Transcript

MIC CAVAZZINI:               Welcome to Pomegranate Health- and our first episode of IMJ On Air. I’m Mic Cavazzini for the Royal Australasian College of Physicians and the IMJ is the Internal Medicine Journal. This is one of the College’s three academic publications along with the Journal of Paediatrics and Child Health and the Occupational Medicine Journal. The IMJ is published every month and we’ve covered articles from there on the podcast before. But this usually requires me to school up on a topic from scratch.

Today we’re starting with an exciting new format. I’ve invited the esteemed editors and reviewers of the IMJ to bring their wisdom along to interview authors directly. So you’re going to hear experts chatting with experts and teasing out issues relevant to your clinical practice.

At times we’ll showcase original research of particular significance, but a good starting point for any generalist are the Clinical Perspectives articles. These reviews summarise the latest updates in management of major medical disorders. Today, for example we’ve got leading respiratory physicians from the Royal Melbourne Hospital giving you a reader’s digest on diagnosis and treatment for severe asthma. The article itself appears in the September issue of the Internal Medicine Journal.

These IMJ specials won’t always have broadcast quality audio because they’ll be recorded over the internet rather than a trusty face-to-face microphone. And instead of our usual documentary-style they will be a bit more raw and conversational.

For our first outing, I’m going to hand you over to guest host Associate Professor Daniel Steinfort. He’s the respiratory medicine section editor for the IMJ on top of his day job at the Royal Melbourne Hospital. Dan Steinfort has recently won an award from the European Respiratory Society for his teams’ leading work on bronchoscopic ablation techniques for lung cancer.

MIC CAVAZZINI:               So now we’re recording. And a good place to start might be for each of you to introduce yourselves for the record. Maybe you take it away, Daniel.

DANIEL STEINFORT:        I'm Associate Professor Dan Steinfort and I'm very pleased to be here with the authors of a recent Clinical Perspectives paper, which presents an overview of recent advances in asthma management. We’ve got Associate Professor Nur-Shirin Harun and Professor Jo Douglass and we also have Ash Witt, who is the lead author on the paper that we're discussing today. So Ash, take it away.

ASHLEIGH WITT:              So my name is Dr Ash Witt. I'm a final year respiratory Advanced Trainee based at the Royal Melbourne Hospital.

DANIEL STEINFORT:        Jo, would you like to tell us about your CV?

JO DOUGLASS:  So my name is Jo Douglass. I'm Professor of medicine at the University of Melbourne, Head of the Department of Medicine there and also Director of Research at the Royal Melbourne. But before that, I was a respiratory physician who spent much of my life in immunology and allergy and care of severe asthma.

DANIEL STEINFORT:        Nursh, would you like to quickly introduce yourself as well?

NUR-SHIRIN HARUN:     Yep. So I'm Nur-Shirin. I am one of the clinical leads for the asthma service at the Royal Melbourne Hospital. I am a general respiratory physician as well and work in general medicine both at the Royal  Melbourne Hospital and the Peter MacCallum Cancer Centre.

DANIEL STEINFORT:        Okay, so perhaps can I start first with; When a patient presents to you with suspected asthma, what are the first steps that you would take for diagnosis of asthma and particularly to begin to define their subtype of asthma?

ASHLEIGH WITT:              So, I think that the most important question when someone gets to us in severe asthma clinic is, “Is this asthma?” The characteristic symptoms of asthma, or dyspnoea, cough ways are not unique to asthma. And often, by the time someone has gotten to severe asthma clinic, they've met many, many doctors. They've met their GP, they've met probably a couple of Emergency Physicians and often a general physician, maybe another respiratory physician. And I think in asthma as in all types of medicine, avoiding anchoring bias is really important and really defining whether this is truly asthma rather than COPD or bronchiectasis.

The diagnosis of asthma has two components’ You have to have a history of the characteristic respiratory symptoms and importantly in asthma, it's not a constant disease. The symptoms vary over time and in intensity and often patients will have exacerbations of very severe symptoms. And then the second part to the diagnosis is confirmed variable airflow limitation.

One of the challenges in asthma is that many asthmatics will have normal spirometry and this doesn't exclude asthma and shouldn't dissuade us from the diagnosis of asthma. And the tools we have in severe asthma clinic, to confirm the diagnosis we can do bronchoprovocations or administering an agent such as mannitol medical and methacholine to prove hyperresponsiveness and induce induce obstruction.

Other tools we have giving the patient a handheld peak flow device and getting them to monitor that peak flow over a two week or longer period. So the hyperresponsiveness of asthma will have variable airflow obstruction over that time, whereas a nonasthmatic won't. Then I think the next important thing is establishing the impact of a patient's symptoms and spirometric values may not correlate with how disabled or how frequently exacerbating a patient is and so ascertaining what the impact of those symptoms on the patient's life is really important.

