Effects of salmeterol on mucosal inflammation in asthma: a placebo-controlled study.

Although the anti-inflammatory effects of inhaled corticosteroids in the treatment of asthma are established, the effects of long-acting beta2-adrenergic receptor agonists on inflammation are the subject of debate. The aim of the present study was to determine the effect of salmeterol on the numbers of inflammatory cells in biopsy samples of distinct immunophenotype and those expressing the genes for interleukin-4 and -5, regulatory cytokines particularly relevant to asthma. Twenty patients (aged 18-55 yrs) with mild stable asthma were randomised in a three-way crossover study to 6 weeks of treatment with: 1) salmeterol (50 microg b.d.; SM50); 2) fluticasone propionate (250 microg b.d.; FP250), or 3) placebo. Compared with placebo, SM50 significantly reduced the numbers of neutrophils in bronchial biopsy samples and the concentrations of myeloperoxidase and soluble E-selectin in serum, each of which reflect neutrophil involvement. Compared with FP250, SM50 reduced neutrophil number and human neutrophil lipocalin level in bronchial lavage fluid and intercellular adhesion molecule-1 level in bronchoalveolar lavage fluid. Compared with placebo, FP250 significantly reduced the numbers of (CD3+) T-lymphocytes, (CD4+) T-helper cells, (CD45RO+) activated T-helper cells and eosinophils in the biopsy samples; it also reduced the percentage of eosinophils and soluble intercellular adhesion molecule-1 in serum. The percentage of symptom-free days and nights and airways hyperresponsiveness improved significantly after SM50 compared to both placebo and FP250. In conclusion, a novel antineutrophilic effect of the inhaled long-acting beta2-adrenergic receptor agonist, salmeterol, in mild asthma is reported.

Endoscopic ultrasound guided biopsy of mediastinal lesions has a major impact on patient management.

BACKGROUND: A study was undertaken to evaluate the clinical impact of endoscopic ultrasound guided fine needle aspiration biopsy (EUS-FNA) in patients with mediastinal masses suspected of malignancy. METHODS: From April 1993 to December 1999, 84 patients were referred for EUS-FNA. In all patients CT scanning had shown a lesion of the mediastinum suspected of malignancy located adjacent to the oesophagus. In order to evaluate the clinical impact of EUS-FNA, the history of each patient up to referral for EUS-FNA was reviewed. A board of thoracic specialists was asked to decide the further course of the patient if EUS-FNA had not been available, and this diagnostic strategy was compared with the actual clinical course after EUS-FNA. RESULTS: For the 79 patients in whom sufficient verification was obtained, EUS-FNA had a sensitivity of 92%, specificity of 100%, PPV of 100%, NPV of 80%, and an accuracy of 94% for cancer of the mediastinum. In 18 of 37 patients (49%) a thoracotomy/thoracoscopy was avoided as a result of EUS-FNA, and in 28 of 41 patients (68%) a mediastinoscopy was avoided. The direct result of the cytological diagnosis obtained by EUS-FNA was that a final diagnosis of small cell lung cancer was made in eight patients resulting in referral for chemotherapy, and in another three patients with benign disease specific treatment could be initiated (sarcoidosis, mediastinal abscess, and leiomyoma of the oesophagus). CONCLUSIONS: EUS-FNA is a safe and sensitive minimally invasive method for evaluating patients with a solid lesion of the mediastinum suspected by CT scanning. EUS-FNA has a significant impact on patient management and should be considered for diagnosing the spread of cancer to the mediastinum in patients with lung cancer considered for surgery, as well as for the primary diagnosis of solid lesions located in the mediastinum adjacent to the oesophagus.

The anti-inflammatory profile of inhaled corticosteroids combined with salmeterol in asthmatic patients.

