Open label study of inhaled aztreonam for Pseudomonas eradication in children with cystic fibrosis: The ALPINE study.

BACKGROUND: Consensus guidelines recommend early treatment to eradicate newly acquired Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) patients although there is no single preferred regimen. Aztreonam for inhalation solution (AZLI) significantly reduces sputum Pa density in CF patients with chronic Pa infection and has been well tolerated in the pediatric population. This single-arm, open-label Aztreonam Lysine for Pseudomonas Infection Eradication (ALPINE) study was conducted to evaluate the safety and efficacy of a 28-day treatment course of AZLI to eradicate newly acquired Pa infection in pediatric CF patients. METHODS: CF patients (3 months to <18 years) with new onset Pa infection were treated with AZLI 75 mg 3 times daily for 28 days. New onset Pa infection was defined as first lifetime Pa-positive respiratory tract culture (throat swab, sputum) or Pa-positive culture after a ≥2-year history of Pa-negative cultures (≥ 2 cultures/year). Sputum or throat swab cultures were collected at study entry (baseline) and at weeks 4 (end of treatment), 8, 16, and 28. Primary endpoint was the percentage of patients with cultures negative for Pa at all post-treatment time points. RESULTS: A total of 105 pediatric CF patients enrolled (3 months to <2 years, n=24; 2 to <6 years, n=25; 6 to <18 years, n=56). Of the 101 patients who completed treatment, 89.1% (n=90) were free of Pa at the end of treatment and 75.2% (n=76) were free of Pa 4 weeks after the end of treatment. Of the 79 patients evaluable for the primary endpoint, 58.2% were free of Pa at all post-treatment time points. CONCLUSIONS: AZLI was effective and well tolerated in eradicating Pa from newly infected pediatric patients with CF. These eradication rates are consistent with success rates reported in the literature for various antibiotic regimens, including other inhaled antibiotics studied for eradication. ClinicalTrials.gov: NCT01375049.

Comparison of high-frequency chest wall oscillation and oscillating positive expiratory pressure in the home management of cystic fibrosis: a pilot study.

Enhanced airway clearance is thought to result in better-maintained pulmonary function in cystic fibrosis (CF). Postural drainage, percussion, and vibration (PDPV) have been the primary airway clearance technique (ACT) employed in CF for over 40 years. Two new airway clearance modalities are high-frequency chest wall oscillation (HFCWO) and oscillating positive expiratory pressure (OPEP). This pilot study was undertaken to evaluate the efficacy of these techniques during home use, assess patient satisfaction with them as compared to PDPV, and assess the feasibility of performing a definitive comparative trial. The prospective, randomized, multicenter crossover trial was conducted at three urban academic CF Care Centers. Twenty-nine CF patients, 9-39 years of age, participated. Subjects performed 4 weeks each of HFCWO and OPEP following 2-week lead-in/washout periods. Spirometry, lung volumes, National Institutes of Health and Petty Scores, and a satisfaction survey were performed at baseline and after each treatment period. An ACT preference survey was completed at the conclusion of the study. Twenty-four subjects completed both therapies. There were no statistically significant differences between therapies for spirometry, lung volumes, or clinical scores. No significant safety issues arose during the study period. Compliance between therapies was similar. Significant differences among therapies existed in patient satisfaction. Given a choice of therapy, 50% of subjects chose HFCWO, 37% OPEP, and 13% PDPV. This study suggests that HFCWO and OPEP are safe and as effective as patients' routine therapies when used for airway clearance in a home setting. Patient satisfaction and preference differ among ACTs and should be considered when prescribing home therapy. A definitive, multi-center, comparative study evaluating long-term efficacy of these techniques is feasible.

Anti-inflammatory approaches to the treatment of cystic fibrosis lung disease: past, present and future.

Inflammation has been increasingly recognized as a major factor in the pathogenesis of cystic fibrosis (CF) lung disease. The use of anti-inflammatory medications to slow pulmonary deterioration has been the focus of much research over the past two decades. Oral corticosteroids are effective, but are associated with significant adverse effects when used long-term. Inhaled corticosteroids are being studied as an alternative to systemic steroids. High-dose ibuprofen has also been shown to be of benefit in CF patients but has not been widely used. A variety of other non-specific anti-inflammatory agents, as well as antioxidants and antiproteinases, have been evaluated or are currently under investigation for use in CF. At present, the anti-inflammatory therapies used to treat CF lung disease are limited. There is hope that agents being evaluated in ongoing clinical trials will prove more effective than those already tested and that future research will provide additional anti-inflammatory therapies for CF airway disease.

