Asthma: Signs and Symptoms

20/11/18 12.
32
emedicine.medscape.com
Asthma
Updated: Oct 24, 2018
Author: Michael J Morris, MD, FACP, FCCP; Chief Editor: Zab Mosenifar, MD, FACP, FCCP
Overview
Practice Essentials
Asthma is a common chronic disease worldwide and affects approximately 26 million persons in the United States. It is
the most common chronic disease in childhood, affecting an estimated 7 million children. The pathophysiology of
asthma is complex and involves airway inflammation, intermittent airflow obstruction, and bronchial
hyperresponsiveness. See the image below.
Pathogenesis of asthma. Antigen presentation by the dendritic cell with the lymphocyte and cytokine response leading
to airway inflammation and asthma symptoms.
Signs and symptoms
Signs and symptoms of asthma include the following:
Wheezing
Coughing
Shortness of breath
https://emedicine.medscape.com/article/296301-print Page 1 of 57
20/11/18 12.32
Chest tightness/pain
Other nonspecific symptoms in infants or young children may be a history of recurrent bronchitis, bronchiolitis, or
pneumonia; a persistent cough with colds; and/or recurrent croup or chest rattling.
See Clinical Presentation for more detail.
Diagnosis
Updated guidelines from the National Asthma Education and Prevention Program (NAEPP) highlight the importance of
correctly diagnosing asthma, by establishing the following[1] :
Episodic symptoms of airflow obstruction are present
Airflow obstruction or symptoms are at least partially reversible
Exclusion of alternative diagnoses
Spirometry with postbronchodilator response should be obtained as the primary test to establish the asthma diagnosis.
Pulse oximetry measurement is desirable in all patients with acute asthma to exclude hypoxemia. The chest
radiograph remains the initial imaging evaluation in most individuals with symptoms of asthma, but in most patients
with asthma, chest radiography findings are normal or may indicate hyperinflation. Exercise spirometry is the standard
method for assessing patients with exercise-induced bronchoconstriction.
See Workup for more detail.
Management
For all but the most severely affected patients, the ultimate goal is to prevent symptoms, minimize morbidity from acute
episodes, and prevent functional and psychological morbidity to provide a healthy (or near healthy) lifestyle appropriate
to the age of child.
Pharmacologic treatment
Pharmacologic management includes the use of relief and control agents. Control agents include inhaled
corticosteroids, long-acting bronchodilators (beta-agonists and anticholinergics), theophylline (Theo-24, Theochron,
Uniphyl), leukotriene modifiers, anti-IgE antibodies, and IL-5 antibodies. Relief medications include short-acting
bronchodilators, systemic corticosteroids, and ipratropium (Atrovent).
The pharmacologic treatment of asthma is based on stepwise therapy. Asthma medications should be added or
deleted as the frequency and severity of the patient's symptoms change.
Allergen avoidance
Environmental exposures and irritants can play a strong role in symptom exacerbations. The use of skin testing or in
vitro testing to assess sensitivity to perennial indoor allergens is important. Once the offending allergens are identified,
counsel patients on how to avoid them. Efforts should focus on the home, where specific triggers include dust mites,
animals, cockroaches, mold, and pollen.
See Treatment and Medication for more detail.
Background
Asthma is a common chronic disease worldwide and affects approximately 26 million persons in the United States. It is
the most common chronic disease in childhood, affecting an estimated 7 million children, and it is a common cause of
hospitalization for children in the United States.
The pathophysiology of asthma is complex and involves airway inflammation, intermittent airflow obstruction, and
bronchial hyperresponsiveness. The mechanism of inflammation in asthma may be acute, subacute, or chronic, and
the presence of airway edema and mucus secretion also contributes to airflow obstruction and bronchial reactivity.
20/11/18 12.32
Varying degrees of mononuclear cell and eosinophil infiltration, mucus hypersecretion, desquamation of the epithelium,
smooth muscle hyperplasia, and airway remodeling are present.[2, 3]
Airway hyperresponsiveness or bronchial hyperreactivity in asthma is an exaggerated response to numerous

exogenous and endogenous stimuli. The mechanisms involved include direct stimulation of airway smooth muscle and
indirect stimulation by pharmacologically active substances from mediator-secreting cells such as mast cells or
nonmyelinated sensory neurons. The degree of airway hyperresponsiveness generally correlates with the clinical
severity of asthma.
Spirometry with postbronchodilator response should be obtained as the primary test to establish the asthma diagnosis.
Pulse oximetry measurement is desirable in all patients with acute asthma to exclude hypoxemia. The chest
radiograph remains the initial imaging evaluation in most individuals with symptoms of asthma, but in most patients
with asthma, chest radiography findings are normal or may indicate hyperinflation. Exercise spirometry is the standard
method for assessing patients with exercise-induced bronchospasm.
Physical findings vary with the severity of the asthma and with the absence or presence of an acute episode and its
severity. The severity of asthma is classified as intermittent, mild persistent, moderate persistent, or severe persistent.
Patients with asthma of any level of severity may have mild, moderate, or severe exacerbations.
Pharmacologic management includes the use of relief and control agents. Control agents include inhaled
corticosteroids, long-acting bronchodilators (beta-agonists and anticholinergics), theophylline (Theo-24, Theochron,
Uniphyl), leukotriene modifiers, anti-IgE antibodies, and anti-IL-5 antibodies. Relief medications include short-acting
bronchodilators, systemic corticosteroids, and ipratropium (Atrovent). With severe exacerbations, indications for
hospitalization are based on findings after the patient receives 3 doses of an inhaled bronchodilator. In general,
patients should be assessed every 1-6 months for asthma control.
Anatomy
The airways of the lungs consist of the cartilaginous bronchi, membranous bronchi, and gas-exchanging bronchi
termed the respiratory bronchioles and alveolar ducts. While the first 2 types function mostly as anatomic dead space,
they also contribute to airway resistance. The smallest non-gas-exchanging airways, the terminal bronchioles, are
approximately 0.5 mm in diameter; airways are considered small if they are less than 2 mm in diameter.[4]
Airway structure consists of the following:
Mucosa, which is composed of epithelial cells that are capable of specialized mucous production and a
transport apparatus
Basement membrane
A smooth-muscle matrix extending to the alveolar entrances
Predominantly fibrocartilaginous or fibroelastic-supporting connective tissue.
Cellular elements include mast cells, which are involved in the complex control of releasing histamine and other
mediators. Basophils, eosinophils, neutrophils, and macrophages also are responsible for extensive mediator release
in the early and late stages of bronchial asthma. Stretch and irritant receptors reside in the airways, as do cholinergic
motor nerves, which innervate the smooth muscle and glandular units. In bronchial asthma, smooth muscle contraction
in an airway is greater than that expected for its size if it were functioning normally, and this contraction varies in its
distribution.
Pathophysiology
The 2007 Expert Panel Report 3 (EPR-3) of the National Asthma Education and Prevention Program (NAEPP) noted
several key changes in the understanding of the pathophysiology of asthma[1] :
The critical role of inflammation has been further substantiated, but evidence is emerging for considerable
variability in the pattern of inflammation, thus indicating phenotypic differences that may influence treatment
20/11/18 12.32
responses
Of the environmental factors, allergic reactions remain important. Evidence also suggests a key and expanding
role for viral respiratory infections in these processes
The onset of asthma for most patients begins early in life, with the pattern of disease persistence determined by
early, recognizable risk factors including atopic disease, recurrent wheezing, and a parental history of asthma
Current asthma treatment with anti-inflammatory therapy does not appear to prevent progression of the
underlying disease severity
The pathophysiology of asthma is complex and involves the following components:
Airway inflammation
Intermittent airflow obstruction
Bronchial hyperresponsiveness
Airway inflammation
The mechanism of inflammation in asthma may be acute, subacute, or chronic, and the presence of airway edema and
mucus secretion also contributes to airflow obstruction and bronchial reactivity. Varying degrees of mononuclear cell
and eosinophil infiltration, mucus hypersecretion, desquamation of the epithelium, smooth muscle hyperplasia, and
airway remodeling are present.[2] See the image below.
Pathogenesis of asthma. Antigen presentation by the dendritic cell with the lymphocyte and cytokine response leading
to airway inflammation and asthma symptoms.
Some of the principal cells identified in airway inflammation include mast cells, eosinophils, epithelial cells,
macrophages, and activated T lymphocytes. T lymphocytes play an important role in the regulation of airway
inflammation through the release of numerous cytokines. Other constituent airway cells, such as fibroblasts,
endothelial cells, and epithelial cells, contribute to the chronicity of the disease. Other factors, such as adhesion
molecules (eg, selectins, integrins), are critical in directing the inflammatory changes in the airway. Finally, cell-derived
mediators influence smooth muscle tone and produce structural changes and remodeling of the airway.
The presence of airway hyperresponsiveness or bronchial hyperreactivity in asthma is an exaggerated response to

numerous exogenous and endogenous stimuli. The mechanisms involved include direct stimulation of airway smooth
20/11/18 12.32
muscle and indirect stimulation by pharmacologically active substances from mediator-secreting cells such as mast
cells or nonmyelinated sensory neurons. The degree of airway hyperresponsiveness generally correlates with the
clinical severity of asthma.
A study by Balzar et al reported changes in airway resident mast cell populations from a large group of subjects with
asthma and normal control subjects.[5] A greater proportion of chymase-positive mast cells in the airways and
increased prostaglandin D2 levels were identified as important predictors of severe asthma as compared with other
steroid-treated subjects with asthma.
Chronic inflammation of the airways is associated with increased bronchial hyperresponsiveness, which leads to
bronchospasm and typical symptoms of wheezing, shortness of breath, and coughing after exposure to allergens,
environmental irritants, viruses, cold air, or exercise. In some patients with chronic asthma, airflow limitation may be
only partially reversible because of airway remodeling (hypertrophy and hyperplasia of smooth muscle, angiogenesis,
and subepithelial fibrosis) that occurs with chronic untreated disease.
Airway inflammation in asthma may represent a loss of normal balance between two "opposing" populations of Th
lymphocytes. Two types of Th lymphocytes have been characterized: Th1 and Th2. Th1 cells produce interleukin (IL)-2
and IFN-α, which are critical in cellular defense mechanisms in response to infection. Th2, in contrast, generates a
family of cytokines (IL-4, IL-5, IL-6, IL-9, and IL-13) that can mediate allergic inflammation. A study by Gauvreau et al
found that IL-13 has a role in allergen-induced airway responses.[6]
The current "hygiene hypothesis" of asthma illustrates how this cytokine imbalance may explain some of the dramatic
increases in asthma prevalence in westernized countries.[7] This hypothesis is based on the concept that the immune
system of the newborn is skewed toward Th2 cytokine generation (mediators of allergic inflammation). Following birth,
environmental stimuli such as infections activate Th1 responses and bring the Th1/Th2 relationship to an appropriate
balance. However, unequivocal support for the "hypgiene hypothesis" has not been demonstrated.[8]
Airflow obstruction
Airflow obstruction can be caused by a variety of changes, including acute bronchoconstriction, airway edema, chronic
mucous plug formation, and airway remodeling. Acute bronchoconstriction is the consequence of immunoglobulin E-
dependent mediator release upon exposure to aeroallergens and is the primary component of the early asthmatic
response. Airway edema occurs 6-24 hours following an allergen challenge and is referred to as the late asthmatic
response. Chronic mucous plug formation consists of an exudate of serum proteins and cell debris that may take
weeks to resolve. Airway remodeling is associated with structural changes due to long-standing inflammation and may
profoundly affect the extent of reversibility of airway obstruction.[9]
Airway obstruction causes increased resistance to airflow and decreased expiratory flow rates. These changes lead to
a decreased ability to expel air and may result in hyperinflation. The resulting overdistention helps maintain airway
patency, thereby improving expiratory flow; however, it also alters pulmonary mechanics and increases the work of
breathing.
Bronchial hyperresponsiveness
Hyperinflation compensates for the airflow obstruction, but this compensation is limited when the tidal volume
approaches the volume of the pulmonary dead space; the result is alveolar hypoventilation. Uneven changes in airflow
resistance, the resulting uneven distribution of air, and alterations in circulation from increased intra-alveolar pressure
due to hyperinflation all lead to ventilation-perfusion mismatch. Vasoconstriction due to alveolar hypoxia also
contributes to this mismatch. Vasoconstriction is also considered an adaptive response to ventilation/perfusion
mismatch.
In the early stages, when ventilation-perfusion mismatch results in hypoxia, hypercarbia is prevented by the ready
diffusion of carbon dioxide across alveolar capillary membranes. Thus, patients with asthma who are in the early
stages of an acute episode have hypoxemia in the absence of carbon dioxide retention. Hyperventilation triggered by
the hypoxic drive also causes a decrease in PaCO2. An increase in alveolar ventilation in the early stages of an acute
exacerbation prevents hypercarbia. With worsening obstruction and increasing ventilation-perfusion mismatch, carbon
dioxide retention occurs. In the early stages of an acute episode, respiratory alkalosis results from hyperventilation.
Later, the increased work of breathing, increased oxygen consumption, and increased cardiac output result in
metabolic acidosis. Respiratory failure leads to respiratory acidosis due to retention of carbon dioxide as alveolar
ventilation decreases.
20/11/18 12.32
Etiology
Factors that can contribute to asthma or airway hyperreactivity may include any of the following:
Environmental allergens (eg, house dust mites; animal allergens, especially cat and dog; cockroach allergens;
and fungi)
Viral respiratory tract infections
Exercise, hyperventilation
Gastroesophageal reflux disease
Chronic sinusitis or rhinitis
Aspirin or nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity, sulfite sensitivity
Use of beta-adrenergic receptor blockers (including ophthalmic preparations)
Obesity[10]
Environmental pollutants, tobacco smoke
Occupational exposure
Irritants (eg, household sprays, paint fumes)
Various high- and low-molecular-weight compounds (eg, insects, plants, latex, gums, diisocyanates,
anhydrides, wood dust, and fluxes; associated with occupational asthma)
Emotional factors or stress
Perinatal factors (prematurity and increased maternal age; maternal smoking and prenatal exposure to tobacco
smoke; breastfeeding has not been definitely shown to be protective)
Aspirin-induced asthma
The triad of asthma, aspirin sensitivity, and nasal polyps affects 5-10% of patients with asthma. Most patients
experience symptoms during the third to fourth decade. A single dose can provoke an acute asthma exacerbation,
accompanied by rhinorrhea, conjunctival irritation, and flushing of the head and neck. It can also occur with other
nonsteroidal anti-inflammatory drugs and is caused by an increase in eosinophils and cysteinyl leukotrienes after
exposure.[11]
A study by Beasley et al demonstrated some epidemiological evidence that exposure to acetaminophen is associated
with an increased risk of asthma.[12] However, no clinical studies have directly linked asthma symptoms with
acetaminophen use.
Primary treatment is avoidance of these medications, but leukotriene antagonists have shown promise in treatment,
allowing these patients to take daily aspirin for cardiac or rheumatic disease. Aspirin desensitization has also been
reported to decrease sinus symptoms, allowing daily dosing of aspirin.[13]
Gastroesophageal reflux disease
The presence of acid in the distal esophagus, mediated via vagal or other neural reflexes, can significantly increase
airway resistance and airway reactivity. Patients with asthma are 3 times more likely to also have GERD.[14] Some
people with asthma have significant gastroesophageal reflux without esophageal symptoms. Gastroesophageal reflux
was found to be a definite asthma-causing factor (defined by a favorable asthma response to medical antireflux
therapy) in 64% of patients; clinically silent reflux was present in 24% of all patients.[14]
Work-related asthma
Occupational factors are associated with 10-15% of adult asthma cases. More than 300 specific occupational agents
20/11/18 12.32
have been associated with asthma. High-risk jobs include farming, painting, janitorial work, and plastics manufacturing.
Given the prevalence of work-related asthma, the American College of Chest Physicians (ACCP) supports
consideration of work-related asthma in all patients presenting with new-onset or worsening asthma. An ACCP
consensus statement defines work-related asthmas as including occupational asthma (ie, asthma induced by
sensitizer or irritant work exposures) and work-exacerbated asthma (ie, preexisting or concurrent asthma worsened by
work factors).[15]
Two types of occupational asthma are recognized: immune-related and non-immune-related. Immune-mediated
asthma has a latency of months to years after exposure. Non-immune-mediated asthma, or irritant-induced asthma
(reactive airway dysfunction syndrome), has no latency period and may occur within 24 hours after an accidental
exposure to high concentrations of respiratory irritants. Pay careful attention to the patient's occupational history.
Those with a history of asthma who report worsening of symptoms during the week and improvement during the
weekends should be evaluated for occupational exposure. Peak-flow monitoring during work (optimally, at least 4
times a day) for at least 2 weeks and a similar period away from work is one recommended method to establish the
diagnosis.[15]
To see complete information on Allergic and Environmental Asthma, please go to the main article by clicking here.
Viral exposure in children
Evidence suggests that rhinovirus illness during infancy is a significant risk factor for the development of wheezing in
preschool children and a frequent trigger of wheezing illnesses in children with asthma.[16] Human rhinovirus C
(HRVC) is a newly identified genotype of HRV found in patients with respiratory tract infections. A study of children with
acute asthma who presented to the emergency department found HRVC present in the majority of patients. The
presence of HRVC was also associated with more severe asthma.[17]
Approximately 80-85% of childhood asthma episodes are associated with prior viral exposure. Prior childhood
pneumonia due to infection by respiratory syncytial virus, Mycoplasma pneumoniae, and/or Chlamydia species was
found in more than 50% of a small sample of children aged 7-9 years who later had asthma.[18] Treatment with
antibiotics appropriate for these organisms improves the clinical signs and symptoms of asthma.
Sinusitis
Of patients with asthma, 50% have concurrent sinus disease. Sinusitis is the most important exacerbating factor for
asthma symptoms. Either acute infectious sinus disease or chronic inflammation may contribute to worsening airway
symptoms. Treatment of nasal and sinus inflammation reduces airway reactivity. Treatment of acute sinusitis requires
at least 10 days of antibiotics to improve asthma symptoms.[19]
Exercise-induced asthma
Exercise-induced asthma (EIA), or exercise-induced bronchoconstriction (EIB), is an asthma variant defined as a

