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The authors provide definitions for the different forms of pediatric rhinosinusitis, with an enumeration of the main symptoms and signs. They also provide the indications for CT scan examination and microbiological investigations. In addition, they emphasize the importance of concomitant systemic disease, such as allergy and immunological disorders. The adequate medical management, which is mandatory before any surgery, is considered and discussed, and the indications for surgery are provided.

Aspirin-sensitive rhinitis is characterized by severe perennial nasal congestion and discharge. The study questioned whether this disease, like immunoglobulin E-mediated rhinitis, might be associated with local recruitment and activation of T-lymphocytes, mast cells and eosinophils with parallel increases in "T-helper2-type" cytokines. Nasal biopsies from 10 patients with aspirin-sensitive rhinitis and 12 healthy controls subjects were studied. Nasal mucosal sections were examined by immunohistochemistry in order to determine cell phenotypes and by in situ hybridization to detect cells expressing messenger ribonucleic acid (mRNA) for cytokines. In aspirin-sensitive rhinitis there were increases in total (CD3+) (p=0.05) and activated (CD25+) T-cells (p=0.007), total (major basic protein (MBP) positive) (p=0.004) and activated (monoclonal antibody which recognizes the cleaved form of eosinophil cationic protein (EG2) positive) eosinophils (p=0.003), tryptase+ mast cells (p=0.04) and CD68+ macrophages (p=0.002). Neutrophils and cells expressing human leukocyte antigen-DR were no different. Marked increases were observed in the numbers of interleukin (IL)-5 mRNA+ cells (p=0.004) in aspirin-sensitive patients, whereas lower numbers of IL-4 mRNA+ cells were observed, with a trend for a difference from controls (p=0.07). No differences were observed for either IL-2 or interferon-gamma. In conclusion, in aspirin-sensitive rhinitis there is intense inflammation of the nasal mucosa characterised by T-lymphocytes, eosinophils and mast cells. The predominance of macrophages and disproportionate increase in interleukin-5 compared to interleukin-4 messenger ribonucleic acid expression suggests that factors other than "allergic" mechanisms may be important in this disease.

We attempted to determine the efficacy of endoscopic sinus surgery in adult patients with asthma and chronic rhinosinusitis or nasal polyposis. Fifty asthmatic patients from 17 to 74 years of age with a history of either chronic rhinosinusitis or nasal polyposis were examined. Sinonasal disease was confirmed endoscopically and with computerized tomography, and all had failed aggressive medical management of their sinonasal disease before undergoing endoscopic sinus surgery performed by the same surgeon in all cases. The following were compared for 12 months: preoperative and postoperative overall asthma control, peak flow measurements, asthma medication requirements, including the use of oral steroids, and hospitalizations for asthma. Twenty patients felt that their asthma control had improved postoperatively. Twenty per cent used less steroid inhaler, and 28% less bronchodilator inhaler. Of those 23 patients measuring peak flows, seven achieved higher levels and seven noted fewer dips and swings. Significant reductions in oral steroid requirements (p < 0.001) and hospitalization for asthma (p < 0.025) were also recorded postoperatively. Irrespective of whether the patient had chronic rhinosinusitis or nasal polyposis, both groups improved postoperatively. The commonest symptoms experienced by the group as whole and by the nasal polyposis patients were hyposmia and nasal obstruction. Postnasal discharge and headache were more important in the chronic rhinosinusitis group. Mean visual analog scores improved for all symptoms; in particular for nasal obstruction and sense of smell. Aggressive management of sinonasal pathology can improve asthma status. No major differences were recorded for outcomes when comparing patients with chronic rhinosinusitis or nasal polyposis; in particular there was no evidence for a worsening of asthma after nasal polypectomy.

The aim of this study was to determine the long-term efficacy and safety of mizolastine, a new second-generation antihistamine with European approval, in the treatment of perennial allergic rhinoconjunctivitis. In this study, 141 patients were treated with once-daily mizolastine 10 mg or 15 mg in a 5-month open-label extension of a 1-month double-blind, placebo-controlled trial, which assessed once-daily mizolastine 10 mg. Mizolastine significantly reduced the nasal subscore (sneezing, rhinorrhoea, itch; end-baseline +/- SD, -2.5 +/- 6.3), nasal obstruction (-1.2 +/- 2.6) and rhinoscopy scores (-1.3 +/- 2.6), and improved ocular and total nasal scores after 6 months' treatment. Improvement was maintained for the duration of the study with no loss of drug efficacy. Adverse effects were mild with no specific effects associated with prolonged use. These results clearly demonstrate that mizolastine is effective and well tolerated in the long-term treatment of perennial allergic rhinoconjunctivitis. The significant clinical improvement in nasal blockade may reflect mizolastine's histamine/5-lipoxygenase dual inhibition.

