pRotective vEntilation with veno-venouS lung assisT in respiratory failure: A protocol for a multicentre randomised controlled trial of extracorporeal carbon dioxide removal in patients with acute hypoxaemic respiratory failure.

One of the few interventions to demonstrate improved outcomes for acute hypoxaemic respiratory failure is reducing tidal volumes when using mechanical ventilation, often termed lung protective ventilation. Veno-venous extracorporeal carbon dioxide removal (vv-ECCO2R) can facilitate reducing tidal volumes. pRotective vEntilation with veno-venouS lung assisT (REST) is a randomised, allocation concealed, controlled, open, multicentre pragmatic trial to determine the clinical and cost-effectiveness of lower tidal volume mechanical ventilation facilitated by vv-ECCO2R in patients with acute hypoxaemic respiratory failure. Patients requiring intubation and mechanical ventilation for acute hypoxaemic respiratory failure will be randomly allocated to receive either vv-ECCO2R and lower tidal volume mechanical ventilation or standard care with stratification by recruitment centre. There is a need for a large randomised controlled trial to establish whether vv-ECCO2R in acute hypoxaemic respiratory failure can allow the use of a more protective lung ventilation strategy and is associated with improved patient outcomes.

Type XVIII collagen degradation products in acute lung injury.

INTRODUCTION: In acute lung injury, repair of the damaged alveolar-capillary barrier is an essential part of recovery. Endostatin is a 20 to 28 kDa proteolytic fragment of the basement membrane collagen XVIII, which has been shown to inhibit angiogenesis via action on endothelial cells. We hypothesised that endostatin may have a role in inhibiting lung repair in patients with lung injury. The aims of the study were to determine if endostatin is elevated in the plasma/bronchoalveolar lavage fluid of patients with acute lung injury and ascertain whether the levels reflect the severity of injury and alveolar inflammation, and to assess if endostatin changes occur early after the injurious lung stimuli of one lung ventilation and lipopolysaccharide (LPS) challenge. METHODS: Endostatin was measured by ELISA and western blotting. RESULTS: Endostatin is elevated within the plasma and bronchoalveolar lavage fluid of patients with acute lung injury. Lavage endostatin reflected the degree of alveolar neutrophilia and the extent of the loss of protein selectivity of the alveolar-capillary barrier. Plasma levels of endostatin correlated with the severity of physiological derangement. Western blotting confirmed elevated type XVIII collagen precursor levels in the plasma and lavage and multiple endostatin-like fragments in the lavage of patients. One lung ventilation and LPS challenge rapidly induce increases in lung endostatin levels. CONCLUSIONS: Endostatin may adversely affect both alveolar barrier endothelial and epithelial cells, so its presence within both the circulation and the lung may have a pathophysiological role in acute lung injury that warrants further evaluation.

A case-control study of elderly patients with acute respiratory illness: effect of influenza vaccination on admission to hospital in winter 2003-2004.

Every winter, hospitals face a large increase in emergency respiratory admissions in elderly people. A case-control study was undertaken to assess the effect of routine influenza vaccine in preventing such admissions among a cohort of UK elderly presenting with acute respiratory illness during winter 2003-2004. 157 hospitalised cases and 639 controls (matched for age, sex and week of consultation) were interviewed. In a winter typical of levels of circulating influenza in recent years, influenza vaccine did not show a protective effect on emergency respiratory admissions overall (adjusted OR 1.2 (95%CI 0.8, 1.9). Policy makers should not rely solely on influenza vaccine routinely having a large effect on winter pressures, and should focus on additional preventive strategies.

The effect of sulphurous air pollutant exposures on symptoms, lung function, exhaled nitric oxide, and nasal epithelial lining fluid antioxidant concentrations in normal and asthmatic adults.

