Article

Ibuprofen Therapy and Nasal Polyposis in Cystic Fibrosis Patients

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Abstract

To assess the effects on nasal polyposis from high-dose ibuprofen therapy used in children with cystic fibrosis (CF) pulmonary disease. Retrospective case series. Presence or absence of nasal polyps. Twenty-two patients treated with high-dose ibuprofen therapy to benefit pulmonary function were identified from 235 patients with CF. Sinonasal disease was present in 19 patients, of whom 12 had nasal polyposis. All 12 patients had observed absence of nasal polyps at some point during their ibuprofen course. Nasal polyps were present in five patients during ibuprofen therapy, and all resolved with increased ibuprofen doses. Polyps occurred in six of eight patients after ibuprofen therapy ceased. Five of the 12 patients required endoscopic sinus surgery for polyposis. High-dose ibuprofen therapy chronically administered at appropriate weight-based dosing is a possible treatment option for children and young adults with CF polyposis. More testing is indicated.

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... The potential role of ibuprofen in CF-related NPs' therapy was studied in only one clinical research. This study investigated the influence of ibuprofen at a dose of 40.9 mg/kg/ day on NPs administered in CF children for approximately 52 months [43]. The resolution of NPs was observed during therapy, nevertheless, ibuprofen-induced effects were only temporary as in the majority of patients, NPs re-appeared shortly after treatment discontinuation [43]. ...
... This study investigated the influence of ibuprofen at a dose of 40.9 mg/kg/ day on NPs administered in CF children for approximately 52 months [43]. The resolution of NPs was observed during therapy, nevertheless, ibuprofen-induced effects were only temporary as in the majority of patients, NPs re-appeared shortly after treatment discontinuation [43]. Interestingly, in individuals without NPs before and during ibuprofen therapy, polyps occurred after cessation of treatment implying the potential protective role of ibuprofen against polyps' development [43]. ...
... The resolution of NPs was observed during therapy, nevertheless, ibuprofen-induced effects were only temporary as in the majority of patients, NPs re-appeared shortly after treatment discontinuation [43]. Interestingly, in individuals without NPs before and during ibuprofen therapy, polyps occurred after cessation of treatment implying the potential protective role of ibuprofen against polyps' development [43]. Lindstrom et al. concluded that longterm, high-dose and weight-adjusted ibuprofen use could be a potential therapeutic option for NPs in CF children [43]. ...
Article
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Purpose Chronic rhinosinusitis (CRS) is observed in almost 100% of patients with cystic fibrosis (CF). CF-related CRS treatment is extremely challenging because of the underlying genetic defect leading to its development. CRS in CF is often refractory to standard therapy, while recurrences after surgical treatment are inevitable in the majority of patients. This study provides a precise review of the current knowledge regarding possible therapeutic options for CF-related CRS. Methods The Medline and Web of Science databases were searched without a time limit using the terms “cystic fibrosis” in conjunction with “otorhinolaryngological manifestation”, “rhinology” and “sinusitis”. Results Precise guidelines for CF-induced CRS therapy are lacking due to the lack of large cohort randomized controlled trials. None of the existing therapeutic agents has already been recommended for CRS in CF. Therapy targeting the underlying genetic defect, intranasal dornase alfa administration, and topical delivery of colistin and tobramycin showed promising results in CF-related CRS therapy. Besides the potential effectiveness of nasal steroids, strong recommendations for their usage in CF have not been provided yet. Systemic corticosteroid usage is controversial due to its potential negative influence on pulmonary disease. Ibuprofen revealed some positive effects on CF-related CRS in molecular and small cohort studies. Intranasal irrigation with saline solutions could relieve sinonasal symptoms. Nasal decongestants are not recommended. Endoscopic sinus surgery is the first-line surgical option for refractory CRS. Extensive surgical approaches should be considered as they could improve long-term outcomes in CRS. Conclusion Further studies are warranted to establish consensus for CF-related CRS therapy.
... While not widely studied for the treatment of CRS in any population, high-dose ibuprofen has slowed progression of CF-related lung disease in pediatric patients [117]. In CF patients with NP, a retrospective study of high-dose ibuprofen led to complete resolution of NP in all 12 patients at some point during the course of treatment [118]. However, the vast majority experienced polyp recurrence upon ibuprofen cessation and nearly half additionally required ESS for more definitive treatment [118]. ...
... In CF patients with NP, a retrospective study of high-dose ibuprofen led to complete resolution of NP in all 12 patients at some point during the course of treatment [118]. However, the vast majority experienced polyp recurrence upon ibuprofen cessation and nearly half additionally required ESS for more definitive treatment [118]. Observed effects are likely due to cyclooxygenase inhibition and resultant suppression of neutrophil migration and activation [83]. ...
Article
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Purpose of review: The purpose of this review is to provide otolaryngologists with the most up-to-date advancements in both the medical and surgical management of CF-related sinus disease. Recent findings: Recent studies have supported more aggressive CRS management, often with a combination of both medical and surgical therapies. Comprehensive treatment strategies have been shown to reduce hospital admissions secondary to pulmonary exacerbations in addition to improving CRS symptoms. Still, current management strategies are lacking in both high-level evidence and standardized guidelines. Summary: The unified airway model describes the bi-directional relationship between the upper and lower airways as a single functional unit and suggests that CRS may play a pivotal role in both the development and progression of lower airway disease. Current strategies for CF CRS focus primarily on amelioration of symptoms with antibiotics, nasal saline and/or topical medicated irrigations, and surgery. However, there are no definitive management guidelines and there remains a persistent need for additional studies. Nevertheless, otolaryngologists have a significant role in the overall management of CF, which requires a multi-disciplinary approach and a combination of both surgical and medical interventions for optimal outcomes of airway disease. Here we present a review of currently available literature and summarize medical and surgical therapies best suited for the management of CF-related sinus disease.
