Exercise-Induced Pulmonary Hypertension in Long-Term Survivors of Congenital Diaphragmatic Hernia.

OBJECTIVE: To determine the prevalence of exercise-induced pulmonary hypertension (PH) among long-survivors of congenital diaphragmatic hernia repair. STUDY DESIGN: This is a single-center, retrospective cohort study of CDH survivors who underwent exercise stress echocardiography (ESE) at Boston Children's Hospital from January 2006 to June 2020. PH severity was assessed by echocardiogram at baseline and after exercise. Patients were categorized by right ventricular systolic pressure (RVSP) after exercise: Group 1 - no or mild PH; and Group 2 - moderate or severe PH (RVSP ≥ 60 mmHg or ≥ ½ systemic blood pressure). RESULTS: Eighty-four patients with CDH underwent 173 ESE with median age 8.1 (4.8 - 19.1) years at first ESE. Sixty-four patients were classified as Group 1, 11 as Group 2, and 9 had indeterminate RVSP with ESE. Moderate to severe PH after exercise was found in 8 (10%) patients with no or mild PH at rest. Exercise-induced PH was associated with larger CDH defect size, patch repair, use of ECMO, supplemental oxygen at discharge, and higher WHO functional class. Higher VE/VCO2 slope, lower peak oxygen saturation, and lower percent predicted FEV1, and FEV1/FVC ratio were associated with Group 2 classification. ESE changed management in 9/11 Group 2 patients. PH was confirmed in all 5 Group 2 patients undergoing cardiac catheterization after ESE. CONCLUSIONS: Among long-term CDH survivors, 10% had moderate-severe exercise-induced PH on ESE, indicating ongoing pulmonary vascular abnormalities. Further studies are needed to optimally define PH screening and treatment for patients with repaired CDH.

Number of children in the household influences respiratory morbidities in children with bronchopulmonary dysplasia in the outpatient setting.

BACKGROUND: Bronchopulmonary dysplasia (BPD), a common complication of prematurity, is associated with outpatient morbidities, including respiratory exacerbations. Daycare attendance is associated with increased rates of acute and chronic morbidities in children with BPD. We sought to determine if additional children in the household conferred similar risks for children with BPD. METHODS: The number of children in the household and clinical outcomes were obtained via validated instruments for 933 subjects recruited from 13 BPD specialty clinics in the United States. Clustered logistic regression models were used to test for associations. RESULTS: The mean gestational age of the study population was 26.5 ± 2.2 weeks and most subjects (69.1%) had severe BPD. The mean number of children in households (including the subject) was 2.1 ± 1.3 children. Each additional child in the household was associated with a 13% increased risk for hospital admission, 13% increased risk for antibiotic use for respiratory illnesses, 10% increased risk for coughing/wheezing/shortness of breath, 14% increased risk for nighttime symptoms, and 18% increased risk for rescue medication use. Additional analyses found that the increased risks were most prominent when there were three or more other children in the household. CONCLUSIONS: We observed that additional children in the household were a risk factor for adverse respiratory outcomes. We speculate that secondary person-to-person transmission of respiratory viral infections drives this finding. While this risk factor is not easily modified, measures do exist to mitigate this disease burden. Further studies are needed to define best practices for mitigating this risk associated with household viral transmission.

Pre-Flight Hypoxemia Challenge Testing in Bronchopulmonary Dysplasia.

BACKGROUND AND OBJECTIVES: Former premature infants with bronchopulmonary dysplasia (BPD) are at risk for hypoxemia during air travel, but it is unclear until what age. We aimed to determine pass rates for high altitude simulation testing (HAST) by age in children with BPD and identify risks for failure. METHODS: Retrospective, observational analysis of HAST in children with BPD at Boston Children's Hospital, using interval censoring to estimate the time-to-event curve of first pass. Curves were stratified by neonatal risk factors. Pass was considered lowest Spo2 ≥ 90%, or ≥94% for subjects with ongoing pulmonary hypertension (PH). RESULTS: Ninety four HAST studies were analyzed from 63 BPD subjects; 59 studies (63%) were passed. At 3 months corrected gestational age (CGA), 50% of subjects had passed; at 6 months CGA, 67% has passed; at 12 and 18 months CGA, 72% had passed; and at 24 months CGA, 85% had passed. Neonatal factors associated with delayed time-to-pass included postnatal corticosteroid use, respiratory support at NICU discharge, and tracheostomy. BPD infants who did not require respiratory support at 36 weeks were likely to pass (91%) at 6 months CGA. At 24 months, children least likely to pass included those with a history of PH (63%) and those discharged from the NICU with oxygen or respiratory support (71%). CONCLUSIONS: Children with BPD on respiratory support at 36 weeks should be considered for preflight hypoxemia challenges through at least 24 months CGA, and longer if they had PH or went home from NICU on respiratory support.

