Cystic Fibrosis Sinusitis Research Articles

Manuka honey versus saline sinus irrigation in the treatment of cystic fibrosis-associated chronic rhinosinusitis: A randomised pilot trial.

Manuka honey attacks biofilms, which contribute to bacterial persistence in cystic fibrosis sinusitis. The primary objective was to determine feasibility of investigating manuka honey as an irrigation treatment for cystic fibrosis sinusitis and secondarily to assess the treatment's preliminary effectiveness. Prospective, single-blinded (clinician only), randomised, parallel two-arm pilot trial. Tertiary rhinology clinic. Subjects had recalcitrant cystic fibrosis sinusitis and previous sinus surgery. They received manuka honey or saline sinus irrigations twice daily for 30days. Main outcomes were recruitment/retention rates and tolerability. Preliminary effectiveness was assessed based on quality-of-life Sinonasal Outcome Test-22 and Lund-Kennedy endoscopic change scores and post-treatment culture negativity. Over 10months, 13 subjects were enrolled, and 77% (10/13) were included in the analysis. Manuka honey irrigations were well-tolerated. The quality-of-life change score was clinically significant for manuka honey (-9 [-14,-6]) but not saline (-5 [-9,-1]), although the difference was not statistically significant (P=.29). Lund-Kennedy endoscopic change score was significantly better for manuka honey (-3 [-5,-3]) versus saline (0 [0,0]) (P=.006). There was no difference in post-treatment culture negativity between manuka honey (1/5, 20%) and saline (0/5, 0%) (P=1.00). Manuka honey irrigations were well tolerated, and retention rates were high. Preliminary data showed that manuka honey achieved a clinically important difference in quality-of-life score and a significantly better endoscopic outcome. Microbiological control was difficult to achieve. A future definitive trial would require multi-institutional recruitment.

Inhalable Antimicrobials for Treatment of Bacterial Biofilm-Associated Sinusitis in Cystic Fibrosis Patients: Challenges and Drug Delivery Approaches.

Bacterial biofilm-associated chronic sinusitis in cystic fibrosis (CF) patients caused by Pseudomonas aeruginosa infections and the lack of available treatments for such infections constitute a critical aspect of CF disease management. Currently, inhalation therapies to combat P. aeruginosa infections in CF patients are focused mainly on the delivery of antimicrobials to the lower respiratory tract, disregarding the sinuses. However, the sinuses constitute a reservoir for P. aeruginosa growth, leading to re-infection of the lungs, even after clearing an initial lung infection. Eradication of P. aeruginosa from the respiratory tract after a first infection has been shown to delay chronic pulmonary infection with the bacteria for up to two years. The challenges with providing a suitable treatment for bacterial sinusitis include: (i) identifying a suitable antimicrobial compound; (ii) selecting a suitable device to deliver the drug to the sinuses and nasal cavities; and (iii) applying a formulation design, which will mediate delivery of a high dose of the antimicrobial directly to the site of infection. This review highlights currently available inhalable antimicrobial formulations for treatment and management of biofilm infections caused by P. aeruginosa and discusses critical issues related to novel antimicrobial drug formulation design approaches.

Cystic Fibrosis Sinusitis.

Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the CF transmembrane conductance regulator gene(CFTR) resulting in impaired ion transport. Nearly all people with CF will develop chronic rhino-sinusitis (CRS) and present with the characteristic viscous mucus, impaired mucociliary clearance and chronic inflammation/infection of the sinonasal cavity. While some individuals with CF can appear relatively asymptomatic in terms of their sinus disease, commonly reported symptoms include anosmia, headache, facial pain, nasal obstruction, chronic congestion and nasal discharge. Nasal endoscopy typically reveals mucosal edema, purulent discharge and nasal polyposis. Computed tomography (CT) imaging classically demonstrates the distinguishing findings of sinus hypoplasia or aplasia with generalized opacification, medial bulging of the lateral sinonasal sidewall and a demineralized uncinate process. Current treatment for CF sinusitis includes the use of hypertonic saline, topical and systemic steroids, antibiotics and endoscopic surgery. Research investigating novel therapies designed at targeting the primary defect of CF is showing promise for reversal of CF sinus disease, in addition to potential for disease prevention.

