Ivacaftor improves appearance of sinus disease on computerised tomography in cystic fibrosis patients with G551D mutation.

BACKGROUND: Most patients with Cystic fibrosis (CF) have chronic sinus disease which may require multiple sinus surgeries and antibiotic courses. Ivacaftor can improve lung function, lower sweat chloride levels and improve weight by targeting the primary defect, a faulty gene and its protein product, cystic fibrosis transmembrane conductance regulator (CFTR) in patients with the G551D mutation. Its role in improving sinus disease has not been evaluated. OBJECTIVE: The objective of this study was to evaluate efficacy of ivacaftor in improving CF related sinus disease. DESIGN: Observational study. PARTICIPANTS: Twelve patients with cystic fibrosis and a G551D-CFTR mutation. METHODS: Twelve patients with a G551D-CFTR mutation were monitored for at least one year before and after starting ivacaftor. OUTCOME MEASURES: Sinus disease progression was monitored by comparing computed tomography (CT) of sinuses before and at one year on therapy. Hospital admissions, pulmonary exacerbations, weight, BMI and lung function were also compared. RESULTS: Median age was 17 years (range 10-44). Weight, BMI, FEV1 significantly increased and sweat chloride significantly decreased by six months on ivacaftor therapy. CT of the sinuses in all patients improved. Seven patients had severe sinus disease, improved to moderate in three and mild in remaining four. Four patients had moderate disease which improved to mild in all. One patient had normal sinus CT before and after the therapy. CONCLUSIONS: Patients with CF and G551D mutation, within 6 months of starting ivacaftor had significant improvements in weight, BMI and mean % FEV1. Significant lessening of underlying sinus disease measured by CT scan was noted, suggesting a disease modifying effect.

A phase I study of adenovirus-mediated transfer of the human cystic fibrosis transmembrane conductance regulator gene to a lung segment of individuals with cystic fibrosis.

A third-generation adenoviral vector containing recombinant human cystic fibrosis transmembrane conductance regulator (CFTR) gene was delivered by bronchoscope in escalating doses to the conducting airway of 11 volunteers with cystic fibrosis. Assessments of dose-limiting toxicity (DLT), efficiency of gene transfer, and cell-mediated and humoral immune responses to vector administration were performed. DLT, manifest by flulike symptoms and transient radiographic infiltrates, was seen at 2.1 x 10(11) total viral particles. A highly specific assay for gene transfer was developed using in situ hybridization with an oligoprobe against unique vector sequence. Detectable gene transfer was observed in harvested bronchial epithelial cells (<1%) 4 days after vector instillation, which diminished to undetectable levels by day 43. Adenovirus-specific cell-mediated T cells were induced in most subjects, although only mild increases in systemic humoral immune response were observed. These results demonstrate that gene transfer to epithelium of the lower respiratory tract can be achieved in humans with adenoviral vectors but that efficiency is low and of short duration in the native CF airway.

Effects of feeding on protein turnover in healthy children and in children with cystic fibrosis.

We hypothesized that there is less suppression of whole-body protein breakdown with feeding in patients with cystic fibrosis (CF) who exhibit decreased insulin secretion after a single meal. Using [1-13C]leucine, we measured rates of nonoxidative leucine disappearance (whole-body protein synthesis) and protein breakdown in nine CF patients (6-11 y of age) and five healthy control subjects (8-10 y of age) during feeding and fasting. In the CF patients, synthesis and breakdown (x +/- SD) were 172 +/- 61 and 157 +/- 67 mumol.kg-1.h-1 during feeding and 140 +/- 24 and 178 +/- 26 mumol.kg-1.h-1 during fasting. The respective control values were 129 +/- 27 and 114 +/- 20 mumol.kg-1.h-1 during feeding and 136 +/- 13 and 173 +/- 18 mumol.kg-1.h-1 during fasting. Leucine balance was nearly identical in the two groups. By analysis of variance, there was a significant effect of feeding on protein breakdown but no difference between the groups. However, when each group was analyzed separately, feeding resulted in a 34% decrease in breakdown in the control subjects (P = 0.001) and a 23% increase in synthesis in the CF group (P = 0.058). Plasma insulin concentrations did not differ in the two groups. Thus, feeding may affect protein turnover differently in children with CF than in control children independently of plasma insulin concentration.

Lateral thoracic expansion for Jeune's asphyxiating dystrophy: a new approach.

