Welcome to the Pulmonary SEEK session, the Self-Education and Evaluation of Knowledge program. My name is Darcy Marsnik, and it's good to be with you today. This is my conflict of interest disclosure. So we have five cases, questions to present today. Let's get started. The first is regarding the conduct and interpretation of spirometry, which of the following is a required usability criteria? You have four choices. The first is A, no glottal closure in the first second of expiration. B, difference between the two largest FVC, forced vital capacity values is less than 0.15 litres. And difference between the two largest FEV1s, forced expired volume in one second, values is also less than 0.15 litres. C, the back extrapolated volume, BEV is less than 15% of FEC or 500 ml, 0.5 litres, whichever is less. And then finally, D, end of forced expiration is met, that is an expiratory plateau, less than 500 ml, 0.5 litres in the last three seconds of expiration. So please record your choice. The correct answer is A, no glottal closure in the first second of expiration. So let's look a little bit more into that. Quality assurance in the conduct of spirometry has been traditionally described by acceptability and repeatability criteria. We're going to talk a little bit about those. However, in the most recent technical statement, addressing standardization of spirometry, the concept of usability was introduced to enable clinical utility with patients when all acceptability criteria may not have been achieved. That is maneuvers that do not meet all technical acceptability criteria may still be the best the patient is able to do and may still be clinically usable. So minimal usability criteria, and remember, this is a new set of criterion, include a back extrapolated volume. So if someone hesitates at the beginning, that volume has to be less than 5% of the FEC or 100 ml, whichever is greater. There can't be a faulty zero flow setting. No cough in the first second of expiration for the FEV1 and no glottic closure in the first second of expiration. So choice A was correct. The second choice B was the difference between the two largest FEC values and two largest FEV values is less than 0.15 litre. That is correct, but it is a repeatability, not a usability criteria. So that is incorrect. And in fact, that's been updated and that is the only repeatability criteria. They have to be within 0.15 litres for the FEV1 and FEC. And remember, repeatability describes the intra-session variability of either acceptable or usable individual maneuvers on repeated testing with no change in test conditions. C was the back extrapolated volume was less than 15% of FEC or 500 ml, 0.5 litre, whichever less. And in fact, it's tighter than that. Regarding acceptability and usability, the back extrapolated volume has to be less than 5% or 100 ml, 0.1 litres, whichever is greater. So C was incorrect. And then lastly, the end of forced expiration as determined by a plateau of less than 500 ml, 0.5 litre in the last three seconds of expiration. In fact, it's also quite a bit tighter. It needs to be less than 25 ml, 0.025 litres in the last one second of the FEC to be deemed acceptable. But again, that is not required for usability and hence choice D was incorrect. And I've just reproduced the table from the ATS-ERS standardization document. Brian Graham was the first author published in 2019 in the Blue Journal. And you can see the various criteria for acceptability, FEV1 and FEC, and then the need for usability, what's required for usability. And they're a lot less stringent in terms of the end of flow indicators, the obstructed mouthpiece, the no evidence of leak and maximum expiration after end of flow, coming back after a complete expiration. And those shaded areas in grey do not apply to usability, but they do apply to acceptability. And then here are the references that I've spoken to, again, the standardization document from the ATS-ERS. And then the last two, I just want to call out and I'm a first author on the second one. The issue of race and pulmonary function studies is taking on a lot of importance. So we published in March 2023, a publication looking at the evidence of the effect of race and ethnicity and pulmonary function testing, and then a research statement identifying gaps. And it is quite interesting to really review in detail where we've got and the body of evidence that is supporting some of our practices or not supporting some of our practices. And then more recently in April 2023, the ATS came out with a statement on race and ethnicity and pulmonary function test interpretation, advocating for a race neutral utilizing the GLI, Global Lung Initiative, other in most instances, probably too early to make it onto the exam, but something that will be important in your clinical