Prevalence and Severity of Dysphonia in Patients with Cystic Fibrosis

To assess the prevalence and severity of dysphonia in patients with cystic fibrosis sinusitis. We hypothesized that patients with CF sinusitis, compared with 2 control groups, would have higher self-reported prevalence of dysphonia and greater severity of dysphonia, according to patient-reported outcome measures as well as auditory-perceptual evaluation by expert listeners. Cross-sectional comparative pilot study. Academic tertiary care clinic. Analysis included 37 study participants: 17 patients with CF sinusitis, 10 healthy individuals, and 10 patients with non-CF sinusitis. All participants completed the 10-item Voice Handicap Index (VHI-10) questionnaire and provided voice samples. On all samples, 6 blinded speech-language pathologists independently performed auditory-perceptual evaluation, using Consensus Auditory-Perceptual Evaluation of Voice. To assess severity of sinonasal symptoms, we used the 20-item Sinonasal Outcome Test (SNOT-20). Standard parametric and nonparametric statistical analysis was performed. The differences between the 3 groups in prevalence of abnormal VHI-10 scores were not statistically significant. SNOT-20 scores were similar in the 2 sinusitis patient groups. VHI-10 scores were highest in patients with CF sinusitis, intermediate in patients with non-CF sinusitis, and lowest in healthy individuals (P = .005). Auditory-perceptual evaluation demonstrated greater overall severity of dysphonia in patients with CF sinusitis compared with the 2 control groups (P = .0005). Cystic fibrosis sinusitis appeared to be associated with worse vocal function as measured by patient self-report as well as auditory-perceptual evaluation of voice compared with patients with non-CF sinusitis and healthy controls. Further investigation in this area is warranted.

New insights into the pathogenesis of cystic fibrosis sinusitis

People with cystic fibrosis (CF) sinus disease have developmental sinus abnormalities with airway bacterial infection, inflammation, impaired mucociliary clearance and thick obstructive mucus. The pathophysiology of airway disease in CF is not completely understood, and current treatments in CF sinus disease ameliorate symptoms but do not provide a cure. This manuscript reviews the history of CF, its manifestations in sinus disease, and the potential impact and relationship of CF on the upper and lower airway. There is increasing evidence that CF sinus disease may affect CF lung disease, the most common cause of mortality in CF. We have been limited in treating the symptoms of advanced CF sinus disease with our current therapies. Recent discoveries in the pathophysiology of CF using the CF porcine animal model and exciting treatments that address the primary gene defect that may translate into improved outcomes in CF and non-CF sinusitis in humans.

Surgical management of chronic rhinosinusitis in cystic fibrosis: a systematic review

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.

Adenoviral Gene Transfer Corrects the Ion Transport Defect in the Sinus Epithelia of a Porcine CF Model

Cystic fibrosis (CF) pigs spontaneously develop sinus and lung disease resembling human CF. The CF pig presents a unique opportunity to use gene transfer to test hypotheses to further understand the pathogenesis of CF sinus disease. In this study, we investigated the ion transport defect in the CF sinus and found that CF porcine sinus epithelia lack cyclic AMP (cAMP)-stimulated anion transport. We asked whether we could restore CF transmembrane conductance regulator gene (CFTR) current in the porcine CF sinus epithelia by gene transfer. We quantified CFTR transduction using an adenovirus expressing CFTR and green fluorescent protein (GFP). We found that as little as 7% of transduced cells restored 6% of CFTR current with 17-28% of transduced cells increasing CFTR current to 50% of non-CF levels. We also found that we could overcorrect cAMP-mediated current in non-CF epithelia. Our findings indicate that CF porcine sinus epithelia lack anion transport, and a relatively small number of cells expressing CFTR are required to rescue the ion transport phenotype. These studies support the use of the CF pig as a preclinical model for future gene therapy trials in CF sinusitis.

