Search

Declan J Meagher was a most influential figure in Irish obstetrics and gynaecology during the 1960s, 70s, and 80s, making huge contributions to maternal and infant welfare. He was born in Ferbane, County Offaly, where his father, William Meagher, was the local doctor. This was a time of great turbulence in Ireland between the war of independence and the civil war. Declan was educated initially by the local Christian Brothers and subsequently the Jesuits in Clongowes Wood College in County Kildare. He studied at University College Dublin and graduated with distinction in 1944. He decided on a career in obstetrics and gynaecology and trained initially at the National Maternity Hospital and then at the Hammersmith Hospital in London. By this time he had married Emer McMullin. Later, he was to wryly recall their impecunious postwar London days, living in very spartan, cramped accommodation; meat was a rare treat. On his return to Dublin, now with a young family, he was appointed to the staff of the National Maternity Hospital, the hospital to which he was to devote his life’s work. In 1965 he joined the consultant staff …

Gas exchange during exercise in patients with cystic fibrosis (CF) is characterised by an elevated physiological deadspace to tidal volume ratio. While this has been attributed to alveolar ventilation perfusion mismatch, there are other potential causes of the high proportion of wasted ventilation, including factors relating to the volume and the ventilation of the airway deadspace. CF (n = 6, F = 1, FEV1 26-63% pred) and control (n = 6, F = 2) subjects completed steady-state exercise on a cycle ergometer. Gas exchange was measured breath-by-breath and the volume of the airway deadspace (V(Daw)) determined using the equal areas method. Exercise data were interpolated to a CO2 output of 0.7 l/min. V(Daw) was similar in the two groups both at rest and during exercise. However, the airway deadspace ventilation (V(Daw)) (median (inter-quartile range)), patients, 6.8 (5.1-7.1) l/min; controls, 4.9 (3.5-5.6) l/min, P0.05) was significantly greater in the CF group due to a greater respiratory frequency. These results indicate that in CF patients, abnormally increased V(Daw) is an important contributor to the total (physiological) deadspace ventilation. Exercise performance in CF might be enhanced by efforts directed at facilitating an increase in exercise tidal volume and therefore the adoption of a more efficient pattern of breathing.

The purpose of this study was to examine the role of interstitial collagenases, members of the family of matrix metalloproteinases, in the development of pulmonary fibrosis. The activity, levels and molecular forms of collagenases (matrix metalloproteinases (MMP)-1, -8 and -13), gelatinase B (MM P-9) and its main endogenous inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1) were assessed in bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF) and sarcoidosis patients with varying degrees of pulmonary parenchymal involvement. Collagenase activity was elevated in IPF and group 3 sarcoidosis patients. A positive correlation between BALF collagenase activity and MMP-8 levels was also observed. Western immunoblotting revealed the presence of two isoforms of MMP-8 in patient samples; an 80 kD form representing latent enzyme from polymorphonuclear neutrophils and a 55 kD form representing the fibroblast-type proform. MMP-9 levels were also elevated in both IPF and group 3 sarcoidosis patients, while TIMP-1 levels remained normal, indicating a shift in the balance between the enzyme and inhibitor, favouring MMP-9. Matrix metalloproteinase-8 is the major contributor to the bronchoalveolar lavage fluid collagenase activity in the airways of patients with idiopathic pulmonary fibrosis and sarcoidosis and may initiate collagen destruction and remodelling leading to the development of pulmonary fibrosis.

Repeated bouts of submaximal exercise are an important part of most pulmonary rehabilitation programmes. Patients with moderate-to-severe cystic fibrosis (CF) often demonstrate oxygen desaturation during submaximal exercise, which may limit their ability to participate in these programmes. This study examines whether arterial desaturation contributes to submaximal exercise limitation by testing whether supplemental O2 improves submaximal exercise capacity. Eight patients with CF (mean forced expiratory volume in one second 41% predicted) each underwent two submaximal exercise tests on a bicycle ergometer at 80% of maximal workload. The two tests were identical except for the addition of supplemental O2 (inspiratory O2 fraction 39%) during one of the tests. Exercise duration was significantly longer in the supplemental O2 study versus control (673+/-63 s versus 835+/-99 s). Arterial O2 saturation was also higher in the supplemental O2 study than the control exercise test (96+/-0.3% versus 86+/-1.5%). There was no statistical difference at end exercise between O2 consumption, minute ventilation and heart rate. There was a significant relationship between improvement in exercise capacity and the amount of desaturation during the control exercise test. Results indicate that supplemental oxygen improves submaximal exercise capacity in patients with moderate-to-severe cystic fibrosis. Oxygen therapy may be an important intervention to improve participation and maximise the benefits of pulmonary exercise rehabilitation programmes.

Objective: The anaerobic threshold (AT) is a submaximal index related to endurance exercise performance, which is usually determined by the measurement of blood lactate concentration during an incremental exercise test (lactate threshold [LT]). The LT, and thus the AT, can also be detected noninvasively in normal subjects by means of the gas exchange threshold (GET). This study was undertaken to validate the use of GET in patients with cystic fibrosis (CF) with a wide range of disease severity, and to assess the reproducibility of this index. Methods: In patients with CF (FEV1 range, 23 to 118% of predicted) and control subjects, gas exchange was measured breath by breath during the incremental exercise tests to allow determination of the GET. Arterialized-venous blood was sampled for determination of the LT. The GET and LT were determined in a blinded manner. Results: The mean differences (GET LT) for control subjects (n 18) and patients with CF (n 23) were 40 mL/min and 10 mL/min, respectively, neither being significantly different from zero. The limits of agreement were 550 mL/min and 410 mL/min, respectively. The mean test-retest differences in GET for control subjects (n 14) and patients with CF (n 12) were 50 mL/min and 0 mL/min, respectively, neither being significantly different from zero; the respective limits of reproducibility were 450 mL/min and 350 mL/min. Conclusions: This study demonstrates that in patients with CF, the GET can be used to obtain an unbiased estimate of the LT, and that the GET is reproducible. (CHEST 2002; 121:1761–1770)

In cystic fibrosis (CF), low concentrations of exhaled nitric oxide (NO) and reduced expression of inducible nitric oxide synthase (iNOS) in airway epithelium have been reported. However, abundant iNOS expression has been found in the subepithelial tissues and elevated concentrations of NO metabolites in breath condensate and sputum. These conflicting results may be explained by increased scavenging of NO by superoxide radicals, resulting in rapid conversion to peroxynitrite, so that only a small proportion of the NO produced in the lung tissue reaches the airway lumen. If iNOS were active in the CF lung, exhaled NO would be further reduced by glucocorticoid treatment.CF patients (n=13) were recruited to a double-blind, placebo-controlled study with crossover. Treatment comprised prednisolone or placebo for 5 days with a 9 day washout. After each treatment, exhaled NO was measured, spirometry performed and blood collected for measurement of serum nitrogen dioxide/nitrous oxide (NO2/NO3).Ten patients (8 male) completed the study. Following prednisolone treatment (mean±sd) exhaled NO concentration (3.1±1.6 parts per billion (ppb)) was significantly reducedversusplacebo treatment (4.9±4.2 ppb; p2/NO3concentration were unchanged.These findings support the hypothesis that glucocorticoids suppress nitric oxide production in cystic fibrosis airways by reducing inducible nitric oxide synthase expression or by inhibiting recruitment of neutrophils, cells which express inducible nitric oxide synthase.

Study objectives: To determine whether the adenine (A)-guanine (G) substitution polymorphism at position - 308 on the tumor necrosis factor-a gene confers susceptibility to COPD or to the development of a more severe form of disease. Design: A cross-sectional study was undertaken to compare the frequency of the A allele in a group of 106 patients with COPD with that in a control population (n 5 99). Patients were followed up prospectively for a period of 2 years. Participants and setting: Participants included 106 COPD patients recruited from a respiratory outpatient clinic and 99 control subjects recruited from patients admitted for cardiac catheterization. Measurements and results: DNA was extracted from venous blood, and each subject was genotyped for the polymorphism by polymerase chain reaction amplification and restriction digestion using Nco1. There was no increased frequency of the A allele in patients compared to control subjects. AA homozygous patients had less reversible airflow obstruction (p < 0.05) and a significantly greater mortality (both all-cause and respiratory deaths) on follow-up (p < 0.001), despite a shorter cigarette smoking history. Conclusions: This study suggests that homozygosity for this A allele predisposes to more severe airflow obstruction and a worse prognosis in COPD. (CHEST 2000; 118:971‐975)

Although neutrophil migration from the systemic circulation involves the beta2- (or CD18) integrin family, the existence of an alternative, CD18-independent route of neutrophil extravasation to tissues has been demonstrated in animal models. The molecular interactions involved in this alternative migratory route have not yet been characterized. The objective of this study was to assess the CD18-dependency of neutrophil migration across human endothelial cells from an organ known to support CD18-independent migration, the lung, with a view to establishing an in vitro model to facilitate study of CD18-independent migration. Neutrophil migration across human pulmonary artery endothelial cells (HPAECs) in response to three different chemoattractants, formylmethionyl leucylphenyl-alanine (FMLP), interleukin (IL)-8, and leukotriene (LT) B(4), was examined. Results demonstrated that a function-blocking antibody to CD18 decreased FMLP-stimulated migration by 71.7 +/- 4.4% (P0.001). In contrast, migration in response to LTB(4) was decreased by only 20.5 +/- 10.2% (P0.01), and no significant decrease was observed with migration to IL-8. Neutrophils that migrated to FMLP had 1.7-fold more surface CD11b/CD18 compared with nonmigrated neutrophils (P0.01), whereas this integrin complex was not significantly upregulated on neutrophils that had migrated to IL-8 or LTB(4). Further investigation of this migratory route indicated that it did not involve the beta1 integrins (CD29) or the endothelial selectins, E- or P-selectin, nor did it require the activity of either metalloproteinases or neutrophil elastase. These results indicate that neutrophil migration across HPAECs in vitro to IL-8 and LTB(4) is predominantly CD18-independent and provides a much-needed in vitro system for examination of the neutrophil-endothelial interactions involved in this alternative migratory route.

Objectives Exercise testing in patients with cystic fibrosis (CF) has become an important tool in assessing disease severity and predicting overall outcome. The reproducibility of maximal exercise testing was examined in adult subjects with stable CF. Methods Nine subjects with CF underwent a total of three maximal exercise tests carried out under identical circumstances over a 28-day period. Oxygen uptake ( o 2), minute ventilation ( e ), respiratory frequency (f), heart rate (HR), and arterial oxygen saturation (Sa o 2) were measured at rest, at end exercise, and at 40% and 70% of maximum workload. Results There were no significant differences in these measurements among the three tests. Reproducibility of exercise performance was assessed using the coefficient of variation. The mean within-subject coefficient of variation for test variables at end exercise are as follows: o 2, 6.9%; e , 6.2%; f, 5.8%; HR, 3.0%; and Sa o 2, 1.1%. The mean within-subject coefficient of variation for test variables at 40% and 70% of maximal work rates are as follows: o 2, 5.2% and 4.6%; Sa o 2, 0.3% and 0.9%; HR, 4.0% and 3%; e , 5.7% and 6.5%; and f, 5.8% and 7.2%, respectively. Conclusions Variables measured during clinical cycle ergometer exercise testing in adult patients with stable CF are reproducible. No learning effect was found on repeated testing.