practices. And in particular, if you're supervising laboratories or interpreting results. So that's our first question. Let's go on to the next. Which of the following patients with COPD would be most appropriate to consider initiation of long-term nocturnal non-invasive ventilation? Four choices again, a patient discharged from hospital with acute exacerbation of COPD four weeks ago. Currently the PACO2 is 52 millimeters mercury and the pH is 7.36. They are clinically stable. B would be in hospital still recovering from AECOPD, initially managed with NIV, but now ready for discharge. Currently the PCO2 is 62, pH 7.34 and the clinically improving. Good news. C, discharged from hospital two days ago. Currently the PCO2 is 62, the pH is 7.31, but they're experiencing worsening shortness of breath. And then finally D, discharged from hospital from AECOPD four weeks ago. Current PCO2 is 64, the pH is 7.36, but they're awaiting a polysomnogram overnight PSG because of suspicion for sleep disorder breathing and they are clinically stable. So just record your choice in your mind. And the correct answer is A, discharged from hospital with acute exacerbation of COPD, AECOPD four weeks ago. PCO2 is elevated to 52, pH 7.36, and they're clinically stable. So let's look into this a bit more. There's quite a bit of evidence that's been building, and I've just picked one study published in 2017 that reflects on the use of NIV and its benefit. These are patients who are admitted with an acute exacerbation, required noninvasive ventilation acutely, survived, qualified for supplemental oxygen at discharge, and then were randomized to either oxygen alone or oxygen plus home NIV. And this was goal-directed to reduce the PCO2. And you can see a few messages here. The line in blue is the home oxygen plus home NIV, and the orange line is just home oxygen. Certainly there is a mortality benefit in patients who received NIV plus home oxygen versus oxygen alone. The second observation from here is that this is a bad disease. In either instance, mortality is very high six months afterwards, and certainly there would be many other measures in addition to oxygen and noninvasive ventilation that would be appropriate in this population. But a lot of these studies had some limitations here. The numbers are small, N of 116, but many of these studies have sort of built up our body of evidence and led to guidelines that have been published from the ERS in 2019, the ATS in 2020, and more recently from the Canadian Thoracic Society in 2021. And there is consistency in their recommendations outlining not only the benefit, but also whom is the population most likely to benefit, and then how the therapy should be implemented. So, as mentioned, the data is limited, but it is consistent. There appears to be an improvement in quality of life and also six-minute walk distance during the day, even with nocturnal NIV. Daytime PCO2 falls, dyspnea is reduced, hospital admissions are reduced, an indirect or inferential benefit in terms of mortality, but that's not been directly explored. In general, the population best suited for this from the guideline statements are patients who are stable, two to four weeks after acute NIV, with significant COPD, and hypercapnic respiratory failure. A PCO2 greater than 46, that would be the ERS and ATS, or 52 from the Canadian Thoracic Society CTS recommendations. All of them mentioned to think or consider to screen if it is a diagnostic or clinical possibility to exclude coexistent sleep disorder breathing. Again, it needs to be goal-directed to normalize or more practically lower the PCO2, and as mentioned, it should be overseen by experienced practitioners who routinely care for chronic hypercapnic COPD patients. This is not something you do for the first time. And then it has, as you would expect, significant implications for both clinical practice and resource allocation. There are many patients who would potentially benefit, have implications for access, monitoring, maintenance programs, and so forth. So when we look at the responses, A was the correct answer, patient with COPD who had recovered four weeks following, were stable, had a PCO2 of 52 and a pH 7.36. B was incorrect because the patient was in hospital still, so hadn't had that period of stability. C was incorrect because the patient was just recently discharged. The guidelines would suggest at least two to four weeks, at least two weeks, and this patient was not stable. They were experiencing worsening shortness of breath. And D was incorrect because there was a suspicion of sleep disorder breathing and they were awaiting polysomnography, and as such, once or if a diagnosis of sleep disorder breathing was excluded, then the possibility of NIV would be appropriate in this population, so not the best available