PETER GIBSON: So, every year over 400 people die from asthma in Australia, and when you think that asthma is a treatable disease we don’t think that’s acceptable.
MIC CAVAZZINI: That’s Professor Peter Gibson, senior respiratory specialist at the John Hunter Hospital, and academic at the University of Newcastle.
PETER GIBSON: In the 90s we had a really severe problem and through important efforts death rates dropped until about 2005. But since then there’s been no further improvement. We’ve been recommending the same approaches to treatment all that time but haven’t seen any further improvement.
MIC CAVAZZINI: Australia and New Zealand have a relatively high prevalence of asthma with a population rate of about one in nine. The majority of these patients manage the disease effectively with a combination of reliever and controller medications. Short-acting beta adrenergic agonists like salbutamol used as bronchodilators during wheezing episodes. And inhaled corticosteroids like budesonide reduce the inflammation that leads to airway constriction.
For years the management model has been empirical; the more serious the disease the more the corticosteroid dose is increased. But this therapy doesn’t work for everyone.
PETER GIBSON: Now, a small group of people won’t respond to that intervention either, and they’re the group that have severe refractory asthma. So, a message for a physician would be any asthmatic that gets admitted to hospital you should ask yourself the question, “Why did this happen? What can be done to prevent it? And could this person have a background of severe refractory asthma, and that’s what’s driving the hospitalisation?”
MIC CAVAZZINI: Welcome to Pomegranate Health, a podcast for physicians of the RACP. I’m Mic Cavazzini.
Around ten per cent of asthma patients respond poorly or not at all to maximal therapy. They exhibit a chronic narrowing of the airways that can present like COPD, as measured by forced exhalation volume over one second. And they have frequent exacerbations that can require hospitalisation. This small population represents a high disease burden.
Professor Gibson published a “Clinical Perspectives” review on severe asthma management in June’s Internal Medicine Journal with co-author Vanessa McDonald.
VANESSA McDONALD: I’m Vanessa McDonald, Professor of nursing at the School of Nursing and Midwifery at the University of Newcastle, and a clinical nurse consultant at John Hunter.
MIC CAVAZZINI: We’ll discuss some of Professor McDonald’s work into the social contributors of disease later. But first we’ll describe the three or more pathological pathways underlying of asthma. An inflammatory increase in the airway eosinophil population is associated with the allergic and eosinophilic endotypes of severe asthma.
PETER GIBSON: One thing probably worth noting is endotypes not used apart from severe asthma, and it was a word that was coined by a professor of pharmacology in Melbourne, Gary Anderson. So, we should own the little Australian invention.
And what it refers to is a pathophysiological pathway that’s linked to a clinical phenotype. And when you get those two things linking up you’ve got an endotype and you’re on the path to targeted treatment. So, we have that for allergic asthma and eosinophilic asthma.
They’re two mechanisms that could lead to recruitment of eosinophils. So, the T-helper Type 2 mechanism explains how allergen could drive eosinophilia. The mechanism of that is very well understood now. That results in the production of haematopoietic cytokines such as interleukin-5, interleukin-4, interleukin-13, and they promote the high levels of eosinophils.
But that phenotype where there is non-allergic, late-onset eosinophilic asthma, that’s been a puzzle. And it turns out that there’s another sub-type of lymphocytes found innate lymphoid cells and they can produce IL-5 and recruit eosinophils.
MIC CAVAZZINI: I read that blood eosinophils were not a particularly reliable measure. How did you establish what blood-count would make a useful threshold for disease?
PETER GIBSON: So, what we did was, in a large number of people across several cities around Australia, we collected induced sputum and looked at eosinophil counts and did a full blood-count to measure blood eosinophils. And we then tried to work out “Okay, what’s the blood level that will predict eosinophilic asthma defined as three per cent or more in sputum?”
So, I think what you can say is if a person’s in front of you with symptomatic asthma, on inhaled steroids, and their blood-count shows greater than 0.3 x 109 per litre eosinophils then they most likely will have eosinophilic asthma.
