Pamela J. Byard

Effect of High-Dose Ibuprofen in Patients with Cystic Fibrosis

BACKGROUND Since the inflammatory response to chronic infection contributes to lung destruction in patients with cystic fibrosis, we hypothesized that anti-inflammatory therapy might slow the progression of lung disease. METHODS In a double-blind trial, 85 patients, 5 to 39 years of age, with mild lung disease (forced expiratory volume in one second [FEV1], > or = 60 percent of the predicted value) were randomly assigned to receive ibuprofen or placebo orally twice daily for four years. Doses were adjusted individually to achieve peak plasma concentrations of 50 to 100 micrograms per milliliter. Changes in pulmonary function, the percentage of ideal body weight, the chest-radiograph score, and the frequency of hospitalization were assessed. RESULTS Patients randomly assigned to ibuprofen had a slower annual rate of change in FEV1 than the patients assigned to placebo (mean [+/- SE] slope, -2.17 +/- 0.57 percent vs. -3.60 +/- 0.55 percent in the placebo group; P = 0.02), and weight (as a percentage of ideal body weight) was better maintained in the former group (P = 0.02). Among the patients who took ibuprofen for four years and had at least a 70 percent rate of compliance, the annual rate of change in FEV1 was even slower (-1.48 +/- 0.69 percent vs. -3.57 +/- 0.65 percent in the placebo group, P = 0.03), and this group of patients also had a significantly slower rate of decline in forced vital capacity, the percentage of ideal body weight, and the chest-radiograph score. There was no significant difference between the ibuprofen and placebo groups in the frequency of hospitalization. One patient was withdrawn from the study because of conjunctivitis, and one because of epistaxis related to ibuprofen. CONCLUSIONS In patients with cystic fibrosis and mild lung disease, high-dose ibuprofen, taken consistently for four years, significantly slows the progression of the lung disease without serious adverse effects.

Gender differences in cystic fibrosis: Pseudomonas aeruginosa infection.

The median survival age for females with cystic fibrosis (CF) is approximately 3 years younger than for males. We tested whether earlier acquisition of Pseudomonas aeruginosa (PA) by female CF patients or the greater impact of this organism on their lung disease, or both, contribute to their poorer survival. PA infection status, survival, pulmonary function tests, and chest X-ray scores from patients who were followed at our center for at least 2 years with a minimum of three respiratory cultures per year were analyzed (n = 848). The median age of chronic infection with mucoid PA was 1.7 years earlier in females than in males. Patients infected with mucoid PA had poorer survival, chest X-ray scores, and pulmonary function tests than patients who had either no Pseudomonas species or only the nonmucoid phenotype. Acquisition of mucoid PA was associated with an accelerated rate of decline in pulmonary function. However, the rate of change of pulmonary function after mucoid PA infection was similar for males and females. Moreover, even among patients who had only the mucoid form or only the nonmucoid form, males had better percent predicted forced expiratory volume in 1 sec and better survival. Therefore, factors in addition to earlier acquisition of mucoid PA may contribute to the poorer survival of female CF patients.

Effect of Pseudomonas cepacia colonization on survival and pulmonary function of cystic fibrosis patients

We conducted a historical prospective study of 124 cystic fibrosis (CF) patients colonized with Pseudomonas cepacia (cases) and 124 sex and age matched non-colonized CF patients (controls). Thirty-two of the colonized patients died in the first year following P. cepacia colonization compared to 8 of the control patients, a highly significant difference (p less than 0.001). In the second year, there was no significant difference in mortality between the two groups. Cases as a group had poorer pulmonary function and chest X-ray scores than controls up to 2 years before P. cepacia first appeared in their sputum or throat cultures. Regression analysis of pulmonary function tests (percent predicted FEV1 and RV/TLC) for each subject from 3 years before to 2 years after colonization revealed significant differences between cases and controls in slope for FEV1 and in slope and intercept for RV/TLC. When compared separately according to gender, the differences between cases and controls are significant in females but not in males. These results suggest that patients with poor pulmonary function are more prone to colonization with P. cepacia, that a subgroup of these patients will be dramatically affected and die within a year, and that the organism continues to exert a less dramatic negative effect on the pulmonary function of those patients who survive the initial acute effects of colonization, particularly in female patients.

Identifying treatments that halt progression of pulmonary disease in cystic fibrosis.

Rapid progress in cystic fibrosis research affords the possibility of halting the progress of the lung disease. We used data from 215 patients who had sputum cultures negative for Burkholderia cepacia, at least one outpatient pulmonary function test during 1990, and at least one test a year later to estimate the number of subjects and study duration required to demonstrate that a hypothetical treatment reduces the rate of decline of forced expiratory volume in 1 s (FEV1) to zero. Mean rate of decline of FEV1 (percent predicted) was about 2% predicted per year. Variability decreases with increasing time of observation. For a 1-y study, with α = 0.05 and β = 0.20, over 550 patients must complete the study in each group to show that a treatment halts pulmonary decline. For a 2-y study, 86 subjects in each group are required, and for 4 y, 65. Increasing the number of data points used to determine the rate of decline of FEV1 had only small effect on sample size. Use of pulmonary function data collected at regular intervals for research purposes did not alter these conclusions. Higher initial FEV1 was associated with a greater rate of decline, and among patients with initial FEV1 >60% predicted, younger subjects had a faster decline than did older subjects. Thus, fewer subjects will be required to detect a complete halt in progression of lung disease if the patients are young and have mild pulmonary disease.