condition in which exercise or vigorous physical activity triggers acute bronchoconstriction in persons with heightened
airway reactivity. It is observed primarily in persons who have asthma (exercise-induced bronchoconstriction in
asthmatic persons) but can also be found in patients with normal resting spirometry findings with atopy, allergic rhinitis,
or cystic fibrosis and even in healthy persons, many of whom are elite or cold weather athletes (exercise-induced
bronchoconstriction in athletes). Exercise-induced bronchoconstriction is often a neglected diagnosis, and the
underlying asthma may be silent in as many as 50% of patients, except during exercise.[20, 21]
The pathogenesis of exercise-induced bronchoconstriction is controversial. The disease may be mediated by water
loss from the airway, heat loss from the airway, or a combination of both. The upper airway is designed to keep
inspired air at 100% humidity and body temperature at 37°C (98.6°F). The nose is unable to condition the increased
amount of air required for exercise, particularly in athletes who breathe through their mouths. The abnormal heat and
water fluxes in the bronchial tree result in bronchoconstriction, occurring within minutes of completing exercise. Results
from bronchoalveolar lavage studies have not demonstrated an increase in inflammatory mediators. These patients
generally develop a refractory period, during which a second exercise challenge does not cause a significant degree of
bronchoconstriction.
Factors that contribute to exercise-induced bronchoconstriction symptoms (in both persons with asthma and athletes)
include the following:
Exposure to cold or dry air
20/11/18 12.32
Environmental pollutants (eg, sulfur, ozone)
level of bronchial hyperreactivity
Chronicity of asthma and symptomatic control
Duration and intensity of exercise
Allergen exposure in atopic individuals
Coexisting respiratory infection
The assessment and diagnosis of exercise-induced bronchoconstriction is made more often in children and young
adults than in older adults and is related to high levels of physical activity. Exercise-induced bronchoconstriction can be
observed in persons of any age based on the level of underlying airway reactivity and the level of physical exertion.
Genetics
Research on genetic mutations casts further light on the synergistic nature of multiple mutations in the pathophysiology
of asthma. Polymorphisms in the gene that encodes platelet-activating factor hydrolase, an intrinsic neutralizing agent
of platelet-activating factor in most humans, may play a role in susceptibility to asthma and asthma severity.[22]
Evidence suggests that the prevalence of asthma is reduced in association with certain infections (Mycobacterium
tuberculosis, measles, or hepatitis A); rural living; exposure to other children (eg, presence of older siblings and early
enrollment in childcare); and less frequent use of antibiotics. Furthermore, the absence of these lifestyle events is
associated with the persistence of a Th2 cytokine pattern. Under these conditions, the genetic background of the child,
with a cytokine imbalance toward Th2, sets the stage to promote the production of immunoglobulin E (IgE) antibody to
key environmental antigens (eg, dust mites, cockroaches, Alternaria, and possibly cats). Therefore, a gene-by-
environment interaction occurs in which the susceptible host is exposed to environmental factors that are capable of
generating IgE, and sensitization occurs.
A reciprocal interaction is apparent between the 2 subpopulations, in which Th1 cytokines can inhibit Th2 generation
and vice versa. Allergic inflammation may be the result of an excessive expression of Th2 cytokines. Alternatively,
studies suggest the possibility that the loss of normal immune balance arises from a cytokine dysregulation in which
Th1 activity in asthma is diminished.[23]
In addition, some studies highlight the importance of genotypes in children's susceptibility to asthma and response to
specific antiasthma medications.[24, 25, 26, 27]
Obesity
A study by Cottrell et al explored the relationship between asthma, obesity, and abnormal lipid and glucose
metabolism.[28] The study found that community-based data linked asthma, body mass, and metabolic variables in
children. Specifically, these findings described a statistically significant association between asthma and abnormal lipid
and glucose metabolism beyond body mass association. Evidence is accumulating that individuals with a high body
mass index have worse asthma control and sustained weight loss improves asthma control.[29]
Accelerated weight gain in early infancy is associated with increased risks of asthma symptoms according to one study
of preschool children.[30]
Epidemiology
Asthma affects 5-10% of the population or an estimated 23.4 million persons, including 7 million children.[15] The
overall prevalence rate of exercise-induced bronchospasm is 3-10% of the general population if persons who do not
have asthma or allergy are excluded, but the rate increases to 12-15% of the general population if patients with
underlying asthma are included. Asthma affects an estimated 300 million individuals worldwide. Annually, the World
Health Organization (WHO) has estimated that 15 million disability-adjusted life-years are lost and 250,000 asthma
deaths are reported worldwide.[31]
In the United States, asthma prevalence, especially morbidity and mortality, is higher in blacks than in whites. Although
20/11/18 12.32
genetic factors are of major importance in determining a predisposition to the development of asthma, environmental
factors play a greater role than racial factors in asthma onset. A national concern is that some of the increased
morbidity is due to differences in asthma treatment afforded certain minority groups. Larger asthma-associated lung
function deficits are reported in Hispanics, especially females.[32]
Asthma is common in industrialized nations such as Canada, England, Australia, Germany, and New Zealand, where
much of the asthma data have been collected. The prevalence rate of severe asthma in industrialized countries ranges
from 2-10%. Trends suggest an increase in both the prevalence and morbidity of asthma, especially in children
younger than 6 years. Factors that have been implicated include urbanization, air pollution, passive smoking, and
change in exposure to environmental allergens.
Asthma predominantly occurs in boys in childhood, with a male-to-female ratio of 2:1 until puberty, when the male-to-
female ratio becomes 1:1. Asthma prevalence is greater in females after puberty, and the majority of adult-onset cases
diagnosed in persons older than 40 years occur in females. Boys are more likely than girls to experience a decrease in
symptoms by late adolescence.
Asthma prevalence is increased in very young persons and very old persons because of airway responsiveness and
lower levels of lung function.[33] Two thirds of all asthma cases are diagnosed before the patient is aged 18 years.
Approximately half of all children diagnosed with asthma have a decrease or disappearance of symptoms by early
adulthood.[34]
Prognosis
International asthma mortality is reported as high as 0.86 deaths per 100,000 persons in some countries. US asthma
mortality rates in 2009 were reported at 1 death per 100,000 persons. Mortality is primarily related to lung function,
with an 8-fold increase in patients in the lowest quartile, but mortality has also been linked with asthma management
failure, especially in young persons. Other factors that impact mortality include age older than 40 years, cigarette
smoking more than 20 pack-years, blood eosinophilia, forced expiratory volume in one second (FEV1) of 40-69%
predicted, and greater reversibility.[35]
The estimate of lost work and school time from asthma is approximately 100 million days of restricted activity.
Approximately 500,000 annual hospitalizations (40.6% in individuals aged 18 y or younger) are due to asthma. Each
year, an estimated 1.7 million people (47.8% of them aged 18 years or younger) require treatment in an emergency
department.[36] For 2010, the annual expenditures for health and lost productivity due to asthma was projected to be
$20.7 billion.[37]
Nearly one half of children diagnosed with asthma will have a decrease in symptoms and require less treatment by late
adolescence or early adulthood. In a study of 900 children with asthma, 6% required no treatment after 1 year, and
39% only required intermittent treatment.
Patients with poorly controlled asthma develop long-term changes over time (i.e., with airway remodeling). This can
lead to chronic symptoms and a significant irreversible component to their disease. Many patients who develop asthma
at an older age also tend to have chronic symptoms.
Patient Education
The need for patient education about asthma and the establishment of a partnership between patient and clinician in
the management of the disease was emphasized by EPR-3.[1]
The key points of education include the following:
Patient education should be integrated into every aspect of asthma care
All members of the healthcare team, including nurses, pharmacists, and respiratory therapists, should provide
education.
Clinicians should teach patients asthma self-management based on basic asthma facts, self-monitoring
20/11/18 12.32
techniques, the role of medications, inhaler use, and environmental control measures.[38, 39, 40]
Treatment goals should be developed for the patient and family.
A written, individualized, daily self-management plan should be developed.
Several well-validated asthma action plans are now available and are key in the management of asthma and
should therefore be reviewed: ACT (Asthma Control Test), ATAQ (Asthma Therapy Assessment Questionnaire),
and ACQ (Asthma Control Questionnaire).[41]
School-based asthma education programs improved knowledge of asthma, self-efficacy, and self-management
behaviors in children aged 4-17 years, according to a systematic literature review by Coffman et al, but the programs
had less effect on quality of life, days of symptoms, nights with symptoms, and school absences.[42]
The 2009 Veterans Administration/Department of Defense (VA/DoD) clinical practice guideline for management of
asthma in children and adults concurs with EPR-3 in recommending self-management education for both the patient
and caregiver as part of the treatment program.[43]
For patient education resources, visit the Asthma Center. Also, see the patient education articles Asthma, Asthma
FAQs, Asthma in Children, and Understanding Asthma Medications.
A patient education video of an overview of asthma is provided below.
Asthma is characterized by chronic inflammation and asthma exacerbations, where an environmental trigger initiates
inflammation, which makes it difficult to breathe. This video covers the pathophysiology of asthma, signs and
symptoms, types, and treatment.
Presentation
History
A detailed assessment of the medical history should address the following:
Whether symptoms are attributable to asthma
Whether findings support the likelihood of asthma (eg, family history)
Asthma severity
Identification of possible precipitating factors
Family history may be pertinent for asthma, allergy, sinusitis, rhinitis, eczema, and nasal polyps. The social history may
include home characteristics, smoking, workplace or school characteristics, educational level, employment, social
support, factors that may contribute to nonadherence of asthma medications, and illicit drug use.
The patient’s exacerbation history is important with respect to the following:
Usual prodromal signs or symptoms
Rapidity of onset
Associated illnesses
Number in the last year
Need for emergency department visits, hospitalizations, ICU admissions, intubations
Missed days from work or school or activity limitation
20/11/18 12.32
The patient’s perception of his or her asthma is important regarding knowledge of asthma and treatment, use of
medications, coping mechanisms, family support, and economic resources.
General manifestations of asthma
Wheezing, a musical, high-pitched, whistling sound produced by airflow turbulence, is one of the most common
symptoms. In the mildest form, wheezing is only end expiratory. As severity increases, the wheeze lasts throughout
expiration. In a more severe asthmatic episode, wheezing is also present during inspiration. During a most severe
episode, wheezing may be absent because of the severe limitation of airflow associated with airway narrowing and
respiratory muscle fatigue.
Asthma can occur without wheezing when obstruction involves predominantly the small airways. Thus, wheezing is not
necessary for the diagnosis of asthma. Furthermore, wheezing can be associated with other causes of airway
obstruction, such as cystic fibrosis and heart failure. Patients with vocal cord dysfunction, now referred to as inducible
laryngeal obstruction (ILO), have a predominantly inspiratory monophonic wheeze (different from the polyphonic
wheeze in asthma), which is heard best over the laryngeal area in the neck. Patients with excessive dynamic airway
collapse (EDAC), bronchomalacia, or tracheomalacia also have an expiratory monophonic wheeze heard over the
large airways. In exercise-induced bronchoconstriction, wheezing may be present after exercise, and in nocturnal
asthma, wheezing is present during the night.
Cough may be the only symptom of asthma, especially in cases of exercise-induced or nocturnal asthma. Usually, the
cough is nonproductive and nonparoxysmal. Children with nocturnal asthma tend to cough after midnight and during
the early hours of morning. Chest tightness or a history of tightness or pain in the chest may be present with or without
other symptoms of asthma, especially in exercise-induced or nocturnal asthma.
Other nonspecific symptoms in infants or young children may be a history of recurrent bronchitis, bronchiolitis, or
pneumonia; a persistent cough with colds; and/or recurrent croup or chest rattling. Most children with chronic or
recurrent bronchitis have asthma. Asthma is also the most common underlying diagnosis in children with recurrent
pneumonia; older children may have a history of chest tightness and/or recurrent chest congestion.
Exercise-induced bronchoconstriction
In patients with exercise-induced bronchoconstriction, the clinical history findings are typical of asthma but are
associated only with exercise. Typical symptoms include cough, wheezing, shortness of breath, and chest pain or
tightness. Some individuals also may report sore throat or GI upset. Initially, airway dilation is noted during exercise. If
exercise continues beyond approximately 10 minutes, bronchoconstriction supervenes, resulting in asthma symptoms.
If the exercise period is shorter, symptoms may develop up to 5-10 minutes after completion of exercise. Higher
intensity levels of exercise result in a more intense attack, with running producing more symptoms than walking.
Patients may note asthma symptoms are related to seasonal changes or the ambient temperature and humidity in the
environment in which a patient exercises. Other triggers may be pollutants (eg, sulfur, nitrous oxide, ozone) or upper
respiratory tract infections. Cold, dry air generally provokes more obstruction than warm, humid air. Consequently,
many athletes have good exercise tolerance in sports such as swimming. A prospective longitudinal study in Britain
found that swimming was associated with increased lung function and lower risk of asthma-related symptoms,
especially among children with respiratory conditions.[44]
Athletes who are more physically fit may not notice the typical asthma symptoms and may report only a reduced or
more limited level of endurance. Several modifiers in the history should prompt an evaluation for causes other than
exercise-induced bronchoconstriction. While patients may report typical obstructive symptoms, a history of a choking
sensation with exercise, inspiratory wheezing, or stridor should prompt an evaluation for evidence of vocal cord
dysfunction.
Physical Examination
The guidelines from the National Asthma Education and Prevention Program highlight the importance of correctly
diagnosing asthma, by establishing the following[1] :
Episodic symptoms of airflow obstruction are present
20/11/18 12.32
Airflow obstruction or symptoms are at least partially reversible
Exclusion of alternative diagnoses.
Manifestations of an acute episode
Acute episodes can be mild, moderately severe, severe, or characterized by imminent respiratory arrest.
Mild episodes
During a mild episode, patients may be breathless after physical activity such as walking; they can talk in sentences
and lie down; and they may be agitated. Patients with mild acute asthma are able to lie flat. In a mild episode, the
respiratory rate is increased, and accessory muscles of respiration are not used. The heart rate is less than 100 bpm,
and pulsus paradoxus (an exaggerated fall in systolic blood pressure during inspiration) is not present. Auscultation of
the chest reveals moderate wheezing, which is often end expiratory. Rapid forced expiration may elicit wheezing that is
otherwise inaudible, and oxyhemoglobin saturation with room air is greater than 95%.
Moderately severe episodes
In a moderately severe episode, the respiratory rate also is increased. Typically, accessory muscles of respiration are
used. In children, also look for supraclavicular and intercostal retractions and nasal flaring, as well as abdominal
breathing. The heart rate is 100-120 bpm. Loud expiratory wheezing can be heard, and pulsus paradoxus may be
present (10-20 mm Hg). Oxyhemoglobin saturation with room air is 91-95%. Patients experiencing a moderately
severe episode are breathless while talking, and infants have feeding difficulties and a softer, shorter cry. In more
severe cases, the patient assumes a sitting position.
Severe episodes
In a severe episode, patients are breathless during rest, are not interested in eating, sit upright, talk in words rather
than sentences, and are usually agitated. In a severe episode, the respiratory rate is often greater than 30 per minute.
Accessory muscles of respiration are usually used, and suprasternal retractions are commonly present. The heart rate
is more than 120 bpm. Loud biphasic (expiratory and inspiratory) wheezing can be heard, and pulsus paradoxus is
often present (20-40 mm Hg). Oxyhemoglobin saturation with room air is less than 91%. As the severity increases, the
patient increasingly assumes a hunched-over sitting position with the hands supporting the torso, termed the tripod
position.
Imminent respiratory arrest
When children are in imminent respiratory arrest, in addition to the aforementioned symptoms, they are drowsy and
confused, but adolescents may not have these symptoms until they are in frank respiratory failure. In status
asthmaticus with imminent respiratory arrest, paradoxical thoracoabdominal movement occurs. Wheezing may be
absent (associated with most severe airway obstruction), and severe hypoxemia may manifest as bradycardia. Pulsus
paradoxus noted earlier may be absent; this finding suggests respiratory muscle fatigue.
As the episode becomes more severe, profuse diaphoresis occurs, with the diaphoresis presenting concomitantly with
a rise in PCO2 and hypoventilation. In the most severe form of acute asthma, patients may struggle for air, act
confused and agitated, and pull off their oxygen, stating, "I can’t breathe." These are signs of life-threatening hypoxia.
With advanced hypercarbia, bradypnea, somnolence, and profuse diaphoresis may be present; almost no breath
sounds may be heard; and the patient is willing to lie recumbent.
Nonpulmonary Manifestations
Signs of atopy or allergic rhinitis, such as conjunctival congestion and inflammation, ocular shiners, a transverse
crease on the nose due to constant rubbing associated with allergic rhinitis, and pale violaceous nasal mucosa due to
allergic rhinitis, may be present in the absence of an acute episode, such as during an outpatient visit between acute
episodes. Turbinates may be erythematous or boggy. Polyps may be present.
Skin examination may reveal atopic dermatitis, eczema, or other manifestations of allergic skin conditions. Clubbing of
the fingers is not a feature of asthma and indicates a need for more extensive evaluation and workup to exclude other
conditions, such as cystic fibrosis.
20/11/18 12.32
Nocturnal Symptoms
A large percentage of patients with asthma experience nocturnal symptoms once or twice a month. Some patients only
experience symptoms at night and have normal pulmonary function in the daytime. This is due, in part, to the
exaggerated response to the normal circadian variation in airflow. Children with nocturnal asthma tend to cough after
midnight and during the early hours of morning.
Bronchoconstriction is highest between the hours of 4:00 am and 6:00 am (the highest morbidity and mortality from
asthma is observed during this time). These patients may have a more significant decrease in cortisol levels or
increased vagal tone at night. Studies also show an increase in inflammation compared with controls and with patients
with daytime asthma.
Staging
Asthma severity is defined as "the intensity of the disease process" prior to initiating therapy and helps in determining
the initiation of therapy in a patient who is not on any controller medications.[1]
The severity of asthma is classified as the following:
Intermittent,
Mild persistent
Moderate persistent
Severe persistent
Patients with asthma of any level of severity may have mild, moderate, or severe exacerbations. Some patients with
intermittent asthma have severe and life-threatening exacerbations separated by episodes with almost normal lung
function and minimal symptoms; however, they are likely to have other evidence of increased bronchial
hyperresponsiveness (BHR; exercise or challenge testing) due to ongoing inflammation.
An important point to remember is that the presence of one severe feature is sufficient to diagnose severe persistent
asthma. Also, the characteristics in this classification system are general and may overlap because asthma severity
varies widely. A patient’s classification may change over time.
DDx
Diagnostic Considerations
Vocal cord dysfunction or inducible laryngeal obstruction (ILO)

