Increased intragastric acid-resistant lipase activity and lipolysis in pancreatic steatorrhoea due to cystic fibrosis.

We measured gastric lipase activity and lipolysis in postprandial gastric samples from 10 adults with steatorrhoea due to cystic fibrosis (CF) and from 10 healthy volunteers of similar age and sex. Gastric samples were aspirated for 2 h following a meal consisting of emulsified long-chain triglyceride. Mean acid-resistant lipase activity was twice as high in CF patients as in controls (596 vs. 299 nmol/ml/min fatty acid released; p = 0.028 for area under the curve). Lipolysis rose from 5 to 10% during the postprandial period in CF patients, compared with a constant 5% in controls (p = 0.036 for area under the curve). We conclude that, in healthy adults, lipolysis of long-chain triglyceride starts in the stomach, while in adults with pancreatic steatorrhoea due to CF, gastric lipase activity and intragastric lipolysis are increased, perhaps in compensation for pancreatic insufficiency.

Platelet abnormalities in patients with cystic fibrosis and obligate heterozygotes.

Following our previous report that thrombocytosis and platelet hyperaggregability (as tested in platelet rich plasma) occur in patients with cystic fibrosis (CF), we have now examined whether this thrombocytosis is related to leukocytosis, and whether platelet hyperaggregability can be documented in whole blood using impedance aggregometry. Our observations show that platelet counts are related to white cell counts (r = 0.34; p = 0.001) and that therefore thrombocytosis may be part of a secondary response to bronchopulmonary infection, which is characteristic of these patients. Platelet counts were, however, not related to serum iron concentration despite the finding of varying degrees of iron deficiency in approximately 50% of patients with cystic fibrosis. Whole blood aggregometry demonstrated platelet hyperaggregability in patients with cystic fibrosis independently of platelet counts. Platelet aggregation (in platelet rich plasma and in whole blood) was normal in obligate heterozygotes, thus suggesting that platelet hyperaggregability in CF is not a consequence of abnormal genetic information.

Serum immunoglobulins and immunoglobulin G subclasses in cystic fibrosis related to the clinical state of the patient.

Levels of serum immunoglobulins and immunoglobulin G subclasses were measured in 32 cystic fibrosis (CF) patients, 30 asthmatics and 27 controls. When compared with the asthmatic patients and controls, the CF patients had raised levels of all IgG subclasses as well as total IgG, IgM and IgA, but there was not a statistically significant increase in IgE. The levels of immunoglobulins in the CF patients were examined in relation to the clinical features of the disease. Raised levels of IgG4 were related to levels of IgE, but these raised levels of IgG4 appeared to be part of a general increase in total IgG and not an isolated feature. There was a significant correlation between the total IgG level and its subclasses, IgG1, IgG2, IgG3, IgG4 and IgA. IgG1 was significantly correlated with IgG2 and IgG4; IgG2 with IgG4; and IgG4 with IgE. Total IgG was the immunoglobulin most closely correlated with poor lung function. Serum IgA was higher in patients with positive immediate skin prick reactions to pollens (p less than 0.005) and death within two years of the study was related to high levels of total IgG (p less than 0.01), IgG3 (p less than 0.001), IgA (p less than 0.001), and IgE (p less than 0.005).

Infection control revisited: dilemma facing today's bronchoscopists.

The emergence of the acquired immune deficiency syndrome has provoked a widespread review of policies for infection control. Incomplete knowledge about the human immunodeficiency virus (HIV), hepatitis B virus, and mycobacteria has until now been compensated for by adopting "overkill" precautions for patients who were thought to harbour these organisms. This policy is no longer tenable, given the difficulty in identifying infected patients. The control of infection in hospitals must instead be based on the routine use of high standards of hygiene that are adequate to contain all pathogens. Attempts by bronchoscopists to formulate such a policy have been frustrated by the lack of a suitable disinfectant and by ignorance of the susceptibility of microorganisms to cleaning and disinfection in a clinical environment.

