Microbial contamination of domiciliary nebulisers and clinical implications in chronic obstructive pulmonary disease.

BACKGROUND AND PURPOSE: Domiciliary nebulisers are widely used in chronic obstructive pulmonary disease (COPD) but nebuliser cleaning practice has not been assessed in patients with COPD who are often elderly and may have severe disease and multiple comorbidities. We aimed to evaluate microbial contamination of home nebulisers used by patients with COPD. METHODS: Random microbiological assessment of domiciliary nebulisers was undertaken together with an enquiry into cleaning practices. We also examined the effectiveness of the trust-wide cleaning instructions in eradicating isolated microorganisms in a laboratory setting. RESULTS: The mean age of patients in this study was 71 (range 40-93) years, and in 68% of patients a large number of significant comorbidities were present. Forty-four nebuliser sets were obtained and 73% were contaminated with microorganisms at >100 colony forming units/plate. Potentially pathogenic bacteria colonised 13 of the 44 nebulisers (30%) and organisms isolated included Pseudomonas aeroginosa, Staphylococcus aureus, multidrug resistant Serratia marcesans, Escherichia coli and multiresistant Klebsiella spp, Enterobacteriaceae and fungus Fusarium oxysporum. Washing of nebuliser masks, chambers and mouthpieces achieved complete eradication of Gram-positive bacterial and fungal flora. Gram-negative organisms were incompletely eradicated, which may be attributed to the presence of biofilms. We also found that in patients with pathogenic organisms cultured on the nebuliser sets, there was a higher probability of occurrence of a COPD exacerbation with a mean number of exacerbations of 3.3 (SD=1) per year in the group in whom pathogens were isolated compared with 1.7 (SD=1.2) exacerbations per year in those whose sets grew non-pathogenic flora (p=0.02). CONCLUSIONS: Nebulisers contaminated with microorganisms are potential reservoirs delivering serious pathogens to the lung. Relationships between nebuliser contamination, clinical infection and exacerbations require further examination, but is a potential concern in elderly patients with COPD with comorbidities who fail to effectively maintain reasonable standards of nebuliser cleanliness.

Prognostic performance of inflammation-based prognostic indices in primary operable non-small cell lung cancer.

BACKGROUND: At least 30% of patients with primary resectable non-small cell lung cancer (NSCLC) will experience a relapse in their disease within 5 years following definitive treatment. Clinicopathological predictors have proved to be suboptimal in identifying high-risk patients. We aimed to establish whether inflammation-based scores offer an improved prognostic ability in terms of estimating overall (OS) and recurrence-free survival (RFS) in a cohort of operable, early-stage NSCLC patients. METHODS: Clinicopathological, demographic and treatment data were collected prospectively for 220 patients operated for primary NSCLC at the Hammersmith Hospital from 2004 to 2011. Pretreatment modified Glasgow Prognostic Score (mGPS), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were tested together with established prognostic factors in uni- and multivariate Cox regression analyses of OS and RFS. RESULTS: Half of the patients were male, with a median age of 65. A total of 57% were classified as stage I with adenocarcinoma being the most prevalent subtype (60%). Univariate analyses of survival revealed stage (P<0.001), grade (P=0.02), lymphovascular (LVI, P=0.001), visceral pleural invasion (VPI, P=0.003), mGPS (P=0.02) and NLR (P=0.04) as predictors of OS, with stage (P<0.001), VPI (P=0.02) and NLR (P=0.002) being confirmed as independent prognostic factors on multivariate analyses. Patients with more advanced stage (P<0.001) and LVI (P=0.008) had significantly shorter RFS. CONCLUSIONS: An elevated NLR identifies operable NSCLC patients with a poor prognostic outlook and an OS difference of almost 2 years compared to those with a normal score at diagnosis. Our study validates the clinical utility of the NLR in early-stage NSCLC.

An siRNA screen identifies RSK1 as a key modulator of lung cancer metastasis.

