Diagnosis and Management of Asthma in Adults A Review
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Clinical Review & Education
JAMA | Review
Diagnosis and Management of Asthma in Adults
A Review
Jennifer L. McCracken, MD; Sreenivas P. Veeranki, MBBS, DrPH; Bill T. Ameredes, MS, PhD; William J. Calhoun, MD
Author Audio Interview
IMPORTANCE Asthma affects about 7.5% of the adult population. Evidence-based diagnosis, CME Quiz at
monitoring, and treatment can improve functioning and quality of life in adult patients jamanetwork.com/learning
with asthma. and CME Questions page 295
OBSERVATIONS Asthma is a heterogeneous clinical syndrome primarily affecting the lower
respiratory tract, characterized by episodic or persistent symptoms of wheezing, dyspnea,
and cough. The diagnosis of asthma requires these symptoms and demonstration of
reversible airway obstruction using spirometry. Identifying clinically important allergen
sensitivities is useful. Inhaled short-acting β2-agonists provide rapid relief of acute symptoms,
but maintenance with daily inhaled corticosteroids is the standard of care for persistent
Author Affiliations: Division of
asthma. Combination therapy, including inhaled corticosteroids and long-acting β2-agonists,
Allergy and Clinical Immunology,
is effective in patients for whom inhaled corticosteroids alone are insufficient. The use of University of Texas Medical Branch,
inhaled long-acting β2-agonists alone is not appropriate. Other controller approaches include Galveston (McCracken, Calhoun);
long-acting muscarinic antagonists (eg, tiotropium), and biological agents directed against Department of Preventive Medicine
and Community Health, University of
proteins involved in the pathogenesis of asthma (eg, omalizumab, mepolizumab, reslizumab). Texas Medical Branch, Galveston
(Veeranki); Division of Pulmonary
CONCLUSIONS AND RELEVANCE Asthma is characterized by variable airway obstruction, airway Critical Care and Sleep, Department
of Internal Medicine, University of
hyperresponsiveness, and airway inflammation. Management of persistent asthma requires
Texas Medical Branch, Galveston
avoidance of aggravating environmental factors, use of short-acting β2-agonists for rapid relief (Ameredes, Calhoun).
of symptoms, and daily use of inhaled corticosteroids. Other controller medications, such as Corresponding Author: William J.
long-acting bronchodilators and biologics, may be required in moderate and severe asthma. Calhoun, MD, University of Texas
Patients with severe asthma generally benefit from consultation with an asthma specialist for Medical Branch, 4.116 JSA, 301
University Blvd, Galveston, TX 77555-
consideration of additional treatment, including injectable biologic agents.
0568 (william.calhoun@utmb.edu).
Section Editors: Edward Livingston,
JAMA. 2017;318(3):279-290. doi:10.1001/jama.2017.8372 MD, Deputy Editor, and Mary McGrae
McDermott, MD, Senior Editor.
A
sthma affects about 7.5% of adults in the United States, re- This review presents an evidence-based approach to the diag-
sulting in 1.8 million hospitalizations and 10.5 million phy- nosis and management of mild to moderate stable asthma in adults.
sician office visits per year (Table 1). Asthma is more com- For patients with severe disease, generally manifested as continu-
mon in black (8.7%) and Puerto Rican Hispanic (13.3%) individuals ing symptoms and airway obstruction despite appropriate
than in white individuals (7.6%) and is associated with higher mor- therapy,12,13 consultation with an asthma specialist (allergist or pul-
tality in blacks than in whites (25.4 vs 8.8 per million annually) monologist) should be sought.
(Table 1). Inhaled corticosteroids increase the number of days with-
out symptoms (by 7-21 d/mo), improve lung function (forced expi-
ratory volume in first second of expiration [FEV1]) by 13% and peak
Methods
flow by 23 to 41 L/min,7 and reduce symptoms of dyspnea, cough,
and nighttime awakening.8 The Cochrane Database of Systematic Reviews, Cumulative Index
Asthma exhibits considerable clinical and molecular hetero- to Nursing and Allied Health Literature (CINAHL), EMBASE,
geneity (eg, atopic vs nonatopic, aspirin-exacerbated respiratory MEDLINE, Population Information Online, PubMed, and Web
disease, obesity-associated asthma), which complicates diagnos- of Science were searched for the period from the inception of
tic evaluations and affects therapeutic responsiveness. 9 For each database through March 2017 for randomized clinical
example, patients with asthma who smoke have relative resis- trials, systematic reviews, and/or meta-analyses and for observa-
tance to inhaled corticosteroids.10 Patients with asthma uncon- tional studies using asthma or anti-asthmatic drugs or asthma
trolled by standard treatment and with peripheral blood eosino- management or therapeutic as primary search terms. Titles and
philia may benefit from mepolizumab or reslizumab, and those abstracts of the articles were initially screened, and selected
with elevated perennial allergen-specific IgE could be candidates articles underwent full review. The bibliographies of selected
for omalizumab.11 Clinical history, spirometry, and assessment of articles were manually screened for additional relevant articles.
