Association between Initial Disease Presentation, Lung Disease Outcomes, and Survival in Patients with Cystic Fibrosis

American Journal of Epidemiology Copyright © 2004 by the Johns Hopkins Bloomberg School of Public Health All rights reserved Vol. 159, No. 6 Printed in U.S.A. DOI: 10.1093/aje/kwh083 ORIGINAL CONTRIBUTIONS Association between Initial Disease Presentation, Lung Disease Outcomes, and Survival in Patients with Cystic Fibrosis HuiChuan J. Lai1,2, Yu Cheng2, Hyungjun Cho2, Michael R. Kosorok2,3, and Philip M. Farrell3 1 Department of Nutritional Sciences, University of Wisconsin College of Agriculture and Life Sciences, Madison, WI. 2 Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine, Madison, WI. 3 Department of Pediatrics, University of Wisconsin School of Medicine, Madison, WI. This US study was conducted to determine whether mode of diagnosis and initial disease presentation influence lung disease and survival in patients with cystic fibrosis. The study population included 27,703 patients reported to the 1986–2000 Cystic Fibrosis Foundation Registry. Patients were segregated into four diagnostic categories: meconium ileus (MI), prenatal/neonatal screening (SCREEN), positive family history (FH), and symptoms other than meconium ileus (SYMPTOM). When compared with patients in the SCREEN group, those in the MI or SYMPTOM group were found to have significantly greater risks of shortened survival, Pseudomonas aeruginosa acquisition, and forced expiratory volume in 1 second (FEV1) below 70% of predicted. In the SYMPTOM group, the greatest risks of shortened survival, P. aeruginosa acquisition, and FEV1 <70% occurred for patients presenting with combined respiratory and gastrointestinal symptoms, followed by respiratory or gastrointestinal symptoms alone; the best outcomes were in patients with other presenting features. Additionally, patients with presumably “severe” genotypes (∆F508 plus other class I, II, III mutations in both alleles) had greater risks of shortened survival and P. aeruginosa acquisition compared with patients with presumably “mild” genotypes (class IV or V mutations in one or both alleles). cystic fibrosis; diagnosis; genotype; lung diseases; registries; signs and symptoms; signs and symptoms, respiratory; survival Abbreviations: CFTR, cystic fibrosis transmembrane regulator gene; CI, confidence interval; FEV1, forced expiratory volume in 1 second; FH, group of patients with a positive family history without symptoms; GI, group of patients with gastrointestinal symptoms; MI, group of patients with meconium ileus; OR, odds ratio; OTHER, group of patients with other symptoms; RESP, group of patients with respiratory symptoms; SCREEN, group of patients without meconium ileus and identified via prenatal/ neonatal screening; SYMPTOM, group of patients with symptoms other than meconium ileus. Cystic fibrosis is an inherited disorder characterized by high electrolyte levels in sweat, pancreatic insufficiency, meconium ileus, malnutrition, and progressive lung disease (1). The degree of disease severity manifested in individual patients with newly diagnosed cystic fibrosis is determined by multiple, interrelated factors. These factors include not only cystic fibrosis–specific characteristics, such as genetic abnormalities (e.g., specific mutations of the cystic fibrosis transmembrane regulator gene, abbreviated CFTR) and phenotypic presentations (e.g., meconium ileus and pancreatic insufficiency), but also demographic characteristics (e.g., the well-described gender gap in cystic fibrosis) and mode of diagnosis (e.g., neonatal screening or conventional diagnosis). The intuitive associations among genotype, phenotype, and prognosis are best evidenced by findings from observational studies showing that, in general, patients with homozygous ∆F508 mutations, pancreatic insufficiency, or Pseudomonas aeruginosa colonization experience Reprint requests to Dr. HuiChuan Lai, Department of Nutritional Sciences, University of Wisconsin College of Agriculture and Life Sciences, 1415 Linden Drive, Madison, WI 53706-1562 (e-mail: ). 537 Am J Epidemiol 2004;159:537–546 Received for publication May 19, 2003; accepted for publication October 16, 2003. 538 Lai et al. MATERIALS AND METHODS Study population The Cystic Fibrosis Foundation Registry documents the diagnosis and annual follow-up evaluations of cystic fibrosis patients who are seen at accredited centers in the United States, as described in detail elsewhere (20). In the present study, Registry data reported during 1986 through 2000 were used. Among the 32,229 patients documented during this period, 2,192 were reported once (908 newly diagnosed in 2000, 452 deceased, 832 lost to follow-up); hence, their data could not be used in time-to-event analysis. For another 2,334 patients, information on “reasons leading to cystic fibrosis diagnosis” was missing, and these patients could not be classified according to their timing and conditions at the time of cystic fibrosis diagnosis. The remaining 27,703 patients were included in the present study. Study design We performed a sequence of analyses to examine the hypothesis that survival and lung disease vary among patients with inherently different degrees of baseline risk, which can be reflected by their age at diagnosis and their initial disease profile at the time of cystic fibrosis diagnosis. With this concept in mind, and considering the common clinical practices that lead to identification of cystic fibrosis, we segregated patients into four groups reflective of their age and mode of diagnosis. These four categories of diagnostic groups were constructed according to the following sequence: patients identified at birth because of the presence of intestinal obstruction known as meconium ileus (MI), patients identified shortly after birth via prenatal/neonatal screening (SCREEN), patients identified at variable ages because of a positive family history without symptoms (FH), and patients identified at variable ages because of symptoms other than meconium ileus (SYMPTOM). The sequence of constructing these categories is important because patients may have meconium ileus and were diagnosed via screening. In this case, they were assigned to the MI group because the presentation of meconium ileus, which is manifested at birth, was what prompted the diagnosis of cystic fibrosis. Our first analysis examined whether survival and lung disease differed among these four diagnostic groups. Subsequently, the associations of gender and CFTR genotype with baseline risk were evaluated. The method we used to classify CFTR genotype is described separately under the subheading “Classification of CFTR mutations.” The second analysis was performed to further examine cystic fibrosis patients in the SYMPTOM subgroup to determine whether survival and lung disease were influenced by the timing and type of initial presenting symptoms. The timing of diagnosis was defined by using age at diagnosis. The type of presenting symptoms was define (...truncated)