Refining the continuum of CFTR-associated disorders in the era of newborn screening.

Clinical heterogeneity in cystic fibrosis (CF) often causes diagnostic uncertainty in infants without symptoms and in older patients with milder phenotypes. We performed a cross-sectional evaluation of a comprehensive set of clinical and laboratory descriptors in a physician-defined cohort (N = 376; Children's Hospital of Wisconsin and the American Family Children's Hospital CF centers in Milwaukee and Madison, WI, USA) to determine the robustness of categorizing CF (N = 300), cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (N = 19), and CFTR-related (CRMS) metabolic syndrome (N = 57) according to current consensus guidelines. Outcome measures included patient demographics, clinical measures, sweat chloride levels, CFTR genotype, age at diagnosis, airway microbiology, pancreatic function, infection, and nutritional status. The CF cohort had a significantly higher median sweat chloride level (105 mmol/l) than CFTR-related disorder patients (43 mmol/l) and CFTR-related metabolic syndrome patients (35 mmol/l; p ≤ 0.001). Patient groups significantly differed in pancreatic sufficiency, immunoreactive trypsinogen levels, sweat chloride values, genotype, and positive Pseudomonas aeruginosa cultures (p ≤ 0.001). An automated classification algorithm using recursive partitioning demonstrated concordance between physician diagnoses and consensus guidelines. Our analysis suggests that integrating clinical information with sweat chloride levels, CFTR genotype, and pancreatic sufficiency provides a context for continued longitudinal monitoring of patients for personalized and effective treatment.

Postexercise immune correlates in children with and without cystic fibrosis.

INTRODUCTION: Previous studies have shown that children with cystic fibrosis (CF) are capable of mounting a normal immune response after the stress of exercise. However, few data are available regarding the underlying mechanisms by which this immune modulation occurs. METHODS: In this study, lymphocyte and leukocyte cell counts were measured before and immediately after a single bout of exhaustive exercise in 25 children (ages 8-17 yr; 12 with CF and 13 healthy controls). Catecholamine, cortisol, and insulin levels, age, nutritional parameters, and static and dynamic lung function were measured as potential correlates for immune modulation. We hypothesized that catecholamine levels would be associated with the immune changes seen after exercise in children with CF. RESULTS: Our results demonstrated positive correlations between age and the change in cell counts after exercise for white blood cells (r = 0.44, P < 0.03), lymphocytes (r = 0.60, P < 0.002), monocytes (r = 0.43, P < 0.03), and CD3-CD16+CD56+ cells (r = 0.61, P < 0.002). Lower increases in the lymphocyte and CD3-CD16+CD56+ cells were observed in the CF group. Changes in pre- and post-exercise norepinephrine levels were weakly correlated with the changes in granulocyte, lymphocyte, and monocyte cell counts. Changes in cortisol levels correlated with lymphocyte and CD19+ cell count changes for the CF group but not for the healthy controls. Within the CF group, the severity of lung disease (as indicated by a FEV1) was negatively correlated with changes in lymphocyte (r = -0.66, P < 0.02) and CD3-CD16+CD56+ cell counts (r = -0.67, P < 0.02). CONCLUSION: The results suggest that postexercise changes in cell counts occur in an age dependent, norepinephrine associated manner. Disease severity for children with CF also appears to enhance the postexercise leukocytosis with pronounced increases seen in natural killer cells.

Immune modulation following aerobic exercise in children with cystic fibrosis.

Previous studies have demonstrated altered immune response following exercise in healthy adults and children. As data are lacking in children with cystic fibrosis, we evaluated the immune response following acute exercise and hypothesized that acute increases in cellular changes would be seen but would be blunted in subjects with CF. Leukocytes, lymphocytes, and their subsets as well as natural killer cell number and activity were determined before, immediately after, and one hour post exhaustive exercise in 15 children with cystic fibrosis (8-21 yrs, FEV1 69.5+/-18.0%, colonized with P aeruginosa) and 15 healthy controls (8-18 yrs, FEV1 107.5+/-10.7%). At baseline the cystic fibrosis group had greater leukocytes (9.25+/-2.83 vs. 5.17+/-0.96 x 10(9) cells/liter). Immediately post exercise, the cystic fibrosis group demonstrated increases in cell counts for leukocytes (32.4%), lymphocytes (61.8%), granulocytes (36.4%), monocytes (76.2%), and natural killer cells (315%). Similar percentage increases were seen in cell counts for the controls (leukocytes: 39.5%, lymphocytes: 78.5%, granulocytes: 32.0%, monocytes: 75.9%, and NK cells: 442%). Natural killer cell activity also increased by 57.9% in the group with cystic fibrosis and by 43.6% in the healthy controls. Except for elevated leukocyte and granulocyte counts, values returned to baseline at one hour post-exercise. In conclusion, the cellular immune response to acute exercise in children with mild to moderate cystic fibrosis appears normal.

