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Severe Asthma

PCCSU Volume 25, Lesson 27

PCCSU

The American College of Chest Physicians offers this lesson as a review of a previously offered self-study program. The program provides information on pulmonary, critical care, and sleep medicine issues. CME is no longer available for the PCCSU program.

Objectives

  • Update your knowledge and understanding of pulmonary medicine topics.
  • Update your knowledge and understanding of critical care medicine topics.
  • Update your knowledge and understanding of sleep medicine topics.
  • Learn clinically useful practice procedures.

CME Availability

Effective July 1, 2013, PCCSU Volume 25 is available for review purposes only.

Effective December 31, 2012, PCCSU Volume 24 is available for review purposes only.

Effective December 31, 2011, PCCU Volume 23 is available for review purposes only. CME credit for this volume is no longer being offered

Effective December 31, 2010, PCCU Volume 22 is available for review purposes only. CME credit for this volume is no longer being offered.

Accreditation Statement

The American College of Chest Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

CME Statement

Credit no longer available as of July 1, 2013.

Disclosure Statement

The American College of Chest Physicians (CHEST) remains strongly committed to providing the best available evidence-based clinical information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our faculty members. It is not the intent of CHEST to eliminate all situations of potential conflict of interest, but rather to enable those who are working with CHEST to recognize situations that may be subject to question by others. All disclosed conflicts of interest are reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary, resolved. The CHEST educational standards pertaining to conflict of interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all CHEST CME activities are ensured of independent, objective, scientifically balanced presentations of information. Disclosure of any or no relationships will be made available for all educational activities.

CME Availability

Volume 25 Through June 30, 2013
Volume 24 Through December 31, 2012
Volume 23 Through December 31, 2011
Volume 22 Through December 31, 2010

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PCCSU Volume 25 Editorial Board

Editor-in-Chief

Steven A. Sahn, MD, FCCP
Director, Division of Pulmonary and Critical Care Medicine, Allergy, and Clinical Immunology
Medical University of South Carolina
Charleston, SC

Dr. Sahn has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Deputy Editor

Richard A. Matthay, MD, FCCP
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Yale University School of Medicine
New Haven, CT

Dr. Matthay has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Alejandro C. Arroliga, MD, FCCP
Professor of Medicine
Texas A&M Health Science Center
College of Medicine
Temple, TX

Dr. Arroliga has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Paul D. Blanc, MD, FCCP
Professor of Medicine
University of California, San Francisco
San Francisco, CA

Dr. Blanc has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health, Flight Attendants Medical Research Institute – university grant monies
University of California San Francisco, US Environmental Protection Agency, California Environmental Protection Agency Air Resources Board – consultant fee
Habonim-Dror Foundation Board of Trustees – fiduciary position

Guillermo A. do Pico, MD, FCCP
Professor of Medicine
University of Wisconsin Medical School
Madison, WI

Dr. do Pico has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Ware G. Kuschner, MD, FCCP
Associate Professor of Medicine
Stanford University School of Medicine
Palo Alto, CA

Dr. Kuschner has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Teofilo Lee-Chiong, MD, FCCP
Associate Professor of Medicine
National Jewish Medical Center
Denver, CO

Dr. Lee-Chiong has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health – grant monies (from sources other than industry)
Covidien, Respironics, Inc. – grant monies (from industry-related sources)
Elsevier – consultant fee

Margaret Pisani, MD, MPH, FCCP
Assistant Professor of Medicine
Yale University School of Medicine
New Haven, CT

Dr. Pisani has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Stephen I. Rennard, MD, FCCP
Professor of Medicine
University of Nebraska Medical Center
Omaha, NE

Dr. Rennard has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

AstraZeneca, Biomark, Centocor, Novartis – grant monies (from industry-related sources)

Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, Dey Pharma, Eaton Associates, GlaxoSmithKline, Medacrop, Mpex, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United Biosource, Uptake Medical, VantagePoint – consultant fee/advisory committee

AstraZeneca, Network for Continuing Medical Education, Novartis, Pfizer, SOMA – speaker bureau

Ex Officio
Gary R. Epler, MD, FCCP

Clinical Associate Professor of Medicine
Harvard Medical School
Brigham & Women's Hospital
Boston, MA

Dr. Epler has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Lilly Rodriguez
ACCP Staff Liaison

By Nicholas J. Kenyon, MD, FCCP; and Samuel Louie, MD, FCCP

Dr. Kenyon is Associate Professor of Medicine, Pulmonary and Critical Care; and Dr Louie is Professor of Medicine, UC Davis School of Medicine, Sacramento, California.

