#431 - [Journal Club] - 📌 Rethinking the Link Between BPD Grades and Pulmonary Hypertension

In this episode of Journal Club, Ben and Daphna review a pivotal paper from the Journal of Pediatrics led by the Pediatric Pulmonary Hypertension Network (PPHNet). The study explores invasive hemodynamic metrics and long-term outcomes in infants with BPD-associated pulmonary hypertension. Surprisingly, researchers found an almost equal distribution of pulmonary hypertension across mild, moderate, and severe BPD grades using the Jensen criteria. The hosts discuss the implications of these findings, questioning whether our traditional 36-week assessment timepoint is sufficient and if current grading criteria capture the true severity of pulmonary vascular disease in these vulnerable infants.

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Pulmonary Hemodynamics and Long-Term Outcomes in Children with Pulmonary Hypertension-Associated Bronchopulmonary Dysplasia. Austin ED, Mullen MP, Avitabile CM, Krishnan US, Rosenzweig EB, Keller RL, Kinsella JP, Yung D, Steffes L, Bates A, Elia EG, Romer LH, McGrath-Morrow S, Bernier ML, Mandl KD, Raj JU, Sleeper LA, Abman SH; Pediatric Pulmonary Hypertension Network (PPHNet) Investigators.J Pediatr. 2026 Feb;289:114869. doi: 10.1016/j.jpeds.2025.114869. Epub 2025 Oct 24.

Transcript

Ben Courchia MD (00:00.856) Hello everybody, welcome back to the incubator podcast. We're back today for another episode of Journal Club. Daphna, good morning. How are you?

Daphna Yasova Barbeau MD (00:07.913) I'm doing well. I'm doing very well. I know you had a few more papers that you were very interested in this week.

Ben Courchia MD (00:15.372) Yes, very, very much so. The first paper that I'm going to review is a paper that came out in the Journal of Pediatrics. It is called "Pulmonary Hemodynamics and Long-Term Outcomes in Children with Pulmonary Hypertension Associated Bronchopulmonary Dysplasia". Long title. The first author is Eric Austin. Last author is Steve Abman, and it's coming from the Pediatric Pulmonary Hypertension Network, the PPHNet investigators. It's a very important paper. I know that Dr. Gabriel Altit from our hemodynamics training in Montreal has made it a mandatory read for all the fellows. I don't think he's wrong. I think it's an important paper.

Ben Courchia MD (00:44.59) Let's go through the background. We know that pulmonary hypertension (PH) is quite common, especially in infants who have bronchopulmonary dysplasia, with a prevalence ranging from 6 to 39%, usually diagnosed around 36 weeks of post-menstrual age. In fact, the prevalence of pulmonary hypertension increases as your BPD severity increases, approaching nearly 40% in infants with severe BPD, according to previous classification schemes. If you want to diagnose pulmonary hypertension, there is no question among experts that the gold standard for diagnosis is cardiac catheterization. However, we all know that this is not a simple procedure to perform. It's risky, especially as the babies are smaller. Because of these risks, most of the babies with pulmonary hypertension and associated BPD are diagnosed with an echocardiogram without doing cardiac catheterization. So we lack published studies on BPD-associated pulmonary hypertension that both confirm the diagnosis and provide detailed invasive hemodynamic metrics. That said, the clinical indications for performing the cardiac cath in the BPD populations have been well described and recently reviewed in the literature. This is the key. I think I've mentioned this already once: no matter what people say about hemodynamics and echo, the goal is always to approximate a cath, right? The cath is the gold standard for any measurements related to the heart. It's not surprising to read about that in the introduction.

Ben Courchia MD (03:07.694) Despite many studies showing that pulmonary hypertension is more common in the severe form of BPD, pulmonary hypertension was not actually incorporated into the NRN grade definition of BPD, the Jensen criteria. Furthermore, we haven't really studied the relative differences in pulmonary hemodynamics as defined by cardiac catheterization according to the grade of BPD severity. To give you an idea of the scale of this disease, the PPHNet recently reported on a registry of about 1,500 subjects with all forms of pediatric pulmonary hypertension. In that registry, babies who have pulmonary hypertension associated with BPD as their primary classification were 22%, making it the second most common subtype of pulmonary hypertension in the PPHNet.