Objectives: To (1) provide definitions for the different forms of pediatric rhinosinusitis, with an enumeration of the main symptoms and signs; (2) provide indications for microbiological, allergic, and immunologic assessment as well as for imaging studies; (3) suggest standard medical management with judicious use of antimicrobial agents; and (4) discuss indications for surgery., Data Sources: Clinical studies and literature data relevant to the different topics of pediatric rhinosinusitis., Conclusions: Rhinosinusitis in children is a multifactorial disease in which the importance of several predisposing factors changes with increasing age. Continued study to obtain a better understanding of the disease and carefully controlled comparative evaluations of medical and surgical therapies are suggested.

1. The aim of this study was to characterize the kinin receptor in the human nasal airway using [125I]-Hoe 140 binding to a membrane preparation from human nasal turbinates and to compare Ki values from binding displacement by antagonists with the functional effects of these drugs in vivo. We also investigated the effect of Hoe 140 ([D-Arg0, Hyp3, Thi5, D-Tic7, Oic8]-bradykinin), on bradykinin release into the nasal airway. 2. In a membrane preparation from human nasal turbinates removed during surgery, [125I]-Hoe 140 labelled a single, saturable binding site. The equilibrium dissociation constant (at 20 degrees C) for [125I]-Hoe 140 binding to the receptor was 0.46 +/- 0.08 nM. The Bmax was 0.136 +/- 0.003 pmol mg-1 protein and the Hill coefficient was 1.01 +/- 0.07. 3. The association rate constant for [125I]-Hoe 140 binding to the receptor was 0.20 +/- 0.06 nM-1 min-1 and the dissociation rate constant was 0.14 +/- 0.01 min-1. These values were determined at 4 degrees C. The equilibrium dissociation constant calculated from these rate constants was 0.70 nM. 4. Bradykinin and the B2 receptor antagonists, NPC 567, NPC 17731, NPC 17761, [1-adamantane acetyl-D-Arg0, Hyp3, Thi5,8, D-Phe7]-bradykinin, WIN 64338 and Hoe 140 displaced [125I]-Hoe 140 binding: the Ki values from binding displacement are consistent with values expected from a B2 receptor. The B1 agonist, [des-Arg9]-bradykinin and the B1 antagonist, [des-Arg9]-Hoe 140 failed to displace [125I]-Hoe 140 binding at concentrations up to 1 microM. 5. The bradykinin antagonist, Hoe 140, 10 to 200 micrograms, given by intranasal aerosol, produced a dose-related inhibition of the reduction in minimal nasal cross-sectional area (Amin) induced by bradykinin in normal subjects and by house dust mite antigen in subjects with allergic rhinitis to house dust mite. Hoe 140, 10 to 200 micrograms, also caused a dose-related inhibition of the release of albumin into the nasal cavity following challenge with bradykinin. 6. [1-Adamantane acetyl-D-Arg0, Hyp3, Thi5,8, D-Phe7]-bradykinin, 30 to 200 micrograms, caused a dose-related inhibition of the reduction in Amin and the release of albumin into the nasal cavity induced by bradykinin. NPC 567 ([D-Arg0, Hyp3, D-Phe7]-bradykinin) failed to inhibit the reduction in Amin or the release of albumin into the nasal cavity at a dose of 10 mg. 7. Challenge of allergic subjects with house dust mite antigen caused a significant elevation of the bradykinin concentration in nasal lavage fluid and a reduction in Amin. Hoe 140, 100 micrograms, prevented the antigen-induced reduction in Amin and also abolished the antigen-induced increase of bradykinin in nasal lavage fluid. 8. We conclude that there is a B2 bradykinin receptor in the human nasal airway which mediates nasal blockage and plasma extravasation induced by either bradykinin or antigen challenge. It is possible that Hoe 140 inhibits kallikrein in the human nasal airway as well as blocking the B2 receptor.

