Inflammatory immune response in rabbits with Staphylococcus aureus biofilm-associated sinusitis.

BACKGROUND: Staphylococcus aureus is the most commonly isolated bacterium from patients with surgically recalcitrant chronic rhinosinusitis (CRS). Understanding the immune responses to S aureus biofilms will provide insights into how the host response may be manipulated by therapeutic agents to improve the chances of successfully preventing and treating these infections. In this study, we investigated the inflammatory immune response in a rabbit model of S aureus biofilm-related sinusitis by analyzing the levels of some major inflammatory cytokines. METHODS: Eighteen New Zealand white rabbits were randomly divided into 3 groups: a blank-control group; a negative-control group; and a model group. Four weeks after the biofilm-associated sinusitis models were established, the sinus mucosa was harvested and examined using hematoxylin-eosin (H&E) staining, scanning electron microscopy (SEM), reverse transcription polymerase chain reaction (RT-PCR), and western blotting. The expression levels of inflammatory cytokines were analyzed statistically. RESULTS: Interleukin (IL)-1ß, IL-8, and tumor necrosis factor (TNF)-α expression levels were significantly higher in the model group than in the blank-control group (p < 0.05); mRNA levels were increased by 1600%, 230%, and 130%, respectively, and the protein levels were increased by 180%, 100%, and 100%, respectively. In contrast, IL-4 and IL-5 mRNA levels were reduced by 44% and 70%, respectively, compared with the blank-control group (p < 0.05). CONCLUSION: S aureus biofilms in the rabbit maxillary sinus mucosa were associated with increased IL-1ß, IL-8, and TNF-α expression, and decreased IL-4 and IL-5 expression.

Radiographic Evidence of Sinonasal Inflammation in Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome: An Underrecognized Association.

BACKGROUND: Sinonasal inflammation on both clinical examinations and imaging significantly impacts both asthma and chronic obstructive pulmonary disease (COPD). OBJECTIVE: The objective of this study was to examine the association between sinonasal inflammation and asthma-COPD overlap syndrome (ACOS). METHODS: A total of 112 patients with a ratio of forced expiratory volume in 1 s to forced vital capacity of less than 70% were enrolled. COPD, asthma, and ACOS were clinically diagnosed according to the 2014 Global Initiative for Asthma and Global Initiative for Chronic Obstructive Lung Disease guidelines. Sinonasal inflammatory condition was evaluated using sinus computed tomography, and its severity was assessed according to the Lund-Mackay staging (LMS) system. Ethmoid sinus-dominant shadow was defined as the presence of greater LMS scores for the anterior and posterior ethmoid sinuses than for the maxillary sinus. RESULTS: COPD, asthma, and ACOS were diagnosed in 55 (49.1%), 39 (34.8%), and 18 patients (16.1%), respectively. The frequency of radiographic evidence of sinonasal inflammation in patients with COPD, asthma, ACOS was 60.0%, 94.9%, and 72.2%, respectively. Patients with ACOS and COPD had only mild radiographic evidence of sinonasal inflammation (LMS score, 1-7), whereas moderate (LMS score, 8-11) and severe (LMS score, ≥12) radiographic evidence of sinonasal inflammation were detected only in patients with asthma. Furthermore, the frequency of ethmoid sinus-dominant shadow was significantly higher in patients with asthma than in those with COPD and ACOS. CONCLUSIONS: Radiographic evidence of sinonasal inflammation was a common comorbidity in ACOS. Future studies are required to examine the role of sinonasal inflammation in ACOS.

Staphylococcal enterotoxin burden determines the type of T helper cell response and pathology of the maxillary sinus mucosa in rabbits.