Inhaled corticosteroid (ICS) therapy such as fluticasone propionate (FP) is effective in moderate-to-severe asthma, but for patients on ICS who still experience symptoms, treatment guidelines recommend either increasing the dose of ICS or adding a long-acting beta2-agonist such as salmeterol or formoterol. Several studies have now shown that adding salmeterol provides greater clinical benefit than increasing the dose of ICS, raising the question of whether salmeterol has an additive or complementary anti-inflammatory effect to that of ICS. Recent studies on bronchial biopsies and bronchoalveolar lavage from asthmatic patients treated with either salmeterol. FP or placebo in addition to low-dose ICS have demonstrated that addition of salmeterol produces independent or additional reductions in several pro-inflammatory cells, cytokines and cell adhesion molecules compared with FP. Such complementary anti-inflammatory effects may explain the improved control of asthma symptoms and exacerbations observed when salmeterol is added to low-dose ICS therapy, and may help to modify the long-term sequelae of asthma. These findings also indicate, contrary to earlier speculation, that salmeterol does not have a pro-inflammatory effect or mask persistent airway inflammation. This review presents the results of recent studies and suggests possible mechanisms for the additional antiinflammatory effects of salmeterol.

A prospective evaluation of the clinical value of nation-wide DNA fingerprinting of tuberculosis isolates in Denmark.

SETTING: Denmark, a country with a low incidence of tuberculosis (TB). OBJECTIVE: To evaluate the value of the nation-wide DNA fingerprinting of Mycobacterium tuberculosis isolates performed in Denmark since 1992. DESIGN: Prospective study of consecutive patients with culture-verified TB from five large TB Departments in Denmark during a 7-month period in 1998. Results of IS6110 RFLP and spoligotyping were compared to those in the nation-wide Danish DNA-fingerprint database which covers approximately 95% of all culture-verified TB cases from 1992 onwards. Questionnaires asking about contact tracing and epidemiological links were sent to the patients' treating physicians. RESULTS: Of the 177 patients included in the study, 57 were Danes, one was from Iceland, 111 were immigrants, and eight were from Greenland. Responses to the questionnaires were obtained from 163 patients (92%). Four cases of unsuspected transmission were detected: one of nosocomial spread of TB, one of occupational acquisition of TB and two of transmission in an international school, leading to further contact tracing among 75 schoolchildren. These four cases were all the result of short-term contacts. In 22 cases, contact with one or more TB patient(s) was reported. In six of these, the DNA-fingerprint result revealed that the presumed contact could not be the source of infection, even though in two of the cases the known TB contact was from the household. CONCLUSION: Nation-wide DNA fingerprinting of TB isolates provides information that could not have been obtained otherwise, and contribute to the understanding of TB transmission in Danish society. In some cases the results lead to further contact tracing. Short-term contact can apparently result in transmission of TB.

[Autofluorescence bronchoscopy: Laser imaging fluorescence endoscope]. / Autofluorescensbronkoskopi: "Laser imaging fluorescense endoscope".

The LIFE (laser imaging fluorescence endoscope) system has been shown to increase the diagnosis of dysplasia and carcinoma in situ when used in combination with conventional bronchoscopy. A doubling to tripling of the rate of early centrally located lung cancer diagnosis is a step forward in the detection of early lung cancer. A wide spectrum of interventional procedures for endoluminal treatment of lung cancer in functionally inoperable patients makes it possible to treat this group of patients. The LIFE system works without exogenous sensitisers, with no increase in complications as compared to conventional bronchoscopy, and takes only a little longer in examination time.

Salmeterol reduces the need for inhaled corticosteroid in steroid-dependent asthmatics.

Previous results have demonstrated addition of long-acting beta2-adrenergic agonists to be beneficial in asthma patients already receiving inhaled corticosteroid. The purpose of this study was to determine, qualitatively as well as quantitatively, the steroid-sparing properties of salmeterol in stable asthma patients receiving maintenance inhaled corticosteroids (800-1600 microg day(-1)). In these patients, the daily dose of beclomethasone dipropionate was reduced by 200 microg each week until asthma deteriorated, with the minimal acceptable dose (MAD) being defined as the dose one step above deterioration (sensitivity period). Following this, patients received three times the MAD for 2 weeks. Patients were randomized to receive either salmeterol 50 microg twice daily or placebo and the MAD was again determined (treatment period). Forced expiratory volume in 1 sec (FEV1) was measured each week. Morning and evening peak expiratory flow (PEF), symptom score and use of bronchodilator were recorded each day. Fifteen patients received salmeterol and 19 placebo. The MAD was significantly lower in the salmeterol group compared with placebo during the treatment period (P<0.01). A 50% reduction of the MAD was achieved by more patients treated with salmeterol than placebo (P = 0.001). Salmeterol caused a significantly greater reduction in daytime symptom score and use of as-needed beta2-agoinist therapy between sensitivity and treatment periods compared with placebo (P<0.05 for both). The results demonstrate, that the addition of salmeterol to corticosteroid treatment offers a clinically relevant potential for reduction of inhaled corticosteroid dose in steroid sensitive asthmatics.

