Yaacov Yahav

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

Abstract: 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 (FEV1) 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 FEV1, were investigated by means of univariate and multivariate analyses. The rate of decline of FEV1 was evaluated employing the linear regression model. CF patients with a FEV1 < 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 FEV1 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 FEV1 < 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 FEV1 < 30%, should include rapidly declining FEV1 values and age < 15 yr.

Methacholine bronchial provocation measured by spirometry versus wheeze detection in preschool children

BackgroundDetermination of PC20-FEV1 during Methacholine bronchial provocation test (MCT) is considered to be impossible in preschool children, as it requires repetitive spirometry sets. The aim of this study was to assess the feasibility of determining PC20-FEV1 in preschool age children and compares the results to the wheeze detection (PCW) method.Methods55 preschool children (ages 2.8–6.4 years) with recurrent respiratory symptoms were recruited. Baseline spirometry and MCT were performed according to ATS/ERS guidelines and the following parameters were determined at baseline and after each inhalation: spirometry-indices, lung auscultation at tidal breathing, oxygen saturation, respiratory and heart rate. Comparison between PCW and PC20-FEV1 and clinical parameters at these end-points was done by paired Students t-tests.Results and discussionThirty-six of 55 children (65.4%) successfully performed spirometry-sets up to the point of PCW. PC20-FEV1 occurred at a mean concentration of 1.70+/-2.01 while PCW occurred at a mean concentration of 4.37+/-3.40 mg/ml (p < 0.05). At PCW, all spirometry-parameters were markedly reduced: FVC by 41.3+/-16.4% (mean +/-SD); FEV1 by 44.7+/-14.5%; PEFR by 40.5+/-14.5 and FEF25–75 by 54.7+/-14.4% (P < 0.01 for all parameters). This reduction was accompanied by de-saturation, hyperpnoea, tachycardia and a response to bronchodilators.ConclusionDetermination of PC20-FEV1 by spirometry is feasible in many preschool children. PC20-FEV1 often appears at lower provocation dose than PCW. The lower dose may shorten the test and encourage participation. Significant decrease in spirometry indices at PCW suggests that PC20-FEV1 determination may be safer.

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

Abstract.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 (ΔF508, 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.

Nephrotic syndrome and fibrillary glomerulonephritis

Laufer J, Augarten A, Szeinberg A, Rapoport J, Katzenelson D, Yahav Y (The Chaim Sheba Medical Center, Tel Hashomer, Affiliated to the Sackler School of Medicine, Tel Aviv, Israel). Nephrotic syndrome and fibrillary glomerulonephritis (Case Report). J Intern Med 1997; 242: 83–6.

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 (ΔF508, 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.

Cystic Fibrosis in Israel: Clinical and Microbiological Aspects

Cystic fibrosis (CF) is an inherited genetic disease characterized by progressive lung disease, pancreatic dysfunction, impaired growth, elevated sweat electrolytes, and other less common clinical findings including meconium ileus, nasal polyposis, and hepatobiliary disease [1]. Patients are diagnosed at different ages with various modes of presentation, and there is considerable variability in the severity or rate of disease progression of involved organs. Certain clinical characteristics of disease expression have been delineated to provide some explanation for the heterogeneity in the clinical course and survival amongst patients with this devastating genetic illness. For example, the patients with sufficient residual exocrine pancreatic function to permit normal digestion without the need for enzyme supplements — pancreatic sufficiency [2, 3] are generally diagnosed at a later age, with lower mean sweat chloride levels, milder respiratory abnormalities, normal growth into adulthood and a better overall prognosis than those with pancreatic insufficiency [3, 4]. Subsequently it was suggested that the extreme variability in disease severity in patients with cystic fibrosis is not a consequence of relative preservation of pancreatic function but is a result of different CF gene mutants, which confer mild or severe phenotypes [5]. In this regard, ΔF508 and W1282X were mutations associated with severe phenotypic expression [5, 6] and R117H and 3849 + 10 kb were mutations associated with less severe phenotype [7, 8]. Severe mutations are characterized by early age at diagnosis, presence of meconium ileus, higher levels of sweat chloride, pancreatic insufficiency, lower nutritional status, and worse survival. However, similar variability in pulmonary function was observed among patients with severe and less severe mutations [5–7]. Thus, severity of pulmonary disease could not be attributed to type of genetic mutation only. It was therefore suggested that other factors, genetic or environmental, are responsible for the variability found in severity of lung disease among patients with identical genotype. In this regard comparison of CF patient status and treatment between different countries, with different genetic background, climate, standards and way of living, may contribute to the understanding of the variability in disease presentation in cystic fibrosis.