Download Difficult asthma: Assessment and management, Part 1

Symposium: Issues in difficult asthma management
Difficult asthma: Assessment and management, Part 1
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Aidan A. Long, M.D., and Christopher H. Fanta, M.D.
ABSTRACT
A minority of asthma patients have disease that proves difficult to control with usual medications and experience ongoing symptoms, poor
quality of life, and limitations in activity and/or frequent asthma exacerbations. This group of patients accounts for much of the expense
associated with asthma care and is the focus of national and international collaborative study groups. Distinguishing between “difficultto-manage asthma” and truly “therapy-resistant asthma” is helpful and promotes a systematic consideration of contributory factors. Critical
evaluation of factors contributing to difficult-to-manage asthma including adverse environment, comorbidities, nonadherence, and incorrect
diagnosis is recommended in a systematic fashion in Part 1 of this contribution.
(Allergy Asthma Proc 33:305–312, 2012; doi: 10.2500/aap.2012.33.3583)
I
n recent years, as modern asthma therapies have
made good asthma control achievable in a majority
of patients, difficult or refractory asthma has become
the focus of intense interest from the perspectives of
basic science, translational research, and clinical care.
The following questions have come to the forefront:
What is different about asthma in some patients such
that it does not respond satisfactorily to conventional
therapy with bronchodilators, inhaled corticosteroids,
and leukotrienes modifiers; and how can we as asthma
specialists best manage these patients?
In Part 1 of this review, we will discuss the scope of the
problem, reference ongoing efforts nationally and internationally to study this subpopulation of asthmatic patients in a systematic way, and consider various working
definitions of “difficult asthma.” We will focus on the
assessment of difficult asthma, emphasizing the distinction between “difficult-to-manage” asthma and asthma
that is truly therapy resistant. We will offer our recommendations for a systematic evaluation of the patient
with difficult-to-control asthma and explore potential explanations for the failure of current treatments to provide
adequate control in all patients.
In Part 2 we will consider treatment options for difficult
asthma. We will focus on therapies approved by the Food
and Drug Administration, including lipoxygenase inhibi-
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From the Partners Asthma Center and the Allergy and Clinical Immunology Division
at Massachusetts General Hospital and the Pulmonary and Critical Care Division at
Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
Presented at the Eastern Allergy Conference, Palm Beach, Florida, June 4, 2011
The authors have no conflicts of interest to declare pertaining to this article
Address correspondence and reprint requests to Aidan A. Long, M.D., COX Room
201, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114
E-mail address: [email protected]:
Copyright © 2012, OceanSide Publications, Inc., U.S.A.
tion with zileuton, anti-IgE monoclonal antibody therapy
(omalizumab), and bronchial thermoplasty. We will
briefly consider other therapeutic options not approved
by the Food and Drug Administration for use in asthma,
including ultrahigh-dose inhaled corticosteroids, longacting anticholinergic bronchodilators, macrolide antibiotics, and vitamin D, along with other more toxic and
experimental interventions, such as methotrexate, tumor
necrosis factor ␣ inhibition, and cyclosporine. Our discussion of the management of difficult asthma will conclude
with consideration of specific asthma subtypes, each with
potentially distinct therapeutic approaches.
The prevalence of difficult asthma is uncertain. Estimates have put the number at 5–10% of patients with
asthma. Telephone surveys of randomly selected
American households found the prevalence of active
asthma (defined by the presence of asthmatic symptoms within the past year and report of a doctor’s
diagnosis of asthma) to be ⬃10% among the general
population.1 Among this denominator of patients with
asthma, those who reported symptoms consistent with
severe asthma (as defined by the criteria of Expert
Reports of the National Asthma Education and Prevention Program) constituted ⬃18%. Because these telephone surveys were unable to collect information
about lung function, it is likely that the true prevalence
of severe asthma was underestimated.