Treatment of malignant pleural effusion: pleurodesis using a small percutaneous catheter. A prospective randomized study.

The aim of this prospective, randomized study was to investigate the possibility of performing pleurodesis using a small percutaneous catheter (Cystofix catheter, CH10, 65 cm) inserted at bedside in patients with recurrent malignant pleural effusion and to compare this catheter with a conventional large bore chest tube (CH24) placed in connection with diagnostic thoracoscopy. After drainage pleurodesis was performed with tetracycline as sclerosing agent. Of 18 evaluable consecutive patients (mean age 67.8 years) nine were randomized for pleurodesis with the small and nine for the large catheter. In the former group, the majority (seven of nine) did not find insertion of the catheter more unpleasant than thoracentesis. In the latter group only a few (two of nine) found insertion comparable with thoracentesis (P < 0.05). All patients found the presence of the large catheter very or somewhat unpleasant (two and seven patients), whereas this was only the case for a few (no and two patients) treated with the small catheter (P < 0.05). In the former group three patients required new thoracentesis, whereas this was only the case for two patients in the latter group (P > 0.05). No complications were seen. We conclude that pleurodesis in patients with recurrent malignant pleural effusion can be performed with a small percutaneous catheter (Cystofix) with an effect similar to that obtained with a large-bore chest tube and with less discomfort for the patient.

Medical thoracoscopy, results and complications in 146 patients: a retrospective study.

In a retrospective study the results of medical thoracoscopy in 147 patients were reviewed; 136 of the patients had pleural effusion and 11 patients had diffuse pulmonary infiltration. All the pleural exudates were initially screened three times successively and found to be sterile and without tumour cells. All thoracoscopies were performed with local anaesthesia, with the 'open technique', and nine different doctors performed the thoracoscopies. The overall diagnostic sensitivity was 90.4%. The results demonstrated 62% with malignancy of the pleura, and 38% revealed benign pleural diseases, among them 2% with tuberculosis. The sensitivity for malignancy was found to be 88% and the specificity 96%. The most common primary lung cancer with involvement of the pleura was the adenocarcinoma (62%), and the most common metastatic tumour originated from the breast (28%). The sensitivity for tuberculosis was 100% and the specificity 100%. No mortality was found, and the morbidity was low at about 0.6% (empyema, pleuro-cutaneous fistula, transcutaneous growth of tumour (mesothelioma)). In 64% of the patients the thoracoscopy resulted in treatment (pleurodesis, antituberculous treatment, chemotherapy and peroral steroid therapy). The medical diagnostic thoracoscopy in local anaesthesia is a simple, low-cost investigation with a relatively high diagnostic accuracy, no mortality and a low morbidity.

Artificial pneumothorax by the Veress cannula: efficacy and safety.

In 16 patients with pulmonary fibrosis, an artificial pneumothorax was introduced using the Veress cannula and the Saugman water manometer. Atmospheric air was introduced by fractionated insufflation to a total volume of 800 ml (median). The interpleural space was found on the first attempt, and in all cases, fractionated insufflation of atmospheric air was conducted while the intrapleural pressure was controlled with the water manometer. In one case, the procedure was stopped because of a rise in the pleural pressure after insufflation of only 50 ml air. This was undoubtedly caused by pleural adhesions not visible on chest X-ray. The main concern with air insufflation is air embolism but this was not observed clinically in any of the present cases. The patients in the present study all suffered from pulmonary fibrosis judged by clinical examination, chest X-ray and pulmonary function tests. Despite a diffusion capacity (DCO/VA) with a median value of 48% expected, the procedure was well tolerated. It has previously been shown that artificial pneumothorax preceding thoracoscopy is well tolerated due to hyperventilation, with an increase in respiratory frequency and a fall in arterial CO2 concentration (PaCO2), while pH and arterial O2 concentration (PO2) remain constant. This probably also explains the tolerance of the patients in this material. Insufflation of air as described here should be restricted to senior pulmonologists because it is an infrequent procedure. The present authors found the procedure to be uncomplicated and easy to perform with little discomfort to the patients.

