Increased augmentation index in patients with cystic fibrosis.

Increased large artery stiffness occurs in a range of inflammatory conditions indicating an ageing of the vasculature and additionally being an independent risk factor for cardiovascular events. We determined large artery parameters in adults with cystic fibrosis (CF). 50 clinically stable adult patients with CF (mean+/-sd age 28.0+/-8.2 yrs) and 26 controls matched for age, sex and body mass index were studied. Central aortic blood pressure, augmentation index (AIx) and aortic pulse wave velocity (PWV) were determined using applanation tonometry. Lung function, diabetic status and C-reactive protein (CRP) were also determined. Mean+/-sd AIx was greater in patients than controls, 8.5+/-11.1% and -1.8+/-13.1%, respectively (p<0.001), while PWV was similar. Although AIx was greatest in the sub-group with CF-related diabetes (CFRD), it was also increased in the non-CFRD sub-group when compared with controls. In patients, AIx was related to log(10) CRP (r = 0.33) and forced vital capacity (r = -0.34; both p<0.05), and CRP remained predictive in multiple regression. AIx is increased in adults with CF, in the presence of a normal blood pressure and independent of diabetic status. AIx was related to the systemic inflammatory status. These findings have implications for management and require further exploration so that cardiovascular health can be maintained.

What community measurements can be used to predict bone disease in patients with COPD?

BACKGROUND: Osteoporosis is common in patients with COPD. Previously we have reported that loss of fat-free mass (FFM), measured by dual X-ray absorptiometry (DXA) is associated with loss of bone mineral density (BMD). In addition, in patients with a low body mass index (BMI) and a low FFM, all had evidence of bone thinning, 50% having osteopenia and 50% osteoporosis. We explored the utility of different anthropometric measures in detecting osteoporosis in a community-based COPD population. METHODS: Patients with confirmed COPD and not on long-term oral corticosteroids (n=58) performed spirometry. They underwent nutritional assessment by skinfold anthropometry, midarm circumference, calculation of both % ideal body weight (IBW) and BMI. All had DXA assessment of BMD. RESULTS: A total of 58 COPD patients had anthropometric measurements taken, with a mean age of 66.8 (SD 8.7) years, 31 (58%) were male, with a forced expiratory volume in 1s (FEV(1)) of 54.17 (20.18)% predicted. Osteoporosis was present at either the hip or lumbar region in 14 patients (24%). The useful anthropometric measurements identifying those with osteoporosis were both % IBW and BMI. The adjusted odds ratio for %IBW was 0.93 (95% confidence interval (CI) 0.87, 0.99), p=0.016 and for BMI: 0.79 (0.64-0.98), p=0.03. The receiver operating characteristics (ROC) score for both was 0.88, indicating a good fit. CONCLUSION: Osteoporosis is common, even in patients with mild airways obstruction. Nutritional assessment, incorporating a calculation of their BMI or %IBW may confer an additional benefit in detecting those at risk of osteoporosis and guide referral for BMD measurement.

Attaining a correct diagnosis of COPD in general practice.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is common. Diagnosis should include objective evidence of airways obstruction and spirometry is recommended in guidelines and the general medical services contract in the UK. We assessed the impact of spirometry in general practice. METHOD: We determined by questionnaire the availability, staff training, use and the interpretation results of spirometry in 72% of general practices in Wales. We reviewed the diagnosis of COPD previously made in two general practices without spirometry. RESULTS: Most practices had a spirometer (82.4%) and used it (85.6%). Confidence in use and interpretation of results varied widely: 58.1% were confident in use and 33.8% confident in interpretation. Spirometry was performed more often if confident in use and interpretation (both P<0.001) and was related to greater training periods (P<0.001). Spirometric confirmation of COPD varied widely (0-100%, median 37%). Of the 125 patients previously diagnosed with COPD 61 had spirometric confirmation, while 25 had reversible obstruction (range 210-800 mls), 34 had normal and 5 had restrictive spirometry. CONCLUSION: Despite incentives to perform spirometry in general practice, lack of adequate training in use and interpretation suggests use is confounded and the diagnosis of COPD is likely to be made on imprecise clinical grounds.

The evaluation of a quantitative enzyme-linked immunosorbent assay (ELISA) for anti-Aspergillus fumigatus IgG.

A standard enzyme-linked immunosorbent assay method for anti-Aspergillus fumigatus IgG in human serum was modified to produce a quantitative assay. The resulting assay was reproducible and capable of separating individual precipitin line groups and provided a means of monitoring the variation in antibody levels over long periods in patients with pulmonary aspergillosis.