Validation of an outpatient questionnaire for bronchopulmonary dysplasia control.

INTRODUCTION: Despite bronchopulmonary dysplasia (BPD) being a common morbidity of preterm birth, there is no validated objective tool to assess outpatient respiratory symptom control for clinical and research purposes. METHODS: Data were obtained from 1049 preterm infants and children seen in outpatient BPD clinics of 13 US tertiary care centers from 2018 to 2022. A new standardized instrument was modified from an asthma control test questionnaire and administered at the time of clinic visits. External measures of acute care use were also collected. The questionnaire for BPD control was validated in the entire population and selected subgroups using standard methodology for internal reliability, construct validity, and discriminative properties. RESULTS: Based on the scores from BPD control questionnaire, the majority of caregivers (86.2%) felt their child's symptoms were under control, which did not differ by BPD severity (p = 0.30) or a history of pulmonary hypertension (p = 0.42). Across the entire population and selected subgroups, the BPD control questionnaire was internally reliable, suggestive of construct validity (albeit correlation coefficients were -0.2 to -0.4.), and discriminated control well. Control categories (controlled, partially controlled, and uncontrolled) were also predictive of sick visits, emergency department visits, and hospital readmissions. CONCLUSION: Our study provides a tool for assessing respiratory control in children with BPD for clinical care and research studies. Further work is needed to identify modifiable predictors of disease control and link scores from the BPD control questionnaire to other measures of respiratory health such as lung function testing.

Impact of bowel rotation and fixation on obstructive complications in congenital diaphragmatic hernia.

AIM OF THE STUDY: Small bowel obstruction (SBO) is a known complication after congenital diaphragmatic hernia (CDH) repair, which can require surgery and even extensive bowel resection causing short bowel syndrome (SBS). We investigate whether specific bowel rotation and fixation can be used as a predictor for SBO including volvulus. METHODS: A retrospective review of 256 CDH survivors following repair from 2003 to 2020 was performed. Operative notes and upper gastrointestinal series (UGI) were screened to determine the rotation and fixation of the bowel. Primary outcomes included SBO occurrence, SBO treated surgically, and volvulus. For statistical analysis Fisher's exact test was utilized. RESULTS: Twenty-two (9%) patients presented with SBO and majority, 19 (86%), required surgery. Adhesion were observed in 10 (45%), recurrence in 5 (23%), and extensive volvulus leading to SBS in 3 (14%). Both rotation and fixation were recorded in 117 (46%). Presence of left CDH with malrotation and nonfixation was a significant predictor for SBO requiring surgery (P<0.05 vs all other groups). All 3 patients with extensive volvulus had left CDH with nonfixed bowel (100%), however only 1 had malrotation (33%). CONCLUSIONS: Malrotation and nonfixation are associated with increased SBO in CDH. Normal rotation is not protective and patients are still at risk for volvulus resulting in SBS. SBO requiring surgical intervention is common in CDH. Bowel rotation and fixation are important determinants that, should be routinely documented and education about the risk of SBO should be included in family counseling. LEVEL OF EVIDENCE: Level IV - Case Series.

Discharge Practices for Infants with Bronchopulmonary Dysplasia: A Survey of National Experts.

