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Severe Asthma Management

More research and new treatments are needed to assist severe asthmatics.

With FEV1 lung function of 30%, Stephen Gaudet is always short of breath, but today is worse. Despite daily doses of inhaled and oral steroids and multi-day nebulizer treatments, he isn't getting relief from the medicine. He monitors his breath sounds and oxygen saturation and hopes things don't exacerbate to his "red zone"--when the feeling of a crushing weight settles on his chest and he feels like he is suffocating. An emergency epinephrine needle is on hand for those situations.

If he goes to the hospital, there will be confusion in the emergency room about how to treat him, and he will most likely end up in the ICU. The worst case scenario (other than death): He will end up intubated and placed in an induced coma until his lungs are strong enough to breathe on their own. For now, he boluses his steroids and tries to continue his life.

This is what an exacerbation looks like for Gaudet, a severe asthmatic since birth. Gaudet or "Breathin Stephen," a former respiratory therapist forced to retire at 49 from his 28-year RT career because of his disease, has become the face of severe asthma, with his two online support groups and blog. Though his disease is more extreme than many severe asthmatics, his everyday medical struggles bring to light the obstacles severe asthmatics face: limited treatment options with few on the horizon, clinical research that focuses on mild to moderate asthma therapies, a lack of a national association focused solely on asthma to push for more research, and a medical profession that has less understanding of severe asthma and its ramifications.

Diagnosis, Treatment
Misunderstanding about severe asthma begins at the diagnosis stage. Some patients are labeled severe asthmatics because of asthma-like comorbidities. For example, morbidly obese individuals may be short of breath due to obesity alone or combined with deconditioning. And many people diagnosed with severe asthma may not even have asthma, but rather respiratory symptoms due to vocal cord dysfunction. Or mild to moderate asthmatics may not be taking their medication so they present as more severe.

"All of those things really require a fairly sophisticated trained eye to determine whether it is asthma, severe asthma or something else," says Sally Wenzel, MD, director of the University of Pittsburgh Asthma Institute, and Gaudet's pulmonologist.

To be considered a severe asthmatic today requires that a patient has been treated with high doses of inhaled or oral corticosteroids and a second controller agent (e.g., long-acting beta agonist or leukotriene modifier) and has been managed by a specialist for at least three months.

The biggest change in severe asthma management has been an emphasis on molecular phenotyping patients to identify subtypes. "We don't have as many options as we'd like to for that personalized treatment yet, but that's the direction that we're moving," Dr. Wenzel says.


Molecular Phenotyping
Researchers now use gene expression profiles from lung cells to identify inflammatory characteristics and round out a patient's clinical picture. "We're able to identify molecules that might be abnormal that then can become targets for therapy," Dr. Wenzel says.

A 2010 American Thoracic Society clinical study identified five clinical phenotypes. Findings supported heterogeneity in asthma and the need for new approaches for classifying severity.[1]


Allergic Asthma
There has been a recent push to identify T-helper type 2 (Th2) high versus Th2 low molecular subphenotypes because this population of patients may respond to antiallergic medications. In 2010, findings published in The American Journal of Respiratory and Critical Care Medicine showed lung function improvements with inhaled corticosteroids were restricted to Th2 high asthma.[2]

Th2 cytokines have emerged as therapeutic targets. A 2001 Respiratory Research article reported that cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13 were being tested in clinical trials or were in active development.[3]  Twelve years later, these biologics aren't available yet, Dr. Wenzel says.


Eosinophilic Asthma
At one time, a common misbelief was all asthma was eosinophilic disease. Phenotyping has shown that's not the case.

An August 2012 article in The Lancet found some severe asthma patients have exacerbations associated with eosinophilic airway inflammation. [4] Mepolizumab - a monoclonal antibody against IL-5 - was associated with reduced risk of these exacerbations.


AERD
The only other class of medication with efficacy in severe asthma is Lipoxygenase inhibitors, Dr. Wenzel says. In patients with aspirin-exacerbated respiratory disease (AERD) 5 Lipoxygenase inhibitors can have a better outcome than leukotriene receptor antagonists.


