Immunoglobulin deficiency in patients with chronic rhinosinusitis: Systematic review of the literature and meta-analysis.

BACKGROUND: Several studies have shown a high prevalence of immunoglobulin deficiencies in patients with chronic rhinosinusitis (CRS). OBJECTIVE: We sought to perform a systematic review and meta-analysis to estimate this prevalence more precisely and to identify patients who need substitution treatment. METHODS: All case series published after 1990 describing patients with CRS, which was defined as symptomatic rhinosinusitis for more than 12 weeks and documented immunoglobulin deficiencies (including deficiencies of IgG with subclasses, IgA, and IgM; specific antibody deficiencies; and potential common variable immunodeficiency), were retrieved. A meta-analysis of the proportion of any combination of common variable immunodeficiency, IgG deficiency, IgA deficiency, and IgM deficiency in patients with CRS was performed by using logit transformation of the prevalence. Recurrent CRS was defined as rhinosinusitis not controlled by appropriate conservative management for 4 months, and difficult-to-treat CRS was defined as noncontrollable rhinosinusitis despite successful sinus surgery and appropriate conservative management for at least 1 year. RESULTS: The meta-analysis revealed a prevalence of pooled IgG, IgA, and IgM deficiencies in 13% of patients with recurrent CRS and 23% of patients with difficult-to-treat CRS. The prevalence of IgG subclass deficiency (5% to 50%) and specific antibody deficiency (8% to 34%) was increased in patients with CRS, as was the prevalence of respiratory allergies in patients with recurrent CRS (31% to 72%). CONCLUSION: Immunoglobulin deficiency is a frequent condition in patients with CRS. An even higher prevalence of atopy was observed in patients with recurrent CRS. Therefore immunoglobulin titers and accurate allergy diagnostic workups are strongly recommended in these patients to provide specific treatments for symptom alleviation. However, there is a need for larger prospective studies addressing the effect of specific therapeutic interventions for CRS.

T lymphocytes promote the antiviral and inflammatory responses of airway epithelial cells.

HYPOTHESIS: T cells modulate the antiviral and inflammatory responses of airway epithelial cells to human rhinoviruses (HRV). METHODS: Differentiated primary human nasal epithelial cells (HNEC) grown on collagen-coated filters were exposed apically to HRV14 for 6 h, washed thoroughly and co-cultured with anti-CD3/CD28 activated T cells added in the basolateral compartment for 40 h. RESULTS: HRV14 did not induce IFNγ, NOS2, CXCL8 and IL-6 in HNEC, but enhanced expression of the T cell attractant CXCL10. On the other hand, HNEC co-cultured with activated T cells produced CXCL10 at a level several orders of magnitude higher than that induced by HRV14. Albeit to a much lower degree, activated T cells also induced CXCL8, IL-6 and NOS2. Anti-IFNγ antibodies and TNF soluble receptor completely blocked CXCL10 upregulation. Furthermore, a significant correlation was observed between epithelial CXCL10 mRNA expression and the amounts of IFNγ and TNF secreted by T cells. Likewise, increasing numbers of T cells to a constant number of HNEC in co-cultures resulted in increasing epithelial CXCL10 production, attaining a plateau at high IFNγ and TNF levels. Hence, HNEC activation by T cells is induced mainly by IFNγ and/or TNF. Activated T cells also markedly inhibited viral replication in HNEC, partially through activation of the nitric oxide pathway. CONCLUSION: Cross-talk between T cells and HNEC results in activation of the latter and increases their contribution to airway inflammation and virus clearance.

Superantigens.

Superantigens (SAgs) are derived from diverse sources, including bacteria, viruses, and human hepatic tissue. SAgs initially cause lymphocyte activation but then result in clonal deletion and anergy, leading to immune tolerance. They can also act as superallergens by stimulating a broad spectrum of mast cells and basophils in patients with allergic conditions. The newly described staphylococcal SAg-like proteins subvert innate immune function by several mechanisms, which are distinct from SAgs' effects on lymphocytes and other acquired immune processes. There is mounting evidence to suggest that SAgs play a role in the pathophysiology of inflammatory airway disease. The pathophysiologic role of SAg-like proteins awaits clarification.

