Chronic Lung Disease Of Infancy Research Articles

Respiratory syncytial virus hospitalization trends in infants with chronic lung disease of infancy, 1998-2008.

Objective:Infants with chronic lung disease of infancy (CLDI) are at high risk for severe respiratory syncytial virus (RSV) illness requiring hospitalization. Palivizumab was first licensed in 1998 for the prevention of RSV disease in high-risk infants, including those with CLDI. We performed a retrospective cohort study of all hospitalized children with CLDI aged <2 years between 1998 and 2008 in the USA to determine trends in rates of hospitalizations due to RSV (RSVH) since the launch of palivizumab.Materials and methods:Data from the United States National Hospital Discharge Survey, a multistage systematic survey sample of US hospitals, were assembled. We defined RSVH using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes of 079.6 (RSV), 466.11 (acute bronchiolitis due to RSV), and 480.1 (pneumonia due to RSV). Quarterly rates of RSVH were assessed for children with CLDI (ICD-9-CM code 770.7) and calculated between 1998 and 2008. Because RSV may be miscoded, the analysis was repeated after expanding the definition of RSVH to include all acute bronchitis and acute bronchiolitis (ABH) (ICD-9-CM = 466). Trends were described using linear regression with seasonal indicators included in the model.Results:On average, about 966 RSVH (range 98–1373 RSVH) per year were found for children <2 years with CLDI in the USA between 1998 and 2008. Over the 11-year period, the predicted rate of RSVH statistically significantly decreased by 48% (from 93.78 to 49.06 RSVH per 1 million children) (P = 0.013). Addition of ABH resulted in a nonstatisically significant decrease of 32% over the 10-year period (P = 0.102).Conclusion:These results suggest that there has been a decrease in the rate of RSVH in infants with CLDI between 1998 and 2008. The reasons for this decrease may include improved neonatal intensive care unit and outpatient management of CLDI, and possibly increased use of palivizumab in this high-risk population.

Pathogenesis and treatment of bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of infancy affecting mostly premature infants with significant morbidity and mortality. Improved survival of very immature infants has led to increased numbers of infants with this disorder. Acute and chronic lung injury and impaired postnatal lung growth are thought to be responsible for the development of BPD. Whereas changes in clinical practice have improved the clinical course and outcomes for infants with BPD, over the past decade, the overall incidence of BPD has not changed. This review will describe the prenatal and postnatal factors that contribute to the pathogenesis of BPD as well as current and experimental therapies for treatment of BPD. The factors that contribute to the pathogenesis of BPD are well described; however, recent studies have better defined how these factors modulate lung growth. Inflammation, proinflammatory cytokines and altered angiogenic gene signaling contribute to lung injury and impair prenatal and postnatal lung growth resulting in BPD; however, to date no therapy has been identified that potently and consistently prevents or reverses their effects on lung growth. We will discuss the cell signaling pathways affected in BPD and current therapies available for modulating these pathways. Despite current advances in neonatal care, BPD remains a heavy burden on healthcare resources. New treatments directed at either reducing lung injury or improving lung growth are under study.

Computed tomography score and pulmonary function in infants with chronic lung disease of infancy

Chronic lung disease of infancy (CLDI) remains a common outcome among infants born extremely prematurely. In older children and adults with lung disease, pulmonary function and computed tomography (CT) scores are used to follow up respiratory disease and assess disease severity. For infants and toddlers, however, these outcomes have been used very infrequently and most often, a dichotomous respiratory outcome (presence or absence of CLDI) is employed. We evaluated the performance of CT score and pulmonary function to differentiate infants and toddlers with CLDI from a control group. CT scans, forced expiratory flows and pulmonary diffusing capacity were obtained in 39 CLDI patients and 41 controls (aged 4-33 months). CT scans were quantified using a scoring system, while pulmonary function was expressed as Z-scores. CT score outperformed pulmonary function in identifying those with CLDI. There were no significant correlations between CT score and pulmonary function. CT score had a better performance than pulmonary function in differentiating individuals with CLDI; however, these outcomes may reflect differing components of the pulmonary pathophysiology of CLDI. This new information on pulmonary outcomes can assist in designing studies with these parameters. Future studies will be required to evaluate which of the outcomes can better detect improvement with therapeutic intervention and/or lung growth.

