Asthma and obesity

I am enjoying having opportunity this week to catch up on some of the talks from the American Thoracic Society conference, which was held in New Orleans just over two weeks ago. I’m impressed that they are available online already.

One symposium looked at the interaction between obesity and respiratory / critical care medicine. I’ll probably blog more about this as I work through the talks.

Dr Stephanie Shore, PhD, from the Harvard School of Public Health, gave an excellent lecture on obesity and asthma at that session. The following is a summary of what I got out of that talk.

Firstly, we do know that asthma and obesity interact in the following ways:
- there is an increased prevalence of asthma amongst obese individuals;
- as people become more obese, the likelihood of new asthma developing increases;
- obesity leads to reduced control of asthma;
- obesity leads to increased severity of asthma;
- weight loss helps improve asthma control;
- and obese mice…..

What have mice got to do with it? Well, many data relevant to human health were initially derived from mice, so it turns out that obese mice have something to teach us. And obese mice have a tendency to develop asthma. But more of that later.

Why is there more asthma amongst people who are obese? Is this a new sort of asthma? Does obesity give some people asthma? Or is it the same old sort of asthma, with obese individuals simply predisposed.

It looks more like the former suggestion – ie obese individuals with asthma have a particular sort of asthma. Obese individuals with asthma have less eosinophils in bronchoalveolar lavage fluid (fluid that is washed through the smallest airways at bronchoscopy). They also are less sensitive to the impact of corticosteroid. All of this suggests that they do not have ‘allergic asthma’ of the sort that occurs almost universally in children with asthma, but less frequently in older asthmatics.

What’s going on there? There is ‘more thought than data’ when it comes to how obesity may contribute to asthma development. The ideas include the suggestions that there may be:
1. Common aetiologies. The same processes that contribute to the development of obesity may contribute to the development of asthma. These may be congenital / in-utero issues; dietary factors; genetic abnormalities or acquired exposures
2. Co-morbid problems. People with obesity suffer from more lipid abnormalities, gastro-oesophargeal reflux, obstructive sleep apnoea, diabetes and hypertension. Do these associated problems contribute to the development of asthma. GORD and OSA have been shown to. The others, maybe.
3. Obesity impacts on lung mechanics, leading to reduced functional residual capacity and reduced tidal volume. Either of these mechanisms may lead to airway hyperresponsiveness – and asthma.
4. Systemic inflammation or other systemic consequences of obesity may contribute to development of asthma.

With regards to this last issue, in particular, Dr Shore embarked on a little tutorial on adiponectin. I didn’t know too much about this hormone, so was helped by the tute. Like leptin, adiponectin is produced in fat cells (adipocytes) and circulates in several different forms in the blood stream. Its levels are reduced in obesity. It sensitizes to the effect of insulin (so low levels contribute to insulin resistance) and it has anti-inflammatory properties (so low levels in obesity can lead to more inflammation). Dr Shore’s lab had researched the impact of this compound in the lungs of mice. In mice given adiponectin, allergen –induced airway hyperresponsiveness (AHR) and inflammation is reduced. In adiponectin deficient mice there is increased allergen induced AHR and inflammation. Transgenic mice that overexpress adiponectin demonstrate reduced airway inflammation. The suggestion (idea rather than data) is that adiponectin may be a mediator of airway inflammation in people who are obese – not just in mice – contributing to the development of asthma.

The important clinical information for now is that weight loss helps. There have been, in the last 10 years, 10 studies looking at patients with bariatric-surgery – induced weight loss and 4 looking at patients with dietary weight loss, with regards to the impact of weight loss on asthma control. They have demonstrated:
- improved lung function parameters;
- reduced medication use;
- reduced symptoms;
- improved asthma control;
- improved asthma-related quality of life;
- reduced severity of asthma and reduced frequency of hopitalisation ….

….as a consequence of weight loss in people with asthma.

So, there is evidence that obese patients with poorly controlled asthma should be encouraged to lose weight. It will help bring their asthma under control.

Andrew

Eosinophilic bronchitis, asthma and bronchoprovocation

Many people are referred to our practice with longstanding symptoms of cough. While our management of such patients is tailored to the individual, and depends very much on the presenting history (characteristics of the cough, sputum production, smoking history, dangerous exposures etc) there are some investigations which we perform very frequently. Of course, spirometry – that first and most basic of investigations – is performed almost universally. It helps pick up people with uncontrolled asthma or chronic obstructive pulmonary disease almost before they come in the door.

