PDF Chronic Lung Disease in Early Infancy

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Early Developmental Assessment Center

Additional longitudinal studies are needed to determine outcomes beyond the second decade, and define risk factors and optimal treatment for late sequalae of disease. From Eugenio Baraldi, M. Oxygen saturation target range for extremely preterm infants: In addition, contemporary management, including use of high-flow nasal cannula, is not addressed and can result in misclassification. Mechanisms of lung injury and bronchopulmonary dysplasia. Role of vitamin a in lung development. Persistent chemoreceptor dysfunction has been documented in survivors of BPD [ , ].

Clinical and experimental studies have suggested that chorioamnionitis induces early lung maturation with increased surfactant production and decreased risk of RDS [ 42 , 43 ]. However, studies have also raised concerns for associated lung injury and decreased alveolarization. Administration of Escherichia Coli endotoxin to pregnant ewes resulted in amplified inflammation with ventilation of the exposed preterm lambs including evidence of cellular apoptosis and compromised alveolar development [ 44 , 45 ].

While several clinical studies have reported an association between chorioamnionitis and BPD, a meta-analysis including 59 studies and over 15, infants suggested that limited association between chorioamnionitis and BPD existed when adjustments were made for gestational age [ 43 ]. This paper also raised concerns for publication bias and concluded that chorioamnionitis cannot be definitively considered a risk for BPD [ 41 ].

Controversy exists as variable definitions have been used to classify chorioamnionitis and the term itself may represent a range of pathology. Recent analysis of data from a year cohort of over very-low-birth weight infants concluded that sepsis, but not chorioamnionitis, increased risks of developing moderate or severe BPD [ 46 ]. Less controversy exists regarding the contribution of postnatal inflammation or nosocomial infection to the increased risk of developing BPD [ 47 , 48 ].

This data raises concerns that the presence of resistant organisms may result in more severe infection, advocating for judicious use of prophylactic or prolonged antibiotics in premature infants at risk. Non-infectious exposures, including oxygen and mechanical ventilation, cause further injury to the preterm lung resulting in secondary insult via inflammatory mediated responses. Preterm infants that are small for gestational age SGA at birth or with intrauterine growth restriction IUGR are at increased risk for adverse pulmonary outcomes [ 53 , 54 ].

In addition, birthweight for gestational age is an important predictor of BPD-associated pulmonary hypertension [ 57 ]. While the association of growth restriction and BPD is in part secondary to compromised lung development, studies in bovine and murine IUGR models have demonstrated impacts on endothelial cell function, surfactant expression and inflammatory responses further influencing risks [ 58 , 59 , 60 ]. Extremely premature infants are at additional risk for postnatal growth restriction secondary to challenges of delivering optimal nutrition. Postnatal growth failure influences risks of developing BPD with data suggesting that delivery of adequate nutrition in the first week plays a critical role [ 7 , 53 ].

Studies have further identified that provision of optimal enteral feeding as compared to parenteral nutrition decreases risks of developing BPD [ 8 ]. Of interest are recent studies which demonstrate a decreased risk of BPD despite compromised growth with exclusive use of breast milk [ 61 ]. Despite evidence of normal alveolarization, murine models of postnatal growth restriction have identified pulmonary vascular remodeling, right ventricular hypertrophy and altered expression of key regulators of lung development including VEGF, HIF and mTOR, supporting the key contribution of postnatal nutrition to pulmonary vascular pathology and severity of disease [ 62 ].

While BPD results from cumulative exposures to both the pre- and postnatal factors noted above, there is a growing interest in the heritable contributions to development of BPD. A total of twin pairs were analyzed using mixed-effects logistic-regression and a latent variable probit model in a multicenter retrospective study. Subsequent multicenter studies confirmed the heritability of BPD by way of data identifying greater similarity in monozygotic as compared to dizygotic twins.

More recently, several genome-wide association studies GWAS have been conducted to identify candidate single nucleotide polymorphisms associated with BPD. The largest evaluated over infants and failed to identify genomic loci or pathways that accounted for the previously described heritability for BPD [ 66 ]. A second, smaller analysis concluded that the SPOCK2 gene may represent a possible candidate susceptibility gene and a key regulator of alveolarization [ 67 ]. Rapid advances in genomics and proteomics suggest that regulators of susceptibility may eventually be identified, potentially allowing for targeted or individualized therapy to prevent and treat BPD.