Staphylococcal enterotoxin (SE) induces T lymphocyte activation along with nasal allergic inflammation during rhinosinusitis, but it is under debate on which types of T helper (Th) cells respond exclusively or whether they respond synergically. We hypothesize that their responses may vary based on dose of SE. To test this hypothesis, we initiated to determine the nature of the T cell response and pathological feature upon repeated exposure to staphylococcal enterotoxin A (SEA) at different doses in the maxillary sinus of rabbits. SEA (0.6 or 60 ng) was instilled daily into the left maxillary sinus of rabbits for 28 days. The right maxillary sinus receiving normal saline was used as control. Mucosal histological changes were examined by hematoxylin-eosin and toluidine blue staining. Tissue expression of myeloperoxidase (MPO), eosinophil cationic protein (ECP), T-box expressed in T cells (T-bet), and GATA binding protein 3 (GATA-3) were examined using immunohistochemistry. Mucosal levels of representative pro-inflammatory cytokines were measured using ELISA. SEA at 60 ng/day induced acute rhinosinusitis, as confirmed by CT scan. Histopathologic examination revealed epithelial disruption, subepithelial edema, and inflammatory cell infiltration. MPO and T-bet expression, as well as interleukin (IL)-2 and interferon (IFN)-γ levels, were up-regulated. However, 0.6 ng/day SEA did not cause discharge. Histological examination revealed prominent eosinophilic infiltration. ECP and GATA-3 expression, as well as IL-4 and IL-5 levels, were increased at this lower dose. In conclusion, SEA induces acute rhinosinusitis associated with a Th1-type immune response at high dose, and a predominantly Th2-biased allergic inflammation at low dose.

Unilateral nasal allergic reactions increase bilateral sinus eosinophil infiltration.

We have previously shown that unilateral nasal challenge with antigen causes an increase in the number of eosinophils in the ipsilateral maxillary sinus. Here we aimed to determine whether there was an eosinophil response in the contralateral maxillary sinus after unilateral nasal challenge with antigen. Twenty subjects with a history of seasonal allergic rhinitis and a positive nasal challenge to ragweed or grass allergens were studied outside of their allergy season. Catheters were placed in both maxillary sinuses and the subjects were challenged with antigen via the left nostril. The subjects recorded nasal symptoms before and after each allergen challenge and hourly for 8 h afterward. We performed nasal lavages of the nose and sinuses at the same time as symptoms were recorded. The lavages were analyzed for the number of eosinophils and levels of albumin. Subjects showed a symptomatic response to challenge accompanied by an influx of eosinophils into the nose and increased vascular permeability. The number of eosinophils increased in both maxillary sinuses. The total change from diluent in eosinophils during the late phase response was higher in the ipsilateral maxillary sinus (median = 8,505; range = 0-100,360) compared with the contralateral sinus (median = 1,596; range = -13,527-93,373; P = 0.03). We conclude that eosinophils increase in both maxillary sinuses after unilateral nasal challenge. We speculate that a central neurologic reflex initiated in the nose by the nasal challenge contributes to the bilateral eosinophil response in the maxillary sinuses. We further speculate that, since there are more eosinophils in the ipsilateral compared with the contralateral maxillary sinus, there is also an axonal reflex into the ipsilateral maxillary sinus that contributed to the eosinophil response.

Age-related Epstein-Barr Virus-positive lymphoproliferative disorders of the orbit and maxillary sinus : a case report.

We report a rare case of age-related Epstein-Barr virus (EBV)-positive B-cell lymphoproliferative disorder (aEBVBLPD) primarily involving the orbit and maxillary sinus. Lesions in the left orbit and maxillary sinus were observed in a 59-year-old man presenting with pain in the left orbit and maxilla. Owing to the presence of Reed-Sternberg-like cells, the initial diagnosis was nodular sclerosis-type Hodgkin's lymphoma. Clinical stage was IIAE, and response to chemotherapy and radiotherapy was favorable. Further immunohistochemical and in situ hybridization analyses of the Reed-Sternberg-like giant cells revealed CD30, CD15, CD20, Bob-1, Oct-2, EBV-encoded RNAs (EBERs) and latent membrane protein-1 (LMP-1) expression. The characteristics of the present case, which included immunohistochemical findings, sites of primary lesions, absence of other lymph node lesions and relatively old age, suggested aEBVBLPD. Owing to the similarity in morphology, higher frequency at extranodal sites and poor prognosis, aEBVBLPD represents a differential diagnostic issue from classical Hodgkin's lymphoma when Reed-Sternberg cells are positive for EBV.