AIMS: To explore the effects in normal and asthmatic adults of exposure to 200 ppb sulphur dioxide (SO2) and 200 microg/m3 and 2000 microg/m3 aerosols of ammonium bisulphate (AB) and sulphuric acid (SA) (MMD 0.3 microm). METHODS: Exposures were placebo controlled, for one hour at rest, double blind in random order. DeltaFEV1 was the primary outcome; secondary outcomes included symptoms, ventilation, exhaled nitric oxide (NO) concentrations, and nasal lavage fluid ascorbic (AA) and uric acid (UA) concentrations. RESULTS: There were no significant changes in spirometry or symptoms with any exposure in either group. SO2 exposure was associated with an increased respiratory rate relative to air exposure in the asthmatic group (SO2: 958.9 breaths/hour; air: 906.8 breaths/hour) but the mean volume breathed did not differ significantly (SO2: 318.8 litres; air: 311.4 litres). AB exposures were associated with a significant rise in [NO] in the asthmatic (+1.51 ppb, and +1.39 ppb), but not in the normal group. Mean pre- and post-exposure [AA] tended to be higher in the normal than in the asthmatic group. Within each group, [AA] did not change significantly with any exposure. Post-exposure [UA] were greater than pre-exposure concentrations for all exposures, significantly so in the normal group for all exposures except SO2. There were no significant differences in the mean change in [UA] for any exposure relative to air. CONCLUSIONS: The pollutant exposure concentrations employed in this study were generally much greater than ambient. It is unlikely that short lived exposures at lower concentrations would show significant effects, but effects of longer term lower concentration exposures cannot be ruled out.

The effect of exposure to sulphuric acid on the early asthmatic response to inhaled grass pollen allergen.

Particulate sulphates, including sulphuric acid (H2SO4), are important components of the ambient aerosol in some areas and are regarded as air pollutants with potentially important human health effects. Challenge studies suggest little or no effect of H2SO4 exposure on lung function in asthmatic adults, although some epidemiological studies demonstrate an effect of acid species on symptoms in subjects with asthma. To date, the effect of H2SO4 on allergen responsiveness has not been studied. The effect of exposure to particulate H2SO4 on the early asthmatic response to grass pollen allergen has been investigated in 13 adults with mild asthma. After establishment of the provocative dose of allergen producing a 15% fall in forced expiratory volume in one second (FEVI) (PD15) for each subject, they were exposed to air, 100 microg m(-3) or 1,000 g x m(-3) H2SO4 for 1 h, double-blind in random order > or =2 weeks apart, through a head dome delivery system 14 h after each exposure subject underwent a fixed-dose allergen challenge (PD15). Ten subjects completed the study. The mean early asthmatic responses (maximum percentage change in FEV1 during the first 2 h after challenge) following air, 100 microg x m(-3) H2SO4, and 1,000 microg m(-3) H2SO4, were -14.1%, -16.7%, and -18.4%, respectively. The difference between 1,000 microg x m(-3) H2SO4 and air was significant (mean difference: -4.3%, 95% confidence interval (CI: -1.2-7.4%, p=0.013). The difference between air and 100 microg m(-3) H2SO4 approached significance (mean difference: -2.6%, 95% CI: 0.0-5.3%, p = 0.051). These results suggest that, at least at high mass concentration, sulphuric acid can potentiate the early asthmatic response of mild asthmatic subjects to grass pollen allergen, although the effect is limited.

The effect of sulphur dioxide exposure on indices of heart rate variability in normal and asthmatic adults.

Sulphur dioxide (SO2) is an important air pollutant and causes bronchoconstriction in normal and asthmatic adults. This paper has explored the autonomic consequences of SO2 exposure using the spectral analysis of heart rate variability. Electrocardiogram recordings were made in 12 normal and 12 asthmatic adults undergoing pollutant exposures. Exposures were of a 1 h duration, double blind, in random order, > or = 2 weeks apart and included air and 200 parts per billion SO2. Spectral analysis of R-R intervals was performed. SO2 exposure was associated with an increase in total power (TP) and high (HF) and low frequency (LF) power in the normal subjects, and a reduction in these indices in the subjects with asthma. The difference in TP with SO2 exposure compared to air was +1730 ms2 in the normal group and -1021 ms2 asthmatic group (p<0.003). For HF the respective values were +964 ms2 and -539 ms2 (p=0.02) and for LF, +43 7 ms2 and -57 2 ms2 (p=0.01). No change in lung function or symptoms was observed in either group. This suggests that SO2 exposure at concentrations which are frequently encountered during air pollution episodes can influence the autonomic nervous system. This may be important in understanding the mechanisms involved in SO2 induced bronchoconstriction, and of the cardiovascular effects of air pollution.

