Sputum and serum calprotectin are useful biomarkers during CF exacerbation.

BACKGROUND: Adequate monitoring of cystic fibrosis lung disease is difficult. CF exacerbation offers a unique setting to test the utility of biomarkers in the assessment of changing airways inflammation. We hypothesised that levels of calprotectin in sputum (and serum) would change informatively following treatment of an exacerbation. METHODS: 27 patients with CF were recruited at onset of pulmonary exacerbation. Sputum and serum were collected at the start and end of anti-biotic therapy. Sputum calprotectin, interleukin-8 (IL8), and myeloperoxidase (MPO) were measured, as were serum calprotectin, CRP and vascular endothelial growth factor (VEGF). RESULTS: Sputum calprotectin decreased following treatment of an exacerbation (p<0.05), and was superior to other sputum markers. Serum calprotectin, CRP, and VEGF also decreased significantly (p=0.002, p=0.002, p=0.013 respectively). Serum calprotectin level following treatment had predictive value for time to next exacerbation (p=0.032). CONCLUSIONS: This study demonstrates the superiority of calprotectin (in sputum and serum) as a biomarker of CF exacerbation over better-established markers.

Ventilation heterogeneity in children with well controlled asthma with normal spirometry indicates residual airways disease.

BACKGROUND: In adults with asthma, ventilation heterogeneity, independent of inflammation, has been hypothesised to be associated with airway remodelling. Bronchial biopsy in preschool children with wheeze demonstrates early structural changes. Ventilation heterogeneity is sensitive to airway disease in other paediatric respiratory conditions such as cystic fibrosis, so may be sensitive to early airway disease in asthma. An observational study was performed in which it was hypothesised that ventilation heterogeneity (lung clearance index (LCI) and phase III slope indices (S(cond) and S(acin))) were more sensitive than conventional measurements (forced expiratory volume in 1 s (FEV(1)) and exhaled nitric oxide (Feno)) for detecting residual airways disease in children with well controlled asthma. METHODS: In 31 children with asthma of mean age 10.6 years (range 5-15), FEV(1), LCI, S(cond) and S(acin) were measured at two separate visits, before and after blinded salbutamol or placebo, with Feno measured once. 29 healthy volunteers of mean age 11.2 years (range 5-16) completed measurements at one visit only. RESULTS: Baseline mean (SD) LCI was significantly higher in children with asthma than in controls (6.69 (0.91) vs 6.24 (0.47), p = 0.02). There were no significant differences in FEV(1) or median Feno. Following salbutamol there was a small significant change in mean (SD) FEV(1) (from -1.26 (1.25) to -0.93 (0.23), p = 0.03) but not in LCI, S(cond) or S(acin). Importantly, LCI remained significantly higher after bronchodilator in children with asthma than in controls (6.64 (0.69), p = 0.01). CONCLUSION: This study identifies the presence of residual ventilation heterogeneity in children with well controlled asthma and normal FEV(1). The role of LCI in measuring early airway disease in children with asthma requires further exploration, possibly as a surrogate of structural remodelling.

Lung clearance index is a sensitive, repeatable and practical measure of airways disease in adults with cystic fibrosis.

BACKGROUND: Lung clearance index (LCI) is a sensitive marker of early lung disease in children but has not been assessed in adults. Measurement is hindered by the complexity of the equipment required. The aims of this study were to assess performance of a novel gas analyser (Innocor) and to use it as a clinical tool for the measurement of LCI in cystic fibrosis (CF). METHODS: LCI was measured in 48 healthy adults, 12 healthy school-age children and 33 adults with CF by performing an inert gas washout from 0.2% sulfur hexafluoride (SF6). SF6 signal:noise ratio and 10-90% rise time of Innocor were compared with a mass spectrometer used in similar studies in children. RESULTS: Compared with the mass spectrometer, Innocor had a superior signal:noise ratio but a slower rise time (150 ms vs 60 ms) which may limit its use in very young children. Mean (SD) LCI in healthy adults was significantly different from that in patients with CF: 6.7 (0.4) vs 13.1 (3.8), p<0.001. Ten of the patients with CF had forced expiratory volume in 1 s > or = 80% predicted but only one had a normal LCI. LCI repeats were reproducible in all three groups of subjects (mean intra-visit coefficient of variation ranged from 3.6% to 5.4%). CONCLUSIONS: Innocor can be adapted to measure LCI and affords a simpler alternative to a mass spectrometer. LCI is raised in adults with CF with normal spirometry, and may prove to be a more sensitive marker of the effects of treatment in this group.