Screening for staphylococcal superantigen genes shows no correlation with the presence or the severity of chronic rhinosinusitis and nasal polyposis.

BACKGROUND: Staphylococcus aureus secretes numerous exotoxins which may exhibit superantigenic properties. Whereas the virulence of several of them is well documented, their exact biological effects are not fully understood. Exotoxins may influence the immune and inflammatory state of various organs, including the sinonasal mucosa: their possible involvement in chronic rhinosinusitis has been suggested and is one of the main trends in current research. The aim of this study was to investigate whether the presence of any of the 22 currently known staphylococcal exotoxin genes could be correlated with chronic rhinosinusitis. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a prospective, multi-centred European study, analysing 93 Staphylococcus aureus positive swabs taken from the middle meatus of patients suffering from chronic rhinosinusitis, with or without nasal polyposis, and controls. Strains were systematically tested for the presence of the 22 currently known exotoxin genes and genotyped according to their agr groups. No direct correlation was observed between chronic rhinosinusitis, with or without nasal polyposis, and either agr groups or the presence of the most studied exotoxins genes (egc, sea, seb, pvl, exfoliatins or tsst-1). However, genes for enterotoxins P and Q were frequently observed in nasal polyposis for the first time, but absent in the control group. The number of exotoxin genes detected was not statistically different among the 3 patient groups. CONCLUSIONS/SIGNIFICANCE: Unlike many previous studies have been suggesting, we did not find any evident correlation between staphylococcal exotoxin genes and the presence or severity of chronic rhinosinusitis with or without nasal polyposis.

Chemosensory function in Wegener's granulomatosis: a preliminary report.

Despite the fact that Wegener's granulomatosis affects the nasal and paranasal cavities and the cranial nerves regularly, chemosensory impairments have not been reported. The objective of this study is to test the three chemosensory systems, olfaction, taste, and intranasal trigeminal function in Wegener disease patients. We tested olfactory, gustatory, and intranasal trigeminal function in nine patients (5 women, 4 men, mean age 57 years) with confirmed Wegener's granulomatosis. Olfaction was tested with the Sniffin'Sticks, gustatory function with the "Taste strips" and intranasal trigeminal function with a lateralization task. One patient had anosmia (11%), four patients had hyposmia (44%) and four patients were normosmic (45%). Gustatory testing function showed pathological taste strip results in five patients (55%) and normal results in three patients (33%). One patient did not undergo taste testing. Intranasal trigeminal function was lowered in five patients (56%) and normal in four patients (44%). Neither previous nasal surgery status nor endoscopic status was associated to a higher frequency in pathological scores for any of the three chemical senses. In conclusion, these preliminary results suggest a consistent affection in chemosensory functions in Wegener's granulomatosis patients.

Olfactory function and nasal nitric oxide.

PURPOSE OF REVIEW: To highlight two often forgotten nasal functions, olfaction and nasal nitric oxide production, which have both received more attention over the last two decades with consequent findings that are now entering the routine clinical setting. RECENT FINDINGS: Olfactory measurements have been optimized and normative data are available, giving clinicians the possibility of testing olfactory function quickly within a patient's workup. The results can lead to more thorough investigations if necessary. Olfactory disorders concern more than just a few people, and these disorders can be a very early sign of Parkinson's disease. Nasal nitric oxide is hypothesized to play a role as an airborne messenger and as an antiinfectious agent in the nose and sinuses and to contribute to the mucociliary clearance. Evidence is growing that the nasal nitric oxide level is a good parameter for diagnosis of ciliary beat impairments and a suitable parameter to monitor treatment success in chronic rhinosinusitis. SUMMARY: Both nasal nitric oxide and olfactory function are worth testing routinely in any rhinology workup. Valuable clinical information for diagnostic and follow-up purposes can be gained.

Gustatory function after microlaryngoscopy.