P76 General and respiratory health outcomes in adult survivors of bronchopulmonary dysplasia: a systematic review

Introduction and objectivesBronchopulmonary dysplasia (BPD) is the most common form of chronic lung disease in infancy and the second most common after asthma in children. With the improved survival of...

144 Incidence, Risk Factors and Severity of Pulmonary Morbidity in Infants with Congenital Diaphragmatic Hernia Born in High-Volume Centres in Europe

Background and aims: Newborns with congenital diaphragmatic hernia (CDH) may develop chronic lung disease (CLD). Our aim was to determine the incidence, severity and risk factors of CLD in infants with CDH. Methods: Data were collected about 426 CDH patients born between 2005 and 2008 at 8 high-volume centres (> 10 admissions of infants with CDH per year) in Europe. The primary endpoint was CLD, defined as oxygen dependency at day 28. The severity of CLD (mild: FiO2 0.21; moderate: FiO2 0.22-0.29; severe: FiO2 ≥ 0.30 or CPAP/mechanical ventilation) was determined at day 56 or at discharge, whichever came first. Results: At day 28, the mortality rate was 28% and the CLD incidence was 31%. Of all patients with CLD, 31% had severe CLD, 15% moderate CLD and 54% had mild CLD. Compared to patients without CLD, patients with CLD had a lower lung-to-head ratio (p< 0.001), more often had an intrathoracic liver position (p< 0.001), required treatment for pulmonary hypertension (p< 0.001), had a patch repair (p< 0.001), developed a pneumothorax (p< 0.001) and required ECMO (p< 0.001). Independent risk factors for CLD were an intrathoracic liver position (OR 5.9, 95% CI 3.9-10.4) and a lower gestational age at birth (OR 0.86, 95% CI 0.73-0.97). Patients with severe CLD more often had a pneumothorax (p< 0.001), patch repair (p=0.035) and ECMO treatment (p< 0.001) than patients with mild to moderate CLD. Conclusion: Pulmonary morbidity, which is a major problem in infants with CDH, can be identified antenatally.

29 Ventilation and Perfusion Abnormalities in Infants with Bronchopulmonary Dysplasia

Introduction and aims: BPD is the most common chronic lung disease in infancy causing substantional morbidity. It is currently graded at 36 weeks according to the need for supplemental oxygen and/or positive pressure support1. Our aim was to investigat whether the increased oxygen need was related to ventilation/perfusion abnormalities using single photon computed tomography (SPECT) and if abnormalities increased relative to an increasing severity score. Method: We used quantitative SPECT technique to study the regional ventilation/perfusion matching. Perfusion was mapped with 99mTc-albumin and ventilation by inhalation of an 99m-tc marked aerosol. 29 infants with BPD born at Karolinska University hospital were investigated at 36 weeks corrected age. Results: Table [V/Q matching in three infants. Normal:50%, 0,6-1,4] Conclusion3-D ventilation-perfusion scintegraphy enables a more accurate and functionally oriented severity grading in infants with BPD. Increasing V/Q abnormalities were seen on SPECT with increasing clinical severity grade. SPECT illustrates the regional mismatch between ventilation and perfusion. An inhomogenious distrubution of V and Q even if the V/Q matching is good is a bad prognostic factor according to our findings.

Techniques of Early Respiratory Management of Very Low and Extremely Low Birth Weight Infants

The generalized anatomic and physiologic immaturity of preterm infants of very low birth weight (VLBW) (<or=1,500 g) and extremely low birth weight (ELBW) (<or=1,000 g) places them at high risk for death or associated negative sequelae, including chronic lung disease of infancy (CLDI). The standard treatment for pulmonary immaturity, mechanical ventilation (MV) at birth, can lead to barotrauma, volutrauma, pulmonary edema, infection, and inflammation. To minimize these negative outcomes, multiple treatment strategies have been proposed and evaluated as to their subsequent clinical course. This article compares, contrasts, and integrates the use of MV, nasal continuous positive airway pressure (NCPAP), and surfactant administration to encourage and support consideration of their use in the VLBW and ELBW population. Supporting a reduction of the use of MV in favor of NCPAP is safe and recommended because this practice is likely to decrease the probable sequelae of CLDI while permitting an individualized approach.