Ben Courchia MD (03:07.694) The researchers hypothesized that patients with grade 3 BPD on the Jensen classification would have more severe hemodynamic indices of pulmonary hypertension on cardiac catheterization near the time of diagnosis, as well as worse overall survival. To test this hypothesis, they aimed to do three things. First, they wanted to study the epidemiology of patients who have BPD-associated pulmonary hypertension using the new BPD definition of the Neonatal Research Network, the Jensen criteria. Second, they aimed to evaluate the invasive hemodynamic metrics from cardiac catheterization performed around the time of the diagnosis, stratified by BPD severity. Finally, they wanted to examine how these invasive hemodynamic metrics at diagnosis relate to long-term outcomes, including survival.

Ben Courchia MD (05:33.164) In terms of the study itself, they utilized data from subjects born before 32 weeks of gestation who had a confirmed diagnosis of pulmonary hypertension. These patients consented to participate in a multi-center longitudinal study, specifically the PPHNet registry across 14 pediatric pulmonary hypertension centers in North America. Enrollment began in 2014, and this specific report includes follow-up data all the way through April 2024. The registry includes subjects diagnosed with pulmonary hypertension before 21 years of age based on established pediatric guidelines. For this particular cohort, the diagnosis of pulmonary hypertension was made using an echocardiogram at the discretion of the treating pediatric specialist. The cohort included babies born before 32 weeks, and they excluded infants if they lacked a complete electronic case report form, or if they had a diagnosis of congenital diaphragmatic hernia, omphalocele, or defined genetic syndromes. Basically, this led to a population of 320 babies. It's unusual to see the actual sample size in the methods, but here it's reported already.

Ben Courchia MD (05:33.164) The diagnosis of severe BPD was done using the Jensen criteria. I think that we are now all familiar with the Jensen criteria, but it's a good opportunity to review. This system of classification defines three grades. Grade 1 is defined as nasal cannula support with flow of less than two liters per minute. Grade 2 is nasal cannula support with flow of two liters per minute or more, or non-invasive respiratory support like CPAP. Grade 3 is the use of invasive mechanical ventilation.

Ben Courchia MD (07:08.05) The researchers and the team recorded the use of specific pulmonary hypertension medications, grouping them into different classes: calcium channel blockers, inhaled nitric oxide, phosphodiesterase V inhibitors like sildenafil—this is board review stuff—endothelin receptor antagonists, prostacyclins like treprostinil, and selexipag. It's important to note that cardiac catheterization was not a requirement for enrollment, and it was performed based on the clinical team's discretion at each institution. For those who did undergo the cath, their response to acute vasodilator testing was categorized as reactive versus non-reactive based on established criteria. They used different criteria: the Sitbon, the Barst, and the modified Barst criteria. The primary outcome of the study was a composite of time to the earliest occurrence of either death or lung transplant, analyzed according to BPD severity. A secondary analysis looked at competing risks, including death, lung transplant, and resolution of pulmonary hypertension, with resolution defined simply as cessation of pulmonary hypertension medications.

Daphna Yasova Barbeau MD (07:05.525) We don't usually see lung transplant as an outcome in our studies.

Ben Courchia MD (07:08.05) I know. You read about it and you're like, we discharge these babies and I never mention, even on a grade 3 BPD patient, whether they might be subject to a lung transplant. I never mention it. To be very honest with everybody. I don't know if you guys do, but I never mention that. I never even discussed that with families. Let's get into the results.

Ben Courchia MD (07:36.814) For the 320 subjects, the mean gestational age at birth was 25.8 weeks, ranging from 22 to 31 weeks. The mean birth weight was 721 grams. The researchers had sufficient data to determine the BPD grade at 36 weeks for 278 of these subjects, which is about 87% of the cohort. Among these 278 subjects, 27% were grade 1 BPD, 44% were grade 2, and 29% were grade 3. Almost an equal one-third, one-third, one-third, maybe a little bit more prevalence of grade 2. There were no significant differences among the three BPD grades when looking at sex, age of diagnosis, ethnicity, or race. Prenatal histories were also not notably different among grades one, two, or three. Looking at early neonatal and infant conditions, a history of necrotizing enterocolitis was significantly more prevalent in the more severe BPD group. It occurred in 28% of those with grade 3 BPD, 10% of grade 2, and 16% of grade 1. We don't know very much about the gut-lung axis. We talk about it, but these kinds of associations make you wonder how much the two are at play with one another. Additionally, 30% of the overall cohort was small for gestational age, but this did not really vary by the different BPD grades.