Asthma severity reflects an intrinsic property of the
disease process such that low-to-medium doses of inhaled corticosteroids, combined with long-acting bronchodilators and/or leukotriene modifying drugs, are
inadequate to achieve control. However, many patients
with severe asthma find their disease well controlled
on high-dose inhaled steroids together with a second
or third controller agent. These patients require inten-
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sive treatment, but on this intensive regimen their
asthma is mostly inactive and does not pose a problem
for either the patient or his/her physician. They have
infrequent symptoms, good functional capacity, normal or near-normal lung function, and infrequent
asthma exacerbations.
Difficult asthma refers to the group of patients who
despite being prescribed an appropriate and intensive
treatment program for severe asthma continue to have
frequent symptoms, have exercise limitation due to
their asthma, have impaired lung function, and/or
have frequent asthmatic exacerbations. Even if this
group of patients with difficult asthma represents only
10% of all patients with severe asthma, one might
estimate the prevalence of the problem to be ⬃2% of all
patients with asthma or as many as half a million
Americans. This small subset of patients with asthma
bears a disproportionately large burden of morbidity
and risk of mortality from their disease. They often
have poor quality of life due to limitations imposed by
their illness and toxicities caused by its treatment; and
they typically require frequent medical visits, including emergent outpatient and inpatient care, with attendant large costs to the medical system.
In 1999 a European Task Force developed a consensus statement to highlight the importance of difficult
asthma and to begin to consider a systematic approach
to its evaluation and treatment.2 Soon thereafter, the
American Thoracic Society released the results of its
Difficult Asthma Workshop (2000)3; and thereafter an
International Workshop assembled in Paris for the
same purpose (2006).4 Their definitions of difficult
asthma varied slightly, but the emphasis was the same:
patients who despite treatment with oral or high-dose
inhaled steroids continued to experience poorly controlled asthma, including acute asthmatic attacks. The
criteria for difficult asthma developed by the American
Thoracic Society Workshop group are shown in Table 1.
Ongoing collaborative scientific investigations into
the biology of difficult asthma emerged from these
conferences and used the definitions developed therein
as inclusion criteria for patient recruitment. These include the European Network for Understanding Mechanisms of Severe Asthma5 and, in the United States, the
Severe Asthma Research Program.6 Initial cross-sectional observations from these studies, each reporting
findings from ⬃150 –200 patients, include the following findings. As many as one-third of the patients
require daily oral steroids; 25– 40% have been hospitalized for asthma at least once in the preceding year; 12%
have received intensive care unit treatment for their
asthma; and common associated features are aspirin
sensitivity, gastroesophageal reflux disease (GERD),
rhinosinusitis, and a history of pneumonia.
Most recently, a group of investigators in the European Union have come together in the Unbiased Bio-
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Table 1 Definition of refractory asthma (American
Thoracic Society Workshop, 2000)
Refractory asthma is defined by the presence of one
or both major criteria and two or more minor
criteria.
Major criteria (required to achieve asthma control to
the level of mild–moderate persistent asthma)
Treatment with continuous or near-continuous
(⬎50% of the year) oral corticosteroids
Treatment with high-dose inhaled corticosteroids
Minor criteria
Need for daily treatment with a controller
medication in addition to inhaled corticosteroids
Asthma symptoms requiring daily or near-daily
short-acting ␤-agonist use
Persistent airflow obstruction (FEV1 of ⬍80% of
predicted)
More than one urgent care visit for asthma per
year
More than three oral steroid “bursts” per year
Prompt deterioration with ⬍25% reduction in oral
or inhaled steroid dose
Near fatal asthma event in the past
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Adapted from Ref. 3.
FEV1 ⫽ forced expiratory flow in 1 s.
markers for the Prediction of Respiratory Disease Outcomes consortium of the Innovative Medicines
Initiative.7 They have highlighted the potential value of
distinguishing difficult asthma subtypes, including
those prone to asthma exacerbations, those who have
irreversible airflow obstruction, and those who are dependent on oral steroids for asthma control.