Hyposmia is a neglected symptom in patients with rhinitis. We studied 25 patients presenting with perennial rhinitis. Fifteen patients expressed hyposmia as a significant symptom. University of Pennsylvania smell identification test (UPSIT) and visual analogue scales (VAS) were used to score the symptoms of hyposmia, nasal obstruction and nasal discharge before and after six weeks treatment with betamethasone sodium phosphate drops. Those patients with initial symptoms of hyposmia significantly improved their UPSIT scores (p = 0.00009) and their VAS scores for hyposmia (p = 0.00133). Despite a significant decrease in the sensation of nasal obstruction, the non-hyposmics showed no increase in UPSIT scores after betamethasone therapy. There was no clear correlation between UPSIT results and other symptom scores. The judicious use of betamethasone drops in the treatment of rhinogenic hyposmia can be recommended.

In non-allergic subjects, histamine induced a reduction of minimal nasal cross-sectional area (Amin) and an increase in albumin release into nasal lavage. The effect of histamine on albumin release was inhibited by pretreatment with NG-nitro-L-arginine methyl ester (L-NAME), 1 mumol but not by D-NAME, 1 mumol. L-NAME, 1 and 10 mumol, did not inhibit the histamine-induced reduction of Amin. In subjects allergic to grass pollen, antigen challenge induced a reduction in Amin that was not changed by pretreatment with L-NAME, and an increase in albumin release that was inhibited by L-NAME, 1 mumol. The data support a role for nitric oxide in mediating plasma extravasation in the nose induced by antigen challenge or histamine.

Background: Fluticasone propionate is a new potent, topically active corticosteroid with negligable oral bioavailability. Data on its comparative efficacy in perennial allergic and non-allergic rhinitis are limited., Objective: To compare the efficacy and safety of fluticasone propionate aqueous nasal spray (FPANS) 200 micrograms once or twice daily with beclomethasone dipropionate aqueous nasal spray (BPD) 200 micrograms twice daily and placebo in patients with allergic and non-allergic perennial rhinitis., Methods: The 12-week study had a multicentre, double-blind, randomized, parallel group design. Efficacy was assessed from symptom scores recorded on daily diary cards., Results: FPANS 200 micrograms once or twice daily was significantly better than placebo but not better than BDP in relieving the nasal symptoms of rhinitis. FPANS at either dose was equally effective in the treatment of allergic and non-allergic perennial rhinitis. There were few adverse events and no treatment-related abnormalities in laboratory measurements in either FPANS-treated group. Comparison between treatment groups indicated that FPANS was as well tolerated as placebo and BDP at the doses studied., Conclusions: In the majority of patients FPANS 200 micrograms once daily in as effective as BDP 200 micrograms twice daily in the relief of perennial allergic rhinitis.

The aim of the study was to investigate the effect of short-term treatment with fluticasone propionate on the response to nasal allergen challenge in patients with allergic rhinitis. Responses to nasal allergen challenge were assessed subjectively by recording symptom scores on visual analogue scales, and objectively by measuring histamine, PGD2 and LTC4 in nasal lavage and by measuring nasal inspiratory peak flow following challenge. Nasal allergen challenge resulted in an increase in all symptom scores (P < 0.05); an increase in histamine and PGD2 (P < 0.05), and a decrease in nasal inspiratory peak flow at 1 h, 5 h and 7 h following challenge (P < 0.05). The allergen-induced changes in symptom scores, mediator levels and nasal inspiratory peak flow were attenuated by treatment with fluticasone propionate (P < 0.05 for all parameters measured). Post-challenge nasal obstruction was decreased by 45%; sneezing, itching and rhinorrhoea by 73, 78 and 80% respectively in the group as a whole comparing scores whilst on fluticasone propionate with those on no therapy. Fluticasone propionate, 200 micrograms twice daily for 2 weeks is effective in reducing significantly the early and late response to nasal allergen challenge.