CONCLUSION: Quantitative gustatory alterations are rare after microlaryngoscopy (MLS), whereas transient qualitative taste distortions occur more often. Patients undergoing MLS should know that mild but transient qualitative taste disorders may occur. OBJECTIVE: Suspension MLS requires neck extension and tongue compression. Little is known about taste disorders following MLS. To investigate qualitative and quantitative gustatory function after MLS we tested and questioned patients before and several weeks after the MLS. SUBJECTS AND METHODS: This was a prospective controlled study carried out in a tertiary care centre. Forty-three patients participated, 33 of whom underwent MLS and 10 septoplasty. Tongue compression time was recorded during MLS. Patients received taste evaluation before and at 1 and 14 days after the intervention. Patients were asked to indicate subjectively changed taste perceptions. RESULTS: Psychophysical (quantitative) taste results showed no significant differences before and at 1 and 14 days after the intervention (p = 0.60). Tongue compression time (MLS group) had no influence on measured post-MLS taste scores. In the MLS group four patients reported distorted taste perception the day after the MLS, whereas no patient in the septoplasty group did so. In all, four patients distorted taste perception, had disappeared after 14 days.

Rhamnolipids are virulence factors that promote early infiltration of primary human airway epithelia by Pseudomonas aeruginosa.

The opportunistic bacterium Pseudomonas aeruginosa causes chronic respiratory infections in cystic fibrosis and immunocompromised individuals. Bacterial adherence to the basolateral domain of the host cells and internalization are thought to participate in P. aeruginosa pathogenicity. However, the mechanism by which the pathogen initially modulates the paracellular permeability of polarized respiratory epithelia remains to be understood. To investigate this mechanism, we have searched for virulence factors secreted by P. aeruginosa that affect the structure of human airway epithelium in the early stages of infection. We have found that only bacterial strains secreting rhamnolipids were efficient in modulating the barrier function of an in vitro-reconstituted human respiratory epithelium, irrespective of their release of elastase and lipopolysaccharide. In contrast to previous reports, we document that P. aeruginosa was not internalized by epithelial cells. We further report that purified rhamnolipids, applied on the surfaces of the epithelia, were sufficient to functionally disrupt the epithelia and to promote the paracellular invasion of rhamnolipid-deficient P. aeruginosa. The mechanism involves the incorporation of rhamnolipids within the host cell membrane, leading to tight-junction alterations. The study provides direct evidence for a hitherto unknown mechanism whereby the junction-dependent barrier of the respiratory epithelium is selectively altered by rhamnolipids.

Postoperative/posttraumatic gustatory dysfunction.

Clinical taste testing in humans is far from being routinely performed in ear, nose and throat (ENT) clinics. Consequently, most reports on posttraumatic and postoperative taste disorders are case reports and mainly consist of qualitative (e.g. dysgeusia, metallic taste) taste changes after either head injury or ENT surgery. Since quantitative taste deficiencies (ageusia, hypogeusia) often go unnoticed by the patients, the real incidence of ageusia and hypogeusia after head trauma and various surgical procedures remains largely unknown. This lack of reliable clinical data is partly due to the lack of easy, reproducible and rapid clinical taste testing devices. The present chapter tries to resume the current knowledge on postoperative and posttraumatic taste disorders. Despite the sparse literature, the chapter focuses on those ENT surgical procedures where at least some prospective and systematic studies on gustatory dysfunction exist. Accordingly, taste disorders after middle ear surgery, tonsillectomy and dental interventions are largely discussed.

Long-term cultures of polarized airway epithelial cells from patients with cystic fibrosis.

The poor ability of respiratory epithelial cells to proliferate and differentiate in vitro into a pseudostratified mucociliated epithelium limits the general use of primary airway epithelial cell (AEC) cultures generated from patients with rare diseases, such as cystic fibrosis (CF). Here, we describe a procedure to amplify AEC isolated from nasal polyps and generate long-term cultures of the respiratory epithelium. AEC were seeded onto microporous permeable supports that carried on their undersurface a preformed feeder layer of primary human airway fibroblasts. The use of fibroblast feeder layers strongly stimulated the proliferation of epithelial cells, allowing the expansion of the cell pool with successive passages. AEC at increasing passage were seeded onto supports undercoated with airway fibroblasts and exposed to air. Either freshly isolated or amplified AEC could differentiate into a pseudostratified mucociliated epithelium for at least 10 mo. Thus, CF epithelia cultures showed elevated Na+ transport, drastic hyperabsorption of surface liquid, and absence of cAMP-induced Cl- secretion as compared with non-CF cultures. They were also characterized by thick apical secretion that hampered the movement of cell surface debris by cilia. However, CF respiratory epithelia did not show increased production of mucins or IL-8. The method described here is now routinely used in our laboratory to establish long-term cultures of well differentiated respiratory epithelia from human airway biopsies.