Cyclooxygenase 2 and Lipoxin A4 in Nasal Polyps in Cystic Fibrosis

The etiology of nasal polyps (NPs) and sinusitis in cystic fibrosis (CF) patients is still unknown. This study investigates the presence of cyclooxygenase 2 (COX-2) and lipoxin A(4) (LXA(4)) in epithelial cultures derived from NPs and turbinates in patients with CF and without CF. NPs and turbinates were evaluated from eight CF patients with obstructing NPs undergoing sinus surgery. NPs and tissue from the hypertrophic inferior turbinate from 14 patients without history of CF undergoing sinus surgery served as control specimens. After tissue culturing, the presence of COX-2 protein and LXA(4) (ELISA) was detected in CF polyps and turbinates and compared with that of the control group. COX-2 and LXA(4) were detectable in tissue specimens of all CF patients and control patients. COX-2 was highest in CF polyps, but the difference was not significant compared with CF turbinates or polyps and turbinates of patients not suffering from CF. LXA(4), however, was significantly higher in CF NPs compared with CF turbinate tissue. Compared with NPs of patients not having CF disease, CF polyps showed markedly higher concentrations of LXA(4). LXA(4) is significantly elevated in CF NPs, whereas COX-2 is only slightly increased. The present data support the concept that LXA(4) plays an important role in CF nasal polyposis. Chronic infection in nasal polyposis and, because of inflammation, induced COX-2 in CF NPs may be related to increased LXA(4). The suspected interaction of COX-2 and LXA(4) needs further investigation.

Are lower airway or throat cultures predictive of sinus bacteriology in cystic fibrosis?

The choice of antibiotics for sinusitis in children with cystic fibrosis (CF) is empirical or based on lower airway cultures, because sinus cultures are difficult to obtain. The aim of this study was to identify the main organisms cultured from CF children with chronic sinusitis, and to evaluate the concordance of concomitant sinus, oropharyngeal swab (OP), and bronchoalveolar lavage fluid (BALF) cultures. OP and BALF cultures were done preoperatively, and sinus cultures were obtained during clinically indicated sinus surgery. The genetic identity of the bacteria was compared if the same organisms were present in upper and lower airway cultures. In total, 45 paired sinus-BALF cultures from 31 patients were included. Twenty-four of these had matched OP cultures. The mean age of patients was 9.5 +/- 4.3 years, and 19 patients were DeltaF508 homozygous. Bacterial sinus infection was present in 96%, caused by S. aureus (49%), P. aeruginosa (42%), and H. influenzae (22%). The diagnostic accuracy of BALF or OP cultures was low in predicting sinus infection, particularly at younger ages. Positive and negative predictive values (PPV and NPV) of BALF for P. aeruginosa infection were 65% and 67%, and for S. aureus, 76% and 63%, respectively. Predictive values for OP cultures were similar. Bacterial species were the same in sinus and OP or BALF samples of 12 patients of these bacteria 83% showed genetic identity. We conclude that S. aureus is an important pathogen in pediatric CF sinusitis, and that BALF or oropharyngeal cultures are poor predictors for organisms present in the sinuses.

Abnormal expression of the cystic fibrosis transmembrane regulator in chronic sinusitis in cystic fibrosis and non-cystic fibrosis patients.