Respiratory heat and moisture loss is associated with eosinophilic inflammation in asthma.

Increased mucosal vascularity is a hallmark of airway inflammation in asthma. It was hypothesised that this would lead to a detectable increase in respiratory heat and moisture loss (RHML), which would reflect the degree of airway inflammation present. A total of 23 subjects with asthma and 18 healthy controls had RHML measured in a cross-sectional study. The measurements were made using a device that combines temperature and humidity measurement during inspiration and expiration and allows precise control over inspirate conditions and ventilatory pattern. The subjects with asthma underwent parallel measurements of exhaled nitric oxide, sputum eosinophil percentage and exhaled breath condensate pH. Mean+/-SD RHML was elevated in patients with asthma (98.1+/-7.3 J.L(-1)) compared with control subjects (91.9+/-4.5 J.L(-1)). RHML measurement in asthma correlated with sputum eosinophil percentage. This novel correlation between thermal and cellular measurements in asthma suggests that both of these noninvasive indices are sensitive to the degree of underlying chronic airway inflammation.

Breath condensate ammonium is lower in children with chronic asthma.

Exhaled breath condensate pH and ammonium reflect asthmatic status and acute exacerbations in adults. The aim of this study was to assess whether pH and ammonium could reflect asthma and its severity in children. The current study comprised two parts: 1) a cross-section of 74 children with asthma (median age 10.5 yrs) compared with 47 healthy controls (median age 10 yrs); and 2) longitudinal assessment of eight children (mean age 8.5 yrs) admitted with asthma exacerbation. Condensate pH and ammonium were compared with clinical observations. In the cross-sectional part of the study, lower per cent forced expiratory volume in one second was associated with more symptoms and treatment. There was no significant difference between median pH in children with stable asthma (6.05) compared with controls (5.90). Ammonium was significantly lower in children with asthma (median 258 microM) compared with controls (median 428 microM). No association was found between ammonium or pH and lung function or symptom-free days. In the longitudinal study, significant improvements in oxygen saturation and respiratory rate with treatment of an acute exacerbation were not reflected by changes in pH or ammonium. In conclusion, pH does not appear to reflect disease or severity in children with asthma. Ammonium was significantly lower in children with asthma when compared with controls.

Effects of breathing pattern and inspired air conditions on breath condensate volume, pH, nitrite, and protein concentrations.

BACKGROUND: The effects of breathing pattern and inspired air conditions on the volume and content of exhaled breath condensate (EBC) were investigated. METHODS: Total exhaled water (TEW), EBC volume, pH, nitrite and protein concentrations were measured in three groups of 10 healthy subjects breathing into a condenser at different target minute ventilations (Vm), tidal volumes (Vt), and inspired air conditions. RESULTS: The volumes of both TEW and EBC increased significantly with Vm. For Vm 7.5, 15 and 22.5 l/min, mean (SD) EBC was 627 (258) microl, 1019 (313) microl, and 1358 (364) microl, respectively (p<0.001) and TEW was 1879 (378) microl, 2986 (496) microl, and 4679 (700) microl, respectively (p<0.001). TEW was significantly higher than EBC, reflecting a condenser efficiency of 40% at a target Vm of 7.5 l/min which reduced to 29% at Vm 22.5 l/min. Lower Vt gave less TEW than higher Vt (26.6 v 30.7 microl/l, mean difference 4.1 (95% CI 2.6 to 5.6), p<0.001) and a smaller EBC volume (4.3 v 7.6 microl/l, mean difference 3.4 (95% CI 2.3 to 4.5), p<0.001). Cooler and drier inspired air yielded less water vapour and less breath condensate than standard conditions (p<0.05). Changes in the breathing pattern had no effect on EBC protein and nitrite concentrations and pH. CONCLUSION: These results show that condensate volume can be increased by using high Vt and increased Vm without compromising the dilution of the sample.