Dr. Kenyon has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within this chapter:
National Institutes of Health – grant monies
American Asthma Foundation – grant monies
State of California Center for Health Nutrition Research – grant monies
Boston Scientific – Consultant Fee

Dr. Louie has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within this chapter:
Merck, Boehringer-Ingelheim, and Pfizer – Consultant Fee
Merck, Boehringer-Ingelheim, Pfizer, AstraZeneca, Genentech, GlaxoSmithKline, and Novartis – Speaker Bureau

Objectives

  1. Define severe asthma.
  2. Develop a framework for understanding severe asthma phenotypes.
  3. Provide a simplified approach to the evaluation of patients with severe asthma.
  4. Identify gaps in the understanding of the management of severe asthma.
  5. Understand advanced treatments for asthma.

Key words: eosinophil, omalizumab, severe asthma, Th-2

Abbreviations: ENFUMOSA = European Network for Understanding the Mechanisms of Severe Asthma; FDA = Food and Drug Administration; ICS = inhaled corticosteroids; IL = interleukin; LABA = long-acting β-agonist; LTRA = leukotriene antagonist; NAEPP = National Asthma Education and Prevention Program; NIH = National Institutes of Health; NO = nitric oxide; PEFR = peak expiratory flow rate; RAST = radioallergosorbent test; SARP = Severe Asthma Research Program; Th2 = T-helper lymphocyte type 2

Not all asthma is equal. While asthma is a complex syndrome that affects an estimated 26 million people in the United States, including 17 million adults, the majority of the $15 billion in annual costs incurred from asthma hospitalizations and emergency room visits is spent on the 5% to 10% of patients with severe asthma. Although asthma mortality in the United States is among the lowest in the world, approximately 3,000 to 4,000 asthma-related deaths still occur annually.1 Asthma is also reported as a contributing factor in nearly 7,000 other deaths each year.2 The highest rates of asthma death are in African Americans, Puerto Rican Americans, Cuban Americans, women, and people ≥65 years of age. It has been suggested that 1% to 7% of people with severe asthma will die of their disease each year, and perhaps 17% of those who survive near-fatal attacks will eventually succumb to asthma.3

Clinical trials demonstrate that response and outcomes measured vary broadly across multiple therapeutic interventions. The majority of all asthma patients respond well to a written asthma action plan of pharmacotherapy with inhaled corticosteroids (ICS) often combined with a short- or long-acting β-agonist (LABA) bronchodilator and a leukotriene antagonist (LTRA).4 Why the 5% to 10% of asthmatics who have severe asthma do not respond to this prescribed regimen is not clear and there is no single answer. There are many gaps in the recognition and management of severe asthma, and guidelines such as the National Asthma Education and Prevention Program Expert Panel Report 3 (NAEPP) do not address this population well.5 Extrapolating results from relatively short randomized clinical trials (ranging from weeks to 1 or 2 years) to a broad and heterogeneous population of asthmatics treated in community settings can result in poorer outcomes and safety concerns. Gaps in our knowledge and experience include an understanding of how to recognize severe asthma, how to coordinate and integrate the outpatient resources and specialty care needed to properly care for severe asthmatics, how best to identify severe asthmatics promptly, when to further phenotype patients with severe asthma to facilitate treatment, and in which patients advanced treatments like bronchial thermoplasty are appropriate. In this article, we will define severe asthma and present a framework for understanding severe asthma in adults and a timeline for the management and referral of severe asthma to asthma specialists while emphasizing common problems, such as misdiagnosis.

Definition of Severe Asthma

Most adults with severe asthma developed their disease in childhood. Childhood-onset asthma either persists into adulthood or emerges again in the third to fourth decade of life, and this asthma is typically allergic in character. Allergic, lifelong asthma would seemingly be more amenable to antiinflammatory treatment, but this is not the case with severe adult asthma. The less common adult-onset asthma may develop in response to occupational or other environmental exposures and is recognized as the development of episodic wheezing, dyspnea, and coughing in patients >18 years of age. Severe asthma encompasses any or all of the following asthma characteristics: the failure to achieve asthma control despite confirmed adherence to treatment with ICS, the repeated need for emergency health-care services for asthma attacks, the need for chronic daily oral corticosteroid therapy, and reduced lung function. The most commonly applied definition of severe asthma was developed as part of an American Thoracic Society workshop and has been adopted by the 10-year-old Severe Asthma Research Program (SARP) funded by the National Institutes of Health (NIH).6,7 Severe asthma is defined by at least one major criterion and two minor criteria. The major criteria are as follows: (1) requirement for treatment with high-dose ICS (>800 μg/d fluticasone or equivalent); and (2) treatment with oral corticosteroids for >50% of the year. Minor criteria are as follows: (1) requirement for additional daily preferred controller treatments (LABA, theophylline, omalizumab, LTRA); and (2) asthma symptoms requiring albuterol on a daily basis; (3) persistent airway obstruction [FEV1 <80%, peak expiratory flow rate (PEFR) >20%]; (4) one or more urgent care visits per year; (5) three or more oral corticosteroid bursts per year; and (6) near-fatal asthma event in the past.8 A second research group, the European Network for Understanding Mechanisms of Severe Asthma (ENFUMOSA), defined severe asthma as a distinct clinical entity that included any three of the following: treatment with high-dose ICS (≥1,200 μg/d budesonide or equivalent), the need for 2 years of evaluation by asthma experts, a prior episode of respiratory failure, persistent symptoms affecting quality of life, and reduced FEV1 <70% of predicted.9 A few differences exist between these two research cohorts of severe asthma subjects—for example, the prevalence of women in SARP is approximately 65%, while it is 80% in ENFUMOSA—but collectively they have provided an opportunity to revisit the mechanisms of severe asthma and reflect on current practices in managing it.