allergic sensitivities are important for diagnosis of asthma.12,13 All authors agreed on the final bibliography. Emphasis was given
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Table 1. Prevalence, Mortality, and Health Care Utilization Among Adults
sinusitis, exercise, and cold air. Nocturnal symptoms indicate
With Asthma in the United States more severe disease, causing awakening in the early morning
hours (for those with a normal diurnal schedule). The clinical pre-
Measure Value
sentation of asthma is variable with respect to severity, underly-
Prevalence, %a
ing pathogenic mechanisms, effect on quality of life, and respon-
Overall prevalence 7.4
siveness to treatment.9
Sex
Asthma may develop at any age, although onset is more fre-
Male 5.1
quent in childhood and young adulthood. Familial clustering
Female 9.6
occurs, suggesting that genetic factors are important.12-16 Risk fac-
Race/ethnicity tors for asthma include heredity, exposure to environmental
White non-Hispanic 7.6 tobacco smoke, viral infections in the first 3 years of life, and
Black non-Hispanic 8.7 socioeconomic factors such as income level, the presence of
Hispanic 5.8 cockroach or rodent infestations in the home, and access to medi-
Others 6.8 cal care.12 Heritable factors include genes regulating IgE-related
Hispanic of Puerto Rican origin 13.3 mechanisms,12,13 glucocorticoid response,14 airway smooth muscle
Hispanic of Mexican origin 4.9 development (ADAM33),15 and components of the immune system
Asthma-Specific Mortality (Deaths per Million per Year)b (HLA-G).16 Tobacco smoke is a common exacerbating factor in
Overall 14.1 patients with asthma.13
Race/ethnicity Physical findings in stable asthma are nonspecific, and physi-
White non-Hispanic 8.8 cal examination findings can be normal when the patient is
Black non-Hispanic 25.4 well. Poorly controlled asthma may exhibit auscultatory wheezing
Hispanic 7.7 or rhonchi, but the intensity of wheezing is a poor indicator of the
Others 9.9 severity of either airflow obstruction or disease pathology. In an
Health Care Utilization
acute exacerbation of asthma, tachypnea, pulsus paradoxus (eg, a
Inpatient discharges (rate per 10 000 per year)c
decrease of more than 10 mm Hg in systolic blood pressure dur-
ing inspiration), cyanosis, and use of accessory muscles of respira-
Overall 13.0
tion may be evident.
Race
The term “exacerbation” may be used to indicate a short-
White 8.7
lived worsening of symptoms managed effectively with short-
Black 29.9
acting β2 agents. It also may be used to indicate a more serious
Other 12.6
deterioration of lung function, of longer duration, associated with
Emergency department visits (in millions per year)d 1.8
increased symptoms and commonly precipitated by exposure to
Physician office visits (in millions per year)e 10.5
allergens or viral infections, that may require intensification of
Hospital outpatient department visits (in millions per year)f 1.3 anti-inflammatory therapy.12,13
a
Asthma prevalence by age, sex, and race/ethnicity as reported in 2014 Atopic or allergic asthma is frequently associated with allergic
National Health Interview Survey. rhinitis and conjunctivitis. Food allergies and atopic dermatitis
b
Asthma mortality (deaths per million) as reported in 2014 National Centers for may also be observed. Nonatopic asthma, defined as not associ-
Health Statistics surveys. Death rates by age are age-adjusted to 2000 US
Standard Population.
ated with allergies, is less frequent than atopic asthma in patients
c
Inpatient discharges as reported in the 2010 National Hospital Discharge Survey.
with mild asthma (20%) or severe asthma (29%)17 and is more
d
Emergency department visits as reported in the 2013 National Ambulatory
common in older adults compared with children; its evaluation
Medical Care Survey. and pharmacologic management are otherwise similar to that for
e
Physician office visits as reported in the 2012 National Ambulatory Medical atopic disease.12,13
Care Survey. Adverse consequences of systemic steroid treatment may
f
Hospital outpatient department visits as reported in the 2010 National occur if frequent courses of systemic steroid therapy are neces-
Hospital Ambulatory Medical Care Survey. sary (Table 2). Allergic bronchopulmonary mycoses, including
allergic bronchopulmonary aspergillosis, may have a prevalence
to randomized clinical trials and articles that included information as high as 25% among people with asthma,31 although the patho-
of interest to a general medical readership. genesis and causes of this complication remain uncertain.12
In the setting of the above symptom complex and airway
obstruction reversible by β2-agonists, the diagnosis of asthma can
usually be made. A proposed algorithm for the diagnosis of
Results
asthma is presented in Figure 1. The combination of asthma-like
Clinical Presentation symptoms and β2 agonist–reversible bronchial obstruction usually
Asthma is a heterogeneous clinical syndrome affecting the is sufficient to establish the diagnosis of asthma. Appropriate
lower respiratory tract. It presents as episodic or persistent symp- diagnostic testing should be conducted to confirm a diagnosis of
toms of wheezing, dyspnea, air hunger, and cough. Symptoms asthma or suggest alternatives. Diseases of the heart and great
may be precipitated or exacerbated by exposure to allergens vessels, the pulmonary parenchyma, and the upper airway can
and irritants, viral upper respiratory tract infections, bacterial mimic the clinical presentation of asthma (Box).
