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1.  Clinical investigation of an outbreak of alveolitis and asthma in a car engine manufacturing plant 
Thorax  2007;62(11):981-990.
Background
Exposure to metal working fluid (MWF) has been associated with outbreaks of extrinsic allergic alveolitis (EAA) in the USA, with bacterial contamination of MWF being a possible cause, but is uncommon in the UK. Twelve workers developed EAA in a car engine manufacturing plant in the UK, presenting clinically between December 2003 and May 2004. This paper reports the subsequent epidemiological investigation of the whole workforce. The study had three aims: (1) to measure the extent of the outbreak by identifying other workers who may have developed EAA or other work‐related respiratory diseases; (2) to provide case detection so that those affected could be treated; and (3) to provide epidemiological data to identify the cause of the outbreak.
Methods
The outbreak was investigated in a three‐phase cross‐sectional survey of the workforce. In phase I a respiratory screening questionnaire was completed by 808/836 workers (96.7%) in May 2004. In phase II 481 employees with at least one respiratory symptom on screening and 50 asymptomatic controls were invited for investigation at the factory in June 2004. This included a questionnaire, spirometry and clinical opinion. 454/481 (94.4%) responded and 48/50 (96%) controls. Workers were identified who needed further investigation and serial measurements of peak expiratory flow (PEF). In phase III 162 employees were seen at the Birmingham Occupational Lung Disease clinic. 198 employees returned PEF records, including 141 of the 162 who attended for clinical investigation. Case definitions for diagnoses were agreed.
Results
87 workers (10.4% of the workforce) met case definitions for occupational lung disease, comprising EAA (n = 19), occupational asthma (n = 74) and humidifier fever (n = 7). 12 workers had more than one diagnosis. The peak onset of work‐related breathlessness was Spring 2003. The proportion of workers affected was higher for those using MWF from a large sump (27.3%) than for those working all over the manufacturing area (7.9%) (OR = 4.39, p<0.001). Two workers had positive specific provocation tests to the used but not the unused MWF solution.
Conclusions
Extensive investigation of the outbreak of EAA detected a large number of affected workers, not only with EAA but also occupational asthma. This is the largest reported outbreak in Europe. Mist from used MWF is the likely cause. In workplaces using MWF there is a need to carry out risk assessments, to monitor and maintain fluid quality, to control mist and to carry out respiratory health surveillance.
doi:10.1136/thx.2006.072199
PMCID: PMC2117138  PMID: 17504818
2.  Regulation of vascular endothelial growth factor bioactivity in patients with acute lung injury 
Thorax  2005;60(2):153-158.
Methods: Forty one patients with ARDS, 12 at risk of developing ARDS, and 16 normal controls were studied. Bioactive VEGF, total VEGF, and sVEGFR-1 were measured by ELISA in plasma and bronchoalveolar lavage (BAL) fluid. Reverse transcriptase polymerase chain reaction for sVEGFR-1 was performed on BAL cells.
Results: sVEGFR-1 was detectable in the BAL fluid of 48% (20/41) of patients with early ARDS (1.4–54.8 ng/ml epithelial lining fluid (ELF)) compared with 8% (1/12) at risk patients (p = 0.017) and none of the normal controls (p = 0.002). By day 4 sVEGFR-1 was detectable in only 2/18 ARDS patients (p = 0.008). Patients with detectable sVEGFR-1 had lower ELF median (IQR) levels of bioactive VEGF than those without detectable sVEGFR-1 (1415.2 (474.9–3192) pg/ml v 4761 (1349–7596.6) pg/ml, median difference 3346 pg/ml (95% CI 305.1 to 14711.9), p = 0.016), but there was no difference in total VEGF levels. BAL cells expressed mRNA for sVEGFR-1 and produced sVEGFR-1 protein which increased following incubation with tumour necrosis factor α.
Conclusion: This study shows for the first time the presence of sVEGFR-1 in the BAL fluid of patients with ARDS. This may explain the presence of reduced bioactive VEGF in patients early in the course of ARDS.
doi:10.1136/thx.2004.027912
PMCID: PMC1747283  PMID: 15681505
3.  Which patients are prescribed inhaled anti-asthma drugs? 
Thorax  1994;49(11):1090-1095.