Serum vascular endothelial growth factor is elevated in cystic fibrosis and decreases with treatment of acute pulmonary exacerbation.

Chronic bacterial infection and neutrophilic inflammation characterize cystic fibrosis (CF) pulmonary disease. In many disorders, inflammation and angiogenesis are codependent phenomena. We previously noted excessive angiogenesis in CF tissues and elevated vascular endothelial growth factor (VEGF) in random serum samples from subjects with CF. To further explore this finding, we measured serum VEGF in 38 subjects with stable CF and in 25 subjects with other pulmonary diseases. Mean VEGF was elevated in both groups compared with reference values, but it was higher in CF: 403 +/- 280 versus 255 +/- 169 pg/ml, p = 0.02. VEGF was negatively correlated with FEV(1) in CF, r = -0.51, p = 0.007. To assess the effect of airway infection on VEGF, 10 subjects with CF were studied before and after intravenous antibiotic therapy for pulmonary exacerbation. VEGF levels decreased with antibiotic therapy, from 537 +/- 220 to 259 +/- 176 pg/ml, p = 0.001. We conclude that circulating VEGF is increased in subjects with CF and other inflammatory pulmonary disorders. In CF, VEGF elevation is related to airway infection. We speculate that increased circulating VEGF is related to chronic inflammation, which is robust in CF. Elevated circulating VEGF may result in tissue angiogenesis, furthering the progression of pulmonary disease.

Energy metabolism during anaerobic exercise in children with cystic fibrosis and asthma.

PURPOSE: The nature of a child's daily physical activity requires both aerobic and anaerobic energy metabolism. Aerobic exercise becomes compromised with advancing airway obstruction in children with cystic fibrosis (CF) and asthma (AS). Whether children with CF will have altered metabolic responses to supramaximal exercise when compared with asthmatics or healthy controls is still undetermined. METHODS: Twenty-five children with CF, 22 with AS, and 23 healthy controls (CN) performed an incremental graded aerobic and Wingate anaerobic test (WAnT) on a cycle ergometer. Analysis of gas exchange and ventilatory data was collected and averaged every 5 s to estimate ventilatory kinetics and energy system contributions during both tests. RESULTS: The CF and AS groups had mild lower airway obstruction (FEF25-75% < 80%) as compared with the CN. All three groups demonstrated similar anaerobic (mean and peak power during the WAnT) and aerobic exercise performance (peak oxygen consumption). In contrast to the AS or CN groups, children with CF used a lower percentage of their peak VO2 and V(E) during each phase of the WAnT, suggesting a preferential use of ATP/phosphocreatine and glycolytic energy stores compared with aerobic pathways. Greater reliance on anaerobic pathways during the WAnT in children with CF could be due to the physiologic sequelae underlying chronic obstructive lung disease. CONCLUSIONS: Oxygen uptake kinetics appeared similar for all three groups. Although the energy needed to perform the WAnT can be met by subjects with CF, abnormalities in energy metabolism may exist for this group during exercise.

Parental attitudes about exercise regarding their children with cystic fibrosis.

Despite the well-recognized benefits of exercise on general health and pulmonary function, lack of participation in regular exercise remains a concern with respect to children with cystic fibrosis (CF). Data are lacking regarding parental perceptions about exercise in children and adolescents with CF. Sixty-nine parents of children with CF and 70 parents of healthy children completed the 'Exercise Benefits/Barrier Scale" self administered inventory. Fifteen additional items addressing exercise issues for people with CF were also included. Data were reported as total score, and subdivided into barriers and benefits scales for analysis. Data on the CF specific questions were also reported. Parents of children with CF scored lower on both the total score and benefits portion of the inventory and scored slightly greater on the barriers portion (p < .05) representing less favorable perception of the benefits of exercise along with increased barriers. The presence of a healthy child in addition to a child with CF appeared to increase both the total score and benefits score as well as resulting in a more positive outlook on exercise related uses in CF. It appears that significant differences in parental perceptions regarding exercise indeed exist not only when compared to healthy children but within varying intra-structures of families with a child who has CF.