An industry-sponsored observational study of difficult-to-control asthma, called the Epidemiology and
Natural History of Asthma: Outcomes and Treatment
Regimens, used less stringent criteria for patient recruitment, but enrolled ⬎4500 asthmatic patients from
allergy and pulmonary practices across the United
States.8 Patients were eligible if deemed to have “difficult-to-treat” asthma by their physician and either
required intensive medication treatment or had frequent asthma exacerbations. A minority of patients in
the Epidemiology and Natural History of Asthma:
Outcomes and Treatment Regimens were on high-dose
inhaled steroids, and only ⬃50% were judged to have
severe asthma. Nonetheless, this large cohort of patients again highlighted the “unmet need” of patients
with difficult asthma. Depending on the level of lung
function, within the preceding 3 months 44 – 48% of
patients had an unscheduled office visit, 43–56% had a
steroid burst, 4 –9% had been hospitalized for asthma,
and 13–19% required an emergency department visit.
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Eight to 20% gave a history of intubation for respiratory failure due to asthma.8
As we begin our consideration of the assessment and
treatment of difficult asthma, we offer our own working definition, derived from our daily personal experiences in clinical practice. We consider patients to
have difficult-to-control asthma when, despite treatment with high-dose inhaled steroids, long-acting
␤-agonist bronchodilator, and a leukotriene receptor
antagonist, they continue with poor asthma control (as
defined by frequent asthmatic symptoms, suboptimal
lung function, and/or frequent exacerbations) and/or
can only achieve asthma control with daily oral steroids.
ASSESSMENT: DISTINGUISHING DIFFICULTTO-MANAGE FROM TRULY THERAPYRESISTANT ASTHMA
In approaching the challenge of the patient with
difficult asthma, it is helpful to work through a systematic process to determine whether the patient fits
into one of two broad categories, either “difficult-tomanage asthma” or ”therapy-resistant asthma.” This
distinction is of importance because a majority of patients in the former category may not be candidates for
expensive innovative therapies while many patients in
the latter category may indeed require innovative therapeutic approaches. There are many potential contributing factors to difficult-to-manage asthma, and it is
possible that more than one might be at play in any
given patient. The factors contributing to this category
can be divided into the following groups:
1. Adverse environment.
2. Nonadherence.
3. Comorbidities.
4. Incorrect diagnosis.
5. Psychosocial problems.
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Working through each of these potential contributing groups of factors in a systematic fashion will frequently identify the reason(s) behind the patient’s difficulty with controlling their asthma. Probing history
taking is frequently sufficient to help identify issues
related to an adverse environment, nonadherence, or
psychosocial issues, whereas additional diagnostic
workup will likely be required in the evaluation of
comorbidities or alternative diagnoses.
ADVERSE ENVIRONMENT
In evaluating the patient’s environment for potential
contributory factors in difficult-to-manage asthma, one
needs to consider allergen and irritant exposure both in
the home and in the workplace. It is well established
that a majority of asthmatic patients, children more so
than adults, have an atopic basis for their asthma.9,10
Several recent studies have highlighted the contribu-
tion of perennial aeroallergens such as house-dust
mites, domestic animals, and environmental molds to
asthma. For example, a study of randomly selected
women from Detroit, MI, identified based on residence
in specific ZIP codes, evaluated the association between physician-diagnosed asthma (identified in
19.9% of the 702 women studied) and evidence of
sensitization to aeroallergens. It was determined that
the odds ratio of being diagnosed with asthma was
approximately five times higher in the setting of allergic sensitization to cat, four times higher for dog sensitization, and approximately double for sensitization
to house-dust mites.11 Similarly, data from epidemiological studies indicate that the prevalence of sensitization to either cat, dog, or dust mites is ⬎30% in
asthmatic patients and significantly lower in nonasthmatic patients.12 Seminal studies documented a key
role for dust-mite allergy in the development of
asthma,13 and more recent studies from the inner-city
asthma consortium and other investigators have highlighted the role of cockroach sensitization in relationship to emergency department visits for asthma.14,15
The importance of determining the nature of the
individual asthmatic patient’s particular allergic sensitivities has been increasingly highlighted by the emergence of evidence indicating that environmental control measures need to be both comprehensive and
specific if they are to be effective. Several studies highlight that nonspecifically targeted strategies, such as
provision of permeable dust-mite covers (without
other dust-mite control measures),16 –18 or placement of
HEPA filters (without other control measures)19,20 in
the homes of unselected asthmatic patients, do not
have any measurable effect on asthma outcomes. These
studies have been interpreted to show that partial environmental control measures, applied indiscriminately to all asthmatic patients, are not likely to be
helpful. In contrast, determining the nature of an individual asthmatic patient’s allergic sensitivities followed by focused and comprehensive environmental
modification measures are far more likely to be of
benefit.21 Thus, an allergy evaluation coupled with
targeted education and follow through to ensure implementation of recommendations is a very important
facet of optimally managing the patient with difficultto-control asthma.