The arthropathy of cystic fibrosis.

Musculoskeletal symptoms are frequent in cystic fibrosis (CF). Here the clinical features of 29 patients with CF who had significant arthropathy are described. Twelve had episodic arthritis (EA) characterised by repeated short attacks of severe, incapacitating polyarthritis, which in seven was associated with fever and erythema nodosum. Ten patients had hypertrophic pulmonary osteoarthropathy (HPOA). The onset of symptoms in the group with HPOA was usually later (mean age 20 years v 16 years for EA) and was associated with significantly worse lung function than in patients with CF, either without arthropathy or with EA. Seven patients had arthropathies which could not be classified as EA or HPOA.

Vitamin D and parathyroid hormone and bone mineralisation in adults with cystic fibrosis.

Vitamin D and parathyroid hormone concentrations were assessed in 31 adults with cystic fibrosis (mean age 24, range 17-52 years), in 28 of whom the bone mineral index in the forearm was also determined. Serum 25-hydroxyvitamin D was subnormal in eight patients, of whom five were receiving vitamin D supplements in standard doses. 1,25-dihydroxyvitamin D and parathyroid hormone concentrations showed no consistent abnormalities. The bone mineral index was lower in patients with cystic fibrosis (p less than 0.02) than in controls. Five patients with unequivocally reduced bone mineral index had a subnormal mean serum 25-hydroxyvitamin D and significantly worse lung function than the other patients. There was a positive correlation between age and bone mineral index (r = 0.68, p less than 0.001). Thus a significant proportion of patients with cystic fibrosis living in a temperate climate are at risk of vitamin D deficiency. Osteopenia is common and is probably related to a combination of hypovitaminosis D, delay in puberty, hypo-oestrogenism in women, and reduced physical activity, rather than to secondary hyperparathyroidism. Since most patients with deficiency of 25-hydroxyvitamin D were receiving oral supplements, parenteral vitamin D supplementation may be appropriate for selected patients who are unable to maintain adequate 25-hydroxyvitamin D concentrations despite oral vitamin D supplements.

Enteric coated microspheres of pancreatin in the treatment of cystic fibrosis: comparison with a standard enteric coated preparation.

In an open, randomised crossover study enteric coated microspheres of pancreatin were compared with a standard preparation of enteric coated pancreatin over two consecutive 28 day treatment periods in 23 adults with steatorrhoea due to cystic fibrosis. Lipase intake was equal to the patients' previous requirements and was the same during the two months. Patients performed 72 hour faecal collections at the end of each month and completed diary cards daily throughout. Comparison of the month of treatment with enteric coated microspheres with the month of standard enteric coated tablets showed a significant increase in body weight on microsphere capsules (p less than 0.02). There was also a reduced frequency of bowel actions (p less than 0.001) and abdominal pain (p less than 0.05), and improvement in stool character (p less than 0.001) on microsphere capsules. Faecal fat excretion was reduced by 44% with the microsphere capsules (p less than 0.01), and 86% of patients showed an increased coefficient of fat absorption (mean increase 13%, 95% confidence limits 6.5-19.1%; p less than 0.001). Eighty one per cent of patients preferred microsphere capsules of the two treatments. Thus enteric coated microsphere capsules are more effective in treating steatorrhoea in cystic fibrosis than standard enteric coated tablets.

Cystic fibrosis in adolescents and adults.