[Invasive aspergillosis of the maxillary sinus in an immunocompetent patient]. / Aspergillose invasive du sinus maxillaire chez un patient immunocompétent.

INTRODUCTION: Invasive aspergillosis of the maxillary sinus is a severe infection most commonly observed in immunocompromised patients. We report a pseudo-tumoral presentation of invasive aspergillosis of the maxillary sinus, in immunocompetent adult. CASE REPORT: A 70-year-old female patient consulted for chronic rhino-sinusitis resistant to medical treatment. Computed tomography scan revealed a hyperdense mass filling the left maxillary antrum, with erosion of sinus walls. The ethmoidal and right frontal sinuses were involved. The histological and mycological examination of the surgical resection confirmed the diagnosis of invasive aspergillosis. The patient was given voriconazole as first line treatment. The outcome was good at 18 months. DISCUSSION: Invasive aspergillosis of the maxillary sinus is a rare disease, usually observed in immunodepressed patients. It is very rarely observed in immunocompetent patients.

Inflammation and remodelling patterns in early stage chronic rhinosinusitis.

BACKGROUND: A distinct set of inflammatory and remodelling factors have been found elevated in chronic rhinosinusitis. OBJECTIVE: The investigation of their expression in early stage disease may reveal early events in this common disease. METHODS: Sinonasal mucosal samples from nine patients with early stage CRSsNP were taken from the inferior and middle turbinates, the uncinate process, maxillary sinus, anterior ethmoid, bulla ethmoidalis and the posterior ethmoid and measured for TGF-beta 1 and it's receptors, MPO protein as well as pro-inflammatory cytokines (TNF-alpha and IL-1beta) and the Th1 cell signature (IFN-gamma and T-bet). As outcome parameter for TGF-beta signalling collagen deposition was analysed. Inferior turbinates from patients undergoing (rhino-) septoplasty were collected as controls. RESULTS: TGF-beta 1 protein concentrations were significantly increased in the maxillary sinuses (P = 0.006), the uncinate process (P = 0.01), the anterior ethmoid including the bulla ethmoidalis (P = 0.005) and the posterior ethmoid (P = 0.037) when compared to the inferior and middle turbinates. Collagen deposition was significantly increased in the maxillary sinus when compared to the inferior turbinates (P = 0.008). In contrast, mRNA for TGF-beta receptors, Th1 related markers (IFN-gamma and T-bet), pro-inflammatory cytokines (IL-1 beta and TNF-alpha), and MPO protein as neutrophil marker were expressed at all locations but showed no significant differences between the various locations. TGF-beta 1 mRNA expression in inferior turbinates of CRSsNP was significantly higher when compared to inferior turbinates of controls (P = 0.017). The pro-inflammatory cytokines and Th1-related cytokines did not show an upregulation in inferior turbinates of CRSsNP when compared to controls. CONCLUSIONS: In early stage chronic sinus disease, TGF-beta protein is expressed in significantly higher concentrations within the paranasal sinuses when compared to turbinates, whereas pro-inflammatory, neutrophilic and Th1 markers did not show any difference. These findings suggest that TGF-beta plays a central role in the initiation of CRSsNP, and represents a major target for further research and future intervention.

Multiple IgG4-related sclerosing lesions in the maxillary sinus, parotid gland and nasal septum.