Bronchial Thermoplasty
Bronchial thermoplasty (BT) is an FDA-approved treatment for severe asthma. However, studies on the therapy have defined severe asthma as FEV1 greater than 60 percent of predicted lung function, which doesn't qualify as severe asthma under recent guidelines, Dr. Wenzel says. The Asthma Intervention Research Trial evaluating effectiveness/safety of BT found BT reduced severe exacerbations and healthcare post-treatment, but differences were less if treatment-related exacerbations were factored in, Dr. Wenzel explains.

"BT is not a simple, no-risk procedure," she says. "It requires three bronchoscopies--putting a tube down into the airways of patients and heating up the airways, and in many cases will cause severe exacerbations."

Michael Schatz, MD, MS, staff allergist, Department of Allergy, Kaiser Permanente Medical Center, who served on the FDA Pulmonary Allergy Drug Advisory Committee evaluating BT (and consultant for Boston Scientific), says, "There's no doubt that as a group, the patients who got [BT] did better, and some individual patients describe very impressive results. I think the biggest question is who should get it--which patients with severe disease are most likely to respond."

 

Other Strategies
A few other management strategies are employed for certain severe asthmatic phenotypes. Tiotropium bromide, a long-acting, anticholinergic bronchodilator to manage chronic obstructive pulmonary disease, can be used off-label in patients not controlled by combination inhaled corticosteroid/long-acting beta agonist, Dr. Schatz says. And montelukast (a leukotriene receptor antagonist) may be a helpful add-on therapy for AERD patients. A subgroup of patients presenting with allergic bronchopulmonary aspergillosis (an asthma complication) or mold hypersensitivity and steroid-dependent asthma may benefit from antifungal therapy, he adds. And macrolide antibiotics along with systemic steroids--particularly methylprednisolone-- can have an anti-inflammatory effect in steroid-resistant patients, he says.

But for a small percentage of severe asthmatics, no new interventions exist to adequately help them. "The mainstay of therapy is still steroids which unfortunately cause as many problems as the disease does if you've been on them a long time," Gaudet says. Osteoporosis, weight gain/fluid retention, skin thinning and eye problems (e.g., cataracts, increased intraocular pressure) are some long-term effects.


Morbidity
An Oct. 2009 article in The American Journal of Respiratory and Critical Care Medicine said patients with severe asthma suffer significant morbidity and disability despite use of multiple medications. Gaudet can testify to that. His slow medical decline over the years has brought him to a place where he has symptoms 24/7. "Nothing touches them, so that's probably the most difficult thing for me," he says.

Some severe asthmatics have relatively good or even normal lung function between exacerbations. "But once the disease starts destroying your lungs, once that tissue's gone or the scarring occurs, there's not a lot that can reverse it," Gaudet says.

Every 4 to 6 weeks, Gaudet has an exacerbation that can land him in the hospital. Since he's short of breath all of the time, he doesn't always realize it's happening. He has been intubated 21 times, which he has heard is a world record for an asthmatic. Photos on his blog document Gaudet in a tangle of tubes, hooked up to a ventilator.

This hasn't stopped him from walking eight full and 12 half marathons a few years ago or for continuing his walking regimen of 4 miles a day, even though lung function makes it difficult. For now, Gaudet, a pre-lung transplant candidate, is busy talking to reporters, manning his websites (especially when he needs more support)--and teaching himself the bass guitar. A self-described "loner," he shares his home with his 24-year partner and cat "Winston" and takes one big trip every year; this year it was a polar bear exposition in North Canada. At the end of a blog documenting his trip, he wrote:

"And for those of you suffering with severe breathing problems, I hope this trip inspires you to create your own travel adventure or whatever passion you might have. Don't let your health stop you from living. If I can do it, anyone can."

 

Jill Hoffman is on staff at ADVANCE.

 

References

1. Wendy C. Moore WC, Meyers DA,  Wenzel SE, Teague WG, Li H. Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 2010;181(4); 315-23.

2. Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, et al. T-helper Type 2-driven Inflammation Defines Major Subphenotypes of Asthma. Am. J. Respir. Crit. Care Med 2009;180;388-95.

3. Barnes P. Th2 cytokines and asthma: an introduction. Respir Res 2001;2(2);64-5.

4. Pavord ID,  Korn S,  Howarth P,  Bleecker ER,  Buhl R. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. The Lancet 2012;380;651-9.

 

 


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