Then once the diagnosis of asthma is established, phenotyping is really important in the higher level treatment. So distinguishing between allergic asthma or eosinophilic asthma or other types of asthma is really important when you're going to be prescribing biologics. So things such as serum IgE levels, serum eosinophils and help you to do that. There are kind of accessory tests which don't make a diagnosis of asthma but are useful such as expired nitric oxide, which is a surrogate for a eosinophilic airway inflammation. There's also things like skin prick testing to common aeroallergens, which would be supportive of a diagnosis of allergic asthma but not diagnostic. And then going from there, then we can establish the patient on the treatments based on their phenotype that they have.

DANIEL STEINFORT:        And one of the one of the things that I found relatively novel for me in the article, was the distinction between endotype and phenotype. Is that something that that you begin to explore in the clinic? Or is that more based on biomarkers.

JO DOUGLASS:  So, phenotype refers to the sort of asthma and the things that might actually trigger it. And in particular, I guess we're used to thinking of perhaps allergic or eosinophilic asthma. But in truth, all asthma doesn't have the same underlying inflammation. And over the last really 20 years, there's been a revolution thinking hard about what is actually the inflammatory nature or pattern of the underlying asthma, so that someone who has a onset early in life and clearly has allergic triggers is obviously got quite a different sort of disease than someone who perhaps presents later in life and has dominantly eosinophilic, or very profound eosinophilic inflammation with nasal polyps and aspirin sensitivity.

So understanding the inflammatory pathways, which is certainly contributed to by biomarkers, but also has some historical features to it can underpin our understanding of the inflammatory and endotype of asthma. And that's become even more important in this days of the use of biological agents and in those with severe asthma. So that we recognize that they're not all—that whilst many pathways can lead to the sort of things that Ash has described with reversible airway obstruction, that in fact, the underlying inflammation can be quite different. And it's important to understand that.

DANIEL STEINFORT:        And do you think the different phenotypes and endotypes are relatively well represented in the severe asthma clinics? Do you think it replicates what is seen at community level care? Or are there particular phenotypes that are overrepresented in your specialist asthma clinics?

ASHLEIGH WITT:              I think that phenotyping of asthma doesn't often occur until severe asthma clinic and I certainly in my experience of working on respiratory wards, often patients come to hospital not having a phenotype that they know about. It's often not explored until they've continued to have symptoms on maximal inhaled therapy.

DANIEL STEINFORT:        You've written in the article that a significant proportion of fatal asthma exacerbations occur in patients whose disease had previously been misclassified as mild. So how common are deaths from asthma? How many deaths appear in Australia each year from asthma? Is this something that we don't need to worry about anymore with all these new treatments?

ASHLEIGH WITT:              I don't think so. Four hundred people die every year in Australia from asthma, I don't I don't think it's a disease of the past. I think that one of the challenges is classification of severity is often done retrospectively, after you've had a severe exacerbation. I think that certainly in a clinic or at a GP level we're not attributing severity in the way we do for other diseases. And often the reason we use the word severe asthma is for access to these advanced therapies. And so I think that it's important to note that all of those patients who have severe exacerbations and even fatal exacerbations, they might not necessarily have a label of severe asthma and be on a biologic.

Any asthmatic can have an exacerbation at any time and we don't know what the what the severity of that exacerbation will be. The biggest predictor of future exacerbation is previous exacerbation. And I think that's important that if you've had a severe exacerbation, having the knowledge and the resources to start management early—I think that it's important that we all know especially if the diagnosis of asthma is being made in the emergency department and general respiratory clinic or with the GP, telling patients that even if they've not had an exacerbation, that is something that can happen and making sure they know what to do when that happens.

MIC CAVAZZINI:               Yeah. A sort of follow on from that. The misclassification that you described, where would that likely have occurred at which level of the health system? If they've had an exacerbation in the past and it was sort of brushed off maybe not treated as severe, where's that most likely to happen?

JO DOUGLASS:  I think that's a hard one because I think—you're absolutely right. If someone's had an exacerbation in the past that was severe and they required intensive care then they're at risk for another severe exacerbation, and that needs to be remembered. But I think some of the asthma deaths studies show that some people were recognized as having a severe exacerbation. And to that extent, the notion of severe asthma necessarily being a risk for death from asthma, that is severe asthma as we currently classify it, may not necessarily be the same thing. And I think that's a really big question and a good point you've made  that is really needing to be the subject of further research, and indeed, studies into asthma death.

DANIEL STEINFORT:        And can I ask as a follow on? Obviously, as symptoms escalate, traditionally, we would escalate the dose of inhaled corticosteroids. Is that a good way to measure severe asthma or the other things that we need to be mindful of in classifying patients, regarding this asthma severity?