Cystic fibrosis (CF) patients commonly suffer from chronic sinusitis. Mutations of a single gene, the cystic fibrosis transmembrane conductance regulator (CFTR) gene, have been associated with CF. Functional CFTR protein is localized to the apical cell membrane, while dysfunctional CFTR is commonly found in the cytoplasm. We undertook a preliminary immunocytochemical study of CFTR subcellular localization in CF and non-CF pediatric and adult patients using a newly developed murine monoclonal antibody, TAM. Immunostaining was evaluated for subcellular localization (cytoplasmic versus membranous) and for epithelial layer (basal versus luminal). Analysis of the predominant CFTR distribution patterns demonstrated significant differences in adult versus pediatric groups independent of whether the latter were CF or non-CF (p<.0001 and p<.008, respectively), and no significant difference between the 2 pediatric groups (p = .70). This suggests that the pathophysiology of pediatric sinusitis differs from that of adult sinusitis at the level of secretion production.

Efficient and persistent gene transfer of AAV-CFTR in maxillary sinus

Cystic fibrosis is a common, lethal, genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), and it is an attractive target for gene therapy. Adeno-associated virus (AAV) is a naturally replication-deficient single-stranded DNA parvovirus. Preclinical studies showed that CFTR transcripts and protein can be detected up to 6 months after transduction with an AAV-CFTR vector, 1 Flotte TR Afione SA Conrad C et al. Stable in vivo expression of the cystic fibrosis transmembrane conductance regulator with an adeno-associated virus vector. Proc Natl Acad Sci USA. 1993; 90: 10613-10617 Crossref PubMed Scopus (443) Google Scholar with no pathogenicity, 2 Conrad CK Allen SS Afione SA et al. Safety of single-dose administration of an adeno-associated virus (AAV)-CFTR vector in the primate lung. Gene Ther. 1996; 3: 658-668 PubMed Google Scholar suggesting that AAV performs well as a gene transfer vehicle for CFTR. The maxillary sinuses are attractive for evaluating new treatments of cystic fibrosis because they have ion-transport systems and microbiology similar to those of the lower respiratory tract. 3 Moss RB King VV Management of sinusitis in cystic fibrosis by endoscopic surgery and serial antimicrobial lavage: reduction in recurrence requiring surgery. Arch Otolaryngol Head Neck Surg. 1995; 121: 566-572 Crossref PubMed Scopus (121) Google Scholar , 4 Wine JJ King VV Lewiston NJ Method for rapid evaluation of topically applied agents to cystic fibrosis airways. Am J Physiol. 1991; 261: L218-L221 PubMed Google Scholar Recurrence of maxillary sinusitis may prove to be a surrogate for infectious exacerbations characteristic of cystic fibrosis lung disease.

MANAGEMENT OF SINUSITIS IN CYSTIC FIBROSIS BY ENDOSCOPIC SURGERY AND SERIAL ANTIMICROBIAL LAVAGE

The ESSAL is a successful approach to treatment of sinusitis in cystic fibrosis that reduces recurrent symptoms requiring revision sinus surgery.

Patterns of Sinusitis in Cystic Fibrosis

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.

Impact of sinusitis in cystic fibrosis

The cause of cystic fibrosis has been determined to be faulty ionic transport of chloride across the apical membrane of epithelial cells lining exocrine glands. The subnormal ionic transport leads to dehydration of extra cellular fluids and the development of thickened inspissated mucous secretions. The vast majority of patients with cystic fibrosis develop sinus disease with panopacification of the sinuses present in 90% to 100% of patients older than 8 months of age. Indications for surgical management of sinusitis in children with cystic fibrosis include (1) chronic nasal obstruction with mouth breathing, (2) chronic purulent draining nasal secretions unresponsive to medical treatment, and (3) persistent headaches thought to be related to sinusitis. Operative therapy is based on computerized tomographic scan findings and can be performed endoscopically. Postoperative management is critical for ensuring successful surgical results. Antibiotics, topical steroids, and cleansing of the surgical fields must be performed on a regular basis to ensure adequate healing. The impact of sinusitis on the cystic fibrosis population is significant. Approximately 20% of patients will eventually require surgical treatment of their sinuses. Chronic sinusitis may cause deformities of the external nasal skeleton, a loss of the sense of smell, and headaches.