The maxillary fluid obtained by endoscopic paranasal sinus surgery in 16 cases of chronic sinusitis was examined microbiologically. Ten patients recieved systemic antimicrobial therapy for 1 month before operation, Macrolide was given in 9 patients, cefotiam in 1.
In cases with antibiotic treatment within 1 month before operation, anaerobic bacteria were isolated in 2 out of the 8 culture positive specimens. A total of 14 bacteria, including 2 anaerobic and 12 aerobic bacteria were isolated with an average 1.75 species per specimen. In cases without antibiotic treatment within 1 month before operation, which a total of 24 bacteria, including 9 anaerobic and 15 aerobic were isolated with an average 4 species per specimen. The predominant anaerobic organisms were Peptostreptococcus spp. (36%) and Prevotella spp. (18%).

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Bacteriological examination of the maxillary sinus and the nasal cavity was conducted in 45 chronic sinusitis patients. Bacteriological examination of the larynx was also carried out in patients who had pus retention on the surface of the arytenoid portion of larynx. The results among these examinations were compared to each other. Staphylococcus epidermidis was frequently detected from the maxillary sinus and form the nasal cavity. Various kinds of bacteria were detected from the larynx, which suggested that sputum was mixed in them. The species of the bacteria from the maxillary sinus agreed wiht those from the nasal cavity at a rate of approximately 70%. When chronic sinusitis was based on the anaerobic bacteria, however, it was difficult to detect the causative bacteria from the nasal cavity. The agreement rate between the bacteria from the nasal cavity and those from the larynx was 35%. It was presumed that postnasal drip had significant influence on the laryngeal pus.

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Human paranasal sinusitis mucosa is examined by scanning electric microscopy for the formation of biofilm. The extracellular glycocalyx secreted by bacteria were observed in 5 specimens of patients with paranasal sinusitis. Two specimens showed to form a similar mass of boifilm. Glycocalyx microcolonies was considered to be bacterial virulence which protects from antibacterial agents and phagocytic leucocytes as well as biofilm. The cellular biofilm formation was suggested to make a significant role in these severe paranasal sinusitis.

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To study the regulation of ion transport by the human nasal gland (HNG) cells, we developed a system for culturing HNG cells isolated by enzymatic digestion from human nasal polyps. Erythromycin inhibited acetylcholine-induced Cl^- secretion in human nasal gland cells. On the other hand, erythromycin had no effect on ATPinduced Cl-secretion in human nasal epithelial cells. Thus, erythromycin might have the effect on reducing nasal secretion in chronic sinusitis.

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To evaluate the clinical efficacy of macrolides to hypersecretion of airway, the molecular mechanisms of cyclic AMP activated chloride channels of cultured tracheal epithelial cells excised from guinea pigs were investigated by using the patch clamp technique. The cyclic AMP activated outwardly rectifying chloride channels (ORCC) on the apical membrane of tracheal epithelial cells were significantly inhibited by Roxithromycin, a new 14-membered macrolide, under cell attached patchs. These inhibitory effects were also demonstrated in excised patchs. Our results suggest that Roxithromycin may play a role of inhibitor of hypersecretion as a ORCC bloker.

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Mucociliary transport system in elderly people (over 70 years old) was evaluated with the saccharin transport test and the technique of glycobiology. A median clearance time of the saccharin transport test of 32 elderly people was 17.9 min with a range of 8 to 55 minutes. Siaic acids of nasal mucin in the nasal mucosa obtained from 3 subjects of elderly people were investigated with lectin histochemistry. Sambucus nigra agglutinin (SNA), which recognizes sialic acids, strongly stained glandular mucous cells. Furthermore, expression of mRNA of sialyl-transferase in the nasal glands were detected in the cytoplasm of the nasal glandular mucous cells of elderly people's subjects, using in situ hybridization histochemistry. Glycobiological studies indicated normal functioning of nasal secretory glands of elderly people. These results suggested that normal mucociliary transport system is well maintained in elderly people.