ASHLEIGH WITT:              I think one of the challenges and perhaps this is the reason that we don't label people as having mild, moderate or severe is that it's so variable. And I think that the way that we approach classifying these patients is their spirometry which can be normal; their symptom control which we measure via a tool called ACQ-5 generally in our clinic; and then there are exacerbations. And there are patients who have very severe symptoms day to day, who don't exacerbate frequently. And then there are patients who have no symptoms day to day who exacerbate frequently. And which one of those do you label as severe? I think that it's I there's much more nuance and I think it's a really hard disease to attribute mild, moderate to severe. Well, I guess like, we know what severe is, but we don't we don't say to people that they’re mild or moderate as the way we do and other diseases do.

DANIEL STEINFORT:        It’s also it's easy to know when someone is severe when they're in the hospital all the time. But there are a group of patients who aren't necessarily at the hospital, but probably by many classifications would have severe disease. And I guess it's the markers that signal that that we should be watching out for, that I'd be really interested to know about.

NUR-SHIRIN HARUN:     So I think a lot of it, it could can often be borne out in history, to be honest. So it's the ones that are, as Ash has said, the frequent exacerbators. The ones in hospital that have had even one one admission, but that was to ICU. You know, high dose inhaled corticosteroids or oral corticosteroids use, you know. More than two courses in 12 months is a flag to come to a severe asthma clinic. And so I think those sort of markers are important. I think while the biomarkers are important, it doesn't necessarily classify someone's having severe asthma if they don't have, you know, the clinical correlation to that.

DANIEL STEINFORT:        So, one of the other concepts that I think is relatively new to me that I read in the paper was the was the term treatable traits. I gather this is potentially a new paradigm for responding to persistent symptoms in asthma. How does that actually play out in the clinic?

ASHLEIGH WITT:              So treatable traits are, as you said, a new paradigm for understanding the factors that contribute to asthma control. There's a few different kinds of concepts within treatable traits. I guess the first one that I think of is overlapping disorders. So someone who's had asthma their whole life and also smoked is still at risk of developing chronic obstructive pulmonary disease, but because their asthma won't go away, they can develop an overlap symptom called a ACOS or asthma-COPD overlap syndrome. Patients who had very frequent exacerbations may be at risk of developing bronchiectasis, which needs to be treated in its own of its own merits despite the asthma. Comorbid vocal cord dysfunction or the newer term for that is inducible laryngeal obstruction, which is—asthma is a very frequent, coexisting condition for that, and it relates to the paradoxical movement of the vocal cords, which can present as a wheeze or difficulty breathing. And addressing those overlapping disorders and treating them with their own merits is part of treatable traits.

There's also comorbidities which are not intrinsically linked to asthma but will worsen asthma control. So things like uncontrolled gastro oesophageal reflux disease that could be both causing their cough and exacerbating their asthma. The side effects of corticosteroids and the side effects of inhaled corticosteroids such as dysphonia and weight gain. Then there are lifestyle or environmental factors. So we know particularly in teenagers, teenagers with asthma are more likely to smoke than their counterparts without asthma. And even though it seems very easy to say that smoking will worsen than your asthma and you shouldn't do it, it doesn't mean that patients with asthma don't smoke. And counselling on smoking cessation is really, really important. One of the things that's come up in asthma clinic in the last year that I've noticed is the prevalence of vaping. And how many people have lost control of their previously well controlled asthma because they're vaping. So addressing things like that.

Patients may be working in a workplaces that's triggering their asthma and they've not yet realized. I can give countless examples of doing skin prick testing and saying, you know, “do you know you're allergic to dust?” Or “do you know you're allergic to cats?” And the patient says, “That's ridiculous. I've got 10 cats”. “That's why you're in severe asthma clinic.” So identifying those things and addressing them of their own merits.

One of the advantages of our asthma service is that we're intrinsically linked to our immunology service. And so considering whether patients may need immunotherapy to desensitize them to the aeroallergens for which that's available. And then I think the final part of treatable traits is behavioural factors. So inhaler technique as we've discussed extensively; adherence to their medications; what's stopping them from adhering? Is it the price? If we put them on an inhaler that's combined drugs, and that's less money that needs to be spent, would that help?

Symptom perception is really important. Some people are poor perceivers of symptoms. You know, there's evidence that patients who migrate to Australia and women may underreport or underperceive their symptoms. And that's an important part of making sure people initiate their action plan and receive treatment at the right time. And you're having this social and family support.

One of the things that I think makes asthma different to the other conditions that we treat as respiratory physicians is that it's really sudden, and it's really scary, and you can be living your life and doing your job, and then all of a sudden, you can't breathe. And that's very different to someone with chronic obstructive pulmonary disease, or interstitial lung disease who have symptoms at baseline all the time. And I think the fear of knowing when your next asthma attack is something that's really unique to our population.

