Biomarkers, Early Disease Pathogenesis of Lung Disease
In this episode, Albert Rizzo, MD, interviews MeiLan Han, MD, MS, about chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, asthma, and pulmonary fibrosis, including an overview of recent cohort studies investigating important biomarkers of COPD, early disease pathogenesis, the future of therapies, and identifying patients for spirometry.
Additional Resources:
- Maselli DJ, Bhatt SP, Anzueto A, et al. Clinical epidemiology of COPD: insights from 10 years of the COPDGene study. Chest. 2019;156(2):228-238. doi:10.1016/j.chest.2019.04.135
- Radicioni G, Ceppe A, Ford AA, et al. Airway mucin MUC5AC and MUC5B concentrations and the initiation and progression of chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort. Lancet Respir Med. 2021;9(11):1241-1254. doi:10.1016/S2213-2600(21)00079-5
- Lung Health Cohort Study: Making History. American Lung Association. Accessed November 4, 2022. https://www.lung.org/research/lung-health-cohort-study
MeiLan Han, MD, MS, is a professor of medicine and chief of the division of pulmonary and critical care at the University of Michigan (Ann Arbor, MI) and the author of Breathing Lessons: a Doctor's Guide to Lung Health.
Albert A. Rizzo, MD, is the Chief Medical Officer of the American Lung Association and Pulmonary Staff Physician for the Center for Virtual Health at ChristianaCare (Newark, DE).
TRANSCRIPTION:
Moderator: Hello and welcome to Critical Observations in Pulmonary Medicine, led by the Chief Medical Officer of the American Lung Association, Dr Albert Rizzo.
The views of the speakers are their own and do not reflect the views of their respective institutions or Consultant360.
Dr Albert Rizzo: Just to level set for our listening audience, please explain the terms chronic bronchitis, emphysema, COPD, and how they overlap or intersect when we have this discussion.
Dr MeiLan Han: Well, thanks for that, Al. I think these are always confusing concepts, and so it's always good to go back to basics when we start having a discussion about COPD.
Historically, chronic bronchitis and emphysema were findings noted by clinicians. So emphysema was noted by pathologists. They also saw that the airways of certain individuals had filled up with mucus, and it was really in the 1950s and '60s that these two clinical entities became more and more recognized as being related with smoking, and then ultimately were coined under the larger umbrella of COPD.
It was later that a requirement for spirometric airflow obstruction was added to the definition of COPD, but in reality, what we now have is that, yes, when we talk about chronic bronchitis and emphysema, they are part of that spectrum of COPD. And yes, we require an abnormal airflow limitation to be part of that diagnosis for COPD, but in reality, we know that there are some patients who display symptoms of chronic bronchitis, which is excess cough and mucus production. There are also patients who have holes on their CT scans, which we can describe as emphysema on a CT, who do not actually have airflow obstruction as defined by an FEV1 to FVC ratio less than 0.7.
The majority do, but there's certainly many who do not, and so I think that's something as a medical community we're trying to figure out, what do we do with these two groups of patients, how do we treat them? I think that the treatments for patients with spirometrically defined COPD are a little bit better defined, but we're really trying to figure out what we can do to help all patients, regardless of airflow limitation.
Dr Albert Rizzo: So, I know there are several cohort studies investigating COPD, especially regarding learning some important biomarkers of the disease, specifically referring to COPDGene and SPIROMICS, I believe you're involved in both of these studies. Can you review the basis for these cohorts and the primary aim of these studies and what we may have learned so far?
Dr MeiLan Han: Well, we could be here for hours, but I'll try to keep my responses brief though.
COPDGene is an NIH-funded cohort study that had roughly 10,000 participants, and the requirement was that people had some smoking exposure, but all levels of lung function were accepted. And what they ended up with was a huge mix of patients with GOLD stage one through four disease, but they also had some patients without airflow obstruction that they've coined GOLD 0. It's a little bit confusing because the GOLD committee itself had this term GOLD 0, and then they ultimately got rid of it, but it hasn't died because it's still a relevant concept. This idea that you have patients who are at risk for COPD who don't yet have airflow obstruction.