OBJECTIVE: To establish consensus practices among a panel of national experts for the discharge of premature infants with bronchopulmonary dysplasia (BPD) from the hospital to home. STUDY DESIGN: We conducted a Delphi study that included US neonatologists and pediatric pulmonologists from the Bronchopulmonary Dysplasia Collaborative to establish consensus practices-defined as recommendations with at least 80% agreement-for infants with BPD being discharged from the hospital. Specifically, we evaluated recommendations for diagnostic tests to be completed around discharge, follow-up respiratory care, and family education. RESULTS: Thirty-one expert participants completed 3 rounds of surveys, with a 99% response rate (92 of 93). Consensus was established that infants with moderate-severe BPD (ie, those who remain on respiratory support at 36 weeks) and those discharged on oxygen should be targeted for in-person pulmonary follow-up within 1 month of hospital discharge. Specialized neonatal follow-up is an alternative for infants with mild BPD. Infants with moderate or severe BPD should have an echocardiogram performed after 36 weeks to screen for pulmonary hypertension. Infants with BPD warrant additional evaluations if they have growth restriction or poor growth, pulmonary hypertension, or tachypnea and if they are discharged to home on oxygen, diuretics, or nonoral feeds. CONCLUSIONS: This Delphi survey establishes expert consensus around best practices for follow-up respiratory management and routine evaluation for infants with BPD surrounding neonatal discharge. Areas of disagreement for which consensus was not established are discussed.

Daycare Attendance is Linked to Increased Risk of Respiratory Morbidities in Children Born Preterm with Bronchopulmonary Dysplasia.

OBJECTIVES: To test the hypothesis that daycare attendance among children with bronchopulmonary dysplasia (BPD) is associated with increased chronic respiratory symptoms and/or greater health care use for respiratory illnesses during the first 3 years of life. STUDY DESIGN: Daycare attendance and clinical outcomes were obtained via standardized instruments for 341 subjects recruited from 9 BPD specialty clinics in the US. All subjects were former infants born preterm (<34 weeks) with BPD (71% severe) requiring outpatient follow-up between 0 and 3 years of age. Mixed logistic regression models were used to test for associations. RESULTS: Children with BPD attending daycare were more likely to have emergency department visits and systemic steroid usage. Children in daycare up to 3 years of age also were more likely to report trouble breathing, having activity limitations, and using rescue medications when compared with children not in daycare. More severe manifestations were found in children attending daycare between 6 and 12 months of chronological age. CONCLUSIONS: In this study, children born preterm with BPD who attend daycare were more likely to visit the emergency department, use systemic steroids, and have chronic respiratory symptoms compared with children not in daycare, indicating that daycare may be a potential modifiable risk factor to minimize respiratory morbidities in children with BPD during the preschool years.

Insurance coverage and respiratory morbidities in bronchopulmonary dysplasia.

INTRODUCTION: Preterm infants and young children with bronchopulmonary dysplasia (BPD) are at increased risk for acute care utilization and chronic respiratory symptoms during early life. Identifying risk factors for respiratory morbidities in the outpatient setting could decrease the burden of care. We hypothesized that public insurance coverage was associated with higher acute care usage and respiratory symptoms in preterm infants and children with BPD after initial neonatal intensive care unit (NICU) discharge. METHODS: Subjects were recruited from BPD clinics at 10 tertiary care centers in the United States between 2018 and 2021. Demographics and clinical characteristics were obtained through chart review. Surveys for clinical outcomes were administered to caregivers. RESULTS: Of the 470 subjects included in this study, 249 (53.0%) received employer-based insurance coverage and 221 (47.0%) received Medicaid as sole coverage at least once between 0 and 3 years of age. The Medicaid group was twice as likely to have sick visits (adjusted odd ratio [OR]: 2.06; p = 0.009) and emergency department visits (aOR: 2.09; p = 0.028), and three times more likely to be admitted for respiratory reasons (aOR: 3.04; p = 0.001) than those in the employer-based group. Additionally, those in the Medicaid group were more likely to have nighttime respiratory symptoms (aOR: 2.62; p = 0.004). CONCLUSIONS: Children with BPD who received Medicaid coverage were more likely to utilize acute care and have nighttime respiratory symptoms during the first 3 years of life. More comprehensive studies are needed to determine whether the use of Medicaid represents a barrier to accessing care, lower socioeconomic status, and/or a proxy for detrimental environmental exposures.