And there's things that we can do to address that, you know, referring to psychology, supports, like the Asthma Foundation and support groups are really important in normalizing that. One of the paradoxes of asthma is, the fear of always knowing that you could have an asthma attack is going to make you more anxious. And anxiety is a really common trigger for asthma and managing that can be really complex. And it's overall what treatable traits is. It's not things that make you at higher risk that we can address. All of these things can, often with challenge, be addressed. And that's part of the holistic model of care have a severe asthma clinic.

There are frequently patients who want to get control of some of those treatable traits or comorbidities, their asthma is no longer severe. And many patients who are referred to the severe asthma clinic with the intention of being on a biologic, but then with the support of the clinic, and treating those treatable traits may not end up needing one of the biologic agents. I think the other thing that's really essential to a severe asthma clinic is the nursing support and having the time to go over inhaler technique, which we know it's extremely common to have poor inhaler technique. And your education about asthma management plans and self-managing asthma is a really important part of the severe asthma clinic. It's not just a biologic clinic, it's a holistic clinic that hopefully controls people's asthma in the in the best way for that patient.

JO DOUGLASS:  If I could just answer, the elephant in the room of severe asthma is always not just the vocal cord dysfunction, or the treatable traits, but also the elephant in the room is that 95% of people with asthma in the community will be controlled with moderate doses of inhaled corticosteroid if they have good inhaler technique. And so probably about one in 20 people or something like that, probably actually have severe asthma, and they're the people we want to see in the severe asthma clinic. So it's always the elephant in the room, when you see someone with severe asthma, are they really taking all the good things that will have been prescribed likely by the doctors they've seen before? And that's why Ash’s comments about checking inhaler technique, getting buy into an asthma plan, and actually helping people manage their asthma optimally at that level is always really important before jumping to the next stage of treatment. But nevertheless, really important to verify given all those things.

DANIEL STEINFORT:        For people in general practice or in general medical clinic, how do you how do you actually assess the adequacy of people's technique for use of inhaled corticosteroids?

ASHLEIGH WITT:              So I don't think there's an art to it. I think watching the patient use their inhaler, it can become very apparent that some people have never had a dose of their inhaler they've been on for many years. And I think that when you prescribe inhalers, encouraging the patient that when they take it to the pharmacy to get the patient to take it out of the package and have a dose in front of the pharmacist so that someone can watch them take it is really important. In asthma clinic. We've got lots of devices without medication that we can we can demonstrate, but there we frequently see people who've been on Ventolin for 20 years and then they're not actually administering the ventilation in a way that it's going to get into their lungs.

One of the other really important things is using a spacer, or establishing whether the patient is never going to use a spacer and then putting them on an inhaler that doesn't necessarily need a spacer. And I think lots of people in clinic will say, “Yes, I'll use a spacer every time” but then won't necessarily do that when they get out into the community. And I think that that's something that's also really important in an inpatient setting when someone's admitted under general medicine or respiratory with an asthma exacerbation on the ward round, watching them take their inhalers, it can be very obvious very quickly, how ineffective their dose administration can be.

DANIEL STEINFORT:        Do you think use of combination inhaled corticosteroid and beta-agonist as a reliever medication is a significant component of effective management of mild to moderate asthma?

ASHLEIGH WITT:              Yeah, and I think that that's something that's changed, certainly, since I've finished med school and in my training that—and one of the take home messages from the GINA guidelines in 2019 and our paper is that all asthmatics need to be on an inhaled corticosteroid. And I think of it that Ventolin is opening up their airways and providing temporary relief, but asthma at its core is an inflammatory disorder, and it needs an anti inflammatory medication to control it. And so every time you take your bronchodilator, having an inhaled corticosteroid at that point is going to mean you'll get you'll get more anti inflammatory relief.

I also think that for young people with asthma having one puffer is much simpler. If you forget to take your morning dose but it's your reliever that's in your pocket, you can take your dose later on in the day. For some groups have mild to moderate asthma having their Symbicort just when they need it may be enough to control their symptoms. So I think that it's an important take home from the recent advances. And in particular, one of the things that we've tried to do is working with emergency department that if they're prescribing if they're diagnosing a first presentation asthma, giving the patient an inhaled corticosteroid as part of that treatment regime. And often the easiest way to do that is to be on an ICS/ LABAL that can be used as a preventer and a reliever lever which is called Smart therapy when we're using Symbicort, is a really important way to do that.