Inhaled morphine to relieve dyspnea in advanced cystic fibrosis lung disease.

Inhaled morphine has been used to treat dyspnea in a variety of clinical settings. There are, however, no reports of its use in treating patients with end-stage lung disease due to cystic fibrosis (CF). We report on the use of inhaled morphine sulfate in a 13-year-old boy with CF, advanced lung disease, and acute respiratory failure. Therapy was effective in reducing his subjective feeling of air hunger and improving his BORG score. His sole significant adverse effect was headache after 2 days of treatment at 4-hourly intervals.

Validation of an instrument measuring patient satisfaction with chest physiotherapy techniques in cystic fibrosis.

OBJECTIVES: Chest physiotherapy (CPT) has been an important part of cystic fibrosis (CF) treatment regimens for > 40 years. Techniques with different perceived costs, benefits, and patient satisfaction exist. An instrument measuring patient satisfaction with CPT has not been reported. Our goal was to develop and validate such an instrument. DESIGN: A cross-sectional survey sent to 349 patients seen at a large, urban, academic CF care center. The two-page survey asked 17 questions related to CPT satisfaction (efficacy, convenience, comfort, overall satisfaction), followed by 4 general CF-care questions (disease severity, importance of therapies, prescribed vs missed therapies). A 5-point Likert-type scale was used for responses. Psychometric analysis included itemetric performance, confirmatory factor analysis, test-retest reliability, and evaluation of subject's responses to the general CF-care questions. RESULTS: One hundred twenty-nine individuals returned completed surveys (39%; 66 males and 63 females; age range, 2 months to 47 years). FEV(1)values were 21 to 155% predicted (mean, 76%; n = 82). Disease severity was as follows: 60 mild, 47 moderate, and 14 severe. Seventy-nine subjects used postural drainage, percussion, and vibration (PDPV), 21 used a flutter device, and 14 used high-frequency chest wall oscillation (HFCWO). Five subjects used more than one technique. Internal consistency analysis found an overall coefficient alpha of 0.87 (range, 0.74 to 0.89 for four domains). Factor analysis demonstrated domains for efficacy, convenience, comfort, and overall satisfaction. Mean total satisfaction scores differed significantly among therapies (R(2) = 0. 118; F[ 2,111] = 7.56; p = 0.0008): PDPV, 3.8 (SD = 0.6); Flutter, 4. 3 (SD = 0.5); and HFCWO, 4.1 (SD = 0.5). Therapies also differed significantly on all subscores. Perceived importance of CPT and compliance with CPT increased linearly with disease severity. Overall satisfaction was positively correlated with CPT compliance. CONCLUSIONS: The CPT satisfaction survey has good reliability and content validity. Significant differences in patient satisfaction exist among therapies. Sicker patients recognize the importance of, and demonstrate better compliance with prescribed CPT. Increased satisfaction is associated with better compliance with therapy.

Pulmonary infiltrates with eosinophilia syndromes in children.

Pulmonary infiltrates with eosinophilia (PIE) are a group of heterogeneous disorders having the common findings of lung disease and eosinophilia in the peripheral blood, bronchoalveolar lavage fluid, or pulmonary interstitium. Eleven cases of PIE syndromes were identified through a retrospective and prospective chart review: drug-induced (2), acute eosinophilic pneumonia (3), infant pulmonary eosinophilia (2), parasite-induced (2), Churg-Strauss syndrome (1), and atypical chronic PIE (1). Patient demographics, clinical presentation, and disease severity varied considerably among groups. Therapeutic interventions included bronchodilators (10), oxygen (7), corticosteroids (9), and mechanical ventilation (3). A single patient with acute eosinophilic pneumonia died. Our experience suggests that PIE syndromes are rare in childhood and that clinical presentation can vary widely. Because of the potential for significant morbidity and mortality, aggressive diagnostic evaluations are warranted, particularly in children with respiratory failure of unknown etiology.

Falsely elevated serum tobramycin concentrations in cystic fibrosis patients treated with concurrent intravenous and inhaled tobramycin.

A recently developed tobramycin preparation for inhalation (TOBI(R), Pathogenesis Corp., Seattle, WA) is widely used in CF patients. It is often used in conjunction with intravenous tobramycin. Renal and ototoxicity associated with the use of tobramycin require that serum drug concentrations be monitored during therapy. We report on two patients with falsely elevated, toxic serum tobramycin concentrations while receiving concurrent intravenous and inhaled tobramycin. These cases point out the need for guidelines governing the use and monitoring of simultaneous inhaled and intravenous tobramycin therapy. Pediatr Pulmonol. 2000; 29:43- 45.