High altitude simulation testing in patients with congenital diaphragmatic hernia.

AIM OF STUDY: Congenital Diaphragmatic Hernia (CDH) is associated with lung hypoplasia and pulmonary hypertension. Many patients receive care in specialty centers requiring air travel upon discharge and for subsequent follow-up care. Premature infants can experience significant hypoxia in flight, but this has not been studied in the CDH population. This report describes our center's experience with simulated altitude testing among CDH patients. METHODS: In a single center retrospective cohort study, CDH patients who underwent a High Altitude Simulation Test (HAST) from 2006 to 2019 were analyzed. HAST simulates increased altitude by reducing oxygen tension to an FIO2 of 0.15. Patients were tested only when flight was anticipated. Patients requiring oxygen were challenged on their baseline requirement. To pass, patients had to maintain oxygen saturation > 90%, and 94% if diagnosed with pulmonary hypertension. Supplemental oxygen was titrated as needed to achieve this goal. RESULTS: Of twenty patients tested, only six (30%) passed on their first attempt. Ten (50%) eventually passed, after an average of 3.2 additional attempts over 1.8 years. No patient passed initially who utilized ECMO support, diaphragmatic agenesis, or had elevated right ventricular pressure on echocardiogram. All patients achieved the targeted SpO2 with supplemental oxygen. CONCLUSION: CDH patients experience hypoxia when exposed to the simulated hypobaric nature of air travel and therefore may become hypoxic in flight, requiring oxygen supplementation. Disease severity seems to correlate with risk of in-flight hypoxia. This data suggests that CDH patients should be screened to assess their need for supplemental oxygen to ensure safe air travel. LEVEL OF EVIDENCE: Level 4 case series.

Long-term respiratory and developmental outcomes in children with bronchopulmonary dysplasia and history of tracheostomy.

OBJECTIVE: The long-term morbidity among children with severe bronchopulmonary dysplasia who require tracheostomy (tBPD) relative to those without tracheostomy (sBPD) is not well characterized. We compared childhood lung function and neurodevelopmental outcomes in tBPD and sBPD. STUDY DESIGN: Retrospective case-control study of N = 49 tBPD and N = 280 sBPD subjects in Boston Children's Hospital Preterm Lung Patient Registry and medical record. We compared NICU course, childhood spirometry, and neurodevelopmental testing. RESULT: tBPD subjects were more likely than sBPD to be Black, have pulmonary hypertension, and have subglottic stenosis. tBPD subjects had lower maximal childhood FEV1 % predicted (ß = -0.14) and FEV1/FVC (ß = -0.08); spirometry curves were more likely to suggest fixed extrathoracic obstruction. tBPD subjects had greater cognitive and motor delays <24 months, and greater cognitive delays >24 months. CONCLUSION: Compared to subjects with sBPD who did not require tracheostomy, tBPD subjects suffer from increased long-term impairment in respiratory function and neurodevelopment.

Air quality, Environment and Respiratory Outcomes in Bronchopulmonary Dysplasia, the AERO-BPD cohort study: design and adaptation during the SARS-CoV-2 pandemic.

INTRODUCTION: Almost half of all school-age children with bronchopulmonary dysplasia (BPD) have asthma-like symptoms and more suffer from lung function deficits. While air pollution and indoor respiratory irritants are known to affect high-risk populations of children, few studies have objectively evaluated environmental contributions to long-term respiratory morbidity in this population. This study aimed to examine the role of indoor environmental exposures on respiratory morbidity in children with BPD. METHODS AND ANALYSIS: The Air quality, Environment and Respiratory Ouctomes in BPD (AERO-BPD) study is a prospective, single-centre observational study that will enrol a unique cohort of 240 children with BPD and carefully characterise participants and their indoor home environmental exposures. Measures of indoor air quality constituents will assess the relationship of nitrogen dioxide (NO2), particulate matter (PM2.5), nitric oxide (NO), temperature and humidity, as well as dust concentrations of allergens, with concurrently measured respiratory symptoms and lung function.Adaptations to the research protocol due to the SARS-CoV-2 pandemic included remote home environment and participant assessments. ETHICS AND DISSEMINATION: Study protocol was approved by the Boston Children's Hospital Committee on Clinical Investigation. Dissemination will be in the form of peer-reviewed publications and participant information products. TRIAL REGISTRATION NUMBER: NCT04107701.