Development of a standardized methodology for double-blind, placebo-controlled food challenge in patients with brittle asthma and perceived food intolerance.

OBJECTIVE: To develop a standardized, double-blind, placebo-controlled, food challenge (DBPCFC) methodology for identifying food intolerance in patients with brittle asthma. SUBJECTS/SETTING: Patients with brittle asthma and perceived food intolerance were studied in hospital. DESIGN: Each of 3 protocols began with 5 days of dietary exclusion. Protocol 1 consisted of open food challenges in 29 patients, protocol 2 consisted of 2 daily DBPCFCs in 22 patients, and protocol 3 involved 1 daily DBPCFC in 18 patients. Total immunoglobulin E level was measured and food-specific radioallergosorbent tests and skin prick tests were conducted. A standard panel of hyperallergenic foods were masked in a soup (developed specially for this study) for every food challenge. Peak expiratory flow, forced expiratory volume, and symptoms were assessed as objective measures of response. Open food challenges at home followed each protocol. Each protocol took approximately 14 days in the hospital and 4 to 6 months at home. RESULTS: For protocols 1, 2 and 3, positive reactions were experienced by 52%, 55%, and 66% of patients, respectively. Radioallergosorbent tests and skin prick tests were shown to have 40% and 71% sensitivity, respectively, and 74% and 77% specificity for predicting a positive food challenge. APPLICATIONS/CONCLUSIONS: The high prevalence of food intolerance in patients with brittle asthma was confirmed, as was the poor positive predictive value of skin prick tests and radioallergosorbent tests. The food challenge method developed enables standardized identification of food intolerances in patients with brittle asthma and may be useful in other groups.

Pulmonary function and respiratory symptoms in a population of airport workers.

OBJECTIVES: To assess the prevalence of respiratory symptoms and to measure spirometry in a sample of employees of Birmingham International Airport, United Kingdom, to examine whether occupational exposure to aircraft fuel or jet stream exhaust might be associated with respiratory symptoms or abnormalities of lung function. METHODS: Cross sectional survey by questionnaire and on site measurement of lung function, skin prick tests, and exhaled carbon monoxide concentrations. Occupational exposure was assigned by job title, between group comparison were made by logistic regression analysis. RESULTS: 222/680 full time employees were studied (mean age 38.6 y, 63% male, 28% current smokers, 6% self reported asthma, 19% self reported hay fever). Upper and lower respiratory tract symptoms were common and 51% had one or more positive skin tests. There were no significant differences in lung function tests between exposure groups. Between group comparisons of respiratory symptoms were restricted to male members of the medium and high exposure groups. The adjusted odds ratio (OR) for cough with phlegm and runny nose were found to be significantly associated with high exposure (OR 3.5, 95% confidence interval (95% CI) 1.23 to 9.74 and 2.9, 1.32 to 6.40 respectively) when the measured confounding effects of age and smoking, and in the case of runny nose, self reported hay fever had been taken into account. There was no obvious association between high exposure and the presence of shortness of breath or wheeze, or for the symptoms of watering eyes or stuffy nose. CONCLUSIONS: These findings support an association in male airport workers, between high occupational exposures to aviation fuel or jet stream exhaust and excess upper and lower respiratory tract symptoms, in keeping with a respiratory irritant. It is more likely that these effects reflect exposure to exhaust rather than fuel, although the effects of an unmeasured agent cannot be discounted.

Sensitivity and exposure to indoor allergens in adults with differing asthma severity.