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Table 2. Major Medical Therapies for Stable Asthma in Adults
Category Examples Usual Dosing Treatment Effect Adverse Effects Notes
Standard Therapies
Relievers
Short-acting Albuterol 2 puffs Bronchodilation (7%-15% Nervousness, tremor,
β2-agonists (SABAs) Levalbuterol every 4-6 h increase in FEV1, dose bronchospasm, tachycardia,
Pirbuterol dependent) headache, pharyngitis
Short-acting Ipratropium 2-3 puffs Bronchodilation (7%-15% Bronchitis, COPD
muscarinic antagonists every 6 h increase in FEV1, dose exacerbation, dyspnea,
(SAMAs) dependent) headache
Controllers
Inhaled corticosteroids Fluticasone 2 puffs twice Decreased daytime Upper respiratory tract Comparisons for low,
(ICSs) daily and nocturnal symptoms infection, throat irritation, moderate, and high doses
Budesonide 2-4 puffs sinusitis, dysphonia, of ICSs are detailed
twice daily Reduced exacerbations candidiasis, cough, elsewhere12,13
and death bronchitis, headache
Mometasone Varies by device
Ciclesonide 160-320 μg Improved FEV1 (improvement
twice daily in symptoms, exacerbations,
death, and FEV1 are all dose
dependent18,19)
Leukotriene receptor Montelukast 10 mg daily Decreased daytime Headache, fatigue, abdominal
antagonists (LTRAs) and nocturnal symptoms pain, dyspepsia, mood
Zafirlukast 20 mg changes
twice daily Improved FEV120
Leukotriene synthesis Zileuton 600 mg 4 times Improved FEV121 Headache, pain, abdominal Requires monitoring
inhibitor daily pain, dyspepsia, nausea, of hepatic enzymes
myalgia, increased alanine
aminotransferase Drug interactions
are common
Long-acting Salmeterol 2 puffs Improved FEV122 Headache, rhinitis, bronchitis, These agents should not be
β2-agonists (LABAs) twice daily influenza, dizziness used without a simultaneous
Formoterol 2 puffs ICS agent
twice daily
Vilanterol NA
Long-acting Tiotropium 1 puff daily Improved FEV123 Dry mouth, upper respiratory
muscarinic antagonist tract infection, pharyngitis,
(LAMA) sinusitis, chest pain
Combined ICSs/LABAs Fluticasone/ 1 puff Benefits of both ICSs Nasopharyngitis, URI,
salmeterol inhaler twice daily and LABAs24 headache, sinusitis, influenza,
Fluticasone/ 2 puffs back pain
salmeterol HFA twice daily
Budesonide/ 2 puffs
formoterol twice daily
Fluticasone/ 1 puff daily
vilanterol
Other Therapies
Oral corticosteroids Prednisone 5-20 mg/d Hypertension, increased Doses listed are for chronic
appetite, weight gain, maintenance, not for
Methylprednisolone 4-16 mg/d insomnia, mood changes, exacerbations
gastritis, skin atrophy,
osteoporosis, adrenal Daily use of oral
suppression, avascular corticosteroids is not
necrosis of bone recommended unless other
options are ineffective;
consult with an asthma
specialist
Biologics
Anti-IgE Omalizumab Varies by weight Reduced asthma Injection site reaction, viral Used primarily by asthma
exacerbations infections, URI, sinusitis, specialists
headache, pharyngitis,
Variable benefit in FEV125 anaphylaxis
Anti-IL-5 Mepolizumab 100 mg Reduced asthma Headache, injection site Used primarily by asthma
subcutaneously exacerbations reaction, back pain, fatigue, specialists
monthly oropharyngeal pain
Reslizumab Varies by Small improvement
weight, IV in FEV126-29
administration
Bronchial thermoplasty 3 Bronchoscopic Reduced asthma Short-term worsening of Specialty treatment
treatments, exacerbations, emergency asthma symptoms, cough,
once monthly department visits through wheezing, chest pain, URI, Durability of benefit
for 3 mo at least 1 y30 infection is controversial
Abbreviations: COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in first second of expiration; URI, upper respiratory infection.
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Figure 1. Proposed Algorithm for Initial Diagnosis of Asthma
Adult patient with symptoms consistent with asthma
Obtain spirometry
FEV1:FVCThe Diagnosis and Management of Asthma in Adults Review Clinical Review & Education
Figure 2. National Asthma Education and Prevention Program Approach to Classification of Asthma Severity
Classification of asthma severity (age ≥12 y)
Persistent
Components of severity Intermittent Mild Moderate Severe
Impairment Symptoms ≤2 d/wk >2 d/wk but not daily Daily Throughout the day
Nighttime awakenings ≤2× mo 3-4× mo >1× wk but not nightly Often 7× wk
Short-acting β2-agonist ≤2 d/wk >2 d/wk but not daily, Daily Several times per day
use for symptom control and not more than 1×
(not prevention of EIB) on any day
Interference with normal None Minor limitation Some limitation Extremely limited
activity
Lung function • Normal FEV1, between • FEV1, >80% predicted • FEV1, >60% but • FEV1, 80% predicted • FEV1:FVC normal
40-59 y 75%
60-80 y 70% • FEV1: FVC normal
Risk Exacerbations requiring oral 0-1/y ≥2/y ≥2/y ≥2/y
systemic corticosteroids
Consider severity and interval since last exacerbation
Frequency and severity may fluctuate over time for patients in any severity category
Relative annual risk of exacerbation may be related to FEV1
Recommended step for initiating treatment Step 1 Step 2 Step 3 Step 4 or 5
(see Figure 3 for treatment steps) and consider short course of oral systemic corticosteroids
In 2-6 weeks, evaluate level of asthma control that is achieved and adjust therapy accordingly
An estimate of asthma severity on initial presentation is made on the basis This categorization informs the initial therapeutic approach (Figure 3).
of daytime and nocturnal symptoms, the frequency of need for short-acting EIB indicates exercise-induced bronchoconstriction; FEV1, forced expiratory
β2-agonists for relief of symptoms, the degree to which asthma interferes volume in first second of expiration; FVC, forced vital capacity.
with normal activity, the degree of airway obstruction measured by spirometry, Figure adapted from NAEPP.12
and the history of asthma exacerbations. On the basis of these factors, asthma
can be categorized as intermittent, or persistent (mild, moderate, or severe).
