Systemic inflammatory mediators and cystic fibrosis genotype.

Morbidity and mortality in cystic fibrosis patients is mainly attributed to pulmonary infection and inflammation. Chemokines play a pivotal role in the inflammatory process. Although genotype-phenotype correlation in cystic fibrosis patients has been defined, a clear relationship between the defect in the cystic fibrosis transmembrane regulator (CFTR) gene and pulmonary inflammation has not been established. The aim of this study was to assess whether serum chemokines levels in cystic fibrosis patients correlate with genotype and pulmonary function tests, as well as with other clinical characteristics. Serum levels of interleukin-8, RANTES, and monocyte chemoattractant protein-1 were measured in 36 cystic fibrosis patients grouped according to their genotype. Group A included 25 patients who carried two mutations associated with a pathological sweat test and pancreatic insufficiency (deltaF508, W1282X, G542X, N1303K, S549R). Group B included 11 compound heterozygote patients who carried one mutation known to cause mild disease with borderline or normal sweat test and pancreatic sufficiency (3849+10kb C to T, 5T). Associations between chemokine levels, genotype, pulmonary function, Pseudomonas aeruginosa colonization, age, sweat chloride level, and pancreatic and nutritional status were examined. Mean interleukin-8 and monocyte chemoattractant protein-1 levels were significantly higher in group A than group B (11.4 +/- 2.1 pg/ml vs. 5 +/- 0.9 pg/ml and 157 +/- 16 pg/ml vs. 88.8 +/- 16.4 pg/ml, respectively) (P < 0.01). No difference in RANTES levels were found between groups. interleukin-8 levels were inversely related to forced expiratory volume in 1 s (r = -0.37, P < 0.02), while there was no association between the latter and RANTES and monocyte chemoattractant protein-1 levels. The Pseudomonas colonization rate was higher among group A patients than group B (88% vs. 40%, P < 0.01). No relationship was found between measured chemokines and age, sweat chloride levels, and pancreatic and nutritional status. Our study demonstrates an association between interleukin-8, forced expiratory volume, and cystic fibrosis genotype. Hence, elevated interleukin-8 serum levels could serve as an indicator of an early inflammatory process and encourage the initiation of anti-inflammatory treatment.

Serum CA 19-9 levels as a diagnostic marker in cystic fibrosis patients with borderline sweat tests.

Patients with normal or borderline sweat tests present a diagnostic challenge. In spite of the availability of genetic analysis and measurement of nasal potential difference, there is still uncertainty in diagnosing cystic fibrosis in some patients. CA 19-9 is a tumor-associated antigen whose levels were previously found to be elevated in some cystic fibrosis patients. We investigated whether serum CA 19-9 levels can contribute to establishing the diagnosis of cystic fibrosis in patients with a borderline sweat test, and evaluated the influence of different clinical variables on CA 19-9 levels. Serum CA 19-9 levels were measured in 82 cystic fibrosis patients grouped according to their genotype and in 38 healthy individuals. Group A included 50 patients who carried two mutations previously found to be associated with a pathological sweat test and pancreatic insufficiency (DeltaF508, W1282X, G542X, N1303K, and S549R). Group B included 13 compound heterozygote cystic fibrosis patients who carried one mutation known to cause mild disease with a borderline or normal sweat test and pancreatic sufficiency (3849+10kb C-->T, 5T). Group C included 38 normal controls. Nineteen cystic fibrosis patients carried at least one unidentified mutation. An association between CA 19-9 levels and age, pulmonary function, pancreatic status, sweat chloride, previous pancreatitis, serum lipase, meconium ileus, distal intestinal obstruction, liver disease, and diabetes was investigated. The distribution of CA 19-9 levels was significantly different between the three groups ( p<0.01); high CA 19-9 levels were found in 60% (30/50) of group Apatients and in 46.6% (6/13) of group B patients, but in only 5.2% (2/38) of the controls. CA 19-9 levels were inversely related to forced expiratory volume in 1 s, while no association was found with the other clinical parameters examined. Our findings suggest that the serum CA 19-9 in cystic fibrosis patients originates in the respiratory system, and has a useful ancillary role, particularly when diagnostic uncertainty exists. Hence, the diagnosis of cystic fibrosis should be considered in patients with borderline sweat tests and high CA 19-9 levels, but normal levels do not exclude cystic fibrosis.

