Laryngeal aspergillosis following high dose inhaled fluticasone therapy for asthma.

The case history is presented of a 75 year old man with chronic asthma who was treated with inhaled fluticasone propionate in a daily dose of 2 mg using a Diskhaler. After three years of treatment he developed progressive hoarseness. Both vocal cords were colonised by Aspergillus fumigatus which formed a white slough on the surface. Biopsy specimens showed changes suggestive of laryngeal aspergillosis with an ulcerated epithelium, fibrinopurulent debris, and colonies of fungal hyphae. A slow recovery occurred after three months of treatment with topical amphotericin and with cessation of inhaled corticosteroids. Laryngoscopy is recommended if hoarseness occurs during treatment with fluticasone.

Effect of a novel potent platelet-activating factor antagonist, modipafant, in clinical asthma.

Platelet-activating factor (PAF), proposed as an important inflammatory mediator in asthma, reproduces several of the features of asthma, such as microvascular leakage, mucus secretion, bronchoconstriction, and possibly increased airway responsiveness. Modipafant (UK-80,067) is the (+)-enantiomer of UK-74,505, a potent and specific PAF antagonist. We have assessed the effect of modipafant over 28 d in adult subjects with moderately severe asthma in a placebo-controlled parallel group study. A total of 218 patients with asthma were enrolled into the single-blind run-in, of whom 120 (93 males and 27 females, mean age 41.0 yr) entered the double-blind treatment phase after demonstrating symptomatic asthma in the final week of the single-blind run-in phase. Patients could take up to 1600 micrograms inhaled corticosteroid and an inhaled beta 2 agonist as rescue medication. A total of 59 patients with asthma took modipafant (one 50 mg capsule twice daily), and 61 took matched placebo. There was no significant difference between placebo and modipafant in diurnal variation in PEF, morning and evening PEF, clinic FEV1, rescue bronchodilator usage, symptom score, or airway responsiveness. We previously showed that the racemate UK-74,505 had no effect on antigen challenge, and this study shows that the active (+)-enantiomer modipafant has no effect in chronic asthma. This suggests that PAF is not an important mediator in asthma.

Development of an accurate portable recording peak-flow meter for the diagnosis of asthma.

This article describes the systematic design of an electronic recording peak expiratory flow (PEF) meter to provide accurate data for the diagnosis of occupational asthma. Traditional diagnosis of asthma relies on accurate data of PEF tests performed by the patients in their own homes and places of work. Unfortunately there are high error rates in data produced and recorded by the patient, most of these are transcription errors and some patients falsify their records. The PEF measurement itself is not effort independent, the data produced depending on the way in which the patient performs the test. Patients are taught how to perform the test giving maximal effort to the expiration being measured. If the measurement is performed incorrectly then errors will occur. Accurate data can be produced if an electronically recording PEF instrument is developed, thus freeing the patient from the task of recording the test data. It should also be capable of determining whether the PEF measurement has been correctly performed. A requirement specification for a recording PEF meter was produced. A commercially available electronic PEF meter was modified to provide the functions required for accurate serial recording of the measurements produced by the patients. This is now being used in three hospitals in the West Midlands for investigations into the diagnosis of occupational asthma. In investigating current methods of measuring PEF and other pulmonary quantities a greater understanding was obtained of the limitations of current methods of measurement, and quantities being measured.(ABSTRACT TRUNCATED AT 250 WORDS)

Controlled-release theophylline in the treatment of nocturnal asthma.

A total of 104 asthmatic patients with symptoms of asthma and/or a 'morning dip' in the peak expiratory flow rate (PEFR) who were receiving multiple therapies, including inhaled or oral steroids, were treated in addition once nightly with controlled-release theophylline in an 8-week double-blind, placebo-controlled cross-over study. Theophylline produced an improvement in symptoms of cough, wheeze, sleep disturbance and PEFR in the 73 completing patients compared to run-in and placebo treatment. Theophylline also produced an improvement in the forced expiratory volume in 1 s and forced vital capacity relative to baseline, and in the difference between actual and predicted PEFR values. Nausea was the most frequent side-effect but both patients' and investigator's global impressions of the effect of study medication were in favour of theophylline.

A double-blind group comparative trial of nedocromil sodium and placebo in the management of bronchial asthma.

A 3-month double-blind group comparative trial of nedocromil sodium (4 mg twice daily) and placebo was carried out in 30 adult asthmatic patients maintained on bronchodilator therapy. Fifteen patients received each treatment. Subjective (asthma symptoms and severity) and objective (lung function and use of concomitant medication) variables were measured to monitor the response to trial treatments. Significant differences in favour of nedocromil sodium for night-time asthma, daytime asthma, cough, daytime bronchodilator use and clinic assessment of forced expiratory volume during the first second of expiration were observed by week 4 of the trial. The diurnal variation in peak expiratory flow rate was reduced in the nedocromil sodium treated patients. There were no serious adverse reactions and no treatment related changes in haematological findings, blood biochemistry or urinalysis.

Chylothorax: a review of 18 cases.

