Adenovirus infection in cystic fibrosis patients: implications for the use of adenoviral vectors for gene transfer.

Clinical trials using replication-deficient adenovirus as vectors for gene transfer into the airways of cystic fibrosis (CF) patients are in progress. However, little is known about the prevalence of wild-type adenovirus infections in patients with cystic fibrosis and their effect on lung function. To answer these questions, serum IgG and IgM antibody titers against adenovirus type 5 were prospectively measured by an indirect immunofluorescence assay in 199 CF outpatients and in a control group of 45 healthy children and young adults. In addition, we performed pulmonary function tests when the patients were in stable clinical condition. IgM antibodies against adenovirus were present in 104 of the 199 cystic fibrosis patients (52.3%). IgG antibodies against adenovirus were detected in 192 of the 199 cystic fibrosis patients (96.5%), and were significantly higher in cystic fibrosis patients older than 7 years than in younger patients and in age matched controls. IgG antibody titers measured a second time 11.8 months later in 143 of the 199 patients had increased in 48 (33.6%) patients. In 27 of these 48 patients, who had at least a 2-fold increase in antibody titer, FVC and FEV1 decreased by 9.8% (p < 0.05) and 8.3% (p = 0.05), respectively, over 45 months. In a comparison group matched for age, sex, and chronic Pseudomonas aeruginosa infection but no increase in antibody titers, FVC and FEV1 were unchanged. The results indicate that wild-type adenovirus infections are prevalent in cystic fibrosis patients and that wild-type adenovirus infections in cystic fibrosis patients seem to be associated with deterioration in lung function. These observations may have important implications for efficacy and safety considerations when using adenoviral vectors for gene therapy.

A cystic fibrosis patient with the nonsense mutation G542X and the splice site mutation 1717-1.

A cystic fibrosis patient with the genotype G542X/1717-1 (G----A) was identified by DNA sequencing of exon 11 of the CFTR gene. The available molecular and clinical data are presented. This is the first report of a patient with this rare genotype and may serve to improve our understanding of allele interactions.

Selection of antibiotics for treatment and prophylaxis of staphylococcal infections in cystic fibrosis patients.

Susceptibility in vitro of 179 staphylococcal strains from 107 cystic fibrosis patients against 31 antibiotics indicates that only teicoplanin, vancomycin and netilmicin were active against all strains. The use of betalactam antibiotics is impaired by 11.7% of methicillin-resistant strains. The bactericidal kinetics of cephalexin and flucloxacillin as determined in a pharmacodynamic model demonstrates the killing of strains resistant to cephalexin (MIC 8 mg/l to 32 mg/l) by flucloxacillin. For the rational selection of antistaphylococcal antibiotics for cystic fibrosis patients, both the MIC of the isolates and the concentration of the antibiotics in cystic fibrosis patients have to be considered.

Qualitative and quantitative microbiological analysis of sputa of 102 patients with cystic fibrosis.

A microbiological analysis of 102 patients suffering from cystic fibrosis was conducted over a 22 month period. 20 microbial species with the following incidence were identified: Pseudomonas aeruginosa: 83.4%; Candida albicans: 29.4%; Staphylococcus aureus: 24.5%; Staphylococcus epidermidis: 11.8%; Haemophilus influenzae: 11.8%; Streptococcus pneumoniae; 6.9%; Pseudomonas maltophilia: 6.8%; Aspergillus fumigatus: 5.9%. Other species were present in less than 5% of the patients. In the majority of specimens with P. aeruginosa, more than one type (up to six) was detectable. These strains were identical in colony appearance, O-serotype and pyocin-type. Quantitative analysis revealed concentrations of colony-forming units of 10(7) to 10(9) for P. aeruginosa, 10(6) to 10(8) for P. maltophilia, 10(4) to 10(7) for S. aureus, 10(4) to 10(6) for S. epidermidis and 10(4) to 10(7) for C. albicans in the majority of specimens. Significant differences were observed in the time periods during which the pathogens persisted in the patients. Maximum persistence was observed for P. aeruginosa. P. maltophilia and A. fumigatus had about similar persistence rates, which were lower than those for P. aeruginosa but above those for S. aureus and H. influenzae. S. epidermidis was eliminated within shorter periods than S. aureus. C. albicans, although the second most frequent microorganism identified, showed a very low persistence rate. The microbiological analysis confirms results from other research centers (high incidence of P. aeruginosa), but reveals significant regional differences as well (Pseudomonas cepacia not detectable, higher incidence of P. maltophilia and C. albicans). This underlines the necessity for detailed qualitative and quantitative microbiological analysis of sputa from cystic fibrosis patients as a prerequisite for rational analysis of etiological, epidemiological and therapeutical aspects of cystic fibrosis.