... Topical nasal corticosteroid therapy (betamethasone) proved its efficiency by decreasing polyp size perhaps by having anti-inflammatory effect (21), although it remains controversial in systemic (short course) therapy in combination with antibiotics. NSAIDs (ibuprofen) appears effective in patient with compromised lung function, but at higher doses, which induce some risk of side effects (22). Dornase alfa therapy decreases the risk of recurrence after polyp surgery, sustaines anti-edematous effect and thereby decreases the necessary for invasive rhinosinusal procedures (23). ...
Article
Chronic rhinosinusitis is a rare pathology in pediatric pathology versus adult patients. Clinical manifestations are related, on the one hand, with the anatomical particularities and, on the other hand, with the immune response correlated with the age of the child. Allergy is the main cause in 50% of child rhinitis, 40% of them debuting early until the age of 6 years. The clinical expression of allergic rhinosinusitis in children can sometimes be accompanied by comorbidity manifestations or complications. Impaired mucociliary clearance can be induced by other rare pathological situations that produce mucus rheology modification, as in cystic fibrosis (CF). Through, the clinical heterogenicity of expression is in relation, on the one hand, with immunogenic response and anatomical particularities relative to age of the child, and secondly with the diversity of inducing factors (from very frequent like allergy to the least frequent, CF). It requires a correct diagnosis, early and appropriate treatment by a multidisciplinary team collaboration.
... Uma pequena série de pacientes com FC e polipose nasal mostrou beneficio com o uso desse medicamento, mas maiores estudos são necessários para avaliar sua eficácia. (56) ...
Article
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Resumo A fibrose cística (FC) é uma doença genética irreversível, mas os avanços no tratamento têm aumentado a expectativa de vida dos pacientes. O acometimento das vias aéreas superiores, principalmente por alterações patológicas dos seios paranasais, é prevalente nesses pacientes, embora muitos apresentem poucos sintomas. O objetivo desta revisão é discutir a fisiopatologia e o manejo terapêutico atual da rinossinusite crônica (RSC) na FC. A revisão fundamentou-se nas evidências mais recentes, classificadas em conformidade com os critérios do Oxford Centre for Evidence-Based Medicine. Quando sintomática, a RSC com pólipos nasais pode afetar a qualidade de vida e as exacerbações pulmonares, já que os seios paranasais podem ser colonizados por bactérias patogênicas, principalmente a Pseudomonas aeruginosa. Essa bactéria tem papel crucial na morbidade e mortalidade após o transplante pulmonar em pacientes com FC. Embora o tratamento clínico das vias aéreas superiores seja indicado no manejo inicial, a indicação é muitas vezes extrapolada de estudos sobre RSC na população geral. A cirurgia é a alternativa quando o quadro nasossinusal é refratário à terapia não invasiva. Mais estudos são necessários para compreender melhor o acometimento das vias aéreas superiores e melhorar o manejo da RSC na FC, a fim de preservar a função pulmonar e evitar procedimentos invasivos desnecessários.
... 65 A decade later, observational data from the CFF Patient Registry demonstrated a 29% reduction in the rate of lung function decline among children ages 6-17 who received chronic therapy with ibuprofen compared to those who did not 66 ; these data were similar to that found among Canadian patients with CF. 67 Ibuprofen use may also affect the development of nasal polyposis. 68 Interestingly, in vivo models recently demonstrated that ibuprofen is able to increase cell membrane trafficking of CFTR in human bronchial epithelium as well as in murine models. 69 ...
Article
While a major target in cystic fibrosis (CF) research in recent years has been the development of corrector and potentiator drugs targeting the cystic fibrosis transmembrane conductance regulator (CFTR) protein, these therapies have not yet proven robust enough to replace or eliminate other therapies that have demonstrated improved health outcomes and quality of life in patients with CF. Further, ivacaftor is only indicated for approximately 5% of the US CF population, although the FDA has recently approved lumacaftor/ivacaftor, a combination therapy intended for those homozygous for Phe508del, which should reach a much larger number of patients. This review appraises therapeutics currently available or being studied while we await the next generation of CFTR potentiators and correctors. Pediatr Pulmonol. 2015; 50:S66-S73. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
... Ibp, ibuprofen. 29). However, the risk of adverse effects limits its use to only ϳ3.3% of patients (9a). ...
Article
High-dose ibuprofen, an effective anti-inflammatory therapy for the treatment of cystic fibrosis (CF), has been shown to preserve lung function in a pediatric population. Despite its efficacy, few patients receive ibuprofen treatment due to potential renal and gastrointestinal toxicity. The mechanism of ibuprofen efficacy is also unclear. We have previously demonstrated that CF microtubules are slower to reform after depolymerization compared to respective wild type controls. Slower microtubule dynamics in CF cells are responsible for impaired intracellular transport and are related to inflammatory signaling. Here, it is identified that high-dose ibuprofen treatment in both CF cell models and primary CF nasal epithelial cells restores microtubule reformation rates to wild-type levels, as well as induce extension of microtubules to the cell periphery. Ibuprofen treatment also restores microtubule dependent intracellular transport monitored by measuring intracellular cholesterol transport. These effects are specific to ibuprofen as other cyclooxygenase inhibitors have no effect on these measures. Effects of ibuprofen are mimicked by stimulation of AMPK and blocked by the AMPK inhibitor compound c. It is concluded that high-dose ibuprofen treatment enhances microtubule formation in CF cells likely through an AMPK-related pathway. These findings define a potential mechanism to explain the efficacy of ibuprofen therapy in CF.
... 2) Ibuprofen. Its use and efficiency was shown in 2007 by Konstan et al. 24 and by Lindstrom et al. 25 by reducing the progression of the pulmonary disease and the size of nasal polyps. 3) Macrolide antibiotics. ...
