Dr. Roberta Keller - phaware® interview 412

Apr 25, 2023

Roberta Keller, MD is a neonatologist, an expert in caring for critically ill newborns, and a member of the multidisciplinary pediatric pulmonary hypertension team from UCSF’s Benioff Children’s Hospital. I

n this episode, Dr. Keller discusses the broadening scope of children with PH and how clinical treatment has evolved.

My name's Roberta Keller. I'm a professor of pediatrics at the University of California San Francisco. I practice at the Benioff Children's Hospital in San Francisco. I am a neonatologist, which is a subspecialty pediatrics. I am a member of our multidisciplinary pediatric pulmonary hypertension team. I thought we could talk a little bit about the broadening scope of children with pulmonary hypertension that we treat in our practice today and how that's evolved from the original kind of pediatric pulmonary hypertension clinical practice.

As I mentioned, we have a multidisciplinary pediatric pulmonary hypertension team at UCSF. Our group is pediatric cardiologists with specialty in interventional and diagnostic cardiac catheterization and imaging. Pediatric critical care with specialization in perioperative care of children with congenital heart disease. Neonatology, which is myself with a particular interest in neonatal respiratory failure and extracorporeal memory and oxygenation or ECMO. Pediatric pulmonology, as well as our nurse practitioners that we work with as part of our team, actually probably the leaders of our team. As well as a practice nurse and other members. We have a multidisciplinary team. That has developed over time, but I think even from very early on, we were based as neonatology, pediatric critical care, and cardiology even from very early on. 

We did a study years ago, which was published in 2016, where we assembled retrospectively the cohort of patients. We wanted to look at their functional class at the time of initiation of therapy and then how that changed over time and how that related to the outcome of mortality. We did find that functional class, not surprisingly, was associated with mortality or survival. But also of interest, when we assembled this cohort and looked at the underlying etiologies of pulmonary hypertension, we actually had 60% of our kids who had what we call Group 3 Pulmonary Hypertension, which is pulmonary hypertension secondary to respiratory disease.

The reason this was so interesting was because much of the studies of medications for pulmonary hypertension have been focused on pulmonary arterial hypertension in the Group 1 category, which has been defined as idiopathic or heritable or familial or secondary to congenital heart disease. In fact, we had the majority of our patients who were outside of that Group 1. 

We are part of the pediatric pulmonary hypertension network or PPHNet. In a later study, we published from our registry of I believe nine centers at the time, the Group 3 Pulmonary Hypertension made up about 50% of our cohort. I think that certainly exemplifies how our practice in pediatric pulmonary hypertension has really broadened beyond that Group 1 set of patients. I think as we continue to practice and learn more about children with pulmonary hypertension, we are finding all different types of etiologies and comorbidities that are associated with pulmonary hypertension. Some of them are relatively short-lived and some of them are much more persistent. 

One example, for instance, is children born with birth defects that affect their urinary tract where they have either obstructed urine output before they're born or have decreasing or loss of kidney function and utero. This affects their level of amniotic fluid, which they're developing, which affects their lung development. For instance, we see many of these children who are quite sick at birth from a lung perspective, both in terms of their lung function, but also in terms of pulmonary hypertension. But with good support, they're able to recover and still have the persistent morbidity associated with their kidney dysfunction, but really have minimal or no evident clinical lung disease. Again, I think that's just reflecting the expansion of our practice and expansion of our understanding of what types of lung disease and pulmonary hypertension are reversible and recoverable and which types may not be.

As you are able to show your value as a multidisciplinary team, more people are going to ask your opinion, so that's good. So you are going to see more patients because of that. I think as we have more options for therapy, then there's more reason for our colleagues to refer to us in terms of utilizing that expertise. Also, there's a broader approach to evaluation. Then the expertise becomes more valuable. If you have one medication and one explanation, most people can pick that up on their own. They don't necessarily need a team to consult. I think our practice is growing because of the complexities of the treatments we're able to provide as well as the evaluation. 

The evaluation affects how you're going to pursue your treatment. For instance, when we find genetic modifiers of disease, we still don't know if those children are ever going to come off of all medications or are they always going to be on a medication? We just don't know is it ever going to be safe to take children off of medication completely if they have a genetic variant that's associated with pulmonary hypertension and had a clinical picture of pulmonary hypertension very early on. 

