Diana Costantini

Liver disease in cystic fibrosis: A prospective study on incidence, risk factors, and outcome

Incidence of liver disease (LD) associated with cystic fibrosis (CF) and its clinical characterization still is unsettled. We have assessed prospectively the incidence and risk factors of this complication, and its impact on the clinical course of CF. Between 1980 and 1990, we enrolled 177 CF patients without LD in a systematic clinical, laboratory, ultrasonography screening program of at least a 10‐year duration. During a 14‐year median follow‐up (2,432 patient‐years), 48 patients developed LD, with cirrhosis already present in 5. Incidence rate (number of cases per 100 patient‐years) was 1.8% (95% confidence interval: 1.3–2.4), with sharp decline after the age of 10 years and higher risk in patients with a history of meconium ileus (incidence rate ratio, 5.5; 2.7–11), male sex (2.5; 1.3–4.9), or severe mutations (2.4; 1.2–4.8) at multivariate analysis. Incidence of cirrhosis was 4.5% (2.3–7.8) during a median period of 5 years from diagnosis of liver disease. Among the 17 cirrhotic patients, 13 developed portal hypertension, 4 developed esophageal varices, 1 developed liver decompensation requiring liver transplantation. Development of LD did not condition different mortality (death rate ratio, 0.4; 0.1–1.5) or higher incidence of other clinically relevant outcomes. In conclusion, LD is a relatively frequent and early complication of CF, whose detection should be focused at the first life decade in patients with history of meconium ileus, male sex, or severe genotype. Although LD does not condition a different clinical course of CF, in some patients it may progress rapidly and require liver transplantation. (HEPATOLOGY2002;36:1374–1382).

BMD and body composition in children and young patients affected by cystic fibrosis

Longer survival in cystic fibrosis has led to more bone complications. One hundred thirty‐six young patients were studied for 12‐24 months. Low BMD was found in 66%. Fat mass and lean mass were also reduced. Impaired pulmonary function and total steroid dose had the greatest negative influence on bone.

Effects of liver transplantation on the nutritional status of patients with cystic fibrosis.

The long‐term effects of liver transplantation on nutritional status, body composition and pulmonary function in patients with liver disease associated with cystic fibrosis (CF) are poorly defined. We studied 15 patients with CF‐associated biliary cirrhosis and severe portal hypertension. Seven underwent liver transplantation (age: 14.8 ± 6.2 years), and eight were treated conservatively (age: 15.9 ± 6.7 years). All patients were evaluated at baseline and thereafter yearly for a median duration of 5 years. During follow‐up, transplanted patients gained weight and showed a significant increment in body mass index (P < 0.004), whereas patients without transplantation remained stable (P = 0.063). Baseline bone mineral content (dual energy X‐ray absorptiometry scan) was lower than normal in all patients (more in transplanted patients) and increased in transplanted patients (P < 0.05), but not in patients without transplantation. In both groups percent body fat did not change, whereas fat free mass increased only in the transplant group (P = 0.06) (P < 0.03 versus nontransplanted patients). Only in transplanted patients’ plasma concentrations of vitamin E and A increased (P < 0.05 versus nontransplanted patients). Forced espiratory volume in 1 s and forced vital capacity showed similar deterioration in transplanted and in nontransplanted patients. Liver transplantation is associated with long‐term beneficial effects on the nutritional status of CF patients and seems to favor bone mineralization.

Benefits of breastfeeding in cystic fibrosis: A single‐centre follow‐up survey

Aim: To study the effect of breastfeeding (BF) on growth, lung function and number of infections during the first 3 years of life in children with cystic fibrosis (CF).

Dietary and circulating polyunsaturated fatty acids in cystic fibrosis: are they related to clinical outcomes?

Objective: To assess the relationship between dietary intakes, plasma phospholipid (PL) fatty acid profile and clinical parameters in children with cystic fibrosis (CF) in comparison to healthy controls. Patients and Methods: A cross-sectional survey including 37 patients with CF (ages 8.0 ± 2.9 yrs) and a reference group of 68 healthy children (ages 8.0 ± 0.7 yrs) was carried out by means of a food-frequency questionnaire. At enrolment, all subjects underwent blood sampling for plasma PL fatty acids (FA). In CF patients, pulmonary function tests (forced expiratory volume in 1 second and forced vital capacity), anthropometric measurements and the Shwachman score were also determined. Results: In CF patients, mean z score for weight and height (−0.35 ± 1.16 and −0.28 ± 0.99) were lower than controls (0.83 ± 1.73 and 0.55 ± 1.11, respectively). Patients with CF showed higher energy intakes (110 ± 43 kcal/d) compared with controls (75 ± 22 kcal/d; P < 0.0001), with higher intake of total (saturated and monounsaturated) fats and lower intake of polyunsaturated FA (3.9 ± 1.0% of total macronutrient intake vs 4.3 ± 1.2%, P = 0.05). In CF patients, plasma and PL levels of linoleic and docosahexaenoic acids were lower, whereas those of arachidonic acid were similar compared with controls. The Shwachman score showed significant positive associations with plasma PL levels of arachidonic acid and total n-6 long-chain FA (r = 0.32, P = 0.05, and r = 0.35, P = 0.03, respectively). Conclusions: The data give suggestions that fat intake and CF-associated biomechanisms are bound in a vicious circle, concurring to create the clinical and biochemical picture of CF. The quantity and quality of fat supplementation in CF need careful attention to balance the fat supply with polyunsaturated FA.