A growing number of studies on the mechanism of leukocyte transendothelial migration use endothelial cells grown on microporous filters as an in vitro model of endothelium. Ultrastructural examination of such a model system previously demonstrated that human pulmonary artery endothelial cells (HPAEC) formed confluent monolayers on both sides of the 3-microm-pore filter (Mackarel et al., 1999). To determine whether this was a characteristic specific to pulmonary artery endothelial cells, the growth characteristics of a human pulmonary microvascular endothelial cell type (HMVEC-L) and the widely used human umbilical vein endothelial cells (HUVEC) on 3-microm microporous filters were examined by transmission electron microscopy (TEM). Similar to HPAEC, HMVEC-L and HUVEC were also found to grow on both sides of the filter. All three endothelial cell types were capable of migrating through the 3 microm pores of the filter to form a monolayer on the filter underside. The endothelial cells on the underside were orientated in an inverted position with the luminal surface facing away from the filter. Such 'bilayer' formation was observed at a range of seeding densities and in different culture media. Despite the presence of a bilayer of endothelial cells, TEM demonstrated that neutrophils migrated successfully across the cell-filter-cell system. Previous transmigration reports in which an in vitro model similar to ours was used have often assumed only one layer of endothelial cells. The observations reported here indicate that while endothelial cells on microporous filters are useful models for examining leukocyte-endothelial interactions, they are not appropriate for studies examining endothelial cell 'sidedness.'

Increased exhaled nitric oxide (NO) may reflect respiratory tract inflammation in untreated asthmatics. We compared exhaled NO and bronchoalveolar lavage (BAL) nitrate/nitrite (NO3-/NO2-) in 10 patients who had untreated, active pulmonary sarcoidosis with those of normal control subjects. Exhaled NO concentrations, determined by chemiluminescence, were similar in patients and control subjects (peak NO concentration of patients [mean +/- SD]: 13.6 +/- 5.9 parts per billion [ppb], peak NO concentration of control subjects: 11.2 +/- 5.7 ppb, p = 0.32; mean alveolar NO concentration of patients: 7.8 +/- 4.4 ppb, mean alveolar NO concentration of control subjects: 7.1 +/- 4.2 ppb, p = 0.70; end-tidal NO concentration of patients: 6.9 +/- 4.5 ppb, end-tidal NO concentration of control subjects: 6.6 +/- 4.0 ppb, p = 0.60). BAL NO2- was assayed using a modified Griess reaction after reduction of NO3- to NO2-. There was no significant difference in mean BAL NO2- concentrations, expressed as nanomoles per milliliter of epithelial lining fluid (patients: 544 nmol/ml, control subjects: 579 nmol/ml, p = 0.81) or as nanomoles per milliliter of BAL fluid (patients: 6.7 nmol/ml, control subjects: 5.7 nmol/ml, p = 0.41). These data suggest that excess NO generation does not accompany the respiratory tract inflammation of pulmonary sarcoidosis.

The aim of this study was to examine the hypothesis that alveolar macrophages represent a significant source of matrix-degrading proteinases in the emphysematous lung. Macrophages from bronchoalveolar lavage fluid of 10 patients with emphysema and 10 normal volunteers were maintained in vitro for 24 h and assessed semiquantitatively for mRNA transcript levels of the matrix metalloproteinases (MMPs) gelatinases A and B, macrophage metalloelastase (MME), and interstitial collagenase. Release of these MMPs into the culture medium and secretion of neutrophil elastaselike activity was also assessed. Elevated levels of mRNA transcripts for gelatinase B (p < 0.0005) and interstitial collagenase (p < 0.0005) were observed in macrophages from emphysematous patients. Increased collagenase (p < 0.01) and neutrophil elastaselike activities (p < 0.001) were also measured in conditioned medium from patient macrophages. With gelatinase B, complexed forms of the enzyme were secreted by patient but not by control macrophages. No difference in transcript levels of gelatinase A or MME was observed between patient and control samples, and neither enzyme was detected in macrophage-conditioned media from either group. These results directly demonstrate that alveolar macrophages from the emphysematous lung produce elevated quantities of matrix-degrading enzymes with both elastolytic and collagenolytic activities.

BACKGROUND: Matrix degradation in emphysema has long been attributed to the action of neutrophil elastase (NE). More recently a role for other proteases, particularly the matrix metalloproteinases (MMPs), in the pathogenesis of this disease has been proposed. To date, however, the presence of MMPs in the lungs of patients with emphysema has not been demonstrated. METHODS: Samples of bronchoalveolar lavage (BAL) fluid from 10 patients with emphysema and from control subjects matched for sex and current smoking status were assessed for collagenase, gelatinase, and NE activity. Pulmonary function tests and computed tomographic (CT) scans were carried out on all study subjects. RESULTS: Collagenase activity was detected in BAL fluid samples from all emphysematous patients but in only one smoking control (p < 0.001). Gelatinase B was present in six patients and in two smoking controls (p < 0.03). The concomitant presence of gelatinase B in complex with lipocalin (NGAL) in the gelatinase positive samples suggests that the neutrophil is a significant source of the gelatinase B observed. NE was detected in six of the 10 patients with emphysema and in two smoking controls (p < 0.01), indicating that collagenase was more useful in discriminating between disease and control groups than either NE or gelatinase B. No relationship was observed between any of the enzymes measured and pulmonary function or CT density score. CONCLUSIONS: This study demonstrates, for the first time, the presence of increased levels of matrix metalloproteinases in the lungs of patients with emphysema and suggests that, in BAL fluid, collagenase activity may be a better indicator of the presence of emphysema than elastase.