choice. And then these are the references, the ATS, the ERS, the Canadian, and then I've also shared the reference with the data speaking to mortality or hospital readmission in that population from that figure that I shared with you. So we reviewed usability criteria for spirometry and nocturnal NIV and stable hypercapnic COPD. Next question, preoperative assessment of risk utilizing cardiopulmonary exercise testing. So we have a 71-year-old female referred for exercise testing in the setting of lung cancer and potential surgery. Recently diagnosed with a two centimeter right upper lobe lesion, and after thorough staging investigations is being considered for a surgical resection, a right upper lobectomy. She has an established diagnosis of COPD, management is optimal, and that's very important. If it is not optimal, it needs to be optimized. Her BMI is 23.4, vital signs are normal, breath sounds are reduced, but there's no focal findings. The remainder of the examination is normal, and a resting ECG is also normal. I'm just going to show you some selected pulmonary function test results. At the top we have spirometry, predicted values, lower and upper limit of normal, then the pre-bronchodilator actual percent predicted, and post-bronchodilator actual percent predicted, with a percent change from pre to post-bronchodilator. So the pre-bronchodilator FEV1 was 1.28 liters, and post was 1.32 liters, 53% are predicted, with an FEV1-FC ratio of 0.64. Total lung capacity was normal, residual volume was elevated, consistent with gas trapping, and the diffusing capacity was at the lower limit of normal, or just above it, just below rather, at 73% are predicted, 16.4, the lower limit of normal, 16.8. So the results would be consistent with moderate COPD. And then again, I'm also going to show some selected values from cardiopulmonary exercise testing. So the maximal workload was 74 watts, which was 69% are predicted. The VO2, the peak VO2 at end exercise was 1.47 liters, which is 98% are predicted. And when we were presented as VO2 over kilogram, it was 20.8 mils per minute per kilo, 96% are predicted. Anaerobic threshold was normal. We like to see it above 40% are predicted, and here was 65. Maximal ventilation exceeded the predicted, and we often see this in people with significant obstructive lung disease or COPD. That may be because we underestimated their maximal value, or they may have bronchodilated throat and at the end of exercise, but there was really absent mechanical reserve at the end of exercise. Patient did not desaturate, 94 to 94. Maximum heart rate was near, but not achieved. The O2 pulse, which is a surrogate for stroke volume in certain settings, but it has limitation was within normal limits, given the heart rate of 87% are predicted. Blood pressure response was normal. The patient discontinued exercise because of shortness of breath dyspnea. Modified bar score five for shortness of breath, and three for leg fatigue. And I'll assure you that there were no surprises or other unexpected results with complete interpretation. So based on the information provided, what would be your recommendation regarding lung resection? A, she should undergo a stair climb or shuttle walk test. B, she should undergo a radionuclide perfusion scan to measure the fraction of total perfusion for the resected lung or the remaining lung. C, she's able to undergo lobectomy, or D, she is not a surgical candidate because of her impaired pulmonary function and functional status. So just take a moment to choose the best response. And I would propose that she is able to undergo lobectomy. So let's have a closer look at that. This patient with moderate COPD, FE1, 53% are predicted. Demonstrates, however, normal aerobic capacity, 96% are predicted, and her measured VO2 slash kilogram is 20.8 from the gold standard assessment of cardiopulmonary exercise testing. So as such, she is at low risk of complications from surgery and is able to undergo lobectomy because of that choice C was correct, choice D being incorrect. And the kind of the number, the signal that we have here is the VO2 over kilogram. Because it exceeded 20, and I'll show you the table in a few slides here, there is really no need to undergo a stair climb or shuttle walk test, and as such, choice A is incorrect. Having that normal aerobic capacity is assuring, and it does place her in low risk. It doesn't completely exclude risk, but compared to a greater functional impairment, she is classified as low risk. Now, stair climbing or shuttle walk testing is used to more objectively assess the need for cardiopulmonary exercise testing, not the reverse. So if you have cardiopulmonary exercise testing, it would not be further informative to undertake either stair climbing or shuttle walk testing. And then also radionuclide