Predicting Clinical Outcomes of Severe Bronchopulmonary Dysplasia through New Definitions and Phenotypes

doi:10.21203/rs.3.rs-3794261/v1

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Predicting Clinical Outcomes of Severe Bronchopulmonary Dysplasia through New Definitions and Phenotypes

https://doi.org/10.21203/rs.3.rs-3794261/v1

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Objective: To compare the accuracy of three newly proposed definitions of bronchopulmonary dysplasia (BPD) in predicting outcomes, and to assess the impact of BPD phenotypes (large airway vs. parenchymal vs. vascular disease) on BPD outcomes.

Study Design: Retrospective chart review of 100 infants with severe BPD discharged from a Children’s hospital between 2020-2021. Multivariable models evaluated the associations between BPD definitions and phenotypes with tracheostomy and death.

Result: Jensen’s and BPD collaborative criteria best predicted outcomes associated with tracheostomy and/or death (p < 0.001). Among the three BPD phenotypes, large airway disease independently predicted death or tracheostomy (OR 10.5, 95% CI 1.6, 68.1). The combination of all three phenotypes also predicted death or tracheostomy (OR 9.8, 95% CI 1.0, 93.5).

Conclusion: Newly proposed definitions of BPD better predict outcomes compared to the 2001 NIH definition with BPD phenotypes impacting mortality and short-term outcomes. These data may be useful for counseling families and developing phenotype-based individualized treatment plans.

Biological sciences/Physiology/Respiration

Health sciences/Diseases/Respiratory tract diseases

Health sciences/Diseases/Cardiovascular diseases

Bronchopulmonary dysplasia

BPD classification

tracheostomy

BPD phenotypes

outcomes

Bronchopulmonary dysplasia (BPD) remains the most common cause of morbidity and mortality in preterm infants (1). From its original description by Northway in 1967, BPD has evolved over time in terms of its clinical, anatomic, physiologic, and pathologic definitions (2). The most widely used definition was from the 2001 NIH workshop which classified BPD into mild, moderate, and severe disease based on the degree of respiratory support at 36 weeks post menstrual age (PMA) (1, 3). There are several limitations inherent with this definition including the broad categorization of the most severe form of disease (4, 5). Given the clinical variability within the severe BPD subgroup and the use of newer modalities for providing non-invasive respiratory support for infants with BPD, a need for improved classification that better predict outcomes has emerged (6). Three recently proposed definitions have been published. First, Higgins, et al suggested that BPD be categorized into subtypes grades I, II, and III, to separate out those infants with severe BPD into more distinct categories (3). Secondly, Jensen used a data-driven approach to study 18 distinctive definitions of BPD to develop improved diagnostic criteria techniques (6). Thirdly, the multicenter BPD collaborative group proposed a simplistic two-tier separation of severe BPD into type 1 if receiving non-invasive respiratory support, and type 2 for those on invasive respiratory support (7). Studies investigating the correlation of these newer definitions on short-term pulmonary outcomes are limited.

Another limitation of the original and refined definitions of BPD is the fact that these definitions were based solely on the respiratory support at a specific time point of 36 weeks gestational age, and do not account for the complex interplay of pathophysiologic mechanisms that contribute to clinical spectrum and diagnosis of BPD. BPD is known to be a heterogenous disease with multiple pathophysiological processes that affect the pulmonary mechanics (8). There are three main anatomic components of the developing lung involved in the disease process which include the large airways, the peripheral airways and adjacent lung parenchyma, and the pulmonary vascular bed (9). Each of these components can have an associated pathology that can manifest clinically with isolated airway, parenchymal or vascular phenotype, or more commonly as any combinations of two or three of these clinical phenotypes.

To the best of our knowledge, the ability of the newer definition to predict long-term respiratory outcomes, as well as the impact of individual BPD endotypes or combinations of these endotypes on respiratory outcomes is largely unknown. Therefore, the goals of our study were to compare the ability of each of the three proposed definitions to predict morbidity and mortality associated with severe BPD within a year after initial NICU discharge, and to secondly investigate the association between the severe BPD phenotypes and various clinical outcomes within the first year after initial hospital discharge.