Lung function trajectories in children with post-prematurity respiratory disease: identifying risk factors for abnormal growth.

BACKGROUND: Survivors of prematurity are at risk for abnormal childhood lung function. Few studies have addressed trajectories of lung function and risk factors for abnormal growth in childhood. This study aims to describe changes in lung function in a contemporary cohort of children born preterm followed longitudinally in pulmonary clinic for post-prematurity respiratory disease and to assess maternal and neonatal risk factors associated with decreased lung function trajectories. METHODS: Observational cohort of 164 children born preterm ≤ 32 weeks gestation followed in pulmonary clinic at Boston Children's Hospital with pulmonary function testing. We collected demographics and neonatal history. We used multivariable linear regression to identify the impact of neonatal and maternal risk factors on lung function trajectories in childhood. RESULTS: We identified 264 studies from 82 subjects with acceptable longitudinal FEV1 data and 138 studies from 47 subjects with acceptable longitudinal FVC and FEV1/FVC data. FEV1% predicted and FEV1/FVC were reduced compared to childhood norms. Growth in FVC outpaced FEV1, resulting in an FEV1/FVC that declined over time. In multivariable analyses, longer duration of mechanical ventilation was associated with a lower rate of rise in FEV1% predicted and greater decline in FEV1/FVC, and postnatal steroid exposure in the NICU was associated with a lower rate of rise in FEV1 and FVC % predicted. Maternal atopy and asthma were associated with a lower rate of rise in FEV1% predicted. CONCLUSIONS: Children with post-prematurity respiratory disease demonstrate worsening obstruction in lung function throughout childhood. Neonatal risk factors including exposure to mechanical ventilation and postnatal steroids, as well as maternal atopy and asthma, were associated with diminished rate of rise in lung function. These results may have implications for lung function trajectories into adulthood.

Characteristics of infants or children presenting to outpatient bronchopulmonary dysplasia clinics in the United States.

INTRODUCTION: Bronchopulmonary dysplasia (BPD) is a common respiratory sequelae of preterm birth, for which longitudinal outpatient data are limited. Our objective was to describe a geographically diverse outpatient cohort of former preterm infants followed in BPD-disease specific clinics. METHODS: Seven BPD specialty clinics contributed data using standardized instruments to this retrospective cohort study. Inclusion criteria included preterm birth (<37 weeks) and respiratory symptoms or needs requiring outpatient follow-up. RESULTS: A total of 413 preterm infants and children were recruited (mean age: 2.4 ± 2.7 years) with a mean gestational age of 27.0 ± 2.8 weeks and a mean birthweight of 951 ± 429 grams of whom 63.7% had severe BPD. Total, 51.1% of subjects were nonwhite. Severe BPD was not associated with greater utilization of acute care/therapies compared to non-severe counterparts. Of children with severe BPD, differences in percentage of those on any home respiratory support (p = .001), home positive pressure ventilation (p = .003), diuretics (p < .001), inhaled corticosteroids (p < .001), and pulmonary vasodilators (p < .001) were found between centers, however no differences in acute care use were observed. DISCUSSION: This examination of a multicenter collaborative registry of children born prematurely with respiratory disease demonstrates a diversity of management strategies among geographically distinct tertiary care BPD centers in the United States. This study reveals that the majority of children followed in these clinics were nonwhite and that neither variation in management nor severity of BPD at 36 weeks influenced outpatient acute care utilization. These findings suggest that post-neonatal intensive care unit factors and follow-up may modify respiratory outcomes in BPD, possibly independently of severity.

Longitudinal Analysis of Ventilation Perfusion Mismatch in Congenital Diaphragmatic Hernia Survivors.

