Pediatr Pulmonol

A placebo-controlled, double-blind trial of the long-term effects of albuterol administration in patients with cystic fibrosis.

Konig P. Poehler J. Barbero GJ.
Department of Child Health, University of Missouri, Columbia 65212, USA.
This placebo-controlled study was designed to confirm a previously performed open label study that showed significant improvement in spirometry on maintenance therapy with albuterol for 1 year. In a double-blind, cross-over trial, albuterol (by metered dose inhaler) 180 microg b.i.d. or placebo were given for 6 months each. Spirometry was monitored at the start, and 3 and 6 months following initiation of each arm of the study. Peak expiratory flow rate (PEFR) was measured twice daily at home before and after study drug administration. Only patients with clinically detectable lung disease were enrolled. Twenty-one patients finished the study. All spirometric tests showed a significant improvement from start to end of the 6 month treatment with albuterol; there was no significant change on placebo. Forced vital capacity improved by 8.2% and forced expiratory volume in 1 s by 12.1% on albuterol therapy. Nevertheless, there was no significant difference between change on albuterol and change on placebo. Home measurements of PEFR showed a significant improvement of 4.7% on albuterol and a non-significant change of 2.0% on placebo from the first to the last week of treatment. None of the long-term improvements (spirometry or home PEFR) correlated with mean daily bronchodilation. For albuterol, the number of days of hospitalization was less than half that for patients on placebo (1.0/patient on albuterol versus 2.6 on placebo), but this did not reach statistical significance. These results suggest a beneficial effect from maintenance therapy with albuterol. Bronchodilation alone probably cannot explain the long-term benefits of albuterol, and other mechanisms may play a role. The lack of significant difference between change on albuterol and change on placebo is probably due to too small a number of patients in this study and lack of statistical power.

Effect of smaller droplet size of dornase alfa on lung function in mild cystic fibrosis. Dornase Alfa Nebulizer Group.

Year 1998
Geller DE. Eigen H. Fiel SB. Clark A. Lamarre AP. Johnson CA. Konstan MW.
Division of Pulmonology, The Nemours Children's Clinic, Orlando, Florida 32806, USA.
Aerosolized recombinant human DNase (dornase alfa) reduces mucus viscoelasticity in vitro and improves pulmonary function in patients with cystic fibrosis (CF). We postulated that if dornase alfa could be delivered more peripherally to small airways in the lung in the form of smaller aerosol droplets in patients with early airway obstruction, the increase in pulmonary function from baseline might be improved. CF patients (n = 749) with mild lung disease (baseline forced vital capacity > or = 70% predicted) were randomly assigned to receive dornase alfa 2.5 mg daily for 2 weeks by one of two nebulizer systems: 1) the Medic-Aid Durable SideStream nebulizer powered by the MobilAire Compressor (SS/MA) producing a droplet size with a mass median aerodynamic diameter (MMAD) of 2.1 microm; or 2) the Hudson T Up-draft nebulizer with a DeVilbiss Pulmo-Aide compressor (HT/PA) with an MMAD of 4.9 microm. Spirometry was performed at baseline and following 14 days of treatment. Dornase alfa delivered by both nebulizer systems produced small but statistically significant improvements in pulmonary function compared with baseline. There was a trend (P = 0.06) toward greater improvement in forced expiratory flow in 1 s in the SS/MA group (4.3%) compared with the HT/PA group (2.5%). These results indicate that the short-term spirometric response to dornase alfa is influenced in part by the physical characteristics of the aerosol in patients with mild lung disease. We speculate that this may be true for other therapeutic aerosols, and it appears that localization of disease in the lung plays a role in the response to inhaled agents.

Placebo-controlled, double-blind, randomized study of aerosolized tobramycin for early treatment of Pseudomonas aeruginosa colonization in cystic fibrosis.

