The influence of inhibitors of apoptosis proteins (IAPs) on chronic rhinosinusitis with nasal polyps.

BACKGROUND: Inhibitors of apoptosis proteins (IAPs) modulate the inflammatory process, and may facilitate the formation of chronic rhinosinusitis with nasal polyps (CRSwNP). This study aimed to observe if IAPs were differently expressed between patients with CRSwNP and controls, and to correlate the expression of IAPs with some inflammatory markers, as with the response to nasal corticosteroids in patients with CRSwNP. METHODOLOGY: We obtained nasal biopsies from patients with CRSwNP (n=27) and controls (n=16). qRT-PCR measured the expression of IAPs and caspases, while Luminex assay measured the concentration of cytokines. Unpaired parametric tests and Principal Component Analysis (PCA) were used for statistical analysis. RESULTS: We observed lower expression of IAP genes (XIAP, BIRC2/IAP1, and BIRC3/IAP2) in CRSwNP patients compared to controls, and we identified that patients with bad response to corticosteroids presented lower levels of BIRC2/IAP1, XIAP, BCL2, CASP9, and IL-17, and higher levels of CASP7 and TGF-B. CONCLUSIONS: IAPs expression was downregulated in CRSwNP, and was associated with poorer response to nasal corticosteroids. The present findings suggest the importance of IAPs as a link between environment and the host inflammatory responses, and this pathway could be explored as a potential new target therapy for patients with CRSwNP.

Consensus criteria for chronic rhinosinusitis disease control: an international Delphi Study.

BACKGROUND: Chronic rhinosinusitis (CRS) disease control is a global metric of disease status for CRS. While there is broad acceptance that it is an important treatment goal, there has been inconsistency in the criteria used to define CRS control. The objective of this study was to identify and develop consensus around essential criteria for assessment of CRS disease control. METHODS: Modified Delphi methodology consisting of three rounds to review a list of 24 possible CRS control criteria developed by a 12-person steering committee. The core authorship of the multidisciplinary EPOS 2020 guidelines was invited to participate. RESULTS: Thirty-two individuals accepted the invitation to participate and there was no dropout of participants throughout the entire study (3 rounds). Consensus essential criteria for assessment of CRS control were: overall symptom severity, need for CRS-related systemic corticosteroids in the prior 6 months, severity of nasal obstruction, and patient-reported CRS control. Near-consensus items were: nasal endoscopy findings, severity of smell loss, overall quality of life, impairment of normal activities and severity of nasal discharge. Participants’ comments provided insights into caveats of, and disagreements related to, near-consensus items. CONCLUSIONS: Overall symptom severity, use of CRS-related systemic corticosteroids, severity of nasal obstruction, and patient-reported CRS control are widely agreed upon essential criteria for assessment of CRS disease control. Consideration of near-consensus items to assess CRS control should be implemented with their intrinsic caveats in mind. These identified consensus CRS control criteria, together with evidence-based support, will provide a foundation upon which CRS control criteria with wide-spread acceptance can be developed.

miRNA-205-5p can be related to T2-polarity in Chronic Rhinosinusitis with Nasal Polyps.

BACKGROUND: microRNAs (miRNAs) are directly associated with inflammatory response, but their direct role in CRSwNP (chronic rhinosinusitis with nasal polyps) remains evasive. This study aimed to compare the expression of several miRNAs in tissue samples obtained from patients with CRSwNP and controls and to evaluate if miRNAs correlate to a specific inflammatory pattern (T1, T2, T17, and Treg) or intensity of symptoms in CRSwNP. METHODS: nasal polyps (from patients with CRSwNP - n=36) and middle turbinate mucosa (from control patients - n=41) were collected. Microarray determined human mature miRNA expression, and the results obtained were validated by qPCR. miRNAs that were differentially expressed were then correlated to cytokine proteins (by Luminex), tissue eosinophilia, and SNOT-22. RESULTS: After microarray and qPCR analyses, six microRNAs were up-regulated in CRSwNP samples when compared with controls: miR-205-5p, miR-221-3p, miR-222-3p, miR-378a-3p, miR-449a and miR-449b-5p. All these miRNAs are directly implicated with cell cycle regulation and apoptosis, and to a minor extent, with inflammation. Importantly, miR-205-5p showed a significantly positive correlation with IL-5 concentration and eosinophil count at the tissue and with the worst SNOT-22 score. CONCLUSIONS: miRNA 205-5p was increased in CRSwNP compared to controls, and it was especially expressed in CRSwNP patients with higher T2 inflammation (measured by both IL-5 levels and local eosinophilia) and worst clinical presentation. This miRNA may be an interesting target to be explored in patients with CRSwNP.