Article
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An irreversible disease, cystic fibrosis (CF), is responsible for affecting multiple organ systems containing epithelia. It is well known that the sinonasal disease caused by CF has consequences for the incidence of the lower airway exacerbations, as well as affecting the quality of life of those patients. This review provides an update by evaluating the available literature regarding pathogenesis, management and treatment of cystic fibrosis patients. To gain a better view of the disease and obtain a higher life expectancy, further studies are needed.
... In addition, clinical regression of NPs was noted in five patients during ibuprofen therapy. 94 Confirmatory studies are required to evaluate the effectiveness of this drug in CF CRS. ...
Article
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Advances in the care of patients with cystic fibrosis (CF) have improved pulmonary outcomes and survival. In addition, rapid developments regarding the underlying genetic and molecular basis of the disease have led to numerous novel targets for treatment. However, clinical and basic scientific research focusing on therapeutic strategies for CF-associated chronic rhinosinusitis (CRS) lags behind the evidence-based approaches currently used for pulmonary disease. This review evaluates the available literature and provides an update concerning the pathophysiology, current treatment approaches, and future pharmaceutical tactics in the management of CRS in patients with CF. Optimal medical and surgical strategies for CF CRS are lacking because of a dearth of well-performed clinical trials. Medical and surgical interventions are supported primarily by level 2 or 3 evidence and are aimed at improving clearance of mucus, infection, and inflammation. A number of novel therapeutics that target the basic defect in the cystic fibrosis transmembrane conductance regulator channel are currently under investigation. Ivacaftor, a corrector of the G551D mutation, was recently approved by the Food and Drug Administration. However, sinonasal outcomes using this and other novel drugs are pending. CRS is a lifelong disease in CF patients that can lead to substantial morbidity and decreased quality of life. A multidisciplinary approach will be necessary to develop consistent and evidence-based treatment paradigms.
... .5,6,[12][13][14][15][16][17][18][19][20][21] The systematic review included 701 patients, including both children and adults. Half of the ...
Article
The objective of this work was to systematically review literature on the effectiveness of surgical management for chronic rhinosinusitis (CRS) in cystic fibrosis (CF) patients. We performed a literature search encompassing the last 25 years in PubMed, Embase, and Cochrane CENTRAL. Inclusion criteria included English language papers containing original data, more than 6 subjects, and measurable clinical outcomes. Data was systematically collected on study design, patient demographics, clinical characteristics and outcomes, and level-of-evidence. Two investigators independently reviewed all manuscripts. A quality assessment of the included studies was performed. The initial search yielded 416 abstracts, of which 24 articles met inclusion criteria, detailing 680 adult and pediatric CF patients who underwent surgical therapy. Surgical treatment included primarily endoscopic sinus surgery (ESS) (22/24). Outcome measures included sinonasal symptoms (14/24), endoscopic findings (8/24), pulmonary function testing (8/24), recurrence or revision surgery (5/24), hospitalization (4/24), need for antibiotic therapy (2/24), radiographic findings (2/24), and pulmonary exacerbations (1/24). The level-of-evidence was predominantly Level 4 (21/24); there were no Level 1 evidence studies. Most studies found improvement in symptom measures and endoscopic findings but no improvement in lower airway function after surgical therapy. Postoperative measures of the other outcomes were inconclusive or inconsistent. For adult and pediatric CF sinusitis, ESS yielded clinical improvement as measured primarily by sinonasal symptoms and endoscopic findings. It is unclear if surgical intervention modifies lower airway disease. Future prospective studies with predetermined, objective, and validated outcome measures are needed to determine the effectiveness of surgical intervention for CF-related CRS. Overall evidence Grade B/C.
... В своем изыскании D. Lindstrom и соавт. на небольшой выборке пациентов показали положительный эффект длительного курса высоких доз ибупрофена при терапии полипозного ХРС, выражающийся в снижении потребности в хирургическом лечении, но лишь во время приема препарата [33]. ...
... Ibuprofen is yet another medical therapy that some have trialed for the treatment of CF-related sinonasal disease. One study showed that 12 patients with CF and nasal polyposis had resolution of their nasal polyps at some point during high-dose ibuprofen therapy [42]. However, more than half of patients who stopped ibuprofen had a recurrence of nasal polyps, likely indicating only a temporary benefit [40]. ...
Article
Full-text available
Chronic rhinosinusitis (CRS) is nearly ubiquitous in patients with cystic fibrosis (CF). CF CRS is a challenging entity to define, diagnose, and treat, as patients often have severe refractory sinus disease in addition to complex medical comorbidities. The purpose of this article is to review the literature on the medical management of CF CRS and determine how to best identify, diagnose, and manage CF CRS. Ultimately, the treatment of these patients requires a multi-disciplinary approach involving the pulmonologist and otolaryngologist.
... Recent studies describe the positive effect of chronic highdose ibuprofen treatment on the progression of lung disease in children with CF [29]. A small series of CF patients with nasal polyposis who received ibuprofen all reported absence of nasal polyps at some point during treatment, although 42% subsequently required endoscopic sinus surgery for polyposis [30]. More testing is needed to determine if ibuprofen ameliorates CF polyposis. ...
Article
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Routine CF management often does not include upper airway (UAW) assessment although CFTR defects equally affect the sinonasal mucosa. Up to 50% of CF patients have chronic rhinosinusitis (CRS) and/or nasal polyps, and almost 100% reveal UAW abnormalities on CT scan. CRS impairs quality of life. UAW dysfunction in filtering, humidifying, and warming inspired air affects lower airways and the UAW is a potential site of first colonization and a reservoir for opportunistic bacteria. Therefore, UAW pathology substantially affects overall health in CF. Standard treatments are scarce and mostly lack evidence. Nasal douche can remove mucus and crusts. Recently, delivery of dornase alfa using a vibrating aerosol has shown potential as treatment for CF-related CRS. Surgery is indicated when conservative approaches fail but postoperative relapse is frequent. In summary, upper airway involvement in CF is undertreated and requires prospective investigation and an interdisciplinary consensus on diagnosis and therapy.