Year 1998
Wiesemann HG. Steinkamp G. Ratjen F. Bauernfeind A. Przyklenk B. Doring G. von der Hardt H.
Department of Pediatrics, University Hospital, Essen, Germany.
In chronic Pseudomonas aeruginosa pulmonary infection of patients with cystic fibrosis (CF), antibiotic therapy generally fails to eradicate the bacterial pathogen. The mucoid bacterial phenotype, high sputum production by the host, and low airway levels of antibiotics seem to be responsible for the observed decrease in antibiotic efficacy. We hypothesized that early antibiotic treatment by inhalation in CF patients may be able to prevent or at least delay airway infection. In a prospective placebo-controlled, double-blind, randomized multicenter study, 22 CF patients received either 80 mg b.i.d. of aerosolized tobramycin or placebo for a period of 12 months shortly after the onset of P. aeruginosa pulmonary colonization. Two patients in the tobramycin and six patients in the placebo group stopped inhalation before the 12 month treatment period. Using life table analysis, the time to conversion from a P. aeruginosa-positive to a P. aeruginosa-negative respiratory culture was significantly shorter in the tobramycin-treated group than in the placebo group (P < 0.05, log rank test). Lung function parameters and markers of inflammation did not change in either group during treatment. The results of this study suggest that early tobramycin inhalation may prevent and/or delay P. aeruginosa pulmonary infection in CF patients.

Left ventricular perfusion deficit in patients with cystic fibrosis.

Year 1998
De Wolf D. Franken P. Piepsz A. Dab I.
Department of Pediatrics, AZ VUB, Vrije Universiteit Brussels, Belgium.
Left ventricular failure is not considered an important feature in cystic fibrosis (CF), but abnormalities of left ventricular function have been reported. Except for a few cases of heart failure in neonates with CF, there is no evidence of a primary disorder of the myocardium in patients with CF. Since left ventricular perfusion disturbances can cause left ventricular dysfunction, we decided to investigate left ventricular perfusion during exercise using sestamibi-Tc-99m-labeled macroaggregates. Eighteen CF patients with varying degrees of disease severity participated in the study. They underwent a thorough clinical evaluation, lung perfusion scan, pulmonary function testing, echocardiography, transcutaneous measurement of oxygen saturation at rest and during exercise, and an exercise test with injection of sestamibi-Tc-99m-labeled macroaggregates at peak exercise. Six patients (33%) showed abnormalities of the myocardial distribution of sestamibi-Tc-99m-labeled macroaggregates during exercise. Scanning abnormalities correlated with the clinical score, mean maximum expiratory flow at 50% of vital capacity (MEF50), and arterial oxygen desaturation during exercise. We conclude that deficits in left ventricular uptake of sestamibi-Tc-99m-labeled macroaggregates during exercise seem common in patients with severe CF lung disease. The cause of these deficits is not fully understood, but the occurrence seems to be associated with a poor prognosis.

The anaerobic threshold in cystic fibrosis: comparison of V-slope method, lactate turn points, and Conconi test.

Year 1998
Nikolaizik WH. Knopfli B. Leister E. de Boer P. Sievers B. Schoni MH.
Alpine Children's Hospital, Davos Platz, Switzerland.
Physical exercise can improve sputum clearance in patients with cystic fibrosis (CF). To set up individual training protocols it is desirable to know the anaerobic threshold (AT). Established methods such as blood lactate measurements and ergometry can only be performed in specialized centers. Conconi showed that the heart rate threshold (HRT), i.e., the deflection point from the linear relationship between work load and heart rate, correlated significantly with the AT in healthy adults. To assess the reliability of the HRT in CF, we performed ergometry in 32 CF patients (mean age, 21.0 +/- 5.5 years; mean Shwachman score, 77.8 +/- 12.0) according to the Conconi protocol. The HRT was compared with the aerobic threshold (AeT) as determined by the V-slope method and with two turn points in the lactate performance curve (LTP1, LTP2). An HRT could be obtained in only 17 of the 32 patients (53%). In these 17 patients there was a significant correlation between HRT and the other thresholds, but the absolute values for the AT differed considerably: The mean HRT was 132% higher than the AeT according to Beaver, 107% higher than LTP1, and 19% higher than LTP2. Exercise protocols that rely solely on the HRT in CF will lead to excessive exertion during exercise training programs in these patients. According to these results the HRT of Conconi is not a suitable method to determine appropriate exercise levels in CF training programs and might even be harmful in CF patients. These results also indicate the need to test the reliability of a diagnostic procedure that has been developed only for healthy people.