DANIEL STEINFORT:        On the occasion, when I see someone who has been admitted to hospital with an exacerbation, and they've been on a long-acting beta agonist that isn't effective as a reliever, I'm never quite sure that the patient is that convinced that my suggestion that we change inhaler to use a preventer and reliever as the single puffer. Do you think that distinction is readily understood by patients? And how do you ensure that that element of their drug compliance is up to scratch?

ASHLEIGH WITT:              I think that's really important. I think that making it extremely clear. And, you know, we're often seeing patients who've had asthma for many, many years and their whole life they've had a preventer they're taking the morning, and then they've had a reliever that's a different puffer that they take during the day. And it can take quite a lot of time and quite an effort in the therapeutic relationship to re-establish this different paradigm of care. But ultimately, it's easier and more effective control often for their asthma. I think the other thing that's really important for us to utilize is written action plans and written information about this. And so when you're writing an asthma action plan, having it very clear to the patient that on a day where they have no symptoms, they take their preventer, and then if they develop symptoms, they take their reliever and really spelling out what those two things are and that they're the same puffer. And then having a further graded escalation management plan, which may include starting their oral steroids at home.

I think a difference from in the past the past decade is giving the patient with control of their disease and asthma is a lifelong disease, the patient is going to become an expert in their asthma and giving them the permission and the ownership of their disease that they know when they're having an exacerbation and they don't need to wait until it's at a crisis point where they call an ambulance. They can take their prednisolone at home, they can initiate their action plan at home. And of course, still have the support of contacting the asthma nurse or contact contacting their GP. But if it's a Friday night, not waiting until Monday to see their GP just actioning their plan when it happens.

JO DOUGLASS:  It's also important to say there are the two paradigms and maintenance a reliever treatment is a really good option for many patients. An equally valid option is maintenance treatment with reliever of a short acting beta agonist. I think it's important patients have one or the other. I think there is a risk sometimes with just using maintenance and reliever patients just don't use their maintenance treatment or don't get inhaled steroids are enough of it. So either paradigm can work but as I said, certainly for very mild asthma, so people who have symptoms more than twice a month should be on an ICS/Laba by prefence than a short acting beta agonist or low dose inhaled preventer. But we know the adherence with that is so low in, in people with mild asthma, that probably they would be better on maintenance and reliever treatment. But at the severe end of the spectrum, I think either option is good and has benefits demonstrated in trials when it's used properly.

NUR-SHIRIN HARUN:     And I think it's really this sort of move towards personalised asthma management, where, you know, you can use either paradigm, but it's about assessing, adjusting, you know, seeing how the patient responds and a bit of feedback, you know, both ways to get the best recipe for the patient.You know, the written action plan is really useful, and it's been proven to be effective. I think that, we spend quite a bit of time in the asthma clinics, going through a written action plan. It's reiterated by the nurses. And then oftentimes, we can actually translate it into different languages for patients as well. So I think something that patients can access stick on their, you know, fridge, look at, you know, and often make sure that the GPs have a copy as well, so that it's not confusing for the care providers involved.

DANIEL STEINFORT:        And we we've all been involved in the care of patients who have very frequent, very nasty asthma exacerbations. But severe asthma, I'm sure is a spectrum of disease, and at the less, perhaps not quite so drastic end of severe what are the other clinical features that suggest to you that specialist asthma input should be sought?

ASHLEIGH WITT:              I think that one of the things that I I worry about in our estimate clinic is that there are lots of people whose lives could be drastically improved by coming to asthma clinic that we don't, see. And I think it's important not to make severe asthma clinic this very exclusive club that not everyone can access.

And so we've got these in our paper, we talk about things that we think should trigger referrals; your frequent causes of oral corticosteroids; particularly people who are on maintenance oral corticosteroids; an exacerbation, which is required hospitalization should consider a referral. But if someone has ever been to ICU for their asthma, they should be seen in a severe asthma clinic.

There are kind of there are patients where the diagnosis is in doubt, and I think that severe asthma clinic is a really good place to really work out how much of their symptoms are contributed to by asthma. Patients who are needing things like bronchoprovocation or higher level diagnostics to be diagnosed should be seen there. And then there are kind of the rarer and more tricky phenotypes such as occupational asthma, which we would like to see in that clinic.

But I think that as a general physician, or as a non-asthma, specialized respiratory physician, if you think someone needs to be referred, they probably do. We've all got in our skill set the ability to prescribe inhaled corticosteroids. And if you're not responding to moderate doses, having that specialist input can really be revolutionary for patients.

I remember when I, when I first started advanced training, one of the first patients I saw in our asthma clinic was a, she was a young woman, she was about my age, and she'd been on high dose steroids for three years. She'd been in and out of hospital, she had every quality of high dose steroid use. She had early onset diabetes from the steroids, osteoporosis, she's overweight, had acne, and just felt like her life wasn't worth living. And her GP referred her to us. And she came into the room thinking that we were going to say there was nothing we could do.