Three hundred and sixteen patients with cystic fibrosis were seen at the Brompton Hospital during 1965-83; 178 (56.3%) of them were male and 136 female, and their ages ranged from 12 to 51 years. Most patients presented in infancy with respiratory symptoms and malabsorption, but 19 (6%) were diagnosed in adult life, three in their 30s. Pulmonary disease was almost universal (99.7%), being responsible for 97% of all deaths and three quarters of hospital admissions. All patients had developed a productive cough by the age of 21 and over half before the age of 5. Many complained of wheezing, but reversible airflow obstruction was present in only 40% of those tested. Minor haemoptysis was very common (62%), but major episodes less so (10%). Pneumothorax was seen in 61 cases (19%), and was often recurrent. Some irreversible airflow obstruction was present in all patients with pulmonary disease. Two patients have been followed for over 20 years without showing appreciable decline in lung function. Thirty five patients (11%) had no symptoms of malabsorption. Acute meconium ileus equivalent was seen in 16% and a chronic partial obstruction with episodic symptoms in a further 19%. Diabetes mellitus developed in 36 patients, 13 of whom were insulin dependent. Hepatomegaly was common (29%), often occurring without abnormal results in biochemical tests of liver function; only 1% of patients developed portal hypertension with varices and ascites. Skin reactions to at least one common allergen, including Aspergillus fumigatus, were positive in 70%, but very few patients suffered from hay fever or eczema. One hundred and twenty one patients have died, 97% from infection or other pulmonary complications, and 195 were alive in December 1983 (mean age 23 years). Seventy eight per cent of patients were in full time education or full or part time employment, or were housewives, and only 41 were unemployed for reasons for health. Many patients are married and 10 women have borne children. Most patients were admitted to hospital only three or four times during the period of follow up and 50 individuals (16%) have never been in hospital at all. The improvement in prognosis and quality of life for adults with cystic fibrosis should encourage a positive attitude in those who care for them.

Inhaled ceftazidime compared with gentamicin and carbenicillin in older patients with cystic fibrosis infected with Pseudomonas aeruginosa.

A randomized cross-over study was undertaken to compare nebulized (1) ceftazidime with (2) a combination of gentamicin and carbenicillin, and (3) saline, each given for 4 months, in patients with cystic fibrosis infected with Pseudomonas aeruginosa. Mean peak expiratory flow on ceftazidime, 299 litres/min, and on gentamicin and carbenicillin, 297 litres/min, were greater than on saline, 278 litres/min (P less than 0.02 and P less than 0.05 respectively). Similarly mean forced expiratory volume in 1 second on ceftazidime, 1.70 litres, and on gentamicin and carbenicillin, 1.70 litres, were greater than on saline, 1.48 litres (P less than 0.02 and P less than 0.01 respectively). Mean forced vital capacity on gentamicin and carbenicillin, 2.93 litres, was also greater than on saline (P less than 0.05). We were unable to demonstrate any difference in efficacy between the antibiotic regimens. The patients were admitted to hospital less frequently during the study year compared with the previous year (P less than 0.05). Sixty-nine per cent of patients had a clinically significant (20%) increase in forced expiratory volume in 1 second on an antibiotic regimen compared with that on entry to study, but a minority of patients appear not to respond to this form of treatment.

Lymphocyte subpopulations and function in cystic fibrosis.

Circulating lymphocytes subpopulations and their function have been studied in 25 young adults with cystic fibrosis (CF) and 25 normal controls. Mean absolute numbers of all lymphocyte subsets in the CF group were not significantly different from the controls. Antibody-dependent cell cytotoxicity was significantly higher in the CF patients who had Pseudomonas aeruginosa in their sputum compared with those who had not and compared with the normal controls. Within the CF group the numbers of B cells, total T cells and OKT4+ helper cells fell as percent predicted peak expiratory flow (PEF) declined and similar significant positive correlations were found between lymphocyte subsets and percent predicted body weight. Serum albumin levels also showed a positive correlation with total T lymphocyte numbers (p less than 0.05). In vitro lymphocyte proliferative responses to mitogen were not significantly different from the control group, but again correlated positively with body weight in the CF patients. This provides further evidence that immune function in CF patients may become impaired as pulmonary disease and nutritional status deteriorate.

Amenorrhoea in cystic fibrosis.