The adolescent growth spurt in children with cystic fibrosis

The adolescent spurt in 230 children with cystic fibrosis (CF) treated at the Cleveland CF centre in northeastern Ohio was compared to that found in normal children from the Fels Longitudinal Growth Study in southwestern Ohio. The Preece-Baines Model 1 (PB1) growth equation was applied to longitudinal height data from both samples to describe a large number of data points for each child in terms of a few biologically meaningful parameters, such as age, height, and velocity at the take-off and peak of the adolescent growth spurt. The growth spurt is delayed by an average of 0.8 years and is about 1 cm/year slower at its peak in CF patients compared to the normal controls. This delay should be considered when comparing clinical growth measurements of adolescent CF patients with normal standards. Peak velocity is lower than expected, even for late-maturing normal children, and height at take-off, peak velocity, and adulthood is significantly reduced, especially in boys. These findings are consistent with the clinical impression that the growth spurt is delayed and attenuated in CF patients, particularly those with poor pulmonary function. Girls homozygous for the delta F508 mutation have significantly more growth retardation than those with other CF mutations.

Segregation analysis of speech and language disorders

Complex segregation analysis was performed on pedigrees ascertained through 45 probands (26 males, 19 females) with a history of preschool speech and language disorders. Hypotheses concerning mode of inheritance were, tested using the POINTER segregation analysis program. Although there is strong evidence for familial transmission of this trait, we were unable to distinguish between a major gene and multifactorial transmission model using likelihood-ratio chi-square tests. Future studies with quantitative measures of speech and language disorders are needed to resolve the issue of mode of inheritance for this trait.

Recreational use of psychoactive drugs by patients with cystic fibrosis

We assessed unprescribed psychoactive drug use in 173 adults with cystic fibrosis. Twenty (11%) regularly smoked tobacco. Cigarette smoking ranged from 1 to 30 years (2 to 60 pack-years). Alcohol was used by 60%, and marijuana by 20% of the patients. Pulmonary symptoms were often increased the day after alcohol ingestion. Alcohol occasionally caused nausea, vomiting, and headache if the patient was taking some cephalosporin derivatives (such as cefsulodine) or chloramphenicol. Marijuana often aggravated chronic pulmonary symptoms, although some patients reported transient relief during use. Comparison with a retrospectively selected control group did not show faster short-term pulmonary deterioration in the tobacco smokers. Physicians who deal with cystic fibrosis and other chronic illnesses should be cognizant of interactions of unprescribed and prescribed drugs. Recreational use of unprescribed psychoactive drugs should be considered if unexpected symptoms occur in older patients.

Family resemblance for Preece‐Baines growth curve parameters in the fels longitudinal growth study

The Preece‐Baines Model 1 (PB1) nonlinear regression equation was fit to serial stature measurements from 456 participants in the Fels Longitudinal Growth Study. The resulting model parameters and derived biological parameters, such as age, stature, and velocity at take‐off (TO) and peak velocity (PV) are analyzed for family resemblance in 228 nuclear families through estimation of familial correlations and path coefficients. Significant family resemblance was found for all of the growth parameters. Transmissibility estimates ranged from 41%–71%, suggesting that some of the factors controlling the timing and shape of the adolescent growth spurt are transmitted from parent to child. Significant gender effects were found in sibling resemblance, with brother‐brother pairs more similar than other pairs for age at TO and PV and sister‐sister pairs more alike for stature at TO and PV and for velocity at PV.

Path analysis of family resemblance for cranio-facial traits in Andhra Pradesh nuclear families and twins

Path analysis of 12 cranio-facial measurements from a sample of nuclear families and twins from Andhra Pradesh, India is used to test hypotheses about the familial transmission of these traits. For bigonial breadth and ear dimensions, the transmission from parent to child is consistent with simple autosomal polygenic inheritance, but length, breadth and circumference of the head, facial breadth and nose dimensions show evidence of transmission in excess of polygenic expectations. Additional non-transmissible resemblance of sibling pairs is not significant for any of the variables, but twin pairs do exhibit significant additional resemblance for head circumference, head length, minimum frontal breadth, bizygomatic breadth and ear dimensions. The effect of interobserver measurement differences can be detected for head breadth, minimum frontal breadth, bigonial breadth, total facial height and nose dimensions.

Relationship between clinical parameters and linear growth in children with cystic fibrosis

Mixed longitudinal height data from 1,170 cystic fibrosis patients seen at Rainbow Babies and Childrens Hospital in Cleveland form the basis for this analysis. As a group, the patients experience growth retardation throughout the growth cycle, with median height values below the 25th percentile of NCHS standards until late adolescence. Median height increments are also below normal standards until age 16 years in boys and 14 years in girls. Based on these results, it appears that some CF patients have very delayed adolescent growth spurts, and continue to grow into early adulthood. Pancreataic‐enzyme‐sufficient patients have greater height‐for‐age percentiles than enzyme‐deficient patients after 9 years of age. The overall difference between enzyme‐sufficient and enzyme‐deficient patients is not statistically significant (P=0.058), perhaps because of small sample size for the enzyme‐sufficient group (n=19). The correlation between pulmonary status assessed from lung X‐rays and height increment peaks at age 10 years in girls and age 15 years in boys, with significant negative correlation occurring after age 16 years in both sexes. Although both pancreatic enzyme deficiency and lung disease appear to have some effect on linear growth in CF, especially during adolescence, these two factors explain a relatively small portion of the variation in growth percentiles.