We started her own mepolizumab and over the next six months, watched her life turn around and she got off the steroid, she lost 20 kilos, started working, found a boyfriend. You know, her life just changed. And it was, you know, there's not many things in medicine that are as magic as putting someone with severe asthma on a biologic. And it was a huge reason why I choose or spiritually as a specialty, there's the days where you think, have I made a difference today? The days or have done severe asthma clinic, I really feel like I have. And I think frequently that there are all these people we could be helping. And I worry that prior to respiratory training, I thought biologics were for these really severe in ICU all the time patients, but it's not just for that there. It's for anyone who's not controlled on a moderate dose ICS. And so I think having a lower threshold to refer, I hope is a take home for from our paper.

DANIEL STEINFORT:        It's great that you mentioned the biologic treatment options that are increasingly available for people with severe asthma. How many patients in a severe asthma clinic will be on biologic agents?

ASHLEIGH WITT:              Nursh? Would you like to speak to that?

NUR-SHIRIN HARUN:     Yeah, so I'd say the majority of patients coming through our severe asthma clinic will be on biologics and that's probably a selection bias. So as Ash has said, they've likely come through a GP or other respiratory physicians. They've often tried a lot of other treatments. So I think the purpose of the asthma clinic, obviously, is to try and ensure that we have the correct diagnosis and that we as best we can grip them by endotype/phenotype. Or perhaps they don't have asthma at all. And there might be other things such as vocal cord dysfunction, which needs another treatment pathway.

In our clinic, he large majority of patients requiring biologics are eosinophilic and allergic asthmatics, and that would be the majority that we see. A smaller proportion of that the pauci-granulocytic or neutrophilic asthmas which are often more difficult to treat. And other treatment modalities, such as macrolides, might become more important there.

So essentially, the large majority of patients are on biologics. There are increasing treatment modalities on biologics. So initially, we had the anti-IgE therapies and with antibody therapy on omalizumab which certainly was very effective, and really did revolutionize treatment and improve quality of life substantially for patients. However, there were certain proportions that were still not well controlled on that and the later the anti-IL five treatments are mepolizumab and benralizumab came next and certainly, we're also very effective. We now have dipilimbab that has been recently PBS approved, an anti IL-4. And there are there are certainly further agents overseas which are coming to Australia, such as the IL-33, and Il-4, monoclonal antibodies.

MIC CAVAZZINI:               I'll just chime in there. That's another question in terms of if you're stepping up, after inhaled corticosteroids and oral corticosteroids, what are your choices guided by which of which of the biologics is—do they line up with specific endotypes? Or is it is it sort of empirical, like it always has been?

ASHLEIGH WITT:              Joe, would you like to?

NUR-SHIRIN HARUN:     Sure, so. So omalizumab, which was the first available biologic is an anti IgE. And so that is really useful for allergic asthma. Dipilumab, which is the more recent one, is also indicated for allergic asthma and that antagonizes IL-4 and IL-13, so obviously, a lot of important cytokines on the pathway in allergic disease. The other two that are currently available in Australia, mepolizumab and benralizumab, and both of those are anti eosinophil agents although they work quite differently. And so it's important to understand the endotypes of asthma when prescribing them because it is important, as Ash said, to actually offer patients, the one that's really going to benefit them. And there's no doubt when these drugs work well they're absolutely life changing for people, so it's really a great time to be practicing in that regard. But they do require you to understand the end type of the patient. And there's obviously quite a bit of overlap, because a lot of allergic asthma is eosinophilic and determining that is perhaps some of the skill, and whislt we can swap between them that's often wasted time for patients. So it's important to try and get it right first time if we can.

NUR-SHIRIN HARUN:     I think the other thing to say about the biologics, and particularly PBS access to them—and this is a lot of what we do in the severe asthma clinics—is trying to establish their criteria or who's going to benefit from the biologics. And the previous criteria required to have had asthma for 12 months, and for there to have been a reasonable attempt to optimize that with inhaled corticosteroids or long-acting beta agonists. We have to demonstrate that we definitely do have a diagnosis of asthma, which can sometimes be tricky. but there are various ways to do that. And then, endotyping, phenotyping, biological markers such as eosinophil count that we talked about, IgE levels.

And then this this requirement for high dose corticosteroids or cumulative dose, over 500 milligrams over 12 months, it's sort of that sort of requirement to access some of these biologics. And of course, hospital admission has Ashleigh or a severe exacerbation, or uncontrolled asthma as determined by an estimate of control questionnaire are often criteria that need to be met.

DANIEL STEINFORT:        Asthma was on the front page of the news in a huge way around the globe, following the Melbourne thunderstorm mass event in 2016. And I think you've all been involved closely in in the in the subsequent study of that event. Was that asthma as we know it, or was that a very different a very different event?

