Results of endoscopic surgery and intralesional steroid therapy for airway compromise due to tracheobronchial Wegener's granulomatosis.

BACKGROUND: Upper airway compromise due to tracheobronchial stenosis commonly occurs in patients with Wegener's granulomatosis (WG). There is at present no consensus on the optimal management of this life threatening condition. OBJECTIVE: To assess the results of laryngo-tracheo-bronchoscopy, intralesional steroid therapy, laser surgery and dilatation in managing obstructive tracheobronchial WG. METHODS: Records of 18 previously untreated stridulous patients with obstructive tracheobronchial WG, treated between 2004 and 2006, were prospectively recorded on an airway database and retrospectively reviewed. Information about patient and lesion characteristics and treatment details were recorded. Treatment progress was illustrated using a timeline plot, and intervention-free intervals were calculated with actuarial analysis. RESULTS: There were nine males and the average age at presentation was 40 (16) years (range 13-74). There were 13 patients with tracheal and five with tracheal and bronchial lesions. The average tracheal lesion height was 8 (3) mm, located 23 (9) mm below the glottis. There were 1, 10 and 7 Myer-Cotton grade I, II and III lesions, respectively. Mean intervention-free interval following minimally invasive treatment was 26 (2.8) months. Following endobronchial therapy, the median intervention-free interval was 22 months (p>0.8 vs tracheal lesions). No patient required a tracheostomy or endoluminal stenting. CONCLUSIONS: Intralesional steroid therapy and conservative endoluminal surgery is an effective strategy for treating airway compromise due to active tracheal and bronchial WG, obviating the need for airway bypass or stenting. We recommend the combination of endotracheal dilatation, conservative laser surgery and steroid therapy as the standard of care for treating airway compromise due to obstructive tracheobronchial WG.

Dendritic cells from control but not atopic donors respond to contact and respiratory sensitizer treatment in vitro with differential cytokine production and altered stimulatory capacity.

BACKGROUND: Chemical haptens induce both contact and allergic respiratory disease with dendritic cells (DCs) controlling and directing immune responses in vivo. Contact and respiratory haptens may promote differential cytokine production yet distinguishing these effects in vitro remains difficult due to human donor variability. Objective We sought to determine the effect of atopic status on the ability of DC to respond to contact and respiratory sensitizer treatment in vitro as DC from atopic donors are believed to promote Th2-type responses. METHODS: Enriched DC from control or atopic donors were treated for 4 h with levels of the contact sensitizer 2,4-dinitrochlorobenzene (DNCB) or the respiratory sensitizer trimellitic anhydride (TMA) that did not reduce cell viability. A sensitive intracellular detection technique was used to measure cytokine production, while T cell responses were assessed in a mixed leucocyte reaction. RESULTS: DC from control, non-atopic, donors produced cytokines differentially in response to sensitizer treatment; DNCB treatment significantly increased the production of Th1 cytokines IL-12 and IFN-gamma while TMA induced the production of IL-13. Control donor DC treated with TMA stimulated less in a mixed leucocyte reaction than untreated cells with any response reduced further by blocking IL-13 in culture. However, DC from atopic donors showed no significant alteration in either cytokine production or T cell stimulatory capacity after sensitizer treatment. CONCLUSION: Haptens modulate DC by changing the production of cytokines that may play a role in T cell stimulation and subsequent polarization of the immune response. DC from atopic donors were unresponsive to chemical sensitizer treatment, and may be deficient in inducing divergent T cell responses.

Concurrent therapy (long acting beta agonists and inhaled corticosteroids) in the management of asthma.

