Severe Asthma Remains Poorly Understood

Vol. 20 • Issue 11 • Page 10

Allergy and Asthma

Asthma was Stephen Gaudet’s bread and butter until his own bouts with a severe refractory form of the disease ended his 33-year career as a respiratory therapist. Exacerbations have led to more than 100 hospitalizations and 18 intubations. His lungs are so scarred that he’s been recommended for lung transplantation.

“The problem with severe asthma today,” Gaudet said, “is there are no treatments.”

Up to 15 percent of people with asthma do not respond to standard inhaled corticosteroid therapy, resulting in close to 2 million emergency room visits, 500,000 hospitalizations, and 4,000 asthma deaths annually.1 The heterogeneity of asthma makes finding treatment for this population difficult.

The most important question a clinician can ask patients with severe asthma is when they developed their disease – as a child or as an adult. “That very simple differentiation leads to all sorts of further differentiation,” said Sally Wenzel, MD, director of the University of Pittsburgh Asthma Institute, Pa., and a professor of medicine in the university’s division of pulmonary, allergy, and critical care medicine. Early-onset severe asthma is a more allergic-associated disease that responds to standard therapy than late-onset severe asthma.

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Emerging evidence from the Severe Asthma Research Program is elucidating a possible third asthma type that is minimally responsive to high doses of corticosteroids, prednisone, and omalizumab. Although the mechanisms behind it are not clear, there appears to be components of Th1 and Th2 inflammation. A blood test for eosinophils above 6 percent or 350 total can help to determine whether the patient has an unchecked source of Th2 inflammation, but a surgical lung biopsy is needed for diagnosis. Immunosuppressant agents commonly used to prevent organ rejection, such as azathioprine or mycophenolate, can help these patients decrease their oral steroids; however, clinical trials are needed to establish that the benefits outweigh the toxicities associated with blocking these pathways.

“All of this is really in its infancy, but clearly identifying subtypes and phenotypes of asthma is the direction we’re moving,” Dr. Wenzel said.

Predicting response to therapy

Genetic factors may help to predict patients’ response to urgent therapies currently available. A small study genotyping pediatric patients in status asthmaticus have suggested that patients with Gly (16) Gly genotype at amino acid position 16 are more responsive to standard continuous albuterol therapy and less likely to need nebulized and intravenous beta2-adrenergic receptor agonists than subjects with Arg(16) Arg or Arg(16) Gly genotypes.2 This leads to significantly shorter intensive care unit and hospital stay despite similar clinical asthma scores on admission. But a Gly Gly polymorphism at this site is significantly less common in patients with status asthmaticus, so more research is needed to tailor treatment to Arg(16) Arg or Arg(16) Gly genotypes.3

“We are throwing the kitchen sink at (these patients) to see if they will get better,” said Christopher Carroll, MD, the study’s author. “I would like to get at the hidden things.”

Avoiding complications

Critical care for patients with severe asthma remains ripe for study, agreed Samuel Louie, MD, director of the UC Davis Asthma Network in Sacramento and professor of medicine at University of California-Davis. He pointed to early evidence that has shown ketamine and general anesthetics can act as potent adjunctive bronchodilators to help avoid dynamic hyperinflation that can lead to barotrauma and pneumothorax in intubated severe asthmatics. Halothane, sevoflurane, and isoflurane have been shown to facilitate positive pressure ventilation, while a small study of ketamine showed it increased partial pressure of oxygen and decreased partial pressure of carbon dioxide in arterial blood of patients in status asthmaticus who did not respond to conventional mechanical ventilation.4

Controversy over using general anesthetics outside of surgery has been inflamed by the investigation of propofol’s role in the 2009 death of Michael Jackson. “Like anything else, you have to monitor,” Dr. Louie said. “It falls back to experience and teamwork in the intensive care unit to prevent iatrogenic complications and future status asthmaticus.”

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Kristen Ziegler can be reached at [email protected].