lymphocytes, mast cells, neutrophils) and is commonly initiated Activation of IL-17, CD4+ T cells (TH17 cells), and IL-12/IL-23 is
by allergen-dependent release of histamine and other mediators distinct from type 2 factors noted above and is more closely associ-
from mast cells47 and subsequent infiltration of lymphocytes ated with neutrophilic inflammation.58 Neutrophil infiltration and
(particularly T-helper type 2 [TH 2]) and granulocytes into the activation contribute to the severity of uncontrolled and severe
airway.48 IgE occupies a central role in the pathogenesis of allergic asthma, and neutrophilic inflammation is less responsive to stan-
asthma; inflammatory responses are mediated by allergen-specific dard therapies, making the neutrophil an attractive potential target
IgE, generated during allergic sensitization, and bound to mast cells for novel asthma therapy.59
which are activated by reexposure to allergen. Elevated levels of
proinflammatory cytokines IL-4, IL-5, and IL-13 are observed.49,50 Assessment and Diagnosis
Airway inflammation accentuates obstruction by promoting The diagnosis and severity of asthma are established based on
mucosal infiltration and edema, mucus secretion, and airway clinical criteria: history, physical examination, and evidence of
hyperresponsiveness; it also predisposes to exacerbations. either reversible airflow obstruction, or airway hyperresponsive-
Structural changes, termed airway remodeling, include increased ness (Figure 1).12,13 The US National Asthma Education and Pre-
smooth muscle mass, 51 goblet cell hyperplasia, 52 and lamina vention Program (NAEPP) approach to classifying asthma sever-
reticularis thickening.51 The TH2 hypothesis (activation of TH2 cells) ity is based on 2 domains: impairment and risk. The impairment
provides conceptual understanding of the development of domain includes measured airway obstruction, the frequency and
inflammation associated with asthma. 53 More recently it has intensity of daytime and nocturnal symptoms, frequency of
been recognized that type 2 innate lymphoid cells also contribute short-acting β2 agonist use for symptom relief, and interference
to eosinophilic airway inflammation. This phenomenon is termed of daily activities by symptoms. The risk domain assesses the
“type 2 inflammation.”54 Eosinophilic inflammation and asthma frequency of exacerbations (Figure 2). These data collectively
may develop in the absence of overt allergy. 55 Endogenous define both asthma severity and asthma control.12,13 Physical
anti-inflammatory mediators appear to be important in control- findings of accessory muscle use or audible wheezing during nor-
ling and resolving airway inflammation in individuals without mal breathing may be present only during times of asthma exac-
asthma, and these mechanisms may be insufficiently or ineffec- erbation and have poor negative predictive value to exclude the
tively activated in asthma: eg, reduced production of the anti- diagnosis of asthma.
inflammatory factors IL-10 and lipoxin A4 has been identified in Spirometry is the most important diagnostic procedure
patients with asthma.56,57 for evaluating airway obstruction and its reversibility. It should
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Table 3. Diagnostic Modalities Useful in Diagnosis and Treatment of Stable Asthma in Adults
Diagnostic Modality Suggests Asthma Other Differential Features
Clinical history Wheezing, coughing, chest tightness Occupational exposures
May only be present or worsened with exertion, upper respiratory Dyspnea only on exertion may suggest COPD
infection, seasonal or perennial allergies Family history is often positive in atopic asthma
Nocturnal cough, particularly 2 AM to 4 AM Seasonal variation of symptoms or asthma severity is
Need for short-acting β2-agonist inhaler for relief of symptoms consistent with atopic asthma
Personal or family history of atopy
Spirometry Airway obstruction evidenced by FEV1:FVC ratio 50 ppb in patients aged ≥12 y Levels >20 may identify omalizumab-responsive patients
Abbreviations: CDC, complete blood cell count; COPD, chronic obstructive pulmonary disease; CT, computed tomography; FEV1, forced expiratory volume in first
second of expiration; FVC, forced vital capacity.
be performed in all patients in whom asthma is a diagnostic Impedance oscillometry, a technique that measures airway re-
consideration. The maximal volume of air forcibly exhaled from the sistance without forced expiration, can measure central and periph-
point of maximal inhalation (forced vital capacity, FVC), the volume eral airway resistance in those patients for whom the forced expi-
of air exhaled during the first second of this maneuver (FEV1), ratory maneuver is difficult or impossible, including elderly
and FEV1:FVC ratio are 3 key measures. An FEV1:FVC ratio less than patients.64 However, there is no consensus on the incremental value
the lower limit of normal (0.7-0.8 in adults, depending on age) of impedance oscillometry over spirometry alone, nor are there suf-
(Figure 2) indicates airway obstruction, although asthma may be ficient data to establish the performance characteristics (sensitiv-
present even without demonstrable airway obstruction (Figure 1). ity, specificity) of oscillometry vs spirometry alone in asthma.
Reversibility of airway obstruction is indicated by an increase in In stable asthma, measurement of arterial blood gas values is
FEV1 of 200 mL or greater and 12% or greater from baseline after rarely necessary, although it may be helpful in cases of acute
inhalation of short-acting β 2 -agonists. In patients who have decompensation and exacerbation. Periodic monitoring of pulse
smoked cigarettes, distinguishing asthma with partially reversible oximetry, with or without exercise, may be useful. Allergy evalua-
obstruction from chronic obstructive pulmonary disease is chal- tion has become increasingly important in recent years, as biologic
lenging and has led to the description of an asthma–chronic agents have become available for treatment. A total serum IgE and
obstructive pulmonary disease overlap syndrome, the existence specific IgE for common aeroallergens may be performed,12,13 as
and clinical importance of which is controversial.60 No validated these tests can guide allergen avoidance strategies and suggest the
approaches for differentiating these entities has been identified. A potential use of anti-IgE monoclonal therapeutics. Allergy skin test-
low diffusing capacity for carbon monoxide suggests an element of ing may be substituted for serum measures of allergen-specific
emphysema rather than asthma. Pulmonary function testing is less IgE. 12 A complete blood cell count with an elevated absolute
informative when performed during exacerbations of asthma and eosinophil count can identify appropriate candidates for anti-IL-5
is best obtained during times of disease stability. therapies (mepolizumab ⱖ150/μL and reslizumab ⱖ400/μL).