We performed a kinome-wide siRNA screen and identified 70 kinases altering cell migration in A549 lung cancer cells. In particular, ribosomal S6 kinase 1 (RSK1) silencing increased, whereas RSK2 and RSK4 downregulation inhibited cell motility. In a secondary collagen-based three-dimensional invasion screen, 38 of our hits cross-validated, including RSK1 and RSK4. In two further lung cancer cell lines, RSK1 but not RSK4 silencing showed identical modulation of cell motility. We therefore selected RSK1 for further investigation. Bioinformatic analysis followed by co-immunoprecipitation-based validation revealed that the actin regulators VASP and Mena interact with RSK1. Moreover, RSK1 phosphorylated VASP on T278, a site regulating its binding to actin. In addition, silencing of RSK1 enhanced the metastatic potential of these cells in vivo using a zebrafish model. Finally, we investigated the relevance of this finding in human lung cancer samples. In isogenically matched tissue, RSK1 was reduced in metastatic versus primary lung cancer lesions. Moreover, patients with RSK1-negative lung tumours showed increased number of metastases. Our results suggest that the findings of our high-throughput in vitro screen can reliably identify relevant clinical targets and as a proof of principle, RSK1 may provide a biomarker for metastasis in lung cancer patients.

Is air travel safe for those with lung disease?

Airlines commonly report respiratory in-flight emergencies; flight outcomes have not been examined prospectively in large numbers of respiratory patients. The current authors conducted a prospective, observational study of flight outcomes in this group. UK respiratory specialists were invited to recruit patients planning air travel. Centres undertook their usual pre-flight assessment. Within 2 weeks of returning, patients completed a questionnaire documenting symptoms, in-flight oxygen use and unscheduled healthcare use. In total, 616 patients were recruited. Of these, 500 (81%) returned questionnaires. The most common diagnoses were airway (54%) and diffuse parenchymal lung disease (23%). In total, 12 patients died, seven before flying and five within 1 month. Pre-flight assessment included oximetry (96%), spirometry (95%), hypoxic challenge (45%) and walk test (10%). Of the patients, 11% did not fly. In those who flew, unscheduled respiratory healthcare use increased from 9% in the 4 weeks prior to travel to 19% in the 4 weeks after travel. However, when compared with self-reported data during the preceding year, medical consultations increased by just 2%. In patients flying after careful respiratory specialist assessment, commercial air travel appears generally safe.

Inhaled allergen-driven CD1c up-regulation and enhanced antigen uptake by activated human respiratory-tract dendritic cells in atopic asthma.

BACKGROUND: Dendritic cells (DC) mediate inflammation in rodent models of allergic airway disease, but the role played by human respiratory-tract DC (hRTDC) in atopic asthma remains poorly defined. Recent data suggest that CD1 antigen presentation by hRTDC may contribute to asthma pathogenesis. OBJECTIVE: To investigate the influence of hRTDC on the balance between atopy and allergic asthma in human subjects and to determine whether CD1 expression by hRTDC is modulated during asthmatic inflammation. METHODS: Sputum cells were induced from steroid-naïve, allergen-challenged and allergen-naïve subjects (atopic asthmatics, atopic non-asthmatics and non-atopic controls). hRTDC were identified using monoclonal antibody labelling and analysis by flow cytometry. RESULTS: hRTDC stained HLA-DR(+) (negative for markers of other cell lineages) were predominantly myeloid and comprised approximately 0.5% of viable sputum cells. Sputum cells were potent stimulators of allogeneic CD4(+) naïve T cells and enrichment/depletion experiments correlated stimulatory potency with DC numbers. Sputum contained cells that exhibited typical dendritic morphology when analysed by electron microscopy. Myeloid hRTDC were endocytically active, but uptake of FITC-dextran was enhanced in cells from asthmatics (P<0.001). Despite their increased endocytic capacity, asthmatic myeloid hRTDC appeared mature and expressed increased levels of maturation markers (P<0.05-P<0.001), CD1c, CD1d and langerin (P<0.05). CD1c expression by asthmatic myeloid hRTDC was enhanced upon in vivo allergen challenge (three to ninefold within 24 h; P<0.05). CD11c(-)CD123(high) hRTDC were only detected in asthmatic sputum and were increased in number following allergen challenge. CONCLUSION: Despite limited cell numbers, it proved possible to analyse human RTDC in induced sputum, providing evidence that increased antigen uptake and enhanced CD1 presentation by activated hRTDC may contribute to allergic airway disease. CD1 presentation by hRTDC in atopic asthma may therefore constitute a novel target for future intervention strategies.