Exercise‐induced flow limitation in adults with a history of bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of infancy characterized by poor pulmonary function at term that persists into adolescence. Because exercise causes a significant increase in ventilation, we hypothesized that adults with a history of BPD would be susceptible to flow limitation during exercise at relatively low metabolic rates. Resting pulmonary function and maximal oxygen consumption (VO2max) on a cycle ergometer were determined in six subjects (1 female) born preterm (&amp;#8804;32 weeks) with a documented history of BPD. On a separate day, exercise flow‐volume loops were recorded during each 4 min exercise stage at 25, 50, 75 and 90% of VO2max. Resting forced‐expiratory flow at 50% of vital capacity was 2.9(1.6) L/s, mean(SD), [57(32)], [%predicted(SD)] and VO2max was 40.2(18.2) mL/kg/min [110.8(36)]. Flow limitation (%tidal volume) occurred at rest in one subject (96); 25% of VO2Max, in 2 subjects (22.7–83.7); 50% of VO2Max, in 3 subjects (47–87); and in all subjects at 75 and 90% VO2Max,(17–87) and (58.4–92.5), respectively. Exercise‐induced flow limitation was observed in all BPD subjects at low to moderate metabolic rates. Our data suggest that because individuals with BPD are flow limited during exercise, they would likely have an increased work of breathing for a given ventilation compared to their full term counterparts who do not have flow limitation. Support: AHA SDG 2280238

Growth of Lung Parenchyma in Infants and Toddlers with Chronic Lung Disease of Infancy

The clinical pathology describing infants with chronic lung disease of infancy (CLDI) has been limited and obtained primarily from infants with severe lung disease, who either died or required lung biopsy. As lung tissue from clinically stable outpatients is not available, physiological measurements offer the potential to increase our understanding of the pulmonary pathophysiology of this disease. We hypothesized that if premature birth and the development of CLDI result in disruption of alveolar development, then infants and toddlers with CLDI would have a lower pulmonary diffusing capacity relative to their alveolar volume compared with full-term control subjects. We measured pulmonary diffusing capacity and alveolar volume, using a single breath-hold maneuver at elevated lung volume. Subjects with chronic lung disease of infancy (23-29 wk of gestation; n = 39) were compared with full-term control subjects (n = 61) at corrected ages of 11.6 (4.8-17.0) and 13.6 (3.2-33) months, respectively. Alveolar volume and pulmonary diffusing capacity increased with increasing body length for both groups. After adjusting for body length, subjects with CLDI had significantly lower pulmonary diffusing capacity (2.88 vs. 3.23 ml/min/mm Hg; P = 0.0004), but no difference in volume (545 vs. 555 ml; P = 0.58). Infants and toddlers with CLDI have decreased pulmonary diffusing capacity, but normal alveolar volume. These physiological findings are consistent with the morphometric data obtained from subjects with severe lung disease, which suggests an impairment of alveolar development after very premature birth.

Abstract 5428: Nuclear Factor Kappa B Mediates Postnatal Alveolarization by Promoting Pulmonary Angiogenesis via Vascular Endothelial Growth Factor Receptor-2 Regulation