EPOS2020: development strategy and goals for the latest European Position Paper on Rhinosinusitis.

BACKGROUND: The European Position Papers on Rhinosinusitis from 2005, 2007 and 2012 have had a measurable impact on the way this common condition with high impact on quality of life is managed around the world. EPOS2020 will be the latest iteration of the guideline, addressing new stakeholders and target users, presenting a summary of the latest literature and evolving treatment modalities, and formulating clear recommendations based on all available evidence. METHODOLOGY: Based on the AGREE II framework, this article demonstrates how the EPOS2020 steering group will address six key areas to ensure consistency in quality and presentation of information in the latest rhinosinusitis clinical practice guideline: scope and purpose; stakeholder involvement; rigour of development; clarity of presentation; recommendations and applicability; editorial independence. RESULTS: By analysing the guidance from AGREE II, we formulated a detailed development strategy for EPOS2020. We identify new stakeholders and target users and ratify the importance of patient involvement in the latest EPOS guideline. New and expanded areas of research to be addressed are highlighted. We confirm our intention to use mixed methodologies, combining evidence-based medicine with real life studies; when no evidence can be found, use Delphi rounds to achieve clear, inclusive recommendations. We also introduce new concepts for dissemination of the guideline, using Internet and social media to improve accessibility. CONCLUSION: This article is an introduction to the EPOS2020 project, and presents the key goals, core stakeholders, planned methodology and dissemination strategies for the latest version of this influential guideline.

The pathogens profile in children with otitis media with effusion and adenoid hypertrophy.

OBJECTIVES: To evaluate the presence of viruses and bacteria in middle ear and adenoids of patients with and without otitis media with effusion (OME). METHODS: Adenoid samples and middle ear washes (MEW) were obtained from children with OME associated with adenoid hypertrophy undergoing adenoidectomy and tympanostomy, and compared to those obtained from patients undergoing cochlear implant surgery, as a control group. Specific DNA or RNA of 9 respiratory viruses (rhinovirus, influenza virus, picornavirus, syncytial respiratory virus, metapneumovirus, coronavirus, enterovirus, adenovirus and bocavirus) and 5 bacteria (S. pneumoniae, H. influenzae, M. catarrhalis, P. aeruginosa and S. aureus) were extracted and quantified by real-time PCR. RESULTS: 37 OME and 14 cochlear implant children were included in the study. At the adenoid, virus and bacteria were similarly detected in both OME and control patients. At the middle ear washes, however, a higher prevalence of bacteria was observed in patients with OME (p = 0.01). S. pneumoniae (p = 0.01) and M. catarrhalis (p = 0.022) were the bacteria responsible for this difference. Although total virus detection was not statistically different from controls at the middle ear washes (p = 0.065), adenovirus was detected in higher proportions in adenoid samples of OME patients than controls (p = 0.019). CONCLUSIONS: Despite both OME and control patients presented similar rates of viruses and bacteria at the adenoid, children with OME presented higher prevalence of S. pneumonia, M. catarrhalis in middle ear and adenovirus in adenoids when compared to controls. These findings could suggest that these pathogens could contribute to the fluid persistence in the middle ear.

Hypertrophic adenoid is a major infection site of human bocavirus 1.

Human bocavirus 1 (HBoV1) is associated with respiratory infections worldwide, mainly in children. Similar to other parvoviruses, it is believed that HBoV1 can persist for long periods of time in humans, probably through maintaining concatemers of the virus single-stranded DNA genome in the nuclei of infected cells. Recently, HBoV-1 was detected in high rates in adenoid and palatine tonsils samples from patients with chronic adenotonsillar diseases, but nothing is known about the virus replication levels in those tissues. A 3-year prospective hospital-based study was conducted to detect and quantify HBoV1 DNA and mRNAs in samples of the adenoids (AD), palatine tonsils (PT), nasopharyngeal secretions (NPS), and peripheral blood (PB) from patients undergoing tonsillectomy for tonsillar hypertrophy or recurrent tonsillitis. HBoV1 was detected in 25.3% of the AD samples, while the rates of detection in the PT, NPS, and PB samples were 7.2%, 10.5%, and 1.7%, respectively. The viral loads were higher in AD samples, and 27.3% of the patients with HBoV had mRNA detectable in this tissue. High viral loads and detectable mRNA in the AD were associated with HBoV1 detection in the other sample sites. The adenoids are an important site of HBoV1 replication and persistence in children with tonsillar hypertrophy. The adenoids contain high HBoV1 loads and are frequently positive for HBoV mRNA, and this is associated with the detection of HBoV1 in secretions.