Bronchoprovocation with methacholine can be helpful in pa- These diagnostic modalities are summarized in Table 3. The
tients with suspected asthma and normal spirometry because a nega- NAEPP12 presents a severity classification system based on histori-
tive test result makes the diagnosis of asthma unlikely (Figure 1).61 cal features and spirometric measurements, and recently updated
Outside the United States, mannitol may be used as an effective Global Initiative for Asthma (GINA) guidelines are also now
bronchoprovocation agent.62 Methacholine and mannitol used as available.13 Severity classes of intermittent, mild persistent, moder-
bronchoprovocation agents both have a sensitivity of approxi- ate persistent, and severe persistent asthma are defined, and
mately 80% and specificity of approximately 65%.63 severity categorization determines initial therapeutic approaches
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Figure 3. National Asthma Education and Prevention Program Recommendations for Asthma Therapy
Intermittent asthma Persistent asthma: daily medication
Consult with asthma specialist if step 4 care or higher is required.
Consider consultation at step 3.
Step 6
Preferred:
High-dose ICS + LABA
Step 5 + oral corticosteroid
Preferred: And Assess control
High-dose ICS + LABA Consider omalizumab
Step 4 for patients who have Step up if needed
And (first check adherence,
allergies
Preferred: Consider omalizumab environmental
Medium dose ICS + for patients who have control, and comorbid
LABA allergies conditions)
Step 3
Alternative:
Preferred: Step down if possible
Medium dose ICS +
Low-dose ICS + LABA (and asthma is well
either LTRA, or
or controlled at least
Step 2 zileuton
Medium-dose ICS 3 mo)
Preferred: Alternative:
Low-dose ICS Low-dose ICS + either
Step 1 Alternative: LTRA, or zileuton
LTRA
Preferred:
SABA as needed
Each step: Patient education, environmental control, and management of comorbidities.
Steps 2-4: Consider subcutaneous allergen immunotherapy for patients who have allergic asthma.
Quick-relief medication for all patients
• SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to 3 treatments at 20-min intervals as needed.
Short course of oral systemic corticosteroids may be needed.
• Use of SABA >2 d/wk for symptom relief (not prevention of EIB) generally indicates inadequate control and the need to step up treatment.
All patients with asthma should have a rescue inhaler composed of a preferred or alternative therapy. EIB indicates exercise-induced
short-acting β2-agonist (eg, albuterol). Preferred initial therapy is outlined by bronchoconstriction; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist;
step. Periodic reevaluation of asthma symptoms, lung function, and LTRA, leukotriene receptor antagonist; SABA, short-acting β2-agonist.
exacerbations is necessary to guide adjustments in treatment. Alphabetical Figure adapted from NAEPP.12
order is used when more than 1 treatment option is listed within either
(Figure 3). The GINA guidelines also outline assessment of severity important history of smoking or significant occupational expo-
in patients already receiving effective controller therapy.13 sures such as mineral or organic dusts, have persistent symptoms
Asthma symptom control, using validated patient question- despite therapy, or present with long-standing disease may be at risk
naires (Asthma Control Test [ACT], Asthma Quality of Life Ques- for chronic obstructive pulmonary disease or lung cancer.12,13 The
tionnaire [AQLQ], or Asthma Control Questionnaire [ACQ]) to pro- optimal imaging modality has not been established; low-dose, high-
vide a quantitative assessment of symptoms, may be assessed resolution computed tomographic scanning provides considerably
at each visit.12,65,66 (Because asthma symptoms and pulmonary more information than a standard chest radiograph, but with in-
function may not correlate well, measurement of both can inform creased radiation exposure and higher cost.
adjustments to therapy.) Spirometry should be repeated every
1 to 2 years or with clinically significant change of asthma con- Treatment
trol to identify accelerated loss of lung function.12 Home peak The goals of asthma treatment are reducing impairment (reducing
flow monitoring may be useful in some patients for whom routine symptoms, maintaining normal activities, achieving [nearly] normal
office spirometry cannot be performed. Patients with relatively pulmonary function test values) and minimizing risks associated
normal pulmonary function test results, but persistent symptoms with the disease (future exacerbations, medication adverse
(eg, abnormal ACT, ACQ, or AQLQ scores) may be candidates effects). Because of the heterogeneous nature of asthma and the
for intensification of treatment. Persistently abnormal findings limited availability of predictive biomarkers for treatment success,
from pulmonary function tests suggest the need for intensification clinicians must approach patients with a guideline-based plan
of the controller regimen. The utility of routine monitoring of the that recognizes specific environmental triggers and their mitigation
concentration of exhaled nitric oxide has not been established; (eg, allergens, viruses, or irritants encountered in occupational,
however, patients who are not receiving adequate doses of inhaled household, or environmental settings), individual variability in the
steroids may show elevated concentrations (ie, >50 ppb) of dose and particle size of inhaled corticosteroids, the class of long-
exhaled nitric oxide.67 acting bronchodilator (long-acting β2 agonist vs long-acting musca-
There is little evidence to demonstrate the value of routine chest rinic antagonist), and other individual factors to provide an indi-
radiography in asthma. Chest imaging, beginning with a standard vidualized treatment plan. A written asthma action plan that details
2-view chest radiograph, may help to exclude other pulmonary in lay language the signs and symptoms indicating worsening
pathology.12 Patients who are older than 65 years, have a clinically of asthma, such as increased dyspnea or cough, or need for more
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frequent use of the β2 agonist inhaler, and the steps required to and Drug Administration–approved package insert of each long-
mitigate that worsening, is a key component of management. acting β2 agonist contains a black box warning of the increased