Phenotyping Severe Asthma

Identifying the worst forms of asthma is not new, but increased research funding to “personalize” medicine has led to renewed efforts in this area. Brittle asthma, a term coined by Turner-Warwick10 in the early 1970s may have been the first attempt to identify patients with more severe asthma. She described asthma patients with dramatic fluctuations in daily PEFR despite oral corticosteroids and she further divided them into two subtypes: Type I, with large variations in PEFR despite appropriate treatment, and Type II, with sudden, unexpected drops in PEFR during clinically stable period.11 Status asthmaticus and near-fatal asthma are historical terms used to describe the most severe common asthma emergencies faced by critical care physicians and they are still used today. Status asthmaticus is defined as an acute, severe asthma exacerbation that does not respond readily to initial intensive therapy, while near-fatal asthma refers loosely to status asthmaticus that progresses to respiratory failure.

Corticosteroid-resistant asthmatics do represent an important subset of patiens with severe asthma. These patients are uncommon—corticosteroid resistance has been estimated to occur in 0.01% to 0.1% of all asthmatics (Fig 1)12—but at National Jewish Hospital in Denver, a retrospective review did report the incidence of corticosteroid resistance to be as high as 25% among their patients with severe asthma.13 Corticosteroid resistance in asthmatics is defined as a <15% improvement in FEV1 or PEFR after a 2-week trial of ≥40 mg of prednisone or an equivalent. Corticosteroid resistance based on this definition is not equivalent to the variability in patient response to high-dose ICS found in prior studies by Szefler and Martin and colleagues.14,15 A response to ICS in the PRICE study15 was defined as >5% improvement in FEV1 after 2 weeks of treatment. In that study, a normal Gaussian distribution of percent improvement in FEV1 centered with the majority of subjects having a 0% to 12% improvement in FEV1 after 6 weeks of treatment with 160 μg of inhaled beclomethasone.15 Corticosteroid resistance (defined as ≤5% FEV1 improvement after 6 weeks of beclomethasone) was noted in 46% of the enrolled study participants, leading investigators to conclude that some people with severe asthma may not need daily ICS in their action plan.

Figure 1. Cluster analysis of patients with severe asthma in Severe Asthma Research Program. Reprinted with permission of the American Thoracic Society. Copyright © 2012 American Thoracic Society. Moore WC, Meyers DA, Wenzel SE, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. American Journal of Respiratory and Critical Care Medicine. 2010;181(4):315-323. Official Journal of the American Thoracic Society.

Two main mechanisms have been proposed for corticosteroid resistance. The first is genetically determined and affects all cells. Patients with genetically determined corticosteroid resistance neither respond to corticosteroids nor show corticosteroid side effects. The second mechanism has been linked to a failure of corticosteroids to suppress interleukin (IL)-4 and IL-5 mRNA in the subepithelial layer on endobronchial biopsies,16 and peripheral blood T-lymphocyte numbers.17 Recently, alternative splicing of the glucocorticoid receptor has been proposed as the cellular mechanism for corticosteroid resistance in asthma.17,18