Study population

This is a retrospective cohort study of infants discharged between January 1, 2020, and December 31, 2021, with a diagnosis of severe BPD based on the 2001 NIH workshop definition as the need for positive pressure support and/or ≥ 30% fraction of inspired oxygen (FiO2) at 36 weeks PMA. The Center for Infant and Pulmonary Disorders (CIPD), located in Children’s Mercy Kansas City (CMKC), MO, USA provided de-identified data for this study with CMKC Institutional Review Board approval.

New BPD definitions and BPD phenotypes

The three new definitions of BPD by Higgins, et al (2018), Jensen, et al (2019), and Guaman, et al (2021) were used to reclassify all subjects based on the respiratory support at 36 weeks PMA (if born < 32 weeks gestational age) or at 56 days of life (if born ≥ 32 weeks gestational age) (3, 6, 7). Details of each of these new classifications are shown in Table 1. Higgins criteria was developed by an expert panel at the National Institute of Child Health and Human Development (NICHD) workshop in 2016 that proposed a new definition of BPD based on prior definitions and current management strategies for treating BPD. New respiratory strategies made some patients with BPD unclassifiable based on the previous 2001 standard BPD definition. They proposed a three-grade system namely, Grade I included patients with non-invasive respiratory support ≥ 3 liter per minute (LPM) with FiO2 21, nasal cannula support between 1–3 LPM with FiO2 22–29, and nasal cannula support < 1 LPM with 22–70 FiO2. Grade II included patients with invasive ventilation with FiO2 21, non-invasive respiratory support ≥ 3 LPM with FiO2 22–29, nasal cannula support between 1–3 LPM with FiO2 ≥ 30%, and nasal cannula support < 1 LPM with > 70 FiO2. Grade III included patients with invasive ventilation with FiO2 > 21 and any non-invasive respiratory support ≥ 3 liter per minute with FiO2 ≥ 30 (3).

Table 1

Newly proposed definitions of BPD
Grades	Higgins	Jensen	BPD Collaborative
I/1	NC < 1 L/min at 22–70% FiO₂; NC 1–3 L/min at 22–29% FiO₂; nCPAP, NIPPV, or NC ≥ 3 L/min at 21% FiO₂	NC < 1 L/min at 22–70% FiO₂; NC 1–3 L/min at 22–29% FiO₂; NC ≥ 3 L/min, nCPAP, or NIPPV at 21% FiO₂	NC at > 30% FiO₂; HFNC, CPAP, or NIV at 21–100%
II/2	NC < 1 L/min at > 70% FiO₂; NC 1–3 L/min at ≥ 30% FiO₂; nCPAP, NIPPV, or NC ≥ 3 L/min at 22–29% FiO₂; Invasive PPV at 21% FiO₂	NC < 1 L/min at 71–100% FiO₂; NC 1–3 L/min at 30–100% FiO₂; NC ≥ 3 L/min, nCPAP, or NIPPV at 22–29% FiO₂; Invasive PPV at 21% FiO₂	IPPV at 21–100% FiO₂
III	nCPAP, NIPPV, or NC ≥ 3 L/min at ≥ 30% FiO₂; IPPV at > 21% FiO₂	NC ≥ 3 L/min, nCPAP, or NIPPV at 30–100% FiO₂; IPPV at 22–100% FiO₂	––
CPAP continuous positive airway pressure, FiO2 fraction of inspired oxygen, HFNC high flow nasal cannula, IPPV invasive positive pressure ventilation, NC nasal cannula, nCPAP nasal continuous positive airway pressure, NIPPV non-invasive positive pressure ventilation, NIV non-invasive ventilation

Jensen used a data-driven approach to study 18 distinct definitions of BPD to develop improved diagnostic criteria that best predicted adverse respiratory and neurological outcomes using current respiratory care techniques. The proposed definition used a three-grade scale namely, Grade I included patients with nasal cannula support ≤ 2 LPM. Grade II included patients with nasal cannula support > 2 LPM or non-invasive respiratory support. Grade III included patients with invasive mechanical support (6). Guaman utilized data from six centers involved in the BPD Collaborative Registry which divided the 2001 NIH Workshop definition of severe BPD into two sub-categories, namely, type 1 which includes those receiving nasal cannula or non-invasive respiratory support and type 2 which includes those receiving invasive respiratory support (7).

