Episode 2: CRIB Team and COVID-19

Synopsis:
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. 

*Shazia Bhombal, MD, is no longer with Stanford Medicine Children’s Health More 

Host:
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. (Shazia Bhombal, MD, is no longer with Stanford Medicine Children’s Health)

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 cannula [VJR1] [SVW2] 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   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 they're 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, you 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.

Host:
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 www.stanfordph.org.

Follow the Wall Center at Stanford on Twitter, Facebook, YouTube, Linkedin & Instagram. Subscribe to the PH at Stanford Podcast on iTunes. Contact us: wallcenter@stanford.edu #PHatStanford

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Episode 3: Adult Clinical Approach

Synopsis:
In the 3rd part of our 3-Part Series on Ways to Attack Pulmonary Vascular Disease, Stanford Pulmonary Hypertension specialists Drs. Vinicio de Jesus Perez, Edda Spiekerkoetter & Andrew Sweatt discuss the adult clinical approach and ways the Wall Center is fighting pulmonary hypertension across multiple fronts.

Host:
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 3rd in a three-part COVID-related series on Ways to Attack Pulmonary Vascular Disease. Stanford PH Drs. Vinicio de Jesus Perez, Edda Spiekerkoetter, and Andrew John Sweatt, discuss the adult clinical approach and ways the Wall Center is fighting pulmonary hypertension across multiple fronts.  More 

Edda Spiekerkoetter, MD:
My name is Dr. Edda Spiekerkoetter. I'm an adult pulmonologist at Stanford, and I'm treating patients with pulmonary hypertension and also have a basic research lab where I study the pathogenesis of pulmonary hypertension, right heart failure and vascular malformations in the lung.

Andrew John Sweatt, MD:
Hi, I'm Dr. Andrew Sweatt. I'm also in the division of pulmonary and critical care at Stanford, treating adult patients with pulmonary hypertension and other general pulmonary conditions. And my clinical research focus is in pulmonary hypertension.

Vinicio de Jesus Perez, MD:
My name is Dr. Vinicio de Jesus Perez. Like my colleagues, I'm an adult pulmonary critical care specialists and physician scientist with expertise in pulmonary arterial hypertension and other pulmonary vascular disorders.

Today, we're going to talk to you about what the Stanford Pulmonary Hypertension Program is doing to fight pulmonary hypertension across three fronts. Number one, the repurposing of drugs, discovery of biomarker through omics technologies and the use of wearables for monitoring pulmonary hypertension patients.

I will start first by telling you about our work with wearables. This is work that has been done in partnership with our friends at phaware [global association], and it is a tool that will combine the use of the technology in the Apple watch together with an application developed with our colleagues at phaware, that will allow our patients to capture six minute walk data from the comfort of their living place, whether it's their home or their local park.

Now, why is this important? Well, many of us have been affected by the COVID epidemic. As you all know, when you visit your physician, one of the key tests that the physician will offer is the six minute walk test. Why? It tells us how well your heart and lungs are working together. It also tells us whether the medications and interventions that we are offering you are having the expected impact.

The problem being that with COVID is it has become incredibly hard to host patients in our clinic. The six minute walk test, is traditionally a test that has to be done in clinic under the supervision of a respiratory therapist and with a proper assessment of the pulmonary hypertension specialist. For many of us it's become very difficult to gauge how our patients are doing through video consultation in regards to the level of activity and how their medications are actually influencing that.

To overcome that barrier, phaware and our group have partnered to test this new app, which is the phaware Walk.Talk.Track™. This is actually an app that works with the Apple watch, and it links wirelessly with your Apple phone. What the app does is it actually instructs you on how to capture a six minute walk test from the comfort of your home or any place locally where you can actually walk. It's simple. The app allows you to initiate the test, capture your symptoms, and then it tells you to walk for six minutes. It tells you when to rest. Once you're done, that information is uploaded to a cloud. That information comes to us using sophisticated algorithms that we have been developing. We can capture these numbers, your symptoms at rest, how much you walk, your heart rate, the changes in your heart rate. And, this information is captured on a daily basis, or as frequently as you can do.