BACKGROUND: Asthma is a clinical syndrome characterised by chronic inflammation of the lower respiratory tract in which many cells and cellular elements play a role, in particular mast cells, eosinophils, T-lymphocytes, macrophages, neutrophils and epithelial cells. Patients often require long-term anti-inflammatory and reliever drugs to achieve a normal life. This review aims to highlight role of concurrent therapy in the optimal management of asthma. METHOD: A review of relevant literature was conducted using available medical journals and Science direct via the Internet. The key words employed were: asthma, concurrent therapy, long acting beta agonists and corticosteroids. British Thoracic Society and The National Heart, Lung and Blood Institute websites were also used in sourcing information for this review. RESULTS: Several studies support adding long acting beta agonists (LABA) to inhaled corticosteroids (ICS) than doubling the dose of ICS. This improves lung function, symptoms control and allows the dose of each drug to be adjusted to the patients'needs. CONCLUSION: This review was able to show that concurrent use LABA and ICS in asthmatics helps in adjusting their treatment within limits hence achieving control of the condition with minimal side effects.

Estimation of sympathetic activity in essential hypertension.

The estimation of sympathetic nervous activity by measurement of plasma norepinephrine (NE) concentration assumes a constant relation between this and the synaptic cleft concentration. This assumption would be incorrect if the clearance of plasma NE could be varied without affecting its removal from the synaptic cleft, so we compared the clearance of plasma NE in mild hypertensives and normal subjects by measurement of its plasma concentration during a 0.5-hr infusion at 0.07 microgram/kg/min; there were no differences. The simultaneous infusion of isoproterenol, 0.02 microgram/kg/min, led to an increase in heart rate and NE clearance. There was partial inhibition of catechol-O-methyltransferase by a single oral dose of alpha-methyldopa, 250 mg, which reduced the clearance of both catecholamines (CAs) by about 20%. After the end of the infusions containing isoproterenol, the tachycardia persisted for more than 1 hr and declined more slowly in the hypertensives than the normals. In contrast, plasma concentrations of both CAs returned to basal values within a few minutes. The persistent tachycardia may be due to rerelease of isoproterenol into the synaptic cleft, since stimulation of sympathetic activity by assumption of the erect posture was associated with an exaggerated increase in heart rate (by 48/min after infusion and 23/min before infusion). The study therefore suggests that synaptic cleft and plasma CA concentrations can be independently manipulated and the relation between them may be different in hypertensive patients and normal control subjects.

Intrahepatic kinetics of indium-111-labelled platelets.

The intrahepatic kinetics of 111indium-labelled platelets have been studied using dynamic gamma camera scintigraphy immediately following injection. Platelets labelled in saline with 111In-oxine or 111In-acetylacetonate underwent rapidly reversible hepatic sequestration, indicating that they were "activated". Platelets labelled in plasma with 111In-tropolonate, however, did not display this phenomenon. On the assumption that plasma-labelled platelets display a normal initial bio-distribution, mean intrahepatic platelet transit time, as a factor of the transit time of 99m-Tc labelled red cells, was 1.45 +/- SE 0.12 (n = 6), implying the normal presence of a small intrahepatic platelet pool. Unlike the liver, transit through the spleen was not sensitive to the labelling medium; thus the mean intrasplenic transit time of plasma-labelled platelets was 9.3 +/- SE 0.7 min (n = 10), and of saline-labelled platelets 9.5 +/- SE 0.3 min (n = 8).

Increased concentrations of cyclic 3',5'-adenosine monophosphate without a physiological response after antidiuretic hormone.

Treatment of the serosal surface of the isolated bladders of toads (Bufo marinus) with phospholipase C inhibited the hydro-osmotic response to ADH, but did not prevent the rise in cyclic AMP concentrations associated with hormone action.

Histamine is released from skin by substance P but does not act as the final vasodilator in the axon reflex.

