Safety of repeated intermittent courses of aerosolized recombinant human deoxyribonuclease in patients with cystic fibrosis.

OBJECTIVES: To determine the effect of repeated doses of aerosolized recombinant human deoxyribonuclease (rhDNase) on the development of anti-rhDNase antibodies, acute allergic reactions, and pulmonary function in patients with cystic fibrosis. DESIGN: A multicenter, open-label study in which 184 patients received 10 mg aerosolized rhDNase twice a day for 14 days followed by a 14-day washout period for a total of 6 treatment cycles. Serial determinations of anti-rhDNase antibodies and pulmonary functions were performed. RESULTS: Detectable anti-rhDNase antibodies developed in 16 (8.7%) patients. These patients had no changes in their symptoms from the time they entered the trial. Antibodies detected were all of the IgG isotype. Increases in both forced expired volume in 1 second and forced vital capacity were noted from the beginning to the end of each cycle of treatment returning to baseline during the off-treatment period of each cycle. Seropositivity to rhDNase was not associated with allergic reactions and had no relationship on improvement in pulmonary function. CONCLUSIONS: Development of anti-rhDNase antibodies occurred in a small number of patients and was not associated with side effects. Intermittent administration of rhDNase for 24 weeks to patients with cystic fibrosis was well tolerated and was not associated with anaphylaxis in any patient. Pulmonary function improved significantly during the 14-day cycles while rhDNase was administered and returned to baseline when rhDNase was discontinued.

Efficacy and safety of short-term administration of aerosolized recombinant human deoxyribonuclease in patients with cystic fibrosis.

Chronic endobronchial bacterial infection evokes purulent airway secretions in patients with CF. The viscoelastic properties of these secretions is primarily due to the presence of polymerized DNA from degenerating leukocytes. Recombinant human DNase I (rhDNase) reduces the viscosity of CF sputum in vitro. To test the hypothesis that rhDNase would improve pulmonary function in children and adults with CF, we compared the efficacy and safety of 10-day administration of three doses of aerosolized rhDNase (0.6, 2.5, or 10.0 mg twice daily) in 181 outpatients using a randomized, placebo-controlled parallel design. Forced vital capacity (FVC) improved 10 to 12% (p < 0.05 to 0.001), and forced expiratory volume in one second (FEV1) improved 10 to 15% (p < 0.001) across all doses of rhDNase compared with placebo. The magnitude of effect was dose dependent for both FVC and FEV1 through study Day 21 (p < 0.001). rhDNase was associated with a decreased perception of dyspnea and an improved perception of well-being. No patients developed detectable anti-rhDNase antibodies or bronchial reactivity to rhDNase. Some patients experienced mild upper airway irritation, but no major adverse events were reported. Administration for 10 days of aerosolized rhDNase to pediatric and adult outpatients with CF improves lung function and is well tolerated. Although all three doses were efficacious, the greatest improvement in FEV1 and FEV1/FVC ratio was demonstrated in the 2.5 and 10.0 mg rhDNase treatment groups.

Efficacy of aerosolized tobramycin in patients with cystic fibrosis.