Pharmacologic options are classified as either reliever (short- risk of adverse outcomes and death. However, recent prospective
term benefit) or controller (longer-term benefit) medications evidence suggests that long-acting β 2 -agonists, when used
(Table 2). All patients with asthma should have access to a short- appropriately (ie, always in combination with inhaled corticoste-
acting β2 agonist inhaler (commonly albuterol) for treatment of acute roids), do not confer adverse safety consequences and in fact
symptoms; this intervention alone is appropriate for patients with reduce the risk of exacerbations and adverse events in adults with
intermittent asthma, defined as symptoms less than twice weekly moderate to severe asthma compared with inhaled corticoste-
with (near) normal pulmonary function. For patients with persis- roids alone.69
tent asthma (defined as symptoms more than twice weekly or ab- For suboptimally controlled asthma, a physician should search
normal pulmonary function), a daily maintenance controller is gen- for common problems such as incorrect inhaler technique, poor
erally appropriate. The initial choice of medication is directed by adherence, exposure to allergens, exposure to personal or second-
severity of asthma classification (intermittent; mild, moderate, or se- hand tobacco smoke, gastroesophageal reflux, sinusitis, or inter-
vere persistent [Figure 2]) at diagnosis. In the United States, guide- current viral infections. If control is not optimal, intensification of
lines recommend treatment based on 6 steps (Figure 3),12 but the the therapeutic regimen is usually indicated. The precise timing of
GINA guidelines define 5 steps, which are not strictly comparable follow-up visits is a matter of clinical judgment, as no prospective
to the US guidelines.13 trials exist that directly address this question. Follow-up may range
In the US treatment guidelines, step 1 therapy is used for from several days or weeks for patients with very poorly controlled
patients with intermittent asthma and consists of short-acting or severe disease, to months for patients with well-controlled,
β2-agonists, administered as needed. (These agents are also used milder, and stable asthma. Once asthma is well controlled for 2 to 3
for quick symptom relief in all patients with asthma, irrespective months, treatment may be stepped down to the lowest dose of
of severity.) Step 2 therapy is indicated for mild persistent asthma medication that adequately controls symptoms and lung
and preferably consists of low-dose inhaled corticosteroids, function.12,13 Guidelines for deintensification of asthma therapy are
which improve asthma outcomes such as lung function, symp- not as well established as those for intensification, and there are no
toms, and exacerbations7,8,12,13 in a dose-dependent, but not nec- randomized clinical trials of step-down therapy on which to make
essarily dose-proportionate, manner (eg, a doubled dose of specific recommendations.
inhaled corticosteroids will not produce doubled improvement in For patients who continue to have uncontrolled asthma
lung function). The dose response to inhaled corticosteroids var- despite standard inhaled therapies, several parenteral biologic
ies by the outcome measured (symptom reduction, lung function agents (monoclonal antibodies) are available. These agents act sys-
improvement, reduction in exacerbation).12 Inhaled corticoste- temically by influencing the immunopathogenesis of asthma,
roids reduce the infiltration and activation of eosinophils, rather than treating the consequences of inflammation and bron-
TH2 cells, and other inflammatory cells. An oral leukotriene re- chospasm from within the airway, as standard controller therapies
ceptor antagonist may be as effective as inhaled corticosteroids do (Figure 4). The central role of IgE in the pathogenesis of allergic
and is an alternate first-line treatment.68 These agents block the airway disease makes IgE an attractive target for asthma therapy.
action of cysteinyl leukotrienes, key mediators of airway smooth Omalizumab is an anti-IgE monoclonal antibody used in allergic
muscle contraction. asthma accompanied by moderately elevated IgE level (30 to
Patients with moderate persistent asthma should start at step about 1000 IU/mL, depending on body weight) and evidence of
3 therapy with medium-dose inhaled corticosteroids or a combina- sensitization to perennial aeroallergens. It reduces allergen-
tion of low-dose inhaled corticosteroids and a long-acting β2 ago- induced mast cell activation and decreases expression of IgE high-
nist (Table 2). Longer-acting bronchodilators increase airway cali- affinity receptors on mast cells70 (Figure 4). Omalizumab is given
ber for 12 to 24 hours. Spacers (large volume-holding chambers) may by subcutaneous injection every 2 to 4 weeks, at a dose and fre-
improve pulmonary delivery, reduce pharyngeal delivery, and re- quency determined by body weight and serum IgE levels, and is
duce local adverse effects when used with compatible pressurized principally effective in reducing exacerbations and need for oral
metered-dose inhaler systems, particularly for those patients for steroids.70 Retrospective analysis of omalizumab trials suggests
whom consistent coordination of inhalation with actuation of the that serum eosinophil counts in excess of 260/μL and fractional
device is a concern. excretion of nitric oxide of at least 19.5 ppb may identify patients
Patients diagnosed with severe persistent asthma, commonly likely to improve with omalizumab. However, no biomarker has
characterized as near-continuous chest symptoms, the need been subjected to rigorous prospective confirmation to determine
for multiple inhalations daily of rescue β2 agonist, nightly awaken- its predictive value.70 Little improvement in pulmonary function is
ings from asthma symptoms, or FEV1 less than 60% predicted, observed, so lung function testing is not a good monitoring tool to
should start at step 4, 5, or 6 and be referred for consultation with assess omalizumab response. Measurement of serum IgE levels
an asthma specialist (an allergist or pulmonologist).12,13 Medica- after initiating treatment is not useful. The primary clinical out-
tion options for these patients include medium- or high-dose comes by which response may be judged are asthma exacerbations
inhaled corticosteroid plus long-acting β2 agonist combinations, and symptoms.