We have explored in man the hypothesis that histamine released from dermal mast cells by neurotransmitters from afferent nerves contributes to vasodilatation of the axon reflex. The ability of substance P to release histamine from human skin in vivo, and the effects of a histamine H1-receptor antagonist on capsaicin-induced axon reflex flares were studied. Intradermal injections of substance P (50 pmol) produced a weal and flare response which was associated with increased histamine concentration in blood draining the site (mean plasma histamine concentration before injection 0.17 +/- 0.02 ng ml-1 (+/- s.e.mean), concentration one minute after injection 1.26 +/- 0.28 ng ml-1, n = 6). Terfenadine, an H1-receptor antagonist, had no effect on the flare response to intradermal injection of capsaicin at a dose which inhibited by more than 60% the flare response to exogenous histamine and to histamine released from dermal mast cells by substance P. Substance P releases histamine from human skin in vivo. However, whatever the nature of the neurotransmitter released from afferent nerves during the axon reflex, it does not produce vasodilatation through release of histamine from dermal mast cells. Histamine may still contribute to the flare by initiation of the reflex.

In vivo quantification of pulmonary beta-adrenoceptor density in humans with (S)-[11C]CGP-12177 and PET.

The in vivo regional distribution of pulmonary beta-adrenoceptors was imaged and quantified in humans with the hydrophilic beta-adrenoceptor antagonist (S)-CGP-12177 labeled with carbon-11 [(S)-[11C]CGP-12177] and positron emission tomography (PET). Six normal male volunteers and eight patients with hypertrophic cardiomyopathy were studied. PET scanning consisted of transmission (tissue density), C15O (blood volume), and (S)-[11C]CGP-12177 (beta-adrenoceptor) emission scans. High-specific-activity (S)-[11C]-CGP-12177 (7.1 +/- 2.0 micrograms, 6.5 +/- 2.1 GBq/mumol) was given intravenously followed by a low-specific-activity (S)-[11C]CGP-12177 injection (34.0 +/- 4.8 micrograms, 2.3 +/- 0.8 GBq/mumol). Binding capacity (Bmax) was calculated in each region of interest as picomoles per gram by normalizing it to the local extravascular tissue density. In normal subjects, average Bmax for all regions of interest was 14.8 +/- 1.6 (SD) pmol/g, which is similar to previously reported in vitro values. In both groups there were no differences in beta-adrenoceptor density between peripheral and central regions nor between right and left lungs. In patients with hypertrophic cardiomyopathy, extravascular tissue density was 24% higher than in normal subjects; Bmax per milliliter thoracic volume was correspondingly higher but was not different from that in normal subjects when expressed per gram tissue (15.8 +/- 2.6 pmol/g). These data suggest that in vivo beta-adrenoceptor density may be quantifiable in humans with the use of PET. This should offer a means to study physiological regulation through repeat measurements.

Heart rate response to peptide histidine valine in human subjects is not mediated through beta receptors.

Peptide histidine valine (PHV) is a 42 amino acid polypeptide closely related to the neuropeptides VIP, PHI and PHM. We have performed a placebo-controlled, double-blind study to assess the hypothesis that the cardiovascular response to PHV infusion may be mediated via the sympathetic nervous system. Four subjects received atenolol or matched placebo 90 min prior to a controlled incremental infusion of PHV, with monitoring of heart rate, blood pressure and skin temperature. Following placebo all subjects showed a dose-related increase in heart rate and skin temperature with no effect on blood pressure during PHV infusion. beta-Blockade had no effect on skin temperature response. Pre-treatment with atenolol reduced the resting blood pressure and the maximum heart rate achieved, but did not affect the percentage increase in heart rate during PHV infusion. This suggests that the action of PHV does not involve beta-receptors. The lack of effect of PHV infusion on blood pressure, despite tachycardia and marked cutaneous vasodilatation, implies that PHV has a different effect on the resistance vessels from that of other peptides such as VIP.

Anti-leukotriene intervention: is there adequate information for clinical use in asthma?