A rapid radioassay for human IgG produced in lymphocyte in vitro culture systems.

Protein A bearing Staphylococcus aureus was used to develop a solid-phase radioassay for IgG immunoglobulins. The assay was specifically optimised for use with in vitro human lymphocyte culture work. Compared with a solid-phase radioimmunoassay for IgG produced in lymphocyte culture, this assay had similar performance profile and the advantages of rapidly and technical ease.

C-reactive protein measured in dried blood spots from patients with cystic fibrosis.

There was no significant difference in C-reactive protein concentration determined in paired serum and eluates from dried blood spots collected on Guthrie cards; mean difference 0.6 microgram/ml (95% CI -3.3-2.2 micrograms/ml; n = 101). Dried blood spot samples were stable for up to 21 days and were unaffected by posting to the laboratory. In eight patients with cystic fibrosis undergoing specific antibiotic treatment for Pseudomonas aeruginosa pulmonary infection the fall in C-reactive protein concentration was not significantly different between serum and dried whole blood spot specimens. This method could be used to monitor infection and the response to antibiotic treatment.

Biological effects of 131I and 125I isotopes of iodine in the rat.

From the differences in radiation profiles between 131I and 125I isotopes of iodine it would be expected that they would show different effects on thyroid function. The differences should lead to lower rates of thyroid gland destruction with 125I and hence less post-irradiation hypothyroidism. This difference in biological effect has been demonstrated in rats by indirect assessment of thyroid function. In this report the long-term effects of a range of similar doses of 131I and 125I were compared, in male and female rats, by direct assessment of thyroid function. Seventeen months after receiving 25 and 125 muCi of 131I, male and female rats showed significant elevation of serum TSH concentration and a reduction in 3 h radioiodine uptake. Rats receiving 1 and 5 muCi of 131I and all doses of 125I showed no significant changes in thyroid function. These findings confirm the previously reported differences in effect between the 131I and 125I isotopes of iodine in the rat.

Effect of cardiopulmonary bypass on systemic release of neutrophil elastase and tumor necrosis factor.

Leukocyte counts, plasma neutrophil elastase, tumor necrosis factor-alpha and C-reactive protein were determined serially in 19 patients undergoing elective coronary artery surgery with cardiopulmonary bypass. Neutrophil counts (mean +/- standard deviation 3.85 +/- 1.20 x 10(9)/L preoperatively) peaked 4 hours postoperatively at 10.35 +/- 4.24 x 10(9)/L (p < 0.001) and remained significantly elevated 48 hours postoperatively at 7.80 +/- 2.70 x 10(9)/L, p < 0.05. Plasma neutrophil elastase level (187 +/- 74 ng/ml preoperatively) peaked at 698 +/- 323 ng/ml at the end of surgery (p < 0.001) and remained significantly elevated at 424 +/- 146 ng/ml 48 hours postoperatively (p < 0.01). Peak elastase levels correlated significantly with duration of bypass (r = 0.47, n = 19, p < 0.05). Monocyte counts (0.29 +/- 0.19 x 10(9)/L preoperatively) peaked 4 hours postoperatively (0.87 +/- 0.41 x 10(9)/L, p < 0.001) and fell to baseline levels by 48 hours postoperatively. Plasma tumor necrosis factor-alpha, detectable in 10 of the 19 patients preoperatively (median 0.39 U/ml, range up to 10.1 U/ml), did not change significantly during or after bypass. Plasma C-reactive protein level (median 1.67 [range 0.69 to 34.33] micrograms/ml preoperatively) rose significantly to 3.99 (range 1.95 to 12.55) micrograms/ml 4 hours postoperatively (p < 0.01) and rose 48 hours postoperatively at 303 (210 to 410) micrograms/ml, p < 0.001. Oxygenation, determined by the respiratory index, was impaired at the end of operation (2.07 +/- 0.82) and remained impaired 24 hours postoperatively (2.48 +/- 0.83). Impairment of oxygenation was temporally related to elevated elastase levels, but neither peak elastase levels nor the change in elastase levels with lung reperfusion correlated significantly with the area under the respiratory index curve up to 6 hours postoperatively. This study demonstrates neutrophil elastase release during cardiopulmonary bypass but fails to show a definite role for neutrophil activation or tumor necrosis factor-alpha in the etiology of pulmonary dysfunction after cardiopulmonary bypass.

