Willem Bakker

A Cystic Fibrosis Mutation Associated with Mild Lung Disease

BACKGROUND Cystic fibrosis is the most common lethal autosomal recessive disorder among whites. Among Dutch patients with cystic fibrosis, delta F508 is the most common mutation and A455E the second most common mutation of the cystic fibrosis transmembrane conductance regulator gene on chromosome 7. A455E is associated with preserved pancreatic function and residual secretion of chloride across membranes. We investigated whether it is also associated with less severe pulmonary disease in patients with cystic fibrosis. METHODS A total of 33 patients with compound heterozygosity for the A455E mutation were matched according to age and sex with patients who were homozygous for the delta F508 mutation. The pairs were analyzed with respect to the following outcome variables: age at diagnosis, pulmonary-function values, and the frequency of pseudomonas colonization, pancreatic sufficiency, and diabetes mellitus. RESULTS Cystic fibrosis was diagnosed at a later age in the patients with the A455E mutation than in the delta F508 homozygotes (mean age at diagnosis, 15.0 vs. 3.1 years; P < 0.001). Fewer patients with the A455E mutation had pancreatic insufficiency (21.2 percent vs. 93.9 percent, P < 0.001), and none had diabetes mellitus (0 percent vs. 27.3 percent, P = 0.004). Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were significantly higher in the patients with the A455E mutation (mean FEV1, 73.9 percent of the predicted value vs. 54.3 percent of the predicted value; P = 0.002; mean FVC, 88.7 percent of the predicted value vs. 76.3 percent of the predicted value; P = 0.04). Fewer patients with the A455E mutation were colonized with Pseudomonas aeruginosa (33.3 percent vs. 60.6 percent, P = 0.02). CONCLUSIONS A455E is a common mutation causing cystic fibrosis in the Netherlands. Although several mutations are known to be associated with less severe pancreatic disease, our findings demonstrate a correlation between the A455E mutation and mild pulmonary disease. Because mortality in this disease depends primarily on the progression of pulmonary disease, patients with the A455E mutation have a better prognosis than patients who are homozygous for the delta F508 mutation.

Genetic and clinical features of patients with cystic fibrosis diagnosed after the age of 16 years.

BACKGROUND--Cystic fibrosis is usually diagnosed in childhood, but a number of patients are not diagnosed until adulthood. The aim of this study was to investigate whether patients diagnosed at an older age had a different genetic constitution, manifestations of disease, and prognosis from those diagnosed at an early age. METHODS--Clinical data and results of lung function tests and DNA analysis of 143 adult patients with cystic fibrosis were entered into a computerised database. Patients diagnosed before their 16th birthday (early diagnosis, ED) were compared with those diagnosed at 16 years of age or older (late diagnosis, LD). RESULTS--Mean age of diagnosis of the ED group was 4.6 years compared with 27.7 years for the LD group. Mean (SD) percentage predicted pulmonary function was better for the LD group than for the ED group: forced expiratory volume in one second (FEV1) 72.5 (31.1)% and 52.0 (24.8)%, and forced vital capacity (FVC) 89.8 (25.7)% and 71.9 (23.0)%, respectively. Colonisation with Pseudomonas aeruginosa was present in 70% of the ED group and 24% of the LD group. In the ED group 81% had pancreatic insufficiency compared with only 12% of the LD group. None of the LD group was homozygous for delta F508 compared with 58% of the ED group. In the LD group 72% were compound AF508 heterozygotes and 28% had two non-delta F508 mutations. CONCLUSIONS--Among this group of 143 adult patients with cystic fibrosis late diagnosis is caused mainly by delayed expression and mild progression of clinical symptoms. Late diagnosis is associated with milder pulmonary disease, less pancreatic insufficiency, and different cystic fibrosis mutations. Since mortality in cystic fibrosis depends on the progression of pulmonary disease, patients with a late diagnosis have a better prognosis than those diagnosed early.

Improvement of fecal fat excretion after addition of omeprazole to pancrease in cystic fibrosis is related to residual exocrine function of the pancreas

Pancreatic function tests were performed in 11 adult cystic fibrosis (CF) patients with a fecal fat excretion of more than 10% during treatment with pancrease 2 capsules three times a day. These tests included urinary p-aminobenzoic acid (PABA) excretion, fasting serum trypsin and pancreatic polypeptide (PP), and glucose and insulin in fasting and postprandial serum. Subsequently, the patients entered a double-blind placebo-controlled crossover study to assess the effect of gastric acid inhibition by 20 mg omeprazole on fecal fat excretion. Adjunct therapy with omeprazole resulted in a reduction of fecal fat excretion in patients with residual pancreatic function. This improvement showed significant positive correlations with urinary PABA excretion and the increase in serum PP after the meal (P<0.02 and P<0.05), but not with the other parameters studied. Therefore, the addition of omeprazole to pancrease is most successful in CF patients with residual pancreatic function, determined by urinary PABA excretion or incremental PP.

Post-operative intrapleural BCG in lung cancer: a 5-year follow-up report

SummaryOf a total study group of 99 patients 56 received intrapleural BCG in three different dosages (5 patients 16×106, 25 patients 32×106, and 26 patients 64×106 culturable particles) following resection treatment for lung cancer. This study group was compared with an historical control population, very closely matched with regard to age, sex, stage of disease, histology and type of operation.Although the clinical condition of the patients selected for BCG treatment was above average, no survival benefit ensued from the intrapleural BCG. On the contrary, disease-free survival in BCG receivers with stage I and II squamous cell carcinoma was shortened significantly at 2 years follow-up due to the earlier appearance of local recurrences, with the same tendency still present after 5 years. This observation suggests an enhancement of tumour growth by the intrapleural BCG treatment. This alarming phenomenon could be a warning to clinicians when planning clinical immunotherapy trials to be aware of the potentially deleterious effects of such treatment.

Complications of postoperative intrapleural BCG in lung cancer.

Sixty-four patients received bacillus Calmette- Guérin (BCG) in different dosages intrapleurally through a chest drain following resection for lung cancer. In 27 patients this procedure was followed by fever for a few days; the fever was attributed to the BCG. Late complications attributable to the BCG included recurrent fever in 4 patients, abscesses at the site of the drain in 4, wound infections in 2, consolidations on the chest roentgenogram in 3, 1 of whom had subsequent cavitation, and hemoptysis in 2. Side-effects were not dose-dependent. No relationship was found between the preoperative tuberculin response and the frequency or severity of complications. Treatment with isoniazid and rifampin failed to induce an apparent clinical response in patients with complications. We conclude that the intrapleural administration of BCG is not a safe procedure. The side-effects may considerably impair the patients quality of life.