Ben Courchia MD (10:00.834) Looking at medication within a month of the diagnosis, 35% of the cohort were treated with a single pulmonary hypertension-specific drug. Another 11% were treated with two or more drugs. The remainder, 54% of the cohort, were not treated with any drug specific for PH around the time of diagnosis. The median follow-up time for the cohort was 3.6 years, during which 48% underwent cardiac catheterization at least once. In terms of the subjects who underwent cardiac catheterization—69 out of 320 within a month of diagnosis at a median age of 0.7 years—their hemodynamic measurements were consistent with what's known as precapillary pulmonary hypertension. What is precapillary pulmonary hypertension? It means that the pulmonary hypertension is most likely taking place between the right ventricular outflow tract and the lungs. Postcapillary would be something like pulmonary vein stenosis. Their indexed pulmonary vascular resistance was 7.2 Wood units times square meter, and they did not have an elevation in pulmonary capillary wedge pressure, which averaged 9.4 millimeters of mercury. The pulmonary to systemic blood flow ratio, the Qp:Qs, was 1.32. Ten of these subjects had a Qp:Qs greater than 1.5, showing a lot of pulmonary overcirculation. Of these 69 subjects who were catheterized early, 59 had a known BPD grade: 19 had grade 1, 20 had grade 2, and 20 had grade 3.

Ben Courchia MD (10:00.834) Let's look a little bit at survival and long-term outcomes. In terms of mortality, 8% of the cohort died during the study period. While the BPD grade was unknown for three of the patients, of the 22 who had a determined grade, 13 were grade 3, five were grade 2, and four were grade 1. That's interesting to see that this is, as we expect, skewed towards the more severe form of BPD. Interestingly, six of the 25 patients who died had a concurrent diagnosis of pulmonary vein stenosis. This is postcapillary pulmonary hypertension. Among these six patients, the BPD grade was unknown for one, and the other five all had grade 3 BPD. Right heart failure was progressive in 10 subjects. Of these, five had grade 3 BPD, two had grade 2, two had grade 1, and one had an undetermined grade. Three subjects unfortunately died during cardiac catheterization. A reminder of how tricky this procedure can be. When exploring survival at five years post-diagnosis, the transplant-free survival rate was 94% for babies with BPD grades 1 and 2, compared to only 87% for babies with grade 3, but this difference was not statistically significant. Competing risk analyses evaluating time to death or lung transplant also showed no statistical significance according to BPD grade. Even the time to cessation of pulmonary hypertension-specific medication, which increased from grade 1 to grade 2 to grade 3, did not reach statistical significance. Finally, looking back at the hemodynamic data at diagnosis, these metrics did not differ according to BPD severity grade.

Ben Courchia MD (12:26.35) How do we put it all together? Let's highlight some of the key takeaways regarding the distribution and severity of disease. The authors found an equal representation of subjects from all grades of BPD severity. I think that's the number one thing that is important to note. This is in contrast to prior studies, which show that the most severe forms of BPD are probably the ones associated with BPD-associated pulmonary hypertension in very high proportions. Here in this study, we see that mild BPD patients, or grade 1 BPD patients, are actually represented in the cohort. For the 69 subjects who had a cardiac cath within a month of diagnosis, there was a clear precapillary hemodynamic condition, yet neither these hemodynamic metrics nor overall survival were statistically significantly different across the BPD severity grades. In fact, grade 3 BPD had similar invasive hemodynamic metrics to grade 1 and grade 2 at diagnosis. This suggests that the severity of lung disease at 36 weeks, when BPD is graded, is not directly indicative of the severity of pulmonary vascular disease. This is a point that is very well recognized by the Jensen criteria and authors, saying that we use 36 weeks as a time point to assess BPD because that's what we do. But if you could wait a bit longer, you would probably be more accurate. Because you see some babies with some form of mild BPD, the question has to be asked: are you assessing BPD at the right time point? It's a very interesting question.