A new procedure is described for thoracic expansion in Jeune's asphyxiating dystrophy. The chest wall is enlarged by division of ribs and underlying tissue in a staggered fashion so that either rib or periosteum covers the lung. New bone formation has been demonstrated so that a viable enlargement has been obtained. The clinical result is excellent to date.

Gender related differences in airway tone in children.

The effects of gender, volume history, and inhaled atropine and isoproterenol on lung mechanics were assessed in 16 normal boys and 14 normal girls using lung volumes, flow-volume curves, and oscillatory resistances. Flows were measured from full and partial forced expiratory flow-volume curves. Six girls and 6 boys were studied before and after inhaled atropine, and 10 boys and 8 girls before and after inhaled isoproterenol. Girls demonstrated a significant increase in flows on full and partial curves with a deep inspiration [Vmax-partial 0.73 +/- 0.34 (SD) to Vmax-full 0.80 +/- 0.37 and 0.83 +/- 0.20 to 1.06 +/- 0.29 TLC/s in each group] and following inhalation of isoproterenol on the partial curves only (0.73 +/- 0.34 to 0.93 +/- 0.40 TLC/s). Boys showed a small but significant increase in Vmax with isoproterenol on full curves but not on partial curves. Following atropine, boys demonstrated a significant increase in Vmax on partial flow-volume curves (0.78 +/- 0.28 to 1.00 +/- 0.35 TLC/s) and a significant decrease in specific respiratory resistance (7.6 +/- 2.7 to 5.1 +/- 0.9 cmH2O/s), whereas girls had no such changes. These data suggest that boys have greater resting airway tone than girls and that this tone is less responsive to deep inspiration and isoproterenol independently, although a combination of isoproterenol and a deep inspiration will produce increased flows in boys. Atropine reduces airway tone predominantly in boys, suggesting that the increased resting airway tone in boys is partially mediated via the vagus nerve.

Spirometric and endoscopic evaluation of airway collapse in infants with bronchopulmonary dysplasia.

We evaluated eight infants with bronchopulmonary dysplasia (BPD) at ages from 2 to 13 months who had repeated episodes of clinical respiratory deterioration associated with agitation. These episodes limited further weaning from ventilation or necessitated recurrent intubation and reinstitution of ventilation. All infants underwent spirometric evaluation and six also had endoscopic examination during simulated agitation episodes (elicited by toe pinching). All babies were found to have a very prolonged near zero expiratory airflow pattern, accompanied by vigorous diaphragmatic and abdominal muscle activity and rapid development of hypoxia. Six patients had endoscopically documented tracheal collapse under the same simulated circumstances. The episodes ceased with calming or sedation of the infants.

Functional residual capacity (FRC) measurements by plethysmography and helium dilution in normal infants.

Comparative measurements of functional residual capacity (FRC) made by plethysmography (FRCpleth) and by helium dilution (FRCHe) were obtained on 27 infants and young children without known pulmonary disease (14 males, 13 females; 4 weeks-26 months; mean age 32.2 weeks) while under chloral hydrate sedation. Clinical histories, clinical examinations, and pulmonary functions were normal for all members of the group. FRCpleth, whether measured near end expiration (EE) or near end inspiration (EI), and corrected to mean expiratory levels of at least 3 breathing cycles, was consistently and significantly greater than FRCHe. Comparative values for mean (+/- standard deviation) were FRCpleth EE, 182.0 (+/- 79.7) mL and FRCpleth El, 171.8 (+/- 77.4) mL vs. FRCHe, 154 (+/- 72.2) mL, P < 0.0001 and P < 0.005, respectively. Normalizing values by weight, FRCpleth EE was 23.8 mL/kg (+/- 5.3) vs. FRCHe, 20.2 (+/- 4.7) mL/kg, mean (+/- standard deviation). The difference between FRCpleth and FRCHe, expressed as FRCpleth - FRCHe/FRCpleth x 100, was 9% for occlusions at end inspiration and 16% for occlusions at end expiration. The following equations describe our FRC results in relation to length: In (FRCHe) = 2.74 x ln (length) - 6.53 r2 = 0.781 slope = 2.74 +/- 0.29 SE Y intercept = 6.53 +/- 1.12 SE ln (FRCPleth EI) = 2.69 x ln (length) - 6.21 r2 = 0.752 slope = 2.69 +/- 0.31 SE Y intercept = 6.21 +/- 1.29 SE The difference between FRCpleth and FRCHe was more marked when occlusions were performed at end expiration than at end inspiration.(ABSTRACT TRUNCATED AT 250 WORDS)

Feeding-induced changes in energy expenditure in children with cystic fibrosis.

