Survival effect of lung transplantation among patients with cystic fibrosis.

CONTEXT: Patients with cystic fibrosis (CF) are the second largest group of lung transplant recipients in the United States. The survival effect of transplantation on a general CF population has not previously been measured. OBJECTIVE: To determine the impact of bilateral lung transplantation on survival in patients with CF. DESIGN, SETTING, AND PATIENTS: Retrospective observational cohort study of 11 630 CF patients who did not undergo lung transplantation (controls) and 468 transplant recipients with CF from 115 CF centers in the United States, 1992-1998. Patients were stratified into 5 groups based on a 5-year survival prediction model (survival group 1: <30%; survival group 2: 30 to <50%; survival groups 3-5: 50 to <100%.) MAIN OUTCOME MEASURE: Five-year survival from date of transplantation in 1992-1997 in the transplant group and from January 1, 1993, in the control group. RESULTS: Lung transplantation increased 5-year survival of CF patients in survival group 1. Survival group 2 had equivocal survival effects, and groups 3-5 had negative survival effects from transplantation. From 1994-1997, there was a mean annual prevalence of 238 patients in survival group 1 and mean annual incidence of 154 patients entering the group, approximately 1.5 times the number of lung transplantations performed each year in CF patients (mean, 104). Use of the criterion of forced expiratory volume in 1 second of less than 30% resulted in an equivocal survival benefit and identified 1458 potential candidates for transplantation in 1993. CONCLUSIONS: Cystic fibrosis patients in group 1 have improved 5-year survival after lung transplantation. The majority of patients with CF have equivocal or negative survival effects from the procedure. Selection of patients with CF for transplantation based on group 1 survival predictions maximizes survival benefits to individuals and may reduce the demand for scarce donor organs.

The association of socioeconomic status with outcomes in cystic fibrosis patients in the United States.

There is considerable variability in the clinical course of disease in cystic fibrosis (CF). Although currently unidentified modifier genes might explain some of this heterogeneity, other factors are probably contributory. Socioeconomic status (SES) is an important predictor of health status in many chronic polygenic diseases, but its role in CF has not been systematically evaluated. We performed a historical cohort analysis of pediatric CF patients in the United States using National Cystic Fibrosis Foundation Patient Registry (NCFPR) data for 1986 to 1994, and used Medicaid status as a proxy for low SES. The adjusted risk of death was 3.65 times higher (95% confidence interval [CI]: 3.03 to 4.40) for Medicaid patients than for those not receiving Medicaid. The percent predicted FEV(1) of surviving Medicaid patients was less by 9.1% (95% CI: 6.9 to 11.2). Medicaid patients were 2.19 times more likely to be below the 5th percentile for weight (95% CI: 1.91 to 2.51) and 2.22 times more likely to be below the 5th percentile for height (95% CI: 1.95 to 2.52) than were non-Medicaid patients. Medicaid patients were 1.60 times more likely to require treatment for a pulmonary exacerbation (95% CI: 1.29 to 1.98). There was no difference in the number of outpatient clinic visits for Medicaid and non-Medicaid patients. We conclude that low SES is associated with significantly poorer outcomes in children with CF. Barriers in access to specialty health care do not seem to explain this difference. Further study is indicated to determine what adverse environmental factors might cluster in CF patients of low SES to cause worse outcomes.

Predictive 5-year survivorship model of cystic fibrosis.

The objective of this study was to create a 5-year survivorship model to identify key clinical features of cystic fibrosis. Such a model could help researchers and clinicians to evaluate therapies, improve the design of prospective studies, monitor practice patterns, counsel individual patients, and determine the best candidates for lung transplantation. The authors used information from the Cystic Fibrosis Foundation Patient Registry (CFFPR), which has collected longitudinal data on approximately 90% of cystic fibrosis patients diagnosed in the United States since 1986. They developed multivariate logistic regression models by using data on 5,820 patients randomly selected from 11,630 in the CFFPR in 1993. Models were tested for goodness of fit and were validated for the remaining 5,810 patients for 1993. The validated 5-year survivorship model included age, forced expiratory volume in 1 second as a percentage of predicted normal, gender, weight-for-age z score, pancreatic sufficiency, diabetes mellitus, Staphylococcus aureus infection, Burkerholderia cepacia infection, and annual number of acute pulmonary exacerbations. The model provides insights into the complex nature of cystic fibrosis and supplies a rigorous tool for clinical practice and research.