Methotrexate therapy of oral corticosteroid-dependent asthmatics reduces serum immunoglobulins: correlation with clinical response to therapy.

BACKGROUND: Concomitant methotrexate (MTX) therapy of oral corticosteroid (CS)-dependent asthmatics has been shown to spare CS therapy, but the mechanism is unknown. In a previous report, we showed that MTX increases T cell inhibition by CS. In this report we focus on effects of MTX on immunoglobulin concentrations and their possible clinical relevance. OBJECTIVE: To monitor changes in circulating leucocytes and Ig in a group of these patients during MTX therapy, and to relate these changes to clinical 'response' as defined by oral CS reduction. METHODS: Sixteen severe asthmatics dependent on oral prednisolone 15 (7.5-25) mg/day in addition to high dose inhaled CS were treated with MTX 15 mg intramuscularly, weekly for 28 weeks. Prednisolone dosages were maintained constant for 12 weeks then reduced systematically over the next 16 weeks provided that asthma control did not deteriorate. Patients were classified a priori as 'responders' or 'non-responders' to MTX (reduction of initial oral prednisolone requirement by >or=50% or <50%, respectively). Patients were followed-up for a further 12 weeks after MTX withdrawal. Serum Ig and differential blood leucocyte counts were measured at baseline, 12, 28 and 40 weeks. RESULTS: MTX therapy allowed significant, but individually variable, reductions in oral prednisolone dosages (P<0.00001) without alteration of lung function or symptoms. This was associated with significant reductions in mean serum concentrations of Ig of all classes, which reversed following MTX withdrawal. Reductions in IgE and IgG were significantly greater in the MTX 'responders' as compared with 'non-responders', and changes in IgE, IgG and IgM correlated with changes in prednisolone requirements. Differential blood leucocyte counts showed no significant variation. CONCLUSION: MTX therapy reduced oral CS requirements in these severe asthmatics to a degree which correlated with reduced circulating Ig but not lymphopaenia, suggesting a possible cause and effect relationship. These reductions might also contribute to the documented incidence of opportunistic infection in these circumstances.

Safety of formoterol by Turbuhaler as reliever medication compared with terbutaline in moderate asthma.

The present study compared the safety of 4.5 microg formoterol with 0.5 mg terbutaline, both by Turbuhaler and used as needed, in addition to regular formoterol in moderate asthma. In this double-blind parallel-group study, 357 patients taking a moderate-to-high dose of inhaled corticosteroids and additional terbutaline (2-5 inhalations x day(-1) during run-in) were randomised to either formoterol or terbutaline as needed in addition to formoterol 9 microg b.i.d. over 12 weeks. Adverse events, serum potassium levels, electrocardiogram, vital signs and lung function were assessed monthly; peak expiratory flow and severe asthma exacerbations were recorded daily. Patients used 2.16 (range 0.0-6.3) formoterol and 2.34 (range 0.1-7.5) terbutaline relief inhalations x day(-1). No clinically significant differences in safety variables were found between treatments. Statistically greater increases in cardiac frequency (2.6 beats x min(-1), p=0.03) were found on terbutaline. There were 44 and 52 severe asthma exacerbations with formoterol and terbutaline, respectively, with no significant difference in time to first exacerbation. There was also no difference between treatments for other efficacy measures (peak expiratory flow, forced expiratory volume in one second and morning/evening symptom scores). Formoterol 4.5 microg as needed was at least as safe, well tolerated and effective as terbutaline 0.5 mg in stable patients (requiring up to 6 relief inhalations x day(-1)) taking formoterol plus inhaled corticosteroids regularly over 12 weeks.

Analysis of mechanical stresses within the alveolar septa leading to pulmonary edema.

Mechanical ventilation has been associated with pulmonary edema in the clinical setting, but the pathophysiological mechanisms of this process have not been clearly defined. Experimental studies have shown that high transpulmonary pressures resulting from ventilation may damage the capillary walls, thereby leading to edema. Knowledge of the stress distribution within the alveolar septa would be an important step in understanding this phenomenon. A newly developed saline-filled alveolar sac model was utilized for analysis of septal stresses in young and aging healthy lungs, in order to examine their vulnerability to pulmonary edema during ventilation. Significant stress concentrations were shown to develop near highly curved regions (small local radii of less than 4 mum in a lung inflated to 80% could be as high as 25 times that of average septal stresses. The combination of elevated stress sites that are formed in the stiffer parenchyma of the aging lung, together with the cyclic loading of ventilation, may explain the gaps and breaks previously observed in pulmonary edema.

