David M. Orenstein

The Prognostic Value of Exercise Testing in Patients with Cystic Fibrosis

BACKGROUND Previous studies have shown female sex, impaired pulmonary function, older age, malnutrition, and colonization of the respiratory tract with Pseudomonas cepacia to be associated with a poor prognosis in patients with cystic fibrosis. We sought to determine the prognostic value of exercise testing in addition to the other prognostic factors. METHODS A total of 109 patients with cystic fibrosis, 7 to 35 years old, underwent pulmonary-function and exercise testing in the late 1970s. They were followed for eight years to determine the factors associated with subsequent mortality. Survival rates were calculated with standard life-table methods. Cox proportional-hazards regression models were used to determine crude relative risks of mortality and relative risks adjusted for age, sex, body-mass index, forced expiratory volume in one second (FEV1) end-tidal partial pressure of carbon dioxide (PCO2) at peak exercise, and oxygen consumption at peak exercise (VO2 peak). RESULTS Patients with the highest levels of aerobic fitness (VO2 peak, > or = 82 percent of predicted) had a survival rate of 83 percent at eight years, as compared with rates of 51 percent and 28 percent for patients with middle (VO2 peak, 59 to 81 percent of predicted) and lowest (VO2 peak, < or = 58 percent of predicted) levels of fitness, respectively. After adjustment for other risk factors, patients with higher levels of aerobic fitness were more than three times as likely to survive than patients with lower levels of fitness. Colonization with P. cepacia was associated with a risk of dying that was increased fivefold. Age, sex, body-mass index, FEV1, and end-tidal PCO2 at peak exercise were not independently correlated with mortality. CONCLUSIONS Higher levels of aerobic fitness in patients with cystic fibrosis are associated with a significantly lower risk of dying. Although better aerobic fitness may simply be a marker for less severe illness, measurement of VO2 peak appears to be valuable for predicting prognosis. Further research is warranted to determine whether improving aerobic fitness through exercise programs will result in a better prognosis.

The Quality of Well-being Scale. Applications in AIDS, cystic fibrosis, and arthritis.

The Quality of Well-being (QWB) Scale combines preference-weighted measures of symptoms and functioning to provide a numerical point in-time expression of well-being that ranges from zero (0) for death to 1.0 for asymptomatic optimum functioning. The QWB includes three scales of function: mobility, physical activity, and social activity. Each step of these scales is associated with preference weights. Preference adjustments for symptoms are also included. This paper describes how this general system was used to evaluate outcomes in three different clinical conditions: acquired immune deficiency syndrome (AIDS), cystic fibrosis, and arthritis. In one study, the QWB was administered to 31 patients participating in evaluation of azidothymidine (AZT) treatment for AIDS. The QWB system demonstrated substantial benefits of AZT treatment in comparison to placebo. In a second study, the QWB and a series of pulmonary function measures were administered to 44 patients with cystic fibrosis. The QWB was demonstrated to be significantly correlated with measures of pulmonary function, including FEV1 and maximal midexpiratory flow rate (MMEFR). In addition, there were significant associations between the QWB and measures of exercise tolerance. In the third study, the QWB and an arthritis-specific measure were administered to 83 arthritis patients before and after their treatment. The QWB was at least as capable of detecting clinical change in this population as was the disease-specific measure. For all three conditions, the QWB considered side effects and benefits of treatment in a common unit. Clinical trial data are cited to suggest that the QWB is a valuable outcome measure in arthritis treatment evaluation. We conclude that the QWB has substantial validity as a general health outcome measure and that the system can be used with different populations.