The NIH-funded SARP consortium investigators have invested heavily in phenotyping research with the hope of ultimately targeting potential treatments to certain subgroups of patients (Fig 1). A breakthrough study by Wenzel and colleagues19 defined two populations of severe asthma based on the pattern of inflammatory cells found in endobronchial biopsy samples. Patients referred to the investigators’ clinic who required ≥10 mg of prednisone during >75% of the year underwent evaluation with bronchoscopy. In 14 patients with severe asthma, biopsy samples yielded solely neutrophils, while 20 patients had both eosinophils and neutrophils. Members of the latter group had significantly more episodes of respiratory failure requiring intubation and ventilatory support and a lower ratio of FVC to slow vital capacity. While the importance of finding neutrophils with the expected eosinophils in these corticosteroid-requiring asthmatics is unclear, it does demonstrate the heterogeneity of the inflammatory response in severe asthma. More recently, Woodruff and colleagues20 outlined “Th-2-high” and “Th-2-low” groups. The T helper type 2 (Th-2) lymphocytes are defined by the cytokines, namely IL-4, IL-5, and IL-13, all of which are important in the development and persistence of eosinophilic airway inflammation. In this 8-week study, Th-2-high subjects had an average increase of 300 mL in FEV1 and this was significantly greater than the increase in either the Th-2 low or the placebo-control group. This study was one of the first to show clear responses to therapy tailored to the specific phenotype of severe asthma.

More broadly, the SARP investigators have proposed a “clustering” paradigm for severe asthma patients based on baseline FEV1, max FEV1 (the maximum FEV1 effort after serial albuterol doses of up to 8 puffs), and age of onset of asthma.6 Patients in severe asthma clusters 4 and 5 who had a baseline FEV1 <68% of predicted, with or without a max FEV1 >65% of predicted, had a high rate of hospitalization per year (23% and 28%, respectively) and required oral corticosteroid bursts (≥3/y) frequently (46% and 42%, respectively). It is these groups that require the most attention in future clinical trials.

Research on obesity and the metabolic syndrome has greatly expanded our understanding of systemic inflammation and disease linkages. A strong relationship between obesity (defined as a body mass index >30) and asthma is incontrovertible. Studies in the past showed a correlation between increased incidence of severe asthma and obesity among children in an inner-city environment.21 More recently, the ENFUMOSA study reported an increased incidence of obesity in people with severe asthma when compared with the general population, particularly in women. Not all studies supported this correlation, however.22,23 Obesity in patients with severe asthma may result from long-term corticosteroid use or an inability to exercise, but a direct link between preexisting obesity and asthma is likely. Scott and colleagues24 recently showed that obese asthmatics had higher levels of the nonspecific inflammatory mediator IL-6 and C-reactive protein compared with either nonobese asthmatics or obese control individuals. Similarly, sputum neutrophil percentage levels were higher in obese asthmatics compared with these groups, and this was more pronounced in obese asthmatic women. Taken together, this evidence suggests that the combination of obesity and asthma, particularly in women, can be a potentially self-sustaining and self-potentiating inflammatory condition independent of exposures usually considered worrisome for asthma attacks.

Is Remodeled Asthma a Phenotype of Severe Asthma?

Repetitive epithelial injury, inflammation, and repair occur throughout the bronchial tree in severe asthma. There is increasing concern that the more distal airways (<5 mm) are untreated in this subset and this affects lung function and symptoms in 10% or more of asthmatic individuals.25 Structural airway alterations occur with the chronic inflammation that comprises the remodeling phenomenon in asthma. Airway wall thickening, subepithelial collagen and matrix protein deposition, smooth muscle cell hypertrophy, and goblet cell metaplasia develop even in patients with mild asthma. In severe asthma, most or all of these changes are striking. Some studies show a correlation between airway wall thickness, a surrogate for remodeling as a whole, and lung function or asthma severity, but as with inflammatory mediators, remodeling changes should not be equated directly with severe asthma.26,27 Improvements in imaging technology probably represent our best opportunity to begin to understand the degree to which structural airway changes occur in this group. In the SARP cohorts, it appears that even in persons with baseline FEV1 <68% predicted, approximately 40% to 50% of them will have a bronchodilator response.6 Still, that leaves a significant group in which “remodeling“ may predominate. It is well recognized that some patients with severe asthma experience a decline in lung function akin to that seen with COPD. Ulrik and Lange28 and Lange and colleagues29 reported a decrease in FEV1 of 60 mL/y in some patients, comparable to the decline seen in smokers.

Should We Be Genotyping Severe Asthma Patients?