Time-frequency analysis of breathing signals: in vitro airway model.

Sound signals of respiratory airflow represent summations of acoustic waves of various frequencies, which basically depend on the characteristics of the flow and on those of the surrounding tissue. This study was designed to examine the capability of time-frequency distribution (TFD) of respiratory signals in order to differentiate between unobstructed and obstructed upper airways. In order to investigate the TFD characteristics of defined upper airway geometry we conducted a controlled basic study in a laboratory system with an in vitro isolated airway model, which was either unobstructed or had concentric obstructions of various degrees at different locations along the tube. Pressure fluctuations were acquired with a microphone proximal to the airway opening. A short-term Fourier transform was used to study the TFDs of these signals. The results of the in vitro study showed that the energy of the higher frequencies increased for relatively small incremental changes in: i) reduction of the lumen cross-section, ii) decrease of distance from measurement site to obstruction, and iii) increase of breathing effort. Further development of this method may lead to noninvasive clinical techniques for early diagnosis of upper airway obstructions.

Analysis of stress distribution in the alveolar septa of normal and simulated emphysematic lungs.

The alveolar septum consists of a skeleton of fine collagen and elastin fibers, which are interlaced with a capillary network. Its mechanical characteristics play an important role in the overall performance of the lung. An alveolar sac model was developed for numerical analysis of the internal stress distribution and septal displacements within the alveoli of both normal and emphysematic saline-filled lungs. A scanning electron micrograph of the parenchyma was digitized to yield a geometric replica of a typical two-dimensional alveolar sac. The stress-strain relationship of the alveolar tissue was adopted from experimental data. The model was solved by using commercial finite-element software for quasi-static loading of alveolar pressure. Investigation of the state of stresses and displacements in a healthy lung simulation yielded values that compared well with experimentally reported data. Alteration of the mechanical characteristics of the alveolar septa to simulate elastin destruction in the emphysematic model induced significant stress concentrations (e.g., at a lung volume of 60% total capacity, tensions at certain parts in an emphysematic lung were up to 6 times higher than those in a normal lung). The combination of highly elevated stress sites together with the cyclic loading of breathing may explain the observed progressive damage to elastin fibers in emphysematic patients.

A technique for global assessment of respiratory muscle performance at different lung volumes.

A system for noninvasive assessment of an all-inclusive function of respiratory muscles at different lung volumes is presented. The apparatus was based on the interrupter technique and facilitated simultaneous measurements of mouth pressure and airflow rate during dynamic or quasistatic manoeuvres. In this study, mouth pressure values were continuously acquired during and after interruption of a forced inspiratory or expiratory manoeuvre for as long as the subject could sustain an elevated mouth pressure against the obstructed opening. These measurements provided information on both muscle strength and power. A total of 420 forced maximal inspiratory and expiratory manoeuvres performed by six healthy subjects were monitored at different lung volumes. The pattern of maximal pressure-time curves was consistent for the same subject regardless of lung volume. Similar values of maximal mouth pressure can be generated by healthy subjects by using either a flange-style mouthpiece or facial mask. For both methods mouth pressure shows a significant (p < 0.05) second order dependency on lung volume for both inspiration and expiration. The standard deviation of measurements from a single subject about a second order curve is of the order of 5-15%. The findings of interchangeability between methods of measurement may be useful in allegedly non-compliant patients.

Transport phenomena in the human nasal cavity: a computational model.

Nasal inspiration is important for maintaining the internal milieu of the lung, since ambient air is conditioned to nearly alveolar conditions (body temperature and fully saturated with water vapor) on reaching the nasopharynx. We conducted a two-dimensional computational study of transport phenomena in model transverse cross sections of the nasal cavity of normal and diseased human noses for inspiration under various ambient conditions. The results suggest that during breathing via the normal human nose there is ample time for heat and water exchange to enable equilibration to near intraalveolar conditions. A normal nose can maintain this equilibrium under extreme environments (e.g., hot/humid, cold/dry, cold/humid). The turbinates increase the rate of local heat and moisture transport by narrowing the passageways for air and by induction of laminar swirls downstream of the turbinate wall. However, abnormal blood supply or mucous generation may reduce the rate of heat or moisture flux into the inspired air, and thereby affect the efficacy of the process.