The BPD phenotypes were based on the presence of pathology in any one or a combination of two or three anatomic components of the lungs namely, central airways, peripheral airways and parenchyma, or pulmonary vascular compartment. For central airway pathology, the presence of tracheobronchomalacia (TBM) or upper airway lesions was based on bronchoscopy performed by either a pediatric otolaryngologist or pulmonologist. The presence of severe BPD pathology in the peripheral airway and surrounding parenchyma was based on chest x-ray films taken at around 36 weeks (+/- 1 week) PMA and were reviewed and rated independently by 2 neonatologists and a neonatal fellow using the Weinstein scoring tool with scores 4–6 designating severe parenchymal disease (10). Inter-rater analysis using Intraclass Correlation Coefficient (ICC) was found to be 0.953 for individual grading and 0.976 for the average grading, and were consistent with excellent reliability (11). The presence of vascular pathology in the form of pulmonary hypertension (PH) was based on echocardiogram reports performed at or after 36 weeks PMA.

Demographic data and BPD outcomes

Demographic and clinical outcome data were collected up to 1 year after the day of initial NICU discharge. Primary outcome data included the need for tracheostomy and/or death prior to initial NICU discharge. Secondary outcomes included ventilatory support or oxygen support (if applicable), diuretic medication use, PH medication use, and need for tube feeding (gastrostomy or nasogastric tube) at the time of initial NICU discharge, at 6 months, and at 12 months after the day of initial NICU discharge. In addition, hospital readmissions secondary to respiratory diagnosis within the first 12 months after discharge were also collected.

Statistical analysis

Relationships between grades and outcome variables were analyzed using chi-square or Fisher’s exact tests. Logistic regression models were used to get odds ratios (ORs) and 95% confidence intervals (CIs). In cases where zero events happened within a grade, exact logistic regression models were used. A significance level of 0.05 was used for all tests. SAS version 9.4 (SAS Institute Inc., Cary, NC) was used for all analyses.

A total of 100 infants met the inclusion criteria of having severe BPD based on the 2001 NIH workshop definition. Out of 100 infants in the cohort, 60 were male (60%). Fifty-three (53) were Caucasian (53%) and 33 were African American (33%). The mean gestational age at birth was 26 weeks (SD ± 2.4) and 98 were born < 32 weeks gestation (98%). The mean birth weight was 769 grams (SD ± 304). Using Higgins criteria, 11 infants (11%) were reclassified as grade I, 18 infants (18%) as grade II, and 71 infants (71%) as grade III BPD. Using Jensen criteria, 10 infants (10%) were reclassified as grade I, 64 infants (64%) as grade II, and 26 infants (26%) as grade III BPD. Using the BPD collaborative definition, 74 infants (74%) were reclassified as type 1 and 26 infants (26%) as type 2 BPD as shown in Table 2. The distribution of study subjects based on the grading or typing used by the three new definitions of BPD revealed that Jensen’s grades II and III closely matched with the BPD Collaborative’s type 1 and 2 respectively, while the Higgins definition had grade III as the most predominant subgroup.