Stenotrophomonas maltophilia in cystic fibrosis: incidence and prevalence.

Year 1998
Demko CA. Stern RC. Doershuk CF.
Case Western Reserve University School of Medicine, LeRoy W. Matthews Cystic Fibrosis Center, Rainbow Babies and Childrens' Hospital, Cleveland, Ohio, USA.
Stenotrophomonas maltophilia (SM) was recovered from 211 of 773 cystic fibrosis (CF) patients followed for at least one year, and seen between 1982 and 1994. Yearly prevalence (5.6% to 8.7%) and incidence rates (1.6% to 5.7%) showed no trends. SM persistence varied greatly and was unlike that of Pseudomonas aeruginosa. Fifty percent of SM-positive patients had only one positive culture and only 24 (11%) remained chronically infected. Although SM-positive patients were more likely to be hospitalized than SM-negative patients, for 55% of SM-positive patients, acquisition did not appear to follow hospitalization. Of 40 SM-positive patients who had a CF sibling, only 10 siblings were ever culture positive. When stratified by FEV1, the two-year survival for SM-positive with mild/moderate disease (98%) and severe disease (78%) was similar to that of our SM-negative patients. Five-year survival was only 40% for SM-positive patients with initially severe pulmonary status, compared with 72% for the SM-negative patients. Seventy percent of the original SM isolates were panresistant (susceptible to no more than one antimicrobial agent). Ten years later, panresistance was 84%. Despite our reassuring experience with SM, including lack of sibling concordance, the fact that the majority of our patients had no hospital exposure prior to acquisition, the high incidence of transient infection, and the seemingly unaffected two-year survival, there are insufficient data to definitively conclude that segregation of these patients would be beneficial. The increasing prevalence of multiply resistant gram-negative pathogens in CF patients suggests the need for continued caution with any panresistant pathogen.

Reproductive health in males with cystic fibrosis: knowledge, attitudes, and experiences of patients and parents.

Year 1998
Sawyer SM. Tully MA. Dovey ME. Colin AA.
Harvard Medical School, Boston, Massachusetts, USA.
Males with cystic fibrosis (CF) are generally infertile as a result of aberrant development of Wolffian duct derivitives. The personal significance of this and related reproductive and sexual health (RSH) issues is unknown. We set out to describe the knowledge, attitudes, and experiences regarding RSH in a group of adolescent and adult males with CF, as well as the knowledge and attitudes of parents. This descriptive study was based on a semi-structured interview utilizing in-depth interview techniques. Questions included aspects of knowledge, attitudes, and experiences. Adolescent (aged 14-17 years) and adult (at least 18 years) males attending the Children's Hospital Cystic Fibrosis Clinic, Boston, MA, USA, or hospitalized at the Children's Hospital over that period were eligible; the accompanying parent of the adolescent was also interviewed. Consecutive eligible males were interviewed over a 3 month period. Summary data are presented, attitudinal data are analyzed qualitatively, and a selection of representative transcript data are reported to describe the range of opinions. Fifty males (10 adolescents, 40 adults) participated; this constituted a consecutive sample of 44% of the eligible clinic population. Ninety percent of adults, 60% of adolescents, and 50% of parents knew of male infertility. The mean age (+/-SD) at which adults recalled first hearing this was 16.0 +/- 4.7 years and 13.9 +/- 1.6 years for those adolescents who knew of infertility. Nineteen (48%) of adults and 5 (83%) of adolescents first heard about infertility from their health care providers. Ninety percent reported no major distress upon first hearing about infertility during adolescence. Increasing significance of infertility with maturity was reported by 12 men (30%); only 4 adults (10%) reported that infertility was not a significant aspect of CF. Forty percent knew that males with CF have a small volume ejaculate, but none had been told this by a health care provider. Thirty percent of men had semen analysis performed and all were azoospermic. We conclude that the majority of males with CF know of likely infertility. The significance of this knowledge changes with time. Poor knowledge and confusion surround a range of RSH issues in males with CF.

The worth of routine spirometry in a cystic fibrosis clinic.