Various mediators of inflammation have been suggested as being important in the pathogenesis of asthma. These include histamine, acetylcholine, bradykinin, adenosine, prostaglandins D2 and F2 alpha, thromboxane A2, leukotrienes, PAF and, more recently, various cytokines. Intervention in the action of these mediators is proposed to offer therapeutic benefit, and recent advances in drug therapy have centred on two main approaches. Specific and potent leukotriene antagonists and inhibitors of leukotriene biosynthesis have emerged, and their effects against allergen challenge, cold-air- and exercise-induced bronchospasm and aspirin-sensitive asthma have been evaluated. A small number of studies have also been conducted in clinical asthma, with both acute and long-term (up to 20 weeks) efficacy studies being reported. A considerable degree of inter-individual variation is seen in the degree of protection afforded by leukotriene intervention. The extent to which inhibiting one set of inflammatory mediators can be expected to attenuate the asthmatic response can be questioned. As yet, there is no way of distinguishing leukotriene-related asthma from other types. It is likely, however, that leukotriene intervention may be useful in some patients with specific forms of the disease; for example, aspirin-sensitive asthma. Leukotriene intervention is unlikely to replace inhaled corticosteroids in the treatment of asthma, and its position in the guidelines for the management of asthma remain unclear thus far.

Time course of recovery of lung function in sulphasalazine-induced alveolitis.

Interstitial lung disease has long been recognized as one of the side effects of sulphonamide drugs (1) but we have found only 13 case reports of alveolitis in association with sulphasalazine (2-8). Although the clinical picture and radiological changes are known to be reversible, there is little information regarding the lung function abnormalities and no description of the time course of its recovery. We describe a patient with very severe impairment of gas exchange secondary to sulphasalazine which completely recovered after the drug was stopped.

Bronchial hyperresponsiveness in patients recovering from acute severe asthma.

Bronchial hyperresponsiveness is widely recognized as a marker of airway inflammation in asthma. The degree of bronchial hyperresponsiveness following acute severe attacks of asthma and the time course of its recovery has not previously been studied. Bronchial responsiveness to histamine was measured in 18 unselected patients admitted to hospital because of acute severe asthma, during their acute admission, and geometric mean PD20 histamine was 0.08 (range 0.02-0.32) mumol. In nine patients, further measurements were performed at 3-4 and 12 weeks following discharge. Geometric mean PD20 histamine was 0.09 mumol acutely, 0.23 mumol at 3-4 weeks (n = 9, p = 0.05 by analysis of variance) and 0.59 mumol at 12 weeks (n = 8, P = 0.04). For the eight patients studied at 12 weeks, a mean 10.3-fold increase in PD20 was shown, with no suggestion of a maximum effect having been achieved. In contrast, spirometry had returned to the normal range by 4 weeks. The dissociation between improvement in bronchial hyperresponsiveness and spirometry is of interest. The delayed reduction in hyperresponsiveness may have important clinical implications for the duration of anti-inflammatory corticosteroid treatment following acute severe asthma.

Early clinical investigation of Viozan (sibenadet HCl), a novel D2 dopamine receptor, beta2-adrenoceptor agonist for the treatment of chronic obstructive pulmonary disease symptoms.

Viozan, (Sibenadet HCl, AR-C68397AA) is a dual D2 dopamine receptor, beta2-adrenoceptor agonist that combines bronchodilator activity with the sensory afferent modulating effects associated with D2-receptor agonism. Investigation in animal models of key chronic obstructive pulmonary disease (COPD) symptoms has demonstrated that sibenadet effectively inhibits sensory nerve activity, thereby reducing reflex cough, mucus production and tachypnoea. The results of the early clinical evaluation of this novel agent are reported. An initial proof of concept study (Study 1) aimed to determine the clinical potential of this novel agent by assessing the effects of three doses of sibenadet therapy relative to placebo, with two commonly used bronchodilators, intended to provide a benchmark against which sibenadet activity could be judged. In all, 701 patients were randomized to one of three sibenadet dose groups (400, 600 or 1000 microg ex valve), salbutamol 200 microg, ipratropium bromide (IB) 40 microg or placebo, all three times daily via pressurized metered dose inhaler (pMDI) for 4 weeks. Once the results of Study 1 had been evaluated, a dose-ranging, study (Study 2) involving 872 patients randomized to receive sibenadet (45, 270, or 495 microg ex actuator), or placebo all three times daily via pMDI, for 6 weeks commenced. Both studies were preceded by a 2-week baseline phase and followed by a 2-week follow up period.The primary efficacy variable identified changes in key COPD symptoms over the treatment period (compared with baseline data) as determined by the novel Breathlessness, Cough and Sputum Scale (BCSS). In addition, data on lung function, health-related quality of life and adverse events were collected. Patients receiving sibenadet therapy three times daily exhibited statistically significantly greater improvements in BCSS total score than those receiving placebo or bronchodilator therapy alone. A clear dose-response was evident in Study 2. Symptom improvement in this study was also accompanied by improved lung function and health-related quality of life. Sibenadet therapy was well tolerated with an adverse events profile comparable to current bronchodilator therapy. These data were viewed as extremely encouraging, warranting further, large-scale clinical investigation.