Table 2

Demographic data and outcomes of infants included in reclassification of BPD
		Study cohort (n = 100)
Sex
	Male, n (%)	60 (60)
	Female, n (%)	40 (40)
Race
	White, n (%)	53 (53)
	Black, n (%)	33 (33)
	Other, n (%)	14 (14)
Gestational age at birth in weeks, mean (SD)		26 (2.4)
Birth weight in grams, mean (SD)		769 (304)
Inborn vs Outborn
	Inborn, n (%)	31 (31)
	Outborn, n (%)	69 (69)
Higgins classification at 36 wk PMA
	Grade 1, n (%)	11 (11)
	Grade 2, n (%)	18 (18)
	Grade 3, n (%)	71 (71)
Jensen definition at 36 wk PMA
	Grade 1, n (%)	10 (10)
	Grade 2, n (%)	64 (64)
	Grade 3, n (%)	26 (26)
BPD Collaborative definition at 36 wk PMA
	Grade 1, n (%)	74 (74)
	Grade 2, n (%)	26 (26)
BPD bronchopulmonary dysplasia, PMA post menstrual age, SD standard deviation

Of the 100 subjects, 19 (19%) had a combined outcome of tracheostomy or death, 14 (14%) had tracheostomy and 7 (7%) died. 2 of the 7 infants who died had tracheostomy. Applying the three new classifications, we found that Jensen’s and BPD collaborative classifications accurately predicted tracheostomy (p = < 0.01), death (p = < 0.01), and the combined outcomes of tracheostomy or death (p = < 0.01), while Higgin’s classification did not predict those outcomes as shown in Table 3. In addition, both Jensen’s and BPD Collaborative classifications significantly predicted oxygen use at discharge, PH medication use at discharge, and tube feeding at discharge and at 6- and 12-month time periods. The Higgin’s classification was able to predict only the use of oxygen at discharge and tube feeding at discharge and at 6- and 12-month time points as shown in Table 3. Of note, none of the new classifications accurately predicted the rate of rehospitalization within 12 months after NICU discharge.

Table 3

Outcomes based on new severe BPD classifications
	Higgins				Jensen				BPD Collaborative
	G I n = 11	G II n = 18	G III n = 71	p-value	G I n = 10	G II n = 64	G III n = 26	p-value	G 1 n = 74	G 2 n = 26	p-value
Death	1 (9%)	1 (6%)	5 (7%)	1	1 (10%)	0 (0%)	6 (23%)	< 0.01 *	1 (1%)	6 (23%)	< 0.01 *
Trach	1 (9%)	1 (6%)	12 (17%)	0.65	1 (10%)	2 (3%)	11 (42%)	< 0.01 *	3 (4%)	11 (42%)	< 0.01 *
Death/Trach	1 (9%)	2 (11%)	16 (23%)	0.42	1 (10%)	2 (3%)	16 (62%)	< 0.01 *	3 (4%)	16 (62%)	< 0.01 *
Vent at d/c	0 (0%)	1 (6%)	9 (13%)	0.66	0 (0%)	2 (3%)	8 (31%)	< 0.01 *	2 (3%)	8 (31%)	< 0.01 *
Vent at 6 m/o	0 (0%)	1 (6%)	8 (11%)	0.63	0 (0%)	2 (3%)	7 (27%)	< 0.01 *	2 (3%)	7 (27%)	< 0.01 *
Vent at 12 m/o	0 (0%)	1 (6%)	6 (9%)	1	0 (0%)	1 (2%)	6 (23%)	< 0.01 *	1 (1%)	6 (23%)	< 0.01 *
Oxygen at d/c	5 (50%)	6 (35%)	49 (75%)	< 0.01 *	4 (44%)	39 (61%)	17 (90%)	0.03 *	43 (59%)	17 (90%)	0.01 *
pHTN med at d/c	0 (0%)	1 (6%)	11 (17%)	0.32	0 (0%)	6 (9%)	6 (32%)	< 0.01 *	6 (8%)	6 (32%)	0.02 *
NG/GT feeds at d/c	2 (20%)	5 (29%)	40 (62%)	< 0.01 *	1 (11%)	30 (47%)	16 (84%)	< 0.01 *	31 (43%)	16 (84%)	< 0.01 *
NG/GT feeds at 6 m/o	2 (20%)	3 (19%)	39 (62%)	< 0.01 *	1 (11%)	27 (44%)	16 (84%)	< 0.01 *	28 (40%)	16 (84%)	< 0.01 *
NG/GT feeds at 12 m/o	1 (11%)	2 (13%)	35 (57%)	< 0.01 *	0 (0%)	23 (39%)	15 (79%)	< 0.01 *	23 (34%)	15 (79%)	< 0.01 *
Rehospitalization	3 (30%)	5 (29%)	21 (32%)	0.97	3 (33%)	22 (34%)	4 (21%)	0.54	25 (34%)	4 (21%)	0.27
d/c discharge, G grade, GT g-tube, m/o month, NG nasogastric, pHTN pulmonary hypertension, trach tracheostomy, vent ventilator

