DEFINITION AND PHENOTYPES
 
Chronic lung disease of prematurity (CLDP) refers to various respiratory disorders resulting from prematurity. With the continuous rise in birth and survival rates of premature infants, the incidence of CLDP has increased. In Brazil, 11.94% (302,528) of live births in 2023 were premature (born at < 37 weeks of gestation), and 0.59% (15,134) were extremely premature (born at < 28 weeks).(1) This improved survival of extremely preterm newborns is largely due to advancements in neonatal intensive care over recent decades. Strategies to enhance preterm infant survival include new antimicrobials, corticosteroid therapy for high-risk pregnancies, artificial surfactants, and assisted ventilation methods that are more effective, like CPAP.(2)
 
Although survival rates have improved, morbidity and mortality have shifted to later stages, often due to sequelae of prematurity such as CLDP, which involves changes in lung structure, including altered septation, vascularization, and a reduced number of alveoli. Those changes, which lead to impaired gas exchange and reduced lung function, can persist into adulthood.(2,3)
 
As detailed in Chart 1, CLDP encompasses a spectrum of respiratory conditions in premature infants, from minimal symptoms to severe conditions like bronchopulmonary dysplasia (BPD). Inflammatory processes significantly influence those conditions, with cytokine storms exacerbating disease progression. Medical interventions, particularly invasive ventilation, contribute to pro-inflammatory cascades and play a crucial role in CLDP pathogenesis.

 
During the intrauterine period, airway development progresses through several stages. Many preterm infants are born during the saccular stage (24-36 weeks gestation), with compromised surfactant production and underdeveloped bronchioles and airways. Prenatal factors, such as fetal growth and gestation duration, and postnatal factors, such as ventilatory interventions, can significantly affect lung development into adulthood.(2)
 
The most severe form of CLDP is BPD, defined by the need for supplemental oxygen or ventilation for 28 days or more, up to 36 weeks post-conception. The etiology of BPD is multifactorial, with inflammation and prolonged mechanical ventilation as key contributors. It is characterized by chronic respiratory disease, with consequences lasting beyond the neonatal period. Children with BPD are at higher risk for lower respiratory tract infections, airway hyperresponsiveness, and hospitalization in the first two years of life.
 
Within BPD, there are various phenotypes. Some preterm infants exhibit significant lung function impairment without meeting the criteria for BPD or showing signs of neonatal respiratory disease. Others may have severe lung disease, requiring long-term mechanical ventilation or oxygen supplementation. With less aggressive neonatal ventilation techniques, the histological phenotype of BPD has shifted from post-traumatic conditions to a form characterized by arrested alveolar development. Recent studies suggest that patients with BPD are at increased risk for subclinical pulmonary hypertension, exercise-induced lung disease, hypertension, right ventricular dysfunction, and autonomic dysfunction.
 
Premature birth alters lung structure, increasing vulnerability to acute viral infections in early life. These infections, typically mild in full-term infants, are more severe in preterm infants, with a higher risk of hospitalization and ventilatory support, particularly in infants infected with respiratory syncytial virus (RSV). Many preterm infants develop recurrent wheezing and asthma-like symptoms, often treated with bronchodilators and inhaled steroids, though the response is generally poor. Symptom management should be tailored to individual severity, including RSV prevention and inhaled steroids for patients with atopy and asthma symptoms. Immunostimulants like bacterial lysates may also be considered.
 
MANAGEMENT
 
Various treatments for BPD are under study, including inhaled or systemic corticosteroids, bronchodilators, and supplemental oxygen, though interventional studies are limited.(4) The 2020 European Respiratory Society consensus recommends lung function tests for monitoring BPD in children, with pulmonary imaging reserved for severe cases. Bronchodilators should be used for patients with recurrent hospitalizations, exercise intolerance, or asthma-like symptoms, while inhaled corticosteroids should not be used for BPD treatment. If supplemental oxygen is needed, the target saturation should be at least 90%.(4) Palivizumab and, in the future, nirsevimab, can be used to prevent severe RSV infection in high-risk populations, including those with congenital heart disease, BPD, and prematurity.(5)
 
The main limitations in BPD treatment stem from the scarcity of high-quality studies, leading to a low level of evidence for many guidelines. More prospective studies are needed in order to monitor development of preterm children into school age and adulthood, as well as randomized clinical trials to determine the most effective treatments.(4)
 
AUTHOR CONTRIBUTIONS
 
GABS, MPH, and ECH contributed to data collection and drafting of the manuscript. MHJ and LAP contributed to drafting, reviewing and editing the manuscript.
 
CONFLICTS OF INTEREST
 
None declared.
 
FINANCIAL SUPPORT
 
This study received financial support from the Pontifícia Universidade Católica do Rio Grande do Sul (Pontifical Catholic University of Rio Grande do Sul Young Investigator Grant no. BPA/PUCRS 2023-24). LAP and MHJ are recipients of a Research Productivity Grant from the Brazilian Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Council for Scientific and Technological Development; Grant no. 309074/2022-3).
 
REFERENCES
 
1.           Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Análise Epidemiológica e Vigilância de Doenças Não Transmissíveis [homepage on the Internet]. Brasília: Ministério da Saúde; [cited 2024 Aug 1]. Painel de Monitoramento de Nascidos Vivos. Available from: http://plataforma.saude.gov.br/natalidade/nascidos-vivos/
2.           Walicka-Serzysko K, Postek M, Borawska-Kowalczyk U, Szamotulska K, Kwaśniewicz P, Polak K, et al. Long-term pulmonary outcomes of young adults born prematurely: a Polish prospective cohort study PREMATURITAS 20. BMC Pulm Med. 2024;24(1):126. https://doi.org/10.1186/s12890-024-02939-5
3.           Humberg A, Fortmann I, Siller B, Kopp MV, Herting E, Göpel W, et al. Preterm birth and sustained inflammation: consequences for the neonate. Semin Immunopathol. 2020;42(4):451-468. https://doi.org/10.1007/s00281-020-00803-2
4.           Duijts L, van Meel ER, Moschino L, Baraldi E, Barnhoorn M, Bramer WM, et al. European Respiratory Society guideline on long-term management of children with bronchopulmonary dysplasia. Eur Respir J. 2020;55(1):1900788. https://doi.org/10.1183/13993003.00788-2019
5.           O’Hagan S, Galway N, Shields MD, Mallett P, Groves HE. Review of the Safety, Efficacy and Tolerability of Palivizumab in the Prevention of Severe Respiratory Syncytial Virus (RSV) Disease. Drug Healthc Patient Saf. 2023;15:103-112. https://doi.org/10.2147/DHPS.S348727