Whilst clinical success of endoscopic surgery for chronic rhinosinusitis has necessarily depended primarily upon subjective evaluation, a range of objective techniques are now available which may facilitate our interpretation of results. A group of 200 patients underwent assessment of symptoms by sequential visual analogue scoring, olfaction by qualitative and quantitative testing, nasal airflow by forced inspiratory peak flow, anterior rhinomanometry, nasomucociliary function by ciliary beat frequency and nasal topography by acoustic rhinometry performed pre- and post-operatively. Significant improvement was demonstrated in all symptoms examined, olfactory tests and ciliary beat frequency whilst acoustic rhinometry provided an attempt to quantify the surgical cavities. These results offer an interesting perspective on the pathology of rhinosinusitis and the rationale for surgery within the ostiomeatal complex.

In subjects with allergic rhinitis to house-dust mite (HDM), antigen challenge produced a significant increase in nasal blockage but had no effect on nasal vascular permeability. The B2 kinin receptor antagonist, [D-Arg0,Hyp3,Thi5,D-Tic7,Oic8]-bradykinin (Hoe 140), 200 micrograms administered by intranasal aerosol 2 min prior to challenge with HDM, 500 u significantly reduced nasal blockage induced by the antigen challenge. The data are compatible with a role for B2 kinin receptors in the nasal response to challenge with antigen which is responsible for nasal blockage.

Sera from seventy-four adult patients with chronic or recurrent rhinosinusitis (mean duration 10.3 years) were tested for levels of total immunoglobulin and IgG subclasses. Fourteen (19%) had low levels of one of the major immunoglobulin classes and 23 (31%) had one or more IgG-subclass deficiencies, i.e. values less than the mean minus 2 standard deviations of a control population sample. Nineteen patients had low IgG3 levels. The group as a whole showed significantly low mean levels of IgG3, 46.9 +/- 19.5 mg/dl compared to 76 +/- 21 mg/dl for the controls, p < 0.0005 (Student's t-test). Since there was no clinical difference between those with and without IgG3 deficiency, there exists the possibility of an underlying immune defect, possibly involving heavy chain switching, in all these patients.

The nasal cycle has been demonstrated in man using several techniques, including magnetic resonance imaging, anterior rhinoscopy, rhinomanometry, all of which have limitations due to expense, discomfort, limited scope or poor reproducibility. Acoustic rhinometry is a new technique which analyses nasal geometry throughout the nasal cavity, not just at the flow-limiting segment. Six adult volunteers were examined at 15-to 30-min intervals using acoustic rhinometry. The classical alternating cycle was seen in three subjects, a non-classical cycle was seen in two, and no cycle seen in one subject. Changes occurred throughout the nasal cavity and corresponded with fluctuations in subjective scores of obstruction and, in one case, with nasal resistance measurements. Acoustic rhinometry is a rapid, reproducible and non-invasive technique. This pilot study demonstrates that it has potential for studying in detail the physiology of the nasal cycle.

The role of immunological defence mechanisms in the development of acute recurrent or chronic sinusitis is obviously of considerable importance but the incidence of such immune problems is unknown. To elucidate this situation, a prospective study of 47 patients with chronic rhino-sinusitis were examined for abnormalities of serum immunoglobulins, both major class and subclasses. Deficiencies of minor IgG subclasses may be obscured by only measuring the major IgG class and should be specifically sought in clinically suspicious cases. The clinical and therapeutic implications are considered.

Considerable clinical success has been claimed for functional endoscopic sinus surgery but objective assessment of prospective series is lacking in the literature. Twenty-four patients with chronic rhino-sinusitis underwent assessment of symptoms by visual analogue scoring, nasomucociliary function by ciliary beat frequency, olfaction by qualitative olfactometry and nasal airway resistance by anterior rhinomanometry pre- and post-operatively. This demonstrated a significant improvement in all symptoms examined and in ciliary beat frequency. Quantitative olfaction and anterior rhinomanometry were not improved despite diminished symptoms. These results offer quantitative evidence of clinical improvement following functional endoscopic sinus surgery which supports the pathophysiological concepts on which the technique is based.

In several conditions objective assessment of nasal obstruction would be of great value. In this study we have compared two different methods for this purpose. Anterior rhinomanometry is a well established method, which measures nasal airway resistance (NAR). This was compared with nasal inspiratory peak flow (NIPF) measured with a Youlten peak flow meter. The assessments were undertaken in patients with allergic rhinitis, before and after challenge with hyperosmolar saline solution. After challenge there was a fall in NIPF value as a mean of 17.4%, that was mirrored by a rise in NAR of 15.6%. There was also a statistically significant negative linear correlation between these two methods (p less than 0.01). We conclude that NIPF is a cheap, easily performed and quick method suitable for assessing nasal airway patency in e.g. allergics during treatment and during challenge.