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Chronic sinusitis is characterized by purulent paranasal sinus effusion and nasal discharge with numerous emigrated neutrophils. Recent advances in sinusitis research have revealed that interleukin-8 (IL-8) largely participates in this phenomenon. In the present study, effects of 14-membered macrolide antibiotic on neutrophil recruitment and IL-8 level in the nasal discharge were studied in chronic sinusitis patients.
Twelve non-allergic chronic sinusitis patients were orally given 150 mg roxithromycin per day without other treatments for 3 months. The number of neutrophils in the nasal smear was estimated in a grading scale, and the IL-8 concentration in the nasal discharge was measured by ELISA. The number of neutrophils was decreased in 7 cases out of 12 (58%) at 2 month and 6 cases out of 10 (60%) at 3 month. The IL-8 level in the nasal discharge was significantly lowered after 3-month-administration (14.3±3.8 nM vs. 5.3±1.7 nM, p<0.005). Moreover, grading of neutrophils in the nasal smear was correlated with the IL-8 level in the nasal discharge. These findings suggest that roxithromycin inhibits positive feedback mechanism of neutrophil recruitment and IL-8 production by the recruited neutrophils. To investigate the mode of action of macrolide antibiotics may lead to the development of a cytokine therapy for chronic sinusitis.

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The effect of the metabolized Roxithromycin (RXM), RU 28111, RU 39001, RU 44981 and RU 45179 on inflammation have not been well studied. The aim of the present study is to report the effects of the metabolized RXMs on IL-1β, IL-8, and TNF-α production from human monocytes induced by E. coli lipopolysaccharide (1.0μg/ml) in vitro. Monocytes from human peripheral blood were cultured with different doses of metabolized RXMs. The culture supernatants were obtained 24 hr after culture and assayed for cytokine concentrations.
The results show that all four types of metabolized RXM significantly (P<0.05) inhibited IL-β production at the concentrations of 0.5μg/ml, 1.0μg/ml and 3.0μg/ml. In the case of IL-8, only RU 44981 at the concentration of 1.0μg/ml significantly (P<0.05) inhibited its production. Otherwise, metabolized RXM type used in this study at any concentrations had no inhibitory effects on TNF-α production. These results suggest that metabolized RXMs have an important immunoregulatory function in some cases of inflammation.

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The low-dose and long-term macrolide therapy (the macrolide therapy) has been introduced for chronic sinusitis. The mechanism of the therapy has not been apparent yet. We have recently known that this therapy is very effective for a majority of patients with chronic sinusitis (effective group) but not for some (non-effective group). In this paper, we examined the histology of nasal polyp from both the effective group and the non-effective group by immunohistochemical technique. Eosinophil infiltration was seen in both group, but number of eosinophils in the noneffective group was more than that in the effective group. Eosinophils in the non-effective group were positive for both EG 1 and EG 2 antibody, whereas eosinophils in the effective group showed week staining for EG 2 antibody. Nasal polyp contained a lot of vessels that were identified by anti-von Willebrand factor antibody. In the noneffective group, many vessels in the nasal polyp were positive for anti-VCAM-1 antibody but negative for anti-ICAM-1 antibody. In the case of the effective group, vessels in the nasal polyp expressed ICAM-1 more than VCAM-1. Therefore, histological characteristics of the non-effective group compared with the effective group were massive infiltration of activated eosinophils and expression of VCAM-1 on the vessels. These results indicate that some feature of inflammation of the non-effective group are different from that of the effective group. These difference may be due to altered cytokine network activation and contribute diverse effects of the macrolide therapy.

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The nasal mucosa is the first site of contact with in halated antigens and pathogens. It is suggested that, in patients with chronic sinusitis, the local immune responses are suppressed. Mucosal IgA immunity plays an important role in preventing infections and excluding pathogens. Induction of the IgA immune response is regulated by cytokines. In this study, we investigated the effective induction of specific mucosal immunity and the modulation of mucosal immunity by intransal administration of cytokines.
Haemophilus influenzae is one of the most frequently isolated-organisms in patients with sinusitis. P 6 is one of the major outer membrane proteins of non-typable Haemophilus influenzae (NTHi), well conserved in the strain, antigenically stable, and has been proposed as an attractive candidate for preventive vaccine against NTHi infection.
Twenty-seven BALB/c mice were intranasally immunized with P 6, twice, with 2 weeks in between, with or without intranasal cytokine treatment. The intranasal immunization evoked anti-P 6 specific mucosal immunity. In addition, intranasal administration of rIL-5 and IL-6 enhanced anti-P 6 specific immune response. The activity peaked at the 14th day, and then gradually decreased, but was maintained for 21 days.
These results suggest the possibility of intranasal immunization and advantage of intranasal administration of cytokines for mucosal immunity.