Originally the goal for COPDGene was to understand genetic determinants of disease, and they've done a lot of analysis in that regard. I would say what they've found for the most part is that there's many genes that contribute to lung function, as well as tobacco susceptibility. But outside of Alpha-1 antitrypsen deficiency, I think there's probably no single gene that's been identified as the COPD gene. But the more genes we look at, I think that the better our ability to understand disease susceptibility increases.
But there's so much more that's been learned from the COPDGene study in terms of radiographic abnormalities and phenotypes, just hundreds and hundreds of manuscripts that have been published looking at various aspects of the disease. I'd say one of the more interesting findings from COPDGene, however, is this group that's been called PRISm, which stands for preserved ratio impaired spirometry, so it's essentially COPD patients who have restrictive physiology, and typically we sort of thrown them outside of the COPD bucket. But one of the things that COPDGene did determine is that many of these patients actually go directly into GOLD 2 disease. And so it may be that they have restrictive physiology for a variety of reasons that sort of maybe masking underlying COPD-like abnormalities. And so I think understanding that PRISm group is definitely something that, and highlighting that is something that COPDGene has contributed to the literature.
SPIROMICS is a smaller study, but also NIH funded. And this study, which is closer to 3,000 patients, the goal for that study was to understand intermediate outcome measures and developed biomarkers for COPD. And so, one of the things that makes that study unique is they did a much greater deeper dive into biologic biomarkers. So there were bronchoscopy, there was sputum, there were CT scans, of course, there was an exacerbation substudy, there was urine, there was a lot of biologic specimen collection.
And so there are a lot of interesting things that have been learned in the SPIROMICS study as well. One of the things that they identified was that patients who have a lot of cough and sputum production do actually have increased levels of mucin, and that may be the case regardless of whether the patient has airflow obstruction on spirometry or not.
That actually led to our hypothesis that bronchodilators would help these patients without airflow obstruction. But it turns out in a spinoff study called RETHINC, which was just published in the New England Journal of Medicine that Dr. Woodruff and I helped to lead, we were able to show that, unfortunately, the combination, a dual bronchodilator combination, does not help with symptoms in this symptomatic but not obstructed patient population. Which has then led to the conclusion that we maybe need better targets for mucin production.
They've also shown that mucus plugs on CT scans may help to identify unique phenotype of patients that has increased susceptibility for exacerbations, for instance. So I think one take-home message though from both of these studies is that we're really beginning to understand the heterogeneity of the disease as well as the fact that there can be significant abnormalities even in the absence of airflow obstruction. So trying to understand what to do with those patients and focusing on early disease pathogenesis, I think is now a focus for many of us that are in this field.
Dr Albert Rizzo: Thank you. And I guess that feeds right into my next comment. I was going to bring up another cohort study that we believe is going to be very important in the field of respiratory diseases, and that's the American Lung cohort study, again, which you were a part of. It's working through our Airways Clinical Research Center at the American Lung Association. The recruitment of these 4,000 millennials aged 25 to 35 years old, with presumed peak lung function is going to be followed for many years to identify a marker of when the decline in lung function occurs, and what, if any, markers will be able to predict a disease such as asthma, COPD, pulmonary fibrosis for that matter. And be able to use this as a possible target for modifying disease progression. Can you comment on your hopes for what this study will help us find, and if you feel there are currently any modifying therapies in COPD today, aside from smoking cessation?
Dr MeiLan Han: So, you're right, Al, we have a lot of hopes for the American Lung Association Lung Health cohort study. As you know, we've never really had a study of its kind before, to target younger individuals and follow them over times that we can understand exactly when disease develops. I think one of the things that we've come to realize, although perhaps it should have been obvious, is that if you study patients with mild disease who are old, those may actually be the absolute worst patients to study, because if they were going to progress and be significantly susceptible, they would've done so by the time they were old.
We've generally relied on convenient sampling and one of the problems is that we don't actually screen for lung disease much, so by the time patients are picked up, they're usually quite late in the course of disease and therefore it's very difficult to show modification of disease progression. So many have compared the Lung Health Cohort study to Framingham, and I think we certainly hope that it can deliver just like Framingham identified factors like cholesterol and blood pressure to be important markers for cardiovascular disease, we're hoping that we can identify similar markers of lung disease or the genesis of lung disease in the Lung Health Cohort study and hopefully modifiable risk factors.