Eighteen patients who had developed a chylothorax during a 25 year period, 1955-80, were reviewed. The chylothoraces occurred as a complication of cardiothoracic surgery in 11 patients, of whom eight were children in the first decade of life. Five cases followed operations for coarctation of the aorta and two occurred as a complication of a Blalock shunt for Fallot's tetralogy. The chylothorax was evident within 48 hours of the operation in all but two patients. In seven cases a second operation was performed to prevent further chylous leakage and in two infants the thoracic duct was ligated. The remainder of the postsurgical chylothoraces responded to either continuous drainage or repeated aspiration and a low fat diet. There were no late sequelae of chylothorax following surgery. Spontaneous chylothorax was identified in seven patients and in five of these it was bilateral. Patients with spontaneous chylothorax were all adults and, despite treatment, had a poor prognosis. Three with malignant disease and two with pulmonary lymphangioleiomyomatosis had died within two years of the appearance of the chylothorax. Two patients with chronic idiopathic chylothoraces survived for more than two years and one of these developed a secondary fibrothorax.

Effect of danazol on the biochemical abnormality of inherited antithrombin III deficiency.

Seven members of a family affected by hereditary antithrombin III deficiency were identified. The disorder was associated with recurrent spontaneous episodes of phlebitis, deep venous thrombosis, and pulmonary embolism in middle age. Danazol, a 17-alkyl derivative of ethinyl testosterone, which has been used to treat other antiprotease deficiency states, was assessed in the management of two men with antithrombin deficiency. In a dose of 600 mg a day danazol appeared to correct the antithrombin deficiency. This drug may provide a useful adjunct to anticoagulant treatment, particularly before surgery.

Inhaled lodoxamide tromethamine in the treatment of perennial asthma: a double-blind placebo-controlled study.

The efficacy of lodoxamide tromethamine in the treatment of asthma was studied in a 16-week double-blind, placebo-controlled study of 68 perennial allergic subjects with asthma. Patients received either lodoxamide tromethamine, 0.25 mg four times daily, or placebo, administered by metered-dose inhaler. Response to treatment was assessed by analyzing changes in asthma symptoms, inhaled bronchodilator requirements, and pulmonary function when compared to a 2-week baseline period. Patients treated with lodoxamide tromethamine demonstrated an improvement in daytime breathing difficulty, cough, sputum production, and sleep (p less than 0.01 to 0.05), but improvement was not significantly different from that demonstrated by placebo-treated patients. Patients from both treatment groups were able to reduce their inhaled bronchodilators (p less than 0.01), but again no significant difference was apparent between lodoxamide tromethamine and placebo treatment, nor were there any differences in peak expiratory flow rate or FEV1 between the two groups. Seven patients who received lodoxamide tromethamine withdrew because of a sensation of heat and gastrointestinal symptoms. Thus, although lodoxamide tromethamine possesses potent mast cell-stabilizing activity in vitro, we have failed to demonstrate any useful long-term effect in the treatment of mild allergic asthma.

Comparison between the effects of inhaled isoprenaline and fenoterol on plasma cyclic AMP and heart rate in normal subjects.

The time course of changes in plasma cyclic AMP, heart rate and bronchial tone after inhalation of fenoterol or isoprenaline from a dose-metered aerosol are reported in a group of normal subjects. After isoprenaline, plasma cyclic AMP increased rapidly reaching a peak by 10 min and returned to basal levels within 60 min. A rapid, transient rise in heart rate occurred that was maximal by 5 min and returned to a basal level by 45 min. After fenoterol, the changes in cyclic AMP and heart rate were of much longer duration. The rise in plasma cyclic AMP was slower in onset and of greater magnitude than for isoprenaline, reaching a peak by 20 min and remaining above basal level for more than 6 h. The maximum increase in heart rate after fenoterol was less than that observed with isoprenaline but an elevated rate persisted for 4 h after inhalation of fenoterol. Fenoterol is known to have a longer duration of action as a bronchodilator in comparison with isoprenaline. The prolonged rise in plasma cyclic AMP in normal subjects given inhaled fenoterol may reflect this long duration of action. The concomitant rise in heart rate, however, suggests that the duration of plasma cyclic AMP response may in part be due to the systemic effect of the fraction of inhaled fenoterol known to be absorbed via the buccal and intestinal routes.

The late reaction following bronchial provocation with house dust mite allergen. Dependence on arachidonic acid metabolism.

The involvement of arachidonic acid metabolism in early and late bronchial reactions has been studied in four asthmatic subjects sensitive to Dermatophagoides pteronyssinus. Pre-treatment with either indomethacin (an inhibitor of the cyclo-oxygenase pathway) or benoxaprofen (an inhibitor of both cyclo-oxygenase and lipoxygenase pathways) failed to affect the amplitude, but did produce some foreshortening of the early response to allergen. If benoxaprofen is an effective inhibitor of SRS-A formation in vivo, then these observations question the role of SRS-A as a spasmogen in allergen-induced bronchospasm. Both drugs were effective inhibitors of the late reaction, implying involvement of cyclo-oxygenase products (endoperoxides, prostaglandins or thromboxanes) in the genesis of a late response to allergen.