inhaled long-acting muscarinic agonists (tiotropium),23 and bio- Interleukin 5 is centrally involved in the synthesis, maturation,
logic therapy.11-13 homing, and activation of eosinophils, suggesting a role for anti-
Long-acting bronchodilators should never be prescribed IL-5 in managing eosinophilic airway disease. Anti-IL-5 monoclonal
without an accompanying inhaled corticosteroid. The US Food antibodies (mepolizumab and reslizumab) have recently been
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Figure 4. Contrasting Standard vs Biologic Therapies in Asthma
AIRWAY LUMEN
Biologic therapy Standard therapy
Allergen
Anti-IgE therapy
SMOOTH
EPITHELIUM Omalizumab MUSCLE
Binds free IgE EPITHELIUM
Decreases expression
of FcεR1 receptor Mast cell
B cell Corticosteroids
IgE Degranulation
Allergen processing and and release of Reduce inflammatory
T cell differentiation inflammatory Airway inflammation gene expression
and activation mediators Eosinophilic inflammation
FcεR1 receptor
IL-4
Histamine Antileukotrienes
IL-13 IL-5 Cysteinyl
leukotrienes Montelukast
AIRWAY
Airway Zafirlukast
ILC2 cell activation LUMEN
by epithelial cell hyperresponsiveness Zileuton
TH2 cell Decrease smooth
IL-25 and IL-33
muscle contraction
Cytotoxic Decrease inflammation
Anti-IL-5 therapy proteins
IL-5
IL-5 Bronchoconstriction
Mepolizumab Airway obstruction β2-Agonists
ILC2 cell Reslizumab
IL-5 Antimuscarinics
Binds IL-5
Prevents IL-5 receptor Eosinophil Bronchodilation
activation
Inhibits IL-5 signaling
Airway remodeling
Eosinophil inflammatory response
Eosinophil maturation in bone marrow
BLOOD
VESSEL
Migration through blood vessels
Activation in airway wall
Standard asthma therapy is commonly delivered via the airway, by therapeutic lymphoid cells (ILC2), and by activated mast cells. IL-5 has protean effects on
aerosols of inhaled corticosteroids (ICSs) or bronchodilators, and by design eosinophil poesis, maturation in the bone marrow, emigration into the
have effects largely limited to the environment of the airway. The cysteinyl circulation, migration to sites of inflammation, and activation to produce
leukotriene receptor (type 1) antagonist montelukast (and others) is delivered oxidative damage and toxic eosinophil granule protein release. Mepolizumab
to the airway by the systemic circulation and reduces smooth muscle and reslizumab reduce the activity of IL-5 at all these sites and reduce
contraction and inflammation, particularly that due to activated eosinophils. eosinophilic inflammatory responses. Individually and collectively, airway
Biologic therapy in asthma acts upstream of the inflammatory process in the inflammation, airway hyperresponsiveness, and bronchoconstriction may
airway.11 Omalizumab reduces mast cell activation and release of mediators of produce structural airway changes of increased smooth muscle mass, thickened
bronchoconstriction (principally histamine and cysteinyl leukotrienes) and lamina reticularis, and mucus gland hypertrophy, collectively known as airway
reduces production of proinflammatory cytokines, including IL-5. IL-5 is wall remodeling. It has not been proven than that any asthma therapy reduces
produced by several types of cells, including TH2 lymphocytes and type 2 innate or eliminates airway wall remodeling.
approved in the United States for patients with severe asthma and Special Considerations
peripheral eosinophilia.11 Mepolizumab reduces the rate of exacer- Consultation with an asthma specialist is warranted for patients who
bations by almost 50%; the need for oral corticosteroids is also are at step 4 or higher in the US guideline13 or who have a life-
reduced by 50%, with little effect on lung function.26,27 No specific threatening exacerbation, poor responsiveness to prescribed treat-
level of peripheral blood eosinophilia is listed in the package insert, ment, occupational triggers, atypical presentation, need for more
but the referenced clinical trials required at least 150 eosinophils/μL. than 2 bursts of oral corticosteroids, or who need specialized test-
This level of eosinophilia has not been prospectively assessed as ing for allergies, lung function, or bronchoscopy.12,13 Asthma may pre-
a predictive biomarker of therapeutic response. Mepolizumab sent with symptoms predominantly in association with exercise. The
is administered by injection every 4 weeks, at a standard dose of timing of symptoms is generally within a few minutes of cessation
100 mg subcutaneously. of exercise and is termed “exercise induced bronchospasm.” Pre-
Reslizumab is administered every 4 weeks by intravenous in- treatment with albuterol 15 minutes prior to anticipated exercise can
fusion, using weight-based dosing (3 mg/kg). Reslizumab reduces minimize or eliminate these symptoms.12,13 Management of comor-
the rate of exacerbations by about 50%, reduces symptoms, and bid conditions (allergic rhinitis, sinusitis, gastroesophageal reflux,
improves FEV1 by 110 mL.28,29 Clinical trials referenced in the pack- obstructive sleep apnea) improves asthma control.12,13 Adding ex-
age insert required at least 400 eosinophils/μL for entry, but this re- ercise as a component of lifestyle change in overweight patients with
quirement has not been validated as a predictive biomarker. Both asthma appears to improve asthma control.71
mepolizumab and reslizumab reduce biologic activity of IL-5 in the
pathogenesis of eosinophilic inflammation (Figure 4). Selected Current Controversies
Oral steroids are an effective option for uncontrolled disease and All long-acting β2-agonists marketed in the United States carry a
for asthma exacerbations but have significant adverse effects, in- black box warning for increased risk of death and serious adverse
cluding glucose intolerance, weight gain, and salt and water reten- events, based primarily on results from a large observational study
tion, if used continuously (Table 2). with important limitations in study design.72 More recent evidence
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suggests that the appropriate use of long-acting β2-agonists in that treatment for an extended period will likely be necessary. In
