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May 1, 2021

In the 2nd episode in our 3-Part Series on Ways to Attack Pulmonary Vascular Disease,
Lucile Packard Children’s Hospital Drs. Shazia Bhombal, Mike Tracy, and Rachel Hopper, who developed the multidisciplinary Cardiac and Respiratory Care for Infants with BPD also known as neonatal chronic lung disease, discuss Stanford’s CRIB program and Covid-19. @StanfordChild

Rachel Hopper, MD

Michael Tracy, MD

Shazia Bhombal, MD

Welcome to the PH at Stanford Podcast. This new podcast series comes to you from the Vera Moulton Wall Center for Pulmonary Vascular Disease at Stanford, with the goal to eradicate pulmonary vascular disease by discovering fundamental causes, developing innovative therapies, disseminating crucial knowledge, and delivering transformative care.

Today, is the 2nd in a three-part COVID-related series on Ways to Attack Pulmonary Vascular Disease. Lucile Packard Children’s Hospital Drs. Shazia Bhombal, Mike Tracy and Rachel Hopper, who developed the multidisciplinary Cardiac and Respiratory Care Program for Infants with BPD also known as neonatal chronic lung disease, discuss Stanford’s CRIB program and Covid-19.

Rachel Hopper, MD:
My name is Rachel Hopper, I'm a pediatric cardiologist and pulmonary hypertension specialist at Stanford Children's Hospital, and co-director of the CRIB team.

Michael Tracy, MD:
Hi, my name is Michael Tracy, I'm a pediatric pulmonologist at Stanford Children's Hospital, and I am a co-director of the CRIB team.

Shazia Bhombal, MD:
Hi, my name is Shazia Bhombal, I'm a neonatologist and cardiologist at Stanford Children's Hospital, and I'm co-director of the CRIB team.

We're really excited to talk to you all today about our CRIB program at Stanford Children's Hospital. And give you a little description to talk about prematurity, chronic lung disease and pulmonary hypertension.

So, to start off we'll talk a little bit about prematurity. Babies generally need about 40 weeks to mature and be ready for being born. A premature baby is a baby born more than three weeks before their due date. In the U.S., about one in 10 babies are born preterm. In general, premature babies have more health problems and longer hospitalizations than babies born full term. Babies who are born preterm may not be fully developed at birth, and some need to spend time in the hospital after birth, in the neonatal intensive care unit for additional medical care, such as helping with breathing, feeding, and maintaining temperature. With advances in medical care babies are surviving earlier and earlier. Some babies in the hospital for days, weeks, some for months or even longer as they gain weight and learn to keep warm without help from the incubator, and learn to feed and breathe. Some may need to go home with special medical equipment, and will have continued close follow-up as they leave the hospital.

One major complication of extreme prematurity is chronic lung disease, also called bronchopulmonary dysplasia (BPD). Baby's lungs continue and develop and grow during the pregnancy, so when they're born early, their lungs may be underdeveloped. The higher risk of this can occur the earlier that they are born. In the United States, BPD impacts about 10,000 - 15,000 infants per year, and is diagnosed in about half of all infants weighing less than about two pounds at birth. Up to a quarter of these infants with BPD will develop pulmonary hypertension, or high blood pressure in the lungs. This causes extra work for the right side of the heart, as it pumps into the higher pressure of the lungs. And if untreated can cause heart failure and even death. Early diagnosis and treatment of pulmonary hypertension are important, as many patients respond well to therapies.

Dr. Tracy and Dr. Hopper will explain more about lung disease and heart issues that can come up in premature babies.

Michael Tracy, MD:
So moving forward in talking more about what is BPD, bronchopulmonary dysplasia, again is a term used to describe long-term breathing problems in premature babies. It involves abnormal development of the lungs and in the most severe cases, the lungs can become scarred and inflamed. BPD was first defined at Stanford in 1967, though has changed substantially over the years. In particular the development of surfactant, which was administered to premature babies along with improved ventilators has very much changed this population and allowed younger premature infants to survive. The BPD we see now, again, develop some premature babies with underdeveloped lungs. It can also be called chronic lung disease or neonatal chronic lung disease.