Vascular development drives alveolarization via vascular endothelial growth factor receptor-2 (VEGFR-2) signaling. Chronic lung disease of infancy, bronchopulmonary dysplasia (BPD) results from arrested alveolar and vascular development. However, the transcription factors that control alveolarization are unknown. Recent data identified a novel, developmentally regulated, anti-inflammatory role for the transcription factor nuclear factor kappa B (NF κ B) in the neonatal lung, as opposed to its recognized, pro-inflammatory role in the mature lung. Thus, we hypothesized that NF κ B is essential for alveolarization. To test this hypothesis, neontal mice were treated with the NF κ B inhibitor, BAY 11–7082 (BAY), or vehicle (PBS). At 8h, lung was procured for gene and protein expression. At 24h, lungs were fixed at 25 cm H2O pressure for morphometric analysis, determination of apoptosis (TUNEL), and immunohistochemistry (IHC) to detect proliferating cell nuclear antigen (PCNA) and capillary density (CD31). Chromatin immunoprecipitation (ChIP) was performed on lung tissue to evaluate if the NF κ B subunit, p65, binds the VEGFR2 promoter. Pulmonary endothelial cells (EC) were isolated using CD31 coated beads to determine VEGFR2 expression and VEGF-mediated survival and proliferation. At 8h, NF κ B blockade (BAY) decreased VEGFR2 mRNA and protein in the lung (p&lt;0.01, versus PBS). At 24h, lungs of BAY treated mice had increased alveolar area (p&lt;0.05) and decreased radial alveolar counts (p&lt;0.01), in association with decreased capillary density (p&lt;0.01), reduced proliferation (p&lt;0.001), and increased apoptosis (p&lt;0.05). ChIP demonstrated that, in control lungs, p65 binds the VEGFR2 promoter. Furthermore, NF κ B blockade with BAY caused a dose-dependent reduction of VEGFR2 mRNA and protein in pulmonary EC, and impaired VEGF mediated EC survival and proliferation. In summary, NF κ B blockade disrupts postnatal alveolarization by decreasing VEGFR2, demonstrating that NF κ B promotes alveologenesis through VEGFR2 mediated pulmonary EC survival and proliferation. We speculate that during lung development: NF κ B promotes lung angiogenesis; and impaired NF κ B activity may play a causal role in the arrest of alveolar formation characteristic of BPD. This research has received full or partial funding support from the American Heart Association, National Center.

The initial ventilation mode as a risk factor for chronic lung disease in infants with congenital diaphragmatic hernia

Aims: Newborns with congenital diaphragmatic hernia (CDH) may develop chronic lung disease (CLD).High frequency oscillation (HFO) as an initial ventilation mode may reduce CLD and mortality in newborns with CDH.

O/E LHR and O/E FLV as predictors for chronic lung disease in infants with congenital diaphragmatic hernia

Aims: Prenatal measurement of the observed-to-expected lung-to-head ratio (O/E LHR) and the observed-to-expected fetal lung volume (O/E FLV) may be useful in predicting mortality in patients with congenital diaphragmatic hernia (CDH). Prenatal measurements to predict pulmonary morbidity, such as chronic lung disease (CLD), are lacking.

Reduction in the Incidence of Chronic Lung Disease in Very Low Birth Weight Infants: Results of a Quality Improvement Process in a Tertiary Level Neonatal Intensive Care Unit

Our objective was to reduce the incidence of chronic lung disease by introducing potentially better practices in our delivery room and NICU. We compared the incidences of chronic lung disease in infants with birth weights of 501 to 1500 g in 2002 and 2005, after implementation of the changes. Medical records for infants of 501 to 1500 g who were born in 2002 and 2005 were reviewed for maternal characteristics, care of the infant in the delivery room and the NICU (including surfactant usage, duration of ventilation, duration of continuous positive airway pressure therapy, and duration of oxygen treatment), length of stay, and short-term clinical outcomes (eg, pneumothorax, severe intracranial hemorrhage, retinopathy of prematurity, and weight gain). There was a significant reduction in our incidence of chronic lung disease, from 46.5% in 2002 to 20.5% in 2005. The number of infants discharged from the hospital with oxygen therapy also decreased significantly, from 16.4% in 2002 to 4.1% in 2005. The overall relative risk reduction for chronic lung disease in 2005, compared with 2002, was 55.8%. By using a quality improvement process that included avoidance of intubation, adoption of new pulse oximeter limits, and early use of nasal continuous positive airway pressure therapy, we demonstrated a significant reduction in the incidence of chronic lung disease in infants with birth weights of <1500 g in 2005, in comparison with 2002. These results have persisted to date. There were no significant short-term complications.