Bronchopulmonary dysplasia. Impact of surfactant replacement therapy.

Bronchopulmonary dysplasia is a major contributor to the morbidity and mortality of infants born prematurely. Surfactant replacement therapy has had a significant impact on the death rate from respiratory distress syndrome, yet the impact on bronchopulmonary dysplasia is minimal. Despite these findings, the overall incidence and severity of bronchopulmonary dysplasia are likely to decline over time as neonatal care continues to advance.

High prevalence of allergic sensitization in children with habitual snoring and obstructive sleep apnea.

STUDY OBJECTIVE: To determine whether allergic sensitization occurs frequently in children with habitual snoring and whether allergy predicts the occurrence of obstructive sleep apnea syndrome (OSAS) in snoring children. DESIGN: Prospective study of 39 children with habitual snoring who were referred for polysomnography. SETTING: Pediatric pulmonary sleep disorders clinic in a tertiary referral center. MEASUREMENTS: Subjects underwent a complete history and physical examination. To assess for the presence of allergic sensitization, a multiantigen radioallergosorbent test (RAST) was performed on serum samples. Subjects then underwent nocturnal polysomnography to determine the presence and severity of OSAS. RESULTS: Fourteen subjects (36%) demonstrated sensitivity to allergens; this is higher than expected for the general pediatric population. The frequency of OSAS was increased in subjects with positive RAST results compared to those with negative RAST results (57% vs 40%; chi 2 = 9.11; p < 0.01). CONCLUSION: Allergy is frequently present in pediatric patients with habitual snoring. Furthermore, the presence of allergy is associated with an increased risk of OSAS in this population.

Polysomnography after adenotonsillectomy in mild pediatric obstructive sleep apnea.

OBJECTIVES: a) To determine the need for intensive monitoring on the first operative night of surgery in children undergoing adenotonsillectomy for mild obstructive sleep apnea; b) to examine the effect of narcotics on postoperative obstructive sleep apnea. DESIGN: Randomized, prospective study. SETTING: University hospital. PATIENTS: Children, ranging in age between 1 and 18 yrs, presented to the Pediatric Otolaryngology Clinic for adenotonsillectomy for mild obstructive sleep apnea defined as from one to 15 obstructive apnea events per hour on preoperative polysomnogram. INTERVENTIONS: Patients were assigned to receive either a narcotic- or a halothane-based anesthetic for adenotonsillectomy. A postoperative polysomnogram was performed in the pediatric intensive care unit on the first operative night. MEASUREMENTS AND MAIN RESULTS: Eighteen patients were recruited, 15 of whom met inclusion criteria: nine patients received a halothane-based anesthetic and six patients received a fentanyl-based anesthetic. When the data were analyzed by pooling both groups, the differences between pre- and postoperative sleep studies demonstrated a reduction in the number of obstructive events and less severe oxygen desaturations on the operative night. Total sleep time between the two sleep studies decreased from 371 +/- 13 to 304 +/- 14 mins. The number of obstructive apnea events/hr decreased as well. The lowest oxygen saturation measured during rapid eye movement sleep was 78 +/- 5% preoperatively and 92 +/- 1% postoperatively. CONCLUSIONS: Our data suggest that children without underlying medical conditions, neuromotor diseases, or carniofacial abnormalities, 1 to 18 yrs of age, who suffer from mild obstructive sleep apnea, have improvements documented by polysomnography on the night of surgery following adenotonsillectomy and do not necessarily need to be monitored intensively. These findings were not significantly affected by the choice of intraoperative anesthetic.

Polysomnography in the evaluation of readiness for decannulation in children.

OBJECTIVE: To determine whether polysomnography is useful in the evaluation of readiness for decannulation in children with long-term tracheotomy. DESIGN: Descriptive, retrospective case series. SETTING: Tertiary care pediatric center, pediatric sleep disorders laboratory, and pediatric otolaryngology referral center. PATIENTS: Children (younger than 18 years) with tracheotomy undergoing polysomnography to assess their dependence on tracheotomy. INTERVENTION: Polysomnography in all patients; endoscopy and decannulation in those judged clinically ready. MAIN OUTCOME MEASURES: Success of decannulation. RESULTS: Thirteen of 16 patients with favorable polysomnographic data were successfully decannulated. CONCLUSION: Polysomnography is a useful supplement to airway endoscopy in the evaluation of readiness for decannulation in children with long-term tracheotomy and dynamic airway issues.