[A cross-over study on the effectiveness of ofloxacin and ciprofloxacin administered orally]. / Kreuzstudie über die Wirksamkeit von Ofloxacin und Ciprofloxacin bei oraler Anwendung.

Efficacy of Oral Ofloxacin and Ciprofloxacin. Cross-over Study. The efficacy of the 4-quinolones ciprofloxacin (CPX) and ofloxacin (OFX) was studied in a cross-over study. Twenty out-patients with cystic fibrosis and chronic colonization of the respiratory tract with Pseudomonas aeruginosa were treated for ten days with OFX, then another ten days with CPX, and vice versa. Drug concentrations in serum and sputum were assayed. The patients' clinical and laboratory parameters were monitored. The side-effects that appeared did not require interrupting treatment. The serum and sputum concentrations were found to be above the minimal inhibitory concentration. Although P. aeruginosa was not eliminated by the therapy, two-thirds of the patients showed improvement during the infection that could be observed clinically and in laboratory measurements. Oral treatment with OFX and CPX is efficacious.

Malignant gastric sarcoma--diagnosis by ultrasound and endoscopy.

A 14-year-old boy was presented with a mass in the epigastrium. The tumor developed 13 years after removal of a neuroblastoma of the left adrenal gland. Therapy of the primary tumor had included irradiation and chemotherapy. Diagnosis of the gastric tumor was made by ultrasound and endoscopy. A total gastrectomy was performed showing a malignant undifferentiated sarcoma. Primary malignant tumors of the stomach such as gastric teratoma of the newborn [4], leiomyosarcoma [6], malignant lymphoma and carcinoma [1] are very rare in childhood. As cancer is treated more aggressively with radiation and cytostatics, more therapy-induced-tumors, including gastric sarcoma, must be expected in children.

[Hypertrophic osteoarthropathy in a patient with cystic fibrosis]. / Hypertrophische Osteoarthropathie bei einem Patienten mit cystischer Fibrose.

An 11-year-old boy with cystic fibrosis additionally suffered from hypertrophic osteoarthropathy. Despite a mild pulmonary involvement the polyarthritis was surprisingly long-standing and resistant to antiinflammatory treatment. The arthropathy completely disappeared within two months after antibiotic therapy of the bronchopulmonary staphylococcus infection.

The fluorescent immunosorbent test for IgG gliadin antibodies and the leucocyte migration inhibition test in coeliac disease; comparison of diagnostic value.

The diagnostic value of the fluorescent immunosorbent test for IgG gliadin antibodies (FIST) has been investigated in comparison with the LIF test--the competence of the gluten subfractions B2 and B3 in releasing lymphokines from peripheral lymphocytes in vitro--in 96 patients with coeliac disease (CD) under various dietary conditions. In untreated children with CD during their first 2 years of life, the FIST showed 100% sensitivity with 95% specificity, whilst the LIF test showed only 70% sensitivity and 73% specificity. Therefore it can be concluded that the FIST as a screening test is superior to the LIF. In older children with a proved recurrence of the mucosal abnormality after reintroduction of a normal diet, only 44% showed increased IgG gliadin antibody titres whereas 70% proved to be positive in the LIF test. Under a controlled gluten challenge all six patients reacted with a distinct increase in gliadin antibody titres whereas the LIF test changed from positive to negative and vice versa without following any clear principle. These results emphasize the inadequacy of the LIF test as a diagnostic method, both in untreated CD and under controlled gluten challenge.

[Severe protracted diarrhea in infancy ("intractable diarrhea")]. / Die schwere protrahierte Säuglingsdiarrhoe ("intractable diarrhoea").

In most cases, protracted diarrhea in infants is due to lack of human breast milk, and iatrogenic malnutrition. Damage to the mucosa of the small intestine maintained by cow's milk proteins and malnutrition constitute main parts of a vicious circle interrupted by completely parenteral nutrition for some time, and slow reintroduction of human breast milk. This kind of therapy reduced mortality significantly. The best prophylaxis is the full support of breast feeding. As differential diagnosis the familial lethal diarrhea of the breast fed infant has to be considered. Furthermore, in case of diarrhea lasting for longer than two weeks, other less frequent causes have to be thought of, as pointed out briefly.

A reliable screening test for childhood celiac disease: fluorescent immunosorbent test for gliadin antibodies. A prospective multicenter study.