Environmental exposure to allergens in the workplace can also be an important contributor to difficultto-manage asthma.22 This effect has perhaps been best
exemplified with respect to plicatic acid exposure in
woodworkers in the Pacific Northwest23; latex exposure in sensitive individuals in health care or glove
manufacturing environments24 –26; animal allergies in
laboratory animal workers,27,28 employees of breeding
facilities, and, occasionally, workers in veterinary facilities29; and yeast allergy among bakers.30 Exposure to
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nonspecific irritants, including volatile chemicals, tobacco smoke, and environmental pollutants, can also
contribute to poorly controlled asthma and should be
evaluated by a detailed history of the patient’s environmental exposures.31
Remediation of these adverse environmental exposures can be helpful but frequently requires significant
time and resources on the part of the patient coupled
with comprehensive education and reinforcement on
the part of the caregivers. In the ongoing dialog between patients and caregivers, which is strongly endorsed by the national asthma management guidelines, routine reevaluation of environmental exposures
is emphasized as an integral part of adherence in aiming for optimal asthma control in the long term.32 This
aspect of caring for the asthma patient frequently suffers from inadequate focus in today’s fast-paced health
care environment, in favor of reliance on medication
adjustment.
Included in the notion of adverse environment, one
might also consider exposure to pharmaceutical agents
that might be contributing to difficult-to-manage
asthma. Such agents potentially include ␤-blockers, aspirin, and nonsteroidal anti-inflammatory medications,
each of which can significantly worsen asthma, or angiotensin converting enzyme inhibitors, which can
cause coughing and might complicate the diagnostic
picture.33 Based on review of oral challenge testing, it
has been estimated that up to 20% of asthmatic patients
experience worsening with exposure to aspirin or other
nonsteroidal anti-inflammatory medications.34 Aspirin-exacerbated respiratory disease is frequently observed as an acquired phenomenon with a history of
previous tolerance of this category of medications. This
sensitivity to cyclooxygenase 1 inhibitors is not simply
classic allergy, i.e., not typically related to immediatetype hypersensitivity, but rather is felt in large part to
be related to abnormalities in metabolism of arachidonic acid leading to excessive production of leukotrienes.
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ADHERENCE
Poor rates of adherence to prescribed medications
are well documented in many chronic medical conditions, and asthma is certainly no exception to this
problem. Data published in 2005 from analysis of
United Health Care databases addressed the rate of
refill of asthma controller prescription medications and
showed that most monthly prescriptions were refilled
between two to four times per year.35 At a minimum,
this indicates that for more than two-thirds of the time
most asthmatic patients are not taking the prescribed
medications in the recommended doses. Other studies
have indicated similar low rates of adherence with
prescribed asthma medications and their associations
with difficult-to-control asthma.36,37 In our current
health care environment in United States, it is not easy
for the treating physician to access data about medication adherence. However, one can sometimes gain insight from asking when the patient last refilled his/her
controller medication or by looking at the renewal date
on the medication if the patient happens to have it with
them at an office visit.
The reasons for nonadherence are multiple. A recent
patient survey sought to let patients identify the reasons for noncompliance with asthma medications.
High on the list were fear of side effects, belief that the
medication was not necessary, belief that the illness
was not serious, a sense of the need for only intermittent use of medication, and concern that the medication
would lose effectiveness over time.38 What is remarkable is that all of these factors are amenable to better
education and could be potentially improved by better
dialog between the asthma patient and the caregiving
team. Although cost of medication is often cited as the
primary reason for noncompliance, this ranks as number seven among reasons patients cited for nonadherence. Strategies to improve adherence with chronically
prescribed medications have been evaluated, sometimes with disappointing results.39 Repeated patient
education at office visits about the importance of maintenance therapy, including emphasis that medication
efficacy will not be lost with continuous use, simplification of therapeutic regimens and exploration with
patients about what factors contribute to their own
noncompliance are likely to be most helpful.