It’s also worth thinking that the upper limit of normal given by most pathology labs is 0.4 or 0.5, so we’re often talking about levels that are just touching the upper limit of normal or just above, but it may be that the upper limit of normal isn’t exactly accurate. Also if you’ve got any eosinophils and you’re taking steroids then that indicates some degree of refractory disease because blood eosinophils melt away with, you know, any systemic steroid. Another way to measure it is exhaled nitric-oxide, that can also indicate airway eosinophilic inflammation.
MIC CAVAZZINI: Can you explain exactly how corticosteroids affect eosinophil numbers?
PETER GIBSON: Yeah, they do a couple of things. They target T-lymphocytes, turn off IL-5 and then they prevent release of eosinophils from the marrow, and then they induce apoptosis in circulating eosinophils.
MIC CAVAZZINI: A review in the European Respiratory Journal from a couple of years ago suggested that the reason inhaled corticosteroids aren’t effective in severe asthma is that the extreme inflammation prevents the drugs from getting into the smallest airways but that oral or intramuscular delivery allows the drug to reach those targets via the bloodstream.
PETER GIBSON: That’s not the only possibility. Another possibility is that there’s a significant bone marrow component to refractory eosinophilic asthma and that you’re actually targeting that by systemic treatment. If you give systemic steroids you’ll achieve a better result but at a greater toxicity.
MIC CAVAZZINI: So what are the side-effects of systemic corticosteroids to be aware of?
VANESSA McDONALD: I guess they’re associated with multiple side-effects particularly with longer-term use. So, they’ll affect the bone health, lead to hypertension, mood disturbance, disturbed sleep, adrenal insufficiency. Cataracts. Diabetes.
PETER GIBSON: Worsened diabetes.
VANESSA McDONALD: Diabetes. Yeah.
PETER GIBSON: Obesity.
VANESSA McDONALD: So, the adverse effects associated with oral corticosteroids are many, and people are acutely aware of this as well. So are often averse to taking oral corticosteroids. I mean the approach in severe asthma is to rationalise the use of oral corticosteroids only to those that need it, and then to use it for exacerbation management in shorter bursts to minimise the side-effects.
PETER GIBSON: So, everyone that needs maintenance oral steroids is going to get some sort of side-effect and they can be disastrous. So, you’ve got this aggressive disease that might kill you, on the one hand, and on the other hand you’ve got his very toxic treatment that will give some control but not complete control to the disease.
The real breakthrough with focused or targeted therapy has been that we’ve all of a sudden got an effective treatment that doesn’t have the toxicity and where you can show, at least in the case of the anti-IL-5 treatments, that you can reduce the maintenance dose of oral steroid and even get people off oral steroids. So, that’s the basis for the great excitement about this approach to treatment in severe asthma because it’s solved an awful problem for patients and clinicians.
MIC CAVAZZINI: Can you tell us how this new monoclonal antibody, mepolizumab, works? Is that something clinicians need to know?
PETER GIBSON: Well if you’re going to use this drug you would want to know about it. So, we mentioned earlier that we’ve got a really good understanding of the mechanism, and Interleukin-5 is the main hematopoietic cytokine that controls the growth, differentiation and production of eosinophils. And monoclonal antibodies have now been developed that specifically block interleukin-5 or block its receptors.
So, mepolizumab is registered for use in Australia at the moment, but there are several others that are in various stages of development. They’re all highly efficacious in reducing blood eosinophil counts, and in the setting of severe refractory eosinophilic asthma they lead to substantial reductions in asthma attacks.
MIC CAVAZZINI: And am I right that another feature separating eosinophilic asthma from allergic is that it can emerge quite late in life?
PETER GIBSON: So, there’s a particular phenotype that clinicians should recognise and that is late-onset eosinophilic asthma that often is progressively severe over time and associated with nasal polyps. So, they’re people who haven’t had asthma as a kid but in their late 40s they started to develop asthma, and they can also be sensitive to aspirin and non-steroidal anti-inflammatory drugs.
MIC CAVAZZINI: There is significant overlap between patients with airway eosinophilia and those that also have allergy. The Th2 cells that recruit eosinophils also generate interleukins 4 and 13. These in turn activate B-cells to produce specific IgE antibodies that can be detected in blood. But IgE is also elevated in a group of subset without increased eosinophils, and allergy underlies disease in about 70 percent of asthmatics generally.