The diagnostic value of gliadin antibody determination using the fluorescent immunosorbent test was examined in a prospective multicenter study comprising 251 children with malabsorptive disorders. Antibodies to gliadin were found in all 72 patients (100%) with active celiac disease (29 children with celiac disease proved by challenge, 43 with probable celiac disease). All children up to the age of 7 years had antibodies in high titers. By contrast, 96 (84%) of 114 children with other malabsorptive disorders and a normal mucosa or with partial villous atrophy had no gliadin antibodies, 14 (12%) had a low titer, and only four (3.5%) showed moderate to high titers. Four children with gastrointestinal tract symptoms of cow milk intolerance and a flat mucosa also showed no antibodies. In 24 of 29 children (83%) with cystic fibrosis and six of seven children with Crohn disease (biopsies not performed in either group), no antibodies could be detected. The others had low or elevated titers. In 25 children with acute gastroenteritis (not biopsied) antibodies were not found at hospital admission nor six weeks later after reintroduction of gluten. The determination of antibodies to gliadin with the fluorescent immunosorbent test is a reliable screening test for childhood celiac disease. In our series there were no false negative results in children with untreated celiac disease. A positive gliadin antibody titer is not proof of celiac disease. In each child the diagnosis must be confirmed by small intestinal biopsy even if the gliadin antibody titer is high. The detection of high titers of cow milk antibodies in 27% of patients with celiac disease is of no value.

[The usefulness of the Chrispin-Norman score in the evaluation of pulmonary status in patients with cystic fibrosis]. / Die Wertigkeit des Chrispin-Norman-Score in der Beurteilung der pulmonalen Situation von Patienten mit Cystischer Fibrose.

Its objectivity and reproducibility having been checked by for independent researchers, the Chrispin-Norman score has proved to be a useful yardstick for evaluating pulmonary changes in cystic fibrosis. The correlation to arterial pO2 was r = 0.68, and to the Schwachman-Kulczycki score, r = 0.75. Scores still consistent with a good general clinical condition were 10.5 in patients under 8 years of age; 13.4 in patients aged between 8 and 13; and 15.5 in the 13-20 age group. An average increase of more than 2 points a year indicates a particularly high danger level.

Extrinsic allergic alveolitis combined with celiac disease in childhood.

A 13-year-old boy suffering from celiac disease (CD) developed shortness of breath at exercise and episodes of malaise, fever and acute dyspnea following contact with pigeons. Lung function testing and chest X-ray suggested interstitial lung disease. Serum precipitins and a combined systemic and pulmonary reaction 4 h after challenge with an extract of pigeon droppings confirmed bird-fancier's lung. This case exhibits two points of interest. Extrinsic allergic alveolitis was found in childhood in combination with CD and it may be considered that both these diseases are based on one common immunologic disorder; HLA-typing of the boy's family showed that he carried HLA-DR 3 in a double dose and was therefore homozygous for HLA-DR 3. This is of some interest because extrinsic allergic alveolitis and CD are both associated with HLA-DR 3.

Vitamin B12 absorption and exocrine pancreatic insufficiency in childhood.

The absorption of vitamin B12, labelled with radioactive 58Co, was measured in 19 patients with cystic fibrosis and one child with the Shwachman-Diamond syndrome using the whole body counting technique. We found vitamin B12 absorption reduced to 7.97 on average, compared to 59.2% for the control group. The low vitamin B12 absorption correlated well with the reduced fat retention coefficients. After adding 0.212 pancreatin to the radioactive vitamin B12 test dose, the absorption quotas improved in all cases, the average being 61%. A meal poor in vitamin B12 tended to increase the absorption of the radioactive test dose to 23% on average. As yet there is no satisfactory explanation for the effect of the diet on the absorption of vitamin B12 in exocrine pancreatic insufficiency. This could be the reason why the malabsorption of vitamin B12 in patients with EPI can go unnoticed for many years and could possibly explain why vitamin B12 malabsorption in exocrine pancreatic insufficiency does not cause symptoms and signs of vitamin B12 deficiency for many years.

The treatment of intractable diarrhea by the method of "Baustein" principle using a casein hydrolisate.

Ten infants with intractable diarrhea, celiac disease and small bowel resection were treated with a special dietetic regimen called "Baustein" principle. The three major food constituents were added to the formula stepwise: first glucose and maltodextrin followed by protein and vegetable oil or MCT oil. The protein source was a newly developed casein hydrolisate also containing minerals, trace elements and vitamins.