Management strategies are aimed at protecting against lung injury and the development of BPD. As the pathogenesis of disease is multifactorial, diverse approaches have been adopted including both ventilation and medical strategies. Interestingly, both antenatal steroids and surfactant reduce rates of RDS and improve survival; however, neither has been shown to reduce incidence of BPD [ 26 ]. However, the data to support this strategy has been inconsistent and long-term neurodevelopmental outcomes remain unknown [ 68 , 69 ].

Gentle ventilation has also advocated for volume-targeted ventilation with meta-analysis to support this strategy in reducing rates of BPD and ventilator-associated inflammation [ 72 , 73 , 74 ]. Randomized clinical trials have demonstrated that both high-frequency jet HFJV and oscillatory ventilation HFOV have potential to reduce risk of BPD [ 75 , 76 ]; however, a Cochrane review of elective HFOV revealed only a small reduction in the incidence of chronic lung disease with notable inconsistency across the 19 studies included [ 77 ].

As many infants require more sedation with high frequency ventilation HFV , prophylactic use of HFV remains controversial. Significant efforts have been made to move away from use of invasive ventilation over the past two decades [ 26 ]. Meta-analysis of randomized clinical trials comparing prophylactic or early use of surfactant to initial support by continuous airway pressure CPAP have identified reduction in the combined outcome of death or BPD with avoidance of intubation [ 78 , 79 , 80 ]. These meta-analyses each included slightly different papers in their reviews, compiling data from studies using both prophylactic surfactant followed by rapid extubation INSURE or INtubate, SURfactant, Extubate and those which randomized to routine intubation.

Despite variable studies included, the common finding of decreased risk of BPD strengthens recommendations for use of non-invasive strategies. Use of alternative non-invasive modalities including non-invasive positive pressure ventilation NIPPV , bilevel nasal CPAP biPAP and high-flow nasal cannula HFNC is also increasing with some evidence to suggest these modes may also be effective in managing neonatal respiratory disease [ 81 , 82 , 83 ]. This systematic review and research on NIPPV are challenged by highly variable clinical practices and management strategies.

Synchronization can be achieved and has been described in premature infants using an abdominal pneumatic or Graseby capsule to detect diaphragmatic descent. This approach has the theoretical advantage of ensuring glottis patency before flow is triggered. More recently, some units have moved towards use of non-invasive ventilation with neurally adjusted ventilator assist NAVA to deliver synchronized breaths [ 87 ].

While this approach in theory may improve the patient-ventilator interaction and improve pulmonary outcomes, data to support this practice is still needed. Finally, for those infants who do require intubation, an early trial of extubation is encouraged to potentially reduce risks of ventilator-induced lung injury. Studies have identified that an early attempt at extubation alone may decrease the risk of BPD, regardless of need for reintubation or duration of ventilation [ 88 , 89 ]. These provocative studies were both retrospective suggesting a need for additional prospective trials.

Extensive efforts have been made to define optimal saturation targets for premature infants with ongoing concerns for the quality of evidence available [ 90 ]. Use of higher saturation targets will inherently increase documented rates of BPD as infants cannot be weaned until they can maintain these higher goals. Nonetheless, the meta-analysis including all five studies still failed to identify a significant difference in rates of oxygen requirement at 36 weeks [ 92 ].

Postnatal glucocorticoids are recognized to reduce rates of BPD via reduced inflammation as well as the induction of lung maturational changes. However, the potential benefits of systemic steroids are often outweighed by concerns for long-term neurodevelopmental sequelae including increased risk of cerebral palsy CP [ 98 , 99 ]. Inhaled corticosteroids are used in some units as they are thought to be safer than systemic steroids; however, systematic reviews of inhalation corticosteroids have found inadequate data to support these practices [ , ].