Now, why is that important? Because I'm not depending only on me seeing you every three months in order to know whether your functional capacity is improving or not, or maybe worsening. In an ideal situation where I have access to this technology, I can potentially identify a level of worsening that will prompt me to introduce a therapeutic intervention. For you, it means waiting less time in order to get the treatment that you require so that we can keep your quality of life and your level of function high, which is something that you will appreciate, your loved ones will appreciate, and for us, it will make our jobs much easier. This is currently being tested. We recently had two successful presentations at the American Thoracic Society that were featured as part of the program that I invite you all to check.

We're currently conducting these studies. We hope to be able to put this out very soon. Once we publish and validate this, this will be available free to all users. And as I said, this is thanks to the support provided by phaware. We're very proud to be part of this incredible project. I'm hoping that this is of great interest to you. Now I'm going to pass the baton, if you will, to my colleague Dr. Spiekerkoetter, who will tell you about drug repurposing in pulmonary hypertension.

Edda Spiekerkoetter, MD:
Thank you so much, Vinicio, for this introduction. I would like to switch gears a little bit and talk to you about what Stanford does to find better treatments for pulmonary hypertension. So to start with, I'll give you a little bit of an overview about pulmonary hypertension. Pulmonary hypertension is characterized by narrowing of the lung vessels, in particular the pulmonary arteries. This is due to cell growth in the vessels, which we also call neointima formation. Many of the current approved drugs that we have mainly dilate the pulmonary arteries, but they don't affect the cell growth in the vessels. The disease often progresses, despite treatments and patients at some point worsen, develop heart failure and some even need to be transplanted, and receive a new lung. What we're trying to do is finding new drugs that could really reverse the cell growth in the lung vessels to reduce the resistance and make it easier for the heart to pump blood through the lungs. A way that we have been trying to achieve this to repurpose or reposition drugs used for other diseases.

Repurposing of drugs means that you use drugs that are not approved yet by the FDA, but that have been tested by pharmaceutical companies yet that have failed for a certain disease. It is possible to use these drugs for a different purpose and see for example whether they work in pulmonary hypertension. One drug, for example, that we're actively working on is the repurposed Lymphoma drug Enzastaurin. I will tell you a little bit more about this later. Repositioning of drugs means that a drug already FDA approved for a different disease or indication is used for a new indication. By doing so, we're using off-target effects or side effects of the drug to see whether they might be beneficial for pulmonary hypertension and can improve the disease. One example of a repositioned drug that we are studying is the immunnosuppressive drug FK506, or Tacrolimus. Often the terms repositioning and repurposing are used interchangeably--and generally mean using "old drugs" for new indications.

In pulmonary hypertension, many drugs have been repurposed over the years and maybe probably the best drug that you know is Sildenafil. Sildenafil, also called Viagra, was originally developed to treat angina chest pain because it was known that it relaxes smooth muscle cells. Then it was found as a side effect that men develop erections and so that's when some smart people had the idea to say, well, let's use this as a good drug for erectile dysfunction. Then it was repurposed again for the use of pulmonary hypertension, knowing that, well, if this dilates vessels, relaxes vessels, it might even help pulmonary hypertension. That's how we got the drug Sildenafil for PH, which many of you guys are using for pulmonary hypertension at a lower level than it was originally developed for.

The advantages of drug repurposing is actually that it's much more cost effective than if you develop drugs de novo. It's also much faster because new drug development often takes 12 to 15 years, whereas when you repurpose drugs, you can skip many of the different steps in drug development:  The toxicology is known, the dosing as well as the side effects are known. Therefore, you can really start testing promising drugs in patients and perform Phase II clinical trials in patients early on, without having to spend time with lengthy preclinical testing.

Because the side effects are known, it's often possible that repurposed drugs can be used at a lower dose. This has many advantages for the treatment for pulmonary hypertension. The downside is that  the repurposed drugs are often generic. Many pharmaceutical companies are hesitant or less interested in funding larger trials. That's where for example, centers like the Vera Moulton Wall Center for Pulmonary Vascular Disease or the National Institutes of Health or other funding opportunities play a big role to help fund those clinical trials and make these drugs available and test them in patients.