Ultimately, physicians hope to prescribe asthma medications based on pharmacogenomics, which may provide a clearer understanding of which patient may benefit from a particular drug. Genetic studies in asthma are difficult to interpret because of the sheer number of gene abnormalities that correlate positively with the presence of asthma. Investigators have identified more than 100 genes of potential interest in asthma. Much has been discovered in the last decade about the genetics of asthma, but no definitive conclusions have been drawn. In general, most genotype investigations have found a inherited predisposition for airways hyperresponsiveness and atopy, two key features in most asthmatic individuals.30,31 A number of polymorphisms of these and other candidate genes likely are factors in severe asthma pathophysiology. Certain polymorphisms for IL-4 and its receptor correlate loosely with severe asthma.30 Variation in one gene, corticotropin-releasing hormone receptor 1 (CRHR1), which is involved in the release of corticotropin, was consistently associated with enhanced response to corticosteroids. Genetic variants in CRHR1 may adversely influence the clinical response to corticosteroids and lead to severe asthma. Another factor that may play a role in predisposition to severe asthma is 5-lipoxygenase activating protein.32 Perhaps the most clinically relevant gene that has been identified in genome association studies is ADRB2, which encodes for the β2-adrenergic receptor.33 ADRB2 is of interest to clinicians as there is good evidence that ADRB2 genotypes are associated with diverse patient responses to β2-agonist agents, such as albuterol. The variability of the response to bronchodilators has been attributed to single-nucleotide polymorphisms on the ADRB2 gene, and this work has led to a black box Food and Drug Administration (FDA) warning of the increase in asthma deaths from LABAs.

How Can Severe Asthma Be Recognized Quickly?

Patients with severe asthma typically tell personal histories of suffering from limited physical and social activities, frequent nocturnal awakenings, a pattern of acute and often severe exacerbations that send them to the physician or ED, and unremitting symptoms that are only briefly relieved by albuterol. Patients will be the first to recognize their impairment from the symptoms of severe asthma if they are taught to recognize them beforehand. They will complain of how “refractory” their symptoms are to established asthma drug therapies, eg, “I have tried everything” or “nothing works.” Wheezing is often replaced by progressive dyspnea with exertion, which heralds a more chronic condition where there is persistent air trapping with static and dynamic hyperinflation. The patient and his/her family may subjectively dismiss the clinical severity or an inexperienced physician may misjudge the clinical presentation and severity. For example, they may ignore abnormal spirometry findings, asthma symptoms that require short-acting β2-agonist use on a daily or near-daily basis, diurnal PEFR variability of >20%, one or more urgent-care visits for asthma per year, or three or more oral corticosteroid bursts per year (Table 1). Patients and physicians must develop a true partnership and share their perceptions of asthma control or lack thereof in order to recognize severe asthma early. To do otherwise is to neglect the patient and risk progressive decline in lung function and the quality of life.

Table 1Signs and Symptoms Suggesting a Diagnosis of Severe Asthma

Signs and Symptoms Suggesting Severe Asthma

Failure to respond to an appropriate and adequate course of asthma drug therapy, including high-dose ICS or oral corticosteroids

Reliance on albuterol several times per day to relieve symptoms

Symptoms of wheezing and cough throughout the day

Dyspnea or shortness of breath on exertion

Nocturnal awakening ≥4 times/wk

Extremely limited physical and social activities

3 or more acute asthma exacerbations in the past year

Pitfalls and Mimics

Every physician makes mistakes in the diagnosis and treatment of asthma because of the prevalent pitfalls and mimics of asthma. The most common cause of “severe asthma” may be a misdiagnosis of asthma in lieu of other conditions. Severe asthma must be distinguished from persistent asthma that is poorly controlled because of (1) inappropriate or inadequate prescribed therapy, (2) poor patient education, (3) cigarette smoking (which reduces the effectiveness of inhaled and oral corticosteroids), (4) nonadherence by the patient, or (5) poor inhaler and/or spacer technique by the patient.34,35 Important investigations concurrent with efforts to better control asthma symptoms should include a search for triggers at work or home. Triggers may include dust mites, a comorbid condition (eg, gastroesophageal reflux disease, which is clinically silent in 50% of patients), and medications (eg, aspirin, β- blockers). Need for multiple courses of antibiotics should suggest COPD (particularly in smokers) or an infectious cause of chronic bronchitis, eg, pertussis or Mycoplasma (Table 2). Adults with severe asthma (women much more than men) often have partially reversible spirometry, lung volumes that reveal static hyperinflation made worse by dynamic inflation with exercise or tachypnea, and a greater sensitivity to methacholine challenge, circumstantial evidence for a major contribution from the parasympathetic nervous system.