So I think my hope is that just even by doing this study, we could better understand how to pick up people early. And I think that that will contribute to our ability to modify all sorts of lung diseases, COPD and interstitial lung disease, etc.
In terms of what therapies we have right now that are potentially disease-modifying, one of the problems that we have in trying to study any of the therapies that we have right now is, again, most of our studies have patients that are old and quite advanced. So this is trying to prove that a soil erosion prevention program prevents soil erosion when you're going into a piece of land where the soil's already gone, it's very difficult to do so.
But having said that, when you look at pulled data from meta-analyses, etc., I think the therapies we do have likely do help to slow lung function decline, particularly in patients with milder disease. We know we can help prevent exacerbations and some do believe that that in itself is disease-modifying. And then we have a couple studies more recently which show mortality benefit. So I do think we can modify the course of disease in COPD today, but I think our ability to show that has been impaired by the fact that we've mostly studied patients with very severe disease to begin with.
Dr Albert Rizzo: Great point. Do you feel we're making progress in recognizing and diagnosing COPD at these earlier stages, especially at the level of the primary healthcare provider?
Dr MeiLan Han: I have to admit, I've been doing this for, I don't know, 20 years now or so, and I'm not sure I'm convinced that we've actually made any progress. I think one of my very first papers, maybe 15 years ago or so, looked at the percentage of patients in the US that had a diagnosis of COPD but it actually had confirmatory spirometry and it was only about a third. And unfortunately, many studies have borne out that similar figure.
We actually recently did an analysis at Michigan, just looking at patients that had come out of the hospital for COPD exacerbation, and we figured out that 15% of those patients didn't even have COPD, they had something else. So unfortunately we have a lot of primary care providers who don't think about the disease, don't screen for the disease, or just make a diagnosis without getting confirmatory spirometry, which also then opens the window for misdiagnosis.
The question and really the problem though is we don't have great proven recommendations or methods for those primary care providers to say, well, this is how you should be doing it. We tell them, well, you should look for risk factors or we've got some questionnaires. I myself am working on what we call a case-finding study, where you would administer some questionnaires and peak expiratory flow to try to identify who should go on to do spirometry.
But what makes this such a challenge is that you have patients with symptoms who don't have airflow obstruction, and we have a lot of patients with airflow obstruction and no symptoms. So it makes it very, very difficult to figure out who the right patient is. And I've almost wondered and thought to myself whether we should just be very bold. It's hard because the use for blood pressure and proving that identifying blood pressure and modifying it could impact outcomes. The evidence basis for that was generated before we lived in the world of evidence-based medicine.
So doctors in the early 19 hundreds did a lot of blood pressure measurements because they liked doing them. They thought it made them look talented and skilled for wealthy clients, not because they thought that it was part of some evidence-based medicine program for preventive health. We now know that it's important and that there are things that we could do, but that evidence basis was actually built before, we got the cart before the horse a bit.
And so the problem for spirometry is that it was always a little bit more difficult to do, the uptake by primary care has been slower. We also, when you think about it, nobody does a blood pressure measurement in the way it was supposed to be done. So ideally you would have someone sit down for 10 minutes in a quiet room, you'd measure three times, you'd get an average, etc. But we do hold spirometry to that standard. It has to be reproducible and meet ATS standards, and it means our numbers have high quality, but at the expense of people not doing them.
And so I thought a lot about this. I can't admit that I necessarily have the solution, but it does make me wonder whether we should be a bit bolder, because when you think about it, spirometry is not expensive, very little harm, and there's no radiation exposure. Maybe we should just be more bold in recommending who gets it. Because one of the things that we're learning is that for people who develop COPD, while the old thinking was that most people get COPD because of accelerated lung function decline in adulthood, we now realize that many people are getting into adulthood without normal lung function to begin with. And while, perhaps, we as providers wouldn't necessarily make– maybe there is no intervention other than telling people not to smoke or vape, maybe there's no drug we could give them at that point– but maybe patients themselves would make different choices about lifestyle, about getting their immunizations, about the kind of job they did, about how much exercise they got if they knew that they were entering adulthood with impaired lungs.
So sometimes I wonder whether the solution to this is just going to be for us to go rogue and just start suggesting we get more people with spirometry, you turn 18, I don't know, you get it. I feel like we're headed towards a solution like that. I know it may be difficult to defend from a cost perspective, but this has just been a really challenging problem.