BACKGROUND--Prescribing rates for inhaled anti-asthmatic drugs in the UK vary considerably from area to area and between individual practices. The objectives of this study were to determine the prevalence of patients prescribed inhaled steroids and beta agonist bronchodilators, the indications for these prescriptions, and to relate prescribing to the recorded levels of morbidity for specific respiratory disease. METHODS--Anonymised patient-specific prescription and diagnostic data were extracted from computerised general practice records for the 41 practices in the Northern region (total population 330,749) whose data had been validated for inclusion in a research databank. Patients were included if they were either prescribed an inhaled steroid or bronchodilator during a 12 month period, or had a recorded diagnosis of asthma, bronchitis or chronic obstructive pulmonary disease. Prescribing of inhalers per 1000 population was determined within age, sex, and diagnostic groups. Respiratory diagnosis rates within different patient groups were used to measure the underlying level of morbidity in the population. RESULTS--Inhaled anti-asthma drugs were prescribed for 5% of the study population. Prescribing prevalences peaked at ages 5-14 (steroids 40 per 1000 population; bronchodilators 68 per 1000) and at ages 65-74 (steroids 53 per 1000; bronchodilators 79 per 1000). Prescribing frequency for both drugs increased from two or three items per patient annually at age 0-14 to about six in the over 65 age group. Of the 39,424 respiratory patients 38% received inhalers and 7% only non-inhaler medication. Inhaler therapy was used in only 6% of patients with bronchitis, but in 66% of those with asthma, though the proportions varied with patient age and gender. Study practices differed in their overall levels of both inhaler prescribing and respiratory diagnosis, and had lower prescribing patterns of these drugs than other practices in the Northern region. CONCLUSIONS--Inhaled steroid and bronchodilator prescribing have age-related and gender-related prevalences. Treatment for respiratory diagnoses varies with patient age and gender, and with the diagnosis. Prescribing differences between practices are attributable to variation in both diagnostic rates for respiratory disease and therapeutic intervention patterns. For asthma patients study practices show consensus in approach, perhaps illustrating the value of clear guidelines for asthma prescribing.
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PMCID: PMC475267  PMID: 7831622
4.  The site of disruption of the bronchial epithelium in asthmatic and non-asthmatic subjects. 
Thorax  1992;47(7):499-503.
BACKGROUND: Attention has recently been focused on the basal cells of the tracheobronchial epithelium as the mechanism of anchorage of the tall columnar cells, which themselves do not appear to form hemidesmosomes with the basement membrane of the epithelium. Residual basal cells have been described as remaining attached to the basement membrane after epithelial denudation. This led this group to formulate the hypothesis that there may be a potential plane of cleavage between the basal cells and the overlying columnar cell layer within the bronchial epithelium, which becomes disrupted in asthma. METHODS: Bronchoalveolar lavage samples were obtained during bronchoscopy from eight patients with atopic asthma and four normal controls. Ultrathin sections of lavage cell pellets were examined by electron microscopy and the number of columnar and basal cells found in each epithelial cell cluster was counted. Cytocentrifuge preparations of the lavage samples from the same subjects were also examined for free epithelial cells and epithelial cell clusters. RESULTS: Electron microscopic examination of the cell pellets showed that basal cells were present in very small numbers in the epithelial clusters in all subjects (mean 0.03 (SE 0.02)/cluster) and the ratio of columnar cells to basal cells was far greater than was encountered in the intact bronchial epithelium (167 nu 4). The cytocentrifuge preparations showed an increased number of epithelial cell clusters and epithelial cells in the asthmatic patients. Although these clusters were similar in size in the two groups of subjects (6.3 nu 5.1 cells/cluster) the ratio of free epithelial cells to cells within the cluster was higher in the non-asthmatic subjects. CONCLUSIONS: It is proposed that shedding of epithelial cells occurs along a suprabasal plane and that there is a potential plane of cleavage between the suprabasal and the basal cell layers, which might be more vulnerable to the various insults.
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PMCID: PMC463857  PMID: 1412091
5.  Effect of hyperthyroidism on bronchial reactivity in non-asthmatic patients. 
Thorax  1989;44(7):603-604.
Thyrotoxicosis may be associated with deterioration in asthma. To determine whether bronchial reactivity to histamine is increased in hyperthyroidism 10 thyrotoxic non-asthmatic patients were assessed before and after treatment of their thyrotoxicosis. No significant change in bronchial reactivity was found after treatment.
PMCID: PMC461977  PMID: 2772862
6.  Effect of verapamil and sodium cromoglycate on leukotriene D4 induced bronchoconstriction in patients with asthma. 
Thorax  1986;41(10):753-758.
Leukotriene D4 (LTD4) may be an important mediator in asthma. The effect of verapamil and sodium cromoglycate on LTD4 induced bronchoconstriction has been examined in seven patients with asthma. The bronchoconstrictor response to increasing concentrations of inhaled LTD4 (0.0032-50 micrograms/ml) was assessed by measuring changes in FEV1, specific airways conductance, and flow rate at 30% of vital capacity (V30(p)). Results were expressed as the provocation concentration (PC) producing a 10% fall in FEV1 (PC10FEV1), a 35% fall in specific airways conductance (PC35SGaw), and a 30% fall in flow at 30% of vital capacity (PC30 V30(p)). Neither verapamil nor cromoglycate inhibited LTD4 induced bronchoconstriction in asthmatic subjects. These results suggest that in asthmatic patients LTD4 induced bronchoconstriction is not mediated via verapamil or cromoglycate sensitive mechanisms.