Many asthmatic patients will, however, have entirely normal spirometry. In such patients, the diagnosis of asthma will often be made with bronchoprovocation studies.

We perform mannitol bronchoprovocation studies frequently in our lab. They are an important part of the evaluation of many patients with chronic cough. For this reason I have been reading with interest the results of a very small study published in Respirology journal in April; a study which looks at the differences between asthma and eosinophilic bronchitis with regards to indirect bronchoprovocation challenges, such as mannitol bronchoprovocation.

First, a brief word about these two diagnoses. I explain to all of our patients with newly diagnosed asthma that there are two important aspects to the pathology of asthma in the airways which need to be understood, and which make sense of why we use the medications we do. Those two are:
- airway inflammation
- airway hyperresponsiveness.

The former is usually mediated by allergic processes in kids, but is more of a mixed bag in adults. ‘Mast cells’ ( a type of white blood cell particularly involved in some allergic reactions) infiltrate the airway lining and muscle. Inhaled steroids help suppress this process. The latter process involves contraction of airway muscles, often experienced as breathlessness and chest tightness. Medications such as salbutamol, an asthma ‘reliever’ help control this process (as do formoterol and salmeterol).

This Journal paper reminds us that eosinophilic bronchitis, estimated to be the cause of cough in up to 15% of chronic cough seen in chest clinics, sees a disconnect between the two processes. That is, mast cell-mediated inflammation occurs in the airways (with lots of ‘eosinophils’ in an induced sputum or bronchoscopy sample) without airway hyperresponsiveness. This is not a new idea. The definition of EB is essentially that there is eosinophilic airway inflammation without abnormal airflow on spirometry and without a drop in lung function on bronchprovocation testing with methacholine. However, airway inflammation in asthma has been demonstrated to be better associated with hyperresponsiveness to mannitol than to methacholine. Likewise, some asthmatics will react to indirect challenges and not to direct challenges. This study was arranged to further test the hypothesis that EB really does exist, I suppose, and to really prove that patients with EB do not have airway hyperresponsiveness to indirect challenges.

This hypothesis was tested in a small number of patients. Patients with diagnoses of EB (all of whom had had previous mannitol bronchoprovocation) and patients with a diagnosis of asthma were compared with each other and with healthy controls. An induced sputum sample was obtained on the day that tests were performed to help confirm the diagnoses. Bronchoprovocation studies were then performed with either AMP or mannitol (both ‘indirect’ challenges that lead to airway hyperresponsiveness in asthma via secondary pathways ) or both.

Now the study was small. There were only 11 healthy and 14 asthmatic patients, with 8 patients suffering from eosinophilic bronchitis. Asthmatic and EB patients had similar levels of eosinophils in their sputum, where healthy controls had none. Asthmatic patients generally reacted to the indirect challenge (7 of 10 asthmatic patients given mannitol had positive responses). None of the healthy controls or EB patients reacted to the mannitol (or to the AMP).

This paper is a good reminder of the diagnosis of eosinophilic bronchitis. I like the idea they put forward that this is a process where the inflammation occurs only in the airway mucosal lining and not in the smooth muscle. I’d like to know for certain, however, that simple treatments like inhaled steroids help. In my experience that’s not necessarily the case, although the disease is supposed to be very responsive to inhaled steroids. The problem at that point is that in asthma we have useful tools such as spirometry and bronchoprovocation studies for objectively monitoring our treatment regimes. In EB, when those tests are normal to begin with, it’s difficult to know how to objectively evaluate treatment effect when symptoms don't settle.

Andrew

Fixing the ugly asthma blog post

A couple of weeks ago I posted a blog about asthma phenotypes which was lacking in graphics. To try to make up for this, today's blog is all about the missing graphics.

That post discussed a paper from the blue journal from the USA, which surveyed hundreds of asthmatics and found that they clustered in five quite distinctive clinical groups. Details are in the previous blog, or indeed the original paper.

Although a wide range of variables were used in the analysis to assign people to clusters (initially 34, whittled down to 11 ultimately). However, using three variables only (basline FEV1, maximum FEV1 after maximal bronchodilator, and age of onset of asthma) as follows...