The potential role of neutrophil elastase in causing lung damage and exacerbating the inflammatory response in cystic fibrosis (CF) has received considerable attention. Although another potent neutrophil-derived enzyme, collagenase, is implicated in tissue destruction in several interstitial lung disorders, there has been no reference to this enzyme in CF. The objective of this study was to determine whether neutrophil collagenase is present in active form in CF sputum and, if so, whether it is related to disease severity. High levels of active collagenase were detected in sputum from patients with CF, and the majority of the enzyme present was of neutrophil origin. In a group of 16 patients with CF, negative relations between sputum collagenase activity and Shwachman score (r = -0.55, p < 0.05) and FEV1 (r = -0.59, p < 0.02) were noted, indicating an association between high collagenase activity and severity of disease. A positive correlation was observed between sputum collagenase and elastase activity (r = 0.62, p < 0.05). These results suggest that both neutrophil elastase and collagenase may play a significant role in lung destruction in CF.

Patients with cystic fibrosis (CF) have a high prevalence of Pseudomonas aeruginosa infection which causes chronic infection of the mucosal surfaces of the lung. This results in recurrent immune stimulation and hypergammaglobulinemia. The present study examines the levels of circulating Ig classes, IgG and IgA subclasses in 13 adult patients with CF during acute pulmonary infection and post-exacerbation. Total serum IgG levels were raised in the patients during infection and post-treatment when compared to the normal range (mean +/- SEM: 17.21 +/- 1.4 g/l vs 16.45 +/- 1.5 g/l respectively; normal range 8-16 g/l). In contrast, total IgM (2.6 +/- 0.26 vs 2.69 +/- 2.74 g/l; normal range 0.6-2.8 g/l) and IgA levels (2.5 +/- 0.52 vs 2.41 +/- 0.48 g/l; normal range 0.5-4 g/l) remained unchanged when examined during all stages of the disease. Of the 13 patients studied, 69%, 39% and 31% had IgG, IgM and IgA levels respectively raised above the normal range values. The mean levels of individual IgG subclasses examined in this group of patients revealed values within the normal ranges, however IgG2 and IgG3 were increased in 31% and 46% of patients. Individual IgG3 levels fell in 77% (10/13) and IgG4 in 62% (8/13) of the patients post-exacerbation. With regard to IgA subclasses, significant reduction in the IgA1 levels were observed post treatment (3687 +/- 539 mg/l vs 2713 +/- 498 mg/l, p0.01). In contrast, IgA2 levels were increased from 279 +/- 49 mg/l to 421 +/- 69 mg/l, although statistical significance was not reached. Upon antibiotic treatment for infection, the findings in this study show that IgA1 which is susceptible to bacterial proteases is reduced with a concommitant increase in the protease resistant IgA2 subclass. Moreover, patients colonised with non-mucoid strains of P. aeroginosa had higher total IgA levels due to the raised IgA1 subclass whereas they had lower IgG levels due to low IgG2 and IgG4 subclasses.

The potential role of neutrophil elastase in exacerbating pulmonary infection and tissue damage in cystic fibrosis (CF) has led to proposals for treatment of lung disease in CF with the elastase inhibitor, alpha 1-proteinase inhibitor (alpha 1PI). Reports that alpha 1PI is inactivated in the CF lung suggest that the effectiveness of alpha 1PI therapy depends on the quantity of elastase present and the extent of alpha 1PI inactivation, both of which are expected to vary with disease severity. In this study we assessed the elastase-alpha 1PI profile in sputum and plasma from CF patients with various degrees of pulmonary involvement. Levels of active elastase in sputum samples increased with severity of pulmonary disease (F ratio = 5.63, p < 0.01), as did sputum levels of alpha 1PI (F ratio = 4.88, p < 0.01). A positive correlation was observed between sputum levels of active elastase and alpha 1PI (r = 0.68, p < 0.005). Plasma alpha 1PI levels were also elevated in CF patients compared with control subjects (p < 0.005), indicating a compensatory increase in plasma and sputum levels of alpha 1PI in response to increased elastase load. Molar levels of total immunogenic neutrophil elastase were, on average, 12 times higher than alpha 1PI in CF sputum. These results suggest that the major contributor to the elevated levels of active elastase observed in the CF lung is an increase in elastase release rather than inactivation of alpha 1PI.

Chronic eosinophilic pneumonia (CEP) is a rare disorder of unknown etiology characterized by striking systemic and pulmonary manifestations such as fever, weight loss, blood eosinophilia, characteristic fluffy peripheral opacities on chest radiograph, and a prompt response to corticosteroid therapy. While the initial phase has been well documented, there is very limited information concerning the long-term natural history and treated course of this condition. We report the clinical and laboratory findings together with the long-term follow-up data on 12 patients with classic CEP who were followed up for a mean of 10.2 years (range, 4 to 13 years). The most striking feature of the long-term follow-up was the occurrence of relapses of CEP (often on multiple occasions) when corticosteroid therapy was discontinued or the dose was tapered. In those nine patients in whom steroid withdrawal was commenced, there was a clinical, hematologic, and radiologic relapse in seven (58 percent). However, prompt reinstitution of therapy led to a rapid resolution of symptoms. By contrast, two patients (17 percent) showed no evidence of relapse when steroid therapy was discontinued. A further three patients (25 percent) are maintained on a regimen of low-dose steroid therapy with no episodes of relapse. Reassuringly, all 12 patients are well at the end of a long period of follow-up. These data suggest that the long-term prognosis for patients with CEP is excellent but the majority will require long-term low-dose oral corticosteroid therapy in order to prevent relapse.

