Melanie Cole (Host): Welcome, we’re talking today about the Successful Clinical Response and Pneumonia Therapy Systems Biology Center or SCRIPT. My guest today is Dr. Richard Wunderink. He’s a pulmonologist with Northwestern Medical Group. Dr. Wunderink, tell us about the current state of pneumonia today, what’s the prevalence and what are you seeing as global impact?

Dr. Richard Wunderink (Guest): So pneumonia is the single most important infection frankly around the world, and this includes both patients who have what we call community acquired pneumonia who come into the hospital because of pneumonia or are treated in emergency departments are physician’s offices, but also hospital acquired pneumonia. That combination of coding for pneumonia is actually the most common infection, most common cause of death around the world – most common cause of infectious death around the world. In about 75% of all infectious deaths in the US are caused by pneumonia. So it’s a common disease. It’s a frequent disease. It’s a lethal disease, and the important things that are occurring are 1) there’s more and more antibiotic resistance developing, that’s particularly in the hospital acquired pneumonia strain, and our understanding of the underlying pathogenesis of pneumonia has also changed dramatically. What we’ve found is that there are normal bacteria that are in the lung, in the alveoli in the lung that have an important role in pneumonia and has kind of changed our concept. Our idea about pneumonia in the past is that we had bacteria or viruses, sometimes fungi that are being breathed in or aspirated and they’re going into a sterile space, where now we realize that it’s not sterile and there are normal bacteria there that may play an important role in the whole development of pneumonia or protection from pneumonia.

Host: Why are have some therapies for serious pneumonia proven to be unsuccessful and tell us a little bit about the relationship to specific pathogen genomic profiles that have been associated with unsuccessful outcomes?

Dr. Wunderink: So what we’re seeing – in the past we thought the problem was that we didn’t have the right antibiotics, and so what we’re seeing now is that there are patients who get the right antibiotics for the particular bacteria that is causing their pneumonia but that they’re still having bad outcomes. So that’s leading to the idea that there are other factors besides antibiotic resistance that are leading to these poor outcomes, and it is potentially both within the bacteria itself, and it’s also in the host response either exaggerated or inadequate host response, and then this new concept of the normal lung microbiome is leading to a third possibility that somehow in the treatment of the original pneumonia we’re changing that lung microbiome to where it’s no longer protective, but actually may be conducive to either ongoing pneumonia or recurrent pneumonia. We have a – know that this occurs in the GI tract, when we give antibiotics to the patient that it changes the microbiome there, and it makes great sense that this is also happening in the lung.

Host: Expand a little bit more on the host response to infection and how you’re looking at that as a way to improve the diagnosis.

Dr. Wunderink: So we use the host response in many ways to help us diagnose pneumonia at the very beginning, so a big part of the SCRIPT study is looking at patients who have neutrophils that get into the alveoli of the lung, and so we’re sampling deep into the lung with something called non- bronchoscopic bronchoalveolar lavage. We can also do this with a bronchoscope, but this non-bronchoscopic BAL is done by respiratory therapists. So we have greater flexibility in obtaining this specimen and so they’re routinely available in our intensive care unit in patients who are ventilated, and so we look in that fluid to see are there neutrophils because that should be the normal response particularly in patients who have neutrophils, who do not have leukemia or have recently had chemotherapy and don’t have peripheral neutrophils. So that’s kind of where we start, and that’s telling us that there’s a pneumonia, there’s a host response that’s responding to some infectious insult there and there are a few other things that do that, but that’s the main thing, and then what we’re doing with the SCRIPT study is actually looking at specific cells that start to come back into the lung as part of recovery. So recovery of the normal lung macrophages, some of them are coming into the lung as monocytes from the bloodstream, we’re looking at lymphocytes that are either present or coming in as part of the host response to recovery from pneumonia and looking at what in the patterns of those cells help us understand how patients don’t recovery from pneumonia and don’t respond appropriately to antibiotics.

Host: Dr. Wunderink, tell us a little bit more about the Successful Clinical Response and Pneumonia Therapy Systems Biology Center, or the SCRIPT Center. What’s unique about what you’re doing there at Northwestern Medicine?

Dr. Wunderink: So a couple of things are unique first about the systems biology, what we’re looking at is trying to get the entire picture of what’s going on there, and that’s what systems biology is about, looking at a variety of, what we call omex, so we’re looking at transcriptome, what messenger RNA is being produced by the different cell types that are in the bronchoalveolar lavage. We’re looking at epigenomics, so some of the patterning responses that we see in lymphocytes in response to infection, and then we’re looking at the microbiome and metagenomics of that, and then we’re also looking at the bacteria. So what about the bacteria may be making them more virulent or preventing the host from completely eliminating them and so we’re looking at the genomics of the bacteria itself and we’re focused principally on pseudomonas, which is probably one of the most serious pathogens and it has a variety of accessory genome elements that are part of the chromosome of the bacteria but are not found in every strain of pseudomonas and may be associated with different virulents, different proteins that they may secrete or may make them more resistant to elimination from the lung. So it’s this system response rather than looking at each component piecemeal and a big part of the grant is to use modeling to try and understand how all of these parts fit together, and so we’re using mathematical modeling and machine learning to try and put this together into a cohesive story. So it’s this systems biology approach. What’s also unique about this SCRIPT grant is that we have routine access to these bronchoalveolar lavages. That’s somewhat unusual in the US, in particular, and more importantly is that the SCRIPT grant is looking at serial lavage, and so we’re looking at what happens over time rather than just what is the situation at the time that we diagnose pneumonia. So we’re trying to get serial samples at various time points after the original diagnosis of pneumonia and focusing on the sickest patients, and I think that’s a little bit unusual as well.

Host: And it’s absolutely fascinating as well. Dr. Wunderink, as we finish, tell other providers if you have anything to add to this segment and when you feel it’s important that they refer to the specialists at Northwestern Medicine.

Dr. Wunderink: So I think that what we see is pneumonia is a leading reason for why patients get stuck on mechanical ventilation, unable to be weaned from the ventilator, and we also see that it is not just an acute illness, but it ends up being more of a chronic illness. So pneumonia is one of the major reasons that elderly patients go from independent living to requiring a nursing home, and so it’s the patient who is unable to get weaned from the ventilator, pneumonias that keep recurring, that would be particularly good patients to send to a center where we’re doing some of these studies on pathogenesis but also have available clinical trials for new kinds of treatment for some of these series infections as well.

Host: Thank you so much Dr. Wunderink for coming on and explaining these biology systems to us so well and sharing your expertise. This is Bette Edge, a Northwestern Medicine podcast for physicians. For more information on the latest advances in medicine, please visit nm.org, that’s nm.org. This is Melanie Cole, thanks so much for tuning in.