In attempt to more reliably deliver corticosteroids directly to alveoli of infants at risk of early lung injury, co-administration of budesonide with surfactant has been considered. Additional multicentered, randomized evaluation and follow-up studies of this practice are needed.

In the recent randomized, multicenter Caffeine for Apnea of Prematurity CAP trial, early initiation of caffeine was found to result in lower incidence of BPD as well as a shorter course of respiratory support as compared to controls [ ]. The specific mechanism by which caffeine protects against lung injury remains unclear, and improved outcomes may have been due to decreased duration of ventilation alone.

The benefits of caffeine were validated in additional cohorts and these data have collectively influenced practices in numerous units, including early initiation of caffeine in infants at risk of BPD [ , ]. Vitamin A deficiency may predispose to chronic lung disease as it plays a critical role in maintaining the integrity of respiratory tract epithelium and is a key regulator of normal lung growth [ , ].

While meta-analysis suggests supplementation of preterm infants with vitamin A results in reduction in the combined outcome of death and BPD, the use of this therapy is highly variable as benefits were only observed in infants less than grams and the results were marginal [ ]. Administration requires intramuscular injections which is associated with significant discomfort and potentially an increased risk of infection [ ]. A large trial is currently in progress evaluating the efficacy of oral vitamin A supplementation with hopes that a simper route of administration may also be effective [ ].

Inhaled nitric oxide iNO for prevention of bronchopulmonary dysplasia deserves mention as it has been explored in numerous studies with inconsistent findings [ , ]. While a day protocol initiated between 7 and 21 days was associated with decreased rates of BPD, combined evidence from the 14 randomized controlled trials in premature infants less than or equal to 34 weeks gestation showed equivocal effects on pulmonary morbidity, survival, and neurodevelopmental outcomes [ , ].

While this meta-analysis included highly variable protocols with respect to timing of initiation and dosing, the authors concluded that early use of iNO in preterm infants did not impact risk of brain injury or improve survival without BPD and that later use to prevent BPD might be effective but required further study.

Subsequent individual-patient data meta-analysis suggested no specific benefit with prematurity and stated routine use could not be recommended [ ]. Expert review of the topic resulted in consensus opinions from both the NIH and the American Academy of Pediatrics dissuading the routine use of iNO in premature infants [ , ]. Despite these statements, off-label use of iNO in extremely premature infants remains on the rise [ ]. This may be due to use in grave circumstances where neonatologists feel that offering therapy is better than doing nothing [ ].

There are also arguments that subpopulations may be more responsive and appropriate to consider for treatment, with data to suggest benefit after preterm premature rupture of membranes PPROM [ , ]. Long-term outcomes of BPD remain difficult to characterize as adult populations currently available to study represent survivors of outdated care. While BPD tends to improve with ongoing lung development, data available from follow-up studies identify concerns for persistent pulmonary sequelae of disease.

Notably, the impact on late pulmonary health as well as the consequences of additional infectious or environmental exposures remain poorly characterized. It is important to recognize the tremendous emotional, medical, and financial efforts invested into care of extremely premature infants. The mean length of hospitalization for those born under grams is approximately 60 days with high rates of need for additional medical support including rehospitalization after discharge [ ].

Additional studies have shown that the incidence of sudden infant death syndrome was seven times greater in infants with BPD [ ]. Follow-up studies of child and young adult survivors of BPD demonstrate concerns for compromised pulmonary function and defenses, asthma-like symptoms, pulmonary hypertension and exercise intolerance with altered responses to hypoxia. Numerous studies have evaluated long-term pulmonary function after premature birth alone. A meta-analysis including 59 articles identified that percent of predicted forced expiratory volume in 1 second FEV1 is decreased in preterm-born survivors, even in patients who did not have a history of BPD [ ].

This study further identified an association between growth in length and improvements of lung function, highlighting the important contribution of adequate nutrition in BPD survivors. Additional studies have raised concerns for the persistence of pulmonary disease in patients with BPD.

Correlation between maximal flow at functional residual capacity in infancy and forced expiratory flow at 8 years raises concerns that limited recovery occurs during late stages of alveolarization [ ]. In addition, one longitudinal study of 8- and year-old BPD survivors demonstrated deterioration of pulmonary function with age [ ].