Dr Albert Rizzo: Excellent coverage of an ongoing issue about the primary care and spirometry. My next question, I think you've touched on this a bit, but I want to just bring it up again. You've published on information regarding that many smokers who have symptoms compatible with COPD seem to have preserved lung function with spirometry. What kind of information do you think this gives us as far as understanding of the tobacco exposure and how that plays a role in disease process? Or does this just go back to genetics, do you think, at this point?
Dr MeiLan Han: Well, I think some people will ultimately get COPD and some will not, but I think it shows us that there are many, many things that tobacco smoke can do. So I mentioned earlier in the podcast today we were talking about patients who have the symptoms without development of airflow obstruction, and that unfortunately they did not respond to bronchodilators well. As I mentioned, it looks like this may be an airway inflammation, a mucin, mucus-driven phenomenon. And those patients, regardless of whether they get COPD or not, are having exacerbations, they have symptoms, some of them even getting hospitalized. They deserve treatment and we probably need to look at targeted mucin-based therapies.
Some of those patients are going to go on to develop obstruction, but I think that there are so many other mechanisms besides those that produce early on symptoms though, that are silent, that we have to have other ways of picking those patients up. Because the symptomatic patients, while there is a relationship between symptoms and disease progression, they aren't the majority of patients who progress.
And so, unfortunately, we're going to need other things besides symptoms to try to help us identify who these patients are at risk, because a lot of this stuff is silent, it's happening under the surface, patients don't know what's going on and only until there's a much larger portion of the lung that's destroyed do these patients actually develop symptoms. So that's why at GOLD, we've come up with this concept of pre-COPD, where it could be symptoms, but it might be a radiological abnormality, it might be a physiologic abnormality that's very subtle, and you may not be associated with symptoms, where we could at least clue in that there's something going on, there's something wrong with the lungs, there's some kind of damage that has occurred that's going to put that person at risk for having significant lung problems at an older age.
But it's a challenging problem. Unlike diabetes, we don't really have a great A1C equivalent. Although, I guess similar to A1C, we are beginning to realize it should have been obvious, but we are beginning to realize that patients with perhaps borderline spirometry are the ones that in a few years probably are going to have actual barometric abnormalities. So that's probably a first group, but unfortunately there are many other things that can go on with the lung where stand spirometry maybe just doesn't quite pick it up. So I think this is an active area of research for us right now, trying to figure out how we identify these patients.
Dr Albert Rizzo: And speaking about early disease and whether or not spirometry is abnormal. I know you've been part of some workshops that have looked at the potential role of imaging findings on CT scans that may be showing areas of emphysema or changes in bronchial wall anatomy that predate clinical disease. Do you feel there will be a role for this information to be analyzed with artificial intelligence and machine learning and ultimately reported in a helpful manner to a treating clinician with regard to the disease presence or process?
Dr MeiLan Han: So this is a really active area of research right now and is definitely something that I'm interested in. So traditionally when we've examined CAT scans, we've looked at quantitative features. So we've actually measured the lung density and looked at the percentage emphysema or wall thickness or air trapping, etc. And I still think, to be honest, that those quantitatively extracted measures probably still have the most value. At a first pass, more and more health systems are developing ways to generate that type of quantitative data and deliver it back to clinicians in real time. And I think particularly, for instance, when we're, for example, examining COPD patients for advanced therapies, we already look at distribution of emphysema for deciding who would benefit, for instance, from lung volume reduction surgery or from endobronchial valve placement.
So there's already kind of a role for that. And I think we're trying to understand even more how these quantitative measures can help. But then that next level would be, okay, can you apply an artificial intelligence or machine learning approach to the data, where they just look at it and try to extract features that in a little bit more of an agnostic approach that are associated with disease progression. And I think we're making progress in that regard. I think sort of the holy grail would be that there's some, I don't know, bot behind the system that's combing the EMR and looking at imaging data, looking at, oh, this patient had three prescriptions for an antibiotic last year, they're a smoker, they were born premature, ding, ding, ding, somebody should think about screening this patient for COPD. And I still have some hope that we'll get there.