... Carlile et al. demonstrate that ibuprofen is a CF transmembrane conductance regulator (CFTR) protein corrector and suggest that ibuprofen may be suitable in a CF combination therapy (Carlile, et al., 2015). Additionally, Lindstrom et al. suggest that high doses of ibuprofen administered based on weight can treat polyposis in children with CF (Lindstrom, et al., 2007). There are 3 more studies (Konstan, et al., 1995;Konstan, et al., 2007;Lands, et al., 2007) in agreement that high doses of ibuprofen slow the progression of lung disease in CF without serious adverse effects. ...
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Subject Fibrotic diseases cover a spectrum of systemic and organ-specific maladies that affect a large portion of the population, currently without cure. The shared characteristic these diseases feature is their uncontrollable fibrogenesis deemed responsible for the accumulated damage in the susceptible tissues. Idiopathic Pulmonary Fibrosis ( IPF ), an interstitial lung disease, is one of the most common and studied fibrotic diseases and still remains an active research target. Objective We highlight unique and common (i) genes, (ii) biological pathways and (iii) candidate repurposed drugs among nine fibrotic diseases. We bibliographically explore the resulting candidate substances for potential anti-fibrotic mode of action and focus on diseases that appear to be more similar to IPF so as to jointly examine potential treatments. Methodology We identify key genes for the 9 fibrotic diseases by analyzing transcriptomics datasets. We construct gene-to-gene networks for each disease and examine these networks to explore functional communities of biological pathways. We also use the most significant genes as input in Drug Repurposing (DR) tools and re-rank the resulting candidates according to their structural properties and functional relationship to each investigated disease. Results We identify 7 biological pathways involved in all 9 fibrotic diseases as well as pathways unique to some of these diseases. Based on our DR results, we suggest captopril and ibuprofen that both appear to slow the progression of fibrotic diseases according to existing bibliography. We also recommend nafcillin and memantine, which haven’t been studied against fibrosis yet, for further wet-lab experimentation. We also observe a group of cardiomyopathy-related pathways that are exclusively highlighted for Oral Submucous Fibrosis ( OSF ). We suggest digoxin to be tested against OSF , since we observe cardiomyopathy-related pathways implicated in OSF and there is bibliographic evidence that digoxin may potentially clear myocardial fibrosis. Finally, we establish that IPF shares several involved genes, biological pathways and candidate inhibiting-drugs with Dupuytren’s Disease , IgG4-related Disease , SSc and Cystic Fibrosis . We propose that treatments for these fibrotic diseases should be jointly pursued.
... Carlile et al. demonstrate that ibuprofen is a CF transmembrane conductance regulator (CFTR) protein corrector and suggest that ibuprofen may be suitable in a CF combination therapy [94]. Additionally, Lindstrom et al. suggest that high doses of ibuprofen administered based on weight can treat polyposis in children with CF [95]. There are 3 more studies [96][97][98] in agreement that high doses of ibuprofen slow the progression of lung disease in CF without serious adverse effects. ...
Article
Full-text available
Fibrotic diseases cover a spectrum of systemic and organ-specific maladies that affect a large portion of the population, currently without cure. The shared characteristic these diseases feature is their uncontrollable fibrogenesis deemed responsible for the accumulated damage in the susceptible tissues. Idiopathic Pulmonary Fibrosis , an interstitial lung disease, is one of the most common and studied fibrotic diseases and still remains an active research target. In this study we highlight unique and common (i) genes, (ii) biological pathways and (iii) candidate repurposed drugs among 9 fibrotic diseases. We identify 7 biological pathways involved in all 9 fibrotic diseases as well as pathways unique to some of these diseases. Based on our Drug Repurposing results, we suggest captopril and ibuprofen that both appear to slow the progression of fibrotic diseases according to existing bibliography. We also recommend nafcillin and memantine, which haven’t been studied against fibrosis yet, for further wet-lab experimentation. We also observe a group of cardiomyopathy-related pathways that are exclusively highlighted for Oral Submucous Fibrosis . We suggest digoxin to be tested against Oral Submucous Fibrosis , since we observe cardiomyopathy-related pathways implicated in Oral Submucous Fibrosis and there is bibliographic evidence that digoxin may potentially clear myocardial fibrosis. Finally, we establish that Idiopathic Pulmonary Fibrosis shares several involved genes, biological pathways and candidate inhibiting-drugs with Dupuytren’s Disease , IgG4-related Disease , Systemic Sclerosis and Cystic Fibrosis . We propose that treatments for these fibrotic diseases should be jointly pursued.
... nasal polyposis, larger studies are needed in order to evaluate its efficacy. (56) ...
Article
Beginning in preschool age, during their lives, upto 50% of cystic fibrosis (CF) patients experience obstructing nasal polyposis (NP), which is rare in non-CF children. Pathogenetic factors of NP in general and especially in CF are still obscure. However, defective epithelial ion transport from mucosal glands plays a central role in CF, and viscous secretions impair mucociliary clearance, promoting chronic pathogen colonization and neutrophil-dominated chronic inflammation.Presently, CF-NP is not curable but can be clinically stabilized,though the large variety of proposed treatment modalities indicates a lack of standardization and of evidence of treatment efficacy. When conservative measures are exhausted, surgical intervention combining individually adapted endoscopic sinus surgery and supportive conservative treatment is performed. Topical steroids, approved as the gold standard for non-CF NP, may be beneficial, but they are discussed to be less effective in neutrophilic inflammation,and CF-specific antimicrobial and mucolytic therapy, as is true of all treatment modalities, urgently requires evaluation by controlled clinical trials within interdisciplinary networks.