Comparative Efficacy and Safety of 4 Randomized Regimens to Treat Early Pseudomonas aeruginosa Infection in Children With Cystic Fibrosis

OBJECTIVE To investigate the efficacy and safety of 4 antipseudomonal treatments in children with cystic fibrosis with recently acquired Pseudomonas aeruginosa infection. DESIGN Randomized controlled trial. SETTING Multicenter trial in the United States. PARTICIPANTS Three hundred four children with cystic fibrosis aged 1 to 12 years within 6 months of P aeruginosa detection. INTERVENTIONS Participants were randomized to 1 of 4 antibiotic regimens for 18 months (six 12-week quarters) between December 2004 and June 2009. Participants randomized to cycled therapy received tobramycin inhalation solution (300 mg twice a day) for 28 days, with oral ciprofloxacin (15-20 mg/kg twice a day) or oral placebo for 14 days every quarter, while participants randomized to culture-based therapy received the same treatments only during quarters with positive P aeruginosa cultures. MAIN OUTCOME MEASURES The primary end points were time to pulmonary exacerbation requiring intravenous antibiotics and proportion of P aeruginosa -positive cultures. RESULTS The intention-to-treat analysis included 304 participants. There was no interaction between treatments. There were no statistically significant differences in exacerbation rates between cycled and culture-based groups (hazard ratio, 0.95; 95% confidence interval [CI], 0.54-1.66) or ciprofloxacin and placebo (hazard ratio, 1.45; 95% CI, 0.82-2.54). The odds ratios of P aeruginosa- positive culture comparing the cycled vs culture-based group were 0.78 (95% CI, 0.49-1.23) and 1.10 (95% CI, 0.71-1.71) comparing ciprofloxacin vs placebo. Adverse events were similar across groups. CONCLUSIONS No difference in the rate of exacerbation or prevalence of P aeruginosa positivity was detected between cycled and culture-based therapies. Adding ciprofloxacin produced no benefits. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT00097773.

Habitual physical activity in children and adolescents with cystic fibrosis.

PURPOSE This study was conducted to: 1) measure total physical activity levels, including the intensities of the various types of activities, in children and adolescents with CF compared with non-CF healthy control subjects; and 2) determine whether vigorous activity level was related to aerobic fitness and disease status in patients with CF. METHODS Thirty patients with CF (18 male, 12 female) and 30 control subjects (17 male, 13 female), 7-17 yr old, participated in this study. Habitual physical activity was measured using Kriskas Modifiable Activity Questionnaire (MAQ) and the past years average of total hours, MET-hours, and vigorous (VIG) hours (>6 METs) of activity per week were determined. Aerobic fitness was determined from peak oxygen uptake (VO2peak) obtained via maximal exercise testing on a cycle ergometer. Standard spirometry was used to measure pulmonary function. Body mass index (BMI) was determined from height and weight measurements. RESULTS The CF and control groups were similar in age and gender distribution, but the patients were smaller (BMI, 98 vs 112% of predicted) and less aerobically fit (36.5 vs 41.4 mL x kg(-1) x min(-1)). Total and MET-hours of physical activity did not differ between groups; however, the CF group participated in significantly fewer hours of vigorous activities than the control group (2 vs 3.7 h x wk(-1)). In patients with worse lung disease, VIG-h x wk(-1) were significantly related to VO2peak (r = 0.83). CONCLUSION These results suggest that children with CF engage in less vigorous physical activities than their healthy non-CF peers, despite having good lung function. In view of the progressive nature of the disease, and the association between aerobic fitness and vigorous activity, patients should be encouraged to engage in more vigorous activities that promote aerobic fitness and may ultimately have an impact on survival.

Depression and Anxiety in Pediatric Inflammatory Bowel Disease and Cystic Fibrosis

The lifetime and current prevalence of depression and anxiety disorders was determined in 41 children with Crohns disease, 12 children with ulcerative colitis, and 52 children with cystic fibrosis, using the Kiddie-Schedule for Affective Disorders and Schizophrenia interview. The lifetime prevalence of depression was 29% in Crohns disease, 21% in ulcerative colitis, and 11.5% in cystic fibrosis. The difference in the prevalence of depression between Crohns disease and cystic fibrosis was significant (p less than 0.05). The lifetime and current prevalence of dysthymia was significantly greater in ulcerative colitis than Crohns disease (p less than 0.01) or cystic fibrosis (p less than 0.01). The lifetime prevalence of atypical depression was significantly greater in Crohns disease than cystic fibrosis (22% versus 5.8%, p less than 0.05) and was also greater in ulcerative colitis than cystic fibrosis (21% versus 5.8%, p = 0.1). There was no difference between the groups in the current prevalence of major depression or atypical depression, or in the lifetime or current prevalence of anxiety disorders.