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We compared the effect of low-dose and long-term administration of macrolides several types of chronic sinusitis. Because the effect of macrolides varied between lower respiratory diseases, sinusitis was divided into three groups according to accompanying lower respiratory tract disease. The first group was sinusitis with bronchial asthma. The second was sinobronchial syndrome (SBS), which was sinusitis with chronic bronchitis (CB) bronchiectasis (BE) or diffuse panbronchiolitis (DPB). The third was sinusitis without lower respiratory tract disease.
The effect of macrolide (RXM, CAM or EM) on sinusitis was evaluated clinically. Macrolide therapy was effective for sinusitis with SBS and without lower respiratory tract disease. There was no difference in improvement among sinusitis with SBS. Sinusitis with asthma was not improved sufficiently by this therapy. The effect for sinusitis without lower respiratory tract diseases was almost similar to that for sinusitis with SBS.
Because the pathogenesis of these lower respiratory tract disease are thought to be varied, heterogeneous pathogenesis may also exist in sinusitis. The heterogeneity in pathogenesis or the inflammatory process are suggested to contribute to different effect of macrolide therapy for various sinusitis.

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In the past, when evaluating the efficacy of sinusitis medicine for the treatment it was necessary to rely on patients subjective evaluations in such areas as condition of mucous membranes, status and volume of nasal discharge, nasal obstruction, headaches etc. However, because such evaluations are not rigorous and leave room for uncertainty, we are using an endoscope to observe the condition of the ostium and the amount of nasal discharge.
We administered RXOM to sinusitis patients and observed its effect on the nasal cavity of two contrasting groups of patients-groups I that did not undergo surgery and groups II that did undergo surgery and afterwards complained of a recurrence of inflammation. Both groups received two daily dosages of 150 mg RXM for four weeks.
We used a Hopkins endoscope attached to a VTR system which made video prints from which we could make evaluations.
The results was that we observed an improvement in the nature of the discharge in 70% of the patients in group I, 80% of the patients in group II, for an average of 75%.
The amount was 100% in group I, 90% in group II for an overall average of 95%.
As a result of observing the video prints, we can conclude that the effect of RXM on sinusitis is to cause nasal discharge to change from pus to mucus and to decrease in volume.

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There have been many reports about the mechanisms for the development of chronic sinusitis, but there remainsmany unclear points in its mechanisms. In this study, we investigated the conditions of the maxillary sinus with sinoscopy in which X-ray revealed abnormal shadow, and samples were also taken from the antrums to examine the pathological findings. We found that the mucosae of the maxillary sinus with chronic sinusitis were often edematous especially at the bottoms of the antrums, and in patients with nasal allergy. The number of eosinophils in the mucosa of the maxillary sinus significantly increased in nasal allergy compared with non-allergic sinusitis. And we found the process that the edematous mucosa had been healing. These results suggested that type-I allergic reaction might occur in the maxillary mucosa as well as in patients with nasal allergy.

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To clarify the relation between nasal allergy and chronic sinusitis, we retrospectively investigated both Xray findings and histopathological findings of chronic sinusitis on nasal allergic patients. Four-hundred and forty-six patients with nasal allergy were treated at Oita Medical University Hospital during 51 months between January 1991 and March 1995.
X-ray examinations of the sinuses were done in all patients. In 229 cases (51.3%), inflammatory shadow of the maxillary sinuses were detected, and these shadow were classified into three types. One hundred sixteen (50.7%) cases were thickening type, 59 (25.8%) cases were polyp type and 54 (23.5%) were diffuse type.
We performed endoscopic sinus surgery or maxillary sinus surgery for 26 adult patients. and obtained the mucosae of paranasal sinuses. According to the histopathological examination of these mucosae, nine (34.6%) cases were edematous type, 10 (38.5%) cases were fibrous type and 7 (26.9%) were mixed type. These histological changes were proliferation of the goblet cells and hypersecretion of the glands in the epithelium, basement membrane thickening and infiltration of eosinophils at edematous lamina propria.
These findings suggested that type I allergic reactions were thought to occur in mucosae of inflammatory paranasal sinuses. In order to improve of clinical symptoms and X-ray findings, therapy for allergic reaction is needed in these patients.