Immune response to influenza vaccination in children with renal disease.

Although immunization with influenza vaccine is recommended for children with chronic renal disease and after organ transplantation, the antibody response in these children has not been well described. We studied the response to the 1993-1994 trivalent influenza vaccine in children, aged 1-21 years, with chronic renal failure (n = 15), end-stage renal disease requiring dialysis (n = 10), and post renal transplantation (n = 17). Each group's antibody response was compared with that of a control group (n = 7). No significant differences were found in seroconversion rates, percentage of patients achieving protective hemagglutination-inhibition titers post vaccination or change in geometric mean titers from pre to post vaccination between study groups and controls. These results suggest that pediatric patients with renal disease will respond and therefore will benefit from currently recommended influenza immunization.

Inability of clinical history to distinguish primary snoring from obstructive sleep apnea syndrome in children.

STUDY OBJECTIVE: To determine whether primary snoring (PS) could be distinguished from childhood obstructive sleep apnea syndrome (OSAS) by clinical history. DESIGN: Retrospective study of clinical history of 83 children with snoring and/or sleep disordered breathing who were referred for polysomnography. SETTING: Tertiary referral center; pediatric pulmonary sleep apnea clinic. MEASUREMENTS: We evaluated the ability of a clinical obstructive sleep apnea (OSA) score and other questions about sleep, breathing, and daytime symptoms to distinguish PS from OSAS in children. Parents were asked about the child's snoring, difficulty breathing, observed apnea, cyanosis, struggling to breathe, shaking the child to "make him or her breathe," watching the child sleep, afraid of apnea, the frequency and loudness of snoring, and daytime symptoms such as excessive daytime sleepiness (EDS). RESULTS: Based on polysomnography results, 48 patients were classified as PS and 35 as OSAS. Peak endtidal CO2 (49 +/- 3.2 vs 55 +/- 8.2 [SD] mm Hg); lowest arterial oxygen saturation measured by pulse oximetry (95 +/- 1.9 vs 82 +/- 14%); and apnea/hypopnea index (0.27 +/- .3 vs 8.4 +/- 6 events/h) indicated that the diagnostic criteria for PS versus OSA were reasonable. There were no differences between PS and OSA patients with respect to age, sex, race, failure to thrive, obesity, history of EDS, snoring history, history of cyanosis during sleep, or daytime symptoms except for mouth breathing. There were no significant differences in sleep variables between PS patients and those with any severity of OSAS. The OSA score misclassified about one of four patients. Comparing PS and OSA patients, significant findings were daytime mouth breathing (61 vs 85%; p = 0.024); observed apnea (46 vs 74%; p = 0.013); shaking the child (31 vs. 60%; p = 0.01); struggling to breathe (58 vs 89%; p = 0.003); and afraid of apnea (71 vs 91%; p = 0.028). However, none of these were sufficiently discriminatory to predict OSAS. CONCLUSION: We conclude that PS in children cannot be reliably distinguished from OSAS by clinical history alone.

Polysomnographic characteristics of patients with Rett syndrome.

During wakefulness, patients with Rett syndrome have disordered breathing. To understand further this ventilatory control disorder, we performed polysomnography in 30 patients with Rett syndrome and 30 control subjects (female subjects with primary snoring). The median age was 7 years (range, 1 to 32 years) for Rett syndrome and 6 years (range, 1 to 17 years) for control subjects. During periods of wakefulness, 67% of patients with Rett syndrome had the characteristic pattern of disordered breathing (i.e., episodes of hyperventilation followed by central apnea and desaturation). No such events occurred during sleep. Sleep efficiency and sleep architecture were similar for both groups. During sleep, there was no difference in duration of periodic breathing, number of episodes of central apnea with desaturation, or number of episodes of obstructive apnea or end-tidal carbon dioxide tension between the two groups. Although arterial oxygen saturation during rapid eye movement (REM) sleep was slightly lower in patients with Rett syndrome (nadir, 94% +/- 2% vs 96% +/- 2%), it remained within the normal range. Parental history reflected the awake respiratory findings in most cases. We conclude that patients with Rett syndrome have normal breathing during non-rapid eye movement (NREM) sleep. We speculate that patients with Rett syndrome have normal brain-stem control of ventilation, and that the disordered breathing seen during wakefulness is due to an abnormality of the cortical influence on ventilation.