In the term bronchopulmonary, broncho refers to the airways, the bronchial tubes through which the oxygen breathe travels into the lungs and then pulmonary refers to the lungs, tiny air sacks or alveoli, where oxygen and carbon dioxide are exchanged. Dysplasia, means abnormal changes in the structure or organization of a group of cells. And the cell changes and BPD take place in the smaller airways along alveoli, making breathing difficult and causing problems with lung function and gas exchange.

What causes BPD? BPD occurs in premature infants as Shazia said, born at 32-weeks gestation or before. These babies are more likely to be affected by infant respiratory distress syndrome or RDS. And they're often on a mechanical ventilator for a longer period of time. The use of mechanical ventilators in premature infants allows babies to breathe when they can't breathe on their own, because their lungs are too immature to supply oxygen to their lungs. Oxygen is delivered through the breathing tube into the baby's trachea, and is given under pressure from the machine to move air into these stiff underdeveloped lungs. Although mechanical ventilation is essential to survival, over time the pressure from the ventilation and oxygen can cause injury to the infant's lungs. Almost half of extremely, low birth weight infants will develop some form of RDS and if symptoms persist, then the condition is considered BPD, if the baby is oxygen dependent at 36 weeks post conceptual age.

All of the above, ventilation, oxygenation again lead to this pattern of inflammation and scarring we associate with BPD. The diagnosis of BPD occurs if the baby's requiring prolonged oxygen and continues to show signs of respiratory problems at that 36-week post conceptual age. Again, for a 28-week infant for example, this would occur at two months of age if they were still requiring oxygen. Chest x-rays can be helpful in making the diagnosis, to confirm underlying lung abnormalities. Ultimately, we have infants who come to us outpatient on no oxygen, infants who come on low flow oxygen through a nasal in their nose, or infants with severe BPD, with tracheostomies on ventilators. So, it's quite a diverse population with different needs depending on the severity of the underlying lung disease.

Next, Dr. Hopper will talk about what is pulmonary hypertension.

Rachel Hopper, MD:
Most people have heard the term hypertension, meaning high blood pressure. In this scenario, we're talking about just high blood pressure in the lungs, in the blood vessels that carry blood from the right side of the heart, into the lungs. And in premature babies with BPD, we think that the pulmonary hypertension is mostly due to the lungs being underdeveloped. In the same way that Dr. Tracy talked about the underdevelopment of the tubes in the lungs and the air spaces, we know that the blood vessels in the lungs can also be underdeveloped, and not fully formed. Babies with more severe BPD are at a higher risk of pulmonary hypertension, and studies suggest that it's roughly a quarter to a third of infants with BPD who develop pulmonary hypertension.

In addition to development, we know that if the lungs aren't properly supported, or if there are processes that cause inflammation or damage to the lungs, things like viral illnesses or aspiration of food into the lungs, these things can worsen pulmonary hypertension. So, it's very important to take a comprehensive look at each infant to understand how the pulmonary hypertension is related to the development of the lungs. And how much we as a medical team can do to modify the pulmonary hypertension with changes in respiratory support or feeding. And the reason this is so important, and the reason we focus on this so much is because as Dr. Bhombal alluded to, pulmonary hypertension can cause the heart to have to do more work.

The right side of the heart is not used to pumping against high pressure and high resistance. So, the right side of the heart can fail and we believe that infants with BPD and pulmonary hypertension may be at a higher risk for sudden death. The diagnosis of pulmonary hypertension, and some of these other heart complications in infants with BPD can be challenging to us, because the signs and symptoms of pulmonary hypertension can be subtle, and they can sometimes overlap with other respiratory symptoms. Something as simple as breathing more quickly can be a sign of something going on in the lungs, or can be a sign of pulmonary hypertension.

One of the tools we use is echocardiogram or ultrasound of the heart. We also often use CT scans to look at the lungs and look at the blood vessels in the lungs, and our gold standard test for diagnosing pulmonary hypertension is something called a cardiac catheterization, which is an invasive measurement of blood pressure in the lungs. We typically reserve this test for infants who have more severe cases of pulmonary hypertension, or in babies who have pulmonary hypertension and some sort of structural heart abnormality like a hole in the heart.