Chapter
Nasal polyps are common in cystic fibrosis (CF). Nasal polyps in children should prompt appropriate investigations for the potential diagnosis of CF. Possible etiologies for nasal polyp formation in CF include direct consequence of ΔF508 affecting chromosome 7, colonization with microorganisms including Pseudomonas aeroginosa and fungi, and IgE-mediated inflammation. Neutrophils are more common in polyps from CF patients compared with non-CF nasal polyposis. Conservative management with nasal irrigations and nasal steroids constitute first-line treatment. Surgical management of persistent and symptomatic polyps may also improve lung function, and consequently, quality of life. Simple polypectomy has a high rate of early recurrence, and thus, surgery should include at a minimum uncinectomy, middle meatal antrostomy, and anterior ethmoidectomy. Topical delivery of novel medications may reduce the need for surgery.
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Over the past four decades, the average life expectancy for patients with cystic fibrosis (CF) has increased from 13 to 37 years of age. With increasing survival and improved pulmonary management, otolaryngologists are now seeing an increasing number of CF patients with chronic rhinosinusitis (CRS). Although CRS is a commonly treated disease process, there are a number of subtleties specific to CF. As the life expectancy of CF patients increases, quality of life issues gain importance. It is essential for otolaryngologists to understand the current therapeutic modalities to treat this challenging subset of CRS patients. The sinonasal mucosa of CF patients has distinct differences including impaired mucociliary clearance and a predominantly neutrophilic polyp profile. Performing more aggressive surgical intervention, especially in the setting of revision cases may lead to improved outcomes. A recent study demonstrated that extensive sinus surgery with postoperative management can eradicate pathogenic bacteria from the sinuses of CF patients for up to 1 year. With increasing life expectancy in CF, patients will require long-term follow-up with an otolaryngologist. Understanding the intricacies of the presentation of this disease in patients with CF is important for optimizing management.
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Introduction: Nasal polyposis is often found in patients with cystic fibrosis. Objective: To assess the incidence of nasal polyposis, the response to medical treatment, recurrence and the need for surgical intervention in children and adolescents with cystic fibrosis during a three-year follow-up. Methods: Clinical symptoms (pulmonary, pancreatic insufficiency, malnutrition, nasal obstruction), two positive sweat chloride tests, and genotype findings in 23 patients with cystic fibrosis were analyzed. All patients underwent nasal endoscopy every 12 months from January 2005 to December 2007, to assess the presence and grade of Nasal Polyps. Nasal polyposis, when present, were treated with topical corticosteroids for 6-12 months, with progress being evaluated within the 3 years of follow-up. Results: In the first evaluation, nasal polyposis was diagnosed in 30.43% of patients (3 bilateral and 4 unilateral), recurrent pneumonia in 82.6%, pancreatic insufficiency in 87%, and malnutrition in 74%. The presence of nasal polyposis was not associated with chloride values in the sweat, genotype, clinical signs of severity of cystic fibrosis, or nasal symptoms. In the three-year period of follow up, 13 patients (56.52%) had at least one event of polyposis, with the youngest being diagnosed at 32 months of age. Only one patient underwent surgery (polypectomy), and there was one diagnosis of nasopharyngeal carcinoma. Conclusion: The study showed a high incidence of nasal polyposis. Monitoring through routine endoscopy in patients with cystic fibrosis, even in the absence of nasal symptoms, is highly recommended. The therapy with topical corticosteroids achieved good results. Thus, an interaction between pediatricians and otolaryngologists is necessary.
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Drug delivery into the nasal cavity has an established role in local delivery of over-the-counter medicines used to treat allergic rhinitis and blocked sinuses. Whilst older dosage forms (such as nasal bougies) have fallen from favour over the years, nasal sprays and nasal drops remain the staple dosage forms for drug delivery into the nasal cavity. This chapter discusses the anatomy and physiology of the nasal cavity, and then describes the many pathological disorders that affect mucociliary clearance (MCC) by obstruction, lesions or changes to the nasal secretions or cilia. Although some compounds can diffuse freely across the nasal epithelia, this passive route is only accessible by highly lipophilic compounds. As a result, drug moieties and their formulations are increasingly being designed to exploit endogenous membrane transporters to enhance drug permeation. The olfactory epithelium presents a drug absorption route, which bypasses the blood-brain barrier, allowing direct nose-to-brain absorption.
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The use of high-dose ibuprofen as an anti-inflammatory therapy in cystic fibrosis (CF) has been shown to be an effective intervention although use is limited due to potential adverse events. Identifying the mechanism of ibuprofen efficacy would aid in the development of new therapies that avoid these adverse events. Previous findings demonstrated that ibuprofen treatment restores the regulation of microtubule dynamics in CF epithelial cells through a 5'-adenosine monophosphate-activated protein kinase (AMPK)-dependent mechanism. The goal of this study is to define the AMPK pathway that leads to microtubule regulation. Here, it is identified that inhibition of acetyl-CoA carboxylase (ACC) is the key step in mediating the AMPK effect. ACC inhibition with 5-(tetradecyloxy)-2-furoic acid (TOFA) increases microtubule reformation rates in cultured and primary CF epithelial cells to wild-type (WT) rates. TOFA treatment also restores microtubule-dependent distribution of cholesterol and Rab7-positive organelles, as well as reduces expression of the proinflammatory signaling molecule RhoA to WT levels. ACC activation with citrate replicates these CF phenotypes in WT cells further supporting the role of AMPK signaling through ACC as a key mediator in CF cell signaling. It is concluded that ACC inhibition is the key step in the efficacy of AMPK activation at the cellular level and could represent a novel site of therapeutic intervention to address inflammation in CF.
Chapter
Rates of chronic rhinosinusitis (CRS) in patients with cystic fibrosis (CF) approach 100%. A combination of surgical interventions and aggressive systemic and topical therapy is required for the adequate treatment of CF CRS. Appropriate CRS treatment reduces sinonasal colonization of pathogenic bacteria and delays gram-negative pulmonary infections.