Differences between orthonasal and retronasal olfactory functions in patients with loss of the sense of smell.

OBJECTIVE: To investigate differences between orthonasal and retronasal olfaction in patients with loss of the sense of smell without taste complaints. DESIGN: Electrophysiological and psychophysical testing of orthonasal and retronasal olfactory functions. SETTING: Outpatient clinics. PATIENTS: A series of 18 patients who had olfactory loss due to various reasons but no "taste" complaints. MAIN OUTCOME MEASURES: Orthonasal and retronasal olfactory functions assessed by olfactory event-related potentials and psychophysical smell tests. RESULTS: Psychophysical testing revealed retronasal olfaction to be normal or slightly altered, whereas orthonasal olfaction was either absent or severely compromised. Findings from nasal endoscopic examinations and computed tomographic scans were within the reference range in all subjects. In response to orthonasal stimulation there were neither detectable olfactory event-related potentials nor any with small amplitudes, whereas olfactory event-related potentials in response to retronasal stimulation were clearly present in some patients. CONCLUSION: These clinical observations, together with the psychophysical and electrophysiological findings, suggest that orthonasal and retronasal olfaction might be processed differently.

Evidence of an intracellular reservoir in the nasal mucosa of patients with recurrent Staphylococcus aureus rhinosinusitis.

Severe infections due to Staphylococcus aureus require prolonged therapy for cure, and relapse may occur even years after the first episode. Persistence of S. aureus may be explained, in part, by nasal carriage of S. aureus, which occurs in a large percentage of healthy humans and represents a major source of systemic infection. However, the persistence of internalized S. aureus within mucosal cells has not been evaluated in humans. Here, we provide the first in vivo evidence of intracellular reservoirs of S. aureus in humans, which were assessed in endonasal mucosa specimens from patients suffering from recurrent S. aureus rhinosinusitis due to unique, patient-specific bacterial clonotypes. Heavily infected foci of intracellular bacteria located in nasal epithelium, glandular, and myofibroblastic cells were revealed by inverted confocal laser scan fluorescence and electron microscopic examination of posttherapy intranasal biopsy specimens from symptom-free patients undergoing surgery on the sinuses. Intracellular residence may provide a sanctuary for pathogenic bacteria by protecting them from host defense mechanisms and antibiotic treatment during acute, recurrent S. aureus rhinosinusitis.

Effects of amphotericin B on ion transport proteins in airway epithelial cells.

Topical intranasal application of the antifungal Amphotericin B (AmphoB) has been shown as an effective medical treatment of chronic rhinosinusitis. Because this antibiotic forms channels in lipid membranes, we considered the possibility that it affects the properties and/or cell surface expression of ion channels/pumps, and consequently transepithelial ion transport. Human nasal epithelial cells were exposed apically to AmphoB (50 microM) for 4 h, 5 days (4 h daily), and 4 weeks (4 h daily, 5 days weekly) and allowed to recover for 18-48 h. AmphoB significantly reduced transepithelial potential difference, short-circuit current, and the amiloride-sensitive current. This was not due to generalized cellular toxicity as judged from normal transepithelial resistance and mitochondrial activity, but was related to inhibitory effects of AmphoB on ion transport proteins. Thus, cells exposed to AmphoB for 4 h showed decreased apical epithelial sodium channels (ENaC) activity with no change in basolateral Na(+)K(+)-ATPase activity and K(+) conductance, and reduced amount of alphaENaC, alpha1-Na(+)K(+)-ATPase, and NKCC1 proteins at the cell membrane, but no change in mRNA levels. After a 5-day treatment, there was a significant decrease in Na(+)K(+)-ATPase activity. After a 4-week treatment, a decrease in basolateral K(+) conductance and in alphaENaC and alpha1-Na(+)K(+)-ATPase mRNA levels was also observed. These findings may reflect a feedback mechanism aimed to limit cellular Na(+) overload and K(+) depletion subsequently to formation of AmphoB pores in the cell membrane. Thus, the decreased Na(+) absorption induced by AmphoB resulted from reduced cell surface expression of the ENaC, Na(+)K(+)-ATPase pump and NKCC1 and not from direct inhibition of their activities.