NUR-SHIRIN HARUN:     I think it was certainly an extraordinary event. It was not a unique event for Australia. We've had many thunderstorm asthma events previously, but it probably was one of the biggest around the world. There were about 3000 Emergency Department presentations. Some required intubation and ICU. Tragically about 10 patients died out of that, some of which never made it to hospital. And I suppose the factors that were thought to be implicated, and why that was such a difficult and catastrophic episode was that it was essentially a susceptible population. So patients were highly sensitized in Melbourne. We had a day that there was high humidity, it was very hot and there was rain activity. And it occurred at about 5pm, so people were in the streets, you know, outside, when there was, you know, a gust of hot rainy weather, which often brings the pollen particles down to inhalable level. And the humidity ruptures the pollen particles that they can get down into the airway. So it was a series of events that, you know, sort of the Swiss cheese lining up where certain bottom one environmental factors lined up and many patients were exposed. And patients that had no idea that they were at risk of asthma got caught up in that.

These 3000 patients that are affected, it occurred within a very short period of time, most of them occurring within the first 30 hours. So that really overwhelmed emergency services, it overwhelmed hospital EDs, and was really unprecedented in terms of the chaos that ensued. So if we look at the figures they're kind of stark. There was a 992% excess asthma-related hospitalizations across Geelong and metropolitan Melbourne that day. It wasn't just the hospital system that was overwhelmed. There were local pharmacies and GPs that were also pretty overwhelmed with patients, running out of salbutamol from pharmacies. And same thing occurred actually in hospitals, so patients were often discharged either without proper follow up or proper action plans, in some instances proper medication wasn't given. You know, that that was just a symptom of an overwhelmed health system.

And what it really brought to light was, I guess, the prevalence of asthma in the community. In Australia, abput 10% of people have asthma, so it's pretty common. But it really drove home that people can have no symptoms and be affected by asthma in the correct circumstances. We published in the Journal of Allergy and Clinical Immunology, the TAISAR study. Some of the things that came out of that; a third of patients didn’t actually have an asthma diagnosis. And some of those patients that died actually did not have an asthma diagnosis. But what were the things that we can learn from this event? And were their markers before that maybe might have led us to the fact that these patients were at risk.

So we have looked at the cohorts of particularly patients in Australia, and there are patients overseas, in Italy, Canada, and various other places in the UK that have been affected by thunderstorm asthma. But nearly universally, all patients had a history of seasonal allergic rhinitis, hay fever. They were sensitized to, often, ryegrass, so there was IgE-specific ryegrass sensitivity that we could detect in blood. And the patients often had low FEV1s when you looked at them, higher severity asthma scores when you when you looked at the questionnaire, high pheos and high eosinophils.

So I think some of the lessons that came out of it were that—I’ll look at the individual sort of aspects, and then the sort of population aspects. From the individual aspects, some of it was common sense about optimizing asthma control. You know, use of inhaled corticosteroids which a lot of patients went off on, that ran into trouble; action plans which we've talked about; and then treatment of allergic rhinitis, because we think that this is a huge risk factor for this sort of event. And then that leads on to, you know, potentially looking at other treatments such as immunotherapy desensitization, as add-ons for some patients.

For the population, I think there are a lot of campaigns that came out of it. So your at-risk days, your pollen counts, it's now publicized or televised, it on comes on the radio, if there's a high pollen day or there's a risk of thunderstorm asthma. And, you know, it might be that, that patients that are at risk, that know that they’re at risk, stay indoors during that time, make sure that they’re asthma is optimized that they have enough medications. But it's also highlighting in patient that don't have history of asthma, what are some of the symptoms of asthma, what are the some of the symptoms of allergic rhinitis. Further to that, I think things like preparedness even in the emergency departments; we've done quite a bit of work with having a asthma packs in emergency departments that have action plans. Your reliever ICS in that pack, so that's your first step rather than a lot of the Ventolin that was being given to patients and taken home in 2016, which we think was less than ideal. So it's about getting education out there, preparedness packs and that comes through GPs, pharmacies, EDs, not just respiratory physicians and severe asthma clinics.

DANIEL STEINFORT:        You noted there, that there was a shortage of Ventolin around the thunderstorm asthma event. And I think on an earlier episode of the podcast on this Pomegranate Health series, it was suggested that perhaps Ventolin should be made available as part of an action plan. What's your views on that approach?

NUR-SHIRIN HARUN:     So I think that notwithstanding the recent changes, where we think that inhaled corticosteroids really should be in the mix we wouldn't advocate for short-acting beta agonists to be used up front or on their own anymore. I think access better than no access. So I don't think it's a bad thing that salbutamol is available if account and if nothing else, it allows the interaction with a health professional of some form, often the pharmacists, who are pretty cluey in terms of education, highlighting, you know, when patients might need to seek medical attention. And they often have oversight about, you know, how many scripts are being provided, for instance. So, I think there's an opportunity there.

