Phase II of the International Study of Asthma and Allergies in Childhood (ISAAC II): rationale and methods.

International comparative studies, investigating whether disease incidence or prevalence rates differ between populations and, if so, which factors explain the observed differences, have made important contributions to the understanding of disease aetiology in many areas. In Phase I of the International Study of Asthma and Allergies in Childhood (ISAAC), the prevalence rates of symptoms of asthma, allergic rhinitis and atopic eczema in 13-14-yr-olds, assessed by standardised questionnaires, were found to differ >20-fold between the 155 study centres around the world. Phase II of ISAAC aims to identify determinants of these differences by studying informative populations. A detailed study protocol was developed for use in community-based random samples of children aged 9-11 yrs. The study modules include standardised questionnaires with detailed questions on the occurrence and severity of symptoms of asthma, allergic rhinitis and atopic eczema, their clinical management, and a broad range of previous and current exposure conditions. In addition, standardised protocols were applied for examination of flexural dermatitis, skin-prick testing, bronchial challenge with hypertonic saline, blood sampling for immunoglobulin E analyses and genotyping, and dust sampling for assessment of indoor exposures to allergens and endotoxin. To date, ISAAC II field work had been completed or started in 30 study centres in 22 countries. The majority of centres are in countries that participated in International Study of Asthma and Allergies in Childhood Phase I and reflect almost the full range of the observed variability in Phase I prevalence rates.     

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

Summary 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 chronicPseudomonas aeruginosa infection but no increase in antibody titers, FVC and FEV ₁ 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.

---

Adenovirusinfektion bei Patienten mit zystischer Fibrose: Bedeutung für den Einsatz adenoviraler Vektoren für den Gentransfer

Zusammenfassung Gentechnisch hergestellte rekombinante replikations-defiziente Adenoviren sind als Genvektoren für die somatische Gentherapie der pulmonalen Manifestation der zystischen Fibrose von Interesse. Der Einsatz rekombinanter Adenoviren für den Transfer von Genen in die Atemwege ist jedoch problematisch: Ein positiver Antikörper-Status gegen Adenoviren kann bereits bei der Erstapplikation adenoviraler Genvektoren zu einer Immunantwort führen, wodurch der erfolgreiche Gentransfer verhindert werden könnte. Eine Entzündungsreaktion gegen die infizierten Zellen könnte zu einer Schädigung der Lunge führen. Das Ziel dieser Studie war es, die Prävalenz von Antikörpern bei CF-Patienten und den Einfluß von Adenovirus-Infektionen auf den Verlauf der Lungenfunktion bei CF-Patienten zu bestimmen. IgM und IgG Serum-Antikörper Titer wurden bei 199 CF-Patienten und einer Kontrollgruppe von 45 Kindern und jungen Erwachsenen gemessen. 52% der CF-Patienten hatten positive IgM Antikörper gegen Adenovirus. CF-Patienten hatten im Vergleich zur Kontrollgruppe signifikant höhere IgG Antikörperspiegel. Nur 7 von 199 CF-Patienten hatten keine nachweisbaren IgG Antikörper gegen Adenovirus. Bei 143 CF-Patienten konnte nach einem mittleren Zeitintervall von 12 Monaten ein zweiter Antikörper-Status bestimmt werden. Patienten mit einem Anstieg des Antikörperspiegels zeigten eine Verschlechterung der Lungenfunktionsparameter. Aus den Daten läßt sich schließen, daß Adenovirus-Infektionen bei CF-Patienten häufig sind und mit einer Verschlechterung der Lungenfunktion einhergehen. Diese Beobachtungen könnten von Bedeutung sein für den zukünftigen Einsatz von adenoviralen Genvektoren bei CF-Patienten.