Myasthenia gravis is a disorder of autoimmunity in which neuromuscular transmission is impaired by autoantibodies to the acetylcholine receptor (AChR). There is evidence for more than one form of the disorder with differing genetic susceptibilities. The aetiology is unknown, but thymic involvement is suggested by abnormal histology and by the beneficial response of the disorder to thymectomy in more than two-thirds of patients. Thymectomy is indicated in most patients unless the symptoms are minimal or are confined to the extraocular muscles alone, or the patient is elderly. Thymectomy alone results in remission in about one-third of patients, but, in addition, most patients require symptomatic anticholinesterase drugs to prolong the action of acetylcholine at the muscle end-plate. Over-dosage of these drugs can also cause weakness. Immunosuppression with corticosteroids or azathioprine may also improve myasthenia; at present, these drugs are used mainly in patients who do not respond to thymectomy or in those patients considered unsuitable for operation. Plasma exchange can cause a rapid, though temporary, involvement in myasthenia, but it probably has no long term place in its treatment. Future therapy will probably involve specific immunotherapy, such as anti-idiotype antibodies.

Acetylcholine receptor (AChR)-bearing membranes from the BC3H-1 cell lines were injected, without adjuvant, either intrathymically (i.t.) followed by intraperitoneal (i.p.) booster doses, or i.p. alone, into (C57BL X BALB/c)F1 mice. Over 75% of the animals developed serum anti-AChRs which reacted with the cell-line AChR and with normal mouse endplate AChR. The titres were within the lower range of those of myasthenia gravis patients, and some mice showed reduced miniature endplate potential (m.e.p.p) amplitudes. these results indicate that loss of tolerance to acetylcholine receptors can result from immunization against syngeneic AChR without adjuvant. This approach may provide a useful model for studying mechanisms of autoimmunity against acetylcholine receptor.

In a double-blind placebo-controlled cross-over trial, low dose sublingual therapy with house dust mite was effective in relieving symptoms in 72% of the group of patients with perennial rhinitis due to house dust mite (P less than 0.03). Following active treatment, there was a significant increase in morning peak nasal inspiratory flow rate (P less than 0.01) in those who improved (thirteen out of eighteen) and resistance to nasal provocation with house dust mite also increased, in some cases up to 1000-fold (P less than 0.05). Oral therapy is safe and avoids the side effects of desensitizing injections which can be serious. The potential for oral desensitization is great and further studies on this form of treatment are needed.

D-Penicillamine added to lymphocyte cultures from myasthenia gravis patients infrequently and inconsistently stimulated anti-AChR production. This usually occurred in the presence of pokeweed mitogen (PWM), and often only at a single concentration of D-penicillamine which varied among patients. The change was typically paralleled by an increase in total IgG production of similar magnitude, suggesting that the effect was nonspecific. D-penicillamine did not affect AChR expression in cultured thymic adherent cells. These data provide no evidence that penicillamine induces myasthenia gravis by direct stimulation of anti-AChR antibody-producing cells.

Antiacetylcholine receptor antibody (anti-AChR) was spontaneously synthesized by cultured thymic tissue from 19 of 35 patients with myasthenia gravis. Two other thymus cultures produced antibody after stimulation by pokeweed mitogen. Antibody production correlated with histologic evidence of thymitis, long duration of symptoms, or high serum anti-AChR values. None of seven thymomas synthesized antibody in culture, but evidence suggested that there had been in vivo synthesis or trapping of anti-AChR. Clinical improvement after thymectomy, during the short period of study, did not correlate with synthesis rates of anti-AChR production by the removed thymus. The rates of anti-AChR production in culture were too low to suggest that the thymus is the major source of this antibody. Although we did not find a clear relationship between anti-AChR antibody and clinical state within 3 months of thymectomy, in a study of 25 nonimmunosuppressed, nonthymoma patients followed for 1 to 4 years, we found a significant correlation (p less than 0.05, Spearman Rank correlation) between fall in anti-AChR antibody and clinical improvement after thymectomy (unpublished observations).