IgG4-related sclerosing disease is recognized as a distinct clinicopathological entity. It is well known that this disease can occur in the salivary, lacrimal and pituitary glands, in the head and neck region. The nasal cavity is an extremely rare site of involvement of IgG4-related sclerosing disease. Herein is reported a case of multiple IgG4-related sclerosing lesions in the maxillary sinus, parotid gland and nasal septum. A 73-year-old Japanese man presented with nasal obstruction and tumors of the right maxillary sinus and parotid gland were detected, after which resections of these tumors were performed. One year after the last surgery, he noted swelling of the nasal septum, and the tumor was resected. These three tumors had similar histopathology, such as conspicuous fibrosclerotic changes with dense lymphoplasmacytic infiltration and occasional obliterative phlebitis. Immunohistochemistry indicated abundant IgG4-positive plasma cell infiltration and high ratios of IgG4-positive/IgG-positive plasma cells (>70%) in all three lesions. The diagnosis of multiple IgG4-related sclerosing lesions was made. The present case suggests that IgG4-related sclerosing lesion can occur in the maxillary sinus and nasal septum, and represents an extension of the spectrum of IgG4-related sclerosing disease.

Immunopathology of chronic rhinosinusitis in young children.

OBJECTIVE: Previous investigation demonstrated predominantly lymphocytic inflammation in sinus mucosa of young children with chronic rhinosinusitis (CRS) rather than eosinophilic inflammation typical of adult CRS. Immunohistopathological study was undertaken to define further the cellular response in pediatric CRS. STUDY DESIGN: Maxillary mucosal biopsies from children and adults with CRS were stained for CD3 (T lymphocytes), CD4 (helper T lymphocytes), CD8 (cytotoxic T lymphocytes), CD20 (B lymphocytes), CD68 (monocytes/macrophages), CD56 (natural killer cells), kappa and lambda (plasma cells), and myeloperoxidase (MPO; neutrophils). RESULTS: Nineteen children with CRS (median age, 3.0 years; range, 1.4-8.2 years) had more CD8+, MPO+, and CD68+ cells (P < or = .03) and a trend toward more CD3+ and CD4+ cells (P = .06) in their epithelium and more CD20+, kappa+ and lambda+, MPO+, and CD68+ cells (P < or = .05) and a trend toward more CD4+ cells (P = .06) in their submucosa compared with adult control subjects. Immunostains from children with positive sinus cultures were similar to those with negative cultures except for more MPO+ cells in the submucosa (P = .04). CONCLUSION: The inflammatory response of young children with CRS is characterized by a mixed lymphocyte population, macrophages, and neutrophils. Differences between pediatric and adult CRS suggest differing pathogenic mechanisms or progression in the inflammatory response with protracted disease.

Tissue-specific immunoglobulin E in maxillary sinus mucosa of allergic fungal sinusitis.

OBJECTIVE: The objectives of this prospective study were to analyze the specific immunoglobulin E (sIgE) in maxillary sinus mucosa and to determine the importance of local tissue sIgE in the patients with allergic fungal sinusitis (AFS). METHODS: We investigated tissue-specific IgE in the maxillary sinus mucosa. Thirty-four patients with rhinosinusitis and nasal polyposis were included in the study. The patients were divided into three groups--AFS, fungal sinusitis and chronic rhinosinusitis (CRS). The sIgE profile of the maxillary sinus mucosa was studied by the CAP method. Other parameters, such as allergic symptoms, presence of fungi hyphae and eosinophilic mucin in the sinus cavities as well as computed tomography (CT) scanning findings were also evaluated in all groups. RESULTS: All patients in the AFS group had allergic symptoms, and the serum IgE test was positive to mites or house dust, but none had a positive serum IgE response to Aspergillus. However, 85.7% of this group had tissue sIgE to Aspergillus. CONCLUSIONS: The local tissue sIgE profile is more specific than the systemic sIgE profile in determining the allergic status of AFS patients. Tissue sIgE for fungi may be considered as a part of AFS diagnostic criteria.