Menstrual history in relation to nutritional status and lung function was assessed in 45 adolescent and adult patients with cystic fibrosis (CF). Twenty patients had regular menstrual cycles (of whom six had been pregnant), 12 had primary or secondary amenorrhoea, 11 had irregular cycles and two were premenarcheal. Patients with regular menstruation had a significantly higher body mass index and percentage body fat (estimated from skinfold thickness measurements) than those with amenorrhoea (P less than 0.001), and also better lung function (P less than 0.01). A linear discriminant analysis indicated that of the four indices studied percentage body fat was the most important predictor of menstrual function. Ovarian and uterine morphology were studied by ultrasonography in 28 patients and 17 healthy controls. In 10 patients multicystic ovaries were noted. Even in patients with regular cycles uterine size was reduced (P less than 0.01) and in those with amenorrhoea appeared to be related to thinness. Amenorrhoea in CF is an appropriate adaptive response in preventing pregnancy, but the resultant oestrogen deficiency and psychological effects must be considered.

Platelet hyperaggregability in cystic fibrosis.

Platelet function was investigated in 15 patients with cystic fibrosis (CF) and in ten age-matched controls. Marked hyperaggregability of platelets to adrenaline, collagen and arachidonic acid was observed in platelet rich plasma (PRP) prepared from patients with cystic fibrosis. Thromboxane A2 (TXA2) release from these platelets was also markedly enhanced. Hyperaggregability and increased TXA2 release observed in patients with CF was not due to the higher platelet counts in these patients since hyperaggregability was observed even in those patients whose platelet counts were similar to those in controls. Platelet hyperaggregability and increased thromboxane release in these patients were also independent of their body weight and occurred despite supplementation with vitamin E. Hyperaggregability of platelets in CF may be clinically relevant since it may contribute to the pathogenesis of bronchoconstriction through the release of TXA2 and other bronchoconstrictor platelet products such as serotonin.

Insulin sensitivity and beta-cell function assessed by C-peptide in young adults with cystic fibrosis.

Eight patients with cystic fibrosis (CF) aged 18-34 who had normal random plasma glucose levels were studied with a continuous infusion of glucose with model assessment (CIGMA) and plasma C-peptide to assess beta-cell function, and plasma insulin to assess insulin sensitivity. Two had impaired glucose tolerance, two had impaired beta-cell function and all had normal insulin sensitivity. The results of previous studies suggesting that glucose intolerance is common in CF may reflect the inability of an impaired liver to handle a large oral glucose load. The few CF patients who become diabetic may be those who have a preexisting diabetic trait.

Oral ciprofloxacin compared with conventional intravenous treatment for Pseudomonas aeruginosa infection in adults with cystic fibrosis.

40 adult patients with cystic fibrosis (CF) were admitted to hospital with acute exacerbations of infection associated with isolation of Pseudomonas aeruginosa from sputum. The patients were randomly allocated (20 per group) to receive intravenous azlocillin 5 g and gentamicin 80 mg, or oral ciprofloxacin 500 mg. Both treatments were given three times a day for 10 days. The patients were assessed on days 1 and 10, and at 6 weeks. There was a significant improvement in lung function between days 1 and 10 in both groups (p less than 0.001). Significant improvement was maintained at 6 weeks after ciprofloxacin but not in the intravenous group. Improvement after ciprofloxacin was superior at day 10. Sputum weight decreased in both groups (p less than 0.001). Patient-recorded symptoms also improved in both groups. There was no serious toxicity or side-effects. Drug resistant organisms were isolated no more frequently after ciprofloxacin than after intravenous therapy. 17 of the ciprofloxacin-treated patients said they preferred oral treatment to intravenous therapy. Oral ciprofloxacin is a useful short-term treatment for patients with CF who are infected with Ps aeruginosa.

Pharmacokinetics of contraceptive steroids in patients with cystic fibrosis.