combination with inhaled steroids is not associated with increased patients with mild-moderate asthma whose disease is controlled
serious adverse events.69 Additional well-controlled studies may with a daily regimen of low-medium dose of inhaled corticoste-
clarify this matter. roids, the administration of these agents only at the time that
All biologic agents marketed in the United States require par- short-acting β2-agonists are used for relief of symptoms provides
enteral administration and are costly ($15 000-$30 000 annu- control not different from that achieved with daily inhaled corti-
ally). Omalizumab and reslizumab carry black box warnings for the costeroids, using a reduced dose of inhaled corticosteroids; how-
risk of anaphylaxis, and their use is generally limited to asthma spe- ever, this approach has not yet been incorporated into formal
cialists. No data are available regarding direct comparisons of these guidelines.76
agents, the optimal duration of therapy, or whether combinations Accelerated loss of lung function is seen in some, but not all, pa-
of biologics are superior to individual treatments.11 tients with asthma.77 Loss of lung function is principally observed
Bronchial thermoplasty, a procedure approved in 2010 for se- in patients in whom exacerbations are frequent (2% predicted
vere asthma, delivers radiofrequency energy to the airway. The greater annual loss of FEV1 in patients with exacerbation compared
mechanisms by which this procedure affects the pathogenesis of with those without),78 highlighting the potential importance of pre-
asthma remain unclear; changes in adaptive immunity and airway venting exacerbations. However, no long-term controlled trials hav-
smooth muscle have been suggested but not proven.73 Reduced ex- ing trajectory of lung function as the primary outcome have been
acerbations (50%) and emergency department visits (85%) are seen published, so the effects of guideline-based treatment on loss of lung
for at least 1 year after treatment.74 Trials of up to 5 years were not function remain unclear.
rigorously controlled, so evidence for long-term benefit is limited.30
The GINA,13 but not the NAEPP,12 specify a role for bronchial ther-
moplasty. The American Thoracic Society and European Respira-
Conclusions
tory Society have recommended that bronchial thermoplasty be con-
ducted within the context of a clinical trial or registry.75 Asthma is characterized by variable airway obstruction, airway hy-
perresponsiveness, and airway inflammation. Management of per-
Prognosis sistent asthma requires avoidance of aggravating environmental fac-
Asthma continues to be an important cause of morbidity and some tors, availability of short-acting β2 -agonists for rapid relief of
mortality in the United States (Table 1). Rates of asthma mortality symptoms, and daily use of inhaled corticosteroids. Other control-
are particularly elevated among non-Hispanic African American pa- ler medications, such as long-acting bronchodilators and biologics,
tients (25.4 per million per year) compared with white patients may be required in moderate and severe asthma. Patients with se-
(8.8 per million per year).2 vere asthma generally benefit from consultation with an asthma spe-
Controller agents appear not to modify the natural history of cialist for consideration of additional treatment, including inject-
asthma.12,13 Patients with persistent disease should be counseled able biologic agents.
ARTICLE INFORMATION from the National Center for Advancing 2. Centers for Disease Control and Prevention
Accepted Date: June 6, 2017. Translational Sciences (UL1TR001439). (CDC), National Center for Health Statistics. About
Role of the Funder/Sponsor: The National Center underlying cause of death, 1999-2014. CDC
Author Contributions: Drs McCracken and Calhoun website. https://wonder.cdc.gov/ucd-icd10.html.
had full access to all of the data in the study and for Advancing Translational Siences had no role in
the design and conduct of the study; collection, 2015. Accessed November 30, 2016.
take responsibility for the integrity of the data and
the accuracy of the data analysis. Drs McCracken management, analysis, and interpretation of the 3. Centers for Disease Control and Prevention
and Veeranki contributed equally to this work. data; preparation, review, or approval of the (CDC). Rate of discharges from short-stay hospitals,
Concept and design: All authors. manuscript; and decision to submit the manuscript by age and first-listed diagnosis: United States,
Acquisition, analysis, or interpretation of data: for publication. 2010: National Hospital Discharge Survey. CDC
McCracken, Calhoun. Additional Contributions: We gratefully website. https://www.cdc.gov/nchs/data/nhds
Drafting of the manuscript: All authors. acknowledge the invaluable assistance of Anne /3firstlisted/2010first3_rateage.pdf. Accessed
Critical revision of the manuscript for important Howard (Moody Medical Library, University of November 30, 2016.
intellectual content: All authors. Texas Medical Branch). Ms Howard received no 4. Centers for Disease Control and Prevention
Statistical analysis: Ameredes, Calhoun. additional compensation for her contributions. (CDC). Twenty leading primary diagnosis and
Administrative, technical, or material support: All Submissions: We encourage authors to presence of chronic conditions at emergency
authors. submit papers for consideration as a Review. department visits: United States, 2011: National
Supervision: McCracken, Ameredes, Calhoun. Please contact Edward Livingston, MD, Hospital Ambulatory Medical Care Survey. CDC
Conflict of Interest Disclosures: All authors have at Edward.livingston@jamanetwork.org website. https://www.cdc.gov/nchs/data/ahcd
completed and submitted the ICMJE Form for or Mary McGrae McDermott, MD, /nhamcs_emergency/2011_ed_web_tables.pdf.
Disclosure of Potential Conflicts of Interest. at mdm608@northwestern.edu. Accessed November 30, 2016.
Dr Calhoun reported receiving grant funding from 5. Centers for Disease Control and Prevention
AstraZeneca and the National Institutes of Health; REFERENCES (CDC). Twenty leading primary diagnosis groups for
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