[Formoterol as inhalation powder in the treatment of patients with reversible obstructive lung diseases. A 3-month placebo-controlled comparison of the effects of formoterol and salbutamol, followed by a 12-month period with formoterol alone]. / Formoterolinhalationspulver til behandling af patienter med reversibel obstruktiv lungesygdom. En tremåneders placebokontrolleret sammenligning af effekten af formoterol og salbutamol, efterfulgt af en 12-måneders opfølgningsperiode med formoterol alene.

This article is based on a study first published in Allergy. The bronchodilating effect of the long acting beta 2-agonist formoterol dey powder (dp) 12 micrograms twice daily was compared to salbutamol 400 micrograms four times daily and placebo in patients with reversible obstructive airway disease. The study design consisted of a closed 12-week double-blind, placebo-controlled, multicentre trial followed by an open noncomparative, multicentre 12-month follow-up trial, in which tolerability of formoterol dp was assessed. A total of 304 patients aged 18-79 years were randomized. The bronchodilating effect of formoterol, assessed by morning premedication peak flow rate, was significantly superior to placebo (p < 0.0001) and salbutamol (p < 0.001). Efficacy was maintained during the open follow-up study. Formoterol 12 micrograms twice daily significantly reduced morning and evening asthma symptoms and sleep disturbances, and significantly reduced the need for rescue medication. In conclusion, formoterol 12 micrograms dp twice daily was significantly superior to both salbutamol 400 micrograms dp four times daily and placebo, and reduced asthma symptoms significantly. Overall, formoterol showed a tolerability profile comparable to that of salbutamol, and no tachyphylaxis was observed during one year of treatment.

[Diagnostic invasive procedures in the diagnosis of primary lung cancer. Diagnostic value and complications]. / Diagnostiske invasive undersøgelser ved primaer lungecancer. Diagnostisk voerdi og komplikationer.

The invasive procedures used in the diagnosis of primary lung cancer are reviewed based on the literature. The choice of method should be related to its diagnostic accuracy, complications and cost. The chest x-ray provides the background for the further choice of diagnostic method. In central tumors, bronchoscopy meets the requirements and in peripheral lesions percutaneous transthoracic needle biopsy fulfils the conditions. In some centres, mediastinoscopy is preferred in all cases preoperatively, while others only perform this examination if a CT-scan shows mediastinal lymph nodes larger than 1 cm in diameter. If the latter procedure is followed, 10-30% of the patients will have lymph node metastases. Thoracoscopy is used when a pleural effusion remains undiagnosed after pleuracentesis. A considerable amount of patients will be shown to have pleural neoplastic spread even though cytological examination of the pleural fluid did not demonstrate malignant cells. The complication rates in all methods are low.

Effect of addition of inhaled salmeterol to the treatment of moderate-to-severe asthmatics uncontrolled on high-dose inhaled steroids. European Respiratory Study Group.

The aim of this study was to assess the efficacy and safety of inhaled salmeterol 100 micrograms b.d. (SM) versus inhaled salbutamol 400 micrograms q.d.s. (SB), both via the Diskhaler, when added to concurrent treatment, in asthmatic patients who were not controlled on high doses of inhaled steroids (> or = 1,500 micrograms beclomethasone dipropionate (BDP) or equivalent daily). This was a multicentre, parallel group, double-blind study in which 190 patients with a forced expiratory volume in one second (FEV1) or peak expiratory flow rate (PEFR) of 30-75% predicted and 15% reversibility to inhaled bronchodilator were randomized to treatment for 6 weeks. In the SM group, morning PEFR increased from 281 to 315 L-min-1 during treatment and in the SB group from 311 to 315 L.min-1 (p < 0.001). The SM group showed significantly better reduction in diurnal variation, from 39 to 22 L.min-1 during treatment, than the SB group (34 to 37 L.min-1) (p < 0.001). There was a significantly greater improvement in FEV1 in the SM group (from 1.63 to 1.85 L) than in the SB group (from 1.79 to 1.84 L). The SM group had significantly more symptom-free nights than the SB group (p < 0.001), and also more "rescue-free" nights (p = 0.04). The adverse event profile was similar in both groups. This study indicates that in asthmatic patients, not controlled on high-dose inhaled steroids, inhaled salmeterol 100 micrograms b.d. significantly improves lung function and reduces asthma symptoms.