Airways in cystic fibrosis are acidified: detection by exhaled breath condensate.

BACKGROUND: The loss of cystic fibrosis transmembrane conductance regulator (CFTR) mediated chloride conductance does not fully explain the diverse pathologies evident in patients with cystic fibrosis (CF). Bicarbonate (HCO(3)(-)) secretion is also impaired in CFTR expressing tissues and CFTR is thought to regulate HCO(3)(-) secretion at the apical membrane of epithelial cells. We hypothesised that the epithelial lining fluid (ELF) of patients with CF would be acidified and that this may be worsened during an infective exacerbation due to the increased inflammatory burden. METHODS: pH and nitrite levels in exhaled breath condensate (EBC) from 12 healthy non-smoking controls and 30 patients with CF (11 of whom were in an infective exacerbation) were measured. A further nine patients were studied before and after intravenous antibiotic treatment for an exacerbation of CF. RESULTS: The pH of EBC was significantly lower in patients with stable CF than in controls (5.88 (0.32) v 6.15 (0.16), p=0.017), and was further reduced in CF patients with an exacerbation (5.32 (0.38), p=0.001) compared with stable CF patients. EBC pH increased significantly following antibiotic treatment from 5.27 (0.42) to 5.71 (0.42), p=0.049). Nitrite levels in EBC were increased in CF patients with an exacerbation compared with control subjects (4.4 (4.0) micro m v 1.6 (1.6) micro m p=0.047). No correlation was found between EBC pH and nitrite levels. CONCLUSIONS: These findings support the hypothesis that airway acidification occurs in CF. This acidity is in part a function of inflammation as the pH of the EBC of patients increased significantly with treatment of an exacerbation, although not to control levels. Acidic pH of the ELF may play a role in the pathophysiology of CF lung disease and requires further investigation.

Alveolar macrophage activity and the pulmonary complications of haematopoietic stem cell transplantation.

BACKGROUND: The success of haematopoietic (bone marrow or peripheral blood) stem cell transplantation (SCT) is compromised by pulmonary complications. We hypothesised that a proinflammatory alveolar microenvironment, reflected in alveolar macrophage (AM) cytokine production, would predispose to such complications. METHODS: AM were isolated from adult SCT recipients by bronchoalveolar lavage before SCT (n=32) and during post-transplant pancytopenia (n=23). Concentrations of tumour necrosis factor (TNF)alpha, granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin (IL)-1 beta, IL-6, and IL-8 in 24 hour AM culture medium were measured by enzyme linked immunosorbent assay and compared with both the occurrence of post-SCT lung disease and with subjects' previous respiratory histories. RESULTS: Eleven subjects developed lung disease within 6 months of SCT. These subjects had higher median pre-transplant AM TNFalpha (8 (IQR 1-8) v 2 (1-5) ng/10(6)AM, p=0.01, median difference (D) = 3, 95% CI 0.1 to 7), GM-CSF (5 (0.7-8) v 0.2 (0.1-0.8), p=0.006, D = 4, 95% CI 0.5 to 7), and IL-6 (0.5 (0.1-1) v 0.1 (0.02-0.3), p=0.049, D = 0.3, 95% CI 0.0002 to 1) production than remaining subjects; IL-1 beta and IL-8 did not differ. During pancytopenia high AM GM-CSF production again predicted later lung disease (1 (0.7-9) v 0.1 (0.06-0.3), p=0.01, D = 1, 95% CI 0.1 to 6). A history of recent chest disease was associated with high AM TNFalpha and GM-CSF production and with post-SCT lung disease. Pre-SCT lung function was unrelated to post-SCT lung disease. CONCLUSIONS: Recent respiratory disease and persistent proinflammatory AM behaviour detectable before transplantation are associated with lung disease following SCT. These associations may prove useful in pre-transplant risk assessment.

Atopy influences exhaled nitric oxide levels in adult asthmatics.