Bronchopulmonary Dysplasia (BPD)

Airflow limitation has been attributed to dysanaptic growth, in which airways grow less rapidly than lung parenchyma resulting in fixed small airway obstruction [ ]. High-resolution lung CT imaging obtained on young adult survivors confirmed that architectural distortion persists and correlates with compromised pulmonary function. However, the consequences of these findings on pulmonary disease in late adulthood remains unknown [ , ].

Of concern, animal studies of BPD which allow longer follow-up note that altered lung structure and compromised pulmonary function can persist into late adulthood [ ]. Exposure to environmental insults including respiratory infections, tobacco and pollution may complicate resolution of BPD and prolong risks of pulmonary morbidity [ , ].

Premature infants have increased susceptibility to infection which persists into childhood [ ]. Common respiratory infections can result in severe morbidity and potential mortality in BPD survivors. Associated inflammation with these pulmonary insults may lead to additional lung injury in the already vulnerable recovering lung. Both epidemiologic data and animal models have demonstrated that BPD increases susceptibility to viral infection-induced lung injury with evidence of altered inflammation as a result of disrupted innate immunoregulatory pathways [ , ].

While the evidence is variable, improvement of respiratory status has been reported after Nissen fundoplication of infants with severe chronic lung disease with some programs advocating for this intervention in severe cases [ , , ]. Many survivors of BPD demonstrate a component of reactive airway disease. While children with BPD have asthma-like symptoms, they are less likely to demonstrate airway hyper-responsiveness or response to bronchodilators as they may suffer a fixed peripheral airway narrowing [ ].

In addition, co-morbid bronchomalacia or other central airway disease in ex-premature infants can result in exacerbated wheezing with use of bronchodilator therapy [ ]. Although the evidence is limited with only one randomized trial [ ], benefits from inhaled corticosteroids are also thought to be less consistent for children with BPD as compared to those with asthma [ ]. One series suggests that outcomes of severe disease may be improved with use of chronic low-dose systemic steroids [ ]. The reversibility and impact of this asthma-like phenotype on late adult pulmonary morbidity remains unknown.

Survivors of BPD may experience exacerbation of pulmonary morbidities with exercise or exposure to hypoxia. Significant risk of exercise-induced bronchoconstriction has been demonstrated in children with BPD consistent with concerns for reactive airway disease noted above [ ].

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However, in addition to risk of exercise-induced bronchoconstriction, BPD survivors are noted to have compromised gas exchange with physical activity. Treadmill exercise testing identify reduced gas transfer at rest and during activity which has been attributed to long-term derangements in lung structure or residual right ventricular dysfunction affecting cardiac output [ ].

In addition, higher oxygen uptake during activity has been observed, which could contribute to early fatigability during prolonged exercise [ ]. A recent detailed evaluation of 7 to year-old survivors of BPD noted ventilatory limitation with exercise, including greater use of the ventilatory reserve, lower maximal ventilation and tidal volume. Chemoreceptor function in preterm infants is dysmature, resulting in abnormal ventilatory responses to alterations of oxygen content in these patients.

Specifically, normal responses of increased ventilation with hypoxia as well as decreased ventilation with hyperoxia may be altered. Persistent chemoreceptor dysfunction has been documented in survivors of BPD [ , ].

Inadequate response to hypoventilation and hypoxia may represent significant risk of morbidity in survivors of BPD who may also suffer co-morbid central airway disease or bronchomalacia. Abnormal respiratory muscle function in BPD survivors may further complicate this risk [ ]. Dysmorphic pulmonary vasculature and compromised angiogenesis with BPD results in risk of elevated pulmonary pressures or BPD-associated pulmonary hypertension PH.

Evaluation of all oxygen-dependent infants by echocardiography at 36 weeks has become common in many units [ 13 ]. Identification of patients with elevated pulmonary pressures at earlier time points has been studied but remains of unclear benefit [ ]. As previously noted, patients with BPD and elevated pulmonary pressures are at high risk for PH crisis and early mortality. Those who survive may ultimately demonstrate resolution of disease with additional lung growth.