...patients could be assigned to clusters with 80% accuracy. In this diagram, the blobs represent assignment of cluster based on the three-variable approach as opposed to the 11 variable approach. (ie for cluster 4, 72% of patients assigned to cluster 4 based on 11 variables were also assigned to cluster 4 based on the three variables only).

Just FYI, the colours correspond to clinical state as follows:

Blue = mild atopic asthma
Green = mild to moderate atopic asthma
Yellow = late onset non-atopic asthma
Orange = severe atopic asthma
Red = severe asthma with fixed airflow obstruction.

I think that the possibility of differentiating between clinical phenotypes of asthma based on three simple clinical parameters is very attractive, and could have significant implications for both research and clinical practice.

Andrew

The many faces (various clinical phenotypes) of asthma

I was planning to make this blog post very pretty with some graphs and tables from a recent journal alrticle. Imagine my dismay to discover that my tardiness to renew my ATS membership had resulted in the suspension of my access to the online blue journal. All good now; subs paid, but access not yet restored. Still, the blog must be posted. Ugly though it may be....

Around 8% of the adult Australian population suffers from 'asthma'. This means that asthma is a big public health problem. As such, asthma has been given the 'pathway' treatment; that is, rules and guidelines have been generated to direct asthma management. These rules and guidelines are also brought into play when asthma management is evaluated.

However, all of this 'proceduralising' of asthma mangement assumes that we know and are agreed on what asthma actually is, and how we diagnose it and measure its severity. Unfortunately, this is more of a problem than it should be!

Classically, asthma has been said to be a disease of allergic inflammation in the airways. Eosinophils and mast cells are supposed to be the main mediators of this inflammation; fibrosis and scarring develops early; corticosteroids (such as prednisolone) settle the
inflammation down. If we are agreed on that definition – and that it applies to all ‘asthmatics’ - we then measure severity of asthma by frequency of symptoms and use of bronchodilator medications (such as salbutamol / Ventolin), measurements of airway 'obstruction' (such as spirometry and peak flow variability) and 'exacerbations' requiring attendances at the doctor's clinic or hospital and/or use of oral corticosteroids (such as prednisolone).

Those of us who see lots of patients with asthma know how deeply unsatisfactory this approach to classification can be. Some patients present with profound symptoms which settle quickly on classic treatment with inhaled steroids, while others have persistent symptoms and lung function abnormality in spite of mulitple treatments. Some never take their puffers but struggle on with persistent symptoms, never getting very sick. Others have no symptoms for months and months, take their medication then present desperately unwell after an inadvertent exposure.

We need fresh eyes on asthma classificatoins.

I have been encouraged to read a paper, with accompanying editorial, in the Blue Journal from the middle of February which sought to reevaluate how we 'categorise' asthma sufferers. Over seven-hundred subjects from the 'Severe asthma research program' (SARP) in the USA completed questionnaires as well as physiological tests of lung function. Biological markers of disease were also measured in some patients (exhaled nitric oxide, induced sputum eosinophils). Not all of the subjects had 'severe' asthma.

Ultimately five 'clusters' of patients were identified:

Cluster 1: 15% of subjects. Younger, predominantly women (80%), childhood onset / atopic asthma and normal lung function. 40% on no controller medication; those on controllers generally on two or fewer. 70% reported no significant exacerbations in the previous year. However 30 to 40 % had almost daily symptoms (perhaps predominantly exercise related?)

Cluster 2: 44% of subjects. Slightly older, 67% women. Mainly childhood onset / atopic asthma. Baseline pre-bronchodilator lung function normal or can be reversed to normal in 94% of subjects. More prevalent medication use (only 26% on no medication, more on 3 puffers). Higher doses of inhaled steroids.

Cluster 3: only 8% of subjects. Significantly different. older women, with older age at onset of asthma and more overweight (58% BMI > 30). Less likely to be atopic. Lower baseline FEV1 with only 64% whose lung function 'normalised' after bronchodilator. Higher doses
of medication use and, in spite of this, health care utilisation. (Despite the fact that they are a small portion of the patient population, they are disproprotionately represented in hospitals I think). They have symptoms / quality of life impairments that seem out of proportion to their physiological impairment.