Classification of pulmonary lesions into central and peripheral with a template applied on chest X-ray.

To facilitate the understanding of the anatomical localization of pulmonary lesions and to optimize diagnostic evaluation, a template was designed which, on conventional chest X-rays, could be employed to discriminate between central and peripheral pulmonary lesions. The term 'central' implies that the lesion should be visible in the tracheobronchial tree through a fibre-optic bronchoscope, and the term 'peripheral' suggests that the lesion is not visible through a bronchoscope. In 20 patients examined by fibre-optic bronchoscopy, the bronchoscope was wedged into four pre-selected segmental bronchi in each lung. Using fluoroscopy, the tip of the bronchoscope was marked out on the skin with leadshot. On subsequent chest X-rays, with posterior-anterior and right lateral views, the distances and angles of the markings of the bronchi were mapped out in relation to the main carina. These data were used to design the template.

[DNA-fingerprinting and tuberculosis]. / DNA-fingerprinting og tuberkulose.

DNA-fingerprinting or RFLP (Restriction Fragment Length Polymorphism) is a molecular biological technique which allows differentiation between tuberculosis strains. The technique is based on the occurrence of repetitive elements in the mycobacterial genome and is a powerful tool in epidemiological studies. DNA-fingerprinting is also of value in tracking the spread of infection in patients with tuberculosis. The latter is illustrated in two case stories.

[Percutaneous transthoracic needle aspiration biopsy. Diagnostic yield after negative fiberoptic bronchoscopy in patients with peripheral pulmonary infiltrations]. / Perkutan transtorakal nåleaspirationsbiopsi. Diagnostisk udbytte efter negativ fiberbronkoskopi hos patienter med perifert beliggende lungeinfiltrater.

The diagnostic potential of secondary transthoracic needle biopsy (TNB) following negative fiberoptic bronchoscopy in patients with peripheral circumscribed pulmonary lesions was evaluated in a retrospective study. The records from 224 patients who had TNB performed over a five-year period were reviewed. Of these, 103 patients met the criteria for inclusion in this series. The overall diagnostic yield of TNB in malignancy was 73.8% (54 of 73 patients). TNB allowed cytological classification of the tumour type in 72.2% (39 of 54 patients). Five of the 54 patients (9.3%) presented with small cell anaplastic bronchogenic carcinoma, diagnosed by TNB, and were treated with chemotherapy. Of the 49 patients with a negative TNB, 27 went on to diagnostic surgical procedures; 19 had malignancy, three benign tumour, two infection, and three sequelae after pulmonary infarction. The remaining 22 patients with undiagnosed lesions were followed long term, five showed progression of the pulmonary lesion suggesting malignancy. TNB appeared unsuitable in the diagnosis of benign lesions. Unspecific inflammation was not considered evidence of benignity, and therefore a definitive benign diagnosis was not made by TNB in this series. There were no serious complications to TNB. In 18.1% of the procedures a pneumothorax developed, indicating a chest tube in 8.6% of the procedures. TNB is a suitable diagnostic procedure with a high diagnostic yield in patients with peripheral, malignant pulmonary lesions.

Inhaled formoterol dry powder in the treatment of patients with reversible obstructive airway disease. A 3-month, placebo-controlled comparison of the efficacy and safety of formoterol and salbutamol, followed by a 12-month trial with formoterol.