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The pathogenesis of chronic rhinosinusitis with nasal polyposis is unknown. Chronic inflammation along with local tissue hypoxia may effect polyp's growth. Activation of Cycloxygenases may also be involved. COX-2 up-regulates in response to different stimuli including hypoxia. Its activation is associated with enhanced cell proliferation. Histologically, besides inflammatory cells, increased stromal fibrosis is seen in nasal polyposis. The aims of this study were to test whether hypoxia amplifies nasal polyp fibroblasts proliferation, whether treatment with various COX inhibitors could influence fibroblasts, and whether this effect may be modulated in response to different oxygenation conditions. Polyp fibroblasts were incubated under hypoxic or normoxic conditions with or without NSAIDs at different concentrations for 12 or 24 hours. Cell proliferation was quantified using BrdU ELISA. Metabolic activity was evaluated using MTT assay. Cell death was measured using Annexin V staining and FACS scan. No significant difference was found between proliferation of fibroblasts treated under hypoxia or normoxia. Cells incubated with indomethacin proliferated in a slightly enhanced manner compared with non-treated cells. Celecoxib inhibited fibroblast proliferation (P < .001) but did not influence cell survival. Metabolic activity of cells treated with celecoxib was significantly reduced (P < .003), unlike cells treated with indomethacin or rofecoxib. Hypoxia does not affect fibroblasts proliferation. It may contribute to nasal polyposis pathogenesis in other ways. The anti-proliferative effect of celecoxib may be associated with cell cycle arrest rather than with pro-apoptotic activity. Celecoxib may be considered for treating nasal polyposis.
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Since the inflammatory response to chronic infection contributes to lung destruction in patients with cystic fibrosis, we hypothesized that anti-inflammatory therapy might slow the progression of lung disease. In a double-blind trial, 85 patients, 5 to 39 years of age, with mild lung disease (forced expiratory volume in one second [FEV1], > or = 60 percent of the predicted value) were randomly assigned to receive ibuprofen or placebo orally twice daily for four years. Doses were adjusted individually to achieve peak plasma concentrations of 50 to 100 micrograms per milliliter. Changes in pulmonary function, the percentage of ideal body weight, the chest-radiograph score, and the frequency of hospitalization were assessed. Patients randomly assigned to ibuprofen had a slower annual rate of change in FEV1 than the patients assigned to placebo (mean [+/- SE] slope, -2.17 +/- 0.57 percent vs. -3.60 +/- 0.55 percent in the placebo group; P = 0.02), and weight (as a percentage of ideal body weight) was better maintained in the former group (P = 0.02). Among the patients who took ibuprofen for four years and had at least a 70 percent rate of compliance, the annual rate of change in FEV1 was even slower (-1.48 +/- 0.69 percent vs. -3.57 +/- 0.65 percent in the placebo group, P = 0.03), and this group of patients also had a significantly slower rate of decline in forced vital capacity, the percentage of ideal body weight, and the chest-radiograph score. There was no significant difference between the ibuprofen and placebo groups in the frequency of hospitalization. One patient was withdrawn from the study because of conjunctivitis, and one because of epistaxis related to ibuprofen. In patients with cystic fibrosis and mild lung disease, high-dose ibuprofen, taken consistently for four years, significantly slows the progression of the lung disease without serious adverse effects.
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The authors present two clinical studies performed in the ENT departments of two Belgian Universities. A total of 248 patients with mucoviscidosis (cystic fibrosis, CF) were assessed by means of nasal endoscopy. One hundred eighteen underwent computed tomography of the paranasal sinuses (CT) and 55 were endoscopically operated. This allowed the observation of different clinical patterns of rhinosinusitis: mucopyosinusitis (pseudomucocele) of the maxillary antrum with bulging of the lateral nasal wall (LNW), nasal polyposis with erosion of the LNW, and chronic purulent rhinosinusitis with an isolated prominent uncinate process. The treatment of those patients could be tailored to the individual clinical pattern. Medical therapy consisted of systemic antibiotics and topical drugs delivered by sprays or by lavages with a nose can. Surgery was mainly aimed at removing the massive polyposis when it interfered with the daily life activities. The use of the endoscope enabled to perform safely more extensive procedures resulting in a lower recurrence rate. In patients with chronic rhinosinusitis without polyposis, yet presenting ostiomeatal obstruction, a limited and more functional endoscopic surgery was indicated in order to restore some drainage and to improve the penetration of topical drugs into the affected sinus. A short addendum presents two studies: one about genetics and the other about prevalence of middle ear disease in CF. The first concluded that no clear correlation was found between DF508 (the most common CF mutation) and nasal polyposis. The second revealed that in contrast with the extremely high prevalence of sinus problems, there was no clear evidence of an increased prevalence of middle ear disease in CF.
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It has been pediatric dogma that most children with cystic fibrosis (CF) have pansinusitis and few are symptomatic. To reassess this premise, we compared symptoms, clinical examinations, radiographic and surgical findings, and results of treatment in 19 children with cystic fibrosis who had undergone computed tomography at St. Christopher's Hospital (Philadelphia) from 1991 to 1994. We found two distinct patterns of sinus disease: chronic sinusitis (n = 3) and polyposis (n = 12). Two of the patients with polyposis had ethmoid mucoceles and 1 child had no sinus disease at all. Children with chronic sinusitis had headache as a major complaint, while those with polyposis suffered nasal obstruction alone unless a mucocele was present. Surgery provided marked and lasting improvement in the 14 patients who were operated on.