Ceftazidime monotherapy vs. combined therapy in Pseudomonas pulmonary infections in cystic fibrosis

To evaluate whether the addition of an aminoglycoside might enhance the clinical efficacy of ceftazidime in cystic fibrosis patients with acute exacerbations of chronic Pseudomonas lung infections we carried out a prospective, comparative, randomized blind study with three schedules: ceftazidime vs. ceftazidime plus sisomicin (C/S) vs. piperacillin plus sisomicin, for a total of 60 courses of 14 days of treatment. Each treatment led to clinical and radiologic improvement with marked reduction of signs of acute infection. Statistically there was no significant difference in clinical responses among the schedules. No side effect appeared during treatments with ceftazidime or C/S. Hyperpyrexia was seen in 35% of patients receiving piperacillin. Decrease in Pseudomonas aeruginosa count to less than 10(5) colony-forming units/ml of sputum was achieved in 60% of patients treated with C/S and in 30% of patients who received ceftazidime or piperacillin plus sisomicin (statistically not significant). A transient increase in mean geometric minimal inhibitory concentrations for ceftazidime and piperacillin was observed at the end of the combined therapies. A larger percentage of persistent resistant strains of P. aeruginosa was seen after the combined therapies. We conclude that ceftazidime as monotherapy may be an effective alternative in Pseudomonas lung infections in cystic fibrosis patients. Its clinical efficacy seems not to be enhanced by the addition of an aminoglycoside, although reduction of Pseudomonas in the sputum was better achieved by the combination of C/S.

Fcgamma receptor IIA genotype and susceptibility to P. aeruginosa infection in patients with cystic fibrosis.

It has been suggested that genes other than CFTR could modulate the severity of lung disease in cystic fibrosis (CF). Neutrophil Fcγ receptor II (FcγRII) is involved in host defense against microorganisms and in inflammatory response. We evaluated the association between genetic variability of this gene and both airway infection with Pseudomonas aeruginosa and severity of lung disease in patients with CF. We studied 167 Italian unrelated patients with CF and 50 control subjects. The distribution of FcγRIIA genotypes in CF patients was compared with that in control subjects and the different genotypes were related with the presence or absence of P. aeruginosa infection and markers of disease severity in CF patients. The distribution of FcγRIIA genotypes was not significantly different between CF patients and controls. We observed that in CF patients with the same CFTR genotype (ΔF508/ΔF508), those carrying the R allele of FcγRIIA had an increased risk of acquiring chronic P. aeruginosa infection (P=0.042, R.R.: 4.38; 95% CI: 1.17÷22.4). Moreover, the frequency of R/R genotype in patients with chronic P. aeruginosa infection seems to be higher than that of control subjects and patients without chronic infection. The observation that CF patients carrying the R allele of FcγRIIA are at higher risk of acquiring chronic P. aeruginosa infection suggests that the FcγRII loci genetic variation is contributing to this infection susceptibility.

Borderline sweat test: Utility and limits of genetic analysis for the diagnosis of cystic fibrosis ☆

OBJECTIVE The sweat test remains the gold standard for the diagnosis of Cystic Fibrosis (CF) even despite the availability of molecular analysis of Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR). We investigated the relationship between CFTR mutation analysis and sweat chloride concentration in a cohort of subjects with borderline sweat test values, in order to identify misdiagnosis of CF. DESIGN AND METHODS In the period between March 2006 and February 2008 we performed 773 sweat tests in individuals referred for suspect CF. Ninety-one subjects had chloride values in the border-line range. Clinicians required CFTR gene complete scanning on 66 of them. RESULTS The mean value of sweat chloride in the DNA negative subjects was lower than in those with at least one CFTR mutation. Our data indicate that 39 mEq/l is the best sensitivity trade off for the sweat test with respect to genotype. CONCLUSIONS To optimise diagnostic accuracy of reference intervals, it may be useful to modify from 30 to 39 mEq/l the threshold for sweat chloride electrolytes.

The Management of Enzymatic Therapy in Cystic Fibrosis Patients by an Individualized Approach

We evaluated nutritional status, pulmonary impairment, nutritional intake, and fat absorption in 73 cystic fibrosis (CF) patients to identify the primary factors) influencing growth. In general, the growth pattern in our patients was satisfactory since 60/73 were not underweight. When caloric intake is greater than or equal to 95% of RDA, wasting does not occur regardless of the degree of malabsorption, dietary fat content, or lung involvement. In the group of patients who consume less than the RDA, underweight is related to the severity of pulmonary disease; indeed, 11/13 underweight patients have a chest x-ray score over 15. Steatorrhea is well controlled in most patients; only 11 of 73 show a fat excretion >25% of fat intake. The daily number of capsules of Pan-crease varies from 4 to 57. The amount of Pancrease to be given was individualized to meet each patients requirements using fat balance studies to determine the necessary daily Pancrease dose, then distributing the total dose in proportion to the fat content of each meal.

ACHROMOBACTER XYLOSOXIDANS: FOLLOW-UP OF 20 PATIENTS WITH CHRONIC INFECTION

P55 ACHROMOBACTER XYLOSOXIDANS: FOLLOW-UP OF 20 PATIENTS WITH CHRONIC INFECTION D. Costantini1, A. Biffi2, M.L. Garlaschi3, L. Zazzeron1, G. Clarizia3, C. Colombo1, L. Cariani2. 1CF Centre, Department of Pediatrics, University of Milan; Fondazione IRCCS, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano; 2CF Centre, Microbiology Laboratory, Fondazione IRCCS, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano; 3Microbiology Laboratory, Fondazione IRCCS, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy