Sleep disordered breathing in patients with Prader-Willi syndrome: A multicenter study.

OBJECTIVES: Sleep disordered breathing (SDB) is common in patients with Prader-Willi syndrome (PWS) and systematic screening is recommended, especially before growth hormone treatment. The aim of the study was to describe the baseline SDB and therapeutic interventions in a large cohort of patients. STUDY DESIGN: Retrospective study. SUBJECT SELECTION: Eighty-eight patients with PWS, median [interquartile range] age of 5.1 [1.0-14.5] years old (range 0.3-44.3), who were followed in three centers (France, Italy). METHODOLOGY: Anthropometrics, polygraphy (PG), and gas exchange data were analyzed. RESULTS: Median body mass index (BMI) was 20 [16-34] kg/m(2), BMI z-score for patients aged 2-20 years old was 2.1 [1.2-2.8] SD, mixed-obstructive apnea-hypopnea index (MOAHI) 1.8 [0.6-5.0] events/hr, and central apnea index (CAI) 0.1 [0.0-0.6] events/hr. Minimum pulse oximetry (SpO2) was 88 [84-91]%, percentage of time with SpO2 <90% 0.1 [0.0-1.0]%, and oxygen desaturation index 2 [1-4]/hr. An apnea-hypopnea index (AHI) ≥ 1.5 and ≥ 5 events/hr was observed in 53% of children and 41% of adults, respectively. No correlations were observed between MOAHI and anthropometrics data (age, BMI, BMI z-score), while MOAHI significantly correlated with SpO2 indexes. Age and BMI only weakly correlated with SpO2 indexes. Growth hormone could be initiated in 48 patients. Regarding post-PG therapy, 9 patients had upper airway surgery, and noninvasive CPAP/bilevel ventilation was started in 16 patients. CONCLUSIONS: Patients with PWS exhibit a high prevalence of SDB. The lack of association between obesity and SDB leads to hypothesize that hypotonia and/or facial dysmorphic features may play a major role in the occurrence of SDB.

Primary ciliary dyskinesia presentation in 60 children according to ciliary ultrastructure.

Primary ciliary dyskinesia (PCD) is an inherited disease related to ciliary dysfunction, with heterogeneity in clinical presentation and in ciliary ultrastructural defect. Our study intended to determine if there are phenotypic differences in patients with PCD based on ciliary ultrastructural abnormality. In this retrospective study carried out among 60 children with a definitive diagnosis of PCD, we analyzed clinical, radiological, and functional features at diagnosis and at last recorded visit, according to cilia defect (absence of dynein arms: DAD group, n = 36; abnormalities of the central complex: CCA group, n = 24). Onset of respiratory symptoms occurred later in the CCA than in the DAD group (9.5 versus 0.5 months, p = 0.03). Situs inversus was only observed in the DAD group, while respiratory disease in siblings were more frequent in the CCA group (p = 0.003). At diagnosis, clinical presentation was more severe in the CCA group: frequency of respiratory tract infections (p = 0.008), rhinosinusitis (p = 0.02), otitis complications (p = 0.0001), bilateral bronchiectasis (p = 0.04), and number of hypoxemic patients (p = 0.03). Pulmonary function remained stable in both groups, but outcome was better in the CCA than in the DAD group: less antibiotic therapy and hypoxemic patients (p = 0.004). In conclusion, our results underlined the relationship between the severity of clinical presentation and the ultrastructural ciliary defect.

Lung function, diagnosis, and treatment of sleep-disordered breathing in children with achondroplasia.

Children with achondroplasia are at risk of sleep-disordered breathing. The aim of the study was to evaluate lung function and sleep-disordered breathing in children with achondroplasia. An interview, clinical examination, lung function tests with blood gases, and a polygraphic sleep study were obtained as part of routine annual evaluation in consecutive children with achondroplasia. We included 30 children (median age 3.0 years, range: 0.4-17.1) over a period of 21 months. Habitual snoring and witnessed apneas were observed in 77% and 33% of the patients, respectively. Prior to the sleep study, 10/29 (34%) patients had undergone upper airway surgery and 5/29 (17%) craniocervical decompression operation. Arterial blood gases were abnormal in two (7%) patients. Sleep findings were abnormal in 28/30 (93%) patients. Eleven (37%) patients had an apnea index≥1 event/hr and 26 (87%) had an apnea-hypopnea index≥5 events/hr. The ≥3% desaturation index was >5/hr in 22 (73%) patients. Sixteen (53%) patients had a minimal pulse oximetry<90% but only two (7%) patients had a maximal transcutaneous carbon dioxide pressure>50 mmHg during sleep. As a consequence, the following therapeutic interventions were performed: upper airway surgery in four patients and noninvasive positive pressure ventilation (NPPV) in five other patients, resulting in an improvement in sleep studies in all nine patients. Systematic sleep studies are recommended in children with achondroplasia because of the high prevalence of sleep-disordered breathing. Upper airway surgery and NPPV are effective treatments of sleep-disordered breathing.