Changing Use of Surfactant Over 6 Years and Its Relationship to Chronic Lung Disease

Our goals were to identify the trend of surfactant use over a 6-year period and to determine whether a relationship exists between the incidence of chronic lung disease in infants born weighing <1000 g who receive surfactant and those who do not. Data regarding surfactant use, incidence of chronic lung disease, nasal continuous positive airway pressure use and duration, and demographic data were collected from the Alere (formerly ParadigmHealth) database from 2001 to 2006 (n = 3086). Groups were compared by using chi(2) test, analysis of variance, or Student's t test. Use of surfactant has decreased over time from 67% in 2001 to 59.9% in 2006. Infants who received surfactant were more likely to develop chronic lung disease. Those who received >1 dose of surfactant were more likely to develop chronic lung disease when compared with infants treated with only 1 dose. Chronic lung disease rates have risen over time from 47.8% in 2001 to 57.8% in 2006. There was no difference in survival between groups. Despite the findings that surfactant use decreased during the study period and the rate of chronic lung disease increased, the data do not support a connection. Infants who receive surfactant are more likely to develop chronic lung disease, and chronic lung disease rates are stable in those infants not treated with surfactant. It is concerning, however, that 60% of infants not receiving surfactant developed chronic lung disease.

Letters to the Editor

Letters to the Editor

Development of a neonate lung reconstruction algorithm using a wavelet AMG and estimated boundary form

Objective, non-invasive measures of lung maturity and development, oxygen requirements and lung function, suitable for use in small, unsedated infants, are urgently required to define the nature and severity of persisting lung disease, and to identify risk factors for developing chronic lung problems. Disorders of lung growth, maturation and control of breathing are among the most important problems faced by the neonatologists. At present, no system for continuous monitoring of neonate lung function to reduce the risk of chronic lung disease in infancy in intensive care units exists. We are in the process of developing a new integrated electrical impedance tomography (EIT) system based on wearable technology to integrate measures of the boundary diameter from the boundary form for neonates into the reconstruction algorithm. In principle, this approach could provide a reduction of image artefacts in the reconstructed image associated with incorrect boundary form assumptions. In this paper, we investigate the required accuracy of the boundary form that would be suitable to minimize artefacts in the reconstruction for neonate lung function. The number of data points needed to create the required boundary form is automatically determined using genetic algorithms. The approach presented in this paper is to assist quality of the reconstruction using different approximations to the ideal boundary form. We also investigate the use of a wavelet algebraic multi-grid (WAMG) preconditioner to reduce the reconstruction computation requirements. Results are presented that demonstrate a full 3D model is required to minimize artefact in the reconstructed image and the implementation of a WAMG for EIT.

Hereditary disorders of surfactant homeostasis cause acute and chronic lung disease in infancy

In this issue of Thorax , Doan et al 1 report the clinical and pathological findings from nine paediatric patients with severe acute and chronic lung disease caused by mutations...

Chronic Lung Disease after Premature Birth

Bronchopulmonary dysplasia has become the most common chronic lung disease of infancy. This review summarizes the patterns and pathogenesis of chronic lung impairment that may become clinically significant decades after the use of mechanical ventilation and oxygen supplementation in premature newborns.

LONGITUDINAL ANALYSIS OF A HOME VENTILATOR PROGRAM AT A CHILDREN'S HOSPITAL: AN EIGHT YEAR EXPERIENCE

PURPOSE: Our study is designed to track patients and their clinical outcomes in the Home Ventilator Program at Helen DeVos Children's Hospital since 1998. The hypotheses are that most referrals come from our hospital and that the most common diagnosis for home ventilation is chronic lung disease of infancy (CLDI).

Use of inhaled nitric oxide in the preterm infant

Inhaled nitric oxide is established therapy for term infants with hypoxemic respiratory failure. Laboratory studies demonstrate that inhaled nitric oxide improves lung function and morphology in animal models of bronchopulmonary dysplasia, creating a rationale for clinical studies in premature infants. Four large multicenter randomized trials have now completed enrollment, and one trial has reported neurodevelopmental outcomes at 18-22 months. The purpose of this review is to summarize the results of the most recent preclinical studies and clinical trials. In 2006, short-term outcomes from two large multicenter randomized trials were published. These studies differed in their target population and study design. Early use of inhaled nitric oxide was associated with a decrease in brain injury, and decreased chronic lung disease in infants over 1000 g. Inhaled nitric oxide use in older infants (7-21 days) was associated with decreased chronic lung disease, particularly if started early. Neurodevelopmental outcomes after discharge are still needed from three large multicenter randomized trials. These results will help confirm the long-term implications of the benefits reported in the two most recent trials.