PETER GIBSON: So, allergy in severe asthma is relevant as a trigger factor. So, if you can identify and remove a trigger there will be symptomatic improvement. So, in Australia the most frequent important one for severe asthma is dust-mite, but there are others, so, domestic animals; cats importantly, and fungi and cockroaches.
MIC CAVAZZINI: Vanessa, is the public aware of how to protect themselves from such triggers?
VANESSA McDONALD: Just anecdotally, from talking to people in the clinic, generally no. Like generally people aren’t aware of strategies to go about to reduce their exposure to a lot of those allergens. Or if it’s the cat, for example, aren’t prepared to reduce their exposure.
PETER GIBSON: Some patients their occupation will be driving their asthma and there it’s important to identify and remove triggers. So, in allergic asthma you get allergen-specific IgE on the surface of mast cells. You get an increase in mast cells in the airway mucosa, there’s normally not that many in the airway epithelium but the numbers go up, they move into the epithelium when the person’s sensitised. And then when you inhale the allergen you set off the mast cells, release histamine, leukotrienes, and you get massive airway narrowing and severe asthma. So, omalizumab or anti-IgE acts to block circulating IgE and eventually reduces tissue-bound IgE and then you get reduced allergic responses.
So, at the moment omalizumab’s approved for use in severe, refractory, allergic asthma. So, you’ve got to tick all of those boxes. You have to identify that the person is actually allergic, and that is done by the serum IgE level and also demonstrating allergen-specific IgE either by a blood test or by a skin-prick test.
MIC CAVAZZINI: In the IMJ paper you say that a limitation of the monoclonal therapy is its narrow therapeutic window. Will this make dosing a challenge for clinicians?
PETER GIBSON: So, what we’re referring to there is registered use of the drug is based on a narrow range of serum IgE and bodyweight and that determines the recommended dosing. But if someone has a very high IgE level then they may be outside the dosing table and there hasn’t been randomised trial evidence to advise the efficacy in that situation. But the Australian omalizumab registry collected data on patients who were being treated outside of that dose table, at the upper end, and showed that they responded just as well to those with lower levels of IgE.
MIC CAVAZZINI: Right, that’s interesting because I don’t think that was in the paper.
PETER GIBSON: It hadn’t been published at that point.
MIC CAVAZZINI: Okay, and the treatment is delivered by injection does that make it easier or harder to manage patients?
PETER GIBSON: So, omalizumab is subcutaneous injection every two to four weeks. That’s a hassle for the patient and the clinic, so there has to be staffing to give the injection and monitor the patient afterwards and the patient has to rock up to get their dose every two to four weeks. So, it’s got quite significant resource implications. The only plus of it, I guess, is that the person does get very closely monitored and non-adherence is dealt with by the fact that they turn up or they don’t, and they get a phone call if they don’. So, it addresses those issues but it’s an intensive implementation strategy.
MIC CAVAZZINI: The most baffling group of patients are those that present with normal IgE and normal eosinophil counts, and these make up about half of all asthmatics. Peter Gibson explains how there is further heterogeneity even within this non-eosinophilic phenotype, and a lack of targeted treatments on offer.
PETER GIBSON: And they are further subdivided into those that have elevated neutrophil counts; about 60 per cent or more so that’s quite a high neutrophil count. And then a group where both eosinophils and neutrophils are normal. And our thinking is that that’s a macrophage-driven disease whereas the neutrophil group could be driven by chronic infection or chronic dysfunction of the innate immune system or both. And interleukin-1 beta is a key cytokine that’s driving that condition.
MIC CAVAZZINI: Are patients with this non-eosinophilic asthma the cluster that is most at sea in terms of treatment?
PETER GIBSON: Well, the problems they have are they don’t respond well to inhaled steroids. You can treat their airway obstruction with bronchodilators, which is fine, but we don’t have anything specifically for their endotype, until last week. So, we published in the Lancet last week our clinical trial of azithromycin and macrolide antibiotic, and we showed that it was effective at reducing exacerbations in non-eosinophilic asthma, so a 40 percent reduction.
MIC CAVAZZINI: And some of your research has shown a prevalence of airway microbes in these patients. So is that how you might explain the effectiveness of the macrolide antibiotics?