Genetic variations in inflammatory mediators influence lung disease progression in cystic fibrosis.

The clinical course of cystic fibrosis (CF) varies considerably among patients carrying the same CF-causing gene mutation. Additional genetic modifiers may contribute to this variability. As airway inflammation is a key component of CF pathophysiology, we investigated whether major cytokine variants represent such modifiers in young CF patients. We tested 13 polymorphisms in 8 genes that play a key role in the inflammatory response: tumor necrosis factor, lymphotoxin alpha, interleukin (IL) 1B, IL1 receptor antagonist, IL6, IL8, IL10 and transforming growth factor beta 1 (TGFB1), for an association with lung disease progression and nutritional status in 329 CF patients. Variants in the TGFB1 gene at position +869T/C demonstrated a significant association with lung function decline. A less pronounced rate of decline in forced expiratory volume in 1 sec (FEV(1)) and forced vital capacity (FVC) were observed in patients heterozygous for TGFB1 +869 (+869CT), when compared to patients carrying either TGFB1 +869TT or +869CC genotypes. These findings support the concept that TGFB1 gene variants appear to be important genetic modifiers of lung disease progression in CF.

Mechanical limitation during CO2 rebreathing in young patients with cystic fibrosis.

The aim of the study was to determine whether a decrease in the ventilatory response to carbon dioxide (CO2) in children with cystic fibrosis (CF) is related to a mechanical limitation of the respiratory muscle capacity. The ventilatory response during CO2 rebreathing was performed in 15 patients (mean forced expiratory volume in 1 s (FEV1): 37 +/- 21% predicted, mean arterial CO2: 41+/- 5 mmHg). The slope of the minute ventilation normalised for weight per mmHg CO2 increment correlated negatively with respiratory muscle output, assessed by the oesophageal (p = 0.002), the diaphragmatic pressure time product (p = 0.01), and the tension time index (p = 0.005). In addition, this slope was correlated with dynamic lung compliance (p < 0.0001) and FEV1 (p = 0.03) but not with airway resistance and maximal transdiaphragmatic pressure. Therefore, an excessive load imposed on the respiratory muscles explains the blunting of the ventilatory response to CO2 in young patients with CF.

Influence of interleukin-10 on Aspergillus fumigatus infection in patients with cystic fibrosis.

Recent evidence suggests that genetic polymorphisms that affect the production of interleukin (IL)-10 may play a role in the response to pathogens in cystic fibrosis (CF). The present study was designed to investigate a possible association between alleles carried at position -1082 in the promoter region of the IL-10 gene and clinical data on 378 patients with CF. After adjustment for potential confounding variables, a significant relationship was found between the -1082GG genotype and both colonization with Aspergillus fumigatus and allergic bronchopulmonary aspergillosis. In addition, higher serum levels of IL-10 were observed in patients colonized with A. fumigatus. These results suggest that polymorphisms in the promoter region of the IL-10 gene may influence the host response to A. fumigatus in the context of CF.

Burkholderia cepacia is associated with pulmonary hypertension and increased mortality among cystic fibrosis patients.