Prediction of mortality and timing of referral for lung transplantation in cystic fibrosis patients.

Lung transplantation (Tx) is an optional treatment for cystic fibrosis (CF) patients with end-stage lung disease. The decision to place a patient on the Tx waiting list is frequently complex, difficult, and controversial. This study evaluated the current criteria for lung Tx and assessed additional parameters that may identify CF patients at high risk of death. Data were extracted from the medical records of 392 CF patients. Forty of these patients had a forced expiratory volume in 1 s (FEV(1)) less than 30% predicted, and nine of these 40 patients were transplanted. A comparison was performed between the survival of those transplanted (n = 9) and those not transplanted (n = 31), by means of Kaplan-Meier survival curves. The influence on survival of age, gender, nutritional status, sputum aspergillus, diabetes mellitus, recurrent hemoptysis, oxygen use, and the decline rate of FEV(1), were investigated by means of univariate and multivariate analyses. The rate of decline of FEV(1) was evaluated employing the linear regression model. CF patients with a FEV(1)< 30% and who did not receive a lung transplant had survived longer than CF patients who did receive a lung transplant (median survival 7.33 vs. 3.49 yr, 5-yr survival 73% vs. 29%). Two factors--rate of decline in FEV(1) values and age < 15 yr--were found to influence the mortality rate, while the other parameters examined did not. Our results indicate that the current criterion of FEV(1)< 30% predicted, alone is not sufficiently sensitive to predict the mortality rate in CF patients and time of referral for Tx, as many of these patients survive for long periods of time. Additional criteria to FEV(1)< 30%, should include rapidly declining FEV(1) values and age < 15 yr.

Serum lipase levels as a diagnostic marker in cystic fibrosis patients with normal or borderline sweat tests.

Patients with normal or borderline sweat test present a diagnostic challenge. In spite of the availability of different methods such as genetic analysis and measurements of nasal potential difference, uncertainty in diagnosing cystic fibrosis (CF) in some patients still exists. Neonates with CF have high serum lipase levels, which decline over time in pancreatic-insufficient patients, whereas pancreatic-sufficient patients demonstrate high serum lipase levels beyond infancy. Because patients with borderline or normal sweat test are almost always pancreatic sufficient, this study was aimed to assess whether serum lipase levels may be of help in establishing the diagnosis of CF in these patients. Serum lipase levels were measured in 100 CF patients and in 17 healthy individuals. Patients were grouped according to their genotype. Group A patients (n = 70) carried two mutations previously found to be associated with a pathologic sweat test and pancreatic insufficiency (delta F508, W1282X, G542X, N1303K, S549R). Group B (n = 30) were compound heterozygote patients who carried one mutation known to cause mild disease with borderline or normal sweat tests and pancreatic sufficiency (3849+10kb C-->T, 5T). Group C included 17 healthy controls. Serum lipase levels ranged between 2 and 104.4 U/L (mean +/- SD 16.9 +/- 14.7), 6.1-200 U/L (mean +/- SD 53.9 +/- 47.9), and 8.5-27.8 U/L (mean +/- SD 16.9 +/- 5.1) in Groups A, B, and C, respectively, with some overlapping between groups. The distribution of lipase levels was significantly different in Group B vs Groups A and C (P < 0.01). High lipase levels were found in 63.3% (19/30) of Group B patients, but in only 4.3% (3/70) and 0% (0/17) of Group A and C, respectively. Lipase levels were found to be inversely related to sweat chloride concentrations (r = -0.19, P < 0.05). Patients with borderline or normal sweat tests had high lipase levels, whereas low lipase levels were associated with pathologic sweat tests. Our findings indicate that the serum lipase level is genetically determined and that it has a useful role in the diagnosis of CF. Thus, in patients with borderline sweat tests and high lipase levels, the diagnosis of CF should be considered.