perfusion scanning is recommended to more accurately estimate the predicted post-operative PPO FAV1 or diffusing capacity. It would not be typically relevant for assessment of operative risk after cardiopulmonary exercise testing was performed and hence choice B is incorrect. And this figure taken from the guidelines published in 2013 in CHESS, Brunelli, the first author, provides some additional information and clarity in this. So when we have somebody who we're considering, we would estimate the predicted post-operative FAV1 or DLCO. And if it's greater than 60%, low risk. If it's less than 30%, you would proceed to cardiopulmonary exercise testing. And if it's between 30 to 60, you would potentially do stair climbing or shuttle walk test. Now our patient had an actual FAV1 before surgery of 53%. And so the predicted post-operative would certainly be below 60%. Now she went on to cardiopulmonary exercise testing. Let's say she did do a stair climb or shuttle walk and the stair climb had a greater than 22 meter vertical height or greater than 400 meters. That would be low risk. If it was less than 22 meters vertical height or 400 meters, then you would proceed to cardiopulmonary exercise testing. And as noted, our patient went directly to cardiopulmonary exercise test. With a end exercise VO2 of 20 mils per kilo per minute, she had a 20 point something. So she would be at low risk. If somebody is less than 10, that would correlate with a higher risk. Need to be very thoughtful in that case. And between 20 or 10 to 20 would be moderate risk. And there may be instances when you might proceed, you might not proceed, but you certainly would prepare and be ready for potential complications. Patient would have to be aware and be ready as well. So this provides a nice scheme, a flow for how to navigate patients. Staging is one thing, but resectability and operability, their operability speaking to functional status here. And then these are the references that I've referred to. If you did wanna garner a bit more information. Okay, let's go on to the fourth case. So regarding ICS LABA LAMA versus LABA LAMA. So triple inhaled therapy versus dual bronchodilator inhaled therapy in symptomatic, moderate or severe COPD and a history of frequent or severe exacerbations, AECOPD, which of the following is true? A, LABA LAMA improves lung function and health-related quality of life and reduces side effects compared to ICS LABA LAMA. B, triple therapy, ICS LABA LAMA improves lung function and health-related quality of life and also reduces exacerbations and mortality compared to LABA LAMA. C, ICS LABA LAMA and LABA LAMA similarly improve lung function and reduce exacerbations, but triple therapy improves health-related quality of life compared to dual bronchodilator therapy with LABA LAMA. Or finally, D, the benefits of both are similar, but the risk of pneumonia is increased with ICS LABA LAMA. Lot of abbreviations. Just take a moment to choose the best response. So I would propose the correct answer is B, ICS LABA LAMA improves lung function and health-related quality of life and also reduces exacerbations and mortality compared to LABA LAMA. So let's look into some of the evidence behind that. So we know in symptomatic patients with moderate severe COPD and a history of frequent or severe exacerbations, triple inhaled ICS LABA LAMA improves lung function, symptoms and health status, and also reduces exacerbations and mortality. Relative rate reduction significant, statistically significant compared to dual inhaled LABA LAMA therapy. And as a result, B is correct and the others are incorrect. And there's references at the bottom in support of that. Important to remember or acknowledge, be aware of the population. These are patients with frequent exacerbations, either two or more moderate requiring antibiotic prednisone or severe, which is a hospitalization or emergency department visit in the past year. So that's that population at risk of exacerbations. And we know that exacerbations are the pathway to worse lung function, increased symptoms, reduced health status, and unfortunately increased mortality. So I'm just gonna show you some of the selected data that is from some of those works. This is published in the Blue Journal in 2021. Fernando Martinez was the first author. And this reflects to the budesonide glycopronium for Moterol studies, two arms with the active triple, 320 budesonide at the top, 160 at the bottom. And what's interesting, if we just look at the top in blue, and then you're familiar with the forest plot, to the left would favor triple inhaled therapy, to the right would favor dual bronchodilator therapy. And you can see that with the original publication, there was a significant benefit, hazard ratio of 0.54, P value of 0.01, favoring triple inhaled therapy. When enhanced statistical analysis and data retrieval was undertaken, there was no significant change, although the magnitude of benefit increased 0.51 for the hazard ratio P.0035 for intention to treat. And then finally on treatment, not much difference, but remained statistically significant with a hazard ratio of 0.5, favoring triple therapy. What's interesting in this case is that there was a magnitude of benefit obvious with the higher dose of budesonide 320 and not the 160, as evidence here where the lines cross one. And the on treatment includes deaths within 30 days of the last day of treatment. And then the intention to treat or the middle, the on and off treatment line includes patients randomized and received any study drug. Not shown here, there was no difference in the arms with triple inhaled therapy or the ICS LABA. This reflects the difference shown in this graph between the triple inhaled at the top of 320 with the LABA-LAMA dual bronchodilator therapy. So in contrast to that, there's a concern about pneumonia. And I think it is been shown or has been demonstrated that pneumonia is higher with inhaled therapy containing an ICS compound. But the relative occurrence, but also the magnitude of pneumonia, you know, has not been known, although we have a better understanding here. Mark Drainsfield published in 2021, I think has further informed from the impact trial. And you can see over the course of the trial, the number, the magnitude, the overall tonnage of exacerbations, the solid lines on top versus the dashed lines on the bottom where the incidence of moderate or severe AECOPD is six or eight or 10 times higher. Many more exacerbations, many less incidences of pneumonia benefit versus risk. And then, so that was just a number, but when we look at the implications of that, this is very informative. If we look at just the blue, and again, here's the forest plot to the left would favor triple therapy to the right would favor dual LAMA-LABA therapy. So there's no question that investigator pneumonia and radiographically confirmed pneumonia is less with dual LAMA-LABA therapy. However, when one looks at investigated pneumonia or moderate severe exacerbation or radiographically, again, therapy with triple inhaled therapy is favored. The incidence is much less, 0.78, 0.77, highly statistically significant. And if we look at in the yellow, this would be investigator reported pneumonia or radiographically confirmed pneumonia on the second line resulting in either hospitalization or death or a severe exacerbation. The signal, the benefit is persistent in favor of triple inhaled therapy. So when one looks at the fear or the risk of pneumonia versus the benefit of reducing moderate severe exacerbations and what that leads to, the evidence would suggest the benefit in reducing moderate severe exacerbations and the mortality reduction associated with that carries much more weight. And it's also important to keep in mind that there are many risk factors or associations with pneumonia in this population. This is work that was initially published in 2017 out of a cohort of about 6,800 people retrospective, observational, has some limitations, but it does help inform us. And this was a five-year community-acquired pneumonia risk where you can see at the top severity of disease, prior community-acquired pneumonia, frequent use of oral steroids, BMI less than 18.5, age, LAMA use, current smoking, exacerbation history, and then finally ICS use, which would be, what is that, about 10 on that list. Still significant, still there, but we need to keep into perspective. And we don't want to prevent a patient from realizing the benefit of a medication or constellation of three medications from a risk that in the overall weighing is the risk is much less than the benefit. And a lot of studies that have helped inform our understanding that have also put into clinical guidelines, the most recent GOLD update. And I will also highlight the second to last is the 2019 Clinical Practice Guideline and Pharmacotherapy and COPD that is now updated. It's currently being reviewed and it should, we're hopeful that it will be in press with the Canadian Thoracic Society Journal, but also in chest in the very near future. All right, let's go on to our last case. Methicolin challenge testing. This is a 45-year-old male referred for investigation of shortness of breath with exposure to cold air and with strenuous exercise. Recently empirically prescribed albuterol, short-acting beta-2 agonist, which he rarely uses and an ICS lab accommodation, which he takes regularly morning and night. And this was empirically prescribed pending the results of the methicolin challenge test. On examination, it is normal chest radiograph and ECG are normal and pulmonary function studies, resting measurements