Stanford has a long history of performing what we call investigator-initiated clinical trials. We test promising drugs in very focused small trials with our patients. And I'm sure as a patient at Stanford, you have been asked to participate in several of these trials. We recently completed a trial with the drug FK506 or also called Tacrolimus, which is an immunosuppressive drug that has been used over 30 years in patients after organ transplantation. We tested, whether by activating the BMPR2 pathway that is downregulated in pulmonary hypertension, FK506 reverses the cell growth in the lung vessels, reduced neointima formation and improved pulmonary hypertension. As a second trial we are currently applying for funding at the NIH for a multicenter trial to test whether the cancer drug Enzastaurin, improves pulmonary hypertension.  A pharmaceutical company offered to supply the drug for free.

In the past, it was often that people just looked at side effects of these drugs and then felt okay, if certain drugs have these and these side effects, maybe we can use the side effects for our disease as a beneficial effect. But more and more, we are also doing experimental screening. So high throughput screening of drugs to determine whether certain drugs activate a specific pathway, and this was actually how we found, FK506. More and more, we are also using computational approaches now to predict which drugs might affect certain pathways. That's where bioinformatics, artificial intelligence and drug prediction comes in. So I would like to hand the baton over to my colleague, Dr. Andy Sweatt, who will talk a little bit more about this topic

Andrew John Sweatt, MD:
Thank you, Edda, for the introduction and the segue into what I'll be talking about, which is how we can use and how we've been using artificial intelligence and machine learning to help yield new insights and discoveries in pulmonary hypertension specifically. I think these terms, artificial intelligence and machine learning, are something that people are gaining increasing exposure to over time in the popular media and culture. It's commonly talked about on certain commercials.

We know artificial intelligence has led to self-driving cars, and it's the reason that all the social media platforms are able to tailor advertisements specifically to our individual interests--in interest of trying to get more clicks as well as facial recognition software that's embedded in smartphones. These are only a few common examples of artificial intelligence, which is essentially a field of computer science that aims to mimic human thought processes, learning capacity and knowledge storage to provide useful tools.

Machine learning is actually just a subset of the field within the larger umbrella of artificial intelligence. Machine learning is what I'll be talking mainly about today, which is the use of computational algorithms and statistical models to find hidden patterns in complex datasets that would otherwise be undiscovered, or to make predictions or identify patterns among variables within this complex dataset.

Before I talk more, I think it's important to understand that machine learning approaches can be broadly split into two main categories. Those that are supervised machine learning. These are methods in which you're trying to predict something such as predict a certain outcome or classify or predict a certain feature, such as is this a chicken or a duck, if given a picture and then the machine algorithm will spit out the prediction this is a chicken, this is a duck. Whereas unsupervised machine learning is really designed to divide up a dataset into new subsets within that data set, identifying novel subgroups of something.

For example, in pulmonary hypertension, the use of all machine learning approaches is kind of recent on the stage. Our group has been one leader in this field, but there's other groups also increasingly applying these approaches to help us gain insight. Potential applications in pulmonary hypertension are very, very broad. When it comes to supervised approaches, this is when you have a dataset, if you want it to predict pulmonary hypertension outcomes like survival or something, and develop a tool that can predict how a patient is going to do over time. That's one way to do it.

For example, you could use data from the wearables that Vinicio talked about before, the six minute walk distances over time. We may be able to identify an early signal with the computational algorithms and predict who's at risk for hospitalization or bad outcomes over time. These tools have been used to try to spur early detection of the disease. Pulmonary hypertension, the diagnosis really relies on an invasive procedure as we know right now. So the idea is to use noninvasive data ranging from echo metrics, imaging metrics, or even just claims-based data in diagnostic codes has been used. These have been applied to try to identify who's a pulmonary hypertension patient, and who's not to help diagnosis. More specifically, my interests have been to use machine learning as a way to facilitate what we call deep phenotyping in disease.

My initial interest in this field in general kind of spurred from my desire to combine my undergraduate biomedical engineering and computer science training with my subsequent clinical interests that I gained through medical school, residency and fellowship, which was pulmonary hypertension. I think what I was struck by as I was exposed to my first pulmonary hypertension patients, is that such a wide diverse array of patients developed pulmonary hypertension. It can be due to genetic causes. It can be due to auto-immune diseases. It can be to certain drugs and toxins exposures. Yet they all end up with the same disorder, pulmonary hypertension. Unfortunately, regardless of the cause, we are at the stage in pulmonary hypertension where we treat all the patients the same, kind of a one size fits all approach. This is the way we classify the patients based on the underlying cause.