Cluster 4 and 5: the remaining 33% of subjects. 70 or 80% fulfill the ATS criteria for severe asthma. These are the patients with legitimate bad asthma. Cluster 4 was the only cluster in which both genders were equally represented, and atopy predominated (83%). Cluster 5 was later onset, mainly women with less atopy. Each cluster has long duration of disease, and significantly impaired pre- bronchodilator FEV1 commonly. More subjects in cluster 4 had significant bronchodilator responsiveness. Health care utilisation and medication doses were high in both clusters.

These clusters ring true. They fit with my impression of the population of patients with asthma; they differ significantly in important markers of severity, and in particular health care and medication utilisation; ultimately they may provide us with a step towards identifying groups of patients with asthma who sholud be offered significantly different management programs.

Ultimately, the authors found that discrimination between these clusters was possible 80%of the time simply using FEV1 pre- and post- bronchodilator and gender (this is where the missing diagrams would've been helpful).

We should trawl through our patient data and assign patients to 'clusters' based on lung function and gender. I suspect that we would be weighted towards cluster 3-5. What would be really interesting would be to see if there were medications or management strategies that worked, or failed, for each cluster. Another audit project? Must discuss it with the clinical staff!

Andrew

Non-adherence to treatment regimes in difficult asthma

The accompanying picture of a Seretide ™ combined corticosteroid/ long- acting beta-agonist inhaler device hopefully evens the score a little in the war of the combination puffers on this blog (see comment on the post about use of eformoterol/budesonide in COPD) Each of Seretide ™ and Symbicort™ are excellent medications in airways disease (can I say it often enough?)– particularly asthma…… if our patients take them!

Which brings me to the topic of this post: non-adherence with prescribed medications in difficult asthma. A recent study from Northern Ireland, published in the American Journal of Respiratory and Critical Care Medicine (The Blue Journal) at the start of November, looked at this issue in a population of asthmatics referred to a tertiary – hospital ‘difficult asthma’ program. These were patients with persistent asthma symptoms in spite of regular combination inhaler use (one of the two above), with some on maintenance oral prednisolone. Around forty percent were referrals from other respiratory specialists to the hospital program.

I see many patients with ‘difficult asthma’, although they make up only about 5% of the adult asthmatic population. In general the first question I ask myself is always ‘does this person really have asthma?’ Frequently they do not, and the failure of asthma therapy reflects an initial misdiagnosis. The second question is ‘Is this person really using their medications?’ This recent study is the first that looks rigorously at adherence to prescribed medications amongst adults with ‘difficult asthma’.

The findings were startling. Although everyone claimed to use all of their medication as prescribed when asked at the commencement of the study, of 182 consecutive patients seen in the service 78% used less than their prescribed amount of combination inhaler medication, with at least 35% using less than half of what they were prescribed. Twenty-one percent used more of their combination inhaler (preventer) than had been prescribed, leaving 1% of patients using medication as prescribed!

The study then looked further at patients prescribed maintenance oral prednisolone, and found that 45% were non-adherent with that medication.

There were three variables that were associated with poor adherence to treatment. These were female gender (nearly 2/3 of the group on the whole was female. 42% of them were in the least-adherent group, where only 23% of the men were); low quality of life; and frequent hospitalizations in the previous year.

How was data collected? In Northern Ireland all medications that a patient is taking are prescribed by one GP only. Review of the number of prescriptions issued by that GP, compared against the dose of medication which the person is supposed to be using, allowed a reasonable measure of compliance to be obtained in this study. In the case of oral prednisolone dosing, regular use of prednisolone should lead to suppression of adrenal cortisol secretion. Blood test measures of prednisolone and cortisol levels were used in that patient group to evaluate compliance.

The findings of this study require reflection. Doctors of patients with ‘difficult asthma’ will be considering a range of alternative treatment approaches, including use of maintenance prednisolone orally, use of theophylline or montelukast (Singulair ™) or else a more expensive biological therapy (for example, Xolair™(omalizumab), with others on the horizon). It’s important that we don’t proceed to the more complicated, dangerous or expensive medications without clarifying whether the standard medications are, in fact, being used.

The authors of this study state that they believe ‘the key message off this study – that non-adherence is a significant issue in an unselected population with difficult-to-control asthma and significant asthma-related morbidity….is valid and needs to be proactively identified and addressed’. I agree. I suspect, however, that a systemic change in the way we distribute medication and monitor compliance may be required to effectively achieve this.

