RESUMEN
The sinonasal microbiome remains poorly defined, with our current knowledge based on a few cohort studies whose findings are inconsistent. Furthermore, the variability of the sinus microbiome across geographical divides remains unexplored. We characterize the sinonasal microbiome and its geographical variations in both health and disease using 16S rRNA gene sequencing of 410 individuals from across the world. Although the sinus microbial ecology is highly variable between individuals, we identify a core microbiome comprised of Corynebacterium, Staphylococcus, Streptococcus, Haemophilus and Moraxella species in both healthy and chronic rhinosinusitis (CRS) cohorts. Corynebacterium (mean relative abundance = 44.02%) and Staphylococcus (mean relative abundance = 27.34%) appear particularly dominant in the majority of patients sampled. Amongst patients suffering from CRS with nasal polyps, a statistically significant reduction in relative abundance of Corynebacterium (40.29% vs 50.43%; P = .02) was identified. Despite some measured differences in microbiome composition and diversity between some of the participating centres in our cohort, these differences would not alter the general pattern of core organisms described. Nevertheless, atypical or unusual organisms reported in short-read amplicon sequencing studies and that are not part of the core microbiome should be interpreted with caution. The delineation of the sinonasal microbiome and standardized methodology described within our study will enable further characterization and translational application of the sinus microbiota.
Asunto(s)
Microbiota , Senos Paranasales , Sinusitis , Bacterias/genética , Enfermedad Crónica , Humanos , ARN Ribosómico 16S/genética , Sinusitis/epidemiologíaRESUMEN
BACKGROUND: Chronic rhinosinusitis (CRS) is a chronic inflammatory disease associated with a substantial personal and socioeconomic burden. Monitoring of patient-reported outcomes by mobile technology offers the possibility to better understand real-life burden of CRS. METHODS: This study reports on the cross-sectional evaluation of data of 626 users of mySinusitisCoach (mSC), a mobile application for CRS patients. Patient characteristics of mSC users were analysed as well as the level of disease control based on VAS global rhinosinusitis symptom score and adapted EPOS criteria. RESULTS: The mSC cohort represents a heterogeneous group of CRS patients with a diverse pattern of major symptoms. Approximately half of patients reported nasal polyps. 47.3% of all CRS patients were uncontrolled based on evaluation of VAS global rhinosinusitis symptom score compared to 40.9% based on adapted EPOS criteria. The impact of CRS on sleep quality and daily life activities was significantly higher in uncontrolled versus well-controlled patients. Half of patients had a history of FESS (functional endoscopic sinus surgery) and reported lower symptom severity compared to patients without a history of FESS, except for patients with a history of more than 3 procedures. Patients with a history of FESS reported higher VAS levels for impaired smell. CONCLUSION: Real-life data confirm the high disease burden in uncontrolled CRS patients, clearly impacting quality of life. Sinus surgery improves patient-reported outcomes, but not in patients with a history of more than 3 procedures. Mobile technology opens a new era of real-life monitoring, supporting the evolution of care towards precision medicine.
Asunto(s)
Pólipos Nasales , Rinitis , Sinusitis , Enfermedad Crónica , Estudios Transversales , Humanos , Pólipos Nasales/epidemiología , Calidad de Vida , Rinitis/diagnóstico , Rinitis/epidemiología , Sinusitis/diagnóstico , Sinusitis/epidemiologíaRESUMEN
BACKGROUND: Airway epithelial cells have a well-accepted role in the regulation of local inflammatory processes in allergic and innate defence responses. However, their role the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP) is unclear. The objective was to investigate whether potential differences in the mRNA expression profile of nasal epithelia from healthy individuals and from CRSwNP patients would shed new light on disease mechanisms. METHODS: Primary epithelial cells from nasal polyps of 24 affected individuals and from middle turbinates of 9 healthy controls were obtained using magnetic beat assisted isolation and were used for expression profiling using the Human Genome U133 Plus 2.0 Genechip Array. RESULTS: Multiple gene probes corresponding to 27 genes showed an aberrant expression profile in polyp epithelial cells compared to healthy controls. Most of these genes are linked to pathogenic mechanisms seen in neoplasm formation, including changes in cell-cell adhesion, metabolic processes, cell cycle control, and differentiation. Remarkably, our data additionally suggest a role for maternally expressed genes in the pathogenesis of CRSwNP and reveal two distinct states of polyp epithelium that could not be linked to the presence or absence of atopy in patients or to the level of eosinophilia or neutrophilia of the polyp. CONCLUSIONS: Our data suggest new roles for nasal epithelium in the pathogenesis of CRSwNP.
