Marco Filippone

Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification

Idiopathic infantile arterial calcification (IIAC; OMIM 208000) is characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. We analyzed affected individuals from 11 unrelated kindreds and found that IIAC was associated with mutations that inactivated ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). This cell surface enzyme generates inorganic pyrophosphate (PPi), a solute that regulates cell differentiation and serves as an essential physiologic inhibitor of calcification.

Flow limitation in infants with bronchopulmonary dysplasia and respiratory function at school age

Bronchopulmonary dysplasia is associated with abnormalities in lung function during infancy, yet many infants recover with no respiratory problems in the long term. We therefore did a longitudinal study of pulmonary function in 18 children with moderate to severe bronchopulmonary dysplasia. Forced expiratory volume in 1 s (FEV1) and forced mid-expiratory flow (FEF25-75) at school age were lower than normal in 15 of 18 children, and both showed a significant positive correlation with the maximal flow at functional residual capacity (Vmax(FRC)) at 24 months of age (r=0.68 and 0.85, respectively). Our results suggest that assessment of respiratory function during infancy can help to identify children with bronchopulmonary dysplasia at risk of incomplete recovery of respiratory function during childhood.

Childhood Course of Lung Function in Survivors of Bronchopulmonary Dysplasia

refinement. However, we remain committed to the continual refinement of explicit algorithms because they are the best means of achieving and sustaining long-term gains in performance. Implicit algorithms are the mental models an individual uses to select his or her response to a given situation. Although experience allows the individual to refine these models, that knowledge remains internal and will be lost when the individual dies. Consequently, long-term progress depends on converting that implicit knowledge into explicit algorithms so that they may be further refined by other individuals. This conversion and subsequent communication is the basis of organizational learning. Mentioning explicit algorithms frequently generates a visceral reaction since many people may consider such algorithms to be unduly confining. However, the only available alternative is implicit algorithms; since these will vary from individual to individual, it is exceedingly unlikely that a system built on implicit algorithms will produce a reliable result. We agree that complex problems can rarely be reduced to a single solution or target point. However, the limitations of human information processing, particularly the limited capacity of working memory, necessitate representing solutions as target points or as narrowly defined solution spaces. Even if the chosen target differs from the ideal, reductions in variation provide 2 benefits. First, minimal variation provides assurance that the process is tightly controlled. Second, any difference between the observed and desired result is less likely to be obscured by noise. We also agree that variation, whether due to nuanced observations, subjective hunches, or chance events, can lead to future improvement. Genetic variation provides a useful example. Most mutations are deleterious, but a small percentage are beneficial. The key is to create feedback loops that continually interpret results, recognize the benefit, refine the algorithm to leverage the benefit, and report the result so that others may build on the knowledge gained. We agree with the majority of Wilkinson’s observations. The remaining differences are likely best attributed to the difficulty of communicating ideas such as the benefits of explicit over implicit algorithms and how variation can be considered a 2-edged sword.

Bronchopulmonary dysplasia: The earliest and perhaps the longest lasting obstructive lung disease in humans

Bronchopulmonary dysplasia (BPD) is one of the most important sequelae of premature birth and the most common form of chronic lung disease of infancy. From a clinical standpoint BPD subjects are characterized by recurrent respiratory symptoms, which are very frequent during the first years of life and, although becoming less severe as children grow up, they remain more common than in term-born controls throughout childhood, adolescence and into adulthood. From a functional point of view BPD subjects show a significant airflow limitation that persists during adolescence and adulthood and they may experience an earlier and steeper decline in lung function during adulthood. Interestingly, patients born prematurely but not developing BPD usually fare better, but they too have airflow limitations during childhood and later on, suggesting that also prematurity per se has life-long detrimental effects on pulmonary function. For the time being, little is known about the presence and nature of pathological mechanisms underlying the clinical and functional picture presented by BPD survivors. Nonetheless, recent data suggest the presence of persistent neutrophilic airway inflammation and oxidative stress and it has been suggested that BPD may be sustained in the long term by inflammatory pathogenic mechanisms similar to those underlying COPD. This hypothesis is intriguing but more pathological data are needed. A better understanding of these pathogenetic mechanisms, in fact, may be able to orient the development of novel targeted therapies or prevention strategies to improve the overall respiratory health of BPD patients.