PETER GIBSON: Certainly the people with neutrophilic asthma are more likely to have pathogens in their airway and they respond to macrolides. But just as many don’t have the pathogens and appear to respond. So, what’s going on there we don’t know.
MIC CAVAZZINI: And besides this new result involving macrolides what’s the role for long-acting bronchodilators in therapy?
VANESSA McDONALD: There are a number of options available; there’s budesonide with eformoterol, there’s fluticasone with salmeterol, there’s fluticasone furoate with vilanterol. But in severe asthma long-acting bronchodilators shouldn’t be delivered or prescribed without an inhaled corticosteroid.
The other thing that has recently kind of come out within the literature is the role of long-acting muscarinic agents in a severe asthma population, one example being tiotropium. So, as an additional add-on therapy, that tends to lead to improvements in symptom and bronchodilation. And the leukotriene receptor antagonists are oral medication that can have an effect. It’s not an outstanding effect- maybe about 30 per cent of the population with severe asthma that trial the drug get some benefit from using it, when you get to the end of the line thinking what additional therapies can be added to conventional treatment, and I guess…
PETER GIBSON: So, that’s that guideline paradigm at the moment where you just keep adding stuff in.
MIC CAVAZZINI: Peter, in terms of diagnostics you’ve also been investigating possible proteomic biomarkers and even RNA. Are these a long way off from the lab?
PETER GIBSON: Well, so, we’ve identified the mechanistic pathway of neutrophilic asthma and that’s via innate immune dysfunction, activation of the NLRP3 inflammasome, which then produces IL-1-beta and leads to neutrophil activation and recruitment. And the other thing we’ve done is identify a messenger RNA signature that will distinguish these inflammatory phenotypes.
And the value of that is the test could be automated using existing laboratory technologies, for example, molecular diagnostics of sputum samples is now standard for viral and TB, for example. We think it’s definitely got a place in severe asthma and it’s going to be more likely implemented than, say, cell counts.
MIC CAVAZZINI: Asthma therapy is not just about phenotyping and cutting edge therapy.
A 2015 article in the MJA suggested that a million Australians may have uncontrolled asthma simply due to poor adherence and lifestyle issues, rather than resistance to treatment. It’s important to identify these patients, so that they don’t become subjected to ever-increasing doses of corticosteroids. Vanessa MacDonald describes the comorbidities and behavioural factors that must be considered for effective management of the disease.
VANESSA McDONALD: So, we recognise in severe asthma or complex airways diseases that they are heterogeneous diseases, they’re complicated by multiple comorbidities. So, the approach that we propose is around multidimensional assessment, and this is kind of stepping towards a precision medicine approach. So, we kind of summarise it to three different domains; the domain of the airway, comorbidities, and risk factors. In terms of risk factors there’s things like physical inactivity, smoking, obesity, and these are highly prevalent in a severe asthma population. And then there’s comorbidities like anxiety and depression, osteoporosis, cardiovascular disease that are also common in a severe asthma population.
MIC CAVAZZINI: Can you elaborate on the importance of obesity in this equation?
VANESSA McDONALD: Yeah, so obesity’s a big problem in severe asthma. So, in a national study that we published last year obesity was prevalent in about 45 per cent of the population with severe asthma. And it’s a risk factor for more severe disease as well. And there has been some work that suggests that by losing weight, so as little as five to 10 per cent of someone’s body weight, can actually lead to improved asthma control.
MIC CAVAZZINI: So, is obesity a risk factor in itself or is it simply a consequence of the more sedentary lifestyle?
PETER GIBSON: The answer is yes to both of those. So, there are some people who don’t get asthma until they become obese, and there is some work in small numbers of people who’ve had bariatric surgery for morbid obesity and their asthma goes away. So, at least in some people there’s a fairly convincing case that morbid obesity is a primary cause, but that’s probably not the majority. Most people it’s the severe disease itself, limited physical activity that contributes to obesity in severe asthma.
VANESSA McDONALD: So, people with severe asthma might need to see a number of different healthcare professionals in order to manage their overall disease. Their care might be fragmented and, therefore, the disease kind of is complicated by the financial burdens and the burden of symptoms, and that impacts on their adherence for management.