Table 2Differential Diagnosis of Conditions That Mimic Severe Asthma

Differential Diagnosis of Conditions That Mimic Severe Asthma

COPD

Asthma/COPD overlap syndrome (20% prevalence)

Gastroesophageal reflux disease (>60% prevalence)

Rhinosinusitis (60% to 80% prevalence)

Vocal cord dysfunction (10% prevalence)

Tracheal obstruction (stridor) from thyroid goiter

Tracheomalacia

Tumor

Acute infection with Bordetella pertussis or Mycoplasma pneumoniae

Allergic bronchopulmonary aspergillosis

Bronchiolitis

Diastolic heart dysfunction

Valvular heart disease

Pulmonary sarcoidosis

Pulmonary arterial hypertension

Churg-Strauss syndrome

No laboratory test or biomarker exists to readily distinguish severe asthma from less severe asthma phenotypes or to predict a favorable response to drug treatments. The best predictor of adverse outcomes and excessive use of asthma control medications appears to be baseline FEV1.6,7 Research participants meeting the definition of severe asthma with a baseline FEV1 <68% predicted had a three- or fourfold increased annual risk of requiring hospitalization or chronic oral corticosteroids compared with subjects whose FEV1 was >68% predicted. Testing exhaled breath samples for nitric oxide (NO) levels is of particular interest in severe forms of asthma. Exhaled NO is increased in asthmatic patients and, although NO concentrations vary greatly (normal, <25 ppb in adults), increases and decreases in NO levels correlate well with improvement and deterioration in asthma symptoms, respectively.36 Additionally, NO does not appear to be increased in patients with COPD, making it easier to differentiate between these conditions. The relative expense of this modality no longer precludes its use in general office practice. In patients with severe asthma, however, exhaled NO and sputum eosinophils do not separate asthma patients who respond to ICS from those who do not.15

Spirometry is recommended in all patients with the diagnosis of asthma. Patients with severe asthma seem not only to have a greater degree of airway obstruction, but also show a greater degree of irreversibility than patients with milder asthma. In a 15-year study, among both men and women and among both smokers and nonsmokers, participants with asthma had greater declines in FEV1 over time than those without asthma (P <.001).8 Radiography is of limited utility in patients with mild forms of asthma, but chest radiographs should be obtained for every patient with difficult-to-control asthma to rule out bronchiectasis, allergic bronchopulmonary aspergillosis, sarcoidosis, or emphysema (Table 3). Chest CT scans have been used primarily to ensure that other pulmonary diseases, such as bronchiectasis or interstitial pneumonitis, are not present. Some studies now suggest that CT scans will provide better information about airway structure and static and dynamic hyperinflation in the future.

Table 3Initial Evaluation of Severe Asthma: Tests to Consider

Initial Evaluation of Severe Asthma: Tests to Consider

Pulmonary function testing

Exhaled NO

Chest radiographs, old and new

Chest CT scan

Serum IgE

Serology for fungal sensitivities

Serology for Mycoplasma, Pertussis

Brain natriuretic peptide

Echocardiogram

Bronchoscopy

Experiments and Experience

Controller drug therapies, both NAEPP-preferred and alternative, may be partly or wholly ineffective, leaving severe asthma very poorly controlled and exposing patients to adverse drug side effects, often for years (eg, relative adrenal insufficiency, osteoporosis, more frequent respiratory viral infections). The goal of every management program in asthma is to improve outcomes and bolster patients’ understanding of disease control. As a starting point, every office practice should implement the Ten Key Clinical Activities for quality asthma care (Table 2).5 Every office visit for asthma care should include a patient-centered assessment of the patient’s disease, using a tool such as the validated survey instrument called the Asthma Control Test. One approach to therapy does not fit all and physicians must demonstrate a willingness to try several treatment alternatives at Step 5 and 6 of the NAEPP guidelines and beyond as needed. Apart from daily ICS, the optimal therapy for severe asthma in adults is controversial. There is no study that clearly shows that any drug therapy considerably alters the natural course of the disease in adults. The NAEPP recommendation to see asthma patients every 2 to 6 weeks for regular review of asthma control and drug side effects is pragmatic, allowing early detection of poor responses to treatments. If patients remain not well controlled or very poorly controlled after 3 months of treatment, we recommend that primary-care physicians suspect severe asthma or severe refractory asthma and refer patients promptly to an asthma specialist for consultation.