Vocal cord dysfunction may exist alone or with asthma, it is caused by paradoxical adduction of the vocal cords during
inspiration, and may disappear with panting, speech, or laughing.[45] Patients with chronic symptoms suggestive of
asthma, normal spirometry, poor response to asthma medications, and frequent evaluations should be evaluated for
vocal cord dysfunction.[46] Usually, the diagnosis can be made using direct laryngoscopy, but only during symptomatic
periods or after exercise. The presence of flattening of the inspiratory limb of the flow-volume loop may also suggest
vocal cord dysfunction, but this is only seen in 28% of patients at baseline.[47]
Tracheal and bronchial lesions

A variety of airway tumors are reported to manifest with symptoms similar to those of asthma. These tumors include
endobronchial carcinoid and mucoepidermoid tumors, as shown in the images below. In one case, a 14-year-old boy
20/11/18 12.32
with hyperlucency in the left lung was ultimately found to have a bronchial carcinoid in the left mainstem bronchus.[48]
Asthma. High-resolution CT scan of the thorax obtained during inspiration in a patient with recurrent left lower lobe
pneumonia shows a bronchial mucoepidermoid carcinoma (arrow).
Asthma. High-resolution CT scan of the thorax obtained during expiration in a patient with recurrent left lower lobe
pneumonia shows a bronchial mucoepidermoid carcinoma. Note the normal increase in right lung attenuation during
expiration (right arrow). The left lung remains lucent, especially the upper lobe, secondary to bronchial obstruction with
airtrapping (left upper arrow). The vasculature on the left is diminutive, secondary to reflex vasoconstriction. Left
pleural thickening and abnormal linear opacities are noted in the left lower lobe; these are the result of prior episodes
of postobstructive pneumonia (left lower arrow).
Other tracheal lesions can include bronchocentric granulomatosis, subglottic stenosis, subglottic web, tracheal
hamartoma, bronchogenic cysts, leiomyoma, and tracheobronchopathia osteoplastica. All these types of tracheal
lesions have been reported with symptoms similar to asthma.
Foreign bodies
Foreign body aspiration may cause not only localized wheezing but also generalized wheezing. Wheezing occurs in
toddlers as well as in adults. As described in one patient, foreign body aspiration may necessitate bronchoscopic
retrieval before the patient even recalls the inciting event, and as many as 25% of patients may never recall the event.
[49] Furthermore, aspirated foreign bodies may be radiolucent and therefore not be visible on a chest radiograph.
Radiography may show unilateral hyperinflation (from air trapping), infiltrate (from occlusion of a bronchus), or may be
normal.
20/11/18 12.32
Pulmonary migraine
Pulmonary migraine consists of combined recurrent asthma; cough with thick mucoid sputum; lower back pain
radiating to the shoulder; subtotal or total atelectasis of a segment or lobe; and, occasionally, nausea with vomiting.[50]
The symptoms are often accompanied closely in time by focal headache. Spastic narrowing of the bronchi is
postulated—along with retained mucous secretions, smooth muscle hypertrophy, and thickened bronchial walls—to
cause expiratory collapse of selected airways. Cerebral and abdominal vascular migraine episodes are believed to
accompany pulmonary migraine.
Congestive heart failure

Congestive heart failure causes engorged pulmonary vessels and interstitial pulmonary edema, which reduce lung
compliance and contribute to the sensation of dyspnea and wheezing. Cardiac asthma is characterized by wheezing
secondary to bronchospasm in congestive heart failure, and it is related to paroxysmal nocturnal dyspnea and
nocturnal coughing.[51]
Diffuse panbronchiolitis
Diffuse panbronchiolitis is prevalent in Japan and the Far East, and it may mimic bronchial asthma with wheezing,
coughing, dyspnea on exertion, and sinusitis.[52] High-resolution CT (HRCT) findings include centrilobular nodules
and linear markings that usually are more profuse than the multifocal bronchiolar impaction sometimes observed with
asthma.
Aortic arch anomalies

Aortic arch anomalies may occur later in adulthood. In one case, the anomalies, which simulated exercise-induced
asthma, were noticed first in a young woman only after a vigorous exercise program.[53] On testing, the flow-volume
display of this patient suggested an intrathoracic obstruction. The patient had a right aortic arch with ligamentum
arteriosum that extended anterior to the trachea. This condition caused constriction when increased pulmonary blood
flow, oxygen demand, and tracheal airflow and decreased intratracheal pressure from downstream turbulence distal to
the tracheal ring occurred with exercise; combined, these factors produced wheezing and dyspnea.
Sinus disease
Sinus disease, especially in children, is associated with bronchial asthma and wheezing. Although the association is
not strong in patients with CT evidence of mild sinus mucosal thickening, a scoring system developed by Newman et al
showed that extensive sinus disease was correlated with a substantially higher extent of wheezing than that in patients
with only mild thickening. Of 104 adults, 39% had extensive disease, as visualized on CT scans, which was correlated
with asthma and peripheral eosinophilia.[54]
Gastroesophageal reflux
Cough, recurrent bronchitis, pneumonia, wheezing, and asthma are associated with gastroesophageal reflux (GER).
[55, 56] The incidence of GER in patients with asthma ranges from 38% in patients with only asthma symptoms to 48%
in patients with recurrent pneumonia. Scintigraphic studies performed after technetium-99m sulfur-colloid ingestion
have shown radionuclide activity in the lungs the next day, but no causal relationship between reflux and asthma has
been established. Nevertheless, evidence suggests that increased pulmonary resistance occurs with symptoms of
reflux during acid provocation testing; as some have suggested, the changes may be sufficiently significant to produce
clinically evident bronchoconstriction.[55]
Other conditions and factors

Other extrinsic conditions, such as lymphadenopathy from sarcoidosis or Hodgkin lymphoma of the upper
mediastinum, can contribute to asthma. In addition, aspirin or NSAID hypersensitivity and reactive airways dysfunction
syndrome may be mistaken for asthma. Misdiagnoses as refractory bronchial asthma has resulted in inappropriate
20/11/18 12.32
long-term treatment with corticosteroids.
A significant history of smoking greater than 20-pack years should make the diagnosis of chronic obstructive
pulmonary disease (COPD) a stronger consideration than asthma.
Consideration for alternative diagnoses should be given in all patients, and in particular in those older than 30 years
and younger than 2 years with new symptoms suggestive of asthma. An absence of airway obstruction on initial
spirometry findings should prompt consideration for alternative diagnoses and additional testing.
Differential Diagnoses
Allergic and Environmental Asthma
Alpha1-Antitrypsin Deficiency
Aspergillosis
Bronchiectasis
Bronchiolitis
Chronic Obstructive Pulmonary Disease (COPD)
Chronic Sinusitis
Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome)
Cystic Fibrosis
Foreign Body Aspiration
Gastroesophageal Reflux Disease
Heart Failure
Pediatric Airway Foreign Body
Pediatric Tracheomalacia
Pulmonary Embolism
Pulmonary Eosinophilia
Sarcoidosis
Upper Respiratory Tract Infection
Vocal Cord Dysfunction
Workup
Workup
Approach Considerations
Laboratory assessments and studies are not routinely indicated for the diagnosis of asthma, but they may be used to
exclude other diagnoses. Eosinophilia and elevated serum IgE levels may help guide therapy in some cases. Arterial
blood gases and pulse oximetry are valuable for assessing severity of exacerbations and following response to
treatment.
20/11/18 12.32
Blood and Sputum Eosinophils

Blood eosinophilia greater than 4% or 300-400/µL supports the diagnosis of asthma, but an absence of this finding is
not exclusionary. Eosinophil counts greater than 8% may be observed in patients with concomitant atopic dermatitis.
This finding should prompt an evaluation for allergic bronchopulmonary aspergillosis, Churg-Strauss syndrome, or
eosinophilic pneumonia.
In assessing asthma control, the British Thoracic Society recommends using sputum eosinophilia determinations to
guide therapy. An improvement in asthma control, a decrease in hospitalizations, and a decrease in exacerbations
were noted in those patients in whom sputum-guided therapy was used.[57] A controlled prospective study has shown
that adjusting inhaled corticosteroid (ICS) treatment to control sputum eosinophilia—as opposed to controlling
symptoms, short-acting beta-agonist (SABA) use, nocturnal awakenings, and pulmonary function—significantly
reduced both the rate of asthma exacerbations and the cumulative dose of inhaled corticosteroids.[58] In 2015,
mepolizumab (anti-IL-5 antibody) was FDA approved for the treatment of severe asthmatics with an eosinophilic
phenotype who have a baseline eosinophil count of 150 cells/µL or an eosinophil count of 300 cells/µL within the past
12 months.
Serum Immunoglobulin E
Total serum immunoglobulin E levels greater than 100 IU are frequently observed in patients experiencing allergic
reactions, but this finding is not specific for asthma and may be observed in patients with other conditions (eg, allergic
bronchopulmonary aspergillosis, Churg-Strauss syndrome). A normal total serum immunoglobulin E level does not
exclude the diagnosis of asthma. Elevated serum IgE levels are required for chronic asthma patients to be treated with
omalizumab (Xolair).
Arterial Blood Gas

Arterial blood gas (ABG) measurement provides important information in acute asthma. This test may reveal
dangerous levels of hypoxemia or hypercarbia secondary to hypoventilation; typically, results are consistent with
respiratory alkalosis. Because of the accuracy and utility of pulse oximetry, only patients whose oxygenation is not
restored to over 90% with oxygen therapy require an ABG. The clinical picture usually obviates ABGs for most ED
patients with acute asthma.
Venous levels of PCO2 have been tested as a substitute for arterial measurements, and a venous PCO2 greater than
45 mm may serve as a screening test but cannot substitute for the ABG evaluation of respiratory function.
Hypercarbia is of concern in that it reflects inadequate ventilation and may indicate the need for mechanical ventilation
if the PCO2 is elevated as a result of patient exhaustion; however, the decision to proceed with endotracheal intubation
and mechanical ventilation is a clinical assessment.
Periostin
Periostin is a novel biomarker that is currently under investigation as a diagnostic and treatment adjunct.[59] Evidence
suggests that periostin is a marker of Th2/eosinophilic inflammation and airway remodeling that occurs with asthma.
While there are no therapies currently approved based on periostin testing, several investigational medications are
being studied with periostin as a predictor of medication effect. In one phase IIb study, periostin was a good predictor
of response to lebrikizumab in patients not controlled on inhaled corticosteroids, with an increase in FEV1 of 8.2% for
high periostin levels compared with placebo with an increase in FEV1 of 1.6% for low periostin levels. Currently, there
is no clinical role for routine periostin testing.
20/11/18 12.32
Pulse Oximetry Assessment

Pulse oximetry measurement is desirable in all patients with acute asthma to exclude hypoxemia. The hypoxemia of
uncomplicated acute asthma is readily reversible by oxygen administration. Oxygenation decreases 4-10 mm Hg with
beta-agonist inhalant therapy due to increases in V/Q mismatch. Therefore, all patients with acute asthma should have
oxygen saturation measured by pulse oximetry, or they simply should be placed on oxygen therapy.
In children, pulse oximetry is often used to grade severity of acute asthma. Oxygen saturation of 97% or above
constitutes mild asthma, 92-97% constitutes moderate asthma, and less than 92% signifies severe asthma. Although
an isolated pulse oximetry reading at triage is not predictive in most cases (with the notable exception of severe
attacks that usually are self-evident on visual inspection), serial monitoring of pulse oximetry status can provide more
subtle evidence for or against the need for hospital admission.
Chest Radiography
The chest radiograph remains the initial imaging evaluation in most individuals with symptoms of asthma. The value of
chest radiography is in revealing complications or alternative causes of wheezing and the minor importance of
wheezing in the diagnosis of asthma and its exacerbations. Chest radiography usually is more useful in the initial
diagnosis of bronchial asthma than in the detection of exacerbations, although it is valuable in excluding complications
such as pneumonia and asthma mimics, even during exacerbations.
In most patients with asthma, chest radiography findings are normal or may indicate hyperinflation. Findings may help
rule out other pulmonary diseases such as allergic bronchopulmonary aspergillosis or sarcoidosis, which can manifest
with symptoms of reactive airway disease. Chest radiography should be considered in all patients being evaluated for
asthma to exclude other diagnoses.
Because pneumonia is one of the most common complications of asthma, chest radiography is indicated in patients
with fever to rule out pneumonia. With new-onset asthma and eosinophilia, a radiograph may be useful in identifying
prominent streaky infiltrates persisting less than 1 month, indicating Loeffler pneumonia. The infiltrates of Loeffler
pneumonia are peripheral with central sparing of the lung fields. These findings have been described as the
radiographic negative of pulmonary edema.
Patients with pleuritic chest pain or those with an acute asthmatic episode that responds poorly to therapy, require a
chest film to exclude pneumothorax or pneumomediastinum, particularly if subcutaneous emphysema is present.
Chest CT Scanning
High-resolution CT (HRCT) is a second-line examination. It is useful in patients with chronic or recurring symptoms
and in those with possible complications such as allergic bronchopulmonary aspergillosis and bronchiectasis.[60] In
the last decade, the role of CT in the imaging of airway disease increased after the development of lung HRCT. The
technical progress of thin-section acquisition, high-spatial-frequency data reconstruction (ie, bone algorithm
technique), and targeted reconstruction has allowed the visualization of finer details on HRCT scans; these details
include airtrapping, measurable bronchial wall thickening, atelectasis, centrilobular nodules due to mucous plugging,
and acinar nodules due to low-grade inflammatory changes.[61]
HRCT findings in bronchial asthma include the following:
Bronchial wall thickening
Bronchial dilatation
Cylindrical and varicose bronchiectasis
Reduced airway luminal area
Mucoid impaction of the bronchi
20/11/18 12.32
Centrilobular opacities, or bronchiolar impaction
Linear opacities
Airtrapping, as demonstrated or exacerbated with expiration
Mosaic lung attenuation, or focal and regional areas of decreased perfusions
Note the images below.
High-resolution CT scan of the thorax obtained during inspiration demonstrates airtrapping in a patient with asthma.
Inspiratory findings are normal.
High-resolution CT scan of the thorax obtained during expiration demonstrates a mosaic pattern of lung attenuation in
a patient with asthma. Lucent areas (arrows) represent areas of airtrapping (same patient as in the previous image).
Electrocardiography
Patients with asthma who are severely symptomatic should undergo ECG monitoring, as with any seriously ill patient.
Sinus tachycardia and ECG evidence of right heart strain are common in patients with acute asthma. The use of beta2
-agonist therapy will cause a paradoxical decrease in heart rate as pulmonary function improves and symptoms are
relieved. Supraventricular tachycardia raises the consideration of theophylline toxicity. Arrhythmias, other than
supraventricular tachycardia, are rare.
20/11/18 12.32
MRI
Aside from cardiovascular applications, MRI of the thorax is used primarily as a problem-solving modality in the workup
of patients with lung, mediastinal, or pleural lesions. MRI is a useful alternative to CT pulmonary angiography in
evaluating possible pulmonary embolic disease in patients in whom iodinated contrast agent cannot be administered
and when the avoidance of ionizing radiation is preferred. In bronchial asthma, the most promising work appears to
involve the use of special paramagnetic gases, which amplify the low signal-to-noise ratio of conventional spin-echo
and gradient-echo techniques by several thousand times. The use of such gases offsets the disadvantages of the
large magnetic susceptibility states with consequent shortened T2 signals induced by the air-alveolar interfaces.
Nuclear Imaging
Nuclear medicine technology has been used in the study of aerosol and particulate distribution in the airways.
Technetium-99m DTPA radioaerosol lung scintigraphy is a classic technique that shows the extent of major airway
distribution, peripheral distribution (depending on particle size), and absorption in the oronasal air passages.
Technetium-99m radioaerosol has been used to show improved peripheral lung distribution of corticosteroid both in
normal persons and in persons treating their asthma using dry-powder inhalers as opposed to pressurized metered-
dose inhalers (pMDIs) with a spacer device. Ventilation scanning with Technetium-99m DTPA has also been used as
an indicator of ventilation defects in asthmatic children.
Allergy Skin Testing