OBJECTIVE: To determine the natural history of pulmonary function for survivors of congenital diaphragmatic hernia (CDH). STUDY DESIGN: This was a retrospective cohort study of survivors of CDH born during 1991-2016 and followed at our institution. A generalized linear model was fitted to assess the longitudinal trends of ventilation (V), perfusion (Q), and V/Q mismatch. The association between V/Q ratio and body mass index percentile as well as functional status was also assessed with a generalized linear model. RESULTS: During the study period, 212 patients had at least one V/Q study. The average ipsilateral V/Q of the cohort increased over time (P < .01), an effect driven by progressive reduction in relative perfusion (P = .012). A higher V/Q ratio was correlated with lower body mass index percentile (P < .001) and higher probability of poor functional status (New York Heart Association class III or IV) (P = .045). CONCLUSIONS: In this cohort of survivors of CDH with more severe disease characteristics, V/Q mismatch worsens over time, primarily because of progressive perfusion deficit of the ipsilateral side. V/Q scans may be useful in identifying patients with CDH who are at risk for poor growth and functional status.

Longitudinal Analysis of Pulmonary Function in Survivors of Congenital Diaphragmatic Hernia.

OBJECTIVE: To analyze longitudinal trends of pulmonary function testing in patients with congenital diaphragmatic hernia (CDH) followed in our multidisciplinary clinic. STUDY DESIGN: This was a retrospective cohort study of CDH patients born between 1991 and 2013. A linear mixed effects model was fitted to estimate the trends of percent predicted forced expiratory volume in 1 second (FEV1pp), percent predicted forced vital capacity (FVCpp), and FEV1/FVC over time. RESULTS: Of 268 patients with CDH who survived to discharge, 119 had at least 1 pulmonary function test study. The FEV1pp (P < .001), FVCpp (P = .017), and FEV1/FVC (P = .001) decreased with age. Compared with defect size A/B, those with defect size C/D had lower FEV1pp by an average of 11.5% (95% CI, 2.9%-20.1%; P = .010). A history of oxygen use at initial hospital discharge also correlated with decreased FEV1pp by an average of 8.0% (95% CI, 1.2%-15.0%; P = .023). CONCLUSIONS: In a select cohort of CDH survivors, average pulmonary function declines with age relative to expected population normative values. Those with severe CDH represent a population at risk for worsening pulmonary function test measurements who may benefit from recognition and monitoring for complications.

Does the ex utero intrapartum treatment to extracorporeal membrane oxygenation procedure change morbidity outcomes for high-risk congenital diaphragmatic hernia survivors?

PURPOSE: In high-risk congenital diaphragmatic hernia (CDH), significant barotrauma or death can occur before extracorporeal membrane oxygenation (ECMO) can be initiated. We previously examined ex utero intrapartum treatment (EXIT)-to-ECMO in our most severe CDH patients, but demonstrated no survival advantage. We now report morbidity outcomes in survivors of this high-risk cohort to determine whether EXIT-to-ECMO conferred any benefit. METHODS: All CDH survivors with <15% predicted lung volume (PPLV) from September 1999 to December 2010 were included. We recorded prenatal imaging, defect size, and pulmonary, nutritional, cardiac, and neurodevelopmental outcomes. RESULTS: Seventeen survivors (8 EXIT-to-ECMO, 9 non-EXIT) had an average PPLV of 11.7%. Eight of 9 non-EXIT received ECMO within 2days. There were no significant defect size differences between groups, mostly left-sided (13/17) and type D (12/17). Average follow-up was 6.7years (0-13years). There were no statistically significant differences in outcomes, including supplemental oxygen, diuretics, gastrostomy, weight-for-age Z scores, fundoplication, pulmonary hypertension, stroke or intracranial hemorrhage rate, CDH recurrence, and reoperation. No survivor in our cohort was neurologically devastated. All had mild motor and/or speech delay, which improved in most. CONCLUSIONS: In this pilot series of severe CDH survivors, EXIT-to-ECMO confers neither significant survival nor long-term morbidity benefit. LEVEL OF EVIDENCE: Level III treatment study.

Pulmonary support on day of life 30 is a strong predictor of increased 1 and 5-year morbidity in survivors of congenital diaphragmatic hernia.