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The present study was carried out to determine the correlation between the clinical features and histopathological type of the paranasal mucosa in patients with chronic sinusitis who underwent macrolide therapy. We divided the patients into three groups, i. e. lymphocytic type, neutrophilic type and eosinophilic type by the dominance of inflammatory cells in the submucosal area. The patients with lymphocytic and neutrophilic type responded well to the macrolide therapy, while the patients with marked eosinophilic infiltration in the submucosa were mostly poor responders and tended to accompany with allergic diseases such as bronchial asthma. Purulent rhinorrhea was significantly found in patients with lymphocytic and neutrophilic type compared to those with eosinophilic type. Sinus plain X-ray revealed that patients with eosinophil dominant type showed more intense shadow in ethmoidal sinus than in maxillary sinus. There was no correlation between isolates of pathogenic bacteria from middle nasal meatus and histological types of paranasal mucosa. Thus we concluded that we should consider the clinical characteristics and prospect the efficacy of macrolide therapy in each patient with chronic sinusitis prior to the administration of macrolides.

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In this department, conservative treatment for chronic sinusitis, except for chronic sinusitis caused by nasal polypfullness or advanced lesions, consists of administration oflow doses of macrolide (MLs) for 2-3 months, followedby either surgery or continuation of the conservative therapy, judging by the improvement in symptoms. Since themechanism of action of long term low dose administrationhas not yet been deduced, administration of new quinolone (NQ) can also be considered as an intense supplementaltreatment, if the above treatment does not show any effect.Moreover, the therapeutic effect of NQ manifest within ashort period and its indication for more severe cases, areconsidered important subjects of future research in conservativetherapy. In this study, we have investigated theclinical application of short term administration of NQ athigh dosage and the concurrent use of NQ and MLs in thetreatment of chronic sinusitis.
(1) In the study of the short term, high dosage administrationof NQ, LVFX was given to seven patientswith chronic sinusitis for 7-14 days at a dose of 600mg/day. The clinical efficacy was 57%.
(2) In the study of the coadministration of NQ+ MLs, acombination of LVFX 100-200 mg with RXM 150mg or CAM 200 mg was given daily for 2-4 months.The clinical efficacy was 100%.
No appreciable adverse reactions were observed in both cases. Based on these results, treatment with these antibiotics is considered effective as a conservative therapy for chronic sinusitis. Also, these antibiotics are considered an extension of the long term, low dose conservative therapy of MLs, indicated for the treatment of severe cases and to shorten therapy.

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The YAMIK sinus catheter (YAMIK) with the administration of roxithromycin (RXM) was used as a newtherapeutic modality for the patients with chronic sinusitis in the out-patients clinic. In the 30 cases without nasal polyps, within one month subjective symptoms such as headache, nasal obstruction and postnasal drips were reduced in 23 cases (78%) after the treatment of YAMIK and RXM, and X-ray examination showed the reduced sinus shadows in 18 cases (60%) including 9 cases (30%) with complete cure. The saccharine time significantly improved (p<0.01) after this treatment, which indicated the recovery of the mucocilliary function of the upper respiratory mucosa. Based on the experience of the YAMIK to the 12 cases of chronic sinusitis with nasal polyps, the laser polypotomy was found to make the following YAMIK effective even in the cases with the obstructed middle meatus by nasal polyps. On the other hand, the cases of chronic sinusitis with severe nasal allergy were often resistant to this treatment.

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Clinical efficacy of macrolide antibiotics in the treatment of chronic sinusitis was summarized. Based on the basic studies, macrolides significantly inhibited the adhesion of Pseudomonas aeruginosa and Branhamella catarrhalis to human nasal epithelial cells, the Cl^- secretion from the submucosal nasal gland acinar cells, and the production of IL-8 in patients with chronic sinusitis, suggesting the reversible recovery of mucociliary function. The mucociliary clearance of the maxillary sinus using radionuclide technique was restored by the removal of obstructive lesion of the ostiomeatal complex (OMC). Non-responders to macrolide treatment tended to show severe obstruction of the OMC. Thus, macrolide treatment for chronic sinusitis requires patency between nasal cavity and paranasal sinuses via OMC, in order to the restoration of mucociliary clearance.

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Medical management is the most common modality of reatments for pediatric sinusitis. Sinus lavage and adminstration of antibiotics and/or steroids in a form of aerools are usually employed. Failure of these medical rianagements is an indication for surgical treatment in the patients more than 10 years old. Nasal polyps must be treated surgically.
In the patients more than 16 years old, severe and moderate sinus lesions are treated by surgery. If a patient shows, moderate lesion localized in the maxillary sinus, surgery is indicated only following a failure of adequate medical managements for 3 months. In such cases, the functional sinus surgery is indicated, because ciliated epithelium of the maxillary sinus is well preserved. Medical management is absolutely indicated to the patients with mild sinus lesion.
In aged patients, medical or surgical management of sinusitis must be selected by considering their general conditions and quality of life (QOL).