Table 4

Demographic data and outcomes of infants included in classification of BPD phenotypes
		Study cohort (n = 29)
Sex
	Male, n (%)	15 (52)
	Female, n (%)	14 (48)
Race
	White, n (%)	16 (55)
	Black, n (%)	11 (38)
	Other, n (%)	2 (7)
Gestational age at birth in weeks, mean (SD)		26.8 (2.6)
Birth weight in grams, mean (SD)		720 (300)
Inborn vs Outborn
	Inborn, n (%)	2 (7)
	Outborn, n (%)	27 (93)
Death
	Yes, n (%)	5 (17)
	No, n (%)	24 (83)
Need for tracheostomy
	Yes, n (%)	14 (48)
	No, n (%)	15 (52)
SD standard deviation

Twenty-nine of the 100 infants (29%) in the cohort had complete data to determine the individual or combined clinical phenotypes of severe BPD based on pathology present in the central airway, peripheral airway and parenchyma and/or pulmonary vascular compartment. Of the 29 infants, 18 (62%) had severe parenchymal phenotype, 20 (69%) had central airway phenotype, and 18 (62%) had pulmonary vascular phenotype. The presence of two or more phenotypes in an individual subject is very common such that 9 infants (31%) had the three clinical phenotypes present in them as shown in Fig. 1. Of note, 4 infants (14%) did not have evidence of severe parenchymal, airway nor vascular pathology.

In terms of predicting death and/or tracheostomy based on individual phenotype, we found that central airway phenotype significantly predicts the need for tracheostomy and/or death (OR 10.5, 95% CI 1.6, 68.1; p = 0.014). Additionally, the central airway phenotype also predicts ventilator-dependence at the time of NICU discharge (10.8, 95% CI 1.9, infinity; p = 0.01) and at 6 months after discharge (8.9, 95% CI 1.5, infinity; p = 0.027). The presence of pulmonary vascular phenotype predicts the use of PH medications at the time of NICU discharge (14.0, 95% CI 1.3-147.4; p = 0.027) and at 12 months after discharge (8.8, 95% CI 1.4, infinity; p = 0.037). Furthermore, the combination of the three phenotypes (parenchymal, airway and vascular) significantly predicts the need for tracheostomy or death (OR 9.8, 95% CI 1.0, 93.5; p = 0.043) as shown in Tables 5a and 5b.

Table 5

a: Impact of individual phenotypes on primary outcomes (death, need for tracheostomy)
	Severe Parenchymal Disease			Airway Disease			Pulmonary Vascular Disease
	No n = 11	Yes n = 18	p-value	No n = 9	Yes n = 20	p-value	No n = 11	Yes n = 18	p-value
Death	2 (18.2%)	3 (16.7%)	1	1 (11.1%)	4 (20.0%)	1	0 (0%)	5 (27.8%)	0.126
Trach	3 (27.3%)	11 (61.1%)	0.077	2 (22.2%)	12 (60%)	0.109	4 (36.4%)	10 (55.6%)	0.316
Death/Trach	4 (36.4%)	13 (72.2%)	0.119	2 (22.2%)	15 (75.0%)	0.014 *	4 (36.4%)	13 (72.2%)	0.119
trach tracheostomy
* p-value < 0.05