PURPOSE: Pulmonary support (PS) on day-of-life-30 (DOL-30) has been shown to be the strongest predictor of subsequent morbidity and in-patient mortality in congenital diaphragmatic hernia (CDH). We hypothesized that PS on DOL-30 can also predict long-term outcomes in CDH survivors. METHODS: We analyzed records of 201 CDH survivors followed by a single multidisciplinary clinic (1995-2010). Follow-up was 83 and 70% at 1 and 5years respectively. PS was defined as: (1) invasive support (n=44), (2) noninvasive support (n=54), or (3) room air (n=103). Logistic regression was used to estimate the adjusted association of PS on DOL-30 with outcomes at 1 and 5-years. RESULTS: Use of PS on DOL-30 was significantly associated with pulmonary and developmental morbidities at 1 and 5-years. Even after adjusting for defect-size and presence of ventilation/perfusion mismatch, greater PS on DOL-30 was associated with a significantly increased odds of requiring supplemental oxygen and developmental referral at 1-year, and asthma and developmental referral at 5-years. CONCLUSION: CDH survivors continue to have significant long-term pulmonary and developmental morbidities. PS on DOL-30 is a strong independent predictor of morbidity at 1 and 5-years and may be used as a simple prognostic tool to identify high-risk infants.

First isolations of Segniliparus rugosus from patients with cystic fibrosis.

We report three cases of the new genus Segniliparus isolated from patients with cystic fibrosis. All isolates were unambiguously identified by 16S rRNA gene sequencing as Segniliparus rugosus (GenBank accession no. AY 60892). Drug susceptibility results that may enhance treatment for cystic fibrosis patients with this opportunistic pathogen are presented.

Anionic poly(amino acid)s dissolve F-actin and DNA bundles, enhance DNase activity, and reduce the viscosity of cystic fibrosis sputum.

Bundles of F-actin and DNA present in the sputum of cystic fibrosis (CF) patients but absent from normal airway fluid contribute to the altered viscoelastic properties of sputum that inhibit clearance of infected airway fluid and exacerbate the pathology of CF. Previous strategies to remove these filamentous aggregates have focused on DNase to enzymatically depolymerize DNA to constituent monomers and gelsolin to sever F-actin to small fragments. The high densities of negative surface charge on DNA and F-actin suggest that the bundles of these filaments, which alone exhibit a strong electrostatic repulsion, may be stabilized by multivalent cations such as histones, antimicrobial peptides, and other positively charged molecules prevalent in airway fluid. This study reports that bundles of DNA or F-actin formed after addition of histone H1 or lysozyme are efficiently dissolved by soluble multivalent anions such as polymeric aspartate or glutamate. Addition of poly-aspartate or poly-glutamate also disperses DNA and actin-containing bundles in CF sputum and lowers the elastic moduli of these samples to levels comparable to those obtained after treatment with DNase I or gelsolin. Addition of poly-aspartic acid also increased DNase activity when added to samples containing DNA bundles formed with histone H1. When added to CF sputum, poly-aspartic acid significantly reduced the growth of bacteria, suggesting activation of endogenous antibacterial factors. These findings suggest that soluble multivalent anions have potential alone or in combination with other mucolytic agents to selectively dissociate the large bundles of charged biopolymers that form in CF sputum.

Elastic contributions dominate the viscoelastic properties of sputum from cystic fibrosis patients.

Sputum samples from cystic fibrosis (CF) patients were investigated by oscillatory, creep and steady shear rheological techniques over a range of time scales from 10(-3) to 10(6) s. The viscoelastic changes obtained by mixing sputa with the actin-filament-severing protein gelsolin and with the thiol-reducing agent dithiothreitol (DTT) were also investigated. At small strains sputum behaves like a viscoelastic solid rather than a liquid. A nearly constant steady shear viscosity at low shear rates is only observed after long shearing times which cause irreversible changes in the samples. Creep-recovery tests confirm that sputa exhibit viscoelastic properties, with a significant elastic recovery. The results suggest that measurements of elastic moduli, rather than viscosities are more closely related to the mechanical properties of sputum in situ. Severing of actin filaments lowers the elastic modulus by 30-40%, but maintains viscoelastic integrity, while reduction of thiols in the glycoproteins nearly completely fluidizes the samples.