Allergy skin testing is a useful adjunct in individuals with atopy. Results help guide indoor allergen mitigation or help
diagnose allergic rhinitis symptoms. The allergens that most commonly cause asthma are aeroallergens such as
house dust mites, animal danders, pollens, and mold spores. Two methods are available to test for allergic sensitivity
to specific allergens in the environment: allergy skin tests and blood radioallergosorbent tests (RASTs). Allergy
immunotherapy may be beneficial in controlling allergic rhinitis and asthma symptoms for some patients.
Pulmonary Function Testing

Spirometry assessments should be obtained as the primary test to establish the asthma diagnosis. Spirometry should
be performed prior to initiating treatment in order to establish the presence and determine the severity of baseline
airway obstruction.[62] Optimally, the initial spirometry should also include measurements before and after inhalation of
a short-acting bronchodilator in all patients in whom the diagnosis of asthma is considered. Spirometry measures the
forced vital capacity (FVC), the maximal amount of air expired from the point of maximal inhalation, and the forced
expiratory volume in one second (FEV1). A reduced ratio of FEV1 to FVC, when compared with predicted values,
demonstrates the presence of airway obstruction. Reversibility is demonstrated by an increase of 12% and 200 mL
after the administration of a short-acting bronchodilator.
As a preliminary assessment for exercise-induced asthma (EIA), or exercise-induced bronchospasm (EIB), perform
spirometry in all patients with exercise symptoms to determine if any baseline abnormalities (ie, the presence of
obstructive or restrictive indices) are present. The assessment and diagnosis of asthma cannot be based on
spirometry findings alone because many other diseases are associated with obstructive spirometry indices.
Single-breath counting (SBC) is a novel technique for measuring pulmonary function in children. SBC is the
measurement of how far an individual can count using a normal speaking voice after one maximal effort inhalation.
The count is in cadence to a metronome that is set at 2 beats per second. A study by Ali et al determined that SBC
correlates well with standard measures of pulmonary function.[63] However, further studies are needed to establish
values and to evaluate the use in an ED population of patients with acute asthma exacerbation.
20/11/18 12.32
Bronchoprovocation
Methacholine/histamine challenge
Bronchoprovocation testing with either methacholine or histamine is useful when spirometry findings are normal or
near normal, especially in patients with intermittent or exercise-induced asthma symptoms. Bronchoprovocation testing
helps determine if airway hyperreactivity is present, and a negative test result usually excludes the diagnosis of
asthma. Methacholine is a direct stimulant that acts directly on acetylcholine receptors on smooth muscle, causing
contraction and airway narrowing. Methacholine has been reported to have a high sensitivity to identify airway
hyperresponsiveness and a negative test is often used to exclude asthma.
Trained individuals should perform this asthma testing in an appropriate facility and in accordance with the guidelines
of the American Thoracic Society published in 1999.[64] Methacholine is administered in incremental doses up to a
maximum dose of 16 mg/mL, and a 20% decrease in FEV1, up to the 4 mg/mL level, is considered a positive test
result for the presence of bronchial hyperresponsiveness. The presence of airflow obstruction with an FEV1 less than
65-70% at baseline is generally an indication to avoid performing the test.
Eucapnic hyperventilation
Eucapnic hyperventilation with either cold or dry air is an alternative method of bronchoprovocation testing. It has been
used to evaluate patients for exercise-induced asthma and has been shown to produce results similar to those of
methacholine-challenge asthma testing.
Exercise testing
Exercise spirometry is the standard method for assessing patients with exercise-induced bronchoconstricition. Testing
involves 6-10 minutes of strenuous exertion at 85-90% of predicted maximal heart rate and measurement of
postexercise spirometry for 15-30 minutes. The defined cutoff for a positive test result is a 15% decrease in FEV1 after
exercise.
Exercise testing may be accomplished in 3 different ways, using cycle ergometry, a standard treadmill test, or free
running exercise. This method of testing is limited because laboratory conditions may not subject the patient to the
usual conditions that trigger exercise-induced bronchoconstriction symptoms, and results have a lower sensitivity for
asthma than other methods.
Allergen-inhalation challenge
Allergen-inhalation challenges can be performed in selected patients but are generally not needed or recommended.
This test requires an available allergen solution and specialized centers able to handle potentially significant reactions.
A negative test finding may allow continued exposure to an allergen (eg, family pet); a positive test finding can
dramatically indicate that the patient should avoid a particular allergen. This test is often needed to help diagnose
occupational asthma
Mannitol
Mannitol is a provocation test that uses indirect stimuli, causing smooth muscle contraction by release of endogenous
mediators, including prostaglandins, leukotrienes, and histamine. Mannitol is equivalent for the diagnosis of asthma
compared with methacholine but is not currently available for use in the United States.[65]
Peak Flow Monitoring

Peak expiratory flow (PEF) measurement is common in the ED because it is inexpensive and portable. Serial
measurements document response to therapy and, along with other parameters, are helpful in determining whether to
admit the patient to the hospital or discharge from the ED. A limitation of PEF is that it is dependent on effort by the
patient. FEV1 is also effort dependent but less so than PEF. FEV1 is not often used in the ED except in research
settings.
20/11/18 12.32
PEF in the ED can be compared with asymptomatic (baseline) PEF, if known. Unfortunately, patients often do not know
their asymptomatic PEF. Moreover, the reference group for the ideal PEF percent predicted (based on age, sex,
height) may not be accurate for the patient population seen in many inner-city EDs, since most equations are based on
white populations.
Impulse Oscillometry
Impulse oscillometry (IOS) is gaining attention for the evaluation of obstructive lung disease, including asthma. IOS
uses a speaker to produce pressure oscillations within the airway, resulting in measurement of pressure changes and
flows with calculation of resistance, reactance, and resonance. Different frequencies are used to assess large and
small airways, which is helpful to determine where the primary obstruction is occurring. For example, a patient with
asthma would demonstrate increased resistance at 5 Hz (R5, distal airways) with a normal resistance at 20 Hz (R20,
central airways). The primary benefit of IOS is the effort-independent nature of the test, such that small children and
frail adults can easily perform the test. Therefore, in patients unable to perform spirometry or with normal spirometry
but symptoms suggestive of asthma, IOS could be used to determine if there is increased airway resistance or a
bronchodilator response compatible with bronchial hyperreactivity. IOS is also very quickly obtained, but provides no
information on lung volumes or oxygen diffusion capacity. Currently, routine use of IOS is limited by a lack of
universally accepted reference values across all patient populations.
Exhaled Nitric Oxide

Exhaled nitric oxide analysis has been shown to predict airway inflammation and asthma control; however, it is
technically more complex and not routinely used in the monitoring of patients with asthma.
A prospective, controlled study has shown that when inhaled corticosteroid asthma treatment was adjusted to control
the fraction of exhaled nitric oxide, as opposed to controlling the standard indices of asthma, the cumulative dose of
ICS was reduced, with no worsening of the frequency of asthma exacerbations.[66]
Sinus CT Scanning
Sinus CT scanning may be useful to help exclude acute or chronic sinusitis as a contributing factor. In patients with
chronic sinus symptoms, CT scanning of the sinuses can also help rule out chronic sinus disease. Conventional
wisdom regarding the sinus radiographic evaluation of chronic coughing and asthma suggests that a workup for
chronic coughing should be performed first, as outlined in a Finnish study of hospital admissions for acute asthma.
Admission chest radiographs showed abnormalities in 50% of the patients and resulted in treatment changes in 5%.
The numbers were more remarkable when a paranasal sinus series was obtained in unselected patients who
presented primarily because of asthma.
A sinus abnormality of any kind was found in 85% of patients; maxillary sinus abnormalities occurred alone in 63%. In
29% of patients with a sinus abnormality, treatment was immediately altered. All abnormalities were identified on the
Waters view alone, which is 6 times more useful than chest radiography in directing the treatment of acute asthma.[67,
68]
24-Hour pH Monitoring
A 24-hour pH probe can be used to help diagnose gastroesophageal reflux disease (GERD) if a patient’s condition is
refractory to asthma therapy. Empirical medical therapy is often tried without performing diagnostic tests for GERD,
especially if a patient has symptoms of GERD. In cases of GERD, a prolonged trial of therapy may be necessary. The
median time to improvement of GERD-induced cough has been reported as 3 months.[69] A 2012 study of severe
asthmatics demonstrated that GERD was a significant component in these patients.[70]
20/11/18 12.32
Histologic Findings
Asthma is an inflammatory disease characterized by the recruitment of inflammatory cells, vascular congestion,
increased vascular permeability, increased tissue volume, and the presence of an exudate. Eosinophilic infiltration, a
universal finding, is considered a major marker of the inflammatory activity of the disease.
Histologic evaluations of the airways in a typical patient reveal infiltration with inflammatory cells, narrowing of airway
lumina, bronchial and bronchiolar epithelial denudation, and mucus plugs. Additionally, a patient with severe asthma
may have a markedly thickened basement membrane and airway remodeling in the form of subepithelial fibrosis and
smooth muscle hypertrophy or hyperplasia.
Treatment
Approach Considerations
Medical care includes treatment of acute asthmatic episodes and control of chronic symptoms, including nocturnal and
exercise-induced asthmatic symptoms. Pharmacologic management includes the use of control agents such as
inhaled corticosteroids, long-acting bronchodilators (beta-agonists and anticholinergics), theophylline, leukotriene
modifiers, and more recent strategies such as the use of anti-immunoglobulin E (IgE) antibodies (omalizumab) and
anti-IL-5 antibodies in selected patients. Relief medications include short-acting bronchodilators, systemic
corticosteroids, and ipratropium.
For all but the most severely affected patients, the ultimate goal is to prevent symptoms, minimize morbidity from acute
episodes, and prevent functional and psychological morbidity to provide a healthy (or near healthy) lifestyle appropriate
to the age of child.
A stepwise (step-up if necessary and step-down when possible) approach to asthma management continues to be
used in the current guidelines and is now divided into 3 groups based on age (0-4 y, 5-11 y, 12 y and older).[1]
For all patients, quick-relief medications include rapid-acting beta2 agonists as needed for symptoms. The intensity of
treatment depends on the severity of symptoms. If rapid-acting beta2 agonists are used more than 2 days a week for
symptom relief (not including use of rapid-acting beta2 agonists for prevention of exercise-induced symptoms),
stepping up on treatment may need be considered.
A study by Price et al randomly assigned patients to 2 years of open-label therapy with leukotriene antagonists (148
patients) or an inhaled glucocorticoid (158 patients) in the first-line controller therapy trial and a leukotriene antagonist
(170 patients) or long-acting beta-agonists (182 patients) added to an inhaled glucocorticoid in the add-on therapy trial.
[71] The results of these two trials suggests that a leukotriene antagonist is equivalent to both comparison drugs with
regard to asthma-related quality of life at 2 months, but equivalence was not proven at 2 years.
A Cochrane review found that inhaled corticosteroids are superior to anti-leukotrienes when used as monotherapy in
adults and children with persistent asthma. The superiority of inhaled corticosteroids is most pronounced in asthma
patients with moderate airway obstruction.[72] The 2015 Global Initiative for Asthma (GINA) guidelines identify inhaled
corticosteroids as the preferred controller medication of choice for children and adults.
In general, patients should be assessed every 1-6 months for asthma control. At every visit, adherence, environmental
control, and comorbid conditions should be checked. If the patient has good control of their asthma for at least 3
months, treatment can be stepped down; however, the patient should be reassessed in 2-4 weeks to make sure that
control is maintained with the new treatment.
A study by Bruzzese et al assessed the Asthma Self-Management for Adolescents (ASMA) approach, which is a
school-based intervention for adolescents and medical providers.[73] The study found that ASMA helped improve self-
management and reduced morbidity and urgent health care use in low-income, urban, minority adolescents.
Environmental Control
20/11/18 12.32
Environmental exposures and irritants can play a strong role in symptom exacerbations. Therefore, in patients who
have persistent asthma, the use of skin testing or in vitro testing to assess sensitivity to perennial indoor allergens is
important. Once the offending allergens are identified, counsel patients on avoidance from these exposures. In
addition, education to avoid tobacco smoke (both first-hand and second-hand exposure) is important for patients with
asthma.
Allergen avoidance takes different forms, depending on the specific allergen size and characteristic. Improvement in
symptoms after avoidance of the allergen should result rather rapidly, though the allergen itself (eg, cat dander) may
linger in the environment for months after primary removal of the source. A multifaceted approach is necessary, as
individual interventions are rarely successful by themselves.
Comprehensive allergen avoidance during the first year of life effectively prevents the onset of asthma in individuals
with a high genetic risk, with the effect occurring early in childhood and persisting through adulthood, according to one
study. In the trial, 120 children at high risk for allergic disorders were randomized into prophylactic (n=58) and control
(n=62) groups. The infants in the intervention group were either breast fed (with the mother on a low allergen diet) or
given an extensively hydrolyzed formula. The control group followed standard advice. At age 18, a significantly lower
prevalence of asthma was observed in the intervention arm compared to the control group (10.7% and 25.9%,
respectively). An overall reduction in asthma prevalence from 1 to 18 years was also observed in assessments
performed at ages 1, 2, 4, 8 and 18 years.[74]
Efforts should focus on the home, where 30-60% of time is spent. Patients should clean and dust their homes
regularly.[75] If a patient cannot avoid vacuuming, he or she should use a face mask or a double-bagged vacuum with
a high-efficiency particulate air filter. If possible, consideration can be given to moving to a higher floor in the house
(less dust and mold) or different neighborhood (fewer cockroaches). Active smoking and exposure to passive smoke
must be avoided. Room air ionizers have not been proven to be effective for people with chronic asthma, and the
generation of ozone by these machines may be harmful to some. Specific factors related to the home include dust
mites, animals, cockroaches, mold, and pollen (see Indoor Aeroallergens for more details).
Air pollution caused by traffic may increase the risk of asthma and wheezing, especially in individuals with EPHX1
gene and enzyme activity.[76] This can be mediated through airway oxidative stress generation.
Dust mites
In the case of dust mites (Dermatophagoides pteronyssinus and farina, size 30 µm), the primary allergen is an
intestinal enzyme on fecal particles. The allergen settles on fabric because of its relatively large size; therefore, air
filtration is not very effective. Measures to avoid dust mites include using impervious covers (eg, on mattresses,
pillows, comforters, the most important intervention), washing other bedding in hot water (130°F [54.4°C] most
effective), removing rugs from the bedroom, limiting upholstered furniture, reducing the number of window blinds, and
putting clothing away in closets and drawers. Minimize the number of soft toys, and wash them weekly or periodically
put them in the freezer. Decrease room humidity (< 50%).
A Cochrane Review noted that most trials to date have been small and of poor methodologic quality. Therefore,
clinicians cannot easily offer definitive recommendations on the role of house dust mite avoidance measures in the
management of perennial allergic rhinitis that is sensitive to house dust mites. Conclusions from this analysis suggest
that acaricides and extensive bedroom-based environmental control programs may help reduce rhinitis symptoms. If
such measures are considered appropriate, they should be the interventions of choice. However, analysis also
indicated that isolated use of bedding that is impermeable to house dust mites is not likely to be effective in reducing
rhinitis symptoms caused by dust mites.[77]
Animals
Because of the small size (1-20 µm) of dander, saliva, urine, or serum proteins of cats and other animals, these
allergens are predominantly airborne indoor allergens. Avoidance involves removing animals from the home (or at
least from the bedroom), using dense filtering material over heating and cooling duct vents, and washing cats and
dogs as often as twice weekly. The antigens may remain in a home for 6 months or more after cats are removed from
the home, and cat antigen may be found in homes and offices where cats were never present, highlighting the
importance of frequent cleaning.
Cockroaches
Twenty percent of homes without visible infestation still produce sensitizing levels of cockroach allergen (size 30 µm).
20/11/18 12.32
Successful allergen elimination measures are difficult, especially in poor living conditions. To control cockroaches,
exterminate and use poison baits and traps, keep food out of the bedroom, and never leave food out in the open.
Mold
For indoor molds (size 1-150 µm), avoidance includes keeping areas dry (eg, remove carpets from wet floors),
removing old wallpaper, cleaning with bleach products, and storing firewood outdoors.
Pollen
Pollen (size 1-150 µm) avoidance is difficult or impossible, but efforts to reduce exposure include closing windows and
doors, using air conditioning and high-efficiency particulate air filters in the car and home, staying inside during the
midday and afternoon when pollen counts are highest, wearing glasses or sunglasses, and wearing a face mask over
the nose and mouth when mowing the lawn. In addition, consider increasing medications preseason and vacationing in
a different ecosystem during pollen season.
Allergen Immunotherapy
The use of immunotherapy for the treatment of asthma is controversial. Several large, well-conducted studies did not
demonstrate any benefit, but a meta-analysis of 75 randomized controlled trials confirmed efficacy in asthma.[78] The
National Asthma Education and Prevention Program Expert Panel Report recommends that immunotherapy be
considered if the following criteria are fulfilled:
A relationship is clear between symptoms and exposure to an unavoidable allergen to which the patient is
sensitive.
Symptoms occur all year or during a major portion of the year.
Symptoms are difficult to control with pharmacologic management because the medication is ineffective,
multiple medications are required, or the patient is not accepting of medication.
Repeated injections of small doses of allergen have been used for more than almost 100 years to treat allergic rhinitis.
This treatment is clearly effective, and positive effects may persist even years after treatment is stopped. This
treatment is also considered mandatory for life-threatening bee and wasp sting (hymenoptera venom) reactions. The
role of repeated allergen injections in patients with asthma has been more controversial, ranging from a relative
indication to no indication. Benefit has been shown in individuals with allergy-induced asthma.[79]
Supporters argue that compliance can be ensured, and evidence shows that the underlying disease process can be
modified or even prevented (eg, preventing asthma in children with allergic rhinitis). Acquisition of new sensitivities can
be reduced or eliminated with immunotherapy of monosensitized or oligosensitized children.
Immunotherapy decreased asthma symptoms and the need for medication in a 2003 meta-analysis of 75 randomized
controlled trials by Abramson et al.[80] Another study showed improved peak expiratory flow rate (PEFR) and
decreased use of medications in a highly selected group of children, but only for the first year of therapy.
Patients receiving subcutaneous immunotherapy (SCIT) demonstrated improved medical outcomes and cost savings
in one study designed to evaluate the cost-effectiveness of SCIT in addition to symptomatic therapy (ST), compared
with ST alone.[78]
Allergen immunotherapy should be considered if specific allergens have a proven relationship to symptoms and a
vaccine to the allergen is available; the individual is sensitized (ie, positive skin test or RAST findings); the allergen
cannot be avoided and is present year-round (eg, industrial); or symptoms are poorly controlled with medical therapy.
As discussed above, this treatment is especially useful if asthma is associated with allergic rhinitis.
Referral to an allergist is required, and the patient must commit to a course of 3-5 years of therapy (although a trial of
several months can be considered).
Precautions include serious adverse reactions (occurring in 1 per 30-500 people, usually within 30 min). The estimated
crude annual death rate is 0.7 deaths per million population. Monitoring and resuscitation personnel and equipment
are required. Also, allergen immunotherapy should be avoided if the patient is taking beta blockers or is having an
20/11/18 12.32
asthma exacerbation (ie, PEFR < 70% of patient’s personal best) or has moderate or worse fixed obstruction. A major
risk factor for immunotherapy-related fatalities includes uncontrolled asthma; therefore, appropriate caution should be
exercised.
Dosing of allergen extracts is in bioequivalent allergy units (BAU), weight per volume (w/v), or protein nitrogen units
(PNU), but "major allergen content" may be a more standardized and reliable method of dosing and characterizing
allergen extracts; however, not all allergens have been standardized. Extracts with modifications that decrease
allergenicity (adverse reactions) without reducing immunogenicity (effectiveness) are under investigation.
Sublingual immunotherapy (SLIT) has been shown to improve allergic rhinitis symptoms, including in pediatric patients
and allergic asthma. While adverse reactions do occur, SLIT is safe enough for home administration. Based on limited
data, sublingual therapy, at least in the short term, may be about half as effective as traditional subcutaneous injection.
While SLIT is widely used in European, South American, and Asian countries, as of early 2016, it is not FDA approved
and remains off-label use in the United States.
Monoclonal Antibody Therapy