However, recent data suggests that subclinical right ventricular dysfunction can be detected in children assumed to have recovered from BPD-associated PH [ ]. Longer-term outcomes in adulthood and risks of late pulmonary vascular disease with BPD-associated PH remain poorly defined. Animal models, which allow late follow-up, have raised concern for increased susceptibility to hypoxia-induced PH in adulthood [ ].

While severity of BPD does not predict likelihood of associated pulmonary hypertension, sicker infants with prolonged ventilator and oxygen requirements are at greatest risk [ , ]. Additional risk factors include low gestational age, small for gestation age SGA status and oligohydramnious [ 21 , 22 ].

However, the threshold for intervention and optimal treatment of BPD-associated PH remains elusive with limited evidence to guide care [ ]. While retrospective studies suggest improved echocardiographic evidence of PH with sildenafil, placebo-controlled studies in this patient population are lacking [ ]. Notably, the pathophysiology of vascular disease with BPD differs from IPH, with tendencies to improve over time and a significant component of vascular pruning rather than remodeling. Theoretical concerns for exacerbation of disease with vasodilator therapy exist, as treatment may further inhibit smooth muscle cell proliferation [ ].

In addition, the relationship between pulmonary arterial pressure and disability are poorly defined, making the threshold to treatment difficult to define. Notably, this series identified a wide range to use with significant interinstitutional variation [ ]. Some guidance for treatment has been provided in the literature. However, none of these to date are evidence based [ , ]. These authors suggest that confirmation of PH by catheterization would be an indication for therapy, while the specific choice of medication should be influenced by vasoreactivity tests.

Specifically, they suggest calcium-channel inhibitors should be considered with a positive test and sildenafil followed by bosentan with lack of vasoreactivity. In a retrospective analysis of infants with ventilator-dependent BPD, Gien, et al. The authors further highlighted that identification of pulmonary vein stenosis, aortopulmonary collaterals or LV diastolic dysfunction may influence care as vasodilator therapy in these settings would result in increased pulmonary blood flow and risk of pulmonary edema.

Afterload reduction, including milrinone initially, followed by angiotensin-converting enzyme inhibitors, was suggested. Pulmonary vasodilation acutely with nitric oxide followed by transition to sildenafil and as-needed bosentan was suggested in all other PH cases. While the past decade has been notable for increasing use of vasodilator therapy in the treatment of BPD-associated PH [ ], randomized controlled trials are much in need to clarify the optimal use of these therapies with BPD associated PH.

The definition, pathophysiology, and management of bronchopulmonary dysplasia BPD has evolved significantly since first described by Northway almost 50 years ago. Advances in neonatal care have resulted in increased rates of survival of extremely premature infants leading to both a new set of management challenges as well as an emerging population of long-term survivors of BPD.

Interdisciplinary care to address the complex pulmonary, nutritional and developmental needs of these patients is critical and may itself influence outcomes of severe BPD [ ]. Randomized therapeutic studies in addition to longitudinal evaluation of these patients remains essential to optimize care and further discern risk factors for morbidity. While these studies require significant resources, they are much in need as evidence for optimal treatment is lacking.

In addition, little is known regarding pulmonary outcomes of BPD beyond the second decade of life. Of concern are data highlighting the potential for increased risk of subclinical right ventricular dysfunction, obstructive lung disease, exercise intolerance, and asthma-like symptoms in survivors. Abnormal response to hypoxia and central airway disease may further exacerbate illness with risks of sleep disordered breathing. These baseline morbidities, complicated by environmental and infectious exposures, may represent a significant challenge for the aging cohort of BPD survivors.

As trends demonstrate increasing survival of extremely premature infants, nearly half of whom will be diagnosed with BPD, it is imperative that future studies investigate mechanisms and risk factors influencing long-term morbidity with an overall goal of reducing the burden of disease. National Center for Biotechnology Information , U. Journal List J Clin Med v. Published online Jan 6. Davidson and Sara K. David Barnes, Academic Editor. Author information Article notes Copyright and License information Disclaimer.