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COMORBIDITIES
Evaluation and intensive management of comorbidities can also result in significant improvements in
asthma outcomes for the difficult-to-manage patient.
The comorbidities can be considered under several
categories:
1. Allergic upper airway disease.
2. GERD.
3. Obesity.
4. Obstructive sleep apnea.
Upper airway allergic diseases, including allergic
rhinitis, chronic rhinosinusitis, allergic fungal sinusitis,
and aspirin-exacerbated respiratory disease, are all potential confounding factors in the atopic patient. Studies have indicated that a significant majority of patients
with allergic rhinitis have abnormal bronchial hyperreactivity.40 Chronic sinusitis with or without nasal
polyps may also be associated with increased bronchial
reactivity and directly contribute to increased respiratory symptoms through postnasal drainage of secretions.41,42 One recent survey estimated that 54% of
patients with severe asthma suffers with chronic rhinosinusitis, and twice as many patients with severe
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asthma have required sinus surgery than have patients
with more moderate or mild asthma.6 Churg-Strauss
syndrome, a condition in which patients with asthma
develop eosinophilia and vasculitis manifesting with
rhinosinusitis, pulmonary infiltrates, cardiomyopathy,
and peripheral neuropathy, has been observed with a
higher rate of frequency in patients who are able to
reduce exposure to either parenteral or inhaled steroids as a result of use of alternative antiasthmatic
medications, including leukotriene receptor antagonists and anti-IgE monoclonal antibody.43,44
The contribution of GERD to difficult-to-manage
asthma has been the subject of considerable debate.
The Severe Asthma Research Program estimates that
41% of patients with severe asthma has been diagnosed
with GERD in contrast to only 12–16% of patients with
mild to moderate disease.6 Therapeutic trials of proton
pump inhibitors (PPIs) and other antireflux measures
have been recommended in algorithmic fashion for the
management of patients with severe asthma. A number of studies suggest positive outcomes to such a
strategy, but a systematic review of this literature
points to inconsistent results.45– 47 A more recent study
has raised additional concerns about the benefits of
routine prescription of antireflux therapy for asthmatic
patients in the absence of symptoms of gastroesophageal reflux. Mastronarde and colleagues evaluated 412
patients with poorly controlled asthma who had no or
minimal symptoms to suggest GERD. These patients
were empirically treated with high-dose PPIs (esomeprazole at 40 mg twice a day) for 6 months. The authors
observed no change in the number of episodes of poor
asthma control or in any of the components thereof,
including symptoms, rescue medication usage, lung
function, or quality of life. Strikingly, further analysis
of the subgroup of patients who had an abnormal pH
probe study, confirming silent GERD, showed that this
group fared no better for asthma outcomes with this
therapeutic approach than did the overall group.48 A
recent randomized controlled trial evaluated the benefit regarding asthma symptoms of treatment with a
PPI (lansoprazole) in a large number of children with
poorly controlled asthma without overt GERD symptoms. The study documented no change in asthma
symptoms or lung function attributable to lansoprazole, even in a subgroup with pH probe confirmed acid
reflux disease. Children treated with lansoprazole
were reported to have an increased risk of respiratory
infections.49
An integral aspect of management of GERD is
weight loss. Obesity itself, independent of GERD, has
been linked epidemiologically to asthma. The association is complex and may relate to immunologic, genetic, or pulmonary mechanical factors. In at least one
randomized study, weight reduction was shown to
improve overall lung function, symptoms, and quality
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Table 2 Differential diagnosis of difficult-tocontrol asthma
Chronic obstructive pulmonary disease
Bronchiectasis
Vocal cord dysfunction syndrome
Tracheobronchomalacia
Steroid-withdrawal syndrome*
Churg-Strauss syndrome
Aspirated foreign body/endobronchial obstruction
Bronchiolitis obliterans (e.g., in rheumatoid arthritis
or ulcerative colitis)
Sarcoidosis
Disseminated strongyloidiasis
Pulmonary thromboembolism
Diastolic dysfunction with congestive heart failure
(“cardiac asthma”)
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*Symptomatic deterioration without objective evidence for
worsened airflow obstruction, because of nonrespiratory
symptoms associated with oral steroid withdrawal.