Seven children with cystic fibrosis (aged 7 to 12 years) were studied in the fasted and fed states. Using a primed, constant, intravenous infusion of NaH13CO3, the rate of appearance of CO2 (RaCO2) was estimated. Net CO2 excretion (VCO2) was also measured. Energy expenditure was calculated using the food quotient. RaCO2 (mean +/- SD) (mumol.kg-1.min-1) in the fasted and fed states (297 +/- 59 and 359 +/- 67) was 117% and 105% of VCO2 (259 +/- 48 and 352 +/- 72). Feeding induced a 23% and a 37% increase in RaCO2 and VCO2, respectively, and respective 19% and 33% increases in energy expenditure (p < .05). Measurement of CO2 production by isotopic dilution is a useful index of group changes in energy expenditure, including those induced by feeding.

Pulmonary function is compromised in children with mediastinal lymphoma.

PURPOSE: Lymphomas account for nearly 20% of the malignancies in childhood and the majority of patients with Hodgkin's Disease (HD) and non-Hodgkin's lymphoma (NHL) have radiological evidence of mediastinal involvement at presentation. Children with mediastinal tumors are at risk for the development of lethal airway obstruction during general anesthesia. This study quantitates the degree of the airway obstruction and the functional significance of tracheal compression in a cohort of 51 children with HD and NHL. RESULTS: Thirty patients with HD (mean age, 14.6 years) and 21 with NHL (mean age, 9.2 years) were included in this study. Twenty-five children (49%) had respiratory symptoms at the time of presentation. Respiratory complaints were much more common in children with NHL (76%) when compared with those with HD (30%). Pulmonary function was also significantly worse in the NHL patients who had a mean upright forced vital capacity (FVC) of 66 +/- 21%. The comparable value for the children with HD was 85 +/- 15% (P = .031). Patients with respiratory symptoms at presentation had both obstructive and restrictive deficits of pulmonary function. Their mean upright forced expiratory volume in 1 second (FEV1) was 69 +/- 22% and the FVC was 69 +/- 18%. Children with large mediastinal masses also had significantly decreased pulmonary function compared with those with small tumors. The upright FEV1 for these two groups was 72 +/- 18% versus 98 +/- 15% (P = .016). Their FVC values were 68 +/- 20% and 91 +/- 17%, respectively (P = .049). Mean tracheal compression was measured at 44% in the children with large tumors versus 27% for those with small lesions (P = .048). CONCLUSION: Children with mediastinal lymphomas have both obstructive and restrictive deficits on pulmonary function testing. Pulmonary function is significantly decreased in patients with NHL, children who present with respiratory symptoms, and those with very large mediastinal masses (mediastinal mass ratio > 45%). The extent of tracheal compression correlates with the size of the mediastinal mass.

Bronchopexy for congenital bronchomalacia in the newborn.

Congenital bronchomalacia is a very unusual cause of respiratory distress in the newborn. The surgical management of this anomaly is challenging. The authors report on a newborn with congenital bronchomalacia successfully treated with bronchopexy.

Prolonged parenteral nutrition for cystic fibrosis patients.

To evaluate the clinical impact of prolonged parenteral nutritional (PN) therapy on patients with advanced cystic fibrosis, we conducted a retrospective chart review of 25 cystic fibrosis patients who underwent prolonged PN (median course 295 days) at our institution between August 1988 and May 1992. The patients' survival status, change in percentage of ideal body weight, need for ongoing nutritional intervention, pulmonary function test changes, i.v. antibiotic use, and complication rates were assessed. Patients gained significant weight while receiving PN, but they lost weight when PN was discontinued. PN did not clearly improve pulmonary status. IV antibiotic therapy nearly doubled during PN. Central venous catheter sepsis rates rose from 1.29 to 3.45 per 1000 catheter days during PN therapy. In conclusion, prolonged PN promotes weight gain in cystic fibrosis patients with severe disease; however, the effect is transient and involves a significantly increased risk of sepsis.

Sleep-related breathing disorders.

Disorders of breathing related to sleep are relatively newly recognized and less than fully understood. This review presents the terminology used to describe them, and describes the physiology of sleep and the control of ventilation, the pathophysiology of breathing disorders during sleep, their various clinical manifestations, current diagnostic techniques, and the treatment modalities available at present. Among the diagnostic approaches discussed are airway fluoroscopy during sleep, pneumography, and polysomnography. Approaches to medical and surgical management of these disorders are reviewed. Speculation regarding the underestimation of the prevalence of these disorders, the male predominance, and their relationship to snoring, coronary artery disease, and hypertension, which also show male predominance, are presented. Also suggested is a relationship of sleep apnea, obesity, and mental retardation in childhood-onset or congenital disorders such as Down's syndrome and Prader-Willi syndrome, and in other endocrine dysfunction diseases.