Table 5

b: Impact of the combination of phenotypes on primary outcomes (death, need for tracheostomy)
	Severe Parenchymal Disease + Airway Disease			Severe Parenchymal Disease + Pulmonary Vascular Disease			Airway Disease + Pulmonary Vascular Disease			Severe Parenchymal Disease + Airway Disease + Pulmonary Vascular Disease
	No n = 23	Yes n = 6	p-value	No n = 26	Yes n = 3	p-value	No n = 25	Yes n = 4	p-value	No n = 20	Yes n = 9	p-value
Death	5 (21.7%)	0 (0%)	0.553	5 (19.2%)	0 (0.0%)	1	4 (16.0%)	1 (25.0%)	0.553	2 (10.0%)	3 (33.3%)	0.287
Trach	10 (43.5%)	4 (66.7%)	0.390	13 (50.0%)	1 (33.3%)	1	12 (48.0%)	2 (50.0%)	1	8 (40.0%)	6 (66.7%)	0.245
Death/Trach	13 (56.5%)	4 (66.7%)	1	16 (61.5%)	1 (33.3%)	0.553	14 (56.0%)	3 (75.0%)	0.662	9 (45.0%)	8 (88.9%)	0.043 *
trach tracheostomy
* p-value < 0.05

In this cohort of infants with severe BPD based on the 2001 NIH definition, we found that by reclassifying them based on the three newer classifications of BPD, majority of them had grade III based on Higgins, grade II based on Jensen’s, and type 1 by the BPD Collaborative definition. We also found that both the Jensen and BPD Collaborative definitions were able to reliably predict the need for tracheostomy or death during NICU hospitalization, as well as the need for respiratory support, diuretic, PH medications, and tube feeding at the time of discharge and up to 1 year following NICU discharge. None of the new definitions accurately predicted the need for rehospitalization within 12 months following initial NICU discharge. In addition, based on the clinical BPD phenotyping, we found that those infants with central airway disease, alone and in combination with parenchymal and pulmonary vascular disease accurately predicted the need for tracheostomy or death in our cohort of infants with severe BPD.

Since the recent publications of the newer BPD definitions by Higgins, Jensen, and the BPD Collaborative in 2018, 2019 and 2021 respectively, there have been a handful of studies that evaluated the long-term outcomes of infants with severe BPD based on these new BPD classifications similar to our current study. In 2021, Jeon et al, compared the Higgins’ and Jensen’s BPD classification to the original NICHD 2001 definition and found that infants with severe BPD had significantly increased risks for long-term respiratory mortality and morbidities, neurodevelopmental delay, and growth restriction at 18–24 months corrected age (12) as well as at 3 years of age (13). They suggested that the new definitions should be adopted to identify high-risk infants and improve long-term outcomes (13). In contrast, Ling Sun, et al, compared Higgins classification with the original 2001 NIH definition and found that the latter was a better indicator of severe respiratory morbidities or death during the first 18 to 24 months of life (14). Vyas-Read et al. used data from the Children’s Hospital Neonatal Consortium (CHNC) to reclassify infants with severe BPD based on Higgins’, Jensen’s, and the Canadian Neonatal Network (CNN) BPD definitions, and to assess the association between BPD severity and death, tracheostomy, or length of stay, compared to infants without BPD. They found that mortality was highest among infants with grade III Jensen’s classification, followed by Higgins’ grade III. However, infants with grade II BPD remained at significant risk for death and need for tracheostomy (15). The study by Katz et al. compared Higgins and Jensen definitions to the 2001-NIH definition in predicting neurodevelopmental and respiratory outcomes at a longer period of 2 and 5 years corrected age. They found that all three definitions of BPD had comparable discriminating power for neurodevelopmental impairment and respiratory morbidity, with the exception that Higgins definition had less predictive power for neurologic outcomes at 2 years corrected age (16). Of note, none of these recent studies have correlated the rate of rehospitalizations among infants with severe BPD based on the new definitions. To date, the data is limited as to which definitions of severe BPD best predicts mortality and long-term morbidity outcomes. Our findings add to the ongoing discussion on which definition should be used in the clinical setting. The ideal definition will be one that is simple and easy to use but able to identify infants at highest risk of mortality and long-term morbidity. A multicenter collaborative approach designed to develop the most appropriate definition of BPD to accurately predict short- and long-term outcomes in a prospective fashion is urgently needed.