Adjustable and fixed dosing with budesonide/ formoterol via a single inhaler in asthma patients: the ASSURE study.

Patient-guided management of asthma using adjustable dosing of budesonide/formoterol in a single inhaler (Symbicort) was compared with fixed dosing in an open-label, multicentre, randomised study. Patients, uncontrolled on an inhaled corticosteroid (ICS) or controlled on an ICS and a long-acting beta2-agonist, entered a 4-week run-in period and received budesonide/formoterol (80/4.5 or 160/4.5 microg), 2 inhalations b.i.d. Following randomisation, the fixed-dosing group (n = 764) continued this regimen for a further 12 weeks. The adjustable-dosing group (n = 775) could step down to 1 inhalation b.i.d. if symptoms were controlled, and, at early signs of worsening symptoms, promptly step up to 4 inhalations b.i.d. for < or = 2 weeks. During run-in, National Heart, Lung and Blood Institute symptom-severity grading was maintained in 60% and improved in 31% of patients, clinic peak flow increased from 400 to 4191/min (P<0.001), and health-related quality of life (overall MiniAQLQ) improved from 4.6 to 5.4 (P<0.001). Patients effectively used the adjustable-dosing regimen; 79% reduced budesonide/formoterol dosage and, compared with fixed dosing, the number of inhalations were significantly lowered (3.2 vs. 3.8 inhalations/day, P<0.05). Both regimens were well tolerated. In both groups, symptom control was maintained or improved in 85-86% of patients, and 94% experienced no treatment failures. Consistent with current guidelines, adjustable maintenance dosing with budesonide/formoterol in a single inhaler provides effective asthma control at reduced medication doses.

Bronchoalveolar lavage causes decrease in PaO2, increase in (A-a) gradient value and bronchoconstriction in asthmatics.

The aims of this study were to (1) record the changes of (arterial oxygen partial pressure) PaO2, (arterial carbon dioxide partial pressure) PaCO2, (percentage saturation of haemoglobin with oxygen in arterial blood) SaO2 and alveolar-arterial (A-a) oxygen gradiant resulting from bronchoalveolar lavage (BAL) in asthmatic and normal subjects; (2) measure changes in forced expiratory volume in 1 s (FEV1), vital capacity forced (FVC) associated with BAL; and (3) assess possible predictive factors for the degree of hypoxaemia and impairment of spirometry resulting from BAL. Bronchoscopy and BAL (150 ml) were performed in 24 asthmatics and 15 healthy subjects. Serial arterial blood samples (radial artery) were obtained in all subjects: T1 and before T2 after local anaesthesia; T3 at end of bronchoscopy; T4 after BAL and 5 min, 15 min, 1 h, 2 h, 8 h and 24 h (T5-T10) after the procedure, FEV1 and FVC were measured immediately before and 5 min afer bronchoscopy. Baseline PaO2 was lower in asthmatics (10.2 +/- 0.8 kPa) than in healthy subjects (10.8 +/- 0.8). Both groups showed a significant decrease in PaO2, and a significant widening in (A-a) oxygen tension gradiant at T3-9, with respect to T1 (P < 0.05). PaO2 reached a significantly lower value in asthmatics (7.1 +/- 0.6 kPa) than in HS (7.7 +/- 0.5; P < 0.05). In asthmatics, FEV1, FVC and the ratio FEV1/FVC decreased significantly after BAL (P < 0.001). In healthy subjects, FEV1 and FVC decreased significantly (P < 0.001), whereas FEV1/FVC did not. The fall in FEV1 after BAL was significantly greater in asthmatics (32.4 +/- 10.0%) than in healthy subjects (17.7 +/- 4.6; P < 0.001). Severity of asthma, basline FEV1 or initial PaO2 did not predict the degree of hypoxaemia or the fall of FEV1. It is concluded that BAL causes more severe hypoxaemia and a greater decrease in FEV1 in asthmatics compared to healthy subjects, strongly supporting the recommendation of special caution and careful monitoring when BAL is undertaken in asthmatics.