Omalizumab
Omalizumab is indicated for adults and children aged 6 years or older with moderate-to-severe persistent asthma who
have a positive skin test result or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately
controlled with inhaled corticosteroids. Patients should have IgE levels between 30 and 700 IU and should not weigh
more than 150 kg.
This is a humanized murine IgG antibody against the Fc component of the IgE antibody (the part that attaches to mast
cell surfaces). Use of this antibody prevents IgE from binding directly to the mast cell receptor, thereby preventing cell
degranulation without causing degranulation itself.
Therapy has been shown to decrease free IgE antibody levels by 99% and cell receptor sites for IgE antibody by 97%.
This decrease, in turn, is associated with reduced histamine production (90%), early-phase bronchospasm (40%), and
late-phase bronchospasm (70%), as well as a decrease in the number, migration, and activity of eosinophils. Levels
drop quickly and remain low for at least a month. This therapy is also effective for allergic rhinitis.
Multiple phase 3 trials show that compared to placebo injections, treatment is associated with larger median inhaled
steroid dose reduction (83% vs 50%), higher percentage of discontinuation of inhaled steroids (42% vs 19%), and
fewer asthma exacerbations (approximately 15% vs 30%). Quality of life and use of rescue inhaler and the emergency
department may also be improved. Omalizumab has been shown to reduce the number of asthma exacerbations.
Prescribers must be prepared and equipped to recognize and treat anaphylaxis should it occur. Adverse effects are
rare and include upper respiratory infection symptoms, headache, urticaria (2%) without anaphylaxis, and anaphylaxis
(0.1% in studies and 0.2% in postmarketing surveillance). Transient thrombocytopenia has also been noted but not in
humans. Antibodies are formed against the anti-IgE antibody, but these do not appear to cause immune complex
deposition or other significant problems. To date, decreased IgE levels have not been shown to inhibit one’s ability to
fight infection (including parasites). Registration trials raised a question of increased risk of malignancy, but this has
not been seen in the postmarketing data.
Omalizumab is given by subcutaneous injection every 2-4 weeks based on initial serum IgE level and body weight.
Patients are usually treated for a trial period lasting at least 12 weeks. Costs may be $6,110 to $36,600 annually, so
omalizumab is a second-line therapy for patients with moderate-to-severe persistent allergic asthma that is not fully
controlled on standard therapy.[81]
A study by Busse et al found that omalizumab further improved asthma control, nearly eliminated seasonal
exacerbation peaks, and reduced the need for other medications to control asthma when added to a regimen of
guidelines-based therapy in inner-city children, adolescents, and young adults.[82]
A study by Hanania et al found that omalizumab provided additional benefit in patients with severe allergic asthma that
is insufficiently controlled with inhaled corticosteroids and long-acting beta2-agonists.[83] However, the results of the
study were limited by early patient discontinuation (20.8%) and were limited because the study was not powered to
detect rare safety events or treatment effect in the corticosteroid group.
20/11/18 12.32
Mepolizumab
Mepolizumab is a humanized IgG1 kappa monoclonal antibody specific for interleukin 5 (IL-5). Mepolizumab binds to
IL-5 and therefore stops IL-5 from binding to its receptor on the surface of eosinophils. Inhibiting IL-5 binding to
eosinophils reduces blood, tissue, and sputum eosinophil levels. It is indicated for add-on maintenance treatment of
patients with severe asthma aged 12 years or older and with an eosinophilic phenotype.
Approval was based on three key phase 3 trials (DREAM, MENSA, and SIRIUS). Each trial demonstrated statistically
significant improvement in decreasing asthma exacerbations and emergency department visits or hospitalization.
Mean reduction in glucocorticoid use was 50% in the mepolizumab group, while also reducing the asthma
exacerbation rate. Significant improvement in FEV1 was also observed compared with placebo.[84, 85, 86]
Reslizumab
Reslizumab is an IgG kappa monoclonal antibody that inhibits IL-5. It was approved by the FDA in March 2016 and is
indicated for add-on maintenance treatment of patients with severe asthma aged 18 years and older with an
eosinophilic phenotype. It is administered as an intravenous infusion every 4 weeks. Approval was based on three
multicenter, international trials in patients with asthma who had elevated eosinophils. In two of these studies (n = 953),
patients who received reslizumab had a significant reduction in the frequency of asthma exacerbations of up to 59%
(study 1: rate ratio, 0.50 [95% confidence interval, 0.37-0.67]; study 2: rate ratio, 0.41 [95% confidence interval, 0.28-
0.59]; both P < .0001) compared with those receiving placebo.[87]
Benralizumab
Benralizumab is an IL-5 receptor, alpha-directed cytolytic mAb (IgG1, kappa) approved by the FDA in November 2017.
The IL-5 receptor is expressed on the surface of eosinophils and basophils. Benralizumab reduces eosinophils and
basophils through antibody-dependent cell-mediated cytotoxicity (ADCC). It is indicated for add-on maintenance
treatment of severe asthma in patients aged 12 years or older who have an eosinophilic phenotype.
Approval was based on results from the WINDWARD clinical trial program, including the phase III exacerbation trials,
SIROCCO and CALIMA, and the phase III oral corticosteroid (OCS)–sparing trial, ZONDA.[88, 89, 90]
Results for the 8-week benralizumab dosing regimen from these trials showed the following:
Up to 51% reduction in the annual asthma exacerbation rate (AAER) compared with placebo
Significant improvement in lung function as measured by forced expiratory volume in one second (FEV 1) of up
to 159 mL compared with placebo
Seventy-five percent median reduction in daily OCS use and discontinuation of OCS use in 52% of eligible
patients
Dupilumab
Approval for dupilumab was based on the LIBERTY QUEST (n=1902) and VENTURE (n=210) phase 3 clinical trials.
In the LIBERTY QUEST trial, patients with moderate-to-severe uncontrolled asthma were administered dupilumab add-
on therapy to current maintenance therapy every 2 weeks or matched placebo. Those receiving a 200-mg dose
demonstrated a 47.7% lower rate of annualized severe asthma exacerbations compared with placebo add-on (P<
.001). The 300-mg dose showed a similar response.[91]
In the LIBERTY VENTURE trial, patients with oral corticosteroid–dependent severe asthma were administered
dupilumab add-on therapy or matched placebo to current maintenance therapy every 2 weeks for 24 weeks or
matched placebo. Corticosteroid doses were gradually decreased from week 4 to week 20 and then maintained for 4
weeks. Patients receiving dupilumab had a 70.1% greater corticosteroid dose reduction compared with 41.9% for
placebo add-on (P< .001). Additionally, patients receiving dupilumab had a 59% (95% confidence interval, 37-74)
lower rate of severe asthma exacerbations than those taking placebo add-on.[92]
Bronchial Thermoplasty
20/11/18 12.32
Bronchial thermoplasty (BT) is a novel intervention for asthma in which controlled thermal energy is delivered to the
airway wall during a series of bronchoscopy procedures.
A group of patients (AIR2 Trial Study Group) with severe asthma who remained symptomatic despite treatment with
high-dose inhaled corticosteroids and long-acting beta2 agonists underwent BT and showed superior improvement
from baseline in their score on the Asthma Quality of Life Questionnaire (AQLQ) (BT, 1.35±1.10; sham, 1.16±1.23).
Changes in AQLQ of 0.5 or greater were seen in 79% of BT and in 64% of sham subjects. Although the hospitalization
rate was 6% higher among BT subjects during the treatment period (up to 6 wk after BT), in the posttreatment period
(6-52 wk after BT), the BT group experienced fewer severe exacerbations, emergency department visits, and days
missed from work/school compared with the sham group.[93]
Further results from the AIR2 study showed lasting efficacy at 5 years, as well as a reduction in maintenance treatment
and healthcare utilization. The study also highlights the possibility that more patients may benefit from this treatment.
[94]
Wechsler and colleagues examined the long-term safety and effectiveness of bronchial thermoplasty in 162 patients
with severe persistent asthma from the Asthma Intervention Research 2 (AIR2) trial, which showed a 32% reduction in
severe asthma exacerbations, an 84% reduction in respiratory symptom-related emergency department visits, a 73%
reduction in hospitalizations for respiratory symptoms, and a 66% reduction in time lost from work/school/other daily
activities because of asthma symptoms.[95, 96]
Acute Exacerbation
Prehospital care
The mainstay of ED therapy for acute asthma is inhaled beta2 agonists. The most effective particle sizes are 1-5 µm.
Larger particles are ineffective because they are deposited in the mouth and central airways. Particles smaller than 1
µm are too small to be effective because they move in the airways by Brownian motion and do not reach the lower
airways.
Although studies in patients with COPD reported increased rates of pneumonia associated with inhaled corticosteroid
use, a study by O’Byrne et al found no increased risk in patients with asthma in clinical trials using budesonide.[97]
Standard delivery systems and routes
Albuterol is administered 2.5-5 mg every 20 minutes for 3 doses, then 2.5-10 mg every 1-4 hours as needed; dilution
of 2.5 mg in 3-4 mL of saline or use of premixed nebules is standard. Oxygen or compressed air delivery of the inhaled
beta agonists should be at a rate of 6-8 L/min. For children, use 0.15 mg/kg (minimum dose 2.5 mg) every 20 minutes
for 3 doses, then 0.15-0.3 mg/kg up to 10 mg every 1-4 hours as needed.
An equivalent method of beta-agonist delivery in mild-to-moderate exacerbations is the metered-dose inhaler (MDI)
used in conjunction with a spacer or holding chamber. For severe exacerbations, it is less clear if nebulized versus
MDI/spacer delivery is truly equivalent. Each puff delivers a standard 90 µg of albuterol. The dose is 4-8 puffs every 20
minutes up to 4 hours, then every 1-4 hours as needed. A potential advantage of the MDI/holding chamber is that it
requires little or no assistance from the respiratory therapist once the patient understands how to use the medication;
the patient can be discharged from the ED with the same spacer and albuterol canister. This modality is especially
effective in areas where patients may be unable to afford their inhaled beta agonists.
Side effects may include tremor and a slight tendency toward tachycardia. However, many patients who present with
acute asthma and tachycardia actually decrease their heart rate with inhaled beta-agonist therapy. In addition, inhaled
beta agonists decrease potassium by an average of 0.4 mEq/L.
Patients who respond poorly or not at all to an inhaled beta-agonist regimen may respond to parenteral beta2 agonists,
such as 0.25 mg terbutaline or 0.3 mg of 1:1000 concentration of epinephrine administered subcutaneously. This
treatment should be reserved for patients who are seriously ill and not responding to serial treatments with inhaled
beta-agonist/anticholinergic therapy and other more established therapies.
Ipratropium 0.5 mg has had variable benefit in controlled trials, demonstrating most consistent efficacy in children and
smokers with comorbid COPD. The current NAEPP guidelines (2007) recommend its use in severe exacerbations
20/11/18 12.32
only.[1] Ipratropium should be given in combination with albuterol every 20 minutes for 3 doses, then as needed. The
addition of ipratropium has not been shown to provide further benefit once the patient is hospitalized.
Nebulizer therapy
Continuous nebulization may be superior to the MDI/holding chamber method in a patient with severe exacerbations
(eg, PEF < 200 L/min). The dose of albuterol is 10-15 mg in 70 mL of isotonic saline. For children, this method is
reserved for severe asthma at an albuterol dose of 0.5 mg/kg/h. Based on meta-analyses, there is no advantage of
intravenous albuterol over inhaled albuterol, even in severe asthma. However, the role of parenteral beta agonists in
addition to inhaled beta-agonist treatments is uncertain.
A study by Dhuper et al found no evidence that nebulizers were more effective than MDI/spacer beta agonist delivery
in emergency management of acute asthma in an inner-city adult population.[98] Thus, because they are more cost
effective, MDI/spacer may be a better alternative to nebulizer delivery for some individuals.
Intravenous/oral steroids
Although use of systemic corticosteroids is recommended early in the course of acute exacerbations in patients with
an incomplete response to beta agonists, oral administration is equivalent in efficacy to intravenous administration.
Corticosteroids speed the resolution of airway obstruction and prevent a late-phase response.[99, 100]
In children, long-term use of high-dose steroids (systemic or inhaled) may lead to adverse effects that include growth
failure. However, long-term use of inhaled steroids (budesonide) was shown to have no sustained adverse effect on
growth in children, according to the Childhood Asthma Management Program (CAMP).[101, 102]
In preschool children with asthma, 2 years of inhaled corticosteroid therapy did not change the asthma symptoms or
lung function during a third, treatment-free year. This suggests that no disease-modifying effect of inhaled
corticosteroids is present after the treatment is discontinued.[103]
Complications of long-term corticosteroid use may include osteoporosis, immunosuppression, cataracts, myopathy,
weight gain, addisonian crisis, thinning of skin, easy bruising, avascular necrosis, diabetes, and psychiatric disorders.
Heliox
Heliox is a helium-oxygen (80:20 or 70:30) mixture that may provide dramatic benefit for ED patients with severe
exacerbations. Helium is about 10% as dense as room air and, consequently, travels more easily down narrowed
passages. This property makes heliox of particular value to patients at risk of intubation—by quickly decreasing the
work of breathing and, when the gas mixture is used to drive the nebulizer, by better delivery of the inhaled
bronchodilator.
Despite considerable promise, the literature shows mixed results. Potential explanations include the large number of
small trials (low statistical power) and suboptimal delivery of albuterol to the patient. Briefly, heliox-driven nebulizer
treatments should have the gas set at a rate of 8-10 L/min and with double the usual amount of albuterol. These
adjustments result in the delivery of the appropriate amount of albuterol to the patient but with particles being delivered
in the heliox mixture instead of oxygen or room air. When patients need supplemental oxygen, one can deliver it via
nasal prong. Of course, as the supplemental oxygen is increased, the benefits of using heliox decrease. Oxygen
requirements should determine the ideal mix. The role of heliox in acute asthma remains under investigation.
Indications for intubation
Despite the best efforts of the ED, some patients require endotracheal intubation. Approximately 5-10% of all hospital
admissions for asthma are to an intensive care unit—for further care of already intubated patients or for close
supervision of patients at very high risk of intubation. Mechanical ventilation of patients with acute asthma presents
special challenges, such as the risk of high pressures lowering systemic blood pressure (auto-PEEP) and, less
commonly, complications such as barotrauma, pneumothorax, or pneumomediastinum. The role of permissive
hypercapnia goes beyond the scope of this article but is a ventilator strategy used in the ICU management of some
patients with severe asthma exacerbations.
Indications for hospitalization