Managed care and the cystic fibrosis patient.

Since the first published report of mortality in cystic fibrosis in 1969, the median survival among cystic fibrosis patients has risen from 14 to 31 years. The reasons for this improved survival are complex and include earlier diagnosis; improved control of pulmonary infection; aggressive nutritional intervention; and enhanced monitoring of patients in peer-reviewed, accredited centers for cystic fibrosis care, teaching, and research. Emphasis on the importance of research on changing and improved treatment has been effectively communicated to patients and families. As a result, a group of highly educated medical consumers has been created. During the last decade, another focus of rapid change has appeared, that of cost containment in the medical profession, creating the field of managed care. Practicing medical professionals perceive the need for reduction in excessive spending in medicine and have taken a variety of approaches to balance better the value and cost of medical care while maintaining superb quality. Physicians and consumers continue to have concerns about the potential negative impact of managed care on a relatively rare, specialized, and chronic illness such as cystic fibrosis if managed care concepts are applied without proper understanding of the disease. A great concern is that managed care in cystic fibrosis may cause reversal of trends in improved quality and length of survival. The increased length of survival places an increasing demand on the already stressed system of health care financing. Understanding the changing area of managed care is therefore of paramount importance to clinicians involved in cystic fibrosis care. The Cystic Fibrosis Foundation has presented symposia on managed care at each of the last three annual meetings, including the North American Cystic Fibrosis Meeting, October 1996. The following issues were addressed by speakers and panel discussants, with portions excerpted for this review: trends in managed care, measures and guidelines useful in managed care, Medicaid managed care and cystic fibrosis, and practical aspects of using pathways in caring for patients with cystic fibrosis.

The clinical spectrum of chronic appendiceal abscess in cystic fibrosis.

OBJECTIVE: To describe the varied characteristics seen in patients with cystic fibrosis who develop chronic abscess formation secondary to unrecognized appendicitis. DESIGN: Patient series. SETTING: Cystic Fibrosis Care Centers in Columbus, Ohio, and Tucson, Ariz. PARTICIPANTS: Five patients with cystic fibrosis who developed chronic abdominal abscesses secondary to occult appendicitis are described. Two patients developed fistula formation with purulent fluid drainage before diagnosis. One patient developed an extensive psoas abscess. Another presented with prolonged fever of unknown origin. These patients were identified by retrospective review of the past 20-year experience at two Cystic Fibrosis Care Centers. CONCLUSIONS: Development of chronic abdominal abscess related to unrecognized appendicitis is a rare but important complication in patients with cystic fibrosis. Prompt diagnosis depends on physician familiarity with the varied presentations of this entity. Diagnostic abdominal computed tomography and/or ultrasonography should particularly be considered when patients with cystic fibrosis present with pain, mass, or drainage from the right flank; prolonged fever; a limp; or failure of suspected meconium ileus equivalent syndrome to respond promptly to cathartic measures.

Elevated hepatic glucose production in children with cystic fibrosis.

We hypothesized that elevated hepatic glucose output (HGO) may occur in children with cystic fibrosis (CF) as an early sign of declining insulin secretion and that tolbutamide therapy would correct the defect. We studied eight glucose-tolerant CF patients (mean +/- SD, 9.1 +/- 1.9 y) and five healthy controls (9.0 +/- 1.6 y). Fasting glucose, insulin, and insulin-connecting peptide concentrations were not different in the CF and control subjects; however, meal stimulation tests in the CF patients suggested that insulin secretion was defective in the fed state. HGO (mg.kg-1 body weight.min-1) was 26% higher in the CF patients (4.2 +/- 0.7 versus 3.1 +/- 0.6 in HC) (p = 0.016). When normalized for fat-free mass (mg.kg fat-free mass-1.min-1), HGO was 27% higher in CF (4.9 +/- 0.8 versus 3.8 +/- 0.5) (p = 0.015). However, when expressed as a function of resting energy expenditure (mg.kcal-1), HGO was not significantly different in CF (121 +/- 22) versus healthy controls (116 +/- 30). In seven of the CF group, HGO was re-assessed after a 2-h glucose infusion at a rate of 0.90 +/- 0.02 mg.kg-1.min-1. HGO was suppressed (p < 0.05) by an amount equal to 103 +/- 18% of the glucose infusion rate. Finally, in five CF patients, HGO was re-measured after 2 wk of oral therapy with tolbutamide (750 mg/d). Tolbutamide did not affect HGO (fasting or during the glucose infusion). In conclusion, fasting HGO was elevated in the CF patients in proportion to energy expenditure.