Home oxygen therapy in infants with bronchopulmonary dysplasia: a prospective study

AbstractWe followed the clinical course of 21 infants with bronchopulmonary dysplasia enrolled in a prospective home O2 therapy programme during a 4-year-period. Mean gestational age was 28.5 weeks (range, 25–36 weeks) and mean birth weight 1093 g (range 630–2750 g). Infants were regularly monitored to maintain pulse oximeter O2 saturation over 94%–95%. The source of O2 was liquid oxygen and was delivered by nasal cannula. During the follow up oxygenation was assessed by SatO2 measurement, cardiac function by Doppler echocardiography and respiratory function by the occlusion technique. All patients had an ophthalmological follow up. The mean age of the infants at discharge was 3.7 months (range 1.7–8.6) and mean weight 2830 g (range 2150–3780 g). At discharge 8 infants had right ventricular hypertrophy (RVH) and four of them had pulmonary hypertension. Mean duration of home O2 therapy was 97 days (range 15–320 days) and the mean age of discontinuation of O2 was 6.9 months (range 3–14.7 months). The cardiological follow up was benign: the ECG signs of RVH disappeared by 12 months of age in six out of eight infants and the right ventricular pulmonary pressure, as measured by the Doppler method, normalised in the four patients in whom it was detected. No relationship was found between respiratory mechanics and the duration of O2 therapy. Weight gain was poor with mean growth at the 3rd percentile for females and just below the 3rd percentile for males. Twelve of the 21 infants required 25 rehospitalizations. No one presented deterioration of retinopathy of prematurity that was present in 16 infants at discharge; at 12 months retinopathy was resolved in 14 infants. A total of 2025 hospital days were saved, representing a significant financial saving. Conclusion Home O2 therapy permits the safe early discharge of O2-dependent BPD infants and it reduces significantly the length of time spent in hospital which represents a considerable financial saving.

Metabolic and respiratory effects of theophylline in the preterm infant

BACKGROUND Methylxanthines are often administered to preterm infants for the treatment of apnoea. AIMS To study the effects of theophylline on energy metabolism, physical activity, and lung mechanics in preterm infants. METHODS Indirect calorimetry was performed for six hours before and after administration of a bolus of theophylline (5 mg/kg) in 18 preterm infants while physical activity was recorded with a video camera. Lung mechanics measurements were performed at baseline and 12 and 24 hours after theophylline treatment. RESULTS Theophylline increased mean (SEM) energy expenditure by 15 (5) kJ/kg/day and augmented carbohydrate utilisation from 6.8 to 8.0 g/kg/day, but fat oxidation was unchanged. After theophylline treatment, preterm infants had faster respiration, lower transcutaneous CO2, and improved static respiratory compliance without increased physical activity. CONCLUSIONS A bolus of 5 mg/kg theophylline increased energy expenditure independently of physical activity, increased carbohydrate utilisation, and improved respiratory compliance. The increased energy expenditure could be detrimental to the growth of the preterm infant.

Endothelial progenitor cells, bronchopulmonary dysplasia and other short-term outcomes of extremely preterm birth

AIM To evaluate the impact of endothelial progenitor cells (EPCs), a subset of committed circulatory stem cells, on the development of bronchopulmonary dysplasia (BPD) and other short term outcomes in a cohort of extremely premature newborns. METHODS Progenitor cells were quantified by flow cytometry at birth in 36 neonates born <=28 weeks of gestation and at 36 postmenstrual weeks in 18 of them. Cells expressing the stemness markers CD34, CD133, or both were defined as circulating progenitor cells (CPCs). EPCs were defined as CPCs co-expressing the endothelial marker KDR. RESULTS Mean (SD) gestational age and birth weight of the infants studied were 26.2(1.5) weeks and 761.6(171.8) grams, respectively. EPC levels at birth did not differ between infants who subsequently developed BPD (n=9) and those who did not (n=24) [CD34(+)KDR(+) EPCs: 81(34-41) vs 80(56-110), p=0.7] and were not correlated with the duration of mechanical ventilation or O2-dependence, nor with the need of surfactant replacement. Infants with a hemodynamically significant patent ductus arteriosus (PDA) (n=22) had significantly lower EPC levels at birth than those with no PDA (n=11) [CD34(+)KDR(+) cells: 47(34-92) vs 142(84.5-221), p=0.008]. Data from the 18 infants studied both at birth and at 36 postmenstrual weeks showed that, while CPCs sharply decline over time, levels of all EPCs phenotypes are preserved after delivery. CONCLUSIONS Levels of EPCs at birth did not affect the risk of developing BPD in our group of extremely premature neonates. However, the association between low EPC counts at birth and PDA may be clinically relevant, and deserves further studies.

