So, I'm gonna get started with the first talk, and I'm gonna be, first I have no disclosures. And I'm gonna be talking about the hidden risk of dirty air, ambient air pollution, and the acute respiratory distress syndrome. My learning objectives are to evaluate the impact of chronic elevated air pollution and ARDS risk in the critically ill, understand the individual EPA measured components of ambient air pollution and their relationship to ARDS, and to contextualize air pollution's impact on ARDS risk among other social determinants of health. So, I wanna start by taking you back earlier in the Industrial Revolution, when we would have these time periods where there'd be severe weather events that would result in severe air pollution in our cities. And this was probably the most significant one in 1952, the Great London Fog. This was an event where because of cold air and different weather patterns, air pollution was trapped in the city and the levels of particulate matter in the city were astronomical, where you couldn't even see across the street. And it's been estimated that this event resulted in an excess of 12,000 deaths in just a couple of days. And if you look at the original publication in The Lancet, you can see in the figure on the right that as levels of sulfur dioxide went up in the city of London and the levels of smoke went up, there was also an increase, a concomitant increase in number of deaths. And importantly, even after things improved several days later, there still was an excess number of deaths that lasted several days after the Great London Fog event. And the cause of deaths at the time were things like influenza, pneumonia, bronchitis, other respiratory diseases. And it seems like when we have these huge air pollution events, it's actually inducing acute lung injury and that it's killing patients from acute lung injury. And then we had further evidence showing the impact of air pollution on all-cause mortality from the Harvard Six Cities Study that was published in the 90s. Patients were enrolled in the 70s and followed for over 15 years at six cities in the United States. And they used, at the time, there were only EPA monitors about one a city. So they used the EPA monitors in these six cities and demonstrated a strong association of higher levels of air pollution with all-cause mortality. Now I wanna take a minute to explain to you what I'm talking about when I talk about the components of ambient air pollution. So in the United States, the EPA monitors several different forms of air pollution. The first is particulate matter. So particulate matter is a complex mixture of solid particles, liquids, and vapors. And it tends to come in two categories, fine particulate matter, or PM 2.5, which is a diameter of less than 2.5 microns. This is your diesel exhaust, your black carbon metals and organic compounds. And these compounds get down into the alveoli and are thought to cause direct injury to the alveoli. Coarse particulate matter, or PM 10, is less than 10 microns in diameter and tends to be dust, pollen, mold, and soot. And these don't really get down into the airway and they deposit themselves in the upper airways. We then have ozone. Ozone is a little bit different than the other pollutants because it's not directly emitted by the pollutant source, by the combustion of fossil fuels, but is actually developed by a complex interaction of sunlight with volatile organic compounds and nitric oxides. Nitrogen dioxide tends to be a marker of traffic-related pollution. Sulfur dioxide, a marker of industrial facility pollution, and carbon monoxide caused by the combustion of fossil fuels. And these are the main components of air pollution monitored by the EPA. And we've known for a long time that air pollution has relevance to all kinds of lung diseases and lung health. This is actually an image of Philadelphia, and there was a large oil refinery in South Philadelphia that was a major component of South Philly's air pollution. There was a large fire just a couple of years ago in the oil refinery, and they finally shut it down, which has dramatically improved air quality in South Philadelphia. But we know that air pollution is associated with the development of lung disease, exacerbations of lung disease, and mortality for lung disease. So it makes sense that it might be related to syndromes in the critically ill, like ARDS. And we do have some experimental evidence to suggest that air pollution is relevant in ARDS. This is data from a murine model of ozone exposure. Now, if you expose a mouse to high levels of ozone, it causes lung injury. It's actually a model for acute lung injury. But in this study, what they did is they exposed mice to lower levels of ozone over a period of time or fresh air, and then they did a model of sepsis with LPS exposure. And if you look at the figure on the right, the exposure to ozone itself didn't cause an increase in BAL cytokines, but if the mice were chronically exposed to ozone and then had the LPS exposure, they had a much more robust inflammatory response than if they were just exposed to fresh air ahead of the LPS exposure. And this also held for plasma cytokines, BAL cytokines, and BAL total protein, suggesting that something's going on in the lung when it's chronically exposed to air pollution. We also have some evidence in human models