NF-kappaB expression predicts clinical outcome for nasal polyposis.

OBJECTIVE: To correlate clinical prognosis to the expression of p65, c-Fos, GRalpha and GRbeta in patients with nasal polyps. METHODS: A biopsy was obtained at the first evaluation for patients with nasal polyps (20), and at rhinoplasty for control mucosa (8). Patients with nasal polyps were treated with glucocorticoids and followed for at least 30 months. The expression of each gene (p65, c-Fos, GRalpha and GRbeta) was determined by Real Time-PCR and correlated to clinical outcome. The indication for surgery was considered the end-point of resistance to glucocorticoid therapy. RESULTS: Patients with nasal polyps presented a higher expression of p65 (P<0.05), and a lower expression of GRalpha (P<0.0001), and of GRalpha/GRbeta relation (P<0.0001) than controls. The nasal polyps patients with higher expression of p65 correlated with a poorer response to glucocorticoids (P<0.05), with a four-fold higher risk for surgery to control symptoms. CONCLUSION: Patients with nasal polyps presented higher gene expression of p65, and a reduced expression of GRalpha and of GRalpha/GRbeta relation than controls. Higher p65 (NFkappaB) expression at diagnosis was also associated to a worst response to medical treatment, suggesting this could be considered as one mechanism of cell resistance to glucocorticoid treatment in patients with nasal polyps.

Evaluating budesonide efficacy in nasal polyposis and predicting the resistance to treatment.

BACKGROUND: Cell resistance to glucocorticoids is a major problem in the treatment of nasal polyposis (NP). OBJECTIVES: The objectives of this study were to observe the effect of budesonide on the expression of IL-1beta, TNF-alpha, granulocyte macrophage-colony stimulating factor, intercellular adhesion molecule (ICAM)-1, basic fibroblast growth factor, eotaxin-2, glucocorticoid receptor (GR)-alpha, GR-beta, c-Fos and p65 in nasal polyps and to correlate their expression to clinical response. METHODS: Biopsies from nasal polyps were obtained from 20 patients before and after treatment with topical budesonide. Clinical response to treatment was monitored by a questionnaire and nasal endoscopy. The mRNA levels of the studied genes were measured by real-time quantitative (RQ)-PCR. RESULTS: There was a significant decrease in the expression of TNF-alpha (P<0.05), eotaxin-2 (P<0.05) and p65 (P<0.05) in NP after treatment. Poor responders to glucocorticoids showed higher expression of IL-1beta (3.74 vs. 0.14; P<0.005), ICAM-1 (1.91 vs. 0.29; P<0.05) and p65 (0.70 vs. 0.16; P<0.05) before treatment. Following treatment, IL-1beta (4.18 vs. 0.42; P<0.005) and GR-beta (0.95 vs. 0.28; P<0.05) mRNA expression was higher in this group. CONCLUSION: Topical budesonide reduced the expression of TNF-alpha, eotaxin-2 and p65. Poor responders to topical budesonide exhibit higher levels of IL-1beta, ICAM-1 and nuclear factor (NF)-kappaB at diagnosis and higher expression of both IL-1beta and GR-beta after treatment. These results emphasize the anti-inflammatory action of topical budesonide at the molecular level and its importance in the treatment of NP. Nevertheless, IL-1beta, ICAM-1 and NF-kappaB may be associated with primary resistance to glucocorticoids in NP, whereas higher expression of GR-beta in poor responders only after glucocorticoid treatment may represent a secondary drug resistance mechanism in this disease.

Expression of transcription factors NF-kappaB and AP-1 in nasal polyposis.