Improved breathing capacity during exercise in severe obstructive airway disease.

In severe COPD, ventilation at peak exercise may exceed the resting maximal voluntary ventilation (MVV). We investigated the mechanisms by which the breathing capacity can improve during exercise in COPD. A total of 13 patients with an FEV1 of 32+/-12% (SD) predicted, performed an incremental maximal exercise test and FVC and MVV maneuvers at rest and during constant work rate exercise. Maximal exercise ventilation was 3+/-2 L/min higher than resting MVV. Breathing capacity improved during exercise; resting MVV was 30+/-3 (SE) L/min, while it reached 38+/-3 L/min during exercise (P < 0.002). FEV1 improved from 0.86+/-0.1 L at rest to 1.01+/-0.1 L during exercise (P < 0.004), which is consistent with exercise-induced bronchodilatation. It is concluded that in severe COPD, breathing capacity improves during exercise. Assuming that the change in FEV1 reflects improved airway function, these data suggest that exercise-induced bronchodilatation contributed to that improvement.

Computational model of oscillatory airflow in a bronchial bifurcation.

Airflow distribution in the bronchial tree is an important factor that controls gas mixing in the lungs, especially, in diseased lungs or during high frequency ventilation. A nonlinear analog model has been developed to investigate the dependency of airflow distribution in asymmetric bronchial bifurcations on structural and physiological parameters. The system parameters (electrical analogs) are time-dependent and were extracted from laboratory studies of airway models and physiological measurements. The model was used to study flow distribution in peripheral pathways of normal and pathological airways during different modes of quiet breathing as well as high frequency ventilation. Model simulations revealed that (i) increasing of ventilation frequency or stroke volume increases the time and percentage of pendelluft in each cycle, (ii) diameter asymmetry between parallel pathways is more dominant than length asymmetry and enhances the degree of asynchronous ventilation to peripheral pathways, and (iii) asymmetry in the compliance of peripheral airways and lung parenchyma greatly increases the degree of asynchronous ventilation.

Evaluation of domiciliary long-term oxygen therapy with oxygen concentrators.

Domiciliary long-term oxygen therapy (LTOT) is usually supplied by means of oxygen concentrators (OCs). Various factors that determine the efficacy of such a treatment were evaluated. Sixty-three patients, arbitrarily selected from lists of health care providers, were visited at home by a biomedical engineer and a pulmonary function technician. The evaluation consisted of: i) responses to a directed questionnaire, ii) assessment of the OC output characteristics, and iii) measurement of the patient's oxygen saturation (SaO2) at rest with and without oxygen supplement. Only 33% of patients received oxygen treatment for the recommended 12-24 hours/day and 5% of patients waited the recommended 10 minutes of OC warm-up before connection. Filters were cleaned weekly by only 30% of patients and the concentrator was serviced 3-4 times a year in 25% of cases. The OC was thought to be unduly noisy by 24% of patients and connecting tubing of less than 6 meters was fitted to 90% of OCs, thereby limiting patient mobility. Most of the OCs did not yield the recommended oxygen concentration and the flow rate meters on them tended to underread. Therefore, only 22% of patients received the prescribed oxygen supplement. Whilst breathing room air, a substantial proportion of patients had an SaO2 >90%. Improvements are clearly required in terms of medical indications for LTOT, patient education and supervision, supply and maintenance of concentrators and related equipment.

A risk-benefit assessment of methotrexate in corticosteroid-dependent asthma.