Early diagnosis of cystic fibrosis in the newborn period and risk of Pseudomonas aeruginosa acquisition in the first 10 years of life: A registry-based longitudinal study.

OBJECTIVE: Controlled clinical trial data have suggested that identifying asymptomatic cystic fibrosis (CF) patients through newborn screening improves health outcomes of affected children in the first decade of life. However, it is unclear whether these improvements also include a reduction in risk for bronchial infection, the major determinant of CF morbidity. The authors therefore investigated the association between early CF diagnosis and acquisition of Pseudomonas aeruginosa, the major bronchial pathogen, in the first decade of life. METHODOLOGY: Longitudinal data on 3625 CF patients diagnosed between 1982 and 1990 and before 36 months of age were ascertained from the National Cystic Fibrosis Patient Registry. We compared P aeruginosa acquisition in the first 10 years of life among 4 groups: EAD (early asymptomatic diagnosis)-<6 weeks, by pre/neonatal screening, genotype, family history (n = 157); ESD (early symptomatic diagnosis) (n = 227); LAD (late asymptomatic diagnosis)-6 weeks to 36 months (n = 161); and LSD (late symptomatic diagnosis) (n = 3080). P aeruginosa acquisition was determined from yearly sputum and/or bronchoscopy cultures. Children whose CF diagnoses followed meconium ileus or whose cultures were obtained only from nasal samples were excluded from the study. RESULTS: Kaplan Meier analyses for P aeruginosa acquisition were conducted for each diagnostic group. Regression models were used to generate adjusted relative hazards with EAD as the referent group. Relative hazards were 0.9 (95% confidence interval [CI]: 0.7-1.2) for ESD, 0.8 (95% CI: 0.6-1.2) for LAD, and 1.0 (95% CI: 0.7-1.2) for LSD. The risk of acquiring P aeruginosa was therefore not significantly different between children diagnosed early, late, asymptomatically, or symptomatically. CONCLUSIONS: These data suggest that, despite improvements in other health outcomes from newborn screening for CF, early asymptomatic diagnosis of CF does not affect P aeruginosa acquisition.

Risk of persistent growth impairment after alternate-day prednisone treatment in children with cystic fibrosis.

BACKGROUND: It is uncertain whether the growth impairment that occurs in children during long-term treatment with glucocorticoids persists after the medication is discontinued and ultimately affects adult height. METHODS: We evaluated growth six to seven years after alternate-day treatment with prednisone had been discontinued in 224 children 6 to 14 years of age with cystic fibrosis who had participated in a multicenter trial of this therapy from 1986 through 1991. Of the children, 151 had been randomly assigned to receive prednisone (either 1 or 2 mg per kilogram of body weight) and 73 to receive placebo. We obtained data on growth up to 1997 from the Cystic Fibrosis Foundation Patient Registry and standardized the data to sex- and age-specific norms from the National Center for Health Statistics. We used z scores to compare growth patterns among treatment groups. RESULTS: In 1997, 68 percent of the patients were 18 years of age or older. The z scores for height declined during prednisone therapy; catch-up growth began two years after treatment with prednisone was discontinued. Among the boys, the z scores for height in those treated with prednisone remained lower than the scores for those who received placebo (P=0.02). The mean heights for boys 18 years of age or older were 4 cm less in the prednisone groups than in the placebo group, an equivalent of 13 percentile points (P=0.03). Among the girls, differences in height between those who were treated with prednisone and those who received placebo were no longer present two to three years after prednisone therapy was discontinued. CONCLUSIONS: Among children with cystic fibrosis who have received alternate-day treatment with prednisone, boys, but not girls, have persistent growth impairment after treatment is discontinued.