Respiratory mechanics in infants and young children before and after repair of left-to-right-shunts

ABSTRACT: In an attempt to investigate the relationship between respiratory mechanics and pulmonary hemodynamics, we evaluated pulmonary function in 31 infants with left-to-right shunts and subsequent high pulmonary blood flow, undergoing cardiac surgery. Measurements were performed 1 d before and repeated 10 d and 4–5 wk after correction. The age of the patients ranged from 4 d to 24 mo, body weight from 2.7 to 11.8 kg. Pulmonary artery-pressure, assessed by Doppler echocardiography, was preoperatively elevated in 23 patients (group 1), whereas it was within normal values in eight infants (group 2). Respiratory mechanics were measured using the single-breath occlusion technique in sedated infants. To evaluate specific compliance, functional residual capacity was determined by using an open circuit nitrogen washout technique. A reduced preoperative compliance value (mean with 95% confidence interval) was found in group 1: 34.8 (26.5–43.1) mL. kPa−1. After hemodynamic correction, a progressive significant (p < 0.01) improvement was demonstrated at 10 d and 1 mo with values of 47.5 (39.2–55.8) mL. kPa−1 and 56.5 (45.6–67.4) mL. kPa−1, respectively. A similar trend was noted evaluating specific compliance with values of 0.27 (0.24–0.30) kPa−1 and 0.44 (0.42–0.46) kPa−1, respectively before and after surgery. Preoperative functional residual capacity value was 130 (100–160) mL. In group 2, normal preoperative compliance values were obtained, without significant changes after surgery. In both groups, resistance was within the normal range both before and after surgical correction, and functional residual capacity did not change either. No correlations were found between compliance and pulmonary artery pressure and pulmonary blood flow values. In conclusion, these results show that infants with left-to-right shunts and pulmonary hypertension present with reduced compliance of the respiratory system that rapidly improves after cardiac surgery.

From BPD to COPD? The hypothesis is intriguing but we lack lung pathology data in humans

To the Editors: We read the study reported by Didon et al. 1 and the accompanying editorial 2 with great interest because they deal with an emerging area of paediatric and adult respiratory medicine, i.e. the origins in the early life of chronic obstructive pulmonary disease (COPD) and genetic susceptibility to lung damage. In a rodent model, the study shows that lung-specific epithelial deletion of CCAAT/enhancer binding protein α (C/EBPα) disrupts normal lung morphogenesis in fetal life, subsequently driving the onset of spontaneous severe chronic bronchial inflammation, and ultimately results in pulmonary emphysema in adult mice 1. The authors understandably interpret their observations with reference to bronchopulmonary dysplasia (BPD), the main chronic respiratory complication of prematurity 3. Indeed, their animal model shows both the well-known alveolar and vascular growth inhibition seen after very premature birth, and the COPD-like changes dreaded as a long-term consequence of BPD. We believe …

The term “asthma” should be avoided in describing the chronic pulmonary disease of prematurity

To the Editor : We read with interest the report from Kallen et al . [1] that preterm birth and (to a lesser extent) restricted intrauterine growth both substantially increase the risk of developing “childhood asthma”. Their data are interesting, and several plausible hypotheses are advanced to explain the correlation between prematurity (and intrauterine growth restriction) and the development of asthma later on. As in numerous other studies [2–4], cases of asthma were identified on the strength of anti-asthma drug prescriptions. Rightly enough, a persistent use of anti-asthma drugs (at least five prescriptions) was required to minimise the inclusion of non-asthmatic cases [1]. …