are also normal. So here are the results of the methicolin challenge test. And you might not familiar with this presentation. I'll just explain this. And his inhaled medication was withheld the morning of testing. And you can see the methicolin. So the initial FEV1 just at baseline with normal saline was 4.04 liters. And then with increasing doses of methicolin up to 16 milligrams, the reduction or the change in FEV1 at most was minus 3.2%. And then following albuterol again, there was an increase of 4% with the albuterol, but the patient did not experience cough, wheezing or shortness of breath during or immediately after testing. And the greatest drop in FEV1 at four milligrams was 3.2%. So the question to you is based on the information provided, what would be the next most appropriate step? A, cardiopulmonary exercise testing, B, increase the dose of the inhaled corticosteroid long-acting beta-2 agonist combination, C, add theotropium or D, repeat the methicolin challenge test. So just take a moment to think about the best response. So I'm going to propose to repeat the methicolin challenge test and let's look at why. This patient underwent a methicolin challenge test after withholding the long-acting beta-2 agonist for about 12 hours the morning of the test. In difference to recommendations advising withholding long-acting beta-2 agonist for 36 hours for salmeterol and 48 hours for all the other long-acting beta-2 agonists. Long-acting beta-2 agonists as well as short and long-acting anticholinergics will decrease bronchohyperresponsiveness for extended periods following use causing false negative responses to challenges. And this test was negative. There was no demonstration of increased bronchial reactivity. So the next most appropriate step in management would be to repeat the methicolin challenge test at least 36 hours following the last administered dose of the combination inhaled corticosteroid long-acting beta-2 agonist combination choice D is correct. And the way to prevent this is to provide patients with appropriate instructions. And if they're able to withhold it then you can undertake the test. And if they're not, then to reschedule as what happened in this case. So this is reproduced, a table reproduced from Alan Coates was the author of these ERS technical standards for methicolin challenge test published in the ERJ in 2017. And it provides the minimum time interval in the middle for withholding prior to a methicolin challenge test with supporting references listed here. So for short-acting beta-2 agonist, six hours. For a long-acting beta-2 agonist, if it's salmeterol 36, the others such as endocannerol, olidaterol, volanterol, 48 hours, two days. Ipertropium 12 hours and long-acting anti-muscarinic antagonist about a week. So that's important. And I don't think there's that understanding or realization of the legacy that it can have in effecting methicolin challenge test for that period of time. Then polyethiol, which really isn't used that much at least in North America for up to 24 hours. Inhaled corticosteroids and leukotriene modifiers really have no little or no effect in single dose and do not need to be withheld unless the intent is to offload an anti-inflammatory effect. If that's the case, you really need to withhold it for quite a few weeks in order for that anti-inflammatory benefit to unwind. So although cardiopulmonary exercise testing may be indicated, depending on the results of investigations, it would not be the most appropriate investigation in this case and really may not be necessary. It would be appropriate if a methicolin challenge test was negative in done in an appropriate setting and one we're still pursuing unexplained dyspnea or other investigation. As no diagnosis has yet been established with certainty, it would not be appropriate to empirically increase or further increases ICS-LABA, choice B would be incorrect or adding a new anticholinergic medication, choice C is incorrect because we don't really have an established diagnosis. And so in this case with appropriate withholding of the medication, the repeat methicolin challenge test was positive with a PC20 of 1.8 milligrams per mil. You have a diagnosis then, and then one can appropriately target with management in this case. And so withholding does make a difference in assessing bronchial hyperactivity. And then these are the references that I've spoke to. Also speaking to the effect of ipertropium and teiotropium bromide, the prolonged effect of methicolin challenge test which we need to be aware of. So that's our five phases. I hope this has been a good review. And if you are writing the exam, good luck. Thank you very much.

pulmonary medicine

spirometry

usability criteria

non-invasive ventilation

COPD

triple therapy

methacholine challenge test