Epidemiologic study of cystic fibrosis: design and implementation of a prospective, multicenter, observational study of patients with cystic fibrosis in the U.S. and Canada.

Cystic fibrosis (CF) is a complex illness characterized by chronic lung infection leading to deterioration in function and respiratory failure in over 85% of patients. An understanding of the risk factors for that progression and the interaction of these factors with current therapeutic strategies should materially improve the prevention of this progressive lung disease. The Epidemiologic Study of Cystic Fibrosis (ESCF) was therefore designed as a multicenter, longitudinal, observational study to prospectively collect detailed clinical, therapeutic, microbiologic, and lung function data from a large number of CF treatment sites in the U.S. and Canada. The ESCF also serves an important role as a phase-IV study of dornase alfa. To be eligible for enrollment, subjects must have the diagnosis of CF and receive the majority of their care at an ESCF site. In this paper, the authors present the ESCF study design in detail. Further, enrollment data collected at 194 study sites in 18,411 subjects enrolled from December 1, 1993 to December 31, 1995 are presented in summary form. This comprehensive study is unique in the detail of clinical data collected regarding patient monitoring and therapeutic practices in CF care. Two companion articles present data regarding practice patterns in cystic fibrosis care, including data on resource utilization and prescribing practices.

Issues in implementing prenatal screening for cystic fibrosis: results of a working conference.

PURPOSE: To summarize a conference convened to examine how cystic fibrosis screening might appropriately be introduced into routine prenatal practice. METHODS: Participants included experts from various relevant disciplines. Systematic reviews and data from individual trials were presented; issues were identified and discussed. RESULTS: Judged by published criteria, prenatal cystic fibrosis screening is suitable for introduction. Screening can be performed cost-effectively by identifying racial/ethnic groups at sufficient risk and then using either of two models for delivering laboratory services. Validated educational materials exist. Ethical issues are not unique. CONCLUSIONS: Once adequate facilities for patient and provider education, testing, counseling, quality control, and monitoring are in place, individual programs can begin prenatal screening for cystic fibrosis.

Growth status in children with cystic fibrosis based on the National Cystic Fibrosis Patient Registry data: evaluation of various criteria used to identify malnutrition.

OBJECTIVES: The objectives of this study were to determine growth status and to identify malnutrition with various anthropometric indicators in children with cystic fibrosis (CF) based on cross-sectional analysis of the 1993 National CF Patient Registry data. METHODS: Heights and weights of 13,116 children with CF were evaluated with percentile, percent of reference median, Z-score, and percent ideal weight-for-height based on National Center for Health Statistics/Centers for Disease Control growth references. Malnutrition was defined by four criteria: (1) height-for-age <5th percentile ("stunting") or weight-for-age <5th percentile ("wasting") (2) height-for-age <90% of reference median or weight-for-age <80% of reference median, (3) height-for-age <5th percentile or percent ideal weight-for-height <85%, and (4) height-for-age <90% of reference median or weight-for-height <85% of reference median. RESULTS: Mean and median height- and weight-for-age were found to be at the 30th and 20th percentiles in children with CF. Malnutrition (height- or weight-for-age <5th percentile) was particularly pronounced in infants (47%) and adolescents (34%) and patients with newly diagnosed CF (44%). A significant sex difference (p < 0.01) in the occurrence of stunting (height-for-age <5th percentile) was observed during adolescence: boys 11 to 14 years of age showed lower occurrence of stunting (19%) compared with girls (29%), whereas the opposite trend was observed at 15 to 18 years (34% in male patients vs 28% in female patients). CONCLUSION: Twenty percent of all children in the 1993 National CF Patient Registry were <5th percentile for height- or weight-for-age. A significant discrepancy was found when different criteria were used to distinguish "stunting" versus "wasting" in malnourished children with CF.

Comparison of the clinical manifestations of cystic fibrosis in black and white patients.