The aim of the study was to evaluate the impact of Burkholderia cepacia on cardiovascular status and mortality in cystic fibrosis. Seven patients infected with B. cepacia were matched with 31 patients not infected with this organism for gender, age, height, weight, genotype, and percent predicted forced expiratory volume in one second, partial arterial oxygen pressure, and pancreatic sufficiency status. The pulmonary artery systolic pressure, as assessed by transthoracic echocardiography, was significantly higher in patients infected with B. cepacia (61.3 +/- 17.2 mm Hg) than in controls (37.3 +/- 13.9 mm Hg; P = 0.02), and the mean acceleration time was significantly lower (77 +/- 33 ms versus 108 +/- 25 ms; P = 0.02). The 6-month mortality was significantly higher in patients infected with B. cepacia (57% versus 16%; P = 0.02). Six of the seven patients infected with B. cepacia harbored the same ribotype (genomovar II, B. multivorans). Pulmonary hypertension was significantly more frequent in patients infected by B. cepacia and could contribute to the increased mortality rate.

Nutritional status is an important predictor of diaphragm strength in young patients with cystic fibrosis.

BACKGROUND: The effect of nutritional status and lung disease progression on diaphragm strength in young patients with cystic fibrosis remains unclear. OBJECTIVE: The aim of this study was to investigate the effect of nutritional status and airway obstruction on diaphragm strength. DESIGN: Twitch transdiaphragmatic pressure (Tw Pdi) obtained by bilateral anterior magnetic phrenic nerve stimulation, body mass index (BMI) z score, fat mass, fat-free mass (FFM), arm muscle circumference (AMC), forced expiratory volume in 1 s (FEV(1)), and functional residual capacity (FRC) were measured in 20 patients aged 15.1 +/- 2.8 y (x +/- SD). Values were expressed as a percentage of predicted values. RESULTS: Mean (+/-SD) Tw Pdi was 24.3 +/- 5.5 cm H(2)O. Univariate regression analysis showed positive correlations between Tw Pdi and nutrition scores (BMI z score: r = 0.63, P = 0.003; FFM: r = 0.47, P = 0.04; AMC: r = 0.45, P = 0.04), airway obstruction (FEV(1): r = 0.68, P = 0.001), and arterial oxygen partial pressure (r = 0.68, P = 0.001). Negative correlations were observed between Tw Pdi and dynamic hyperinflation (FRC: r = -0.65, P = 0.005) and arterial carbon dioxide pressure (r = -0.50, P = 0.03). Furthermore, stepwise regression analysis showed that Tw Pdi correlated with BMI z score (r = 0.75, P = 0.0002) and FEV(1) (r = 0.69, P = 0.001). CONCLUSIONS: Diaphragm strength is relatively well preserved in young patients with cystic fibrosis. However, the strength of the diaphragm decreases with the progression of malnutrition and airway obstruction.

Glutathione-S-transferase M1, M3, P1 and T1 polymorphisms and severity of lung disease in children with cystic fibrosis.

OBJECTIVES: Progression and severity of lung disease differs markedly and early between patients with cystic fibrosis (CF). We investigated the hypothesis that polymorphisms in the detoxifying enzymes glutathione-S-transferase (GST) could influence phenotypic presentation of lung disease in CF. METHODS: Genotypes for GSTM1, GSTM3, GSTP1 and GSTT1 were determined in a cohort of 146 children with CF by PCR-based methods. Pulmonary function, assessed by spirometric measures of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), was analysed in children at the age of 9. RESULTS: No association between spirometric measurements, and GSTM1, GSTP1 or GSTT1 genotypes was found. As compared with patients homozygous for GSTM3*A allele, CF children carrying the GSTM3*B allele displayed a significant better lung function, assessed by both mean values of FEV1 and of FVC (respectively P = 0.01 and P = 0.002). These correlations remained significant after adjustment for potential confounding factors (respectively adjusted P = 0.008 and P = 0.002) and also in subgroups of CF patients who carry the deltaF508 CFTR mutation. Haplotype analysis of GSTM3 in combination with GSTM1 indicated that the positive impact of GSTM3*B allele on pulmonary performances was barely influenced by the GSTM1 genotypes of CF children. CONCLUSIONS: These data provide the first evidence suggesting that polymorphism of the GSTM3 gene contributes to clinical severity in CF, which may have prognostic significance and could prompt to start a more targeted therapy in young patients with CF.

Distinct cytokine production by lung and blood neutrophils from children with cystic fibrosis.