Indications for hospitalization are based on findings from the repeat assessment of a patient after the patient receives
20/11/18 12.32
3 doses of an inhaled bronchodilator. The decision whether to admit is based on the following:
Duration and severity of asthma symptoms
Severity of airflow obstruction
Course and severity of prior exacerbations
Medication use and access to medications
Adequacy of support and home conditions
Presence of psychiatric illness
Admit the patient to the ICU for close observation and monitoring in certain situations, such as the following:
Rapidly worsening asthma or a lack of response to the initial therapy in the emergency department
Confusion, drowsiness, signs of impeding respiratory arrest, or loss of consciousness
Impending respiratory arrest, as indicated by hypoxemia (PO2< 60 mm Hg) despite supplemental oxygen
and/or hypercarbia with PCO2 greater than 45 mm Hg
Intubation is required because of the continued deterioration of the patient's condition despite aggressive
treatments.
Status asthmaticus
Status asthmaticus, or an acute severe asthmatic episode that is resistant to appropriate outpatient therapy, is a
medical emergency that requires aggressive hospital management. This may include admission to an ICU for the
treatment of hypoxia, hypercarbia, and dehydration and possibly for assisted ventilation because of respiratory failure.
Asthma in Pregnancy
Asthma complicates 4-8% of pregnancies. Mild and well-controlled moderate asthma can be associated with excellent
maternal and perinatal pregnancy outcomes. Severe and poorly controlled asthma may be associated with increased
prematurity and other perinatal complications, to include maternal morbidity and mortality. Optimal management of
asthma during pregnancy includes objective monitoring of lung function, avoiding or controlling asthma triggers, patient
education, and individualized pharmacologic therapy. Inhaled corticosteroids are the preferred medication for all levels
of persistent asthma during pregnancy. For pregnant women with asthma, it is safer to be treated with asthma
medications than to have asthma symptoms and exacerbations. The ultimate goal of asthma therapy is to maintain
adequate oxygenation of the fetus by prevention of hypoxic episodes in the mother.
With the exception of alpha-adrenergic compounds other than pseudoephedrine and some antihistamines, most drugs
used to treat asthma and allergic rhinitis have not been shown to increase any risk to the mother or fetus. The National
Institute of Health stated that albuterol (Proventil HFA), beclomethasone (QVAR), budesonide (Pulmicort Flexhaler or
Respules), prednisone (Deltasone, Orasone), and theophylline, when clinically indicated, are considered appropriate
for the treatment of asthma in pregnancy.
The American College of Obstetrics and Gynecology issued updated clinical guidelines for 2008.[53] Poorly controlled
asthma can result in low birth weight, increased prematurity, and increased perinatal mortality.
Gastroesophageal Reflux Disease

The presence of acid in the distal esophagus, mediated via vagal or other neural reflexes, can significantly increase
airway resistance and airway reactivity. Patients with asthma are 3 times more likely to also have GERD.[14]
Aggressive antireflux therapy may improve asthma symptoms and pulmonary function in selected patients. Treatment
with proton pump inhibitors, antacids, or H2 blockers may improve asthma symptoms or unexplained chronic cough.
20/11/18 12.32
The treatment of asthma with agents such as theophylline may lower esophageal sphincter tone and induce GERD
symptoms. Some people with asthma have significant gastroesophageal reflux without esophageal symptoms.
Sinusitis
Of patients with asthma, 50% have concurrent sinus disease. Sinusitis is the most important exacerbating factor for
asthma symptoms. Either acute infectious sinus disease or chronic inflammation may contribute to worsening airway
symptoms. Treatment of nasal and sinus inflammation reduces airway reactivity. Treatment of acute sinusitis requires
at least 10 days of antibiotics to improve asthma symptoms.[19]
Nocturnal Asthma
Nocturnal asthma is a significant clinical problem that should be addressed aggressively. Peak-flow meters should be
used to allow objective evaluation of symptoms and interventions. Sleep apnea, symptomatic GERD, and sinusitis
should be controlled when present. Medications should be appropriately timed, and consideration should be given to
the use of a long-acting inhaled or oral beta2 agonist and a leukotriene modifier with inhaled corticosteroids. A once-
daily sustained-release theophylline preparation and changing the timing of oral corticosteroids to midafternoon can be
also be used.
Long-Term Monitoring
For all patients with asthma, monitoring should be performed on a continual basis based on the following parameters,
which helps in the overall management of the disease:
Regarding monitoring of asthma signs and symptoms, patients should be taught to recognize inadequate
asthma control, and providers should assess control at each visit.
To monitor pulmonary function, regularly perform spirometry and peak-flow monitoring.
For quality of life and functional status, inquire about missed work or school days, reduction in activities, sleep
disturbances, or change in caregiver activities.
To monitor the history of asthma exacerbations, determine whether patients are monitoring themselves to
detect asthma exacerbations and if these exacerbations are self-treated or treated by health care providers.
Regarding monitoring pharmacotherapy, ensure compliance with medications and usage of short-acting beta
agonists.
Monitor patient-provider communication and patient satisfaction
Functional Assessment of Airway Obstruction

Perform a functional assessment of airway obstruction with a measurement of the FEV1 or peak expiratory flow (PEF)
initially to assess the patient's response to treatment. PEF measurement is inexpensive and portable. Serial
measurements document response to therapy and, along with other parameters, are helpful in the ED setting for
determining whether to admit the patient to the hospital or discharge from the ED. A limitation of PEF is that it is
dependent on effort by the patient. FEV1 is also effort dependent but less so than PEF.
A study by van den Berge examined the increased interest in small airway disease and new insights that have been
gained about the contribution of small airways to the clinical expression of asthma and COPD. New devices enable
drugs to target the small airways and may have implications for treatment of patients with asthma, particularly those
who do not respond to large-particle inhaled corticosteroids and patients with uncontrollable asthma.[104]
20/11/18 12.32
Perioperative Considerations
Asthma-related complications associated with surgery include acute bronchoconstriction resulting from intubation,
impaired cough, hypoxemia, hypercapnia, atelectasis, respiratory tract infection, and exposure to latex. The likelihood
of these complications occurring depends on the severity of the underlying asthma, the type of surgery (thoracic and
upper abdominal), and the type of anesthesia.[105]
Patients with asthma should have an evaluation before surgery that includes a review of asthma symptoms,
medication use (particularly oral systemic corticosteroids for longer than 2 wk in the past 6 mo), and measurement of
pulmonary function. If possible, attempts should be made to improve lung function preoperatively to either predicted
values or the personal best level. A short course of oral systemic corticosteroids may be necessary to optimize lung
function.
If evidence of airflow obstruction (< 80% of baseline values) is present, a brief course of corticosteroids is
recommended. Patients who have received oral corticosteroids for an asthma exacerbation in the past 6 months
should receive systemic corticosteroids (100 mg hydrocortisone IV q 8 h) in the perioperative period.
Approach to Level of Activity

Activity is generally limited by patients' ability to exercise and their response to medications. No specific limitations are
recommended for patients with asthma, although they should avoid exposure to agents that may exacerbate their
disease.
A significant number of patients with asthma also have exercise-induced bronchoconstriction, and baseline control of
their disease should be adequate to prevent exertional symptoms. The ability of patients with exercise-induced
bronchoconstriction to exercise is based on the level of exertion, degree of fitness, and environment in which they
exercise.
Many patients have fewer problems when exercising indoors or in a warm, humid environment than they do outdoors
or in a cold, dry environment
Dietary Considerations
Information from prospective cohort studies and population-based studies in the past several years suggests an
association between asthma and obesity. Patients with an elevated body mass index have an increased risk for
developing asthma. A prospective cohort study of almost 86,000 adult women in the Nurses' Health Study II observed
for 5 years showed a linear relationship between body mass index and the risk of developing asthma.[10] The 2015
GINA guideline adds that obese patients with asthma have lower lung function and more comorbidities than asthma
patients who are of normal weight.[106] Asthma is more difficult to control in obese patients, but weight loss of 5-10%
can improve asthma control and quality of life.[107]
No special diets are generally indicated. Food allergy as a trigger for asthma is uncommon. Unless compelling
evidence for a specific allergy exists, milk products do not have to be avoided. Avoidance of foods is recommended
after a double-blind food challenge that yields positive results. Sulfites have been implicated in some severe asthma
exacerbations and should be avoided in sensitive individuals.
Consultations
Refer any patient with moderate-to-severe persistent asthma that is difficult to control to a pulmonologist or allergist to
ensure proper stepwise asthma management, or refer for further evaluation to help rule out other diagnoses such as
VCD/ILO. Also, abnormalities found on chest radiography screening should prompt referral to a specialist for further
evaluation.
20/11/18 12.32
Refer patients to an allergist or immunologist for skin testing to guide indoor allergen mitigation efforts and
consideration of immunotherapy to treat seasonal allergic rhinitis.
Refer patients to a pulmonologist for evaluation of symptoms consistent with exercise-induced bronchoconstriction
(EIB). These patients should undergo either exercise or bronchoprovocation testing to document evidence of airway
hyperreactivity and response to exercise.
Refer patients to an otolaryngologist for treatment of nasal obstruction from polyps, sinusitis, or allergic rhinitis or for
the diagnosis of upper airway disorders.
Deterrence
Control of factors contributing to asthma severity is an essential component in asthma treatment. Exposure to irritants
or allergens has been shown to increase asthma symptoms and cause exacerbations. Clinicians should evaluate
patients with persistent asthma for allergen exposures and sensitivity to seasonal allergens. Skin testing results should
be used to assess sensitivity to perennial indoor allergens, and any positive results should be evaluated in the context
of the patient's medical history.
All patients with asthma should be advised to avoid exposure to allergens to which they are sensitive, especially in the
setting of occupational asthma. Other factors may include the following:
Environmental tobacco smoke
Exertion during high levels of air pollution
Use of beta blockers
Avoidance of aspirin and other nonsteroidal anti-inflammatory drugs if the patient is sensitive
Avoidance of sulfites or other food items/additives to which the patient may be sensitive
Occupational exposures
Guidelines
Guidelines Summary
The following organizations have issued guidelines for the management of asthma:
National Asthma Education and Prevention Program (NAEPP)[1]
Veteran’s Administration/Department of Defense (VA/DoD)[43]
Global Initiative for Asthma (GINA)[106]
Classification Guidelines
The 2007 NAEPP guidelines[1] and the 2009 VA/DoD asthma management guidelines[43] use the severity of asthma
classification below, with features of asthma severity divided into three charts to reflect classification in different age
groups (0-4 y, 5-11 y, and 12 y and older). Classification includes (1) intermittent asthma, (2) mild persistent asthma,
(3) moderate persistent asthma, (4) and severe persistent asthma.
Intermittent asthma is characterized as follows:
20/11/18 12.32
Symptoms of cough, wheezing, chest tightness, or difficulty breathing less than twice a week
Flare-ups are brief, but intensity may vary
Nighttime symptoms less than twice a month
No symptoms between flare-ups
Lung function test FEV 1 is 80% or more above normal values
Peak flow has less than 20% variability am-to-am or am-to-pm, day-to-day
Mild persistent asthma is characterized as follows:
Symptoms of cough, wheezing, chest tightness, or difficulty breathing 3-6 times a week
Flare-ups may affect activity level
Nighttime symptoms 3-4 times a month
Lung function test FEV 1 is 80% or more above normal values
Peak flow has less than 20-30% variability
Moderate persistent asthma is characterized as follows:
Symptoms of cough, wheezing, chest tightness, or difficulty breathing daily

Flare-ups may affect activity level
Nighttime symptoms 5 or more times a month
Lung function test FEV 1 is above 60% but below 80% of normal values
Peak flow has more than 30% variability
Severe persistent asthma is characterized as follows:
Symptoms of cough, wheezing, chest tightness, or difficulty breathing that are continual
Frequent nighttime symptoms
Lung function test FEV 1 is 60% or less of normal values
Peak flow has more than 30% variability
In contrast, the 2016 Global Initiative for Asthma (GINA) guidelines categorize asthma severity as mild, moderate, or
severe. Severity is assessed retrospectively from the level of treatment required to control symptoms and
exacerbations, as follows[106] :
Mild asthma: Well controlled with as-needed reliever medication alone or with low-intensity controller treatment
such as low-dose inhaled corticosteroids (ICSs), leukotriene receptor antagonists, or chromones
Moderate asthma: Well controlled with low-dose ICS/long-acting beta2-agonists (LABA)
Severe asthma: Requires high-dose ICS/LABA to prevent it from becoming uncontrolled, or asthma that
remains uncontrolled despite this treatment
The 2013 joint European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines on evaluation and
treatment of severe asthma reserves the definition of severe asthma for patients with refractory asthma and those in
whom response to treatment of comorbidities is incomplete.[108]
The 2016 GINA guidelines stress the importance of distinguishing between severe asthma and uncontrolled asthma,
as the latter is a much more common reason for persistent symptoms and exacerbations, and it may be more easily
improved. The most common problems that need to be excluded before a diagnosis of severe asthma can be made
are the following[106] :
Poor inhaler technique

Poor medication adherence
Incorrect diagnosis of asthma, with symptoms due to alternative conditions such as upper airway dysfunction,
cardiac failure, or lack of fitness
Comorbidities and complicating conditions such as rhinosinusitis, gastroesophageal reflux, obesity, and
obstructive sleep apnea
Ongoing exposure to sensitizing or irritant agents in the home or work environment.
Management Guidelines
20/11/18 12.32
The goals for successful management of asthma outlined in the 2007 NHLBI publication "Global Strategy for Asthma
Management and Prevention" (see the images below) include the following[1] :
Achieve and maintain control of asthma symptoms

Maintain normal activity levels, including exercise
Maintain pulmonary function as close to normal as possible
Prevent asthma exacerbations
Avoid adverse effects from asthma medications
Prevent asthma mortality
Asthma symptoms and severity. Recommended guidelines for determination of asthma severity based on clinical
symptoms, exacerbations, and measurements of airway function. Adapted from Global Strategy for Asthma
Management and Prevention: 2002 Workshop Report.
20/11/18 12.32
Stepwise approach to pharmacological management of asthma based on asthma severity. Adapted from Global
Strategy for Asthma Management and Prevention: 2002 Workshop Report.
Stepwise pharmacologic therapy
The pharmacologic treatment of asthma is based on stepwise therapy. Asthma medications should be added or
deleted as the frequency and severity of the patient's symptoms change. The 2007 NAEPP guidelines offer the
recommendations below.[1]
Step 1 for intermittent asthma is as follows:
Controller medication not indicated

Reliever medication is a short-acting beta-agonist (SABA) as needed for symptoms
Step 2 for mild persistent asthma is as follows:
Preferred controller medication is a low-dose inhaled corticosteroid

Alternatives include cromolyn, leukotriene receptor antagonist (LTRA), [109] or theophylline
Step 3 for moderate persistent asthma is as follows:
Preferred controller medication is either a low-dose inhaled corticosteroid (ICS) plus a long-acting beta-agonist
(LABA) (combination medication preferred choice to improve compliance) [110] or an inhaled medium-dose
corticosteroid
Alternatives include an low-dose ICS plus either a LTRA or theophylline
Step 4 for moderate-to-severe persistent asthma is as follows:
Preferred controller medication is an inhaled medium-dose corticosteroid plus a LABA (combination therapy)
Alternatives include an inhaled medium-dose corticosteroid plus either an LTRA or theophylline
Step 5 for severe persistent asthma is as follows:
Preferred controller medication is an inhaled high-dose corticosteroid plus LABA
20/11/18 12.32
Step 6 for severe persistent asthma is as follows:
Preferred controller medication is an inhaled high-dose corticosteroid plus LABA plus oral corticosteroid
The 2016 GINA guidelines include the following stepwise recommendations for medication and symptom control[106] :
Step 1: As-needed SABA with no controller; other options are to consider low-dose ICS for patients with
exacerbation risks
Step 2: Regular low-dose ICS plus as-needed SABA; other options are LTRA or theophylline
Step 3: Low-dose ICS/LABA plus as-needed SABA or ICS/formoterol maintenance and reliever therapy; other
options are medium-dose ICS or low-dose ICS/LABA
Step 4: Low-dose ICS/formoterol maintenance and reliever therapy or medium-dose ICS/LABA as maintenance
plus as-needed SABA; add-on tiotropium for patients with history of exacerbations; other options are high-dose
ICS/LTRA or slow-release theophylline; refer for expert assessment and advice
Step 5: Refer for expert investigation and add-on treatment; add-on treatments include tiotropium by mist
inhaler for patients with a history of exacerbations, omalizumab for severe allergic asthma, and mepolizumab
for severe eosinophilic asthma; other options are that some patients may benefit from low-dose oral
corticosteroids but long-term systemic adverse effects occur
The 2013 joint European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines include the following
additional recommendations for treatment of severe asthma[108] :
For severe allergic asthma, a therapeutic trial of omalizumab