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Mucosa Nasal , Pólipos Nasales , Rinitis , Sinusitis , Enfermedad Crónica , Humanos , Mucosa Nasal/patología , Rinitis/patología , Sinusitis/patología , Cornetes NasalesRESUMEN
BACKGROUND: Patients with eosinophilic nasal polyposis frequently require surgery, and recurrence rates are high. OBJECTIVE: We sought to assess the efficacy and safety of mepolizumab versus placebo for severe bilateral nasal polyposis. METHODS: This randomized, double-blind, placebo-controlled trial recruited patients aged 18 to 70 years with recurrent nasal polyposis requiring surgery. Patients received 750 mg of intravenous mepolizumab or placebo every 4 weeks for a total of 6 doses in addition to daily topical corticosteroid treatment. The primary end point was the number of patients no longer requiring surgery at Week 25 based on a composite end point of endoscopic nasal polyp score and nasal polyposis severity visual analog scale (VAS) score. Secondary end points included change in nasal polyposis severity VAS score, endoscopic nasal polyp score, improvement in individual VAS symptoms (rhinorrhea, mucus in throat, nasal blockage, and sense of smell), patient-reported outcomes, and safety. RESULTS: One hundred five patients received mepolizumab (n = 54) or placebo (n = 51). A significantly greater proportion of patients in the mepolizumab group compared with the placebo group no longer required surgery at Week 25 (16 [30%] vs 5 [10%], respectively; P = .006). There was a significant improvement in nasal polyposis severity VAS score, endoscopic nasal polyp score, all individual VAS symptom scores, and Sino-Nasal Outcome Test patient-reported outcome score in the mepolizumab compared with placebo groups. Mepolizumab's safety profile was comparable with that of placebo. CONCLUSION: In patients with recurrent nasal polyposis receiving topical corticosteroids who required surgery, mepolizumab treatment led to a greater reduction in the need for surgery and a greater improvement in symptoms than placebo.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Endoscopía , Eosinófilos/inmunología , Inmunoterapia/métodos , Pólipos Nasales/tratamiento farmacológico , Adolescente , Adulto , Anciano , Progresión de la Enfermedad , Femenino , Humanos , Interleucina-5/inmunología , Masculino , Persona de Mediana Edad , Pólipos Nasales/cirugía , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The aim of our study is to systematically review the existing evidence on the role of corticosteroids in patients undergoing functional endoscopic sinus surgery (FESS). METHODOLOGY: Systematic search of MEDLINE (1950- 2014), EMBASE (1980-2014), metaRegister, Cochrane Library and ISI conference proceedings was carried out. RESULTS: Eighteen randomised controlled trials with 1309 patients were included. Use of local and/or systemic corticosteroids with FESS was reported in four categories; operative, anaesthesia related, post-operative outcomes and risk of recurrence. Meta-analysis for operative outcomes demonstrated that, mean operative time (MD -10.70 minutes; 95% CI -15.86, -5.55; P <0.0001) and mean estimated blood loss (MD -28.32 mls; 95% CI -40.93, -15.72; P <0.0001) was significantly lower; and surgical field quality (MD -0.81; 95% CI -1.32, -0.30; P = 0.002) was significantly better in corticosteroid group. Meta-analysis showed that post-operative endoscopic scores (SMD -0.39; 95% CI -0.60, -0.17; P = 0.0004) were significantly better in corticosteroid group compared to no corticosteroid group. There was no increase in risk of sinusitis (RR 0.64; 95% CI 0.32, 1.30; P = 0.22) between use of corticosteroids and no corticosteroids; There was no significant difference in recurrence risk of chronic rhinosinusitis (CRS) in mixed population studies (RR 0.77; 95% CI 0.35, 1.70; P = 0.52) between the two groups but analysis of studies reporting on chronic rhinosinusitis with nasal polyps (CRSwNP) (RR 0.64;95% CI 0.45,0.91;P=0.01) showed significant difference in favour of the corticosteroid group. CONCLUSION: Pre-operative use of local and/or systemic corticosteroids in FESS, results in significantly reduced blood loss, shorter operative time and improved surgical field quality. Studies are limited on the intra-operative use of corticosteroids to reduce postoperative pain. Postoperative corticosteroids improve postoperative endoscopic scores in CRS and recurrence rates in cases of CRSwNP.