Inflammation plays a critical role in lung disease progression in cystic fibrosis (CF). This inflammatory process is dominated by a neutrophil influx in the airways. To determine whether the accumulation of neutrophils in the airways of CF patients is associated with an altered function, we analyzed the capacity of neutrophils isolated from the lung compartment and the blood to release the major neutrophil pro- and anti-inflammatory cytokines IL-8 and IL-1-receptor antagonist (ra) spontaneously and in the presence of LPS. Comparison of cytokine production by blood neutrophils from CF patients and from control subjects showed significantly increased IL-8 and decreased IL-1ra release by CF neutrophils. Comparison of cytokine production by airway and blood neutrophils from CF patients also documented distinct profiles: the spontaneous release of IL-8 and IL-1ra by airway neutrophils was significantly higher than that from blood neutrophils. Culture in the presence of LPS failed to further enhance cytokine production. Analysis of the effect of dexamethasone confirmed the difference in the responsiveness of lung and blood neutrophils in CF. Used at a concentration effective in reducing IL-8 production by blood neutrophils, dexamethasone (10(-6) M) was unable to repress secretion of IL-8 by airway neutrophils. In addition, comparison of cytokine production by airway neutrophils from children with CF and children with dyskinetic cilia syndrome also documented distinct profiles of secretion. These results are consistent with a dysregulated cytokine production by lung and blood neutrophils in CF. They provide support to the hypothesis that not only the CF genotype but also the local environment may modify the functional properties of the neutrophils.

Pulmonary function tests in preschool children with cystic fibrosis.

Pulmonary function tests have rarely been assessed in preschool children with cystic fibrosis (CF). The objective of this multicenter study was to compare pulmonary function in 39 preschool children with CF (height, 90-130 cm; 16 homozygous Delta F508) and in 79 healthy control children. Functional residual capacity (helium dilution technique) and expiratory interrupter resistance (Rint(exp)) (interrupter technique) were measured. As compared with control children, children with CF had significantly higher Rint(exp), expressed as absolute values and as Z-scores (1.05 +/- 0.36 versus 0.80 +/- 0.20 kPa.L(-1). second, p < 0.0001; and 1.31 +/- 1.72 versus 0.19 +/- 0.97, p < 0.0001), and significantly lower specific expiratory interrupter conductance (1.29 +/- 0.34 versus 1.63 +/- 0.43 kPa(-1). second, p < 0.0001). The effect of the bronchodilator salbutamol on Rint(exp) was not significantly different between children with CF and control children. Rint(exp) Z-scores were significantly higher in children with CF who were exposed to passive smoke (n = 8) (p < 0.03). Children with CF and with a history of respiratory symptoms (n = 31) had significantly higher functional residual capacity Z-scores (p < 0.02) and lower specific expiratory interrupter conductance Z-scores (p < 0.04). Genotype did not influence the data. We conclude that Rint(exp) and functional residual capacity measurements may help to follow young children with CF who are unable to perform reproducible forced expiratory maneuvers.

Changes in pulmonary mechanics with increasing disease severity in children and young adults with cystic fibrosis.

As forced expiratory volume in 1 second (FEV(1)) is a major predictor of outcome in patients with cystic fibrosis (CF), we investigated the effect of FEV(1) on pulmonary mechanics in children and young adults with CF. We measured respiratory rate; tidal volume; minute ventilation; arterial blood gases; sniff esophageal pressure; dynamic lung compliance; total pulmonary resistance; intrinsic positive end expiratory pressure; and total, elastic, and resistive work of breathing in 32 patients (FEV(1) range: 12-49% predicted). We observed correlations between FEV(1) and Pa(O(2)) (r = 0.76, p < 0.0001) and Pa(CO(2)) (r = -0.70, p < 0.0001), FEV(1) and respiratory rate/tidal volume (r = -0.41, p = 0.02), FEV(1) and dynamic lung compliance (r = 0.64, p < 0.0001), and FEV(1) and total work of breathing (r = -0.52, p = 0.002) and elastic work of breathing (r = -0.60. p = 0.0003). No correlations were observed between FEV(1) and sniff esophageal pressure (p = 0.5), minute ventilation (p = 0.9), total pulmonary resistance (p = 0.3), intrinsic positive end expiratory pressure (p = 0.3), or resistive work of breathing (p = 0.1). As FEV(1) declines in children and young adults with CF, there is an increase in the elastic load and work of breathing, resulting in a rapid shallow breathing pattern, that is associated with further impairment of gas exchange.