that air pollution may be relevant to ARDS. On the left is an exposure chamber where you can take healthy people and expose them to controlled amounts of air pollution. And we've been able to demonstrate that by doing this, you can increase inflammatory markers in patients that are exposed to air pollution, increase bronchoreactivity. And on the right on the image, this is a picture of Beijing, China. And on the right side of that image, that's during the Olympics when they used multiple different things to try to reduce the amount of air pollution to make it safe for the athletes. And a smart group of researchers in China enrolled subjects before they reduced the air pollution, collected their blood, followed them through the Olympics, and then the post-Olympic time period, and were able to show that the levels of plasma cytokines as well as recruitment of inflammatory cells by flow cytometry were decreased by the reduction in air pollution, suggesting that something chronically goes into, in the lung, an inflammatory process when you're chronically exposed to air pollutants. So that led me to the hypothesis that air pollution somehow primes the lung for injury. So in its own right, it might not be injuring the lungs or the alveolar capillary barrier, but by chronically being exposed to air pollution, if you then go on to get trauma or sepsis or aspiration, you're much more likely to develop more severe lung failure. And that makes sense based on previous environmental risk factors that have been published. This is data showing a link between cigarette smoke exposure as a strong environmental risk factor for ARDS. On the left is data from Carolyn Kalfi's group looking at active and passive cigarette smoking and acute lung injury and blunt trauma. And on the right is from the Lung Transplant Outcomes group looking at cigarette smoking in the donor is highly associated with primary graft dysfunction in the recipient, which is a form of ARDS after lung transplantation. Now the first group to look at ambient air pollutants in ARDS was the group at Vanderbilt led by Dr. Lorraine Ware, who published this study using her VALID cohort study, which is a prospective cohort study of critically ill patients with risk factors for ARDS. She enrolled over 1,500 patients and showed a strong association of ozone exposure and risk of ARDS. And interestingly, this effect was the strongest in their trauma patients. And they saw a really interesting interaction by smoking where if you were a smoker and were exposed to the higher levels of ozone, there seemed to be this multiplicative effect on your risk of ARDS. Now in this study, they did not see an association of the other air pollutants in ARDS risk, but there's some limitations to this cohort. Namely, the Nashville region has significantly less EPA monitors than other parts of the United States. So that led us to try to look at this in collaboration with Dr. Ware, look at this in our Philadelphia cohorts. And we decided to start by looking in our trauma patients. So we have the Penn Trauma Organ Dysfunctions cohort that's been going on since the early 2000s. For this study, we included patients who were enrolled between 2005 and 2015 who had an acute trauma and had an injury severity score of greater than 15. We enrolled about 1,000 patients and we estimated their exposure to air pollution using their geocoded address. And then we used all of the EPA monitors within a 50 kilometer radius of their geocoded address and then used squared inverse weighting to weight closer monitors, taking more into developing the exposure. And we were able to get an exposure for their individual address. We then phenotyped outcome of ARDS by the Berlin definition where investigators reviewed every chest x-ray ordered for clinical purposes. And you can see on the map on the right, that's where all the EPA monitors at that time were located in the Philadelphia region. And if you compare the two studies, the Vanderbilt study and the Penn study, you can really see the big differences in the granularity of data in the Philadelphia region. So these graphs on the x-axis is the number of monitors and the y-axis is the patients that had that number of monitors within 50 kilometers of their home address. And you can see that the average patient had many more monitors in the Philadelphia region than in the Nashville region. And the closest monitor was much closer to their home. So we think exposure misclassification is reduced in the second study, which may explain why our results were a little bit different, which I'm gonna show you in the next slide. So to get to our results, we found strong associations between particulate, fine particulate matter, sulfur dioxide and carbon monoxide in ARDS risk. These graphs are for the three year average exposure to these three pollutants, and the y-axis is the predicted risk of ARDS based on multivariable logistic regression models adjusted for the confounders listed on the bottom of the screen. The odds ratios you see are for the comparison of the 75th to the 25th percentile of air pollution exposure. And you can see these, what appear to be linear and strong associations between each of these pollutants and predicted risk of ARDS. Similarly, we saw associations between nitrogen dioxide and ozone in ARDS risk. They're a little bit weaker than the other