In asthma, it is uncertain whether there is an association between degrees of exposure to domestic allergens and asthma severity. The pattern of sensitivity and exposure to common indoor allergens was examined in subjects with differing asthma severity. Sensitivity to house dust mite, dog and cat allergen and exposure to Der p 1, Can f 1 and Fel d 1 were assessed by skin prick tests and settled dust analysis in 28 subjects with severe asthma and 28 age- and sex-matched subjects with mild asthma (two declined skin prick test). All severe asthmatic subjects had at least one positive skin test and 20 of the 28 subjects were positive to all three allergens. Fourteen of the 26 subjects with mild asthma who took skin prick tests were positive to at least one, and one of these subjects was positive to the three allergens tested. Except for bedroom Fel d 1, the proportion of severe asthmatics both sensitized and exposed to each allergen at each site was significantly greater than the proportion sensitized and exposed in the mild asthma group. The geometric mean allergen concentrations, with the exception of bedroom Fel d 1, were greater in sensitized severe asthmatics than the sensitized mild asthmatics, which was significant for Der p 1 in bedroom samples and Can f 1 in bedroom and living room samples. These results support an association between the degrees of domestic allergen exposure in sensitized individuals and asthma severity.

Dietary antioxidants and magnesium in type 1 brittle asthma: a case control study.

BACKGROUND: Type 1 brittle asthma is a rare form of asthma. Atopy, psychosocial factors and diet may contribute to this condition. As increased dietary magnesium has a beneficial effect on lung function and selenium, vitamins A, C and E have antioxidant properties, a study was undertaken to test the hypothesis that patients with brittle asthma have diets deficient in these nutrients compared with subjects with non-brittle asthma and healthy adults. METHODS: A case control study of the dietary intakes of 20 subjects with brittle asthma, 20 with non-brittle asthma, and 20 healthy adults was performed using five day weighed dietary records. Intake of magnesium was the primary outcome measure with selenium and vitamins A, C and E as secondary outcomes. Serum levels were measured at the same time as the dietary assessment. RESULTS: Sixty subjects (27 men) of mean age 49.5 years were recruited and completed the study. Subjects with brittle asthma had statistically lower median dietary intakes of vitamins A and E than the other groups (vitamin A: brittle asthma 522.5 micrograms/day, non-brittle asthma 869.5 micrograms/day, healthy adults 806.5 micrograms/day; vitamin E: brittle asthma 4.3 mg/day, non-brittle asthma 4.6 mg/day, healthy adults 4.5 mg/day). Median dietary intakes for the other nutrients were not significantly different between groups. Serum levels were within normal ranges for each nutrient in all subjects. Intakes less than the reference nutrient intake (RNI) for magnesium and vitamins A and C, and less than the safe intake (SI) for vitamin E were more likely in patients with brittle asthma than in those with non-brittle asthma. CONCLUSION: Nutrient deficiency and reduced antioxidant activity may contribute to disease activity in type 1 brittle asthma, although a prospective study of replacement therapy will be needed to confirm this hypothesis.

Acute inhalation of cigarette smoke increases lower respiratory tract nitric oxide concentrations.

BACKGROUND: Cigarette smoking is associated with a number of common pulmonary diseases including chronic airflow limitation and bronchial carcinoma. Lower respiratory tract (LRT) nitric oxide (NO) concentrations are reduced in habitual cigarette smokers between cigarettes, and although this finding has been implicated in the pathogenesis of smoking related disease, the underlying mechanisms are unclear. A study was undertaken to determine the nature and time course for changes in LRT NO concentrations following acute inhalation of cigarette smoke. METHODS: Twenty four healthy habitual smokers were studied. The concentration of LRT NO in exhaled breath before, one and ten minutes after smoking a single cigarette was measured using chemiluminescence. RESULTS: LRT NO concentrations increased in all subjects from a mean (SE) of 2.6 (0.27) to 4.8 (0.26) ppb (p < 0.0001) at one minute, and at 10 minutes remained significantly raised above the baseline level at 3.2 (0.25) ppb (p = 0.003). The mean (95% CI) increases in NO concentrations were 2.2 (1.7 to 2.7) and 0.6 (0.2 to 1.0) ppb, respectively. CONCLUSIONS: These findings were unexpected in both their direction and time course. They suggest a novel mechanism for the handling of NO in the human lung. We hypothesise that NO is trapped in the epithelial lining fluid (ELF) of the normal human respiratory tract in bioequivalent forms such as S-nitrosothiols or peroxynitrite and that this trapping mechanism is sensitive to the redox state of the ELF. LRT NO concentrations will thus increase with oxidant exposure and decline as pulmonary antioxidant defence mechanisms take effect. These findings may have implications for the pathogenesis and diagnosis of oxidant mediated pulmonary disease.