Addition of salmeterol to fluticasone propionate treatment in moderate-to-severe asthma.

This study was designed to determine whether the benefit of adding salmeterol was superior to doubling the dose of fluticasone propionate (FP) over 6 months, compared to a control group who remained on a lower dose of FP. The multi-centre, double-blind, parallel group study involved 496 symptomatic asthmatic patients with a history of exacerbations on 500-800 micrograms (microg) inhaled corticosteroids (ICS) twice daily (b.d.) in a broadly representative group of 100 hospitals and general practices in six countries. Two doses of FP--250 microg b.d. (FP250) or 500 microg b.d. (FP500)--were compared with the lower dose of FP plus a long-acting beta2-agonist, salmeterol 50 microg b.d. (SM/FP250). Patients symptomatic on the run-in dose of FP250 alone formed the control group in the treatment period. Over 6 months, SM/FP250 significantly improved mean morning peak expiratory flow rates (amPEF) by 42.1 l/min, more than twice the improvement achieved with either dose of FP alone. SM/FP250 also resulted in more symptom-free days and nights (P < 0.002) and days and nights with no relief medication (P < 0.001). The number of severe exacerbations was low: 3, 6 and 8% in the SM/FP250, low- and high-dose FP groups, respectively. This study confirms that adding salmeterol to low-dose inhaled FP offers greater improvements than either maintaining or doubling the dose of FP. Significant benefit was gained from adding salmeterol in a group of patients who appeared to have been at the top of their steroid dose-response curve receiving FP250. There was no evidence of tolerance and a low incidence of exacerbations in all treatment groups.

The positive bronchus sign in patients with known lung cancer.

The positive bronchus sign is the CT finding of a bronchus leading to or contained within the primary mass. A prospective study was performed for the purpose of establishing the correlation between the above sign on CT and the visual and pathological findings on bronchoscopy. The predictive value for the positive bronchus sign was found to be 94% and that of the negative bronchus sign 62%. CT is useful in predicting the likelihood of subsequent bronchoscopy providing positive results.

Difenacoum poisoning as a cause of haematuria.

A man presented with frank haematuria and a grossly prolonged prothrombin time. He was later found to have taken an overdose of difenacoum--a 'superwarfarin' rodenticide. The diagnosis was confirmed by a serum concentration of difenacoum of 0.6 micrograms ml-1. Overdosage with superwarfarins is discussed and the need for prolonged treatment with vitamin K1 highlighted.

Sputum induction: a method to assess airway inflammation in asthma.

In recent studies, sputum cell counts have been used to examine the cell and molecular markers of airway inflammation. In this paper, we describe three different technical methods of analysing sputum samples: the first using smears, the second using cytocentrifugation after selection of a mucous plug, and the third using cytocentrifugation to analyse the entire sputum sample. These last two techniques have been used in a pilot study to compare the differential cell counts in sputum and bronchoalveolar lavage (BAL). The results show a significant correlation between the percentage of the eosinophils in sputum and bronchial sample of the BAL. Previous results on the study of airway inflammation with the analysis of sputum and the preliminary data on the relationship between sputum and BAL confirm the usefulness of this noninvasive technique in the understanding of the pathogenesis of asthma.