STUDY OBJECTIVE: To examine whether atopy influences exhaled nitric oxide (NO) levels in adults with established asthma. SETTING: Specialist respiratory unit in a university teaching hospital. PATIENTS: Twenty-eight asthmatics (mean FEV(1), 85.7%) receiving short-acting inhaled bronchodilators and a range of inhaled steroids (0 to 4,000 microg/d). INTERVENTIONS: Subjects were studied on two occasions, 5 to 7 days apart, between September and March. MEASUREMENTS AND RESULTS: On the first day, FEV(1), exhaled NO, and histamine challenge were performed. On the second day, exhaled NO, total IgE, and skin-prick testing to six common allergens were conducted. Exhaled NO was measured with the single exhalation method. We found exhaled NO levels to correlate positively with total IgE (r = 0.43, p = 0.02) and number of positive skin-prick tests (p = 0. 002). By contrast, there was no significant correlation between exhaled NO and FEV(1) or the provocative concentration causing a 20% fall in FEV(1). Subanalyses of steroid-treated and steroid-naive patients in this group revealed the same findings. CONCLUSION: Exhaled NO levels in asthmatics correlate more closely with atopy than with bronchial hyperreactivity and lung function.

The current single exhalation method of measuring exhales nitric oxide is affected by airway calibre.

The authors have observed that some patients with acute exacerbations of asthma do not have substantially higher levels of exhaled nitric oxide (NO). The study examined whether this could be explained by the effect of airway calibre on exhaled NO. Exhaled NO, height and forced expiratory volume in one second (FEV1) were measured in 12 steroid-naive asthmatics and 17 normal subjects. For comparison, another group of patients with airways disease (34 cystic fibrosis patients) were also studied. In 20 asthmatics (on various doses of inhaled steroids, 0-3,200 microg x day-1), exhaled NO was measured before and after histamine challenge (immediately after reaching the provocative concentration causing a 20% fall in FEV1) and in 12 of these patients, also after nebulized salbutamol to restore FEV1 to baseline. Studies were also conducted to examine possible confounding effects of repeated spirometry (as would occur in histamine challenge) and nebulized salbutamol alone in exhaled NO levels. Exhaled NO was measured using a single exhalation method with a chemiluminescence analyser at a constant flow rate and mouth pressure. There was a significant correlation between FEV1 and exhaled NO in steroid naive asthmatics (r=0.9, p<0.001) and cystic fibrosis patients (r=-0.48, p<0.05) but not in normal subjects (r=-0.13, p=0.61). Exhaled NO decreased significantly after histamine challenge and returned to baseline after bronchodilation by nebulized salbutamol (mean+/-SEM: 23.6+/-3.6 parts per billion (ppb) (prehistamine), 18.2+/-2.7 ppb (posthistamine) and 23.6+/-3.8 ppb (postsalbutamol) p=0.001). Repeated spirometry and nebulized salbutamol did not affect exhaled NO measurements significantly. Exhaled nitric oxide levels appear to be lower in circumstances of smaller airway diameter. Hence, within a subject nitric oxide levels may be artefactually decreased during bronchoconstriction. This may be caused by increased airflow velocity in constricted airways when the exhalation rate is kept constant.

Measurement of inflammatory markers in the breath condensate of children with cystic fibrosis.

Identifying noninvasive markers of pulmonary inflammation would be useful in assessing new therapies in children. Breath condensate is a simple and potentially acceptable sample medium even in small children. The technique has previously been used in adults, but not children with cystic fibrosis. The technique was assessed in 36 children with cystic fibrosis (mean age 10.4 yrs) and 17 control subjects, analysing samples for nitrite, interleukin(IL)-8 and salivary and nasal contamination. Correlations were made between levels of the inflammatory markers and forced expiratory volume in one second/forced vital capacity, chest radiograph score and use of inhaled steroids. On samples without significant contamination (<10 u x L(-1) amylase) nitrite was detected in 93% of samples at a median concentration of 3.0 microM compared with 50% of control samples at a median of 0.5 microM. Condensate amylase levels did not correlate with the nitrite value obtained (r=0.31). IL-8 was detected in 33% of CF samples. Breath condensate is an acceptable method of sample collection in children. Nitrite was raised in breath condensate from patients with cystic fibrosis when compared with control subjects.

Comparison of Pulmicort pMDI plus Nebuhaler and Pulmicort Turbuhaler in asthmatic patients with dysphonia.