Do not use methotrexate or macrolide antibiotics to treat severe asthma
For severe asthma and recurrent exacerbations of allergic bronchopulmonary aspergillosis (ABPA), antifungal
agents should be given
Do not use antifungal agents for severe asthma without ABPA irrespective of sensitization to fungi (ie, positive
skin prick test or fungus-specific immunoglobulin E in serum)
Exercise-Induced Asthma Guidelines

In 2013, the American Thoracic Society released clinical guidelines for the management of exercise-induced
bronchoconstriction (EIB), which included the following recommendations[111] :
Administration of an inhaled SABA before exercise (strong recommendation); the SABA is typically
administered 15 minutes before exercise
A controller agent is added whenever SABA therapy is used daily or more frequently
Interval or combination warm-up exercise before planned exercise (strong recommendation)
Recommend against daily use of an inhaled long-acting beta2-agonist as single therapy (strong
recommendation)
For patients who continue to have symptoms despite using an inhaled SABA before exercise or who require an
inhaled SABA daily or more frequently: (1) Daily ICS (strong recommendation), (2) Daily administration of an
LTRA (strong recommendation), (3) Administration of a mast cell‒stabilizing agent before exercise (strong
recommendation), and (4) Inhaled anticholinergic agent before exercise (weak recommendation)
For patients with EIB and allergies who continue to have symptoms despite using an inhaled SABA before
exercise or who require an inhaled SABA daily or more frequently consider administration of an antihistamine
(weak recommendation)
For exercise in cold weather, routine use of a device (eg, mask) that warms and humidifies the air during
exercise (weak recommendation)
Medication
Medication Summary
Asthma medications are generally divided into two categories:
20/11/18 12.32
Quick relief (also called reliever medications)
Long-term control (also called controller medications)
Quick relief
Quick relief medications are used to relieve acute asthma exacerbations and to prevent exercise-induced
bronchoconstriction (EIB) symptoms. These medications include short-acting beta agonists (SABAs), anticholinergics
(used only for severe exacerbations), and systemic corticosteroids, which speed recovery from acute exacerbations.
Long-term control
Long-term control medications include inhaled corticosteroids (ICSs),[99, 100] , long-acting beta agonists (LABAs),
long-acting anticholinergics, combination inhaled corticosteroids and long-acting beta agonists, methylxanthines, and
leukotriene receptor antagonists. Inhaled corticosteroids are considered the primary drug of choice for control of
chronic asthma, but unfortunately the response to this treatment is characterized by wide variability among patients. A
study by Tantisira et al showed the glucocorticoid-induced transcript 1 gene (GLCCI1) to be the cause of this decrease
in response.[112]
In a study by Peters et al, the use of the anticholinergic agent tiotropium in 210 asthmatic patients resulted in a
superior outcome compared with a doubling of the dose of an inhaled glucocorticoid, as assessed by measuring the
morning peak expiratory flow and other secondary outcomes. The addition of tiotropium in this study was also shown
to be noninferior to the addition of salmeterol.[113]
Kerstjens et al evaluated 912 patients already taking an ICS/LABA combination who were randomized to 48 weeks of
tiotropium versus placebo in two replicate, randomized, controlled trials. The patients had a mean baseline FEV1 of
62% of the predicted value. The use of tiotropium compared to placebo increased the time to first exacerbation (282
versus 226 days) and resulted in a higher peak change in FEV1 from baseline of 86 ± 34 mL (Trial 1) and 154 ± 32 mL
(Trial 2) for those patients taking tiotropium.[114]
In a cross-sectional population-level comparison study of asthmatics from 1997-1998 and 2004-2005, researchers
evaluated controller-to-total asthma medication ratio (greater than 0.5) with asthma exacerbation rates (dispensing of
systemic corticosteroid or emergency department visit/hospitalization for asthma). They were able to demonstrate an
increased use of asthma controllers based on a 16% increase in controller-to-total asthma medication ratio. However,
there was no change in annual asthma exacerbation rates (0.27/year to 0.23/year) despite this improvement in
controller use.[115]
Two systematic reviews indicate that the regular use of ICSs for the treatment of pediatric asthma may suppress linear
growth in the first year of treatment, but lower ICS doses may minimize such effects.[1, 2, 116] The investigators of
both reviews also noted that head-to-head comparison trials are needed to assess the effects of different ICSs, ICS
doses, inhalation devices, and patient ages on growth suppression over time.
Beta2-adrenergic agonist agents
Class Summary
Beta2 agonists (albuterol sulfate [Proventil HFA, Ventolin HFA, ProAir HFA; pirbuterol acetate [Maxair Autohaler];
levalbuterol [Xopenex]) relieve reversible bronchospasm by relaxing the smooth muscles of the bronchi. These agents
act as bronchodilators and are used to treat bronchospasm in acute asthmatic episodes and to prevent bronchospasm
associated with exercise-induced asthma or nocturnal asthma.
Albuterol sulfate (Proventil HFA, Ventolin HFA, ProAir HFA)

This beta2-agonist is the most commonly used bronchodilator that is available in multiple forms (eg, solution for
nebulization, metered-dose inhaler, oral solution). This is most commonly used in rescue therapy for acute asthmatic
symptoms and is used as needed. Prolonged use may be associated with tachyphylaxis due to beta2-receptor down-
20/11/18 12.32
regulation and receptor hyposensitivity.
Pirbuterol (Maxair Autohaler)

This agent is available as a breath-actuated or ordinary inhaler. The ease of administration with the breath-actuated
device makes it an attractive choice in the treatment of acute symptoms in younger children, who otherwise may not
be able to use a metered-dose inhaler. The Autohaler delivers 200 mcg per actuation.
Levalbuterol (Xopenex)
A nonracemic form of albuterol, levalbuterol (R isomer), is effective in smaller doses and is reported to have fewer
adverse effects (eg, tachycardia, hyperglycemia, hypokalemia). The dose may be doubled in acute severe episodes
when even a slight increase in the bronchodilator response may make a big difference in the management strategy
(eg, in avoiding patient ventilation).
Anticholinergic Agents
Class Summary
The long-acting anticholinergic agent, tiotropium, may be considered for long-term maintenance therapy, but not for
acute treatment of asthma exacerbations.
Tiotropium (Spiriva Respimat)

Tiotropium is a long-acting antimuscarinic agent, often referred to as an anticholinergic. It inhibits M3-receptors at
smooth muscle, leading to bronchodilation. It is indicated for long-term, once-daily, maintenance treatment of asthma
in patients aged 6 years or older.
Ipratropium (Atrovent)
Ipratropium is chemically related to atropine. It has antisecretory properties and, when applied locally, inhibits
secretions from serous and seromucous glands lining the nasal mucosa. It is approved for COPD, but off-label use for
acute exacerbations of asthma in addition to beta2-agonist therapy has been described in the literature. It is a short-
acting anticholinergic agent with an onset of 15 minutes.
Anticholinergic agent combinations
Class Summary
Combination agents with ipratropium and albuterol. A test spray of 3 sprays is recommended before using this
combination for the first time and when the aerosol has not be used for more than 24 hours. Ipratropium is chemically
related to atropine. It has antisecretory properties and, when applied locally, inhibits secretions from serous and
seromucous glands lining the nasal mucosa. Albuterol is beta-agonist for bronchospasm refractory to epinephrine. It
relaxes bronchial smooth muscle by action on beta2-receptors, with little effect on cardiac muscle contractility.
Ipratropium and albuterol (Combivent, DuoNeb)

Ipratropium is chemically related to atropine. It has antisecretory properties and, when applied locally, inhibits
secretions from serous and seromucous glands lining the nasal mucosa. Albuterol is beta-agonist for bronchospasm
refractory to epinephrine. It relaxes bronchial smooth muscle by action on beta2-receptors, with little effect on cardiac
20/11/18 12.32
muscle contractility.
Corticosteroid, oral
Class Summary
Oral steroids (prednisone [Deltasone, Orasone]; prednisolone [Pediapred, Prelone, Orapred]; methylprednisolone
[Solu-Medrol]) are used for short courses (3-10 d) to gain prompt control of inadequately controlled acute asthmatic
episodes. They are also used for long-term prevention of symptoms in severe persistent asthma as well as for
suppression, control, and reversal of inflammation. Frequent and repetitive use of beta2 agonists has been associated
with beta2 -receptor subsensitivity and down-regulation; these processes are reversed with corticosteroids.
Prednisone (Deltasone, Orasone)

Prednisone is an immunosuppressant for the treatment of autoimmune disorders; it may decrease inflammation by
reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity.
Methylprednisolone (Solu-Medrol, Medrol)

Methylprednisolone may decrease inflammation by reversing increased capillary permeability and suppressing
polymorphonuclear leukocyte activity.
Prednisolone (Pediapred, Prelone, Orapred)

This glucosteroid occurs naturally and synthetically. It is used for both acute and chronic asthma. It may decrease
inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity.
Long-acting beta2 agonists
Class Summary
Long-acting bronchodilators are not used for the treatment of acute bronchospasm. They are used for the preventive
treatment of nocturnal asthma or exercise-induced asthmatic symptoms, for example. Currently, 2 LABAs are available
in the United States: salmeterol (Serevent) and formoterol (Foradil). Salmeterol and formoterol are available as
combination products with inhaled corticosteroids in the United States.
Salmeterol (Serevent)
Salmeterol can relieve bronchospasm by relaxing the smooth muscles of the bronchioles in conditions associated with
bronchitis, emphysema, asthma, or bronchiectasis. The effect also may facilitate expectoration. Adverse effects are
more likely when salmeterol is administered at high doses or more frequent doses than recommended.
Beta2-Agonist/Corticosteroid Combinations
Class Summary
These combinations (budesonide and formoterol [Symbicort]; fluticasone and salmeterol [Advair HFA, Advair Diskus];
20/11/18 12.32
mometasone and formoterol [Dulera]) may decrease asthma exacerbations when inhaled short-acting beta2 agonists
and corticosteroids have failed.
Budesonide/formoterol (Symbicort)
Formoterol relieves bronchospasm by relaxing the smooth muscles of the bronchioles in conditions associated with
asthma. Budesonide is an inhaled corticosteroid that alters the level of inflammation in airways by inhibiting multiple
types of inflammatory cells and decreasing the production of cytokines and other mediators involved in the asthmatic
response.
Mometasone and formoterol (Dulera)

Combination corticosteroid and long-acting selective beta-2 agonist (LABA) metered-dose inhaler. Mometasone elicits
local anti-inflammatory effects to respiratory tract with minimal systemic absorption. Formoterol elicits bronchial smooth
muscle relaxation. Indicated for prevention and maintenance of asthma symptoms in patients inadequately controlled
with other asthma controller medications (eg, low- to medium-dose inhaled corticosteroids) or whose disease severity
clearly warrants initiation of treatment with 2 maintenance therapies, including a LABA. Available in 2 strengths; each
actuation delivers mometasone/formoterol 100 mcg/5 mcg or 200 mcg/5 mcg.
Salmeterol/fluticasone inhaled (Advair)

Fluticasone inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease
the number and activity of inflammatory cells, in turn decreasing airway hyperresponsiveness. It also has
vasoconstrictive activity. Salmeterol relaxes the smooth muscles of the bronchioles in conditions associated with
bronchitis, emphysema, asthma, or bronchiectasis, and can relieve bronchospasms. Its effects may also facilitate
expectoration. Adverse effects are more likely to occur when the agent is administered at high or more frequent doses
than recommended.
Vilanterol/fluticasone furoate inhaled (Breo Ellipta)

Indicated for once-daily treatment of asthma for adults not adequately controlled on a long-term asthma control
medication (eg, inhaled corticosteroid), or whose disease severity clearly warrants initiation of treatment with both an
inhaled corticosteroid and a long-acting beta agonist (LABA). Use prescribe strength (25 mcg/100 mcg or 25 mcg/200
mcg per actuation) once daily via oral inhalation. Fluticasone furoate is a corticosteroid with anti-inflammatory activity.
Vilanterol is a long-acting beta agonist (LABA) that stimulates intracellular adenyl cyclase (catalyzes the conversion of
ATP to cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release
of mediators of immediate hypersensitivity from cells, especially from mast cells.
Methylxanthines
Class Summary
These agents are used for long-term control and prevention of symptoms, especially nocturnal symptoms.
Theophylline (Theo-24, Theochron, Uniphyl)

Theophylline is available in short- and long-acting formulations. Because of the need to monitor the drug levels, this
agent is used infrequently. The dose and frequency of administration depend on the particular product selected.
Mast cell stabilizers
20/11/18 12.32
Class Summary
These agents (cromolyn sodium [Intal]) block early and late asthmatic responses, interfere with chloride channels,
stabilize the mast cell membrane, and inhibit the activation and release of mediators from eosinophils and epithelial
cells. They inhibit acute responses to cold air, exercise, and sulfur dioxide.
Cromolyn sodium (Intal)

Cromolyn sodium inhibits the release of histamine, leukotrienes, and other mediators from sensitized mast cells
exposed to specific antigens. It has no intrinsic anti-inflammatory, antihistamine, or vasoconstrictive effects.
Corticosteroid, Inhalant
Class Summary
Inhaled steroids include ciclesonide (Alvesco), beclomethasone (QVAR), triamcinolone, flunisolide (Nasalide),
fluticasone (Flovent Diskus, Flovent HFA), budesonide (Pulmicort Flexhaler or Respules), and mometasone furoate
inhalation powder (Asmanex Twisthaler). Steroids are the most potent anti-inflammatory agents. Inhaled forms are
topically active, poorly absorbed, and least likely to cause adverse effects.
Ciclesonide (Alvesco)
Ciclesonide is an aerosol inhaled corticosteroid indicated for maintenance treatment of asthma as prophylactic therapy
in adult and adolescent patients aged 12 years and older. It is not indicated for relief of acute bronchospasm.
Corticosteroids have a wide range of effects on multiple cell types (eg, mast cells, eosinophils, neutrophils,
macrophages, lymphocytes) and mediators (eg, histamines, eicosanoids, leukotrienes, cytokines) involved in
inflammation.
Beclomethasone (QVAR, Beclovent)

This agent inhibits bronchoconstriction mechanisms; causes direct smooth muscle relaxation; and may decrease the
number and activity of inflammatory cells, which, in turn, decreases airway hyperresponsiveness. It is available as a
40- or 80-mcg/actuation.
Fluticasone inhaled
Fluticasone has extremely potent vasoconstrictive and anti-inflammatory activity. It has a weak HPA-axis inhibitory
potency when applied topically. It is available as a metered-dose inhaler aerosolized product (HFA) or DPI (Diskus).
Budesonide inhaled (Pulmicort Flexhaler or Respules)

Fluticasone has extremely potent vasoconstrictive and anti-inflammatory activity. It has a weak HPA-axis inhibitory
potency when applied topically. It is available as a DPI in 90-mcg/actuation (delivers about 80 mcg/actuation) or 180-
mcg/actuation (delivers about 160 mcg/actuation). A nebulized suspension (ie, Respules) is also available for young
children.
Mometasone (Asmanex Twisthaler)

Mometasone is a corticosteroid for oral inhalation. It is indicated for asthma as prophylactic therapy.
Triamcinolone inhaled (Azmacort)

20/11/18 12.32
Triamcinolone alters the level of inflammation in airways by inhibiting multiple types of inflammatory cells and
decreasing the production of cytokines and other mediators involved in the asthmatic response.
Flunisolide inhaled (Aerospan HFA)