Effect of treatment on maxillary sinus and nasal nitric oxide concentrations in patients with nosocomial maxillary sinusitis.

STUDY OBJECTIVES: In maxillary nosocomial sinusitis (MNS) related to severe sepsis, nitric oxide (NO) concentration in the maxillary sinuses is drastically reduced secondarily to a downregulation of type-2 NO synthase. NO plays a major role in nonspecific immune defense of sinuses. We therefore aimed to study maxillary NO concentration during the treatment of MNS with drainage, daily lavage, and removal of any nasally introduced tube. PATIENTS AND METHODS: Nine patients were studied during the first 4 days of treatment of MNS. We measured the concentration of NO gas in the maxillary sinus and in the nasal cavity, and the NO metabolite levels (nitrites/nitrates [NOx]) in the sinus lavages. MEASUREMENTS AND RESULTS: Maxillary NO concentration (median [25 to 75 percentile]) increased from 70 parts per billion (ppb) [40 to 100 ppb] to 2,050 ppb (1,700 to 3,000 ppb) after 4 days of treatment of MNS (p < 0.0001). In the meantime, nasal NO increased from a median of 100 ppb (98 to 148 ppb) to 180 ppb (180 to 188 ppb) [p < 0.001]. At any time, there was a correlation between maxillary NO (logarithmic value) and nasal NO (r2 = 0.57, p < 0.0001). NOx levels remained stable in the lavages. CONCLUSIONS: We conclude that the treatment of the sinusitis with drainage, daily lavage, and removal of the gastric tube lead to a spectacular increase of maxillary and nasal NO concentrations.

A phase II, double-blind, randomized, placebo-controlled clinical trial of tgAAVCF using maxillary sinus delivery in patients with cystic fibrosis with antrostomies.

tgAAVCF, an adeno-associated cystic fibrosis transmembrane conductance regulator (CFTR) viral vector/gene construct, was administered to 23 patients in a Phase II, double-blind, randomized, placebo-controlled clinical trial. For each patient, a dose of 100,000 replication units of tgAAVCF was administered to one maxillary sinus, while the contralateral maxillary sinus received a placebo treatment, thereby establishing an inpatient control. Neither the primary efficacy endpoint, defined as the rate of relapse of clinically defined, endoscopically diagnosed recurrent sinusitis, nor several secondary endpoints (sinus transepithelial potential difference [TEPD], histopathology, sinus fluid interleukin [IL]-8 measurements) achieved statistical significance when comparing treated to control sinuses within patients. One secondary endpoint, measurements of the anti-inflammatory cytokine IL-10 in sinus fluid, was significantly (p < 0.03) increased in the tgAAVCF-treated sinus relative to the placebo-treated sinus at day 90 after vector instillation. The tgAAVCF administration was well tolerated, without adverse respiratory events, and there was no evidence of enhanced inflammation in sinus histopathology or alterations in serum-neutralizing antibody titer to adeno-associated virus (AAV) capsid protein after vector administration. In summary, this Phase II trial confirms the safety of tgAAVCF but provides little support of its efficacy in the within-patient controlled sinus study. Various potentially confounding factors are discussed.

Substance P immunoreactive sensory axons as a subset of the total axonal population in the maxillary sinus of the rabbit: a characterization of normal and infected mucosa.

Substance P (SP), one of the neuropeptides released from sensory nerves, is thought to mediate neurogenic inflammation. Although SP immunoreactive axons have been described in the sinus mucosa, no attempt has been made to characterize SP fibers as a subset of all axons present in the sinus mucosa. In addition, no study to date has characterized the changes in infected sinus mucosa. The maxillary sinus mucosa of New Zealand white rabbits was harvested from control animals and in animals with induced maxillary sinusitis. Immunohistochemical staining of the sinus mucosa for both Protein Gene Product 9.5 (PGP), a nonspecific marker for all nerves, and for SP was performed on 11 animals: 3 controls and 8 infected. In sinus mucosa from the control rabbits, <50% of all axons labeled by PGP were immunoreactive for SP. In infected mucosa, the absolute number of axons found by PGP staining decreased and nearly all of these remaining fibers were also immunoreactive for SP. We conclude that the phenotypical labeling of nerve fibers seen in normal mucosa is altered by bacterial-induced infection.

