD4(+) T cells. Relative expression of prostaglandin D(2) synthase in ethmoid mucosa was determined by quantitative real-time polymerase chain reaction (PCR). RESULTS: MCs were significantly elevated in CRSwNP patients as compared to CRSsNP patients and HCs. This elevation was not solely dependent on the presence of IgE-mediated hypersensitivity. Relative expression of prostaglandin D(2) synthase was also increased in CRSwNP patients along with an associated presence of a CRTH2(+) memory CD4(+) T cell population. CONCLUSION: Elevated percentages of MCs are found in the sinonasal mucosa of CRSwNP patients, regardless of atopic status. Secreted by MCs, elevated prostaglandin D(2) may play a role in the recruitment of CRTH2(+) cells to the inflamed mucosa of CRSwNP patients.

Long-term use and follow-up of irradiated homologous costal cartilage grafts in the nose.

OBJECTIVE: In 1993, Kridel and Konior published a preliminary report (in the Archives of Otolaryngology-Head and Neck Surgery) on the use of irradiated homologous costal cartilage (IHCC) or homograft cartilage in the nose. This is a follow-up study to share our experience in answering fundamental questions: (1) What are the major long-term complications of IHCC, and are they any greater than with the use of the patient's own cartilage? (2) Is IHCC a reliable and safe implant? (3) Does IHCC resorb over time? (4) What measures are implemented in our practice to minimize the sequelae? DESIGN: We performed a retrospective review of patient medical charts in a university-affiliated private practice setting. A total of 357 patients underwent primary or revision rhinoplasty using IHCC grafts with postoperative follow-up duration ranging from 4 days to 24 years (mean [SD], 13.45 [2.83] years). A total of 1025 IHCC grafts and 373 other grafts (including 218 autogenous cartilage [AC] grafts) were used. A total of 201 grafts were dorsal onlay grafts, and 74 of them have been further followed up since the previous report. The grafts were evaluated for warping, infection, infective resorption, noninfective resorption, mobility, and extrusion. Patient satisfaction evaluation was performed in 42 patients. RESULTS: The total complication rate related to IHCC grafts was 3.25%, which included 10 warped grafts of 941 palpable or superficial IHCC grafts (1.06%), 9 infections of 1025 IHCC grafts (0.87%), 5 cases of infective resorption of 1025 IHCC grafts (0.48%), 5 noninfective resorptions of 943 palpable IHCC grafts (0.53%), and 3 cases of graft mobility of 941 palpable grafts (0.31%). Nine cases of local infection were treated and could have arisen from any of the 1025 IHCC grafts as well as from the 373 other grafts. Among the 9 cases of infection, in 2 patients IHCC grafts were used alone, and in 7 patients IHCC grafts were used in combination with other types of graft materials; therefore, the actual infection rate related to the pure use of IHCC was 2 of 1025 or 0.2%. Of the 218 AC grafts used at the same operative intervention along with IHCC grafts, 3 grafts (1.37%) underwent minimal resorption. The overall comparative resorption rates were 1.01% (IHCC) vs 1.37% (AC). The complication rate in conjunction with the use of 162 IHCC s in 53 cases of septal perforation repair was 2.46% (4 cases), including only 1 case of infection, 1 case of mobility of the graft, 1 case of warping, and 1 case of infective resorption (0.61% for all). Of the 25 AC grafts used in septal perforation cases, there were 2 cases of noninfective resorption (8%). The overall comparative complication rates in septal perforation cases were 2.46% for IHCC vs 8% for AC, which indicated a 3.25-times higher complication with the AC than with IHCC. No allergic reaction or systemic disease was reported by patients as a result of use of the IHCC. Irradiated homograft cartilage also proved to be a reliable graft in 2 patients with progressive autoimmune diseases over 2.08 years and 10 years of follow-up. The average rates of patient satisfaction increased during a mean follow-up of 7.87 years, from 91.31% to 94.18%, in 4 categories, including nasal appearance, nasal breathing, nasal symptoms, and quality of life. CONCLUSIONS: Based on careful and extensive review of the data, we have concluded that IHCC is well tolerated as a grafting material in rhinoplasty and yields superb functional, structural, and cosmetic results in the most complex and challenging operative cases necessitated by previous unsuccessful nasal surgery, septal perforations, and even in autoimmune diseases that led to nasal deformity. Not only did very few complications occur following the use of 1025 IHCC grafts in 357 patients after 386 rhinoplasties over 24 years (rate, 3.25%), but the rate of complications was no greater than rhinoplasty complication rates when AC grafts are used. The results indicate safety and reliability and justify the convenient use of IHCC grafts for primary and revision rhinoplasty without creating donor site morbidity. Irradiated homograft cartilage grafts are quite stable in the nose and maintain structural contour and support in most cases. Irradiated homograft cartilage grafts should be considered as an alternative or even a primary grafting material when the patient does not have adequate quantities of septal or auricular cartilage remaining to provide the correction or when the shape or quality of such an AC does not adequately provide the structure required. Autogenous rib cartilage is also an alternative material but also increases operative and anesthesia time and adds potential morbidity. The use of IHCC is both cost- and time-effective.

Safety and efficacy of radionuclide therapy with high-activity In-111 pentetreotide in patients with progressive neuroendocrine tumors.

The intent of this study was to evaluate the safety and efficacy of high-activity 111In-pentetreotide in patients with neuroendocrine tumors. Thirty-two patients with pentetreotide-avid neuroendocrine tumors received therapy from August 2005 to November 2006. Fourteen (14) patients received 1 treatment and 18 patients received 2 treatments. Patients were followed an average of 12.73 months (range 1.2-24.5). Seventeen (17) patients (53%) had grade I or II hematologic toxicities, and 1 patient had grade III thrombocytopenia. One patient had grade II liver toxicity, which appeared 4 weeks after therapy and resolved on week 5. No patient had renal toxicity. Of the patients who completed 2 treatment cycles, 2 of 18 patients had partial disease regression, and 16 of 18 patients with previously progressive disseminated neuroendocrine disease achieved stable disease by imaging criteria. A decrease in serum tumor markers was observed in 14 of 18 patients given 2 therapies. A clinical response was achieved in 84% of the patients. Upon interim analysis, median survival was approximately 13 months (range 1.2-24.5). These results show that high-activity 111In-pentetreotide therapy is effective in patients with progressive disseminated neuroendocrine tumors.