Chronic upper airway obstruction: value of the flow volume loop examination in assessment and management.

Chronic obstructive lesions of the upper airways such as post-traumatic strictures, bilateral vocal cord paralysis and chronic inflammatory foci are uncommon. The functional assessment of the severity and character of an obstruction is important both for diagnosis and management, and may also allow evaluation of the efficacy of medical and surgical treatment. There are limitations of simple spirometric pulmonary function tests, which are evident when assessing upper airways obstruction. The flow volume loop is a graphic recording of airflow during maximal respiration and expiration at different lung volumes, and may be affected in a characteristic way by alterations in the airway resistance. Three unusual cases of chronic upper airway obstruction are presented which illustrate the value of the flow volume loop examination in their management.

Inhibition of the late asthmatic response to house dust mite by non-steroidal anti-inflammatory drugs.

Bronchial provocation with house dust mite allergen in subjects allergic asthma may be followed by an early and a delayed phase of bronchospasm. The latter can be prevented by DSCG or by corticosteroids. A representative subject was studied to determine the effect of non-steroidal anti-inflammatory drugs (NSAIDs) on the late reaction. Indomethacin, benoxaprofen or acetylsalicylic acid given before allergen exposure inhibited the delayed bronchospasm. Sodium salicylate was ineffective, as were indomethacin or benoxaprofen when given after the early phase of bronchospasm. The mechanism of action of these compounds was thought to be by inhibition of arachidonic acid metabolism via the cyclo-oxygenase pathway and this appears to be a pre-requisite for the appearance of a late reaction following house dust mite inhalation.

Pulmonary disorders associated with Sjögren's syndrome.

Pulmonary disease is recognized to occur as a complication of Sjögren's syndrome and we have studied 17 patients, the majority middle-aged women, with this association. Eight had sicca syndrome alone and nine had Sjören's syndrome in association with a connective tissue disease. Various pulmonary disorders were found: 10 had diseases mainly affecting pulmonary parenchyma (recurrent pneumonia, granulomatous infiltration, pseudolymphoma and fibrosing alveolitis) and six had disorders of the airways (bronchitis, bronchiectasis and asthma). One patient presented with a mediastinal immunoblastic lymphoma. To test the hypothesis that physical factors such as the retention of viscid mucus may play a part in the development of lung disease in Sjögren's syndrome, we have measured mucociliary clearance in patients with Sjögren's syndrome using 99Tc-labelled polystyrene particles. The mucociliary clearance rate was found to be normal from central airways and the whole lung clearance rate was significantly increased in Sjögren's syndrome compared with normal controls. The latter was attributed to the failure of penetrance of the radioaerosol into the periphery of the lung consistent with obstruction of small airways in Sjögren's syndrome. The patients with Sjögen's syndrome and lung disease were characterized by a number of immunological markers irrespective of the presence or type of associated connective tissue disorder. The commonest found were speckled antinuclear antibody by indirect immunofluorescence, antibodies to the acidic nuclear antigen B by counterimmunoelectrophoresis, increased serum DNA binding, increased levels of circulating immunoglubulins, rheumatoid factor in high titre and circulating soluble immune complexes as detected by Clq binding assay.

A pathological study following bronchial artery embolization for haemoptysis in cystic fibrosis.

A detailed post-mortem study is reported on an adult with cystic fibrosis who died in respiratory failure three weeks after selective bronchial artery embolization with gelatin sponge to treat severe haemoptysis. Bronchial arteriography during the procedure showed complete occlusion of the vessel supplying the righ upper lobe and following this the bleeding stopped. However, post-mortem angiography of the same vessel demonstrated disappearance of much of the injected material with contrast bypassing the remaining gelatin to fill the peripheral bronchial arterial bed. This report therefore adds pathological evidence to previous clinical reports which have suggested that this procedure may not produce permanent occlusion of the embolised bronchial artery.

Slow-release oral salbutamol and aminophylline in nocturnal asthma: relation of overnight changes in lung function and plasma drug levels.

In a double-blind controlled trial 14 chronic asthmatic patients with regular nocturnal exacerbations took 16 mg slow-release oral salbutamol (two Ventolin spandets), 450 mg slow-release aminophylline (two Phyllocontin Continus tablets), or placebo at midnight. Mean peak expiratory flow rates on waking were significantly higher on the active drugs than on placebo (p < 0.01 for salbutamol; p < 0.05 for aminophylline) but neither drug abolished the overnight fall in PEFR. Plasma drug levels at 0600 hr were 17.3 ng/ml (+/- 5.3 ng/ml SD) for salbutamol, and 7.1 micrograms/ml (+/- 3.1 micrograms/ml SD) for theophylline. Steady-state derived from plasma levels of salbutamol during intravenous infusion indicated that the morning salbutamol levels were probably in a therapeutic range for asthma. The morning theophylline levels, however, were suboptimal when aminophylline was given only at night.