Pharmacokinetics of ibuprofen in patients with cystic fibrosis.

STUDY OBJECTIVES: To determine the pharmacokinetic disposition of high doses of ibuprofen in patients with cystic fibrosis (CF), and to evaluate the reliability of intrapatient dosage adjustments to achieve recommended peak ibuprofen plasma concentrations. DESIGN: First-order absorption, one-compartment model was fit to serial ibuprofen concentration-time data obtained from patients with CF and receiving high doses of ibuprofen 20-30 mg/kg. SETTING: Medical school-affiliated teaching hospital. PATIENTS: Ninety-eight patients with CF (53 males, 45 females; mean age 12.5 yrs). MEASUREMENTS AND MAIN RESULTS: The time to achieve apparent maximum ibuprofen concentration (Tmax) ranged from 1-3 hours, with maximum concentrations ranging from 21-150 microg/ml (mean 83 microg/ml). Apparent ibuprofen clearance (Cl/F) was significantly correlated with age (r2 = 0.43, p<0.0001) and measures of body size (body surface area [BSA] r2 = 0.50, p<0.0001). The Cl/F ranged from 21.1-114.7 ml/min/m2 (mean 45.5 ml/min/m2), a 5-fold difference. The Cl/F normalized to body weight decreased with increasing age (p=0.0009), but when normalized to BSA, there was no age-related change (p=0.65). Apparent volume of distribution was significantly correlated with age (r2 = 0.69, p<0.0001) and measures of body size (BSA r2 = 0.79, p<0.0001). Fourteen patients had ibuprofen dosage adjustments. The Cl/F was not different among doses; however, Tmax differed by an average of 1.25 hours (range 0-2 hrs). CONCLUSION: The substantial variability in ibuprofen disposition and clearance we report is greater than previously described. Individualized dosages and therapeutic drug monitoring may be required to ensure plasma concentrations considered necessary to prevent pulmonary deterioration in patients with CF.

The use of anti-inflammatory medications in cystic fibrosis: trends and physician attitudes.

STUDY OBJECTIVES: In recent years, there has been considerable interest in the use of antiinflammatory medications to decrease airway inflammation and preserve pulmonary function in patients with cystic fibrosis (CF) lung disease. Long-term use of oral corticosteroids (OCS) and ibuprofen (IBU) has been proven efficacious in slowing the progression of CF. Inhaled corticosteroids (ICS) have not been adequately studied. Little is known regarding use trends and physician attitudes toward these drugs. DESIGN: Cross-sectional survey mailed to 111 directors of Cystic Fibrosis Centers in the United States accredited by the Cystic Fibrosis Foundation. The two-page written questionnaire included items regarding physicians' attitudes toward anti-inflammatories, center demographics, patients receiving therapy, and number of physicians prescribing therapy. RESULTS: Sixty-seven surveys were returned (60%). The responding centers represented 239 physicians and served 9,363 patients, 2,234 (24%) of whom were receiving routine antiinflammatory drugs. Complete data sets were available for 8,803 patients with 2,169 (25%) receiving anti-inflammatory therapy. Ninety-eight (41%) physicians prescribed long-term use of oral steroids for 413 (5%) patients, 103 (42%) prescribed inhaled steroids for 1,032 (12%) patients, and 108 (45%) prescribed high-dose IBU for 723 (8%) patients to control CF. The practitioners reported familiarity and efficacy as the primary reasons for prescribing OCS; concerns over side effects were the major reason for not prescribing. Regarding ICS, the primary reasons for prescribing were familiarity and safety, with lack of efficacy being cited as the major reason for not prescribing. For IBU, efficacy was ranked highest among reasons for prescribing, with concern over safety being the highest ranked reason for not prescribing. CONCLUSIONS: Anti-inflammatory medications appear to be an underutilized therapeutic modality in CF care. This is true for numbers of patients receiving these drugs as well as numbers of care providers prescribing them. Additional studies will be required to address physicians' concerns regarding the long-term efficacy and safety of anti-inflammatory drugs in treating CF.

Foolers: things that look like pneumonia in children.

Pulmonary infiltrates on chest radiographs are common findings in the pediatric age group and are generally associated with acute infectious pneumonias. Occasionally, however, these "pneumonias" fail to respond to appropriate antibiotic therapy. Under these circumstances, noninfectious conditions that may be associated with pulmonary infiltrates should be considered. Thus, it is important that physicians who care for children have some knowledge of these potential "mimickers" of childhood pneumonia.