No large-scale studies of the incidence or disease severity of cystic fibrosis (CF) in black patients have been reported to date. In this study, the CF Foundation National Patient Registry was used to establish new incidence figures and to compare the clinical status of U.S. black (n = 601) and white patients (n = 17,755) with CE Results indicate that the incidence of CF is approximately 1 in 3,200 white and 1 in 15,000 black live births in the United States. Black patients with CF are currently, and were at diagnosis, younger and have poorer nutritional status and pulmonary function than white patients with CF. Fewer have meconium ileus, but more have distal intestinal obstruction syndrome. To control for genotype, each black deltaF508 homozygote (n = 47) was compared with four age- and sex-matched white deltaF508 homozygotes. Only the difference in nutritional status remained. The deltaF508 mutation is associated with higher levels of meconium ileus than other genotypes, independent of race. In conclusion, the clinical manifestations of CF are similar in black and white patients except for poorer nutritional status in black patients, which appears to be independent of age and genotype.

High-dose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis.

BACKGROUND: Fibrosing colonopathy has been reported in young children with cystic fibrosis, the majority of whom take high-strength pancreatic-enzyme supplements to control intestinal malabsorption. We conducted a case-control study in the United States to investigate the relation between dose and type of pancreatic-enzyme supplement and fibrosing colonopathy. METHODS: Children with histopathologically confirmed cases of fibrosing colonopathy who required colectomy for colonic strictures from January 1, 1990, through December 31, 1994, were identified. Each of these patients was matched according to age at the time of surgery and medical center with up to four controls with cystic fibrosis who did not have fibrosing colonopathy. RESULTS: We studied 29 patients (mean age, 5.0 years) with fibrosing colonopathy (case patients) and 105 controls (mean age, 5.2 years). The mean dose of pancreatic-enzyme supplement was 50,046 units of lipase per kilogram of body weight per day for the case patients and 18,985 units per kilogram per day for the controls. A history of gastrointestinal complications attributed to cystic fibrosis and the use of histamine H2-receptor blockers, corticosteroids, or recombinant human DNase (dornase alfa) were associated with a higher incidence of fibrosing colonopathy. After adjustment for a history of such complications and the use of these medicines, the relative risk of fibrosing colonopathy that was associated with a dose of 24,001 to 50,000 units of lipase per kilogram per day, as compared with a dose of 0 to 24,000 units per kilogram per day, was 10.9 (95 percent confidence interval, 1.6 to 71.8), and that associated with a dose of more than 50,000 units per kilogram per day was 199.5 (95 percent confidence interval, 9.9 to 4026.0). The strength, coating, and manufacturer of the products used were not associated with the risk of fibrosing colonopathy. CONCLUSIONS: In young children with cystic fibrosis, we found a strong relation between high daily doses of pancreatic-enzyme supplements and the development of fibrosing colonopathy. Our findings support recommendations that the daily dose of pancreatic enzymes for most patients should remain below 10,000 units of lipase per kilogram.

Clinical characteristics and genotype analysis of patients with cystic fibrosis and nasal polyposis requiring surgery.

OBJECTIVE: To analyze the clinical characteristics and genotypes of patients with cystic fibrosis (CF) and nasal polyposis who require surgery. DESIGN: Cross-sectional analysis of a large patient database. SETTING: Data obtained from the National CF Patient Registry of the Cystic Fibrosis Foundation, Bethesda, Md. PATIENTS: Clinical and genotype data on 20198 patients with CF who were registered in 1992 and 1993 were analyzed. The study group (n = 815) consisted of patients with CF who had undergone surgical procedures for the treatment of nasal polyposis. The comparison group (n = 19383) comprised the remainder of the patients in the database. RESULTS: Statistical analysis revealed that patients with CF and nasal polyposis who required surgery had better pulmonary function (higher percent-predicted forced expiratory volume in 1 second and forced vital capacity), better nutritional status, a higher rate of Pseudomonas aeruginosa colonization, more office visits, more hospitalizations, and a higher rate of acute exacerbations per year (P < .001 for each) than did the comparison group. Among the patients who had mutation analysis performed, patients with nasal polyposis who required surgery were significantly associated with 2 specific genotypes: the delta-F508/delta-F508 (57.5% vs 49.9%, P = .01) and the delta-F508/G551D (12% vs 8%, P = .05) genotypes. CONCLUSIONS: Patients with CF and nasal polyposis who require surgery may constitute a clinical subgroup within the spectrum of the disease. These patients appear to have slightly better pulmonary function and nutritional status; yet, they seem to have a higher degree of health care utilization. The higher rate of P aeruginosa respiratory infection in this patient group suggests an association with the presence of nasal polyposis. Genotype analysis showed a higher prevalence of the delta-F508/delta-F508 and the delta-F508/G551D genotypes in this patient group.