PMCID: PMC460470  PMID: 3097863
7.  In vitro and in vivo effect of verapamil on human airway responsiveness to leukotriene D4. 
Thorax  1986;41(1):12-16.
The mechanism by which leukotriene D4 (LTD4) induces airway narrowing in man is unclear. We have investigated this by examining the effect of the calcium channel blocker verapamil on the sensitivity of in vitro preparations of human bronchi to LTD4 and methacholine, and on the bronchoconstriction induced in normal subjects by these agonists in vivo. In vitro smooth muscle sensitivity was assessed by the concentration of LTD4 and methacholine causing a 50% of maximum contraction (EC50) and as the maximum tension generated. Verapamil did not alter baseline tension or the response to LTD4 but did inhibit contractile responses to methacholine. In vivo studies were performed in six normal subjects; they inhaled increasing concentrations of LTD4 (0.4-50 micrograms/ml) or methacholine (2-64 mg/ml). Airway responsiveness in vivo was expressed as the provocation concentration (PC) of agonist producing a 35% fall in specific airways conductance (PC35sGaw) and a 30% fall in flow at 30% of vital capacity (PC30 V30(p)). Verapamil did not alter baseline sGaw or V30(p). One subject did not respond to LTD4 on either day. In contrast to the in vitro results, verapamil produced a greater than 10 fold reduction in LTD4 induced bronchoconstriction, but had no effect on methacholine induced bronchoconstriction. These results suggest that in normal subjects bronchoconstriction induced by inhaled LTD4 is due to a combination of direct and indirect mechanisms.
PMCID: PMC460245  PMID: 3518128
8.  Airway responsiveness to histamine in man: effect of atropine on in vivo and in vitro comparison. 
Thorax  1985;40(4):261-267.
Airway responsiveness to histamine in man may be determined by the smooth muscle sensitivity to histamine or to the interaction between vagal nerve input and smooth muscle sensitivity. We have compared in vivo responsiveness to histamine with in vitro smooth muscle sensitivity to histamine in 20 non-asthmatic patients and one asthmatic patient undergoing thoracic surgery. Histamine responsiveness was assessed in the first 10 non-asthmatics without atropine pretreatment, in the second 10 after atropine pretreatment, and in the asthmatic patient both with and without atropine. In vivo responsiveness was also measured in 10 normal subjects and 10 asthmatic patients not undergoing surgery. Results were expressed as the provocation concentration (PC) causing a decrease in FEV1 of 20% (PC20FEV1) and in specific airways conductance of 35% (PC35SGaw), and in terms of maximal expiratory flow at 35% vital capacity, measured from the partial (V35(P] and complete (V35(C] flow volume curves of 35% (PC35V35(P); PC35V35(C]. In vitro smooth muscle sensitivity to histamine of bronchial tissue obtained at thoracotomy was expressed as the concentration causing a 50% maximum contraction (EC50) and as the maximum tension generated. There was considerable variation between patients in the in vivo responsiveness but a relatively narrow range for in vitro responses. There was no significant correlation between in vivo responsiveness, either with or without atropine pretreatment, and in vitro results. The asthmatic patient showed hyperresponsiveness in vivo but but not in vitro. These results suggest that in vitro airway smooth muscle sensitivity to histamine is not the sole determinant of in vivo airway responsiveness and that this lack of relationship is not explained by the influence of vagal nerve input on in vivo measurements. The results in the asthmatic patient suggest that airway hyperresponsiveness may be an in vivo phenomenon which is not related to a primary abnormality of airway smooth muscle.
PMCID: PMC460043  PMID: 4023976
9.  Comparison of in vivo airway responsiveness and in vitro smooth muscle sensitivity to methacholine in man. 
Thorax  1984;39(11):837-843.
Airway responsiveness to methacholine varies between normal people and is increased in patients with asthma. The importance of airway smooth muscle sensitivity in determining in vivo responsiveness is unknown. We have examined this question by comparing in vivo airway responsiveness with in vitro airway smooth muscle sensitivity to methacholine in 10 patients undergoing thoracic surgery. In vivo responsiveness was determined by administration of inhalations of doubling concentrations of methacholine. Results were expressed as the provocation concentration (PC) causing a decrease in forced expiratory volume in one second of 20% (PC20FEV1), specific airway conductance of 35% (PC35SGaw), and maximal expiratory flow at 35% vital capacity, measured for the partial (V35(p)) and complete (V35(c)) flow volume curves, of 35% (PC35V35(p); PC35V35(c)). In vitro airway smooth muscle sensitivity was determined from specimens obtained at thoracotomy. Log dose-response curves to methacholine were constructed and the concentration causing a 50% maximum contraction (EC50) was derived. There were differences between patients for both in vivo airway responsiveness and in vitro smooth muscle sensitivity to methacholine. There were no significant relationships between the in vivo and in vitro measurements. The results suggest that factors other than solely the sensitivity of smooth muscle must determine in vivo airway responsiveness to methacholine.
PMCID: PMC459934  PMID: 6390773

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