Longitudinal evaluation of bronchopulmonary disease in children with cystic fibrosis

Abstract

Children with cystic fibrosis (CF) develop bronchopulmonary disease at variable ages. Determining the epidemiology of chronic lung disease and quantifying its severity, however, have been difficult in infants and young children. As part of the Wisconsin CF Neonatal Screening Project, we were presented with an ideal opportunity to assess longitudinally the evolution of symptoms, signs, and quantitative measures of CF respiratory disease. After newborn screening test results led to early recognition, 64 patients diagnosed at a median age of 6.71 weeks were enrolled and studied systematically at a median age of 11.3 years to obtain clinical information, chest radiographs, and pulmonary function tests. Our observations revealed that a frequent cough by history is evident by 10.5 months of age in half the patients. Quantitative chest radiology (CXR scoring) demonstrated that potentially irreversible abnormalities are present in half the children by 2 years. The severity of Wisconsin and Brasfield CXR scores increased in association with respiratory infections. Longitudinal progression of Wisconsin CXR scores was related to age (P < 0.001), pancreatic insufficiency (P = 0.005), and respiratory secretion cultures positive for Staphylococus aureas (P = 0.039). In contrast, serial spirometry showed limited sensitivity, as did lung volume determinations; neither was satisfactory as repeated measures with acceptable quality control until after 7 years of age. Time to event analyses revealed that half the patients had % predicted FEF(25-75) and FEV(1)/FVC values greater than 80% until 10.7 and 9.9 years, respectively. We conclude that of the methods evaluated, quantitative chest radiology is currently the best procedure for frequent assessment of bronchopulmonary disease in CF, and that radiographic progression is evident in approximately 85% of patients by 5 years of age. Our results also suggest that bronchiectasis and other radiographic evidence of chronic infection are apparent prior to airways obstruction in young CF patients.

Cystic fibrosis transmembrane conductance regulator (CFTR) dependent cytoskeletal tension during lung organogenesis

“…These would become more apparent as the lung aged and was subjected to environmental insults. This is consistent with a growing body of evidence that CF patient lungs are abnormal at birth (Sharp, 2002;Farrell et al, 2003); that CFTR heterozygous and knockout lungs are different from homozygous normal mice (Cohen et al, 2004a); that in utero CFTR can reverse the CFTR knockout phenotype in the lungs (Fig. 9) and intestines (Larson et al, 1997); that CFTR is expressed at high levels in the developing lung (Broackes-Carter et al, 2002); and finally that transient in utero knockout of CFTR results in a CF phenotype in animals with a nor- mal CFTR genotype (Cohen and Larson, 2005).…”

“…However, there is increasing evidence that the lung may be functionally and structurally abnormal prior to the appearance of clinical infection. Recent data from several studies now document significant changes in pulmonary function in infants with CF (Sharp, 2002;Farrell et al, 2003). High-resolution computed tomography imaging has demonstrated that infants with CF have more dilated airways (Kadison et al, 2000).…”

Newborn Screening for Cystic Fibrosis: Evaluation of Benefits and Risks and Recommendations for State Newborn Screening Programs—

“…Persons with CF who have normal or subnormal pancreatic enzyme activity, referred to as pancreatic sufficiency, rarely experience nutrition-related symptoms but are at risk for pancreatitis as they age (15). They also experience fewer pulmonary problems and have lower mortality (24,25).…”

“…For example, for a cohort of children with CF followed in Wisconsin, the median age at which a pattern of frequent cough became present was age 10.5 months, and 75% had chronic cough by age 6 years (24). By age 7 years, 15%-25% of these children had lung function below the normal range, with progressive decreases in lung function as the children aged (26,29).…”

“…† † Chest radiograph and clinical scores. Investigators for the Wisconsin RCT longitudinally analyzed chest radiograph scores by using two raters for each chest film and two different scoring methods to calculate reliable measures of progression of lung disease (24,29). An analysis indicated that differences in chest radiograph scores were, if anything, to the disadvantage of the screened group, except at time of diagnosis.…”