Andrew

The 'beta-agonist paradox'

"Clinicians need to be aware of how to identify and manage patients for whom beta-agonist treatment is a problem rather than a solution. They constitute a small but important sub-group of patients with difficult asthma".

As a consequence of recent conversations with hospital staff in Hamilton about our management of a patient with difficult asthma, I thought it would be appropriate to post a blog on this topic. Although beta agonists (such as salbutamol, terbutaline, eformoterol, salbutamol) are essential tools in the management of asthma - either as 'reliever' medications or as part of a 'preventer / maintenance' regime, their role in chronic persistent asthma may not be as simple as we would like to think.

The above quote is from Dr. D.Robin Taylor, at the University of Otago in Dunedin, New Zealand. Dr Taylor was at the coal-face of this issue in New Zealand in the early 1990s, when use of the beta-agonist fenoterol was associated with a spike in asthma related deaths which only ended when that medication was taken off the market. Although the Wikipedia entry on this drug suggests that the surge in deaths was all due to cardiac side effects from patients irresponsibly managing their asthma with massive doses of the medication out of hospital, the issue may not be quite that simple. The 'epidemic' of asthma deaths associated with that medication has helped to generate persistent research into the hypothesis that beta-agonists may paradoxically worsen asthma control in some situations.

I first heard Dr Taylor on this issue as a registrar back in 2002. I was struck by his description of a difficult asthmatic patient who was using bucket-loads of salbutamol as reliever, and who did not improve until - in a carefully managed hospital environment - that beta-agonist was withdrawn. The peak flow record was instructive and convincing.

In a recent issue of the American Journal of Respiratory and Critical Care Medicine (Vol 179, pp976-978) Dr Taylor's summary of evidence and opinion on the question of whether beta-agonists may sometimes be harmful has been published - as a 'clinical commentary'. (The material was initially presented at the 2008 American Thoracic Society conference).

The points I underlined in my copy are as follows:

• the FDA in the USA issued, in 2005, a 'black box' warning about the safety of long acting beta agonists eformoterol and salmeterol. The majority of the relevant committee felt that these medications should only be used in combination with an inhaled corticosteroid (ICS) in treatment of asthma, as the risk of treatment with the beta-agonist alone, without ICS, outweighed the benefit).
• beta-agonists are, if used consistently, pro-inflammatory in human airways (both in-vitro and in-vivo studies). ICS, which are anti-inflammatory, may therefore protect against adverse effects from beta-agonists. To my mind, however, this situation is far from ideal - i.e. that we would need to need to use a medication to treat a medication related side effect.
• although acute use of beta-agonists leads to airway smooth muscle relaxation, in a mouse model chronic beta-agonist stimulation leads to increased airway smooth muscle contractility - and potentially a heightened response to an asthma trigger (i.e. another mechanism - apart from the pro-inflammatory effects - by which the medication may make the disease worse!) "It would appear that acute and chronic B-agonist effects are not the same thing".

So there is evidence that persistent overuse of beta-agonists may cause, within the airways, a process that is difficult/impossible to distinguish from a worsening of the underlying disease process. Now that takes some mulling over!

Two quotes from Dr Taylor's article to summarize:

"...monotherapy with beta-agonists should clearly be avoided, and the use of combination inhalers to some extent guards against the possibility of LABA-related adverse effects. However, the concomitant use of ICS does not mean that adverse effects of beta-agonist are a non-issue: there is likely to be a threshold for adverse effects in relation to total beta-agonist exposure that may be crossed even when patients are taking ...ICS".

"Good asthma management should include appropriate diagnosis and treatment of beta-agonist toxicity......the characteristic features include unstable or intractable asthma with evidence of psychological and/or pharmacological beta-agonist inhaler dependence. The need for frequent "reliever" ... should cause alarm bells to ring, especially if the treatment yields progressively diminishing benefits in a patient with severe asthma (my emphasis)".

Now, I do not want any of my patients to simply stop using their reliever medication. However, we clearly must have a 'zero tolerance' approach to treating asthma with regular beta-agonist alone. Inhaled corticosteroids are essential. If asthma control is difficult then the first priority should be to review the delivery technique for any 'preventer' medication, as even the most competent patients often make a hash of it. But if, in spite of this, more and more salbutamol is required by a patient, with less and less response, then we should ask whether the beta-agonist might be part of the problem - and be ready to do something about that.

Andrew