Received Nov 1; Accepted Dec This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution CC-BY license http: This article has been cited by other articles in PMC. Abstract Bronchopulmonary dysplasia BPD is a chronic lung disease most commonly seen in premature infants who required mechanical ventilation and oxygen therapy for acute respiratory distress.

Introduction Bronchopulmonary dysplasia BPD is a chronic lung disease most commonly seen in premature infants who required mechanical ventilation and oxygen therapy for acute respiratory distress but can also occur in neonates that had a less severe respiratory course [ 1 , 2 , 3 ].

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Table 1 Definition of Bronchopulmonary Dysplasia: Open in a separate window. Pathophysiology of BPD The phenotype seen with BPD is the end result of a complex multifactorial process in which various pre- and postnatal factors compromise normal development in the immature lung. Mechanical Trauma BPD occurs almost exclusively in preterm infants that have received positive pressure ventilation suggesting that mechanical lung over-distension and alveolar stretch play a critical role in the pathogenesis of BPD. Oxygen Toxicity Studies in numerous animal models have identified that exposure to supraphysiologic oxygen alone induces a phenotype comparable to that seen with BPD, including compromised alveolar development and pulmonary vascular remodeling [ 31 ].

Infection and Inflammation Controversy exists regarding the contribution of chorioamnionitis and prenatal inflammation to the risk of developing BPD [ 41 ]. Growth Restriction Preterm infants that are small for gestational age SGA at birth or with intrauterine growth restriction IUGR are at increased risk for adverse pulmonary outcomes [ 53 , 54 ].

Genetics While BPD results from cumulative exposures to both the pre- and postnatal factors noted above, there is a growing interest in the heritable contributions to development of BPD. Saturation Targets Extensive efforts have been made to define optimal saturation targets for premature infants with ongoing concerns for the quality of evidence available [ 90 ].

Corticosteroids Postnatal glucocorticoids are recognized to reduce rates of BPD via reduced inflammation as well as the induction of lung maturational changes. Caffeine In the recent randomized, multicenter Caffeine for Apnea of Prematurity CAP trial, early initiation of caffeine was found to result in lower incidence of BPD as well as a shorter course of respiratory support as compared to controls [ ]. Vitamin A Vitamin A deficiency may predispose to chronic lung disease as it plays a critical role in maintaining the integrity of respiratory tract epithelium and is a key regulator of normal lung growth [ , ].

Nitric Oxide Inhaled nitric oxide iNO for prevention of bronchopulmonary dysplasia deserves mention as it has been explored in numerous studies with inconsistent findings [ , ]. Long-Term Outcomes of BPD Long-term outcomes of BPD remain difficult to characterize as adult populations currently available to study represent survivors of outdated care. Compromised Pulmonary Function Numerous studies have evaluated long-term pulmonary function after premature birth alone.

Compromised Pulmonary Defenses Exposure to environmental insults including respiratory infections, tobacco and pollution may complicate resolution of BPD and prolong risks of pulmonary morbidity [ , ]. Exercise Intolerance Survivors of BPD may experience exacerbation of pulmonary morbidities with exercise or exposure to hypoxia. Abnormal Ventilatory Responses Chemoreceptor function in preterm infants is dysmature, resulting in abnormal ventilatory responses to alterations of oxygen content in these patients.

Conclusions The definition, pathophysiology, and management of bronchopulmonary dysplasia BPD has evolved significantly since first described by Northway almost 50 years ago. Conflicts of Interest The authors declare no conflict of interest. Pulmonary disease following respirator therapy of hyaline-membrane disease.

Chronic lung injury in preterm lambs: Abnormalities of the pulmonary circulation and lung fluid balance. Changes in pathogenesis, epidemiology and definition. Bronchopulmonary dysplasia—trends over three decades.

"Common Pediatric Respiratory Problems" by Monica Kleinman, MD for OPENPediatrics

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Les Miserables.
Bronchopulmonary Dysplasia: Chronic Lung Disease of Infancy and Long-Term Pulmonary Outcomes;
Chronic Lung Disease of Infancy?
Chronic Lung Disease in Early Infancy!

Preterm resuscitation with low oxygen causes less oxidative stress, inflammation, and chronic lung disease.