Interferon gamma levels in the sinus, ear, and airway in a rabbit sinusitis model induced by Bacteroides inoculation.

BACKGROUND: Previously, we found minimal bacterial dissemination and no evidence of systemic inflammation in a rabbit sinusitis model in which the left maxillary sinus was inflamed by Bacteroides inoculation with the ostium closed. However, we observed an increase in anti-Bacteroides IgG antibodies in the contralateral sinus, lower airway, and middle ear, with an apparent increase in interferon gamma (IFN-gamma) messenger RNA expression in the ear and sinus mucosa. OBJECTIVE: To evaluate how IFN-gamma production in the upper and lower airway is associated with localized bacterial sinusitis. DESIGN: Interferon gamma levels were measured in lavage solutions from the sinus, airway, and middle ear and in serum at 1, 2, 3, and 4 weeks following bacterial inoculation. SUBJECTS: The subjects were 6 rabbits at each time point. The controls were untreated (n = 5) and sham-operated (n = 4-5) rabbits at 2 and 4 weeks. INTERVENTION: Bacteroides fragilis (10(8) plaque-forming units) was inoculated into the left maxillary sinus. RESULTS: Interferon gamma levels in the ear and sinus were less than 0.2 microg/g protein in controls. Following bacterial inoculation into the left sinus, IFN-gamma levels increased up to 10-fold in both sinuses and even more in the middle ear at 3 weeks, independent of bacterial dissemination. Mean +/- SD IFN-gamma levels in the airway (0.3+/-0.28 microg/g protein in controls) were not altered by bacterial inoculation into the sinus. Serum IFN-gamma levels were very low (<0.05 microg/g protein) in most rabbits and were unchanged by bacterial inoculation. CONCLUSIONS: Interferon gamma levels increase in the ear and contralateral sinus in response to localized sinus inflammation, indicating concerted mucosal proinflammatory immune responses in the upper airway. Such responses may lead to the aseptic middle ear inflammation often observed in patients with chronic sinusitis.

Increased expression of IL-4, IL-5, IFN-gamma, IL-6, IL-8, and TGF-beta mRNAs in maxillary mucosa of patients with chronic sinusitis.

This study aimed to investigate expression of various cytokine mRNAs, including IL-6, IL-8, TGF-beta, IL-4, IL-5, and IFN-gamma in maxillary sinus mucosa of patients with chronic sinusitis. Maxillary sinus mucosae of six patients with chronic sinusitis and turbinate mucosae of six healthy subjects were obtained. We performed RT-PCR and Southern blot to examine gene expression of the cytokines IL-6, IL-8, TGF-beta, IL-4, IL-5, and IFN-gamma in maxillary sinus mucosa and compared the results with cytokine gene expressions in normal turbinate mucosa. IL-6, IL-8, TGF-beta, IL-4, IL-5, and IFN-gamma mRNAs were expressed more frequently in maxillary sinus mucosa from patients with chronic sinusitis than in normal turbinate mucosa. All the maxillary sinus mucosa specimens revealed relatively higher mean density ratio for each cytokine investigated than did normal turbinate mucosa. IL-6, IL-8, TGF-beta, IL-4, IL-5, and IFN-gamma mRNAs were expressed simultaneously in maxillary sinus mucosa of chronic sinusitis. These cytokines may be responsible for recruitment of inflammatory cells and for mucosal thickening in chronic sinusitis, and thus chronicity of the disease.