BACKGROUND: Dysphonia is a known local adverse effect of inhaled corticosteroids. This symptom was investigated by laryngoscopy and assessment in a voice laboratory. The effects of changing the treatment of patients with dysphonia, reported whilst using the pMDI, to pMDI plus Nebuhaler or Tubuhaler was also assessed. METHODS: Seventy-two patients reporting dysphonia and taking inhaled steroids from a pMDI entered a 12-week, open, parallel group study. Fifty-one completed the study per protocol; 26 in the Nebuhaler group [21 female, mean age 57 years (22-77)] and 25 in the Turbuhaler group [18 female, mean age 58 years (21-81)]. A dysphonia diary card was completed weekly. Voice laboratory assessments and laryngoscopy were performed on entry and at 12 weeks. RESULTS: There were no differences in voice laboratory data, laryngoscopic evidence of disordered glottic closure and diary data between the two groups at 12 weeks. At study entry laryngoscopic appearances were normal in almost half the patients. Vocal cord bowing was rarely seen. Glottic closure changed in nine patients during the study period, but there was no correlation with voice symptoms. The trend of symptomatic improvement of voice status in the Turbuhaler group did not correlate with voice laboratory assessments and laryngoscopic evidence of disordered glottic closure. After 4 weeks, 40% of patients using Turbuhaler and 8% in the Nebuhaler group scored their voice status as better (P < 0.02) but there was no significant difference between the two groups at 12 weeks (Turbuhaler 52%, Nebuhaler 23%, P=0.08). CONCLUSION: This study does not support the view that dysphonia in asthmatics inhaling corticosteroids is usually caused by myopathic bowing of the vocal cord muscles.

Emergency pre-hospital management of patients admitted with acute asthma.

BACKGROUND: Little is known about the management of acute asthma prior to hospital admission. Pre-hospital treatment of patients referred to hospital with acute asthma was therefore studied in 150 patients divided into three groups: those in the Edinburgh Emergency Asthma Admission Service (EEAAS) who can contact an ambulance and present directly to respiratory services when symptoms arise (n = 38), those under continuing supervision at a hospital respiratory outpatient clinic (n = 54), and those managed solely in primary care (n = 58). METHODS: Standardised admission forms detailing aspects of pre-hospital management, case records, GP referral letters, and ambulance patient transport forms were analysed. RESULTS: In each group airflow obstruction had improved upon arrival at hospital, the effect being most marked in patients transported by ambulance (p<0. 001) and in those receiving nebulised beta(2) agonists prior to admission (p<0.005). However, 25% of patients arrived without having nebulised beta(2) agonists and 37% without having glucocorticoids. EEAAS patients were least likely to receive nebulised beta(2) agonists before arrival at hospital (p<0.05). This observation was attributable to a tendency for these patients to travel to hospital by car rather than by ambulance. CONCLUSIONS: There is an important shortfall in administration of bronchodilators and glucocorticoids for acute asthma before arrival at hospital. Ambulances equipped with nebulised bronchodilators provide the optimal mode of transport to hospital for patients with acute asthma. In Edinburgh ambulances are not being used by a significant proportion of the population with asthma, possibly because of the mistaken belief that personal transport arrangements reduce journey time to hospital.

The safety and usefulness of routine bronchoscopy before stem cell transplantation and during neutropenia.

Fibreoptic bronchoscopy with bronchoalveolar lavage (BAL) is used for clinical investigation and research into pulmonary complications of stem cell transplantation. Adverse effects of BAL are common in neutropenic patients with lung disease; there are few data on its safety when used routinely in transplant recipients without lung impairment. We describe the complications and usefulness for infection surveillance of routine BAL pre-transplantation and during neutropenia. Thirty-three patients before autologous or allogeneic BMT or PBSCT (B1) and 24 during post-transplant neutropenia (B2) underwent BAL; patients with pulmonary disease were excluded. Subjects were monitored for adverse effects, and BAL fluid was examined for pathogens. Complications of B2 were compared with events seen in 35 neutropenic patients who did not undergo BAL (C). Eighteen percent B1 and 33% B2 subjects showed complications of BAL. Fever occurred in 12% B1 and 26% previously afebrile B2 subjects, compared to 11% of C (P = 0.3). Epistaxis occurred in one B2 subject and two C. Potentially pathogenic organisms were isolated from 18% B1 and 13% B2 BAL fluids; none caused later respiratory infection. Bronchoscopy and BAL pre- and post-transplant had acceptable safety for a research procedure, but were not clinically helpful for infection surveillance.