Immunogenicity of a new purified fusion protein vaccine to respiratory syncytial virus: A multi-center trial in children with cystic fibrosis

A third generation, purified fusion protein (PFP-3) vaccine was developed to prevent severe respiratory syncytial virus (RSV) disease in high-risk groups. A phase II, multi-center, adjuvant-controlled trial was performed in RSV seropositive children with cystic fibrosis (CF); 151 received the adjuvant-control and 143 received the vaccine. Details of the vaccine-induced immune response are presented. At enrollment, RSV-specific, serum antibodies were comparable between both groups. A highly sensitive and specific serum antibody vaccine profile was established for the PFP-3 vaccine. At post-vaccination and end-of-study, RSV-specific, neutralizing antibody (Nt Ab) and binding antibody (Bd Ab) to the fusion (F) protein were significantly higher in PFP-3 vaccinees. After 28 days post-vaccination, Nt Ab and Bd Ab to F protein titers declined slowly at rates of 0.23 and 0.37 log2 per month, respectively. The PFP-3 vaccine-induced a robust immune response that lasted throughout the RSV season.

Liver Transplantation in Children with Cystic Fibrosis: A Long-Term Longitudinal Review of a Single Center's Experience

BACKGROUND Improved long-term survival in cystic fibrosis (CF) has led to an increased incidence of extrapulmonary complications of this disease. Of these, end-stage liver disease is a significant cause of morbidity and mortality with liver transplantation being the only effective therapy. METHODS Records of all CF pediatric liver transplant recipients were reviewed. RESULTS Twelve children with CF were the recipients of 16 allografts. The 1- and 5-year survival was 91.6% and 75%, respectively. There were 5 deaths at a mean interval of 6.8 +/- 6.3 years. All of these deaths were related to pulmonary disease. Pulmonary function improved or remained stable in 8 of 9 patients tested. Despite an 83% incidence of positive sputum cultures, there was only one early mortality related to pulmonary sepsis in the setting of primary liver allograft nonfunction. CONCLUSIONS Liver transplantation is acceptable treatment for children with CF and end-stage liver disease. Long-term survival is comparable to liver transplantation performed for other indications. Although posttransplant morbidity and mortality is related to lung disease, the authors speculate that as therapeutic improvements prolong the survival in CF, it is expected that longer survival after liver transplantation in this patient population may also be anticipated.

Exercise conditioning in children with asthma

A controlled study of 20 children with asthma who participated in a 4-month running program (30 min/day, 3 days/wk), using inhalation of a beta-2 stimulant prior to each running session to prevent exercise-induced asthma, showed significant increases in work tolerance (120.5±45.0 W before, 131.5±43.5 W after, P=0.002) and cardiopulmonary fitness (peak oxygen consumption 37.6±8.6 ml/kg/min before, 43.1±10.5 ml/kg/min after, P

A comparison of the efficacy and tolerance of pancrelipase and placebo in the treatment of steatorrhea in cystic fibrosis patients with clinical exocrine pancreatic insufficiency

A comparison of the efficacy and tolerance of pancrelipase and placebo in the treatment of steatorrhea in cystic fibrosis patients with clinical exocrine pancreatic insufficiency

Pancreatitis in young children with cystic fibrosis.

Five young children with cystic fibrosis and abdominal pain were found to have pancreatitis. Diagnosis was delayed in four patients because of the belief that pancreatitis occurs only in older patients with cystic fibrosis. In one patient pancreatitis was diagnosed before cystic fibrosis and diagnosis of cystic fibrosis was delayed. Pancreatitis should be considered as a possible cause of abdominal pain in pancreatic-sufficient children with cystic fibrosis and cystic fibrosis should be considered as a possible cause of pancreatitis, even in the young child.