One hundred and four adult patients with cystic fibrosis were evaluated for the presence of liver disease as defined by abnormal liver function tests of six months' duration, histological evidence of fibrosis or cirrhosis, or the presence of portal hypertension, or both. Twenty patients fulfilled these criteria and were evaluated further for the presence of biliary tract abnormalities with biliary scintigraphy using 99Tc diisopropylphenyl-carboxymethyl iminodiacetic acid (DISIDA) and endoscopic retrograde cholangiography. Clearance of 99Tc DISIDA from the liver and biliary tree was diminished at 45 (E45) and 60 (E60) minutes in the patients with liver disease compared with those without liver disease; E45 = 37.8% and 65.8%, p less than 0.01; E60 = 48.2% and 77.5%, p less than 0.01 respectively. Serial analogue images of the extrahepatic biliary tree were consistent with common bile duct obstruction with retention of DISIDA and tapering of the common bile duct in seven of 18 patients with and two of 10 patients without liver disease. Endoscopic retrograde cholangiography showed changes consistent with sclerosing cholangitis, with beading and stricturing of the intrahepatic ducts in 12 of the 14 patients. In all 14 patients, including those in whom biliary scintigraphy had suggested obstruction, no abnormality of the common bile duct was identified. These results indicate that abnormalities of the bile ducts in patients with cystic fibrosis related liver disease are confined to the intrahepatic biliary tree and that common bile duct strictures do not contribute to either the progression or development of liver disease in these patients.

Patients with cystic fibrosis (CF) desaturate during sleep and during exercise but by different mechanisms. To determine the need for supplemental oxygen, many centers measure resting and exercise arterial oxygen saturation (SaO2). We examined the associations among resting, sleep, and exercise SaO2 to ascertain the validity of this approach. We studied 21 adult and adolescent CF patients, eight of whom were hypoxemic (SaO2 less than 95 percent; group A) and 13 of whom were nonhypoxemic (SaO2 greater than or equal to 95 percent; group B) by overnight oximetry and treadmill exercise testing. The whole group desaturated more during sleep than during exercise, the change in SaO2 being 10.59 +/- 8.35 vs 6.25 +/- 4.44 (p less than 0.002). Group B desaturated significantly more during sleep than during exercise, with a reduction in SaO2 of 7.9 +/- 3.3 vs 3.3 +/- 1.49 (p less than 0.05). Group A desaturated more during exercise than group B, with a reduction of 11 +/- 3.2 vs 3.3 +/- 1.5 (p less than 0.001). Despite a strong correlation between awake SaO2 and mean sleep SaO2 (r = 0.68; p less than 0.001), minimum sleep SaO2 (r = 0.55; p less than 0.01), and minimum exercise SaO2 (r = 0.92; p less than 0.001), there was no correlation between awake SaO2 and sleep-related desaturation or between exercise- and sleep-related desaturation. In conclusion, clinically significant oxygen desaturation during sleep may be missed unless specifically checked in CF patients, and awake and exercise SaO2 may not give an indication of the degree of sleep-related desaturation.

Summary The incidence of bacteraemia and fungaemia was determined in 29 adults with cystic fibrosis (CF) during 50 consecutive admissions to hospital for management of infective exacerbations of pulmonary disease. Blood was drawn for aerobic, anaerobic and fungal cultures from all patients who were febrile on admission or who became febrile during treatment. The population included eight patients who had indwelling venous access systems in situ . The overall incidence of positive blood cultures in febrile patients was 3·5 % [95 % confidence interval (C.I.), 1–6%]. We recorded one case of Pseudomonas aeruginosa bacteraemia and two cases of Candida albicans fungaemia. The patient with P. aeruginosa bacteraemia died 5 days after isolation of the organism from her blood. The two patients with C. albicans bacteraemia had totally implantable venous access systems (TIVAS) in situ and both recovered following appropriate therapy. These observations suggest that bacteraemia is rare in patients with CF but that there is a significant risk of fungaemia in a susceptible minority. The implications of these findings, as they relate to management of infections and care of indwelling catheters in such patients, are discussed.

Atypical mycobacterial disease has been described in a small number of patients with cystic fibrosis. Apart from one uncontrolled study, there is little information regarding atypical mycobacterial skin reactivity in this group of patients. We evaluated delayed cutaneous hypersensitivity to purified extracts of Mycobacterium avium, Mycobacterium intracellular, Mycobacterium kansasii and Mycobacterium bovis in 23 healthy controls and 43 adult and adolescent patients with cystic fibrosis. Fifteen of the cystic fibrosis group were receiving regular corticosteroids. Additionally, direct smear examination and Lowenstein Jensen culture were performed on sputum from the cystic fibrosis group. The prevalence of positive skin reactions was similar in the group with cystic fibrosis (30%) and in the control group (57%). Subgroup analysis showed that those cystic fibrosis patients receiving corticosteroids had a markedly lower prevalence of positive reactions (7%) compared to controls (P less than 0.01). When this subgroup was excluded from analysis, the prevalence of positive skin reactions among patients with cystic fibrosis was 43%. In the prospective sputum bacteriology study, one of the 43 cases grew Mycobacterium avium-intracellulare and had clinical and radiological evidence of this disease. Of note, this patient showed positive skin tests to all four mycobacterial species tested. Our data show no difference in the prevalence rate of positive skin reactions to atypical mycobacterial antigens between a control population and an adult cystic fibrosis population. In addition, the predictive value of skin testing is low in cystic fibrosis due to the high prevalence of cross-reactivity between different mycobacterial species and the high prevalence of anergy among those patients with advanced disease receiving treatment with corticosteroids.