Chlamydia pneumoniae and asthma.

BACKGROUND: This study was designed to test the association of Chlamydia pneumoniae infection with asthma in a multi-racial population, after adjustments for several potential confounding variables. METHODS: Antibodies to C pneumoniae were measured by microimmunofluorescence in 123 patients with acute asthma, 1518 control subjects admitted to the same hospital with various non-cardiovascular, non-pulmonary disorders, and 46 patients with severe chronic asthma, including some with "brittle" asthma. Acute infection or reinfection was defined by titres of IgG of > or = 512 or IgM > or = 8 or a fourfold rise in IgG, and previous infection by IgG 64-256 or IgA > or = 8. Logistic regression was used to control for likely confounders, including ethnic origin, age, sex, smoking habit, steroid medication, diabetes mellitus and social deprivation, on antibody levels. RESULTS: Antibody titres consistent with acute C pneumoniae infection were found in 5.7% of patients with acute asthma and 5.7% of control patients, while 14.6% of patients with acute asthma and 12.7% of control patients had titres suggesting previous infection. These two groups did not differ significantly. However, titres suggesting previous infection were found in 34.8% of patients with severe chronic asthma: the difference between this group and the control group was statistically significant with an adjusted odds ratio of 3.99 (95% confidence interval 1.60 to 9.97). CONCLUSIONS: These data raise important questions about the previously demonstrated association of C pneumoniae infection with asthma, and suggest that future studies of this association should give particular attention to the presence or absence of a history of severe chronic asthma.

Post-infection fatigue syndrome following Q fever.

In 1989, 147 individuals in the West Midlands, UK, were infected with Q fever. Five years later, following anecdotal reports of fatigue, we used a questionnaire-based case-control study to determine the prevalence of chronic fatigue syndrome symptoms in this group. Replies from 71 patients were compared with those from 142 age- and sex-matched controls. Increased sweating (52.9% vs. 31.6%, p = 0.006), breathlessness (50.7% vs. 30.6%, p = 0.006), blurred vision (34.3% vs. 17.8%, p = 0.016) and undue tiredness (68.7% vs. 51.5%, p = 0.03) were found in controls compared to cases. These findings were similar to those in Australian abbatoir workers occupationally exposed to Q fever. CDC criteria for chronic fatigue syndrome were fulfilled by 42.3% of cases and 26% of controls. Using visual analogue scores, symptoms were more severe in cases than in controls. Our findings support the existence of a chronic fatigue state following acute Q fever, in a group of patients exposed just once to the organism, and in circumstances free of such confounding factors as lawsuits over compensation.

Psychological morbidity and coping skills in patients with brittle and non-brittle asthma: a case-control study.

BACKGROUND: An association between psychological morbidity and asthma is well recognized and an increase in negative psychosocial factors in brittle asthma has been previously reported. Such factors, apart from affecting patient perceptions, may alter patients' self-management of their condition. METHODS: We have undertaken a case-control study on 29 well characterized brittle and non-brittle asthmatics in the West Midlands Region to assess their level of psychological morbidity, using the General Health Questionnaire (GHQ) and the living with asthma questionnaire, and their responses to changes in asthma symptoms, using the Asthma Symptom Checklist and a taped interview. RESULTS: Significant differences in GHQ (mean score brittle 19.5 vs non-brittle 7.2, P = 0.0002) and living with asthma (mean score brittle 1.30 vs non-brittle 1.00, P = 0.002) reinforced the presence of psychological factors in this group of patients with severe asthma. Interviews regarding responses to hypothetical asthma attacks showed that patients with brittle asthma delayed seeking medical attention more often than those with non-brittle asthma and instead preferred to self-administer beta-agonist medication. Sixteen (55.2%) of the 29 patients with brittle asthma would have delayed 7 days before seeking medical attention in a slow onset attack compared with 6/29 (20.7%) in the non-brittle group. In a fast onset attack 14 (48.3%) patients with brittle asthma would not have summoned help, despite finding it difficult to walk to the kitchen for a drink whereas in the non-brittle group 24 out of 29 (82.8%) would have summoned help. Levels of family support tended to be lower in patients with brittle asthma (mean family APGAR 7.3 vs 8.65 P = 0.09). CONCLUSIONS: Brittle asthma is associated with greater psychological morbidity and altered strategies for coping with deteriorating asthma symptoms. Attention should be paid to the presence of such factors in the management of patients with brittle asthma.