One example of that is TBX4. TBX4 looks like a variant where there's a bimodal presentation. So there's this childhood presentation and there's this adult presentation. But even among the childhood presentation, there is a group of children who are sick as newborns and then they clinically recover and then go on to have more severe expression of pulmonary hypertension later and come back into the awareness of pulmonary hypertension providers. The question is if you diagnose one of those children early on with TBX4, which we now know that it's a condition we should look for. We have genetic tests where we can look for it. So if you diagnose them early on, if you kept them on treatment, could you prevent some of the severe outcomes that sometimes do occur with these children?  We don't know the answer, but obviously we would hope so. 

But those kids, they might not have had clinical pulmonary hypertension for several years. So then you're just treating them even though they don't seem to have the condition you're treating them for, even though you think they're going to have the condition if you don't treat them, or maybe even if you do. I think that's also a new area for us. Maybe we should be considering genetic testing in all of our patients who present with persistent pulmonary hypertension. The newborn, which is this very early neonatal form, pulmonary hypertension, which typically resolves. Even in kids who we've later found out to have a genetic condition which predisposes them to pulmonary hypertension. So should we think about doing genetic testing for all of those children? That may be the direction we move in, particularly if we can identify that we can treat and potentially limit or prevent later outcomes. 

If I had a child who had PPHN (Persistent pulmonary hypertension of the newborn) when they were a baby, I might ask that question. Should I have my child checked again? Should someone take a look? I think some of those findings are subtle. They're all within the range of a typical child. Some kids are more active than others. Some kids have asthma and use an inhaler when they're at PE or playing soccer. Some kids don't gain weight as hardly as other children or their growth isn't as robust as other children. But that's all what's in the range of what we would consider to be typical or normal so we don't really pursue it.

So not to make anyone anxious, but it can be these subtle signs that can manifest later with more severe illness. We all have a story like that. We all have a patient or two patients or five patients who were like that. Some of whom had an illness as an infant, but some of them who didn't. They didn't have an illness as an infant, but they spent five to seven years of their life maybe not being the most active kid in PE. Not anything that necessarily anyone would go running to the pediatrician for, but maybe there is something there. 

In terms of referral, I think we get kids like that who they might have a chest x-ray for some other reason or something. They might have abdominal pain and get an abdominal x-ray or a CT scan, and then somebody sees that their heart looks big, because they can see that at the top of their abdomen. They see that their heart looks big and they said, oh, wait, maybe there's something we should look at here. Then they get diagnosed with pulmonary hypertension. 

We have families that travel to altitude, so we definitely have kids who go on trips to the mountains and have an event. It may not be catastrophic event, but it can be, but it may just be that they get very fatigued. They might look blue. They might be more prone to having acute mountain sickness or something like that. Sometimes, those are the triggers. Patients go to their pediatrician or they start to read about it and they may self-refer. So those are definitely two different ways that kids later on come into our practice. 

I had mentioned about 50% to 60% of children with pediatric pulmonary hypertension in the registry and in our own practice having Group 3 disease, but looks like up to about 30% of our patients may have some atypical etiology that could be a genetic variation or something like that that's contributing to that clinical picture. Even more complicated is the fact that some of these genetic variants are associated with other birth defects, other anomalies. Then we think that that birth defect is related to the pulmonary hypertension, which this is the way we thought for a long time. But then maybe you go back three steps and it's this genetic variant that's related to both the pulmonary hypertension and the birth defect. 

We've certainly started to learn about that more in terms of congenital heart disease. There's always been some group of children with congenital heart disease who are repaired and then go on and have pulmonary hypertension even though they're repaired at the right time and everything seems like it should be recovering and doing fine and go on and live a healthy life. Then they end up having pulmonary hypertension later on. We are learning more and more about genetic defects that both are responsible for the congenital heart disease as well as for the pulmonary hypertension.

So that's just becoming more and more common as our informatics base grows and learning about these things is becoming more and more common that we're uncovering those kinds of conditions. That's the point of this. We just need to be thinking about when do we need to look deeper. Genetics are one way of looking deeper. Informatics in terms of our genomic approaches, it's growing every day, but we're never going to know everything the day we do somebody's tests. We can always go back and reanalyze it, but it's still, there's always going to be a limitation. 

My name is Dr. Roberta Keller, and I'm aware my patients are rare.

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