BACKGROUND: The treatment and prognosis of nasal polyposis (NP) may be influenced by transcription factors, but their expression is poorly understood. OBJECTIVE: To determine the expression of transcription factors [(nuclear factor-kappaB) NF-kappaB and (activator protein) AP-1], cytokines [IL-1beta, TNF-alpha and (granulocytes and macrophage colony-stimulating factor) GM-CSF], growth factor (b-FGF), chemokine (eotaxin-2) and adhesion molecule (ICAM-1) in NP in comparison with nasal mucosa controls. Methods Cross-sectional study. Twenty biopsies of nasal polyps were compared with eight middle turbinate biopsies. p65, c-Fos, IL-1beta, TNF-alpha, ICAM-1, b-FGF, eotaxin-2 and GM-CSF were analysed through RQ-PCR, and p65 and c-Fos were also analysed through Western blotting. RESULTS: NF-kappaB expression was increased in patients with NP when compared with control mucosa (P<0.05), whereas AP-1 expression did not differ significantly between groups. Expressions of IL-1beta, eotaxin-2 and b-FGF were also increased in patients with NP compared with controls (P<0.05). CONCLUSIONS: The transcription factor NF-kappaB is more expressed in NP than in control mucosa. This is important in NP because NF-kappaB can induce the transcription of cytokines, chemokines and adhesion molecules, which play an important role in the inflammatory process. Moreover, transcription factors influence the response to corticosteroids, which are the basis of NP treatment. Transcription factor AP-1 does not seem to have a significant role in the pathological process.

The effects of endoscopic sinus surgery on the nasal cycle as assessed by acoustic rhinometry.

Previous studies have demonstrated that acoustic rhinometry (AR) has a considerable utility in measuring nasal patency and in detecting the nasal cycle. This study was performed in 10 patients with chronic rhinosinusitis who were submitted to endoscopic sinus surgery. AR was used to determine minimum nasal cross-sectional area and volume as the indices of the nasal patency in all patients on the day before the surgery and 3 months postoperatively. We did not find any significant alteration when comparing the pattern of fluctuation, the periodicity, and the amplitude of the nasal cycle demonstrated by patients in the pre and postoperative periods, confirming that this surgery does not have any adverse effect on this physiologic cycle.

Importance of nasal fiberoptic examination in the presence of a normal X-ray of the cavum.

A total of 45 children aged 4-12 years were studied at the Rhinosinusology out-patient clinic of HCFMRP. The patients complained of marked nasal obstruction refractory to any clinical treatment, and a cavum X-ray showed no sign of airway obstruction. All children were submitted to nasal fiberoptic examination in order to determine the number of false-negative results. The examinations showed 12 cases of severe hypertrophy of adenoid vegetations (27%) and 19 cases of moderate hypertrophy (42%). Furthermore, we detected six cases of hypertrophy of the turbinate cauda (13.3%) and three cases of posterior septal deviation (6.6%). These data suggest the importance of the indication of this examination, which permits a tri-dimensional and dynamic evaluation of the cavum area.

Middle turbinate headache syndrome.

The middle turbinate and nasal septum are innervated by the anterior ethmoidal nerve, a branch of the ophthalmic division of the trigeminal nerve. As reported in the classical work of Wolff (1948), stimulation of these regions causes pain in the medial canthus of the supraorbital region. Periorbital pain due to middle turbinate compression against the septum or the lateral wall of the nose may be due to congestion of the nasal mucosa or to pneumatization of the middle turbinate (concha bullosa). The diagnosis is made by exclusion and requires a high index of suspicion, anterior rhinoscopy, computerized tomography (CT), and confirmation by the lidocaine test. We present five cases of middle turbinate headache syndrome, all with concha bullosa. Four were treated surgically by partial middle turbinectomy and septoplasty more than 1 year ago, with excellent results. One patient refused surgical treatment which was suggested after failure of medical treatment with antihistamines, decongestants, and a topical corticosteroid, and continues to be symptomatic. Despite the small number of cases studied, the authors concluded that the procedure used was effective for the resolution of headache.

[Recurrent bacterial meningitis]. / Meningites bacterianas recidivantes.

The study of CSF fistulae, and especially those involving otolaryngological anomalies, must be based on the search for the causative problem of recurrent meningitis. Congenital malformations, post-traumatic and post-operative situations or even diseases involving the cranial bones are basic causes that should be studied. Currently, cranial trauma is the most usual cause of CSF fistulae, with the possibility of recurrent bacterial meningitis.