The recognition of the heterogeneity of BPD disease with multiple pathophysiological processes involving the three different components of the developing lung has enabled the identification of distinct disease phenotypes of BPD that may result into better risk stratification and targeted therapeutic interventions (17). These three disease components include the large airways, peripheral airways and adjacent lung parenchyma, and the pulmonary vasculature. In our study, we found that two thirds of the subjects in our cohort had severe parenchymal disease, or large airway disease or pulmonary vascular disease and one third of them had all the three disease phenotypes present together. This phenotypic disease distribution was similar to what was reported by Wu, et al (9). The incidence of severe parenchymal disease in severe BPD based on chest x-ray and CT findings is expectedly high (18, 19). Large airway disease, most commonly TBM, is present in 10 to 46% of infants with severe BPD (20, 21, 22). Of note, we found that the presence of large airway disease by itself is associated with the need for tracheostomy, which is also consistent with the findings from other single center studies (23, 24, 25). Additionally, large airway phenotype was associated with ventilator use at the time of discharge and at 6 months but not at 12 months after discharge suggesting the resolution of airway disease within that period of time. Our rate of pulmonary hypertension in infants with severe BPD was 62% compared to the reported rates that range from 15–53% (26, 27). One possible reason for this higher rate is the routine surveillance of all infants with severe BPD by 36 weeks PMA in our center. Although the presence of PH alone was not associated with a need for tracheostomy in this present study, we previously reported that PH alone in ventilator-dependent infants with BPD is significantly associated with the need for tracheostomy or death (28). The presence of PH alone and in combination with parenchymal disease not surprisingly were associated with the use of PH medications at discharge and through the first year after discharge. Collectively, our findings add to the growing evidence of the variability of the clinical phenotypes within and between infants with severe BPD.

More significantly, we found that the presence of all the three disease phenotypes in an individual was highly associated with the risk of death or need for tracheostomy. Again, this is consistent with Wu’s findings, and in addition reported that having more disease components was associated with an incremental increase in the risk for death (9). These findings convey that the presence of a single clinical phenotype of the disease does not predict the overall burden of severe BPD disease because very commonly these phenotypes exist in combination. Targeted therapy for a particular disease phenotype will prove challenging for the clinicians when there is more than one disease component present in an individual infant, and treatment of one component may result in improvement but may be detrimental for the other component of the disease. Recognizing the multi-phenotypic nature of severe BPD will be important to address its complex treatment strategies and its long-term outcomes.

The primary limitation of this study is its inherent design as a retrospective review from a single institution. Although the number of subjects (n = 100) was adequate for the BPD reclassification portion of the study, a much small number of subjects (n = 29) was included in the phenotyping of the disease. The diagnosis of large airway disease based on bronchoscopy performed by either a pediatric otolaryngologist or pulmonologist, the timing of the bronchoscopy was not uniform, and the results were abstracted from written report available in medical records. Similarly, echocardiogram results were from written reports and the images were not reviewed specifically for this study. Lastly, our study population was drawn from a level IV regional referral NICU with its own element of selection bias and may not represent the wider inclusion of infants with severe BPD.

The reclassification of infants with severe BPD based on the newer definitions, along with the identification of BPD disease phenotypes improved the identification of infants at highest risk for death, need for tracheostomy, and short-term outcomes after NICU discharge. This study will add to the current literature that are useful to predict important outcomes, help develop standards of care, guide families in clinical decision-making, and design future studies to optimize the overall long-term outcomes of infants with severe BPD.

Funding: No funding was received to complete this project

Disclosures: The authors have no financial or non-financial conflicts of interest

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There is NO conflict of interest to disclose.

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Predicting Clinical Outcomes of Severe Bronchopulmonary Dysplasia through New Definitions and Phenotypes

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Introduction

Materials and Methods

Study population

New BPD definitions and BPD phenotypes

Demographic data and BPD outcomes

Statistical analysis

Results

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