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Nineteen nasal polyps from 13 patients were examined histologically. Nine polyps from seven cystic fibrosis (CF) patients could be positively identified by a triad of observations: delicate, barely visible basement membrane of surface epithelium without submucosal hyalinization, lack of extensive infiltration of eosinophils (Giemsa stains), and a preponderance of acid mucin in glands and cysts of the polyp and in its surface mucous blanket (Alcian Blue-periodic acid-Schiff stains). Two polyps from two patients with CF and atopy showed the characteristic findings of CF without modification. Eight polyps from four atopic patients without CF were identified by the reverse triad of changes: extensive thickening of the epithelial basement membrane and its extension into the submucosa as an irregular hyaline membrane, high stromal eosinophil count, and mainly neutral mucin in mucous glands, cysts, and mucous blanket. Hyperplastic mucous glands, mucous cysts of variable sizes, focal metaplasia of surface epithelium, and acid mucin in goblet cells were considered nonspecific lesions.
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Should surgery be performed earlier and more frequently? Might this prevent the broadening of the nose with the cosmetic problem of pseudohypertelorism and a large broad nose? Might this diminish the chronic postnasal discharge with improvement of lung status? Only carefully controlled prospective studies addressed to these problems will resolve the issue of early surgery before complete nasal obstruction occurs. The entire question of nasal and sinus surgery must be seen in relation to the patient with cystic fibrosis in whom multiple organ systems are involved to varying degrees. In severe respiratory disease, surgery may tilt the course toward respiratory arrest. Combined pediatric-otolaryngologic discussions are mandatory for the best management of each patient.
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Four adult cystic fibrosis patients were selected for aggressive surgical management of sinus disease on the basis of severe pulmonary involvement, high frequency of hospital admission, chronic headache, and wheezing unresponsive to conventional treatment. They underwent bilateral Caldwell-Luc procedure with perioperative anti-Pseudomonas antimicrobials. There were substantial improvements in headache and respiratory symptoms and a significant reduction in the frequency of hospital admission after the operation. These findings suggest that sinus disease is associated with pulmonary exacerbation in patients with cystic fibrosis, and strengthens a similar observation in patients with asthma.
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In recent years an immune-mediated inflammatory process has been implicated in the genesis of the pulmonary damage seen in patients with cystic fibrosis.1,2 A 4-year double-blind, placebo-controlled trial of alternate-day prednisone (2 mg/kg) was conducted in 45 cystic fibrosis patients with mild-to-moderate pulmonary disease to assess the effect of this drug on the pulmonary inflammatory process.3 The patients in the prednisone group showed better growth and pulmonary function and less morbidity compared with those in the placebo group. No complications were reported among the prednisone-treated patients. To extend these observations, the United States Cystic Fibrosis Foundation sponsored a multicenter double-blind, placebo-controlled trial of alternate-day prednisone. Since March 1986, 283 patients with cystic fibrosis, followed up at 15 centers in the United States and Canada, have been enrolled in this trial. Patients 5 through 14 years of age with mild-to-moderate pulmonary disease were randomly assigned to receive prednisone 2 mg/kg (high-dose) every other day, prednisone 1 mg/kg (low-dose) every other day, or placebo. On entry into the study, patients in the three groups were closely matched by a variety of clinical and laboratory parameters (Table 1). Patients are closely monitored at 3-month intervals for both efficacy and side effects. An interim analysis is carried out every 6 months and the results are reviewed by an unblinded study ombudsman. Initially, 95 patients were randomly assigned to the high-dose group, 94 to the low-dose group, and 94 to the placebo group. At the time of the most recent interim analysis, mean duration in the study was 33.9 months for the high-dose group, 35.3 months for the low-dose group, and 36.8 months for the placebo group.
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Cystic fibrosis (mucoviscidosis; fibrocystic disease of the pancreas) is an inherited autosomal recessive disorder that results in generalized dysfunction of exocrine glands. Chronic pansinusitis with nasal polyposis occurs frequently in this disease. Polypectomy and sinus drainage procedures are often required in those cases refractory to medical therapy. Recurrence of nasal polyps following removal is common. Controversy exists regarding the timing and extent of surgery. The management of 40 children with cystic fibrosis who underwent nasal polypectomy, intranasal ethmoidectomy, and Caldwell-Luc procedures to treat extensive sinusitis and nasal polyposis forms the basis for this report. Follow-up data indicate that fewer recurrences and longer symptom-free intervals result when intranasal ethmoidectomy and Caldwell-Luc procedures are combined with polypectomy.
Article
• Nasal polyposis complicated the course of cystic fibrosis in 157 (26%) of 605 patients. Onset before age 5 years or after age 20 years was rare. Polyposis was the initial symptom of cystic fibrosis in 13 patients. Common symptoms included obstruction to nasal air flow, mouth breathing, epistaxis, and rhinorrhea. Intranasal and oral corticosteroids and antihistamines were ineffective in preventing recurrences but did occasionally afford symptomatic relief of obstruction. Nineteen (31%) of 62 patients who never had surgery had spontaneous and permanent disappearance of polyps. Simple polypectomy was an adequate procedure for patients with substantial nasal symptoms. There were no visual complications. Other surgical complications were rare. Children and adolescents with nasal polyps should have sweat tests by pilocarpine iontophoresis to rule out cystic fibrosis. (Am J Dis Child 1982;136:1067-1070)
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Twenty-nine consecutive patients with cystic fibrosis were offered functional endoscopic sinus surgery. Twenty-six of these patients underwent surgery. A symptom questionnaire was obtained from the patient or parent before surgery. At the end of the study this symptom questionnaire was again administered to the same individual, and 21 completed it. There were 14 male and 7 female patients, with a mean age of 12.3 years and a median age of 8.7 years. Mean follow-up was 34.3 months. Results for the following symptoms were significant: nasal airway obstruction was improved (p < 0.0002), olfactory function was improved (p < 0.0037), purulent nasal discharge was decreased (p < 0.001), and activity level was increased (p < 0.001). Other parameters are also reported in the text. In summary, this study prospectively studies the effects of functional endoscopic sinus surgery on symptoms in patients with cystic fibrosis. The study points out several significant areas of symptom improvement and supports the selective use of functional endoscopic sinus surgery in patients with cystic fibrosis. Indications for surgery are provided.