Nutrition in adults with cystic fibrosis.

Improved survival has been associated with better nutritional status in patients with cystic fibrosis (CF). In this study we examined the relationship between nutritional state and other measures of clinical severity in adult patients with CF, attending a regional centre. Eighty-one patients (median age 21 years) were studied. Patients with CF were significantly under weight, compared to healthy individuals but were of similar height. Measurements of lung function, FEV1 and FVC were significantly related to body mass index. Lung function was poorer in patients with chronic pseudomonal infection but body weight and body mass index were not significantly different compared to those without such infection. In 53 patients who were alive 4 years later, FEV1 had declined by -10.5 (2.1)% (P < 0.001) but there was no significant change in body weight 1.5 (6.5) kgs. In 23 patients who died or had lung transplantation the change from 1994 to the date of death or transplantation the FEV1 was reduced by -7.9 (11.2)% (P = 0.004) and body weight -2.8 (4.4) kgs (P < 0.01). In 12 patients who had supplemental enteral feeding, the median increase in body weight was 7|kgs over a period of 12 months. This study confirms that young adult patients with CF are significantly under weight and declining health is associated with significant weight loss. In patients with severe malnutrition significant improvement can be achieved by enteral feeding.

Host inflammatory responses to first isolation of Pseudomonas aeruginosa from sputum in cystic fibrosis.

Pseudomonas aeruginosa infection of the respiratory tract in patients with cystic fibrosis is a major determinant of morbidity and mortality. However, it has been postulated that the earliest phase of colonization is not associated with injury. To test this hypothesis we determined the association of the first recorded isolation of P. aeruginosa from the sputum on circulating markers of the inflammatory response in 6 patients with cystic fibrosis. At this time circulating C-reactive protein was increased in all 6 and neutrophil elastase alpha 1-antitrypsin complex (elastase-complex) was increased in 5 patients compared with healthy controls. This inflammatory response was associated with a reduction in the FEV1 and FVC of all patients [FEV1, 1.42 +/- 0.87 L (mean +/- SD) at first isolation vs. 2.08 +/- 0.74 L before isolation; P < 0.05; FVC, 1.94 +/- 0.93 L vs. 2.87 +/- 1.01 L, P < 0.05]. At a median interval of 10 months, 5 patients had raised titres of positive IgG antibody to P. aeruginosa, indicating significant exposure to this organism. At this time, lung function had returned to preinfection levels, whilst 3 patients showed continuing features of an inflammatory response, and the group mean value for elastase-complex was raised. Our findings demonstrate that at the time of first isolation of P. aeruginosa from the sputum of patients with cystic fibrosis, there is a concomitant systemic host response and an acute deterioration of pulmonary function.

C-reactive protein is not a useful indicator of intermittent bacterial colonization in early lung disease of patients with cystic fibrosis.

C-reactive protein (CRP) is a general marker of the systemic inflammatory response to bacterial infection. Serial measurement of CRP is useful in monitoring respiratory exacerbations in patients with cystic fibrosis (CF) and chronic infection with Pseudomonas aeruginosa. We hypothesized that regular monitoring of CRP in young children with CF prior to colonization with P. aeruginosa might provide an objective guide to the need for antibiotic treatment. Twenty-two children were studied prospectively over a 6 month period. We measured CRP every 2 months and at the beginning and end of respiratory exacerbations. In samples taken when the children were well, median CRP was 0.45 microgram/mL compared with 1.92 micrograms/mL when they were symptomatic with positive culture results (P < 0.05). Despite this difference there was considerable overlap between CRP levels for infected and noninfected patients. A CRP value of > 1.82 micrograms/mL (the upper 95% confidence interval for a control group of well children without CF) had a sensitivity of 49% and a specificity of 83% in determining a symptomatic exacerbation. We conclude that in this group of patients CRP measurements were of little value in monitoring respiratory exacerbations in patients who become intermittently infected with either Haemophilus influenzae or Staphylococcus aureus.

Pulmonary function, serum markers of inflammation, and IgG antibodies to core lipopolysaccharide of Burkholderia cepacia in adults with cystic fibrosis, following colonization with Burkholderia cepacia.