JO DOUGLASS:  And I think, in Australia, it's unlikely ever to change it's so accepted that you can go to your community pharmacy and get salbutamol that there is just no appetite to address this, despite—there have been attempts in the past to change the rules and Australia is unique, internationally, in providing this access. But having said that, I think it's will be unpalatable to the community to try to do so. So we have to use that, as Nursh said, a touch point with the health professional as the best advantage of the system that we have.

DANIEL STEINFORT:        It might be a slight understatement to say that an event bigger than the thunderstorm asthma event was the COVID pandemic. Early on, there was a large degree of concern that asthma patients might actually be a subgroup that were at particularly high risk of severe COVID illness. But I believe that that hasn't actually been borne out in the studies. Do you have any comments on that?

NUR-SHIRIN HARUN:     You’re absolutely right, Dan, you know, early in the pandemic, there was a lot of anxiety about, particularly asthma patients, or patients with chronic respiratory disease and what that would mean for them.  I guess, you know, on the back of the thunderstorm asthma we were all on edge, but thankfully for us, it wasn't it, it was never born out. So there's been quite a number of studies looking at this and the reasons for why, asthma was not found to be a risk factor ranges from, you know, maybe definitions of asthma varied. Or, you know, sort of a heterogenous populations, so it was difficult to actually look at that. Personally, I think that a lot of the asthma patients, particularly those at severe asthma clinic, were also an edge so they were really compliant with their inhaled corticosteroids. We know that that's protective. And they often had action plans. So it might be that asthmatics or severe asthmatics had some sort of background medication that might have been protected for that.

We know that asthma is not a risk factor for either COVID infection, or severity. And we think that there's a role eosinophils in protection against viral infections, for instance. And it might be that these patients with high eosinophils, or propensity to have high eosinophils, were actually protected in some way. We also know that inhaled corticosteroids decreased the expression of pulmonary angiotensin-converting enzyme-2. And this receptors used by the coronavirus, SARS CoV2 virus to enter cells. So there might have been some interactions there that actually might have been protective. So part of the advice around the time for our asthmatics, and still remains the advice is diligence with inhaled corticosteroids, ensuring that asthma is optimized back to those written action plans. And then the other measures that we're interested in COVID, such as mask wearing and hand hygiene, and those sorts of measures, which have, for the most part kept patients out of out of trouble, I think.

JO DOUGLASS:  There's also the recommendation that patients who have severe asthma on biologics actually receive antivirals on the onset of disease, which perhaps the statistics show a slightly greater risk, and those who have severe asthma. So perhaps that's the group that we should be worried about. But having said that, with the availability of antivirals, that's a really positive thing, that we should remind patients with severe asthma, to contact their GP about to get access.

DANIEL STEINFORT:        Well, Mic are you happy if I make some concluding remarks.

MIC CAVAZZINI:               Yeah, I was just about to say I think, we pretty naturally covered all the bases.

DANIEL STEINFORT: So that's a really thorough look at asthma triggered by a really informative paper that I think is quite practical for people involved in day to day care of asthmatics outside the severe asthma clinic. I'm really grateful to Dr Ash Witt, Associate Professor Nur-Shirin Harun and Professor Jo Douglass for joining us. And I think that that's been a fantastic experience for me to talk through those I hope the listeners have found the same.

MIC CAVAZZINI:               Many thanks to Ash Witt, Nur-Shirin Harun and Jo Douglass for contributing to this episode of Pomegranate Health. And special thanks to Dan Steinfort for being our first guinea pig in the guest host’s chair. I should also give an nod to IMJ Editor-in-Chief Jeff Szer who’s been an advocate of the podcast from day one, as well as the other members of the editorial board and staff who helped bring this together.

The Internal Medicine Journal is published by Wiley and all RACP members have complementary access to it, along with the Journal of Paediatrics and Child Health and the Occupational Medicine Journal. Just go to racp.edu.au/fellows/resources/journals and follow the links. There are also instructions for submitting an article of your own. That could be breaking research, a case report of exceptional interest or even a letter to the editor.

Another member service that has been launched recently is the RACP Online Community. It’s a networking tool for members that has discussion rooms for many different specialty interests and areas of College advocacy. There’s also a neat feature to help trainees and mentors find their perfect match. You can log in right now from your mobile by searching for the app called “RACP- the ROC.” 

If you liked this episode of Pomegranate Health, please leave a review at your preferred podcast portal and ask your friends to check us out. I’m Mic Cavazzini, and this podcast was produced on Gadigal land. Thanks for listening.