Inhaled formoterol is a potent selective beta 2-agonist with rapid onset and at least 12-h duration of bronchodilation. The aim of the study was to compare the bronchodilating effect of inhaled formoterol dry powder (dp) 12 micrograms b.i.d. with salbutamol dp 400 micrograms q.i.d. and placebo in patients with reversible obstructive airway disease (ROAD). The study design consisted of a closed 12-week double-blind, placebo-controlled, multicenter trial followed by an open noncomparative, multicenter, 12-month follow-up trial, in which the tolerability of formoterol dp was assessed. A total of 304 patients (146 men, 158 women) aged 18-79 years, ill during 0.1-64 years, were randomized. No demographic or baseline differences were found among the different treatment groups. The bronchodilating effect of formoterol, assessed by morning premedication PEFR, was significantly superior to placebo (P < 0.0001) and salbutamol (P < 0.0001). Efficacy was maintained during the open follow-up study with 12 micrograms b.i.d. in most of the patients. A few patients, however, needed 24 micrograms b.i.d. to control their ROAD. Formoterol 12 micrograms b.i.d. significantly reduced morning and evening asthma symptoms and sleep disturbances, and reduced significantly the need for rescue medication. The tolerability of the three treatment groups was comparable. In conclusion, formoterol 12 micrograms dp b.i.d. was significantly superior to both salbutamol 400 micrograms dp q.i.d. and placebo, and reduced asthma symptoms significantly. Overall, formoterol showed a tolerability profile comparable to that of salbutamol, and no tachyphylaxis was observed during 1 year of treatment.

Diagnostic yield of transthoracic needle aspiration biopsy following negative fiberoptic bronchoscopy in 103 patients with peripheral circumscribed pulmonary lesions.

The diagnostic potential of secondary transthoracic needle biopsy (TNB) following negative fiberoptic bronchoscopy (FOB) in patients with peripheral circumscribed pulmonary lesions was evaluated in a retrospective study. The records from 224 patients who had TNB over a 5-year period were reviewed. Of these, 103 patients met the criteria for inclusion in this series. The overall diagnostic yield of TNB in malignancy was 73.8% (54 of 73 patients). TNB allowed cytologic classification of the tumor type in 72.2% (39 of the 54 patients). Five of the 54 patients (9.3%) presented with small-cell anaplastic bronchogenic carcinoma, diagnosed at TNB, and were referred to chemotherapy. Of the 49 patients with a negative TNB, 27 went on to diagnostic surgical procedures; 19 had malignancy, 3 benign tumor, 2 infection, and 3 sequelae after pulmonary infarction. The remaining 22 undiagnosed patients were followed up over a long period of time, 5 showed progression of the pulmonary lesion suggesting malignancy. TNB appeared unsuitable for the diagnosis of benign lesions. Unspecific inflammation was not considered evidence of benignity, and therefore no definitive benign diagnosis was made by TNB in this series. There were no serious complications to TNB. In 18.1% of the procedures a pneumothorax developed, indicating a chest tube in 8.6% of the procedures. TNB is a suitable diagnostic procedure with a high diagnostic yield in patients with peripheral localized malignant pulmonary lesions.

[Lymphangioleiomyomatosis]. / Lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a rare disease, which only affects women of childbearing age. A case of LAM in a 36-year-old woman is presented. Patho-anatomical findings are smooth muscle hyperplasia leading to obstruction of lymphatics (possibly resulting in chylothorax), blood vessels (possibly resulting in haemoptysis) and bronchi (possibly resulting in emphysema and pneumothorax). High resolution computed tomography (HRCT) of the chest can show the typical multiple small cysts and bullous emphysema distributed diffusely throughout both lungs together with interstitial fibrosis. Treatment of the disease aims at an inhibition of the presumed growth-promoting effect of oestrogen on the smooth muscle cells. However, progression is often seen in spite of treatment.

[Oxygen therapy of chronic lung disease. Testing of a chemical oxygen generator--Vitaria]. / Iltbehandling til kronisk lungesyge. Afprøvning af en kemisk iltgenerator--Vitaria.

Twenty patients (11 females, nine males, mean age: 70.6 years) with chronic obstructive pulmonary disease and hypoxaemia took part in a randomized single blinded placebo-controlled clinical trial, testing the efficacy of a new transportable oxygen delivery system (VITARIA). The system consists of a container and a sodium carbonate containing powder (75 mg). When the powder is stirred in water in the container pure oxygen with a max flow of 1 l/min is delivered over a period of approximately 15 minutes. All patients had been receiving home oxygen treatment of at least 0.5 l/min for at least one month. Their baseline oxygen levels in arterial blood were mean 7.66 kPa, with a mean oxygen response to 0.5 l/min of oxygen of 2.54 kPa. In the placebo group no oxygen responses were seen, while in the Vitaria group a small but insignificant rise in arterial PaO2 was seen. No side effects were seen. In conclusion we find the system handy and easy to use but the recommended dose of powder is insufficient.