Eight patients with cystic fibrosis [CF] colonized with Pseudomonas aeruginosa (P. aeruginosa) had serial lung function, peripheral blood inflammatory markers, and serum IgG antibodies to Burkholderia cepacia (B. cepacia) lipopolysaccharide measured in the months preceding and following colonisation with B. cepacia. One patient experienced a fall in FEV(1) from 33% to 19% of predicted values, coinciding with the first sputum isolation of B. cepacia, and he died 12 weeks later. He had a rise in inflammatory markers preterminally, and this change was refractory to antibiotic therapy. There was no significant fall in FEV(1) % of predicted values in the remaining seven patients, and no significant changes in their serum markers of inflammation following colonization with B. cepacia over a median (range) period of 10.9 (7.3-12.0) months.

Patient satisfaction with information provided at an outpatient clinic for respiratory diseases.

A survey of 374 unselected patients attending the Respiratory Outpatient Department of a teaching hospital revealed that most patients reported receiving information about the treatment of their disease, but only one-quarter received information about its prognosis. Patients reported receiving satisfactory answers to their requests for information on most occasions, and the overall satisfaction rate with information offered was 88.3%. Patients who had attended the clinic on five or more occasions felt that they had received more information on all items compared with those with fewer than five visits, although the increase was statistically significant only for information on treatment. Patients over 75 years of age generally reported less information than younger patients. The great majority (88.4%) of patients preferred verbal information, but 23% also expressed a desire for written information as well. More attention should be paid to the needs of the elderly and to education about the nature and prognosis of disease. Printed material should also be more widely used.

Heart-lung transplantation in cystic fibrosis: predictions for the next decade in England and Wales.

Heart-lung transplantation has become an established treatment for end stage respiratory failure secondary to cystic fibrosis. The success of this form of treatment, and the increasing survival of such patients, suggests there will be an increased need for transplantation over the next decade. We have used cystic fibrosis population predictions and all cause mortality data to estimate the number of cardio-pulmonary deaths, due to cystic fibrosis, over the next decade and to estimate the number of such patients who are likely to benefit from heart-lung transplantation. We estimate that there will be between 85 and 127 potential transplant recipients with cystic fibrosis each year over the next decade. During 1990, 1991 and 1992 there were less than 40 transplants each year in such patients. These data emphasize the need to expand transplantation services and to maintain the availability of donor organs.

Totally implantable venous access devices in adult patients with cystic fibrosis.

Between September 1987 and April 1995, 33 totally implantable venous access devices (TIVADs) were implanted at the Cardiff Adult Cystic Fibrosis Centre, U.K., for the purpose of intermittent antibiotic therapy, including 22 PORT-A-CATH (Simcare Ltd.) devices (PCs) to 18 patients, and 11 P.A.S.PORT (Simcare Ltd.) devices (PPs) to nine patients. There were 50 complications during 25 824 days of catheter function which were severe enough to lead to removal of the devices in eight patients (six PCs and four PPs). Overall, patients' acceptance of these devices was excellent. Despite a shorter functional time and a higher rate of complications in PPs compared with PCs, PPs were preferred by many patients for cosmetic reasons. Totally implantable venous access devices provide safe, effective and convenient means of venous access in cystic fibrosis patients requiring intermittent antibiotic therapy.

The host inflammatory response prior to death in patients with cystic fibrosis and chronic Pseudomonas aeruginosa infection.

The intensity of the host inflammatory response to pulmonary infection with Pseudomonas aeruginosa immediately prior to death was determined in six patients with cystic fibrosis (CF). Plasma concentrations of neutrophil elastase alpha 1-antiproteinase, tumour necrosis factor-alpha (TNF alpha) and serum C-reactive protein (CRP) were increased in the 7 days prior to death (P < 0.05) when compared with a period of clinical stability during the preceding 6 months. An increased inflammatory response was sustained for many weeks prior to death and was associated with poor symptom and lung function responses to apparently appropriate antibiotic treatment.

Inflammatory markers in cystic fibrosis.

Plasma neutrophil elastase-alpha 1 antiproteinase complex, lactoferrin and C-reactive protein (CRP) were determined over a 15-month period in 26 patients with cystic fibrosis, of whom 21 were chronically infected with Pseudomonas aeruginosa. Median concentrations of both neutrophil products and CRP were greater in patients who were clinically stable than in healthy subjects without cystic fibrosis. CRP concentrations increased further at the onset of symptomatic exacerbations. Thirty-five courses of intravenous antibiotics and 22 courses of oral ciprofloxacin were reviewed and revealed similar improvements in clinical scores and lung function tests for both forms of treatment. Intravenous antibiotics reduced the plasma concentrations of both neutrophil products and CRP, while oral ciprofloxacin only significantly reduced the concentration of neutrophil elastase-alpha 1 antiproteinase complex. Plasma concentrations of inflammatory markers were significantly greater in exacerbations associated with fever and leukocytosis. Statistical modelling demonstrated negative within-patient relationships between lung function and both CRP and lactoferrin, and positive relationships between the three inflammatory markers. Neutrophil granule products and CRP reflect the pulmonary inflammatory state in cystic fibrosis and may be of value in monitoring treatment.