The pharmacokinetics of the commonly used contraceptive steroids ethinyloestradiol and levonorgestrel were investigated after oral and intravenous administration in six women with cystic fibrosis. The results were compared with data obtained from healthy women of similar age. The total body clearance of ethinyloestradiol was significantly higher in the patients with cystic fibrosis (0.61 (SD 0.19) l/h/kg) than in control women (0.32 (0.16) l/h/kg; p less than 0.02). In addition, the oral bioavailability of ethinyloestradiol was greater in women with cystic fibrosis than in controls (76.9% (11.7%) compared with 47.3% (7.5%); p less than 0.001). As a result of these two changes, the area under the plasma concentration--time curve after an oral dose of ethinyloestradiol was similar in patients and controls. The pharmacokinetics of levonorgestrel did not differ significantly between patients with cystic fibrosis and healthy women. The data suggest that women with cystic fibrosis will receive similar contraceptive protection from these steroids as do healthy women.

PIP: The pharmacokinetics of the contraceptive steroids ethinyl estradiol and levonorgestrel following oral an intravenous administration were investigated in 6 women with cystic fibrosis. The results were compared with data from healthy controls of similar ages. The bioavailability of ethinyl estradiol was significantly greater in women with cystic fibrosis (76.9%) than in controls (47.3%), but the area under curve after oral administration was similar in both groups. There was a significantly greater total body clearance in women with cystic fibrosis (0.61 1/hr/kg) than in controls (0.32 1/hr/kg). The volume of distribution was not significantly different in patients and controls; thus there was a tendency (nonsignificant) for the elimination half-life and area under curve after the intravenous dose to be less in the women with cystic fibrosis. In terms of levonorgestrel, there were no significant differences between subjects and controls in any of the pharmacokinetic variables studied. These results suggest that the absorption of ethinyl estradiol and levonorgestrel is not impaired by cystic fibrosis. Women with this disease will achieve plasma concentrations of these steroids after an oral dose of a combined oral contraceptive similar to those obtained in healthy women. However, patients with cystic fibrosis should be monitored closely while taking the pill to ensure that vaginal blood loss is regular with no evidence of breakthrough bleeding.

Pharmacokinetics and sputum penetration of ciprofloxacin in patients with cystic fibrosis.

Levels of ciprofloxacin in serum and sputum were studied for eight patients with cystic fibrosis who were infected with Pseudomonas aeruginosa. Patients were studied in a steady state on a dosage of 500 mg every 8 h. Peak levels in serum ranged from 1.27 to 5.6 mg/liter (mean, 3.16 +/- 1.27), and absorption was rapid, the time to peak concentration ranging from 0.5 to 3.0 h (mean, 1.5 +/- 0.9). The antibiotic penetrated sputum well, achieving areas under the curve of approximately 46% of those obtained in serum.

Effect of abnormal liver function on vitamin E status and supplementation in adults with cystic fibrosis.

Patients with cystic fibrosis tend to have reduced serum concentrations of vitamin E and are therefore at risk of developing the neurological complications associated with vitamin E deficiency. Improved survival in cystic fibrosis has resulted in an increasing number of older patients who may develop hepatobiliary complications which may further impair the absorption of vitamin E. In this study the vitamin E status and results of supplementation with oral vitamin E were compared in adult patients with and without evidence of liver involvement as assessed by routine liver function tests. The serum vitamin E concentrations were reduced below normal in 24 of 25 patients. The mean serum vitamin E concentration was significantly lower (p less than 0.05) in those patients with abnormal liver function. When vitamin E status was assessed as the serum vitamin E/cholesterol ratio, however, there was no significant difference between those patients with normal and abnormal liver function. After supplementation with oral vitamin E, either 10 mg/kg/day for one month or 200 mg/day (equivalent to 3.4 to 4.4 mg/kg/day) for up to three months, there was no significant difference in the vitamin E status between the two groups. The results of this study indicate that in general, patients with cystic fibrosis and abnormal liver function do not require increased supplements of vitamin E compared with those with normal liver function.