Bronchopulmonary dysplasia (BPD) is one of the most common chronic morbidities in pre-term infants (1). BPD is commonly defined based on consensus recommendations from a National Institutes of Health (NIH) workshop (2). These recommendations classified BPD in pre-term infants born at <32 weeks as mild, moderate, or severe, according to the amount of supplemental oxygen and the mode of respiratory support administered at 36 weeks post-menstrual age (PMA).

Infants with severe BPD have higher mortality and morbidity than infants with mild or moderate BPD (3). Infants with severe BPD have complicated clinical courses and suffer substantial life-long burdens of pulmonary and neurodevelopmental sequelae (4–8). However, large variation in the severity of the disease is noted even within the severe BPD.

To better define BPD severity, a multi-institution group dedicated to filling knowledge gaps in the care of infants with BPD called the BPD Collaborative recommended that severe BPD be further classified into two phenotypes (9). Infants receiving persistent oxygen and/or nasal continuous positive airway pressure (CPAP) or high-flow nasal cannula (HFNC) at 36 weeks PMA were defined as having type 1 severe BPD, and infants requiring invasive mechanical ventilation were defined as having type 2 severe BPD. The BPD Collaborative reported a point prevalence of severe BPD of 36.5% in pre-term infants born at <32 weeks in tertiary referral neonatal intensive care units (NICUs), and 41% of these patients had type 2 severe BPD (10). Infants with type 2 severe BPD are more likely to die and have neurodevelopmental impairments (11).

However, the baseline characteristics and comorbidities associated with type 2 severe BPD remain understudied given its low incidence. Few reports have focused on perinatal factors that could affect disease severity and variation in the clinical burden within a severe BPD category.

In the present study, we identified the baseline characteristics associated with the development of type 2 severe BPD and assessed the clinical burden of type 2 severe BPD in compare to type 1 severe BPD using a large cohort of very-low-birth-weight (VLBW) infants.

The final study population included 1,328 pre-term (23⁺⁰-31⁺⁶ weeks) VLBW infants. Their mean GA was 27⁺⁰ ± 2⁺⁰ weeks, and their mean birth weight was 893 ± 253 g. Of these 1,328 infants, 983 (74.0%) infants developed type 1 severe BPD, and 345 (26.0%) infants developed type 2 severe BPD.

Our results showed that infants with the type 2 severe BPD had an 18-fold increased risk of mortality, a 2-fold increased risk of f pulmonary hypertension, and a 10-fold increased risk of tracheostomy and a greater clinical burden as indicated by a longer duration of invasive mechanical ventilation and NICU admission than infants with the type 1 severe BPD. Among the baseline characteristics, lower birth weight, SGA, lesser maternal PROM, lower 5-min Apgar score, air leak, pulmonary hemorrhage, surgical ligation of PDA, NEC, and LOS were significantly associated with type 2 severe BPD. These antenatal and postnatal factors may predispose the immature lung to injuries or directly cause injury to the immature lung and contribute to impaired alveolar and pulmonary vascular development, which increases the risk of type 2 severe BPD (18). Other investigators noted similar observations that PDA, sepsis, and surgical NEC had a significant role in the development of severe BPD (19, 20). The presence of PDA has been associated with the development of BPD (21, 22). The persistence of left-to-right shunting through PDA results in pulmonary edema and endothelial injury. These alterations lead to the prolonged need for high levels of respiratory support, including invasive mechanical ventilation and high inspired oxygen concentrations. Surgical ligation of PDA may indicate the greater severity of PDA, which may lead to exacerbation of lung disease, such as type 2 severe BPD. However, in addition to being reflective of a significant left-to-right shunt, there is evidence that surgical ligation of PDA itself may contribute to lung injury directly (23). Sepsis is also related to the development of BPD (17). There is considerable evidence to support that postnatal infection exacerbates the severity of BPD (24, 25). Jung and Lee recently demonstrated that LOS was a risk factor for BPD in extremely low birth weight (ELBW) infants using the KNN database (26). Because we limited LOS to cases that occurred before 36 weeks PMA when the diagnosis of BPD was made, our results support the role of LOS as a risk factor for more severe type of BPD.