Excessive neutrophil recruitment to the lung underlies inflammatory-mediated lung damage in cystic fibrosis (CF). Neutrophils can migrate to the lung using either a CD18-dependent or CD18-independent mechanism. To determine if one of these migratory pathways is preferentially utilized by neutrophils migrating to the CF airways, this study examined the CD18 dependency of neutrophil transendothelial migration stimulated by the soluble fraction of CF sputum (SOL). Results demonstrate the preferential use of the CD18-independent migratory mechanism by both control and CF neutrophils and suggest that selective blocking of the CD18-independent migration pathway may offer a means of decreasing neutrophil influx to the CF airways.

We describe two siblings with a progressive unrelenting and unique syndrome of bilateral fibrosing pleuritis of unknown cause occurring in association with Fanconi's syndrome (renal tubular acidosis). The parents of the siblings were second cousins. Both siblings had identical pleural histologic characteristics and identical urinary metabolic defects. This condition resulted in the development of severe respiratory failure in both patients and ultimately the death of the older sibling at the age of 21 years.

The naturally occurring neutrophil elastase inhibitors, alpha1-proteinase inhibitor (alpha1PI), secretory leukocyte proteinase inhibitor (SLPI), and elafin, are potential therapeutic agents in the treatment of neutrophil-mediated lung disease. However alpha1PI has been shown to be susceptible to inactivation by matrix metalloproteinases (MMPs) released by neutrophils, particularly neutrophil collagenase (MMP-8). The aim of this study was to determine if SLPI and elafin are similarly susceptible to degradation by this neutrophil-specific MMP. The effect of MMP-8 on SLPI and elafin was assessed by determining the neutrophil elastase inhibitory capacity (NEIC) and electrophoretic protein profile of both inhibitors following exposure to purified MMP-8. As a positive control, the effect of MMP-8 alpha1PI was assessed in parallel. Although treatment of alpha1PI with MMP-8 resulted in a significant decrease in its NEIC (P = .025), no similar decrease was observed with SLPI or elatin. Electrophoretic analysis confirmed digestion of alpha1PI by MMP-8 but no digestion of either SLPI or elafin was observed. These results demonstrate that SLPI and elafin are resistant to proteolytic inactivation by MMP-8, a property that may enhance their therapeutic application in neutrophil-mediated inflammatory lung disease.

Paradoxical vocal cord adduction (PVCA) is a rare disorder that may present with symptoms similar to asthma. Incorrect diagnosis may result in patients being unwittingly treated with prolonged high doses of antiasthma medication. PVCA probably forms part of a spectrum of uncommon and complex breathing disorders related to laryngeal dysfunction. Herein, we describe three cases of PVCA that illustrate the spectrum of clinical and physiologic presentation and the long-term natural history over a 10-year follow-up period. We conclude that PVCA, contrary to previous reports, is not always a benign condition; it may feature marked hypoxemia, fail to respond to previously advocated therapeutic strategies, and can persist on a long-term basis.

Neutrophil extravasation during inflammation can occur either by a mechanism that requires the neutrophil integrin complex, CD18, or by an alternative CD18-independent route. Which of the two pathways is used has been shown to depend on the site and nature of the inflammatory insult. More recent evidence suggests that selection may also depend on whether inflammation is chronic or acute, but why this is the case remains unknown. Using an in vitro model that supports both migratory mechanisms, we examined the CD18 dependency of migration of neutrophils isolated from patients with either chronic or acute pulmonary infection. Chronic neutrophils were found to behave like normal neutrophils by migrating to IL-8 and leukotriene B4 using the CD18-independent pathway, but to the bacterial product, FMLP, using the CD18-dependent route. In contrast, migration of acute neutrophils to all of these stimuli was CD18 dependent. Normal neutrophils could be manipulated to resemble acute neutrophils by exposing them to FMLP before migration, which resulted in a “switch” from the CD18-independent to -dependent mechanism during migration to IL-8 or leukotriene B4. Although treatment of normal neutrophils with FMLP caused selective down-regulation of the IL-8 receptor, CXCR2, and acute neutrophils were found to have less CXCR2 than normal, a functional relationship between decreased CXCR2 and selection of CD18-dependent migration was not demonstrated. Results indicate that selection of the CD18-dependent or -independent migration mechanism can be controlled by the neutrophil and suggest that the altered CD18 requirements of acute neutrophils may be due to priming in the circulation during acute infection.

The Birmingham scoring system for chest radiographs was assessed in 40 adult cystic fibrosis patients, with particular reference to correlation with pulmonary function values. Forty 'initial' and forty 'follow-up' chest radiographs were scored. The mean initial age of the group was 17.5 +/- 5.0 years, and the mean age at follow-up was 23.3 +/- 5.3 years. The cross-sectional radiographic score correlated significantly with the values of three commonly measured, pulmonary function parameters (r = 0.65, 0.67, 0.58, P less than 0.0001). There was a significant correlation (r = 0.64, P less than 0.0001), between the change in radiographic score, and the change in percent predicted forced vital capacity (FVC%). There was a less significant correlation (r = 0.45, P less than 0.006) between the change in radiographic score and the change in per cent predicted forced expiratory volume in one second (FEV1%). We conclude that the Birmingham radiographic scoring system is suitable for quantitative radiological evaluation in adult cystic fibrosis.