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Clarithromycin (CAM 400 mg/day) was administered for eight weeks in twenty cases with chronic sinusitis.
The clinical effects were assessed objectively with Xray mucous-membrane function test (X-M.F.T). The mucosal edema in the maxillary sinuses and the mucocilliary clearance function showed ineffective rates of 44% and 36%, respectively.
The shadow of the ethmoid sinuses on X-ray was not improved at a rate of 27.3%.
The overall assessment of subjective symptoms, objective symptoms and X-M.F.T. findings was poor with little improvement in 25%.
The result shows a limit of the CAM therapy (400 mg/ day for 8 weeks) in the treatment of chronic sinusitis.

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The long-term macrolides therapy for chronic sinusitis has been widely accepted in a short time. However there are some problems, existence of ineffective cases, incomplete remission, recurrence of symptoms with discontinued administration, infection caused by macrolides resistant bacteria, etc. Moreover the therapy tends to use macrolides excessively and to be continued without choice of appropriate therapies because of easy doing. From the retrospective analysis of treated 162 cases, followings were concluded. 1) There was no significant correlation between the duration of the disorder and the efficacy, and between the degree of symptoms and the efficacy. However the ratio of the patients who had received surgical treatment or whose duration of the disorder exceeded 10 years was significantly higher in non-effective group than in excellently effective group. 2) More than half of the treated cases had recurrence of symptoms. 3) The surgical therapy was needed to eliminate nasal polyps. 4) The radiological complete remission was rare. 5) The obstructive lesion of sinus required a surgical therapy.

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The clinical usefulness of long-term roxithromycin (RXM) therapy after endoscopic sinus surgery was investigated in 28 patients with chronic paranasal sinusitis treated between May 1994 and June 1995. After surgery, RXM was orally administrated 300 mg per day for an average of 17.6 weeks. Improvement rate of subjective symptoms and objective findings were 66.7%, and 80.0%, respectively. The overall improvement rate assessed by changes in subjective symptoms and objective findings was 66.7%. Normalization of postoperative CT findings was noted in the anterior and posterior ethmoid sinuses. Under endoscopic examination, condition of the mucosa is excellent in over 80% of all the sinuses except for the maxillary sinus. Openings of the middle nasal meatus and fontanelle were 90% and 85%, respectively. Nasal symptoms and anterior rhinoscopic, CT and endoscopic findings were stabilized 16 weeks atter surgery. 1 hese results suggest that long-term RXM therapy after endoscopic sinus surgery is effective in the patients with chronic paranasal sinusitis.

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To evaluate the relation between the clinical effects and the duration of long-term administration of PXM, 49 patients with chronic sinusitis were treated with RXM, 300 mg/day for the first two weeks followed 150 mg/day, for 6 months at least and 4 years at most, averaged 13 months.
The radiological and symptomatic evaluations were carried out at 10 weeks, 6 months after the initial administration and at the time subjective symptoms were disappeared.
The clinical effect was observed in approximately 60% of the patients at 6 months and at the time subjective symptoms were disappeared, and there was no statistical difference of the effect between these administration periods.
From the results, it was concluded that the longterm administration of RXM should not be continued more than 6 months, and the modality of treatment must be altered to the other than administration of RXM.

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We observed paranasal sinus mucosa after functional endonasal sinus surgery (FES) using the fiberscope, and studied the effectiveness and usefulness of Roxithromycin (RXM) on healing process of the sinus mucosa.
Fifteen patients who had had the FES were divided into two groups. For the first group we administrated RXM (300 mg/day) and pronase (36000 units/day) for 12 weeks, and for the second group only pronase was administrated. Subjective symptoms, objective nasal findings and endoscopic observations were studied every 4 weeks, and the healing score was compared between the two groups.
Although there was no significant difference for the improvement of subjective symptoms and objective findings, the group with RXM was improved better than that without RXM in endoscopic observations. The course of endoscopic observations was not compatible with those of subjective symp toms and objective findings. We thought that subjective symptoms and objective findings can only reflect the conditions of the nasal cavity, and that they may not accurately represent the conditions of the sinuses or sinusitis. RXM treatment after endoscopic sinus surgery was effective on the healing process, especially for the pathological sinus mucosa.

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[in Japanese]

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