Colonic strictures in patients with cystic fibrosis: results of a survey of 114 cystic fibrosis care centers in the United States.

We describe 15 cases of stricture of the colon requiring surgery in cystic fibrosis patients identified from a survey of 114 cystic fibrosis care centers in the United States. Patient ages ranged from 2 to 8 years, seven of the 15 patients were female. A history of meconium ileus was reported in nine of the 15 cases. Fibrosis of the submucosa was described in 14 surgical pathology reports. Pancreatic enzyme use history was available from 14 reports. All had taken delayed-release products for 6-96 months at average doses ranging from 6,700 to 29,100 units lipase/kg/meal, but only eight of them used products containing >20,000 units lipase per capsule prior to surgery.

The risk of cancer among patients with cystic fibrosis. Cystic Fibrosis and Cancer Study Group.

BACKGROUND: Anecdotal reports suggest an increased frequency of certain cancers in patients with cystic fibrosis, the commonest genetic disorder of whites. One third of patients with cystic fibrosis now reach adulthood, when cancer is more frequent, implying that cancer rates in these patients will increase over time. We investigated the relation between cystic fibrosis and cancer in North American and European patients with cystic fibrosis. Methods. We performed a retrospective cohort study of the occurrence of cancer in 28,511 patients with cystic fibrosis from 1985 through 1992 in the United States and Canada. The number of cases observed was compared with the number expected, calculated from population-based data on the incidence of cancer. We also analyzed proportional incidence ratios to assess the association between specific cancers and cystic fibrosis in Europe. RESULTS: Thirty-seven cancers were observed in the North American cohort during 164,764 person-years of follow-up, as compared with an expected number of 45.6, yielding a ratio of observed to expected cancers of 0.8 (95 percent confidence interval, 0.6 to 1.1). Thirteen digestive tract tumors were observed, as compared with an expected number of two, for a ratio of observed to expected cancers of 6.5 (95 percent confidence interval, 3.5 to 11.1). In Europe, 11 of 39 cancers originated in the digestive tract, yielding a positive association between digestive tract tumors and cystic fibrosis (odds ratio, 6.4; 95 percent confidence interval, 2.9 to 14.0). CONCLUSIONS: Although the overall risk of cancer in patients with cystic fibrosis is similar to that of the general population, there is an increased risk of digestive tract cancers. Persistent or unexplained gastrointestinal symptoms in these patients should be carefully investigated.

Acquisition of Pseudomonas cepacia at summer camps for patients with cystic fibrosis. Summer Camp Study Group.

To assess the risk of acquisition of Pseudomonas cepacia by person-to-person transmission at cystic fibrosis summer camps, we conducted in 1990 a study at three camps attended by patients with cystic fibrosis who had P. cepacia infection and patients without P. cepacia infection but who were considered susceptible to infection. We obtained sputum or throat cultures from campers on their arrival at, weekly during, at the end of, and 14 to 30 days after camp. We compared the incidence of sputum conversion of patients at camp with that of patients outside camp by culturing specimens from noncamper control subjects with cystic fibrosis who were known not to be infected < or = 2 weeks before and 4 to 6 weeks after camp. We also determined the risk factors for P. cepacia acquisition by determining the relative risk of acquisition between campers who were exposed versus campers who were not exposed to campers known to be infected or to potential environmental sources of P. cepacia at camp. The ribotype of P. cepacia isolates from campers with sputum conversion was compared with that of isolates from other campers and from an environmental source. The cumulative incidence of sputum conversion during the study period was 6.1% (11/181) among campers compared with no incidence (0/92) among noncampers (p = 0.02, Fisher Exact Test). The incidence of sputum conversion at camp varied according to the prevalence of campers with known infection (p < 0.001, chi-square test for trend). The rate of sputum conversion was higher in the camp with longer duration (relative risk = 12.0; 95% confidence interval = 2.7 to 53.5). Ribotyping showed that P. cepacia isolates from all 11 campers with sputum conversion were identical or similar (1 to 2 band difference) to isolates of other P. cepacia-infected campers including co-converters. These results suggest that P. cepacia can be acquired by patients with cystic fibrosis who are attending summer camp for such patients, possibly through person-to-person transmission, and that the risk increases with the prevalence of P. cepacia-infected campers and the duration of camp.