BACKGROUND: Direct aerosol delivery of aminoglycosides such as tobramycin to the lower airways of patients with cystic fibrosis may control infection with Pseudomonas aeruginosa and improve pulmonary function, with low systemic toxicity. We conducted a randomized crossover study to evaluate the safety and efficacy of aerosolized tobramycin in patients with cystic fibrosis and P. aeruginosa infections. METHODS: Seventy-one patients with stable pulmonary status were recruited from seven U.S. centers for the treatment of cystic fibrosis and randomly assigned to one of two crossover regimens. Group 1 received 600 mg of aerosolized tobramycin for 28 days, followed by half-strength physiologic saline (placebo) for two 28-day period. Group 2 received placebo for 28 days, followed by tobramycin for two 28-day periods. Pulmonary function, the density of P. aeruginosa in sputum, ototoxicity, nephrotoxicity, and the emergence of tobramycin-resistant P. aeruginosa were monitored. RESULTS: In the first 28-day period, treatment with tobramycin was associated with an increase in the percentage of the value predicted for forced expiratory volume in one second (9.7 percentage points higher than the value for placebo; P < 0.001), forced vital capacity (6.2 percentage points higher than the value for placebo; P = 0.014), and forced expiratory flow at the midportion of the vital capacity (13.0 percentage points higher than the value for placebo; P < 0.001). A decrease in the density of P. aeruginosa in sputum by a factor of 100 (P < 0.001) was found during all periods of tobramycin administration. Neither ototoxicity nor nephrotoxicity was detected. The frequency of the emergence of tobramycin-resistant bacteria was similar during both tobramycin and placebo administration. CONCLUSIONS: The short-term aerosol administration of a high dose of tobramycin in patients with clinically stable cystic fibrosis is an efficacious and safe treatment for endobronchial infection with P. aeruginosa.

New peripherally inserted midline catheter: a better alternative for intravenous antibiotic therapy in patients with cystic fibrosis.

A study was performed on outpatients with cystic fibrosis (CF) to evaluate the performance of an over-the-needle peripherally inserted midline catheter for the delivery of 2-week courses of antibiotic therapy. The midline is a 7-inch catheter inserted in the antecubital region with the tip located in the axillary region. It is made of a newly developed biomaterial that softens and expands upon contact with body fluids. The hypotheses for the study were that the midline catheter: 1) is useful for intermediate-length therapies; 2) can prevent multiple 3-day conventional peripheral catheter restarts; 3) can prevent or delay the use of more invasive central devices; 4) is comfortable for patients; and 5) is economical. A total of 41 midlines were inserted in 27 patients with an average age and weight of 22 years and 109 pounds, respectively. Prior to this study implanted ports and primarily conventional short peripheral catheters were used to administer I.V. therapy to these patients; fifty percent of these short peripheral catheters failed within 2.6 days. At 2 weeks of dwell, 80% of the midline catheters placed in these patients were still indwelling. Also, 80% of all midline catheter removals were for non-catheter-related reasons. There were no cases of midline catheter phlebitis. In contrast, the phlebitis rates published for peripherally inserted central catheters (PICCs) and conventional short peripheral catheters at 7 days of dwell are 20% and greater than 51% respectively. The midline catheters were comfortable and well liked by most patients and became more economical than conventional peripheral catheters for therapies lasting approximately 6 days through 1 to 2 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Functional status as an overall measure of health in adults with cystic fibrosis: further validation of a generic health measure.

We studied the validity of a generic health measure in a population with a chronic, life-shortening illness. Thirty-seven adults with cystic fibrosis (CF) and 46 of their healthy peers completed a questionnaire which included 12 questions on functional status from the RAND Health Insurance Study. For the CF group, the questionnaire and a medical chart review yielded data on 7 additional health variables, including pulmonary function. After data collection, members of the CF group were followed for 5 years, by which time 11 had died. The functional status of the CF group was significantly lower than that of the comparison group. Within the CF group, functional status correlated significantly with 6 of the 7 other health variables. Analysis using the Cox proportional hazards model showed that functional status alone was a significant (p less than 0.001) predictor of a CF subject's survival time; in a multivariate model a non-significant trend suggested that lowered functional status may be associated with an increased risk of early death even after adjustment for pulmonary function and percent ideal body weight. These results extend previous findings and suggest that functional status can be used as an overall measure of health in a wide variety of studies.

A comparative study of the psychosocial assets of adults with cystic fibrosis and their healthy peers.

Psychosocial assets of 37 adults with cystic fibrosis (CF) and 46 of their healthy peers were assessed by mailed questionnaire. Major sociodemographic variables did not differ significantly between the two groups, nor did indices of emotional social support, social network density, self-esteem, or current life satisfaction. This study revealed adults with CF to function on a par with their healthy peers in nearly all respects, a finding at odds with those from uncontrolled studies and which suggests to us that many previous conclusions about the psychosocial health of adults with CF have been unwarranted. Future psychosocial studies involving patients with CF should include control groups and inferences about the effect of these patients' physical illness on their psychosocial health should not be made in the absence of normative data.