Sin and colleagues13 systematically reviewed the long-term effects of ICS, LABAs, leukotriene pathway modifiers/receptor antagonists, and anti-IgE therapies on clinical exacerbations in adults with chronic asthma. Not surprisingly, treatment with ICS was most effective, reducing exacerbations by nearly 55% compared with placebo or short-acting β2-agonists. The combination of ICS and LABAs decreased exacerbations by 26% compared with corticosteroid monotherapy. Combination therapy with ICS and LABAs is popular and this regimen has been shown consistently to decrease asthma exacerbation rates compared with equivalent or higher doses of ICS alone.37 Most of these seminal studies enrolled subjects with mild to moderate persistent asthma; perhaps the closest population to the severe asthma patient population was included in the FACET trial, which had a mean FEV1 of 75% for all subjects.38 This study showed that a dose of 400 μg of budesonide plus formoterol decreased annual asthma exacerbations by 62% compared with the same dose of budesonide alone. Recently, Woodruff et al20 showed convincingly that the Th2-high severe asthma subjects had a more dramatic improvement in FEV1 with high-dose fluticasone compared to the Th2-low group, suggesting that clinicians can begin to find a rationale for continuing high-dose ICS in some patients with severe asthma. Those patients who do not improve should probably be tapered down from such high doses to avoid side effects. Our preferred approach is to use a 3-month timeline to determine response to pharmacologic and nonpharmacologic interventions while applying the NIH-NAEPP recommendation to see uncontrolled asthma patients every 2 to 6 weeks until they are controlled, then 1 to 6 months to step-up or step-down therapy.

Beyond combination ICS-bronchodilator medications, treatment approaches differ. Step 5 of the NAEPP guidelines suggests considering the anti-IgE therapy omalizumab. Patients consider omalizumab a significant “step up” in treatment because it requires them to receive subcutaneous injections once or twice per month and be observed for evidence of anaphylaxis. Omalizumab was originally approved by the FDA in 2003 and there is now a 10-year collective experience with this medication.39 Recently, it was shown that omalizumab improves asthma control over 1 year and seemingly decreases infection-related flares during peak respiratory virus season.7 While the placebo effect is large in most studies with omalizumab, the drug consistently demonstrates benefit. Choosing this treatment for the appropriate severe asthma patient with elevated serum IgE levels, atopy, and poor asthma control has gotten easier as experience has been positive.

In the more refractory patients, physicians should refrain from prescribing high-dose oral corticosteroids for indefinite periods of time. Still, many asthma specialists will occasionally use corticosteroids, but not in high doses; 3 to 5 mg of daily prednisone added to inhaled combination therapy is often sufficient to improve asthma control in difficult patients. Clusters 4 and 5 in the SARP cohorts were prescribed oral corticosteroids as a controller medications 20% to 30% of the time. Following this, leukotriene antagonists are among the most prescribed asthma medications in the world. Certainly, leukotriene receptor antagonists are indicated for the 10% to 14% of asthma patients who manifest aspirin sensitivity, which is not always recognized in its milder forms. Lipoxygenase inhibitors, such as zileuton, can provide significantly improved asthma control over LTRAs in some severe asthmatics, and this therapeutic option often deserves a 3-month trial.

The contribution of acute and chronic infection to severe asthma cannot be overlooked. As in children, viral infections likely cause the majority of exacerbations in adult severe asthmatics.40,41 Others have suggested that bacterial respiratory infections, particularly with Chlamydia pneumoniae and Mycoplasma pneumoniae, but also Bordetella pertussis, can contribute to persistent airway inflammation and more severe disease.42,43 In a few small studies, administering macrolide therapy to symptomatic asthmatics who had serologic confirmation of atypical infection was associated with clinical improvement.42,43 Antibodies for these organisms should be measured in the nonresponding patient with severe asthma, and it is our practice to treat patients who have evidence of either acute or chronic infection with 1 month of macrolide antibiotics. Lastly, severe asthma with fungal sensitivity (ie, positive IgA or IgM antibodies to Aspergillus species) may respond well to an 8-month course of itraconazole; again, serologies should be checked.44

The newest FDA-approved treatment for severe asthma, bronchial thermoplasty, is more controversial. Approved in 2010, bronchial thermoplasty entails applying 60°C radiofrequency energy to 3 mm and larger airways sequentially during three bronchoscopic procedures.45 Much of the debate centers on the lack of understanding of what is occurring at the level of the airway epithelium as well as how the treatment affects the inflammatory component in both the short and long term. Still, this advanced treatment option is innovative and has generated renewed interest in treatment approaches that do not focus on blocking isolated inflammatory mediators. In our experience, we have seen dramatic improvements in asthma control and lung function in some patients who have exhausted other treatment approaches. Determining the appropriate patient for bronchial thermoplasty remains tricky.

In the future, a move toward more targeted therapies for subgroups of severe asthmatics will continue. The Th2-lymphocyte secreted cytokines IL-4, IL-5, and IL-13 are examples of this. Mepolizumab (anti-IL-5) injections are approved for patients with hypereosinophilic syndrome, and it is natural to presume that there will be some severe asthmatics who benefit from the dramatic reduction in eosinophils that occurs with this therapy.46 Lebrikizumab (anti-IL-13) has been shown to improve FEV1 in asthmatics (mean FEV1, 65% predicted), particularly in those patients with high serum periostin levels, which is a matrix protein involved in numerous cell functions.47 Combination anti IL-4/IL-13 inhibitors are being tested presently, and more combination inhibitors in this realm can be expected. Biologically, these therapies make sense, but identifying the right patients to receive these treatments will be difficult.

