Objective

To determine the pancreatic phenotype of infants with cystic fibrosis (CF) diagnosed in the first week of life by a combined immunoreactive trypsin/mutation screening program.

Design

A prospective evaluation of pancreatic function in infants with CF at the time of neonatal diagnosis and up to the age of 12.

Setting

Two different centres (Verona, Italy and Westmead, Australia) to enable comparison of results between two regions where <60% or ⩾90% of patients, respectively, have at least one single ΔF508 a mutation.

Patients

315 children with CF including 149 at Verona and 166 at Westmead.

Interventions

Fat balance studies over 3–5 days and pancreatic stimulation tests with main outcome measures being faecal fat or pancreatic colipase secretion. Patients with malabsorption are pancreatic insufficient (PI) or with normal absorption and pancreatic sufficient (PS).

Results

34 infants (23%) at Verona and 46 (28%) at Westmead were PS at diagnosis. 15% of those with two class I, II or III “severe” mutations and 26/28 (93%) of those with class IV or V mutations were PS at this early age. Of the 80 infants with PS, 20 became PI before the age of 12. All 20 had two severe mutations.

Conclusion

Neonatal mutational screening programs for CF are less likely to detect PS patients with non‐ΔF508 mutations. Of PS patients who are detected, those with two severe class I, II or III mutations are at particularly high risk of becoming PI during early childhood.

The innate immune response to adenovirus (Ad)-derived gene transfer vectors has been shown to initiate immediately after interaction of Ad with respiratory epithelial cells, through the induction of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and JNK mitogen-activated protein kinase (MAPK), nuclear factor κB (NF-κB), and different proinflammatory genes. Ad serotypes 2 or 5 (Ad2/5) enter respiratory epithelia after initial binding of fiber with the coxsackievirus-adenovirus receptor (CAR) or, alternatively, with cell surface heparan sulfate glycosaminoglycans. Ad2/5 internalization is triggered by binding of penton base to cellular RGD-binding integrins. Here we investigated the role of the Ad5 surface domain proteins constituting the vector capsid, namely, the fiber, the penton base, and the hexon, on the transmembrane signals leading to the transcription of the different proinflammatory genes in the human respiratory A549 cell line. Interaction of Ad fiber with CAR activates both ERK1/2 and JNK MAPK and the nuclear translocation of NF-κB, whereas no activation was observed after exposing A549 cells to penton base and hexon proteins. Moreover, interaction of Ad fiber with CAR, but not heparan sulfate proteoglycans, promotes transcription of the chemokines interleukin-8, GRO-α, GRO-γ, RANTES, and interferon-inducible protein 10. These results identify the binding of Ad5 fiber with the cellular CAR as a key proinflammatory activation event in epithelial respiratory cells that is independent of the transcription of Ad5 genes.