Three patients with myasthenia gravis, in whom a thymoma had been removed during total thymectomy four to 14 years earlier, developed glomerulonephritis presenting as the nephrotic syndrome. All had been treated previously by plasma exchange and were receiving azathioprine. Two were also taking prednisolone. Serum immune complexes containing IgM were present in all three. Renal histology showed either focal segmental glomerulosclerosis, minimal change lesion or focal proliferative glomerulonephritis. No immunoglobulin deposits were seen. Two patients lost their proteinuria on high dose corticosteroid therapy and their renal function improved. Glomerulonephritis occurred in nine per cent of patients with thymoma receiving immunosuppressive treatment with azathioprine for more than two years. We suggest that this treatment may be implicated in its aetiology.

Thymus-derived (T) lymphocytes in the peripheral blood and cellular immune function have been studied in ten patients with myasthenia gravis and in fifteen different myasthenic patients more than 10 years after thymectomy. The results were compared with those of a normal control population. The non-thymectomized myasthenic patients had normal T lymphocyte concentrations measured by rosetting with native sheep red cells. These patients also showed normal sensitization and recall of delayed hypersensitivity, phytohaemagglutinin (PHA) induced lymphocyte transformation and antibody-assisted (K cell) cytotoxicity; however, PHA-induced cytotoxicity was markedly reduced (P less than 0.001). The thymectomized group exhibited a lower mean percentage and absolute number of E-rosette-forming cells, which returned toward normal after in vitro treatment with thymosin. PHA-induced lymphocyte cytotoxicity, however, was normal in the patients who had undergone thymectomy, as were lymphocyte transformation, antibody-assisted cytotoxicity and sensitization to dinitrochlorobenzene (DNCB); there was a decrease in recall of established delayed hypersensitivity. Adult thymectomy in man, therefore, produces a partial and dissociated decrease in T cell responses and it is unlikely that the beneficial effect of this operation in myasthenia gravis is related to immunosuppression.

Patients with well defined reactions to foods were examined for their ability to carry out both sulphur and carbon oxidation reactions by using carbocisteine and debrisoquine as probe compounds. The proportion of poor sulphoxidisers (58 of 74) was significantly greater than that of a previously determined normal control population (67 of 200; p less than 0.005). The proportion of poor carbon oxidisers was not significantly different from the controls. Metabolic defects may play a part in the pathogenesis of adverse reactions to foods.

Antiphospholipid (PL) antibodies have been detected in sera from patients with chronic neurological diseases associated with disorders of immunity. In an isotype specific radioimmunoassay for anti-cardiolipin (CL) antibodies, we found IgM anti-CL (greater than 2 s.d. above mean of controls) in 17/25 (68%) patients with myasthenia gravis (MG), 8/25 (32%) with the Lambert-Eaton myasthenic syndrome (LEMS), 5/17 (29%) with multiple sclerosis and 3/11 (27%) cases of migraine. IgG anti-CL was only found in low titres in sera from 10 patients with MG and three with LEMS. Significant anti-CL activity could not be detected in sera from nine patients with acute Guillain-Barré Syndrome (GBS), 12 chronic cases of epilepsy, 8/9 with oat cell carcinoma and 9/10 with acute stroke. Further tests on 39 sera with the highest anti-CL activity, from all of the above disease groups, showed a significant correlation between IgM anti-CL and IgM anti-ss DNA activities. In a series of competitive inhibition assays six sera from patients with MG were shown to have a proportion of both specific and cross-reactive IgM anti-CL and IgM anti-ss DNA antibodies. Anti-phospholipid antibodies occur in certain neurological diseases, at lower titres than seen in SLE, yet their cross-reactive binding to ss DNA suggests similar antibacterial origins as have been proposed for lupus auto-antibodies. In the absence of overt infection they might reflect a breakdown of tolerance for non-organ specific membrane antigens in diseases with predominantly organ specific membrane bound putative autoimmunogens.

Cultures of thymic tissue or thymic lymphocytes from nine patients undergoing thymectomy for myasthenia gravis were examined for evidence of anti-acetylcholine-receptor-antibody synthesis. One of four thymic tissues and three of five thymic lymphocyte preparations synthesised this antibody.