Source of health care for military dependents with cystic fibrosis.

Health care to military dependents with cystic fibrosis (CF) may be compromised by lack of consistency. Civilian centers provide an alternative for care. A reliable count of dependents with CF is unknown. We surveyed 196 military treatment facilities (MTFs) to obtain data on dependents with CF and compared it with data from the National CF Registry. Seventy-seven percent of the MTFs responded and 143 patients were identified. Registry data identified 373 CHAMPUS patients at 82 civilian centers. There were 284 patients in the Registry only and 54 patients in the MTF survey only. Eighty-nine patients were identified through both data sources. A total of 427 patients were identified. Under current CHAMPUS reorganization plans, MTFs will serve as "gateways" for funding of specialized civilian care. Thus, the influx of these and other chronically ill children into the MTF may tax the resources and capabilities of these facilities.

The changing epidemiology of cystic fibrosis.

Data from 17,857 patients with cystic fibrosis submitted in 1990 to the registry maintained by the Cystic Fibrosis Foundation were used to described their demographic characteristics, survival rates, pulmonary function, anthropometry, microbiologic data, complication rates, and health care utilization. Comparisons with similar data collected in 1969, 1972, and 1978 demonstrated a significant shift in the age distribution of patients with cystic fibrosis. The proportion of adult patients increased fourfold between 1969 (8%) and 1990 (33%). In 1990 the median age of all patients in the cystic fibrosis registry was 12.5 years; the median age at diagnosis was 7 months; cystic fibrosis was diagnosed in 90% of all patients by age 12 years. Meconium ileus at birth was reported for 16% of all patients with a new diagnosis in 1990. Median survival age doubled between 1969 and 1990, from 14 to 28 years. Female patients consistently had a lower median survival age than male patients (25 vs 30 years in 1990). The most frequently reported respiratory pathogen was Pseudomonas aeruginosa, cultured in specimens from 61% of all patients, ranging from 21% of those less than 1 year of age to more than 80% of those aged 26 years or older. Overall, patients with cystic fibrosis are living much longer than in the past but still have chronic pulmonary infections and other medical complications related to their disease, including diabetes, intestinal obstruction, cirrhosis, hemoptysis, and pneumothorax.

Fertility and pregnancy in patients with cystic fibrosis.

Issues related to fertility and pregnancy, once moot, are now extremely relevant to the care of a growing number of CF patients entering adulthood. With rare exception, men are infertile, due to the almost universal presence of malformations of the reproductive tract causing obstructive azoospermia. Emphasis in the care of these patients should be directed toward confirmation of infertility and counseling to allay anxieties. In contrast, a significant albeit unknown proportion of women are fertile and a steadily increasing number of these women are conceiving. The accumulated clinical experience has demonstrated that pregnancy is well-tolerated by patients with mild disease while associated with increased maternal and fetal complications in those with severe disease. In light of current uncertainties in accurately predicting outcome in all but the most clear-cut cases, the physician must exercise clinical judgment in providing a realistic assessment of the medical risks involved and of the advisability of pregnancy. This assessment should be based on a thorough and objective evaluation of the pulmonary, cardiac, and nutritional status of the patient. Future efforts, assisted by data collected for the national CF patient registry, should be directed toward better defining the long-term impact of pregnancy on the natural history of CF and more precisely defining the pregravid parameters useful in predicting outcome for both mother and child.