Systemic inflammatory responses to cardiopulmonary bypass: a pilot study of the effects of pentoxifylline.

The potential of pentoxifylline (PTX) to modify systemic inflammatory responses and lung injury following cardiopulmonary bypass (CPB) was studied in 20 patients undergoing elective coronary artery surgery. Ten control patients were compared with ten patients who received a PTX infusion of 1 mg kg-1 h-1 during surgery. Intra-vascular pulmonary leukocyte sequestration was observed in neither group following discontinuation of CPB. Plasma elastase-alpha-1-antiprotease complex rose three-fold from baseline in both groups to peak at sternal closure. No significant plasma interleukin-1 (IL-1) response was detected. Plasma interleukin-6 (IL-6) rose in both groups from baseline to peak 4 h postoperatively. There was no correlation between plasma levels of elastase complex, IL-1 or IL-6 and impairment of postoperative oxygenation. CPB was associated with significant postoperative hypoxaemia and systemic release of neutrophil elastase and IL-6 but PTX, at the given dose, did not abrogate these responses.

Antibody response to Burkholderia cepacia in patients with cystic fibrosis colonized with Burkholderia cepacia and Pseudomonas aeruginosa.

INTRODUCTION: This study was designed to determine the relationship between formation of serum antibodies to lipopolysaccharide (LPS) core antigen of Burkholderia cepacia and pulmonary colonization with B. cepacia and Pseudomonas aeruginosa in patients with cystic fibrosis (CF), and to define if an enhanced host humoral immune response to B. cepacia was related to a poor clinical outcome. METHODS: Serum IgG to B. cepacia LPS core antigen was measured in adult cystic fibrosis patients colonized with B. cepacia and P. aeruginosa, and serial titres were measured in 13 B. cepacia and 41 P. aeruginosa colonized patients followed prospectively over 18 months. RESULTS: The median B. cepacia antibody titre was significantly greater in the patients colonized with B. cepacia compared to those colonized with P. aeruginosa, a group which grew B. cepacia intermittently from their sputum. and nine healthy controls. The median antibody titre at recruitment into the study was significantly greater in patients who later went into exacerbations compared with those who remained clinically stable. but there was no difference between B. cepacia antibody titres in patients who died and those who survived the study duration. DISCUSSION: The degree of overlap of serum IgG levels to B. cepacia LPS core antigen in cystic fibrosis patients colonized with B. cepacia and P. aeruginosa does not allow this antibody to be used in a clinical context to define infection status. The magnitude of the humoral response to B. cepacia may influence occurrence of pulmonary exacerbations, but a more exuberant humoral immune response to B. cepacia core LPS is not the mechanism by which pulmonary deterioration occurs.

The radiographic differentiation of pulmonary oedema.

A radiographic scoring system has been reported to have a high diagnostic accuracy in the differentiation of pulmonary oedema of renal, cardiac and capillary origin. In the present study, a similar scoring system was used in 51 patients with radiographic appearances of pulmonary oedema due to renal failure (n = 16), cardiac failure (n = 13) and to adult respiratory distress syndrome (ARDS) (n = 22). Evidence of increased pulmonary capillary permeability to transferrin was sought in all patients using a double-isotope method to derive a protein accumulation index (PAI). Using the clinical diagnosis of each type of pulmonary oedema as the "gold standard", sensitivity, specificity and accuracy for the chest radiographic scoring system in pulmonary oedema of cardiac origin were 46, 84 and 75%, respectively. For renal patients these values were 63, 86 and 78% and for ARDS, 89, 33 and 77%. For the PAI in ARDS, sensitivity was 85%, specificity 67% and accuracy 86%. The radiographic scoring system failed to distinguish between pulmonary oedema of renal and cardiac origin and cannot be considered of diagnostic value, but it was more successful in assessment of ARDS. Radiographic appearances suggestive of capillary injury and increased capillary permeability to transferrin occurred in all groups and such findings are not specific to ARDS as currently defined.