of life for obese persons with asthma.50,51 Obesity also
contributes to obstructive sleep apnea, which can complicate assessment of nocturnal awakenings and dyspnea as a manifestation of asthma control.52
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ALTERNATIVE DIAGNOSES
Many of the conditions mentioned previously as comorbidities may in fact represent primary diagnoses
causing respiratory symptoms frequently ascribed to
asthma. Similarly, the distinction between chronic obstructive pulmonary disease (COPD) and asthma can
be difficult. Therapeutic strategies for asthma can result in positive outcomes for COPD, and agents primarily introduced for COPD are showing benefit in
asthma. Patients with severe air trapping or emphysema should be evaluated for ␣-1–antitrypsin deficiency, and the patient with airway obstruction and a
chronic productive cough should be evaluated for diseases causing bronchiectasis, such as cystic fibrosis or
allergic bronchopulmonary aspergillosis. Diagnostic
testing for allergic bronchopulmonary aspergillosis
typically reveals very high serum IgE levels (often in
excess of 1000 IU/mL), skin test sensitivity to Aspergillus, specific serum IgE and IgG to Aspergillus and precipitating IgG antibody to Aspergillus (“serum precipitins”), and Aspergillus isolated on fungal culture of
sputum.
A syndrome of a paradoxical movement of the vocal
cords, often referred to as vocal cord dysfunction, can
be mischaracterized as asthma with the patient making
frequent urgent care visits and often being prescribed
extensive antiasthma therapy. This condition represents involuntary vocal cord adduction during inspiration, which can give rise to many of the clinical signs
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Table 3 Difficult-to-control asthma checklist
General Question
Specific Area of Focus
Required Action
Is there an adverse environment?
Allergen
Irritant
Pharmacologic
What means to assess adherence?
Reasons for nonadherence?
Review environmental history
and medication history, and
perform allergy evaluation
Review medication history and
pharmacy records, interview
family members, and Asthma
Educator Session
pH probe/sleep study/dietetic
help
CT of sinuses/ANCA/Aspergillus
precipitins
Smoke quit Rx/support
Flow volume loop
Is the patient adherent?
Is there a comorbid condition?
GERD, obesity, and OSA
CRS, AERD, CSS, and ABPA
Is the diagnosis of severe asthma
correct?
Smoking and COPD
VCD, glottic dysfunction, and
psychopathologies
Chronic respiratory infections
Bronchiectasis, CF, and
␣-1–antitrypsin deficiency
Are alternative pharmacologics
warranted?
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What has failed? Does the patient
fit a recognized phenotype?
ENT—speech pathology
evaluation, home PEFR
monitoring, social worker
involvement, sputum PCR,
HRCT/sweat test/CFTR
mutation analysis
Sputum analysis? ENO? Future
modalities?
GERD ⫽ gastroesophageal reflux disease; OSA ⫽ obstructive sleep apnea; CRS ⫽ chronic rhinosinusitis; AERD ⫽
aspirin-exacerbated respiratory disease; CSS ⫽ Churg-Strauss syndrome; ABPA ⫽ allergic bronchopulmonary aspergillosis;
COPD ⫽ chronic obstructive pulmonary disease; VCD ⫽ vocal cord dysfunction; CF ⫽ cystic fibrosis; ANCA ⫽ anti-nuclear
cytoplasmic antibody; ENT ⫽ Ear-Nose-Throat specialist; PEFR ⫽ peak expiratory flow rate; PCR ⫽ polymerase chair
reaction; HRCT ⫽ high-resolution chest CT scan; CFTR ⫽ cystic fibrosis transmembrane regulator; ENO ⫽ exhaled nitric
oxide concentration.