An oxidant/antioxidant imbalance has been proposed in patients with idiopathic pulmonary fibrosis (IPF). We tested this hypothesis by measuring various parameters of the oxidant/antioxidant balance in the plasma of 12 patients with IPF (7 nonsmokers and 5 smokers); in the bronchoalveolar lavage fluid (BALF) of 24 patients with IPF (17 nonsmokers and 7 smokers) and 31 healthy subjects (23 nonsmokers and 8 smokers). The trolox equivalent antioxidant capacity (TEAC) in plasma and BALF was lower in nonsmoking patients with IPF (plasma 0.55+/-0.1 mM, p

It has long been speculated that neutrophils deploy proteases to digest subendothelial matrix as they migrate from the bloodstream. Direct evidence for the involvement of proteases in neutrophil transendothelial migration is, however, lacking. To address this issue we used transmission electron microscopy to verify the presence of continuous basal lamina beneath pulmonary endothelial cells grown on microporous filters, and then examined the effects of protease inhibitors on neutrophil migration through the endothelial cells and their associated subcellular matrix. Inhibitors of the two major matrix-degrading protease groups present in neutrophils, the matrix metalloproteinases (MMPs) and serine proteases, were assessed for their ability to modulate neutrophil transendothelial migration in response to the chemoattractant n-formylmethionyl leucylphenylalanine (FMLP). Neither the naturally occurring MMP inhibitor, tissue inhibitor of metalloproteinase-1, nor the hydroxamic acid-based inhibitors GM-6001, BB-3103, or Ro 31-9790 had any significant effect on FMLP-stimulated neutrophil migration across endothelial cells and associated basal lamina, with/= 80% of neutrophils migrating through the system, even in the presence of inhibitors, at concentrations that totally inhibited all the gelatinase B (MMP-9) released upon stimulation with FMLP. Similarly, with serine protease inhibitors no significant inhibition of neutrophil migration was observed with a naturally occurring inhibitor, secretory leukocyte protease inhibitor, or a low molecular-weight synthetic inhibitor, Pefabloc SC. These results indicate that neither MMP nor serine protease digestion of sub-endothelial matrix is required for successful neutrophil transendothelial migration.

The practical use of lactate electrochemical analysers in exercise testing has not been adequately examined. Initial studies have reported differences in lactate concentration between that measured spectrophotometrically and that measured electrochemically. The study described here was undertaken to compare, using the statistical technique of Bland and Altman (1986), two widely available methods of measuring lactate using lysed and non-lysed blood samples and the lactate thresholds derived from the measured lactate values using a log-log transform technique. Thirteen normal, healthy young adults (11 male) undertook progressive exercise tests to exhaustion. Arterialised venous blood samples were taken each minute and the lactate concentration therein was measured both spectrophotometrically and electrochemically and either with or without lysis of the blood samples. The lactate concentrations measured in lysed blood using both methods (182 pairs) were in close agreement. The electrochemical values obtained using non-lysed blood were systematically lower than spectrophotometric values (206 pairs), the difference becoming progressively greater at higher lactate concentrations. Results for the lactate threshold comparisons are given as mean difference (limits of agreement with 95% probability). Lactate thresholds (12 pairs) derived from lysed blood lactate concentrations measured spectrophotometrically and electrochemically were not significantly different -30 (240) ml O2 x min(-1). Lactate thresholds (11 pairs) derived from lysed spectrophotometric and non-lysed electrochemical measurements were also not significantly different + 20 (250) ml O2 x min(-1). Thus, despite the difference in the measured lactate concentrations, the derived lactate thresholds are in agreement and, therefore, electrochemical analysers can be used for lactate threshold determination using the log-log transform technique without sample lysis.

Reactive Airways Dysfunction Syndrome (RADS) has been described following exposure to various irritant gases(1). We describe a case of RADS occurring following exposure to chlorine gas and which has persisted at 6 years follow-up.

Nitric oxide (NO) can be detected in exhaled gas in human subjects. It is produced by nitric oxide synthase (NOS) and is rapidly metabolized to nitrite and nitrate (NO2/NO3). Exhaled NO is reported to be elevated in patients with asthma, bronchiectasis, or upper respiratory tract infection. Recent reports have shown no increase of exhaled NO in stable cystic fibrosis (CF). We hypothesized that NOS activity is increased in patients with acute pulmonary exacerbation of CF. We therefore measured exhaled NO and sputum NO2/NO3 in three subject categories: patients with acute pulmonary exacerbation of CF, patients with stable CF, and healthy control subjects. Mean +/- SD exhaled NO was significantly higher in control subjects (8.8 +/- 4.9 ppb) than in both acute (3.8 +/- 3.9 ppb) and stable (5.0 +/- 2.5 ppb) patients. Sputum NO2/NO3 was significantly higher in acute patients (774 +/- 307 micromol/L) when compared with both stable patients (387 +/- 203 micromol/L) and control (421 +/- 261 micromol/L) subjects. Sputum NO2/NO3 did not return to normal in a subgroup of patients assessed after 2 wk of intensive antibiotic and glucocorticoid treatment. These results confirm that exhaled NO is not a useful measure of airway inflammation in CF. Elevated levels of sputum NO2/NO3 suggest that NOS is activated during acute pulmonary exacerbations of CF.