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Corticoesteroides/administración & dosificación , Atención Perioperativa , Sinusitis/cirugía , Pérdida de Sangre Quirúrgica , Enfermedad Crónica , Humanos , Cirugía Endoscópica por Orificios Naturales , Tempo Operativo , Ensayos Clínicos Controlados Aleatorios como Asunto , Recurrencia , Sinusitis/tratamiento farmacológicoRESUMEN
Meta-analysis of both large outcome studies as well as cohort studies support the safety and efficacy of Endoscopic Sinus Surgery for Chronic Rhinosinusitis. The efficacy of endoscopic sinus surgery is demonstrated in the improvement of both disease-specific and generic QOL as well as objective measures. However, this must be interpreted together with a well-recognized long-term 15-20 % revision rate, seen more often in patients with ASA trias and cystic fibrosis as well as osteitis and previous surgery. The effect of surgery is higher in managing nasal obstruction (effect size 1.7) and less so hyposmia (effect size 0.8). Allergy has an additive role on the symptomatology of CRS; however, its role if any on the outcome of ESS for CRS is unclear. The concurrent presence of aspiring sensitivity and asthma is associated with increased disease burden and more revision surgeries. Improved phenotyping of CRS may lead in the future to better tailoring of surgical treatments.
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Pólipos Nasales/cirugía , Senos Paranasales/cirugía , Rinitis/cirugía , Sinusitis/cirugía , Enfermedad Crónica , Endoscopía , Humanos , Pólipos Nasales/complicaciones , Ensayos Clínicos Controlados Aleatorios como Asunto , Rinitis/complicaciones , Sinusitis/complicacionesRESUMEN
Chronic rhinosinusitis is a heterogeneous and multifactorial disease with unknown etiology. Aberrant responses to microorganisms have been suggested to play a role in the pathophysiology of the disease. Research has focused on the presence, detection, response to, and eradication of these potential threats. Main topics seem to center on the contribution of structural cells such as epithelium and fibroblasts, on the consequences of activation of pattern-recognition receptors, and on the role of antimicrobial agents. This research should be viewed not only in the light of a comparison between healthy and diseased individuals, but also in a comparison between patients who do or do not respond to treatment. New players that could play a role in the pathophysiology seem to surface at regular intervals, adding to our understanding (and the complexity) of the disease and opening new avenues that may help fight this incapacitating disease.
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Bacterias/aislamiento & purificación , Hongos/aislamiento & purificación , Rinitis/inmunología , Rinitis/microbiología , Sinusitis/inmunología , Sinusitis/microbiología , Antiinfecciosos/uso terapéutico , Enfermedad Crónica , Epitelio/inmunología , Fibroblastos/inmunología , Humanos , Inmunidad Innata , Polimorfismo Genético , Receptores de Reconocimiento de Patrones/inmunología , Rinitis/genética , Rinitis/terapia , Sinusitis/genética , Sinusitis/terapiaRESUMEN
BACKGROUND: Endoscopic sinus surgery (ESS) is a common operation for patients with chronic rhinosinusitis with nasal polyps (CRSwNP) when medical therapy alone is insufficient. No randomised controlled trials on the efficacy of ESS have been published. We aimed to assess the efficacy of ESS plus medical therapy versus medical therapy alone in patients with CRSwNP. METHODS: We performed an open-label, multicentre, pragmatic, randomised, controlled trial in three tertiary care centres and 12 secondary care centres in 11 cities in the Netherlands (Almere, Amstelveen, Amsterdam, Blaricum, Den Haag, Deventer, Haarlem, Hoofddorp, Hoorn, Leiderdorp, and Rotterdam). Adults (aged ≥18 years) with CRSwNP and an indication for ESS were randomly assigned (1:1) using block randomisation (block sizes of six), stratified by study centre, to receive either ESS plus medical therapy or medical therapy. ESS was performed according to local practice, although anterior ethmoidectomy was mandatory. Medical therapy was prescribed at the patient's otorhinolaryngologist's discretion, and could be, but was not limited to, nasal corticosteroids, nasal rinsing, systemic corticosteroids, or systemic antibiotics. The primary outcome was disease-specific health-related quality of life (HRQoL) at 12 months of follow up, measured with the validated Sinonasal Outcome Test 22 (SNOT-22; where each item is scored from 0 to 5, where 0 indicated no problems and 5 indicates problems as bad as can be, with a total score of 0-110 points), and the minimal clinically important difference of the SNOT-22 is 9·0 points. Primary and safety analyses were performed on an intention-to-treat (ITT) basis. The ITT population comprised all patients who were randomly assigned to treatment according to their randomisation group and without any protocol violation. This study is registered with the Netherlands Trial Register, NTR4978, and is ongoing. FINDINGS: Between Feb 15, 2015, and Aug 27, 2019, 371 patients were screened for eligibility, of whom 238 were eligible, willing to participate, and randomly assigned to ESS plus medical therapy (n=121) or medical therapy (n=117) and 234 were included in the baseline ITT population (n=118 ESS plus medical therapy; n=116 medical therapy). 142 (61%) of 234 patients at baseline were men and 92 (39%) were women, and the mean age was 50·4 years (SD 12·7). 206 participants were analysed at 12 months for the primary outcome (n=103 in the ESS plus medical therapy group; n=103 in the medical therapy group). At 12 months follow-up, the mean SNOT-22 score in the ESS plus medical therapy group was 27·9 (SD 20·2; n=103) and in the medical therapy group was 31·1 (20·4; n=103), with an adjusted mean difference of -4·9 (95% CI -9·4 to -0·4), favouring ESS plus medical therapy. Adverse events were similar between the groups. The most common adverse events were minor epistaxis or gastrointestinal problems. No treatment-related deaths occurred, but one patient died due to congestive heart failure. INTERPRETATION: ESS plus medical therapy is more efficacious than medical therapy alone in patients with CRSwNP, although the minimal clinically important difference was not met. Long-term follow-up data are needed to determine whether the effect persists. The current results are a basis for further development of evidence-based guidelines. FUNDING: The Netherlands Organisation for Health Research and Development (ZonMw).