In a prospective clinical study, 84 patients aged 3 months to 34 years (mean age: 12 years; 53 males and 31 females), with cystic fibrosis systematically underwent an ENT examination, including rigid endoscopy of the anterior nasal cavity and lateral nasal wall. In 28 cases, CT-scan of the sinuses was performed. Mucopyosinusitis of the maxillary sinus with medial projection of the inter-naso-sinusal wall was present in 10 children (12%, mean age: 4 years; range: 3 months to 8 years). Nasal polyposis was present in 37 patients (45%) from the age of 5 years on (mean age: 15 years). Nasal obstruction was the main complaint when the condition was severe. The routine use of the endoscope makes it possible to diagnose early pathological changes of the lateral nasal wall. Local treatment could then help slow down progress evolution toward a more massive involvement.
The relationship between cystic fibrosis (CF) and sinus disease has been appreciated since at least 1959. Unfortunately the standard methods used to treat sinus disease have been very unrewarding in the CF patients. We evaluated the long-term results achieved on 17 patients with CF that underwent FES surgery between July 1988 and January 1991. This group consisted of 16 pediatric and 1 adult patients with previously diagnosed CF, documented chronic sinus disease and nasal polyposis that had failed long-term maximal medical management. The patients, or their parents, were contacted and asked to rate the severity and frequency of their symptoms associated with chronic sinus disease, pre- and postoperatively. The specific symptoms evaluated were nasal obstruction, nasal discharge, postnasal drip, halitosis and cough. In addition, we attempted to measure the number of hospitalizations and the presence and frequency of headaches. We were able to show that, while there was no change in the relative health of patients as measured by the number of hospitalizations, there was a significant improvement in the quality of life. There was a marked decline in the frequency of nasal obstruction, nasal discharge and postnasal drip and a high level of patient satisfaction with the procedure. No changes were seen in the frequency or nature of the cough, halitosis or headache.
Article
The impact of sinus surgery on the pulmonary status of cystic fibrosis patients is unknown. This retrospective study reviewed the charts of the cystic fibrosis patients presenting to our institution's cystic fibrosis center with nasal obstruction, recurrent sinusitis, and nasal polyposis. This group subsequently underwent endoscopic ethmoidectomy and antrostomy. Fourteen of the 15 patients, ages 5-24 years, received preoperative and postoperative pulmonary function testing obtained by spirometry. The data were compiled and analyzed statistically. Our results suggested no significant improvement in the pulmonary function of cystic fibrosis patients after sinus surgery.
Article
The eosinophil may play a key role in the pathogenesis of nasal polyposis. Polyps in cystic fibrosis, however, have been described as neutrophilic. We compared the cell counts in polyps from 44 patients with cystic fibrosis to polyps from 50 patients without cystic fibrosis. The clinical profile, CT-scan and time to polyp recurrence were also compared with the cell counts in the patients with cystic fibrosis. No significant difference was detected in the number of patients with eosinophils (P > 0.25). Significantly more patients in the group with cystic fibrosis had polyp neutrophils (P < 0.01). Polyps from patients without cystic fibrosis contained more eosinophils (P < 0.001) whilst polyps from patients with cystic fibrosis contained more neutrophils (P = 0.001) and plasma cells (P = 0.038). Significant correlation was found between the neutrophil count and the CT score (P = 0.025) and between the recurrence time of polyps and the macrophage count (P = 0.01). Eosinophils are present in varying degrees in polyps from patients with and without cystic fibrosis and to classify polyps as eosinophilic or neutrophilic may be a false distinction.
Article
The molecular biologic events in the development of nasal polyps are now becoming unraveled. It appears that eosinophils are the dominant inflammatory cell present in this tissue. The events leading up to the extravasation of eosinophils into the lamina propria nasal polyps are regulated by the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1 beta. These cytokines upregulate very late antigen-4 on the surface of eosinophils and vascular cell adhesion molecule-1 on the surface of the endothelial blood vessel. Chemokines such as RANTES (regulated upon activation, normal T-cell expressed and secreted) and eotaxin are responsible for the movement of eosinophils into the lamina propria of the nasal polyp. The release of major basic protein has an effect on alteration of the epithelial architecture and on the sodium and chloride flux into and out of the apical epithelial cell of the tissue. Finally, the alteration of the surface epithelium results in a defect in the migration of the cystic fibrosis transmembrane regulator protein to the apical surface. These two events, the release of major basic protein from the eosinophil and the alteration of the architecture of the surface epithelium, lead to an increase in sodium absorption and resultant edema: the hallmark of the pathology of the nasal polyp.
Article
Among 742 patients with cystic fibrosis studied during the past 4 years, 50 (or 6.7%) were found to have nasal polyposis. Polyps were noted in patients of all ages, the youngest being 2½ years of age. Roentgenograms of the sinuses showed evidence of paranasal sinusitis in each case studied. An allergic investigation was conducted in each of the 50 patients with nasal polyposis. Twenty-four patients presented no evidence of allergy. The clinical severity of the basic disease (cystic fibrosis) was the same in both the allergic and nonallergic group. A brief description of the clinical course of the patient with nasal polyps is presented. The polyps are often multiple, may cause complete nasal obstruction, and tend to regrow. Their course is beneficially influenced by the administration of broad-spectrum antibiotics or systemic steroids. However, polyps did appear in many patients while on constant broad spectrum antibiotic therapy. Conservative management is suggested. Simple polypectomy is carried out when nasal obstruction is complete. In a small number of patients, repeated polypectomies have been necessary over a number of years. The severity of the pulmonary lesion is not reflected by the degree of alteration of the mucosal linings of the paranasal sinuses. Patients with nasal polyposis, regardless of the presence or absence of allergy, should be examined for evidence of cystic fibrosis, including family history, pulmonary evaluation, and appropriate laboratory tests.