A year or so ago we held a roundtable discussion with clinicians managing severe asthma around Australia and the primary care physicians highlighted the fact that they’ve got access to allied health services such as dieticians and psychologists, and they’ve probably got better access to that than we do have in tertiary care. So, finding approaches to management, whether that be within the community or whether it be within a severe asthma clinic I think is the way to go.
MIC CAVAZZINI: One question that often comes up from patients is the relationship between diet and asthma. Peter, you’ve recently presented some research on the benefits of a high-fibre diet on symptoms, haven’t you?
PETER GIBSON: So, what’s happened to our diet in the last 50 years is that we’ve got less fibre, more sugar and more fat, more saturated fat, and what’s the baddie there is not exactly known, but certainly if you eat soluble fibre you allow the gut microbiome to produce anti-inflammatory fatty acids and they get absorbed and then that appears to have some beneficial effects.
MIC CAVAZZINI: And you point out in the paper that inhaler technique has a big influence on adherence?
VANESSA McDONALD: Yeah, so, inhaler technique is a big problem for anyone with lung disease really. I think in an asthma population it’s about 30 per cent of people are able to demonstrate proficient technique; that’s really poor. And you know, if they’re not using their inhaler correctly they’re clearly not getting the prescribed dose of medications. So, you know, you can start really early in the piece ensuring that that continues to be proficient on a regular basis at follow-up and review.
So, having those resources available to patients where they can click on a video and watch how to do it is another resources that we want to develop further. And I think we’ve had an increase in the number of different devices that have become available to people and the more devices they use increases their inability to use them correctly. So, rationalising their therapy so that they can have a minimal number of different devices is likely to lead to better outcomes too.
MIC CAVAZZINI: The MJA article also suggests that another systems’ problem is the fact that people would rather get a reliever medication over-the-counter than go to the trouble of getting a prescription for corticosteroids. Is that a big issue, do you think?
VANESSA McDONALD: So, I think people generally like to simplify life as much as possible. We’re all a little non-adherent in things that we should do such as what we should eat and how often we should exercise. So, if we normalise that non-adherence we’re more likely to be able to establish open communication with patients and they’re more likely to report their actual dose-taking rather than what they want you to know.
So, we would generally tell people, “It’s normal for people to forget to take their medication sometimes. Tell me how many times you’ve missed your doses in the last week, for example?” And I think, as a follow-up, then asking, “Well, you know life gets really busy so I can understand that you might miss some doses, but what are the reasons that you’re not taking it?”
They might not be taking their medication because they’re not necessarily aware of how frequently they should take it, so they’ve misunderstood messages. I guess the other thing that’s really important in terms of asthma self-management is ensuring people have written action plans, and that’s again a personalised treatment plan. And these written action plans, when combined with regular review and self-management, lead to significant reductions in exacerbations.
MIC CAVAZZINI: Finally, I don’t know if we should talk about that asthma storm in Melbourne last November. That wasn’t an example of severe asthma, of course, but a rare allergenic event.
PETER GIBSON: It’s a great story, but—
MIC CAVAZZINI: —it’s intense, isn’t it? Was that such a freakish event that we don’t need to worry about it in the future?
PETER GIBSON: No, no, it’s not. So, it happens across eastern Australia. Asthma can cause sudden epidemics. Nothing has been as big as Melbourne, however. It’s an argument in favour of over-the-counter Ventolin. It could happen with a massive air pollution accident or massive dust accident. You know, you could have a bushfire thing. We’re full of potential risks. What it’s highlighted is the need for epidemic-management and monitoring asthma.
MIC CAVAZZINI: Many thanks to Peter Gibson and Vanessa MacDonald for joining us for this episode of Pomegranate Health. You can read their review on severe asthma in the June issue of the Internal Medicine Journal, while the May issue has an article on preparedness for another storm event. To find other references on asthma management, including inhaler videos for patients, visit the website at racp.edu.au/pomcast.
At the website you’ll also find a list of some other medical podcasts recommended by our listeners. IMReasoning out of Auckland, is an in-depth examination of diagnostic error and bias. And Pediacast CME presents the latest in continuing medical education for paediatric care from the US.
Please continue the conversation for any episode of Pomegranate Health via the comments section, or email us through email@example.com. I’m Mic Cavazzini. I hope you’ve enjoyed the show.