Middle ear pathologic changes associated with chronic anaerobic sinusitis in rabbits.

OBJECTIVE/HYPOTHESIS: To study the histopathologic changes in association with the inflammatory/immune response present in the middle ears of a rabbit model of unilateral chronic anaerobic sinusitis. STUDY DESIGN: New Zealand white rabbits, two at each experimental time point. Normal rabbits and sham-operated animals served as controls. METHODS: Left maxillary sinusitis was induced by inoculating Bacteroides fragilis surgically after closure of the ostium. Cultures, lavages, and mucosa were harvested from bilateral middle ear and sinus cavities at 1, 2, 3, and 4 weeks following inoculation. Parameters analyzed include tissue for histopathologic study, immunoglobulin G antibody (IgG Ab) against B fragilis, and lactate dehydrogenase (LDH) levels in lavage samples, interferon gamma (IFN gamma) messenger RNA (mRNA) expression in mucosal tissue, and bacterial culture. RESULTS: Despite closure of the ostium of the left sinus, mild to moderate dissemination of B fragilis into the right sinus and left and right ears were observed in some but not all rabbits (2/8, 5/7, and 2/8, respectively). Histopathologic changes in the right sinus and middle ears were much less severe in contrast to the severe inflammatory changes in the left sinus. An immune response against B fragilis appeared to occur in the sinuses and ears bilaterally independent of bacterial dissemination, as evidenced by a rise of IgG Ab in lavage fluid and detection of IFNg mRNA. Neither control nor sham-operated animals had detectable levels of IFNg mRNA or IgG Ab. In B fragilis-inoculated rabbits, the magnitude of IgG Ab responses was equivalent in the right and left ear, independent of B fragilis dissemination; IgG Ab levels in the middle ear positively correlated to each other (P < .01) and to the levels in the sinuses (P < .01 and P < .01). LDH levels were closely associated with bacterial growth and degree of tissue inflammation. CONCLUSION: This reproducible model of chronic sinusitis provides an opportunity to study the middle ear infection and inflammatory/immune responses occurring with sinusitis. Our results indicate bilateral middle ear mucosal immune responses to an elicited sinus infection, independent of B fragilis dissemination.

Maxillary sinusitis as a surrogate model for CF gene therapy clinical trials in patients with antrostomies.

BACKGROUND: Assessing the biological activity and clinical efficacy of gene therapy is critically important in cystic fibrosis (CF). It is widely accepted that clinical testing using surrogate markers including pulmonary function will be useful in assessing clinical efficacy. One problem with pulmonary surrogate markers of CF disease is the large number of patients and length of time required to demonstrate clinical efficacy. An alternative to pulmonary testing of new CF treatments is use of the maxillary sinuses as a surrogate model of CF lung disease. Using CF sinusitis as a surrogate model for testing clinical efficacy of new treatments is attractive because CF upper respiratory disease is similar to the lower respiratory disease with respect to electrophysiology and microbiology. METHODS: Sinusitis recurrence in untreated sinuses was analyzed during a prospective, randomized, unblinded, dose-escalation, within-subjects, phase I clinical trial of the adeno-associated virus mediated cystic fibrosis transmembrane conductance regulator (AAV-CFTR) gene transfer. RESULTS: Clinical symptoms combined with sinus endoscopy proved useful in the diagnosis of unilateral and bilateral sinusitis recurrence. Sinusitis recurred at a rate of 45% during one month of follow-up. IL-8 concentration rose in sinus fluids from affected sinuses. Bacterial cultures and increased sinus leukocytes corroborated recurrent sinusitis. Sinus CT scans were also useful in diagnosing recurrent sinusitis in this surrogate model of CF infectious exacerbations. CONCLUSIONS: CF sinusitis as a surrogate for lung disease is particularly well-suited for phase II clinical trials of gene transfer agents, with the potential for measuring clinical efficacy in relatively small numbers of patients over relatively short periods of time.