Chronic panrhinosinusitis without nasal polyps: long-term outcome after functional endoscopic sinus surgery.

OBJECTIVE: The goal of this study was to evaluate the long-term outcome after functional endoscopic sinus surgery (FESS) for chronic panrhinosinusitis without nasal polyps by using symptom scoring and an endoscopic outcome evaluation. STUDY DESIGN: Seventy-seven patients with chronic panrhinosinusitis without nasal polyps (Kennedy computed tomography [CT] scan stages I to III) were followed up for at least 3 years after FESS. Preoperative evaluation included a CT scan and an immunoallergologic evaluation. Three years after FESS, all patients were interviewed and scored endoscopically. RESULTS: Ninety-two percent of the patients showed a marked global improvement after FESS. The endoscopic control showed normal findings in 54% of all ethmoidal cavities. The postoperative endoscopic score correlated significantly with the subjective satisfaction ratings (P < 0.001). The preoperative CT staging proposed by Kennedy was predictive for necessity of revision surgery in 15% of the patients. CONCLUSIONS: Our data suggest that FESS for chronic panrhinosinusitis without nasal polyps has a good long-term outcome on subjective symptoms and endoscopic findings. SIGNIFICANCE: According to this study, subjective improvement correlates significantly with the postoperative endoscopic findings in the ethmoidal cavities of patients with chronic panrhinosinusitis without polyps at a long-term follow-up.

N-acetylcysteine inhibits Na+ absorption across human nasal epithelial cells.

N-acetylcysteine (NAC) is a widely used mucolytic drug in patients with a variety of respiratory disorders. The mechanism of action is based on rupture of the disulfide bridges of the high molecular glycoproteins present in the mucus, resulting in smaller subunits of the glycoproteins and reduced viscosity of the mucus. Because Na(+) absorption regulates airway surface liquid volume and thus the efficiency of mucociliary clearance, we asked whether NAC affects the bioelectric properties of human nasal epithelial cells. A 24-h basolateral treatment with 10 mM of NAC decreased the transepithelial potential difference and short-circuit current (I(SC)) by 40%, and reduced the amiloride-sensitive current by 50%, without affecting the transepithelial resistance. After permeabilization of the basolateral membranes of cells with amphotericin B in the presence of a mucosal-to-serosal Na(+) gradient (135:25 mM), NAC inhibited 45% of the amiloride-sensitive current. The Na(+)-K(+)-ATPase pump activity and the basolateral K(+) conductance were not affected by NAC treatment. NAC did not alter total cell mRNA and protein levels of alpha-epithelial Na(+) channel (EnaC) subunit, but reduced abundance of alpha-ENaC subunits in the apical cell membrane as quantified by biotinylation. This effect can be ascribed to the sulphydryl (SH) group of NAC, since N-acetylserine and S-carboxymethyl-l-cysteine were ineffective. Given the importance of epithelial Na(+) channels in controlling the thin layer of fluid that covers the surface of the airways, the increase in the fluidity of the airway mucus following NAC treatment in vivo might be in part related to downregulation of Na(+) absorption and consequently water transport.

Src signaling links mediators of inflammation to Cx43 gap junction channels in primary and transformed CFTR-expressing airway cells.

Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) is associated with recurrent pulmonary infections and inflammation. We previously reported that tumor necrosis factor (TNF)-alpha decreases gap junction connectivity in cell lines derived from the airway epithelium of non-cystic fibrosis (non-CF) subjects, a mechanism that was defective in cells derived from CF patients, and identified the tyrosine kinase c-Src as a possible bridge between TNF-alpha and Cx43. To examine whether this modulation also takes place in primary epithelial cells, the functional expression of Cx43 was studied in non-CF and CF airway cells, obtained from surgical polypectomies and turbinectomies, which were grown either on culture dishes or permeable filters. Expression of Cx43 was detected by immunofluorescence on cells grown under both culture conditions. Non-CF and CF airway cells also showed intercellular diffusion of Lucifer Yellow. Dye coupling was rapidly abolished in non-CF cells in the presence of TNF-alpha, lipopolysaccharide and lysophosphatidic acid, and could be prevented by tyrphostin47, an inhibitor of Src tyrosine kinases. This down-regulation, however, was not detected in CF airway cells. These data indicate that CFTR dysfunction is associated with altered Src signaling, resulting in the persistence of gap junction connectivity in primary and transformed CF airway cells.

Retronasal olfactory function in nasal polyposis.

OBJECTIVE: To investigate the question of whether there is a difference in retronasal olfactory function between patients suffering from chronic rhinosinusitis with nasal polyposis (NP) and healthy controls. This question was based on the clinical observation that many of these patients present with smell loss without complaining about loss of the appreciation of foods. STUDY DESIGN: Open prospective study comparing symptomatic patients with healthy controls. METHODS: A total of 56 healthy volunteers and 42 NP patients were tested for orthonasal and retronasal odor identification. All subjects received detailed nasal endoscopy; NP was staged according to the Malm classification. Patients rated their olfactory function on visual analogue scales. Orthonasal testing was performed using the "Sniffin' Sticks" test kit. Retronasal testing was evaluated with odorized powders applied to the oral cavity. In both tests, subjects were asked to identify 10 items using a forced choice paradigm. RESULTS: Overall, odor identification was better in controls compared with NP patients (P <.001). Although controls exhibited no difference between orthonasal and retronasal smelling (P =.26), in NP patients, olfactory function was significantly better when odors were applied through the retronasal route (P <.001). Ratings of general olfactory abilities correlated with retronasal and orthonasal olfactory function in NP patients (P <.001) but not in healthy controls (P =.34). CONCLUSION: Better retronasal than orthonasal olfactory function seems to be associated with the presence of mechanical obstruction in the anterior portion of the olfactory cleft. In turn, these data indicate that olfactory loss in NP seems to be caused by regional mechanical or inflammatory factors.

Objective and subjective evaluation of endoscopic nasal surgery outcomes.

BACKGROUND: Chronic rhinosinusitis (CRS) symptoms include nasal obstruction, rhinorrhea, and facial pain associated with rhinosinusitis disability. When resistance to medical treatment is associated with endonasal anomalies, endoscopic nasal surgery (ENS) can be proposed. However, objective and subjective assessment criteria regarding the evaluation of ENS outcomes remain unclear. The aims of this study were to evaluate the correlation between the inflammation in the nasal mucosa, objective recordings of nasal airway resistance (NAR), subjective evaluation of symptom intensity, and the impact of ENS on patient-perceived rhinosinusitis disability. METHODS: Sixty-one consecutive patients (35 men and 26 women; mean age, 37.5 years) suffering from CRS were monitored at 4 months and 2 years after ENS. All middle turbinate mucosa were analyzed for the density of nonspecific inflammatory cells. All patients scored their own subjective rhinosinusitis symptoms and complaints of rhinosinusitis disability. An active anterior rhinomanometry was performed. RESULTS: A good correlation was observed between subjective and objective NAR (p < 0.001). We found a significant correlation between the density of inflammatory cells in the nasal mucosa, subjective nasal obstruction, and the rhinosinusitis disability score (p < 0.001). Recurrent CRS was seen only in subjects with moderate to severe inflammation of the middle turbinate mucosa sampled at the first surgical intervention. Subjective rhinosinusitis symptoms, objective NAR, and rhinosinusitis disability improved significantly after ENS. CONCLUSION: The degree of inflammation seems to be a good prognostic indicator regarding CRS recurrence. Long-term outcome after ENS for CRS showed significant improvement in subjective rhinosinusitis-specific symptoms, objective NAR, and rhinosinusitis disability.