But because there are strong correlations with pulmonary hypertension and survival in BPD, we think that detecting pulmonary hypertension early may help us provide earlier application of things like more aggressive respiratory support, additional medications, or do additional testing like the CT or cardiac catheterization that may help us better understand and treat these babies.

So, this leads in to sort of the goal of our CRIB program, which stands for cardiac and respiratory care of infants with BPD, and Dr. Bhombal is going to talk a little bit more about how we develop this program.

Shazia Bhombal, MD:
So as Dr. Hopper mentioned, there's been an increasing recognition that there are multiple factors that may impact our premature neonates and impact outcomes. And there's been more recognition that interdisciplinary care is important, getting to the other personnel from multiple specialties, that each bring a special expertise to the table, to take care of chronically medically complex kids. Infants with bronchopulmonary dysplasia often have long hospitalizations, with multiple medical needs, at times lifelong health issues. And to help provide the best care, many groups that have a lot experience with working with these types of patients or patients with bronchopulmonary dysplasia, such as The Pediatric Pulmonary Hypertension Network and the Bronchopulmonary Dysplasia Collaborative, have advocated for different specialists, including the neonatologists (doctors for critically ill babies), pulmonologists (lung doctors), cardiologists (heart doctors) to work together to get the best outcomes. So, in order to provide additional support and care to this fragile population, in January, 2018, the three of us formed a multidisciplinary care team at Stanford Children's Hospital, the cardiac and respiratory care for infants with BPD or CRIB program. Our goal was to provide comprehensive and standardized care for some of our most complex and fragile babies in our hospital, with a goal to enhance outcomes and help families and practitioners, with transition of care from inpatient to outpatient settings.

So, the CRIB program focuses on premature infants and children with BPD, at risk for pulmonary hypertension. Because these babies can develop hypertension and BPD over time, we do serial screening assessments of at-risk infants during their hospitalization and with some of the testing that Dr. Hopper had mentioned. And our multidisciplinary team collaborates to optimize respiratory support for these patients, diagnose and treat pulmonary hypertension and track patients with these assessments. We meet about twice a month on rounds, we review premature infants with BPD, and provide recommendations regarding their cardiac and respiratory management with the primary team.

After they discharge from the hospital, many of these babies with BPD are followed in a multidisciplinary outpatient clinic. Another benefit of having the CRIB team following on with patients is that we provide continuity and provide familiarity for the families. So, as we follow the patients and their families, from when they're pretty young babies in the NICU through potentially when they go to the PICU, and then when they're home, the families have a recognition of this team knows my baby. They know what we've been through, and we don't have to repeat everything that happened. And they have some familiarity with us, which has been beneficial for them and for us as well in being able to follow these patients.

Next, Dr. Hopper will talk a little bit about our long-term follow-up.

Rachel Hopper, MD:
Going home from the NICU, is a huge milestone for any premature infant. And we're always very excited about it, but it doesn't mean that our work is over. So, during the first two years of life, this is still a high-risk time for premature infants with BPD and pulmonary hypertension. And I think Dr. Tracy will tell us a little bit more about this. But because we know that our work isn't done, we wanted to continue this multidisciplinary approach in the outpatient clinics. The heart and the lungs are clearly so connected, that everything that affects the lungs can also affect the heart and vice versa. Some infants go home on oxygen, some require a feeding tube, some require medications for both pulmonary hypertension, and their lungs.

So, Dr. Tracy and I find it very useful to coordinate our approaches. This allows us to be thoughtful about how we manage medications, so that we're not making multiple changes for a baby at once. Also, some of the medications we use like diuretics may affect both the heart and the lungs. So, it's helpful for us to discuss the indication, for something like diuretics and make sure that the patient's ready from both the heart and lung perspective. We also know that growth of the lung is so important for improving lung function and pulmonary hypertension over time. So, we're so fortunate to have a great dietician in our clinic, who helps us work with families on managing feeds and keeping a close eye on growth. Dr. Tracy, do you want to talk a little bit more about outcomes and what we see in the outpatient clinic?