Severe BPD results in high mortality and extensive morbidities (3). More specifically, infants with severe BPD are at an increased risk of long-term serious morbidities, including late pulmonary morbidity, pulmonary hypertension, gastroesophageal reflux, feeding difficulty, ROP, systemic hypertension, and neurodevelopmental impairment (4–8). Infants with severe BPD receiving invasive mechanical ventilation at 36 weeks PMA also had an increased risk of late mortality, severe respiratory morbidities, poor growth, and neurodevelopmental impairment than infants receiving noninvasive ventilation at 36 weeks PMA (11). We found that infants with type 2 severe BPD had an 18-fold increased risk of death during the NICU admission compared to infants with type 1 severe BPD, and the mortality rate reached 26% in infants with type 2 severe BPD. Type 2 severe BPD was strongly associated with a longer duration of invasive mechanical ventilation. At NICU discharge, infants with type 2 severe BPD were associated with a 10-fold increase in tracheostomy, a 3-fold increase in supplemental oxygen use, and a 6-fold increase in mechanical ventilator requirement. These results suggest that infants with type 2 severe BPD are at a high risk of having chronic respiratory support and undergoing tracheostomy. These findings may reflect the disease severity and indicate that infants with type 2 severe BPD had more severe lung parenchymal and airway diseases. In our study population, the rates of tracheostomy and mechanical ventilation at discharge were 0.5 and 0.7%, respectively, which were much lower than those of previously reported referral-based cohort (27). According to a report from Children's Hospital Neonatal Consortium on infants with severe BPD born at <32 weeks, 5% had tracheostomy and 4% required mechanical ventilation at the time of discharge (27). The reason for this discrepancy may be due to the different study populations. Their study included pre-term infants who were admitted to tertiary referral hospitals. In contrast, we excluded from the analysis 206 infants who were transferred to another hospital or unit after 36 weeks PMA. These infants were often more ill than those who stayed at their initial hospital until NICU discharge. Of the 206 infants who were transferred, 121 infants had type 1 severe BPD and 85 infants had type 2 severe BPD. Because infants with type 2 severe BPD were transferred twice as many as infants with type 1 severe BPD after 36 weeks PMA, exclusion of these infants might have led to under-reporting of the actual rates of tracheostomy and mechanical ventilator use at discharge. Similarly, exclusion of these infants might have reduced the gaps in mortality, comorbidities, and clinical burden between type 1 and type 2 severe BPD.

We also found that infants with type 2 severe BPD were subject to significant comorbidities, including pulmonary hypertension, PVL, and impaired auditory response. Pulmonary hypertension developed in 20% of severe BPD infants, which is consistent with prior reports and highlights the importance of pulmonary hypertension as a comorbidity in infants with severe BPD (28, 29). After adjusting for confounding variables, the odds of developing pulmonary hypertension were increased 2-fold in infants with type 2 severe BPD compared with infants with type 1 severe BPD. A diagnosis of BPD-associated pulmonary hypertension was consistently associated with 2-year mortality rates as high as 40–50% (30, 31). Pulmonary hypertension has also been linked to an increased risk of death or tracheostomy (32, 33).

Infants with BPD also have difficulty maintaining growth (34). Based on the lower z-scores of weight, height, and head circumference at the time of discharge, we found that infants with type 2 severe BPD grew more poorly. The causes of growth failure in infants with type 2 severe BPD may include increased work of breathing, chronic stress and inflammation, and feeding problems associated with respiratory insufficiency.

The strength of our study is that we evaluated baseline characteristics, mortality, comorbidities, and clinical burden of severe BPD based on disease severity in a large, multicenter prospective cohort. However, there are several limitations that should be mentioned. First, we limited our analysis to infants who survived to 36 weeks PMA. Infants with the most severe BPD might have not survived to 36 weeks PMA. As many as half of all deaths in very pre-term infants before 36 weeks PMA are pulmonary-related (1, 35). This might have led to under-reporting of the disease severity of type 2 severe BPD. Secondly, as mentioned above, exclusion of 206 infants who were transferred after 36 weeks PMA due to unavailability of late morbidity data might have reduced the gaps in comorbidities and clinical burden between type 1 and type 2 severe BPD. Finally, we did not examine long-term outcome data beyond NICU discharge.

In conclusion, the present study identified baseline characteristics, comorbidities, and clinical burden associated with type 2 severe BPD with a cohort of pre-term VLBW infants. Type 2 severe BPD was associated with a substantially high rate of various comorbidities and an enormous clinical burden. Stratifying infants with severe BPD into subtypes based on disease severity will likely improve the care of infants with more severe BPD. Our data highlight the need for a better understanding of the specific etiologies of type 2 severe BPD and a comprehensive, multidisciplinary approach for infants with type 2 severe BPD.

The datasets presented in this article are not readily available because the KNN Publication Ethics Policy adheres to the following research data management and access guidelines: All information about patients and participating NICUs is confidential and is only available to individuals who have access for the purposes of the research activities permitted. Access is only allowed for the purpose of collecting data for the first time, and no access for any other purpose is allowed. Requests to access the datasets should be directed to Yun Sil Chang (yschang@skky.edu).

The registration of data in the KNN was approved by the institutional review board of each participating center. Informed consent was obtained from the parents of each infant prior to participation in the KNN registry. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

H-RK and CC performed the research, analyzed the data, and wrote the manuscript. YJ and CC designed the study. CC reviewed and revised the manuscripts. BK and SK provided suggestions with regard to the content and concept of the manuscript. All authors read and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.