My initial thought is there must be a more elegant way or there's probably another way to classify patients that would more relate to the underlying biology of the disease and potentially help us lead ourselves and pave a path towards targeting certain subgroups of patients with certain therapies who are more likely to respond to these specific therapies. At Stanford, we have a rich history, long before I was here, in making discoveries that relate to inflammation in pulmonary hypertension, as it relates to the development of the disease process.

My foundational work started with measuring a large number of inflammatory proteins and markers in the blood of pulmonary hypertensions, and then applying an unsupervised machine learning approach to really try to find patterns in this complex data, where you are measuring a large number of proteins at the same time. The algorithm detected that there are these four subtypes of inflammation that exist. Lo and behold, when I looked at the clinical outcomes and characteristics over time, these patients had differences in disease severity and outcomes.

Yet these subgroups that I defined did not correlate with the clinical subtypes, such as idiopathic PAH, connective tissue disease PAH. Essentially, this tool is a way to reclassify patients according to this immune phenotyping approach. Now my work is going to be to take this further and look at what happens to immune phenotypes more over time during the disease stage. I'm going to analyze data from clinical trial secondarily, to understand how these immune phenotypes respond to certain therapies to see if they have differential responses.

On that side, I've been kind of applying unsupervised machine learning, and then more recently I've been applying supervised approaches to identify patients who have adverse right heart effects of pulmonary hypertension over time. And as well as a study led by a clinical trial, NIH funded, led by my colleagues, Dr. Mark Nicolls and Dr. Roham Zamanian of Rituximab an immune modulating agent in PAH, kind of a repurposed therapy that has been used for autoimmune diseases in general, for years, similar to what Edda talked about. This is used for specifically patients with scleroderma associated PAH. We measured a bunch of proteins in kind of exploratory fashion in the blood, inflammatory markers, and I defined a signature when measured at baseline before drug exposure predicts a more favorable response to the therapy. However, this was in one small cohort and this signature is something that would need to be further validated and proven in subsequent groups of patients over time.

We've heard already that PAH is a rare disease. It's time consuming to run clinical trials, because it's harder to find the patients to enroll than in more common diseases like coronary artery disease or run of the mill systemic hypertension. A lot of trials of novel therapies have failed in recent years, and the thought is that we need to be targeting certain subgroups of patients who are more likely to respond to these therapies to begin with. Machine learning may be able to help us achieve that fact.

Before I finish, I'll close with the concept that sometimes there's this concept that machine learning and artificial intelligence technologies are something that are going to, you know, "the robots are going to take over the world" mentality. I think that when it comes to self-driving cars, these are machine learning and artificial intelligence algorithms that have been taken to the max level of sophistication, whereas in the pulmonary hypertension and other medical fields we're using the kind of under-the-hood algorithms, the simple algorithms that form the basis of that to help guide our research. Essentially the important thing is that human oversight is very necessary in this process. People don't understand what leads to the predictions that the algorithms make or this. It's going to be important in our field as we apply these approaches, to be very transparent in our approaches and try to present the data in a way that's interpretable for both clinicians and the PAH community at large.

It's also important to be aware of this concept that that has gotten a lot of attention recently called algorithmic bias, where essentially this is when machine learning models make inaccurate predictions and unfairly disadvantage certain subgroups of individuals due to inherent biases in the way the data you use to train these models is collected, labeled and utilized. For example, if you have disproportionate ethnicity breakdown in your data set, you're more likely to unfairly disadvantage certain subgroups. So there's a whole field of science now focused on trying to avoid algorithmic bias. I think the take home point is, is that there has to be a large collaborative effort in our field in order to implement these technologies and approaches in our field, while still being transparent and having a lot of human oversight in the process.

There's a lot of exciting research happening at Stanford and with the Vera Moulton Wall Center for Pulmonary Vascular Disease. We've been able to keep our momentum up despite challenges presented by the COVID pandemic. We're excited to accelerate research now that the viral prevalence is slowing down. As you can see this kind of research that we are all doing would not be possible without all the patients generously volunteering their time and effort. We hope that we can continue these efforts moving forward.

Host:
Thanks to Drs. de Jesus Perez, Spiekerkoetter and Sweatt. And thank you for joining us here today on the PH at Stanford Podcast. Join us next time.

Until then, 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 www.stanfordph.org and be sure to subscribe to the PH at Stanford Podcast on iTunes or wherever you get your podcasts.

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