associations. And what you'll notice in this ozone association is that there's almost a U shape where it's a linear relationship for most of the data, but at the very lowest levels of ozone, we actually have a slightly higher risk of ARDS than at the moderate levels of ozone. And this is actually phenomenon described in air pollution research for ozone in other studies as well. And we hypothesize that it's related to how ozone is released. So like I said earlier, ozone's not directly released by the emitting sources, but is a reaction between sunlight and nitrogen oxide in volatile organic compounds. But this reaction can actually go backwards as well, where if there's really high levels of nitrogen oxide, like right by a highway, that can interact with ozone to develop oxygen and the more stable nitrogen dioxide. So in areas where the highest levels of all the other pollutants, they're actually the lowest levels of ozone, but then when you move away from that area, they start to trend together. And I think that explains why we see a U-shaped curve with the ozone data. Now, trauma's an important population, and they are at risk for ARDS, but there's a much larger population that we see a lot more ARDS in, and that's our sepsis population. So our next step was to look at this in the sepsis population. So we looked within our molecular epidemiology of sepsis in the ICU cohort. This is a prospective cohort study at Penn of critically ill patients with sepsis or septic shock. For the purposes of this study, we included 2,000 patients enrolled between 2008 and 2018. This cohort's about 60% white and 30% black. About 30% of the patients had a pulmonary source of sepsis, so this is certainly not a pneumonia cohort. There is a significant amount of pneumonia, but there's also a significant amount of non-pulmonary sepsis, and they had really high Apache scores. And we again saw, this is kind of a busy table, but we again saw similar associations, and I'll direct your attention to the long-term associations. We saw associations between sulfur dioxide, nitrogen dioxide, and fine particulate matter and risk of ARDS. We did not see associations with coarse particulate matter, and I didn't show you, but we actually didn't see them in the trauma cohort either, which makes sense, because coarse particulate matter doesn't get to the alveoli. And we did not see an association with carbon monoxide. Ozone again showed that U-shaped curve, so it didn't show statistical significance when just looking at it in a linear model, but it actually seemed to be, again, in this U-shape that I showed you previously. And the other thing interesting is that the odds ratios here are significantly smaller than in the trauma cohort, and I think that's because sepsis patients are more complicated, they have more comorbidities, so the component of air pollution going into risk of ARDS may be lower. And another finding we found in our sepsis cohort is we wanted to look at who's at risk. So what we found, not surprisingly, that the people that were exposed to the highest levels of air pollution were our minority populations and people from lower income regions of the Philadelphia region. What these graphs are showing you is for the three major pollutants associated with ARDS risk, these are quartiles of exposure, and on the left you can see that as the exposure goes higher, the percentage that's of non-white, which in our cohort was predominantly black, is significantly higher. And similarly on the right, you can see that the medium household income of the census track of our patients was lower as they got more exposure to air pollution. So the burden of this exposure is significantly felt by non-white and lower income communities. So what are the implications for ARDS care? So first I think there are obvious public health implications to this. ARDS is a significant cause of hospitalization in our ICUs, and when we look at things like COVID-19, we've all seen significantly more ARDS than we have in the past, and there is some data that COVID-19 has similar associations with air pollution and COVID-19 severity. Now this also has important implications to the public health in the developing world where there's still significant amounts of air pollutions in cities, but even in our cities in the United States, we've had dramatic improvement in air pollution quality in our cities, but the disparities have not improved at all. So the differences between communities that were hardest hit by air pollution and wealthier communities that are not hit by air pollution hasn't really changed in the last decades while we've kind of improved everybody, but still not focused on where it could have the biggest bang for our buck. Second, I think there are some precision medicine implications of this potentially. I think it'd be interesting if we can figure out how air pollution primes the lung for injury, and then could we figure out a way to identify patients that have this lung priming and then give them a drug to reverse it. It's kind of forward thinking, but I hope someday we might be able to improve patients by kind of preventing ARDS or treating it very early, specifically in patients with exposure. So thank you so much for your time.

dirty air

acute respiratory distress syndrome

ambient air pollution

lung injury

associations with air pollutants