Potential effects of correction of inaccuracies of the mini-Wright peak expiratory flow meter on the use of an asthma self-management plan.

BACKGROUND: Patient self-management plans for asthma use peak expiratory flow (PEF) meter readings for decisions on adjusting asthma treatment. PEF meters have been shown to be inaccurate and the effect of this inaccuracy on such treatment plans has been determined. METHODS: PEF measurements were made by 127 severe asthmatic patients at least twice a day for at least two weeks using a mini-Wright meter. The daily variation from "best" PEF and the within day PEF variability were calculated before and after correction for the meter's known inaccuracy. The effect of this data correction on the number of days when trigger points were reached for changing asthma therapy was then determined. RESULTS: Continuous PEF readings were available from 114 subjects with a median of 157.5 days of data per subject (range 15-489 days). Correction of the PEF data led to the number of days of satisfactory asthma control being reduced in 72% of subjects with just one subject showing an increase in satisfactory control. Data correction reduced the percentage of total days of satisfactory control from 46% to 36% of days, and increased the days requiring more inhaled steroids from 33% to 36%. The days on which a course of oral corticosteroids was required increased from 16% to 23%. CONCLUSIONS: The accuracy of PEF meters significantly influences the interpretation of currently used asthma self-management plans. Managing asthma with the corrected PEF data would have increased the amount of treatment received by these patients since the severity of the asthma was underestimated by the raw data.

Effect of domestic concentrations of nitrogen dioxide on airway responses to inhaled allergen in asthmatic patients.

Nitrogen dioxide is a common indoor pollutant. In the light of suggestions that outdoor air pollution can harm people with asthma, we investigated the effect of 1 h exposures to domestic concentrations of nitrogen dioxide on the airway response to house-dust mite (HDM) allergen in ten patients with mild asthma. Each subject breathed air, 100 ppb nitrogen dioxide, or 400 ppb nitrogen dioxide for 1 h, in double-blind, random order, then immediately underwent a fixed-dose HDM challenge. Baseline forced expiratory volume in 1 s (FEV1) was not affected by any of the gas mixtures. The mean early asthmatic response (maximum percentage change in FEV1 during first 2 h after challenge) was -14.62% (SD 8.03) after air, -14.41% (7.86) after 100 ppb nitrogen dioxide, and -18.64% (7.28) after 400 ppb nitrogen dioxide. The difference between air and 400 ppb (-4.01%) was significant (95% CI -1.34 to -6.69%, p < 0.009), but those between air and 100 ppb and between 100 and 400 ppb were not (0.21 [-3.10 to 3.53]% and -4.23 [-8.75 to 0.29]%). The mean late asthmatic response (maximum percentage change in FEV1) to challenge after air was -2.85% (3.95), after 100 ppb nitrogen dioxide -7.76% (6.92), and after 400 ppb -8.13% (6.64). The difference in means between the air and 400 ppb exposures was significant (-5.28 [-0.73 to -9.83]%, p < 0.02) but those between air and 100 ppb (-4.90 [-10.60 to 0.78]%) and 100 and 400 ppb (0.37 [3.06 to 3.80]%) were not. These findings suggest that nitrogen dioxide, at concentrations encountered in the home environment, can potentiate the specific airway response of patients with mild asthma to inhaled HDM allergen, although the effect is small.