BACKGROUND: Maximal exercise testing is used in patients with cystic fibrosis to assess functional status and prognosis. The lactate threshold is an index of aerobic fitness with significant advantages over maximal exercise tests. This study was undertaken to determine if the lactate threshold might be identified, non-invasively, in adult patients with cystic fibrosis and mild lung disease by measurement of ventilatory and gas exchange parameters. METHODS: Ten subjects with mild cystic fibrosis (forced vital capacity (FVC) > 70% predicted) and 10 healthy controls undertook an incremental exercise test on a bicycle ergometer. Ventilation and gas exchange parameters were measured continually and arterialised venous blood pH, carbon dioxide tension (PCO2), and lactate concentrations were measured at intervals throughout the tests. RESULTS: In subjects with cystic fibrosis there was no significant difference between the mean gas exchange and lactate thresholds (mean difference 1.0 (95% confidence interval (CI) of the mean -1.5 to 3.44) ml/kg/min). In contrast, there was a significant difference between the mean ventilatory and lactate thresholds (3.8 (95% CI 0.9 to 6.7) ml/kg/min). Arterialised venous PCO2 increased significantly during the exercise tests. In healthy subjects the mean differences between these thresholds were not significantly different from zero and PCO2 fell significantly during the tests. CONCLUSIONS: The ventilatory threshold significantly overestimates the lactate threshold in subjects with cystic fibrosis induced lung disease because of impaired carbon dioxide excretion during exercise. However, the gas exchange threshold may be used to determine the lactate threshold in this patient group.

Fibrosing alveolitis complicating systemic sclerosis (FASSc) carries a better prognosis than lone cryptogenic fibrosing alveolitis (CFA). We wanted to determine whether this improved prognosis is associated with differential neutrophil migration and activation in the lower respiratory tract. We therefore compared bronchoalveolar lavage (BAL) neutrophil numbers and levels of neutrophil-derived enzymes in FASSc, CFA and normal individuals. Bronchoalveolar lavage was performed on 45 subjects (FASSc n = 20; CFA n = 15; normals n = 10); cell counts and levels of neutrophil-derived enzymes, myeloperoxidase, elastase (total elastase and elastase/alpha 1 antitrypsin complexes), collagenase and lactoferrin were measured. Lung function testing was performed in subjects with fibrosing alveolitis. Significant differences in the levels of collagenase, myeloperoxidase and elastase/ alpha 1-antitrypsin complexes were present in the BAL fluid from the three groups. Patients with CFA had significantly higher neutrophil percentages and levels of collagenase and myeloperoxidase than those with FASSc. Disease extent, as judged by lung volumes and gas transfer, was comparable in the CFA and FASSc groups. Forced vital capacity (% predicted) was significantly lower in patients with evidence of increased neutrophil enzyme release than those without. We conclude that: 1) increased neutrophil migration to the lung is accompanied by release both of primary and secondary granule enzymes in cryptogenic fibrosing alveolitis; and 2) the lower amounts of neutrophil products in fibrosing alveolitis complicating systemic sclerosis may account for the improved prognosis, even when disease is as extensive as in cryptogenic fibrosing alveolitis.

To assess the correlation between HRCT and pulmonary function in patients with CF. Further, to assess the prognostic value of HRCT in these patients.Clinical examination, chest radiographs and HRCT scans on 30 CF patients with an average age of 17 were scored using established scoring systems. The results were correlated with FEV1 and FVC both at time of CT scanning and after 30 months. Results were also correlated with the clinical progress of the patients over the follow-up period.HRCT, chest radiograph and clinical examination demonstrated similar correlation (p0.001) with FEV1 and FVC at the time of scanning. HRCT demonstrated the closest correlation with the clinical progress of the patients over the follow-up period and with follow-up pulmonary function. A maximum combined score for bronchiectasis and emphysema on HRCT seemed to indicate a poor prognosis.HRCT in CF patients correlates well with pulmonary function at time of scanning and at follow-up, and with clinical progress. There may be a role for CT in the identification of adolescent/adult patients who can be expected to need aggressive therapy in the future.

Pulmonary aspergillomas usually occur when Aspergillus fungi colonise lung tissue previously damaged by disease. Pulmonary aspergillomas in three adult patients with cystic fibrosis are reported--an association not previously described. At the time of diagnosis all three patients had previous long term colonisation with Aspergillus fumigatus and severe advanced destructive lung disease with lung function less than 25% of the predicted normal values. It is likely that, with increasing survival in cystic fibrosis, more adult patients will develop aspergillomas during the protracted phase of end stage lung disease that characterises the terminal years of this condition.

Many patients with cystic fibrosis have symptoms of dyspnoea and wheeze which are responsive to treatment with bronchodilators. An adolescent woman with cystic fibrosis is described who presented with inspiratory stridor and in whom the classical features of paradoxical vocal cord adduction were found.

In pseudomonal septicaemia, serum levels of antibody to exotoxin A have been demonstrated to be an important independent predictor of survival. Previously, we have demonstrated that exotoxin A directly injures pulmonary endothelial cells, and that dibutyryl-cyclic adenosine monophosphate (Db-cAMP) can attenuate this injury. The object of this study was to examine the mechanisms of this pulmonary endothelial cell injury and the mechanism of Db-cAMP protection. The effects of differing duration of exposure to exotoxin A and a reduction in temperature on endothelial cell injury were examined. In addition, the effect of post-treatment with Db-cAMP on exotoxin A-induced endothelial cell injury was studied. A brief, 5 min, exposure to exotoxin resulted in maximum injury comparable to that produced by 18 h exposure. This injury did not occur at low temperatures, which would inhibit receptor-mediated endocytosis. Db-cAMP protected endothelial cells, even when added up to one hour after exotoxin exposure. These results suggest that, in this model, exotoxin A-induced injury of endothelial cells is receptor-mediated. Furthermore, this injury may be attenuated even after exotoxin A internalization has taken place.

Two patients with cystic fibrosis developed acute onset nephrotic syndrome and died within three months of presentation. Examination of renal biopsy specimens indicated amyloid. The onset of proteinuria or a fall in baseline renal function should alert the physician to this rare complication.