Effects of tolbutamide on growth and body composition of nondiabetic children with cystic fibrosis.

Previously, we reported that nondiabetic children with cystic fibrosis show a blunted insulin response to a meal stimulus. In the study presented here, using tolbutamide, we determined the effects of augmented insulin secretion/action on height and lean body mass of children with cystic fibrosis. Twelve subjects (mean +/- SEM age, 11.0 +/- 0.5 y) were studied for three 4-mo periods: 1) pretreatment, 2) treatment, consisting of 750 mg/d of tolbutamide, and 3) posttreatment. Before the pretreatment period, insulin response to a meal stimulus was evaluated in relation to three doses of tolbutamide: 0, 250, and 500 mg. Growth was monitored during each period, and incremental changes in lean body mass were calculated from height data. To validate the change in lean body mass based on height measurements, we determined lean body mass in seven subjects during the treatment period by using a criterion method (H218O). Growth velocity (cm/4 mo) significantly increased (p less than 0.05) during the treatment (2.58 +/- 0.31) compared with the pretreatment period (0.88 +/- 0.20). The increase in lean body mass calculated from height was greater during the treatment (1.61 +/- 0.29 kg/4 mo) than during the pretreatment period (0.44 +/- 0.18 kg/4 mo) (p less than 0.05). There was also a significant increase (p less than 0.05) in lean body mass during the treatment as measured with H218O (1.91 +/- 0.65 kg/4 mo). Acute administration of either 250 or 500 mg of tolbutamide reduced (p less than 0.05) the area under the glucose concentration curve in response to a meal compared with the control condition of no tolbutamide.(ABSTRACT TRUNCATED AT 250 WORDS)

Recurrent deep venous thrombosis complicating PICC line placement in two patients with cystic fibrosis and activated protein C-resistance.

Two patients with cystic fibrosis and activated protein C-resistance experienced deep vein thrombosis complicating peripherally inserted central catheter (PICC) use. Cystic fibrosis patients may be at increased risk for catheter rotated thrombosis.

Splanchnic uptake of leucine in healthy children and in children with cystic fibrosis.

Interpretation of tracer studies of amino acid kinetics in the fed state is dependent on knowledge of splanchnic uptake of diet-derived amino acids. We studied five healthy control children and five children with cystic fibrosis (CF). After an overnight fast, the children ingested, hourly, a formula diet for 11 h. 5,5,5-[2H3]Leucine was added to the feedings during the last 6 h, and an i.v. infusion of 1-[13C]leucine was administered during the last 2 h of the formula feeding. The mean rate of splanchnic uptake of leucine was similar in the CF and control group, 23.8 +/- 24.0 and 21.5 +/- 21.2 mumol.kg-1.h-1, respectively. Fractional splanchnic uptake of leucine was not significantly different in the patients with CF (0.16 +/- 0.112 mean +/- SD) compared with the control children (0.244 +/- 0.256(-1)). The rate of whole body protein breakdown was not significantly different between the groups (CF versus control) with (159 +/- 18 versus 135 +/- 28 mumol.kg-1.h-1) or without (135 +/- 14 versus 114 +/- 20 mumol.kg-1.h-1) correction for splanchnic leucine uptake. However, for the 10 cases combined, protein breakdown corrected for splanchnic leucine uptake (147 +/- 26 mumol.kg-1.h-1) was 18% greater than uncorrected protein breakdown (124 +/- 20 mumol.kg-1.h-1) (p = 0.009). The data suggest that companion studies of splanchnic uptake might enhance the interpretation of leucine kinetics in the fed state.

Lungs in infants and young children: improved thin-section CT with a noninvasive controlled-ventilation technique--initial experience.

Three sedated young children underwent thin-section computed tomography (CT) of the chest while breathing and during controlled respiratory pauses induced by means of a step increase in positive-pressure ventilation applied via a face mask. Motion-free inspiratory and expiratory thin-section CT images were successfully acquired during 8-12-second respiratory pauses. This simple, reproducible technique produced thin-section CT images that were clearer and more clinically useful than those obtained during quiet tidal breathing.