Michael Tracy, MD:
As Dr. Hopper mentioned children with BPD are at increased risk for both short and long-term lung problems. In the short term, BPD is associated with breathing problems in the first one to two years of life. These problems can include wheezing, shortness of breath, cough, and increased risk for hospitalization. As they enter school age, children with a history of BPD are much less likely to have respiratory symptoms than they did in their early period. But the risk of breathing problems and in particular asthma, is still higher than for those without BPD. In the long-term, there's also increasing evidence of persistent abnormalities in lung function and structure, in former preterm infants. As they progress into adolescence and adulthood, we know prematurity alone is associated with decreased lung function, with likely a greater impairment for those of the history of BPD. Despite this, most children with a history of BPD have similar quality of life and functional status as other preterm infants. But given the risks of these long-term lung problems and possible linked to the development of chronic obstructive pulmonary disease, or COPD in some survivors, we continue to focus on really limiting exposure to infections, environmental toxins in particular cigarette smoke, while continuing our long-term follow-up. In a subset of BPD survivors with long-term breathing issues, pulmonary rehabilitation and ongoing exercise has been shown to be beneficial.

On the subject of protecting lungs and limiting infections in particular viral infections, the current COVID-19 pandemic is a primary focus. Most reported cases of COVID-19 in children, less than 18 years of age appear to be asymptomatic or mild. And this is very different from the pattern we see for infection with other respiratory viruses. RSV or influenza are more common and severe in children than adults. And for many years, we focused on infection control for premature infants in their families. We have the influenza vaccine, for infants greater than six months of age. And Synagis, a monthly shot during the winter for premature infants to help prevent severe RSV infections.

Families of premature infants with BPD or PH have been well-versed at socially distancing far before the start of the COVID pandemic. It remains puzzling why children seem to account for only a small percentage of severe COVID-19 infections and hospitalizations. There's no single explanation that seems to answer this question. A few possibilities include some research which suggests children's immune systems are better equipped to eliminate the SARS-CoV-2 virus than adult's immune systems. Something about their stronger innate immune system response. That first line of defense against SARS-CoV-2.

Another possibility is that children have fewer receptors that allow entry of the SARS-CoV-2 virus into cells. These receptors called angiotensin-converting enzyme 2, or ACE2 receptors are present in many cells throughout the body including the nose and the lung. They're present in small numbers early on in babies and in children, but they increase in adulthood. Lastly, it's possible that when children are exposed to the virus, they receive a smaller dose of the virus than adults. This might be from less environmental exposure, thanks to school closures and social distancing. This understanding of why children are less affected will continue to be explored in the research.

And there's even debate, if children are indeed less infected as the rate of COVID infection is greatly influenced by local testing criteria. For example, there may be more infected children that are not getting tested because children are asymptomatic. Trends and testing for COVID, as schools and new sports are reopening will be important to further understand this. While children infected with SARS-CoV-2 are less likely to develop severe illness compared with adults. Children are still at risk of developing severe illness and complications from COVID-19. Of the children who have developed more severe illness from COVID-19, most appear to have underlying medical conditions. But there's limited evidence about which underlying medical conditions, might increase the risk for severe illness. Current evidence suggests that children with medical complexity, with genetic, neurologic or metabolic conditions, or with congenital heart disease might be at increased risk for severe illness from COVID-19. Other recent studies have suggested obesity, chronic lung disease and prematurity as risk factors. While we await more research to clarify these risk factors, we can say that anecdotally in conversations with many of our large BPD and PH centers, we've seen low numbers of severe COVID-19 infections in our population of children with a history of BPD.

Next, we'll turn to Shazia to talk more about how COVID has impacted neonatology.