A Practical Approach to the Referred Patient

Our preferred approach is to first ascertain that the diagnosis of severe asthma is correct, ie, exclude other diagnoses or identify confounding comorbidities, even if this is the patient’s third or fourth evaluation (Fig 2). After reevaluation of the diagnosis of asthma (eg, SARP FEV1 and age stratification and assessment of comorbidities), the asthma specialist should ascertain whether the patient requires prednisone urgently. If not, rely on the patient’s short-term (2 to 6 weeks) responses to drug treatments to guide clinical decisions. For a hypothetical patient with uncontrolled severe asthma who does not currently need prednisone, our thought process over several visits would include the following:

  1. Check total IgE and perform a radioallergosorbent test (RAST) panel to detect atopy and look for fungal sensitivities.44 Consider a chest CT scan to look for bronchiectasis and bronchopulmonary aspergillosis and see if the diffusing capacity of lung for carbon monoxide is abnormal. With positive serology for spp or other fungus, treat with itraconazole 200 μg bid for 8 months.
  2. Treat the patient with 12 days of prednisone (40 mg for 3 days, 30 mg for 3 days, 20 mg for 3 days, 10 mg for 3 days) in the late afternoon rather than the morning if not currently prescribed, and have the patient return to clinic to determine if his/her asthma is refractory to corticosteroids. With a favorable response in terms of symptoms, exhaled NO, and spirometry, consider continuing with low-dose prednisone (1 to 3 mg daily) in addition to high-dose ICS plus LABA.
  3. Consider zileuton SR 600 mg bid for 2 to 6 weeks to inhibit leukotriene B4 synthesis and modulate neutrophil infiltration. Consider theophylline and roflumilast, which inhibit phosphodiesterase 4; roflumilast is not FDA approved for asthma despite evidence of a mild bronchodilator effect and reduction in sputum eosinophils and neutrophils.48 Continue montelukast only if the patient has derived a clear clinical benefit. Consider adding tiotropium and measure FEV1 in a scheduled follow-up visit 2 weeks later. Tiotropium and LABA have an additive effect on bronchodilation. Discontinue LABA if there is no clinical benefit, continue tiotropium, and rely on albuterol if there is concern about LABA toxicity.
  4. Treat with omalizumab if IgE is elevated and the results of RAST assays are positive for a perennial aeroallergen. It is important to begin treatment within 6 weeks of your consultation because of the 6-month time frame needed to determine efficacy. During this period, continue evaluating responses to other drugs to spare the patient from high-dose ICS and/or prednisone. Monitor the patient in clinic for anaphylaxis for 2 hours after each of the first three injections (this captures 75% of anaphylactic reactions). Discontinue if there is no clinical benefit.
  5. Consider fiberoptic bronchoscopy with bronchoalveolar lavage and endobronchial and transbronchial biopsies. Consider bronchial thermoplasty if the patient fails to improve or proceed to bronchial thermoplasty immediately if the patient elects to pursue that treatment or declines omalizumab.

For patients who need daily prednisone, recommendations 3, 4, and 5 should be considered in addition to evaluation for adrenal insufficiency. For the prednisone-dependent patient with severe asthma who has an FEV1 <60% to 65% predicted and fails to qualify for omalizumab, consider clarithromycin or azithromycin in six weekly doses in addition to the lowest effective dose of prednisone.49 Reconsider recommendations 3 and 5. Evidence to support the use of methotrexate, cyclosporine, or other steroid-sparing agents is not convincing. Nutritional supplementation with fish oils and vitamin D is under active clinical investigation and is worth discussing.

Figure 2. Practical workflow for the evaluation and management of patients with severe asthma. BAL = bronchoalveolar lavage; PFT = pulmonary function test.

Conclusions

There are no simple solutions that ensure easy recognition or successful management of severe asthma patients. Asthma is, after all, a syndrome marked by great clinical heterogeneity and variable response to therapies. Practically all features of severe asthma require first a careful evaluation of the actual patient. It is important to refrain from prescribing a plan of care that is not warranted or justified by the patient’s prior experiences. While it is more systematic to follow a step-wise plan in the approach to severe asthma patients, every patient with severe asthma ultimately deserves a “clinical trial of one” or a carefully executed 3-month drug therapy trial to determine what works and what does not work to control symptoms and prevent acute exacerbations.


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