Year 1998
Wall MA. LaGesse PC. Istvan JA.
Department of Pediatrics, Oregon Health Sciences University, Portland 97201, USA.
In our cystic fibrosis clinic, all patients older than 6 years perform spirometry at each visit just before being seen by the health care team. Upon review, we determined that our perceived rationale for this practice was that the medical history fails to detect deterioration in a sizable minority of patients whose pulmonary decline can be detected by spirometry. Furthermore, the literature and our own experience indicates that physical examination frequently will not detect changes in pulmonary status until the changes are advanced. As part of an ongoing quality/cost assessment, we decided to challenge our rationale for performing routine spirometry. Using standard methodology, we developed a six-item Likert style questionnaire, the purpose of which was to assess perceived changes in pulmonary symptoms since the last clinic visit. The questionnaire had an acceptable degree of internal consistency (Cronbach's alpha = 0.92), although the question about sputum production showed the least correlation with responses to other items. We administered the questionnaire to 103 consecutive different patients and examined the association between reported changes in symptoms and actual changes in spirometric outcomes. Overall, there was a statistically significant, but clinically weak association between symptom scores and change in FEV1, r2 = 0.16, P < 0.001. Twenty-three patients had a decline in FEV1 of > or = 10% from one clinic visit to the next. Depending on the method used to place symptom scores into categories indicating that pulmonary symptoms were "worse," "same," or "better" than at the last clinic visit, 40-60% of these 23 patients indicated they felt the "same" or "better." We conclude that spirometry is a justifiable part of all clinic visits for patients with cystic fibrosis, assuming that one would want to detect and treat declines in pulmonary status before they become advanced.

A step in the right direction: assessing exercise tolerance in cystic fibrosis.

Year 1998
Balfour-Lynn IM. Prasad SA. Laverty A. Whitehead BF. Dinwiddie R.
Respiratory Unit, Great Ormond Street Hospital for Children, London, United Kingdom.
Exercise tolerance may be reduced in patients with cystic fibrosis, but it is not always possible to predict this from standard lung function measurements. Formal exercise testing may, therefore, be necessary, and the test should be simple and readily available. We have developed a "3-minute step test" and compared it with the standard 6-minute walking test. Subjects stepped up and down a 15-cm-high single step at a rate of 30 steps per minute for 3 minutes. The effect of the step test on spirometry was tested first in 31 children with CF (mean age, 12.0 years), who had a mean (range) baseline forced expired volume in 1 second (FEV1) of 64% (18-94%) of predicted values. The step test was then compared with the standard 6-minute walk in a further 54 patients with cystic fibrosis (mean age, 12.5 years), with mean (range) baseline FEV1 of 61% (14-103%) of predicted values. Outcome measures were minimum arterial oxygen saturation (SaO2), maximum pulse rate, and the modified Borg dyspnea score. Post-step test spirometry showed mean (95% CI) changes of -1.1% (-6.0 + 3.9%) for forced vital capacity, of -1.6% (-4.2 + 1.1%) for FEV1, and +0.25% (-2.8 + 3.3%) for peak expiratory flow, although 5/31 children showed >15% drop in one or more parameters. The step and walk tests both produced significant changes (P < 0.0001) in all outcomes, with a mean (range) minimum SaO2 of 92% (75-98%) versus 92% (75-97%), a maximum pulse rate of 145 b.p.m. (116-189) versus 132 (100-161), and a Borg score of 2.5 (0-9) versus 1.0 (0-5), respectively. Comparison of the two tests showed that the step test increased breathlessness (mean change Borg score, 2.3 vs. 0.8; P < 0.0001) and pulse rate (mean change, 38% vs. 24%, P < 0.0001) significantly more than the walk, whereas the decrease in SaO2 was similar (mean change, -2.9% vs. -2.6%; P = 0.12). Some patients with a significant drop in SaO2 (>4%) would not have the decrease predicted from their baseline lung function. Reproducibility for the two tests was similar. The step test is quick, simple and portable, and is not dependent on patient motivation. Although the step test is more tiring, its effect on SaO2 is similar to the 6-minute walking test. It is a safe test that may prove to be a valuable measure of exercise tolerance in children with pulmonary disease, although longitudinal studies are now needed.