Ben Courchia MD (12:26.35) The authors reference a recent three-grade system proposed by the BPD scoring criteria by Jensen as graded based on the predictability of death or serious respiratory morbidity for 81% of the subjects, including 20% mortality for those with BPD. However, the system that Jensen outlined does not incorporate pulmonary hypertension in the diagnosis of BPD, which could be a crucial driver of outcomes. So the Jensen criteria were established based on an outcomes-driven classification. The authors are saying, well, if it's outcomes-driven, then maybe we should include pulmonary hypertension in the criteria. They also talk about data from the BPD collaborative, where they looked at patients discharged on mechanical ventilation via tracheostomy. That study, I believe from 2020, found that the majority of infants survived and improved, and that having pulmonary hypertension did not associate with later liberation from respiratory support compared to BPD alone, suggesting that pulmonary hypertension might not be the key driver of respiratory support requirements. By focusing on the 69 subjects catheterized within a month of diagnosis, the team really wanted to look at patients that were more naive to PH therapies and disease duration. They outline the severe elevation of pulmonary artery pressures and much lower rates of responsivity to formal acute vasodilator testing, only 8% to 10% in this study compared to 30 to 82% in previous reports. For instance, a previous single-center study had found a 35% positive testing rate. Ultimately, even though only 8% of the participants died and one had a lung transplant, the overall freedom from death or transplant in this cohort was slightly higher than in most other studies from the past 15 years.

Ben Courchia MD (14:50.67) The conclusion of the study is that using the large data set from the PPHNet, they found a similar distribution of grade 1, grade 2, and grade 3 BPD-associated pulmonary hypertension with a high proportion of freedom from death or lung transplant. Among those undergoing cardiac catheterization, invasive hemodynamic profiles did not really associate with BPD severity grade, although the majority of deaths occurred among those who had the most severe form of BPD. Further studies are warranted, and reduced survival among those with grade 3 BPD and pulmonary hypertension may be driven by factors independent of pulmonary vascular hemodynamic parameters. I think this was quite interesting. The idea of the presence of BPD in various grades and pulmonary hypertension was obviously quite interesting.

Daphna Yasova Barbeau MD (17:00.67) Yeah, I agree. I thought it was kind of unexpected.

Ben Courchia MD (17:04.417) Yeah. Do you have any thoughts on it?

Daphna Yasova Barbeau MD (17:06.216) I'm wondering, should that change our follow-up referral plans? Do these babies who we think are low grade need to be watched more carefully than I thought? I don't know.

Ben Courchia MD (17:22.252) What this says to me is that the information we gather at 36 weeks is not the most reliable. At 36 weeks, we try to have a serious conversation with the parents about, "Okay, this is the time we make a decision on clinical diagnosis of BPD." But the truth of the matter is that at 36 weeks, you don't know very much. I had read some papers that look at how it would be better if we actually made that assessment closer to 40 weeks. If you think about it, when we talk about really invasive management of BPD, whether it is doing a tracheostomy or anything like that, we don't do it at 36 weeks. Most people wait until 42, 46 weeks, sometimes 52 weeks. We don't really act on anything too much when it comes to 36 weeks, yet we want to label the condition at that moment. The obvious issue is that we need to find a time point where most babies are still in the NICU because if they get discharged, then you can't assess them. First of all, that's not necessarily true. But also, most of the babies with BPD who are on significant respiratory support are not discharged by 36 weeks. They're still in the NICU.

Ben Courchia MD (18:45.198) Very tough, but very interesting nonetheless. And very surprising. I'm going to remind people, the main finding is the association between grades of BPD and pulmonary hypertension...

Daphna Yasova Barbeau MD (19:23.828) You can help yourself. You had to go in for a second shot at the conclusion.

Ben Courchia MD (19:30.289) It's still baffling that among the patients they had, there were 27% grade 1 BPD, 44% grade 2, and 29% grade 3. This is insane. If you had asked me, of the babies who have BPD-associated pulmonary hypertension, how many have grade 1, grade 2, or grade 3? I would have said 80%, 15%, 5%.

Daphna Yasova Barbeau MD (20:02.112) Yeah, in the opposite. Grade 3, 80%.

Ben Courchia MD (20:00.000) Right. All right, buddy, I'll see you tomorrow.

Daphna Yasova Barbeau MD (20:10.000) Sounds good.