Shazia Bhombal, MD:
Thankfully, COVID infections have not really been noted often in our neonatal intensive care unit. And with a lot of literature that's come out since the pandemic on COVID and how COVID affects neonates, we've found that true COVID infection really is rare in the newborn, perhaps partly due to some of the factors that Dr. Tracy had mentioned. Transmission to the baby from the mom is really pretty low. If the babies do contract COVID, numerous studies have reported that a majority of them have mild or no symptoms. Now that may differ in preterm infants, although this might be difficult to differentiate symptoms of COVID in preterm infants from symptoms of respiratory distress syndrome, or how they present that may be common in the population of preterm infants at birth.

Now, there are mixed reports regarding COVID infection in pregnant moms and rates of prematurity. So, does having a COVID infection make moms more likely to deliver premature babies? Well, some studies have reported that overall since the pandemic there's been no increased rates of preterm birth during the pandemic. But there is some evidence, there are a couple of studies that show that pregnant women with COVID may have a slightly higher risk of preterm birth. That being said, there's also studies that show that pregnant women with COVID, have the same risk of having a preterm baby as those without COVID. So, there's still more that we need to learn.

For the pregnant women diagnosed with COVID, have been shown to have higher rates of death and a higher need for heart lung bypass machine or ECMO support. So, we do follow these moms pretty closely if they're coming in with COVID infection, particularly if they have respiratory symptoms. More information continues to come out regarding neonates and COVID infections, and the impact of COVID-19 pandemic on babies and whether there's any long-term effects on the lungs in the premature patients who recover from COVID infection. So more to come.

Dr. Hopper will talk a little bit about PH, (pulmonary hypertension) and COVID.

Rachel Hopper, MD:
We've been very interested about the effect of COVID-19 on patients with pulmonary hypertension. Both pulmonary hypertension and COVID-19 are characterized by extensive dysfunction of the cells that lie in the blood vessels in the lung, as well as inflammation. And so initially, when COVID-19 first came out we were quite worried that patients with underlying pulmonary hypertension were going to be very high risk in this pandemic. However, thankfully reports of COVID-19 in both adults and children with PH have showed that in general, the disease is relatively well tolerated overall with some exceptions of course. But that being said, pulmonary hypertension does not seem to be a huge risk factor for mortality in COVID-19, in the way that some other heart and lung diseases are.

There are some speculation, that some of the pulmonary hypertension medications that affect the blood vessels in the lungs may offer some protection or maybe an advantage for patients with pulmonary hypertension if they contract COVID-19. At this point, we still need more research to understand that, but it seems to be that our patients do quite well. And as Dr. Tracy said, we have had a few of our CRIB patients contract COVID-19 and they generally did quite well with just a little bit of extra respiratory support, and supportive care.

Early in the pandemic, obviously COVID had quite a big impact on the medical system with things like cardiac catheterizations and clinic visits being canceled. Like most centers, we increased our use of telemedicine visits to be able to still connect with our patients and check in on them. And we continue to utilize telemedicine still, especially for patients who travel a far distance to come to Stanford, or for those who have family members with COVID, or family members who are considered high risk if they were to contract COVID. Initially, we also had some issues and concerns with medication supply and shipping delays for our patients who were on pulmonary hypertension medications, that get shipped from a specialty pharmacy. But thankfully, all of that was worked out fairly quickly. And in general, our patients have done quite well during this pandemic. We're optimistic that hopefully with further studies, our patients will be able to receive the vaccines soon.

And just to close, I know Dr. Tracy, Dr. Bhombal and I are the co-directors of CRIB, but we don't operate alone. We'd like to thank the rest our team in particular, our fantastic nurse practitioner Amanda Moy and also Dr. Cristina Alvira, who's one of our pediatric intensivists who has taken the lead in helping manage CRIB patients who are hospitalized in our pediatric intensive care unit.

Thanks to Drs. Hopper, Tracy and Bhombal. And thank you for joining us here today on the PH at Stanford Podcast. Join us next time where we will explore the Adult Clinical Approach in the next part of our COVID related series on Ways to Attack Pulmonary Vascular Disease.

In the meantime, you can learn more about the Vera Moulton Wall Center for Pulmonary Vascular Disease at Stanford’s vision to transform the way pulmonary vascular disease is understood and treated, both locally and globally at

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