One area is, I know you are aware of that is really interesting right now is the whole concept of lung cancer screening because we have many patients who were not getting spirometry, but now they are getting at least lung cancer screening scans. And so because we have all of a sudden this influx of individuals into the health system that are getting CT scans of their lungs for another reason, what can we do with that, either from an artificial intelligence standpoint or just from a low hanging fruit standpoint of the radiologist saying, oh gosh, there's some emphysema. How much emphysema is acceptable, and at what point should I tell the clinician that they should order lung function testing? So I think we're still trying to come to grips with that, and I know the American College of Radiology is really starting to dig in on reporting of incidental findings and helping to understand clinicians about what to do with this kind of information.
But it is a little bit of a funny situation that we're finding ourselves in, where we have all these patients at risk for COPD and suddenly we have all these CAT scans we weren't planning on getting, that they got either for lung cancer screening or because they went into the emergency room with something, but no spirometry. So it does feel a little bit bizarre to be trying to backend into screening for COPD in that direction, but that is sort of where we've found ourselves and I think that there is the potential for a lot of that information to be useful, but we're still kind of working out the details.
Dr Albert Rizzo: Great. My next question will likely need a longer answer. When you're first confronted with a newly diagnosed patient with COPD, what goes into your thought process regarding both the pharmacologic and non-pharmacologic therapies that you'll be using, and what are the important patient education points that will be addressed at that time?
Dr MeiLan Han: So, I think at all points of management, and there will be an update to the GOLD management strategy in about two or three weeks that'll be coming out. So that's something that people can be looking for in November. But the things that I always think about are, how severe is the patient in terms of spirometry, how much emphysema do they have because that could impact management, how short of breath are they, and are they having exacerbations?
So those are the main kinds of things that I think about. Oh, as well as I would add to that cough and sputum production because it may impact management. So I think we've got bronchodilators that can help patients be less short of breath, do more, and also have some impact on reducing exacerbation frequency. We know the addition of inhaled steroids also helps, particularly for reducing exacerbations in patients in particular who have EOS over a hundred. So those are the main things I think about when it comes to pharmacologic therapy. I always think about non-pharmacologic therapies, in terms of who might benefit from rehab, maybe other things to think about, who might benefit from oxygen.
Obviously, there are some other pharmacologic therapies that you could add on, things like I said, through erythromycin, roflumilast, etc. If I have any diagnostic uncertainty or I'm wondering if bronchiectasis might be a key component to this because it could potentially impact management, I'll get a CT scan. But low threshold for referring for pulmonary rehabilitation, I think all patients need to be educated on various aspects of the disease, risk factors to avoid, what an exacerbation is, patients need COPD exacerbation management plans so they know who to call, when to call, what to do. And often they'll get a lot of that in pulmonary rehabilitation.
Once you've kind of got a patient sort of... Oh, the other thing that to think about, of course, is vaccinations. And I feel like that gets more and more complicated every day between influenza, COVID, pneumococcal, shingles, Tdap, the list goes on and on, of all the things that we need to be thinking about for our patients.
And now we've also got these advanced therapies as well. Things like lung volume reduction surgery, lung transplant in some cases, or even interbronchial valves. And the place to really think about that for patients is, I would say FEV1 less than 50% predicted. And if you're a pulmonologist on this column, that's not something that your group does, that is sort of the threshold, if you think the patient has some ephysema and you can get a clue for that from a low diffusion capacity, and you have a patient with the FV1 less than 50% at that point, it's not unreasonable to refer to a group that does some of these more advanced therapies, just to find out.
There's zero harm in sending a patient and finding out that they're not a candidate. But there's certainly going to be a group of patients who are, and unfortunately the workup for that is a little bit more extensive and involves the CTs with specific protocols. So a lot of times the referring centers will really like to do that work up themselves. So that's just something else for people to kind of add now in the back of their mind with patients with more severe disease.
I think that the bar has moved a little bit up in terms of, I used to only get patients referred to me when their FV1 was 20% or less, asking if we could do transplant. But I think some of those more advanced options are opening up. But I think if we happen to have any patients listening to the podcast, if your doctor hasn't given you an action plan for exacerbations, it's something to talk to them about. And if your doctor hasn't talked to you about pulmonary rehab, then that's definitely something to ask about, as well.
As you know, Al, the American Lung Association has the Better Breathers clubs, which are really great resources and there are a lot of online options now for that as well, which is another great resource for patients and for clinicians to recommend to their patients where a lot of great patient ed material.