Expired hydrogen peroxide in breath condensate of cystic fibrosis patients.

Stimulated inflammatory cells release large amounts of hydrogen peroxide (H2O2). Breath condensate H2O2 has been shown to be elevated in stable asthmatic children, chronic obstructive pulmonary disease and intubated adult respiratory distress syndrome. In cystic fibrosis airways, where neutrophilic inflammation dominates, it is postulated that H2O2 in breath condensate would be elevated and may be used as a marker of airways inflammation. Expired breath condensate was collected from 16 clinically stable cystic fibrosis (CF) patients (mean age 25.3 yrs, mean forced expiratory volume in one second (FEV1) 50.2%) and 14 normal subjects (mean age 29.9 yrs). Total plasma leukocyte, neutrophil, monocyte and eosinophil counts and lung function were also measured on the day of collection. A method of breath condensate collection excluding the confounding factors of nasal air and saliva contamination was validated and used and H2O2 measured fluorometrically using an optimized assay. The median level of H2O2 concentration in breath condensate of CF patients was lower than that in normal subjects (0.064 versus 0.089 microM), but this did not reach statistical significance (p = 0.20, Mann-Whitney rank sum test). Within the CF group, there was no correlation between H2O2 concentration and lung function. Expired breath condensate H2O2 is not elevated in patients with cystic fibrosis, and is thus not a suitable marker of airways inflammation in these patients. Possible explanations include physical barriers to its detection caused by viscous airways secretions, reaction with other reactive species or increased antioxidant activity caused by trapping of positively charged antioxidants in negatively charged airways secretions.

Recombinant DNase in cystic fibrosis: a protocol for targeted introduction through n-of-1 trials. Scottish Cystic Fibrosis Group.

Nebulized recombinant human deoxyribonuclease (DNase) reduces sputum viscosity and improves lung function in some cystic fibrosis patients, but individual responses are unpredictable. The aim of this study was to investigate how DNase can be targeted to those cystic fibrosis patients who would benefit most. The Scottish Cystic Fibrosis Group agreed on a randomized, double-blind, placebo-controlled n-of-1 assessment protocol. Patients underwent a maximum of three 4-week assessment periods (2 weeks saline, 2 weeks DNase each). Measurements performed at hospital (exercise, oximetry and spirometry) and home (symptom scores) were used to derive a scoring system to discriminate maximally between DNase and placebo effects. The data on 89 4-week assessments in 52 patients were reported. Twenty-four patients have completed the assessment process (12 responders and 12 nonresponders) to date. Forced expiratory volume in one second (FEVI) was the best discriminator of response, rising by >200 mL after DNase in 33 of 89 (37%) assessments compared with 3 of 89 (3%) after saline. N-of-1 trials, while laborious, permitted genuine treatment effects to be quantified within individuals with confidence, permitting appropriate treatment targeting. This provides a model of how other new expensive therapies may be introduced to maximize patient benefit.

Nitrite levels in breath condensate of patients with cystic fibrosis is elevated in contrast to exhaled nitric oxide.