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Pólipos Nasales , Sinusitis , Adolescente , Adulto , Endoscopía/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pólipos Nasales/complicaciones , Pólipos Nasales/tratamiento farmacológico , Pólipos Nasales/cirugía , Calidad de Vida , Sinusitis/complicaciones , Sinusitis/tratamiento farmacológico , Resultado del TratamientoRESUMEN
This study offers a novel description of the sinonasal microbiome, through an unsupervised machine learning approach combining dimensionality reduction and clustering. We apply our method to the International Sinonasal Microbiome Study (ISMS) dataset of 410 sinus swab samples. We propose three main sinonasal "microbiotypes" or "states": the first is Corynebacterium-dominated, the second is Staphylococcus-dominated, and the third dominated by the other core genera of the sinonasal microbiome (Streptococcus, Haemophilus, Moraxella, and Pseudomonas). The prevalence of the three microbiotypes studied did not differ between healthy and diseased sinuses, but differences in their distribution were evident based on geography. We also describe a potential reciprocal relationship between Corynebacterium species and Staphylococcus aureus, suggesting that a certain microbial equilibrium between various players is reached in the sinuses. We validate our approach by applying it to a separate 16S rRNA gene sequence dataset of 97 sinus swabs from a different patient cohort. Sinonasal microbiotyping may prove useful in reducing the complexity of describing sinonasal microbiota. It may drive future studies aimed at modeling microbial interactions in the sinuses and in doing so may facilitate the development of a tailored patient-specific approach to the treatment of sinus disease in the future.
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Microbiota , Senos Paranasales , Sinusitis , Enfermedad Crónica , Humanos , ARN Ribosómico 16S/genética , Staphylococcus/genéticaRESUMEN
Introduction:Pseudomonas aeruginosa infections are prevalent amongst chronic rhinosinusitis (CRS) sufferers. Many P. aeruginosa strains form biofilms, leading to treatment failure. Lytic bacteriophages (phages) are viruses that infect, replicate within, and lyse bacteria, causing bacterial death. Aim: To assess the activity of a phage cocktail in eradicating biofilms of ex vivo P.aeruginosa isolates from CRS patients. Methods: P. aeruginosa isolates from CRS patients with and without cystic fibrosis (CF) across three continents were multi-locus sequence typed and tested for antibiotic resistance. Biofilms grown in vitro were treated with a cocktail of four phages (CT-PA). Biofilm biomass was measured after 24 and 48 h, using a crystal violet assay. Phage titrations were performed to confirm replication of the phages. A linear mixed effects model was applied to assess the effects of treatment, time, CF status, and multidrug resistance on the biomass of the biofilm. Results: The isolates included 44 strain types. CT-PA treatment significantly reduced biofilm biomass at both 24 and 48 h post-treatment (p < 0.0001), regardless of CF status or antibiotic resistance. Biomass was decreased by a median of 76% at 48 h. Decrease in biofilm was accompanied by a rise in phage titres for all except one strain. Conclusion: A single dose of phages is able to significantly reduce biofilms formed in vitro by a range of P.aeruginosa isolates from CRS patients. This represents an exciting potential and novel targeted treatment for P. aeruginosa biofilm infections and multidrug resistant bacteria.