Dr Albert Rizzo: You touched on the valves, and thank you. What about the role of lung transplant in this population? Is that still an option for these, who tend to be older, COPD patients?
Dr MeiLan Han: So the age cutoff for transplant depends a little bit on the center. At the University of Michigan, which is where I practice, our age cutoff is 65, but I do know there are a few centers that will go a little older. So the patients who are most likely to benefit have a higher BODE index. So just to remind everyone, BODE stands for, it's a combination of B, BMI, O, airflow obstruction, D, dyspnoea index, which is the MMRC, and E, exercise capacity, and you can calculate a BODE score, and it's really the patients with, I would say a BODE seven or more that tend to benefit. And so maybe a BODE of six or so is a good time to refer, but if you've got a 75 year old, probably not. If you've got a 60-year-old or 63 or even a 65-year-old that's getting up there, it never hurts to get a patient into having a discussion with a transplant center to see if it's something that they do qualify for.
Dr Albert Rizzo: Another area that these more advanced patients sometimes need some help really has to do with dealing with palliative care or hospice care. And I know recently the American Lung Association collaborated with the National Partnership for Hospice Innovation and produced a guide for people with advanced lung disease. Can you give us your perspective on how you deal with your patients who may be candidates for this?
Dr MeiLan Han: So these are obviously really hard conversations. I also can say I've had COPD patients graduate from hospice. I've also had COPD patients be in hospice for five plus years. So one of the things that can be very, I guess, sort of a blessing and as well as a curse for COPD is it's very difficult to predict when patients get really, really sick. So it's difficult for me as a physician to have a lot of certainty. And some patients can actually survive a long time, even if their quality of life is poor.
And so trying to help improve that quality of life as much as we possibly can, really ends up being a goal for management. But it can be really, really challenging. And so these are hard conversations to have with patients, where you're talking about balancing quality of life against quantity of life and well, we could keep doing X, but maybe that doesn't benefit you to keep coming in and seeing me and keep doing spirometry and maybe we could pivot. And sometimes those are patients where maybe you do even a little bit of morphine or you do more steroids than perhaps you would otherwise just to keep them out of the hospital and to improve quality of life.
But I think, again, I think if there's any kind of themes to these discussions, it's one, being open and honest with patients. Two, you absolutely have to involve their caregivers, got to get the caregivers on board, because this is going to be a long haul for many of them as well. And so as a physician, I think the relationship with the caregivers and many times is just as important as relationship with the patient. It's trying to set expectations and trying to help them understand what those treatment options are. And then I often try to center these conversations around maximizing quality of life. But like I said, the other, I think, key thing for this is that many times the patients will surprise you. And I've had patients do okay, to be honest, for much longer of periods of time than I ever would've guessed.
Dr Albert Rizzo: So you've given us quite a comprehensive review of all things related to COPD, and I must admit I always learned something when I listen to you. In a few weeks, you're going to be presenting at the GOLD COPD 2022 meeting at Temple University. Are you able to give us any insights into new insights that may be coming from this meeting or is it all embargoed?
Dr MeiLan Han: Well, it is all technically embargoed, but I think I can talk about some general themes to look for. So there will be some updates to the definition of COPD, and it really relates to a lot of the things that we talked about today, the struggle to encompass the disease that isn't completely captured by spirometry. And so I think GOLD is grasping with that and trying to understand and better capture the nuances to the disease.
And then there's also some updates, and I would say simplifications to the initial disease groupings, as well as initial and follow-up treatments. So I think that people will be, I'm hoping people will be, pleased with the updates. I think they're a little bit more streamlined. I know there've been some complaints from people in the past that GOLD is an academic exercise, but perhaps it isn't quite as friendly to the average practicing clinician as it could be. I re-reviewed, I still have one more review to do, but re-reviewed everything recently and I do think that there's been an attempt to really kind of streamline and make the document even more accessible and make sense. So I'm hoping people will be pleased with updates and I think we'll be excited to share them with everyone in November.
Dr Albert Rizzo: Well, thank you for sharing your time and your expertise with us today, and stay safe and hopefully I'll see you at Temple.
Dr MeiLan Han: All right. Thanks for having me, Al.
Dr Albert Rizzo: Right. Bye bye.
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