BACKGROUND: Nitric oxide (NO) is released by activated macrophages, neutrophils, and stimulated bronchial epithelial cells. Exhaled NO has been shown to be increased in patients with asthma and has been put forward as a marker of airways inflammation. However, we have found that exhaled NO is not raised in patients with cystic fibrosis, even during infective pulmonary exacerbation. One reason for this may be that excess airway secretions may prevent diffusion of gaseous NO into the airway lumen. We hypothesised that exhaled NO may not reflect total NO production in chronically suppurative airways and investigated nitrite as another marker of NO production. METHODS: Breath condensate nitrite concentration and exhaled NO levels were measured in 21 clinically stable patients with cystic fibrosis of mean age 26 years and mean FEV1 57% and 12 healthy normal volunteers of mean age 31 years. Breath condensate was collected with a validated method which excluded saliva and nasal air contamination and nitrite levels were measured using the Griess reaction. Exhaled NO was measured using a sensitive chemiluminescence analyser (LR2000) at an exhalation rate of 250 ml/s. Fourteen patients with cystic fibrosis had circulating plasma leucocyte levels and differential analysis performed on the day of breath collection. RESULTS: Nitrite levels were significantly higher in patients with cystic fibrosis than in normal subjects (median 1.93 microM compared with 0.33 microM). This correlated positively with circulating plasma leucocytes and neutrophils (r = 0.6). In contrast, exhaled NO values were not significantly different from the normal range (median 3.8 ppb vs 4.4 ppb). There was no correlation between breath condensate nitrite and lung function and between breath condensate nitrite and exhaled NO. CONCLUSIONS: Nitrite levels in breath condensate were raised in stable patients with cystic fibrosis in contrast to exhaled NO. This suggests that nitrite levels may be a more useful measure of NO production and possibly airways inflammation in suppurative airways and that exhaled NO may not reflect total NO production.

Totally implantable venous access devices in cystic fibrosis: complications and patients' opinions.

The introduction of totally implantable venous access devices (TIVAD) has provided a solution to difficult venous access in patients with cystic fibrosis. Early reports have, however, recognized a number of complications with their use. We report our experience with five devices used over 8 yrs with regard to complications and patient attitudes. Patients' notes were reviewed to record the details of TIVAD insertion, duration of function, and complications. In January 1996 the surviving 30 patients were surveyed on their attitudes to TIVAD and complications by written questionnaire. Sixty one ports were implanted in 42 patients (aged 16-47 yrs) between June 1988 and January 1996, giving a total of 1,510 patient-months' experience. The duration of function ranged from 2 weeks to 6 yrs. Survival analysis showed that the median survival of ports was 53 months, 42 out of 61 (69%) had not failed in service at the end of follow-up or patient death. Twenty-three complications occurred in 19 patients. These included: line occlusion (10 patients), venous thrombosis (4), difficult access (3), infection (2), cellulitis (1), inversion of port chamber (2) and pneumothorax (1). The questionnaire showed that patients had strong views on the positioning of their port. Lifestyle issues included interference with seatbelts (8 patients), sport (4), clothing (2), sexual relations (2) and cosmetic appearance (15). Complication rates were similar to those in other studies, although infection rates and salvage of an occluded port were lower. The survey highlighted a number of lifestyle issues, with cosmetic appearance deemed unsatisfactory by half of the patients. However, the majority (28 out of 30) believed their totally implantable venous access devices to be a better alternative to cannulae or long lines.

Human circulating eosinophils secrete macrophage migration inhibitory factor (MIF). Potential role in asthma.

Macrophage migration inhibitory factor (MIF) is a potent proinflammatory mediator that has been shown to potentiate lethal endotoxemia and to play a potentially important regulatory role in human acute respiratory distress syndrome (ARDS). We have investigated whether eosinophils are an important source of MIF and whether MIF may be involved in the pathophysiology of asthma. Unstimulated human circulating eosinophils were found to contain preformed MIF. Stimulation of human eosinophils with phorbol myristate acetate in vitro yielded significant release of MIF protein. For example, eosinophils stimulated with phorbol myristate acetate (100 nM, 8 h, 37 degreesC) released 1,539+/-435 pg/10(6) cells of MIF, whereas unstimulated cells released barely detectable levels (< 142 pg/10(6) cells, mean+/-SEM, n = 8). This stimulated release was shown to be (a) concentration- and time-dependent, (b) partially blocked by the protein synthesis inhibitor cycloheximide, and (c) significantly inhibited by the protein kinase C inhibitor Ro-31,8220. In addition, we show that the physiological stimuli C5a and IL-5 also cause significant MIF release. Furthermore, bronchoalveolar lavage fluid obtained from asthmatic patients contains significantly elevated levels of MIF as compared to nonatopic normal volunteers (asthmatic, 797.5+/-92 pg/ml; controls, 274+/-91 pg/ml). These results highlight the potential importance of MIF in asthma and other eosinophil-dependent inflammatory disorders.