Methotrexate is a folic acid antagonist with proven anti-inflammatory properties. This originally led to its use in the therapy of some rheumatic and dermatological inflammatory disorders and, since the early 1980s, as a corticosteroid-sparing agent in the therapy of bronchial asthma. Although the exact anti-inflammatory mechanism is not known, it appears that in some patients with severe corticosteroid-dependent bronchial asthma, a reduction of at least 50% in the maintenance corticosteroid dosage can be achieved. Controversies regarding methotrexate efficacy may be a result of the small size and heterogeneity of the patient populations studied and the variable definition of corticosteroid "dependence'. Although the potential for serious short and long term adverse effects resulting from methotrexate therapy cannot be ignored, overall, methotrexate appears to be well tolerated at low dosages. Hepatic and pulmonary toxicity are the main adverse effects of concern. The "lesser evil' approach is logical, but it is imperative to administer the drug for at least 3 months to adequately assess its efficacy in a specific patient.

Re-expansion pulmonary oedema following spontaneous pneumothorax.

Re-expansion pulmonary oedema may occur after chest tube drainage of pneumothorax and can give rise to cardiopulmonary manifestations which range from the mild to the severe. In order to evaluate the prevalence and the clinical manifestations of this complication, all patients with spontaneous pneumothorax managed with chest tube drainage were evaluated over an 8-yr period (1986-1994). A chest radiograph was performed routinely in all patients within 4 h of tube insertion. Lung expansion and the appearance of infiltrates within the lungs were investigated specifically. Re-expansion oedema was noted in three of 320 episodes (0.9%). Two of the three patients needed rapid and extensive clinical treatment.

Atopy, bronchial hyperresponsiveness, and peak flow variability in children with mild occasional wheezing.

BACKGROUND: Children who suffer from recurrent wheezy episodes are often promptly classified as asthmatic. The aim of this study was to evaluate a population of mild wheezy children with repeatedly normal spirometric tests at rest for atopy, bronchial hyperresponsiveness, and peak expiratory flow variability. METHODS: Thirty nine children aged 6-16 years with 1-12 wheezy attacks during the previous year were recruited from a community paediatric primary health care clinic serving an urban Israeli population. The conditions for inclusion were a physician-diagnosed wheeze on auscultation and normal spirometric tests at rest on at least three occasions. Evaluation included skin prick tests for atopy and a physician-completed questionnaire. In addition, two tests of bronchial hyperresponsiveness (BHR) were performed--namely, exercise-induced bronchospasm and inhaled methacholine hyperresponsiveness--as well as diurnal variability of peak expiratory flow (PV). RESULTS: One or more tests of BHR/PV were positive in 27 (69%) but repeatedly negative in 12 (31%). In terms of frequency of wheezing attacks, atopy, and questionnaire responses, there were no differences between BHR/PV and non-BHR/PV children, with the exception of a history of chest radiography proven pneumonia (only noted in the BHR/PV group). Overall, evidence of atopy (mainly indoor allergens) was noted in 21 (56%) of those tested and parental smoking in 29 (74%) of households. Thirty-two (82%) of the children complained of an exercise-related wheeze, yet exercise-induced bronchospasm was only demonstrated in nine (23%). CONCLUSIONS: This selected group of wheezy children appears to be intermediate between a normal and clearly asthmatic population and, despite the recurrent wheezy attacks, some should probably not be classified as asthmatic by conventional criteria. Important aetiological factors in the symptomatology of these children may include parental smoking and atopy as well as other elements such as viral infections.

Methotrexate in steroid-dependent asthma: long-term results.

Treatment of 21 steroid-dependent asthmatic patients with methotrexate (MTX) 15 mg/week was prospectively evaluated for a mean of 14.7 (SD 3.7) months. Before MTX, therapy consisted of a mean prednisone dose of 16.6 (SD 9.2) mg, in addition to inhaled beclomethasone/budesonide (mean daily dose 1157 (SD 330) micrograms) and bronchodilators. Thirteen patients were weaned from all regular systemic steroid therapy, a 50% or more reduction was achieved in four patients, and a less than 50% reduction in four patients. Abnormal liver function tests were noted in six of the 21 patients; this resolved despite continuation of MTX in five. In one patient, MTX was stopped because of symptoms as well as a fivefold rise in serum transaminases, and a speedy resolution was noted. Gastrointestinal side-effects were reported in six patients but were resolved in five with intramuscular MTX. There were no hematologic or pulmonary complications. We conclude that MTX appears to be both safe and efficacious as a steroid-sparing agent in most steroid-dependent asthmatic patients when taken over a long period.