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and symptoms of asthma, including loud expiratory
wheezing. This condition is seen more frequently in
female patients and also in association with exercise
during adolescence, but it is not exclusive to these
demographics.53 Accurate diagnosis can be difficult
because it requires visualization of the vocal cords at a
time when the patient is symptomatic. This condition is
amenable to treatment by relaxation exercises, and referral to speech pathology can be helpful. Other entities
that can manifest with cough and wheeze and potentially be misdiagnosed as asthma are listed in Table 2.
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THERAPY-RESISTANT ASTHMA
It is increasingly recognized that asthma represents a
syndrome rather than a single condition and that there
is great clinical and pathobiological heterogeneity
among the population diagnosed with asthma. This
heterogeneity may extend to include genetically programmed differences in the way asthma patients respond to medications.
Variability in the response to corticosteroids in
asthma has been shown in clinical trials involving both
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adults and children. The pattern of response appears to
exhibit a normal distribution with a proportion of patients actually showing deterioration in lung function
in response to treatment with inhaled steroids.54 A
specific phenotype of steroid-resistant asthma has also
been described and reported with differing prevalences among severe asthmatic patients.55 This phenomenon has been evaluated mechanistically and has
been associated with abnormalities of the glucocorticoid receptor.56 Additionally, smoking has been linked
to resistance to glucocorticoids by inactivating histone
deacetylase 2.57
Separately, other studies have shown that some patients appear not to experience a beneficial bronchodilator effect from either short-acting or long-acting
␤-agonists, and this clinical phenotype can be statistically linked to genetic polymorphisms resulting in
Arg/Arg substitutions at amino acid position 16 in the
␤-adrenergic receptor.58 The clinical relevance of this
observation remains an area of controversy.59 Many of
the patients who have a blunted response to ␤-agonists
do benefit from inhaled anticholinergics. Furthermore,
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studies in children have shown that there is a subgroup
of asthmatic patients who experience improvement in
lung function with inhaled steroids but not from leukotriene antagonists and another subgroup who appear to experience no benefit from steroids but improved lung function with leukotriene antagonists.60
Based on the ideas described previously, we propose
a checklist that can be useful in guiding the approach
to the patient with difficult asthma (Table 3).
CHANGING UNDERSTANDING OF ASTHMA
PATHOGENESIS
It is likely that persistence of the problems of difficult-to-manage asthma and therapy-resistant asthma
relates in no small part to our incomplete understanding of asthma pathogenesis and, accordingly, inappropriately targeted therapies. Concepts of asthma pathogenesis continue to evolve. Because the initial concept
of asthma as a disease primarily of bronchoconstriction
related to smooth muscle contraction (1970s), through
the increased understanding of the role of airway inflammation and bronchial hyperreactivity (1980s and
early 1990s), followed by an additional focus on airway
remodeling (late 1990s and early part of the 21st century), the paradigm continues to shift. The focus on
Th2-type cytokine-dependent inflammation resulting
from adaptive immune responses to allergens as the
primary target of novel therapies is falling short in the
clinic. The initial promise of anti–interleukin-4 (IL-4)
and anti–IL-5 therapies from animal models of asthma
has not been borne out in clinical trials of human
asthma.61 An initial trial of an anti–IL-13 monoclonal
antibody, lebrikizumab, showed only modest benefit
in improving prebronchodilator lung function.62
More recently, emphasis in asthma pathogenesis has
focused on innate immune system responses and epithelial dysfunction. Impairments in barrier function of
the airway epithelium either as an inherent defect or as
a result of proteolytic activity of airway allergens allow
greater access of environmental triggers to the submucosa with consequent promotion of more intense inflammation. Differences in the response of asthmatic
airways to oxidative stress induced by environmental
exposures including pollutants and diesel exhaust particles have been described.63,64 Environmental allergens, viruses, and pollutants can activate or disrupt the
airway epithelium, leading to activation of innate immune responses, including innate cell elaboration of
Th2-type cytokines or skewing adaptive responses toward the Th2 pattern. Perhaps novel therapies targeted
toward these aspects of asthma pathogenesis will
prove beneficial in the future.65
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