Upper airway collapsibility in children with obstructive sleep apnea syndrome.

In adults, the critical nasal pressure (Pcrit) at which the upper airway collapses is higher in patients with the obstructive sleep apnea syndrome (OSAS) than in those with primary snoring. Pediatric OSAS differs clinically from adult OSAS. We therefore compared Pcrit between prepubertal children with OSAS and primary snoring. Pcrit was determined by correlating the maximal inspiratory airflow with the level of positive or negative nasal pressure applied via a nasal mask. As in adults, we found that the maximal inspiratory airflow varied in proportion to the upstream (nasal) rather than the downstream (esophageal) pressure changes. Pcrit was 1 +/- 3 cmH2O in OSAS compared with -20 +/- 9 cmH2O in primary snorers (P < 0.002). In three OSAS patients reevaluated after tonsillectomy and adenoidectomy, Pcrit declined to -7.2 +/- 4.0 cmH2O. We conclude that the pediatric airway behaved as predicted by the Starling resistor model and that Pcrit, a measure of airway collapsibility, correlated with the degree of upper airway obstruction and was reduced postoperatively, consistent with increased upper airway stability.

Respiratory compromise after adenotonsillectomy in children with obstructive sleep apnea.

A retrospective study of pediatric patients with obstructive sleep apnea who underwent adenotonsillectomy between 1987 and 1990 was undertaken to determine the frequency of postoperative respiratory compromise and to determine if risk factors for its development could be identified. Sixty-nine patients less than 18 years old had polysomnographically documented obstructive sleep apnea and were observed postoperatively in the pediatric intensive care unit. Of these, 16 (23%) had severe respiratory compromise, defined as intermittent or continuous oxygen saturation of 70% or less, and/or hypercapnia, requiring intervention. Compared with patients without respiratory compromise, these patients were younger (3.4 +/- 4 vs 6.1 +/- 4 years) and had more obstructive events per hour of sleep on the polysomnogram (49 +/- 41 vs 19 +/- 30). They were more likely to weight less than the fifth percentile for age (odds ratio [OR], 5.1; 95% confidence interval [CI], 1.4 to 18.7), to have an abnormal electrocardiogram and/or echocardiogram (OR, 4.5; 95% CI, 1.3 to 15.1), and to have a craniofacial abnormality (OR, 6.2; 95% CI, 1.5 to 26). Multiple logistic regression analysis revealed the most significant risk factors were age below 3 years and an obstructive event index greater than 10. Children with obstructive sleep apnea are at risk for respiratory compromise following adenotonsillectomy; young age and severe sleep-related upper airway obstruction significantly increase this risk. We recommend in-hospital postoperative monitoring for children undergoing adenotonsillectomy for obstructive sleep apnea.

Differences in expression of cystic fibrosis in blacks and whites.

The recent identification of the cystic fibrosis (CF) gene confirms that genetic heterogeneity occurs in CF. A three-base-pair deletion in exon 10 resulting in a loss of the phenylalanine residue at amino acid position 508 of the gene product, termed the CF conductance regulator protein, accounts for 70% of cases of CF in white subjects. However, this gene defect occurs in only 37% of affected blacks. Analysis of CF genes from American blacks has revealed a number of mutations, most of which are unique to that population. We therefore searched for potential differences in expression of CF between 24 black and 48 white patients with CF matched for birth date and gender. Black patients more frequently presented with only respiratory symptoms (38% vs 10%). Black patients had fewer hospitalizations for pulmonary exacerbations (2 vs 6.9), a better mean forced vital capacity (77% vs 62% of predicted), and higher chest roentgenogram scores (18.2 vs 14.4) than white patients. Complication rates were similar except for a higher incidence of hyponatremic dehydration (21% vs 2%) and peptic ulcer disease (13% vs 0%) in blacks. Survival time appeared to be longer in blacks, but the difference was not statistically significant. We conclude that phenotypic differences exist between black and white patients with CF, which may be due to the genetic heterogeneity between these two populations.