Restricted pulmonary function in cystic fibrosis.

Some patients with cystic fibrosis have reduced pulmonary volumes, indicating a restrictive pattern of pulmonary disease. We identified ten patients with pulmonary functional evidence of restriction among 158 patients with cystic fibrosis followed at the University of California San Diego Medical Center in 1984 and 1985. We characterized the radiographic, pulmonary functional, and clinical characteristics of these restricted patients compared to matched nonrestricted patients. Pulmonary volumes were measured by three different techniques: plethysmography; nitrogen washout; and radiography. Except for plethysmographic pulmonary volumes, there were no significant differences between the matched restricted and nonrestricted patients. Radiographic pulmonary volume tended to overestimate gas volume measured by the other techniques. Differences among these techniques (thought to represent air-space filling) correlated best with radiographic evidence of air trapping and bronchial markings and not with parenchymal lesions. Serial pulmonary function tests demonstrated changes in pulmonary volume in several patients and a trend toward improvement in pulmonary volume in the restricted patients over time. We conclude that restricted pulmonary function does not necessarily indicate more severe disease in patients with cystic fibrosis and may be reversible in some. The mechanism of restriction may be related more to radiographic evidence of airway disease than to parenchymal abnormalities.

K dependence of the Na-K pump is abnormal in erythrocytes from patients with cystic fibrosis and obligate heterozygotes.

The affinity of the Na-K pump for K was significantly (P less than .001) lower in erythrocytes from patients with cystic fibrosis (Km 4.6 +/- 0.35 mM; n = 26) or from heterozygotes (Km 3.9 +/- 0.57 mM; n = 12) than in controls (Km 2.2 +/- 0.10 mM; n = 20). The affinity of the Na-K pump for K was lower in normal erythrocytes than in normal fibroblasts which may explain the variability in the severity of involvement of different organs in cystic fibrosis. We have now shown in human skin fibroblasts and erythrocytes, that the K affinity of the Na-K pump is lower in patients with cystic fibrosis than in controls. Since the abnormality is also present in erythrocytes from heterozygotes who are clinically normal, it is likely that this abnormality is closely related to the genetic defect in cystic fibrosis.

Distribution of specific ventilation in cystic fibrosis.

Continuous distributions of specific tidal ventilation were recovered from nitrogen washouts in 29 patients with cystic fibrosis and 22 normal subjects along with other pulmonary parameters to assess the utility of the recovered distribution in describing the progress of the disease. Normal subjects showed predominantly unimodal distributions of a pattern showing a small amount of ventilation going to units with high specific ventilation. Multimodal distributions were the rule in the cystic population with only subjects with normal pulmonary function having unimodal distribution.

Pulmonary cystic fibrosis in the adult: early and late radiologic findings with pathologic correlations.

Radiographs of 50 patients age 17 or more with documented cystic fibrosis were reviewed. Peripheral nodular and nonvascular linear densities were common early abnormalities. Specific findings of bronchiectasis were found in 90% of all cases. Hyperinflation was seen in 76% of cases, especially in the lower lobes; atelectasis and all other abnormalities were more common in the upper (and middle) lobes. Cystic air spaces developed in 24% of cases. The severity of abnormalities (including hyperinflation, atelectasis, and bronchial changes) increased in 30 of the 39 patients with follow up for a year or more. Eight of the 15 patients who died came to autopsy. The lungs showed acute and chronic inflammation of airways, including peripheral bronchioles, with adjacent parenchymal inflammation of airways peripheral bronchioles, with adjacent parenchymal infiltrates and fibrosis. The surrounding alveoli were aerated and enhanced the visibility of the thick-walled airways, except in regions of lobar atelectasis, scarring, or active pneumonia. Large and small airway shadows can be described more precisely than by the terms "honeycombing," "interstitial" or "bronchovascular markings".