Flunisolide inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease the
number and activity of inflammatory cells, in turn decreasing airway hyperresponsiveness. It decreases inflammation
by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability. It does not
depress the hypothalamus. AeroBid (flunisolide CFC) delivers about 250 mcg per actuation. AeroSpan (flunisolide
HFA) delivers about 80 mcg per actuation.
Leukotriene Receptor Antagonist
Class Summary
Knowledge that leukotrienes cause bronchospasm, increased vascular permeability, mucosal edema, and
inflammatory cell infiltration leads to the concept of modifying their action by using pharmacologic agents. These are
either 5-lipoxygenase inhibitors or leukotriene-receptor antagonists (zafirlukast [Accolate]; montelukast [Singulair]).
Zafirlukast (Accolate)
Zafirlukast is a selective competitive inhibitor of LTD4 and LTE4 receptors.
Montelukast (Singulair)
Montelukast is the last agent introduced in its class. The advantages are that it is chewable, it has a once-a-day
dosing, and it has no significant adverse effects.
Monoclonal Antibodies, Anti-asthmatics
Class Summary
Monoclonal antibody effects vary depending on their receptor target. Omalizumab binds to IgE on the surface of mast
cells and basophils. It reduces the release of these mediators that promote an allergic response. Mepolizumab,
reslizumab, and benralizumab inhibit IL-5 binding to eosinophils and result in reduced blood, tissue, and sputum
eosinophil levels. Dupilumab inhibits IL-4 receptor alpha, and thereby blocks IL-4 and IL-13 signaling.
Omalizumab (Xolair)
Omalizumab is a recombinant, DNA-derived, humanized IgG monoclonal antibody that binds selectively to human IgE
on the surface of mast cells and basophils. It reduces mediator release, which promotes an allergic response. It is
indicated for moderate-to-severe persistent asthma in patients aged 6 years or older who react to perennial allergens
in whom symptoms are not controlled by inhaled corticosteroids.
Mepolizumab (Nucala)
Mepolizumab is a humanized IgG1 kappa monoclonal antibody specific for IL-5. Mepolizumab binds to IL-5 and
therefore stops IL-5 from binding to its receptor on the surface of eosinophils. It is indicated for add-on maintenance
treatment of patients with severe asthma aged 12 years or older and with an eosinophilic phenotype.
20/11/18 12.32
Reslizumab (Cinqair)
Reslizumab is an IL-5 antagonist monoclonal antibody (IgG kappa). It is indicated for add-on maintenance treatment of
patients with severe asthma aged 18 years and older with an eosinophilic phenotype.
Benralizumab (Fasenra)
Benralizumab is a humanized monoclonal antibody (IgG1/kappa-class) selective for the IL-5 alpha subunit of basophils
and eosinophils. It is indicated for add-on maintenance treatment of severe asthma in patients aged 12 years or older
who have an eosinophilic phenotype.
Dupilumab (Dupixent)
Dupilumab inhibits IL-4 receptor alpha, and thereby blocks IL-4 and IL-13 signaling. This, in turn, reduces the cytokine-
induced inflammatory response. It is indicated as an add-on maintenance treatment for moderate-to-severe asthma in
patients aged 12 years or older with eosinophilic phenotype or oral corticosteroid–dependent asthma.
Questions & Answers

Overview
What is asthma, and what is the prevalence of asthma in the US?
Which signs and symptoms are associated with asthma?
What criteria is used to establish a diagnosis of asthma?
Which tests are primarily performed to establish an asthma diagnosis?
What are the goals of asthma management?
Which medications are used in the treatment of asthma and how are they managed?
How do allergens play a role in asthma management?
What is the prevalence of asthma in the US?
Which pathologic features are involved in the pathophysiology of asthma?
How is the clinical severity of asthma determined?
Which tests are performed in the initial stages of asthma diagnosis?
How is the severity of asthma classified based on physical findings?
Which control agents and relief medications are used in the management of asthma, and how are they used?
What is the anatomical structure of the airways of the lungs?
What are the cellular elements of the airways of the lungs, and which dysfunction leads to bronchial asthma?
Which features are the main components of asthma pathophysiology?
What are the categories of airway inflammation in asthma, and what physiologic features contribute to airflow
obstruction?
Which types of cells are involved in airway inflammation associated with asthma?
What mechanisms are involved in airway hyperresponsiveness and bronchial hyperreactivity associated with asthma?
20/11/18 12.32
What is the role of chronic inflammation in asthma, and which common symptoms result from inflammation?
What is the role of Th lymphocytes in airway inflammation associated with asthma?
What is the "hygiene hypothesis" and how does it relate to asthma?
What factors contribute to the different types of airflow obstruction in asthma?
How does airway obstruction in asthma affect the ability to breathe?
What is ventilation-perfusion mismatch, and how does it manifest in the early and late stages of asthma?
What factors may contribute to asthma?
What is the triad of asthma, aspirin sensitivity, and nasal polyps?
What are the treatment options for aspirin-induced asthma?
What is the role of gastroesophageal reflux (GERD) in asthma?
What is the role of occupational factors in the development of asthma?
What are the features asthma types associated with occupational factors?
How does exposure to respiratory virus in infancy relate to the incidence and severity of childhood asthma?
How does sinusitis exacerbate symptoms of asthma?
What is exercise-induced asthma (EIA)?
What factors contribute to exercise-induced bronchoconstriction (EIB) symptoms?
Which age groups are most affected by exercise-induced bronchoconstriction (EIB)?
What role do genetics play in the susceptibility to asthma?
How do genetics and environmental factors influence a child’s susceptibility to asthma?
How is obesity associated with a child's risk of asthma?
What is the worldwide prevalence of asthma?
How do race and environmental factors play a role in the incidence of asthma?
Which countries have the highest prevalence of asthma, and what factors are thought to contribute?
Is asthma more common in males or females?
Which age groups have the highest prevalence of asthma?
What is the asthma mortality rate, and what factors contribute to asthma-related death?
What is the average annual cost of asthma due to lost productivity and healthcare expenditures?
What percentage of children diagnosed with asthma will require less or no treatment by early adulthood?
What are the negative outcomes of poorly controlled asthma?
What are the key elements of patient education about asthma?
What effect does school-based asthma education have on the course of asthma in children?
Who should be provided with patient education for asthma?
What asthma education resources are available?
20/11/18 12.32
Presentation
What are the key elements of a thorough assessment in suspected or diagnosed asthma?
What is the role of wheezing in the assessment of asthma?
What is the role of coughing in the assessment of asthma?
Which chronic or recurrent conditions in children are associated with asthma?
What are the typical symptoms of exercise-induced bronchoconstriction (EIB) (exercise-induced asthma [EIA])?
Which findings are essential to a diagnosis of asthma?
How are the different severities of acute asthma episodes classified?
Which physical findings are associated with an acute asthma episode?
Which physical findings are associated with a moderately severe asthma episode?
Which physical findings are associated with a severe asthma episode?
Which physical findings are associated with a child in imminent respiratory arrest?
Which respiratory and dermatologic findings may be seen between acute episodes of asthma?
Which nocturnal symptoms are associated with asthma?
When is bronchoconstriction most common in asthma?
How is the severity of asthma classified?
Which characteristics of asthma are required to diagnose severe asthma?
DDX
What is vocal cord dysfunction, and what is its relationship to asthma?
What are the similarities of airway tumors and asthma?
What types of tracheal lesions manifest with symptoms associated with asthma?
How is foreign body aspiration presentation similar to asthma presentation?
What is pulmonary migraine and how is it associated with asthma?
How does congestive heart failure manifest with symptoms associated with asthma?
How is diffuse panbronchiolitis differentiated from asthma?
How are aortic arch anomalies differentiated from asthma?
Which symptoms of sinus disease are also associated with asthma?
What is the relationship between gastroesophageal reflux (GER) and asthma?
Which conditions may be mistaken for asthma?
Which factor distinguishes COPD from asthma?
When should alternative diagnoses be considered for patients presenting with symptoms of asthma?
What are the differential diagnoses for Asthma?
Workup
20/11/18 12.32
Which lab studies are indicated in the assessment and diagnosis of asthma?
What is the role of blood eosinophilia in the diagnosis of asthma?
How is sputum eosinophilia used to assess asthma control and guide therapy?
What is the role of serum immunoglobulin E levels in the diagnosis of asthma?
What is the role of arterial blood gas (ABG) measurement in the diagnosis of asthma, and when is an ABG
measurement indicated?
What is the role of PCO2 measurement in the evaluation of an acute asthma episode?
What is the role of periostin measurement in the management of asthma?
What is the purpose of pulse oximetry measurements in acute asthma?
How is pulse oximetry used to determine the severity of acute asthma in children?
What is the role of chest radiography in the initial evaluation of asthma symptoms?
What is the purpose of chest radiography in patients being evaluated for asthma?
When is chest radiography indicated in patients who present with symptoms of asthma?
When is chest CT scanning used in the evaluation of asthma symptoms?
Which high-resolution CT (HRCT) findings are associated with a diagnosis of bronchial asthma?
What is the role of ECG in severe asthma symptoms?
What is the role of MRI in the workup of patients presenting with symptoms of asthma?
What is the role of nuclear imaging in the evaluation of asthma?
What is the role of allergy skin testing and treatment in the management of asthma?
What is the role of spirometry in the diagnosis of asthma?
What is single-breath counting (SBC), and when is it useful in the diagnosis of asthma?
What is the role of bronchoprovocation testing in patients with asthma symptoms?
What is the role of methacholine in the workup of patients with asthma symptoms?
What is the role of eucapnic hyperventilation as a method of bronchoprovocation in asthma?
What is the role of exercise spirometry in the diagnosis of asthma, and how is it administered?
What is the role of allergen-inhalation challenges in the assessment of asthma symptoms?
What is the role of mannitol in the assessment of patients with symptoms of asthma?
What is the role of peak expiratory flow (PEF) measurement in the evaluation of asthma symptoms?
What is the role of impulse oscillometry (IOS) in the evaluation of asthma symptoms?
How is exhaled nitric oxide analysis used in the management of asthma?
What is the role of sinus CT scanning in the evaluation of asthma symptoms?
When is 24-hour pH monitoring used in the evaluation of asthma symptoms?
Which histologic findings are characteristic of asthma?
20/11/18 12.32
Treatment
What are the main elements of medical care in the treatment of asthma?
What is the ultimate goal of treatment in asthma?
What type of approach is used in asthma management?
What is the role of rapid-acting beta2 agonists in the treatment of asthma?
Which drug is the controller medication of choice for children and adults in the treatment of asthma?
How often should patients with asthma be assessed for asthma control, and which factors should be evaluated?
What is the role of school-based intervention in the management of asthma in adolescents?
What is the role of environmental exposures and irritants in the management of asthma symptoms?
What is the role of allergen avoidance in the long-term management of asthma?
What steps can a patient take to avoid allergens and reduce their asthma symptoms?
What is the impact of air pollution on symptoms of asthma?
What measures can be taken to avoid dust mites to help reduce symptoms of asthma?
Which interventions are the most effective approach to dust mite avoidance in the management of allergic rhinitis?
What are the effects of animal allergens and how are they best managed to improve symptoms of asthma?
How can patients reduce cockroach allergen levels to improve their asthma symptoms?
How can patients reduce indoor mold allergens to improve their asthma symptoms?
How can patients reduce exposure to pollen allergens to improve their asthma symptoms?
When is immunotherapy indicated in the treatment of asthma?
What evidence exists to support the use of immunotherapy in the treatment of asthma?
When is allergen immunotherapy indicated for the treatment of asthma?
Which referral is required to initiate allergen immunotherapy?
What precautions are taken during the administration of allergen immunotherapy in asthma?
How is dosing of an allergen extract measured in the treatment of asthma?
Is sublingual immunotherapy (SLIT) proven to improve symptoms of asthma?
What is the role of omalizumab in the treatment of asthma?
What are the outcomes of omalizumab therapy in the treatment of asthma?
What are the potential adverse effects of omalizumab therapy in the treatment of asthma?
What are the protocols and costs associated with omalizumab therapy in the treatment of asthma?
What are the benefits of omalizumab therapy in the treatment of asthma?
What is the mechanism of action of mepolizumab, and when is it indicated for the treatment of asthma?
What is the mechanism of action of reslizumab, and when is it indicated for the treatment of asthma?
What is the mechanism of action of benralizumab and dupilumab, and when are they indicated for the treatment of
20/11/18 12.32
asthma?
What is bronchial thermoplasty?
Which short-term results and long-term outcomes are associated with bronchial thermoplasty in the treatment of
asthma?
What is the role of inhaled corticosteroids in the treatment of acute asthma?
How is albuterol administered to patients with asthma?
Which side effects are associated with albuterol in the treatment of asthma?
Which alternative treatments are available for patients who respond poorly to inhaled beta-agonist therapy in the
treatment of asthma?
When is ipratropium indicated in the treatment of acute asthma?
Which method of nebulizer therapy is recommended for severe exacerbations of asthma?
Have nebulizers been shown to be more effective than metered dose inhalers (MDIs) in the management of acute
asthma?
Which adverse effects are associated with corticosteroid treatment in children with asthma?
Which complications are associated with long-term corticosteroid use in asthma?
What is the role of heliox in the treatment of asthma?
How is heliox administered to a patient in the treatment of asthma?
When is endotracheal intubation indicated in the treatment of severe asthma exacerbations?
When is hospitalization indicated for treatment of a patient with asthma?
When should a patient with asthma be admitted to the ICU?
When is an acute asthmatic episode considered an emergency?
How is asthma managed during pregnancy?
How is GERD managed in patients with asthma?
How is sinusitis treated in the setting of asthma?
How is nocturnal asthma managed?
What is the role of long-term monitoring in the management of asthma?
Which assessments can be used to determine a patient’s response to treatment for asthma?
Which assessments should be included in a preoperative workup for asthma?
What are the general recommendations regarding activity for patients with asthma?
What is the relationship between obesity and asthma?
Which dietary restrictions may be recommended for patients with asthma?
When should patients with asthma be referred for additional consultations?
How can patients manage factors that contribute to their asthma symptoms?
Guidelines
20/11/18 12.32
What are the classification guidelines of asthma?
What is the difference between severe asthma and uncontrolled asthma according to the guidelines?
What are the overall goals of asthma management according to the guidelines?
What are the features of each step in a stepwise approach to pharmacotherapy in the treatment of asthma according
to the guidelines?
What are recommended treatment guidelines for severe asthma?
What are recommended treatment guidelines for exercise-induced bronchoconstriction (EIB) (exercise-induced
asthma)?
Medications
How are asthma medications categorized?
What randomized, controlled trials have been conducted on the use of inhaled corticosteroids in the treatment of
asthma?
Which medications in the drug class Beta2-adrenergic agonist agents are used in the treatment of Asthma?
Which medications in the drug class Anticholinergic Agents are used in the treatment of Asthma?
Which medications in the drug class Anticholinergic agent combinations are used in the treatment of Asthma?
Which medications in the drug class Corticosteroid, oral are used in the treatment of Asthma?
Which medications in the drug class Long-acting beta2 agonists are used in the treatment of Asthma?
Which medications in the drug class Beta2-Agonist/Corticosteroid Combinations are used in the treatment of Asthma?
Which medications in the drug class Methylxanthines are used in the treatment of Asthma?
Which medications in the drug class Mast cell stabilizers are used in the treatment of Asthma?
Which medications in the drug class Corticosteroid, Inhalant are used in the treatment of Asthma?
Which medications in the drug class Leukotriene Receptor Antagonist are used in the treatment of Asthma?
Which medications in the drug class Monoclonal Antibodies, Anti-asthmatics are used in the treatment of Asthma?
Contributor Information and Disclosures
Author
Michael J Morris, MD, FACP, FCCP Clinical Faculty, Pulmonary Disease/Critical Care Service, Department of
Medicine, Brooke Army Medical Center; Assistant Dean for Research, SAUSHEC, Brooke Army Medical Center;
Clinical Professor, University of Texas School of Medicine at San Antonio; Professor, Uniformed Services University of
the Health Sciences
Michael J Morris, MD, FACP, FCCP is a member of the following medical societies: American Association for
Respiratory Care, American College of Chest Physicians, American College of Physicians, Association of Military
Surgeons of the US
Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Janssen Pharmaceuticals; Vyaire Medical.
Coauthor(s)
Daniel J Pearson, MD Chief of Pulmonary Medicine, Wright-Patterson Medical Center
Daniel J Pearson, MD is a member of the following medical societies: American College of Chest Physicians,
20/11/18 12.32
American College of Physicians, American Heart Association, American Thoracic Society, Society of Critical Care
Medicine
Disclosure: Nothing to disclose.
Chief Editor
Zab Mosenifar, MD, FACP, FCCP Geri and Richard Brawerman Chair in Pulmonary and Critical Care Medicine,
Professor and Executive Vice Chairman, Department of Medicine, Medical Director, Women's Guild Lung Institute,
Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine
Zab Mosenifar, MD, FACP, FCCP is a member of the following medical societies: American College of Chest
Physicians, American College of Physicians, American Federation for Medical Research, American Thoracic Society
Acknowledgements
Edward Bessman, MD, MBA Chairman and Clinical Director, Department of Emergency Medicine, John Hopkins
Bayview Medical Center; Assistant Professor, Department of Emergency Medicine, Johns Hopkins University School
of Medicine
Edward Bessman, MD, MBA is a member of the following medical societies: American Academy of Emergency
Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine
Paul Blackburn, DO, FACOEP, FACEP Attending Physician, Department of Emergency Medicine, Maricopa Medical
Center
Paul Blackburn, DO, FACOEP, FACEP is a member of the following medical societies: American College of
Emergency Physicians, American College of Osteopathic Emergency Physicians, American Medical Association, and
Arizona Medical Association
Barry E Brenner, MD, PhD, FACEP Professor of Emergency Medicine, Professor of Internal Medicine, Program
Director for Emergency Medicine, Case Medical Center, University Hospitals, Case Western Reserve University
School of Medicine
Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American
Academy of Emergency Medicine, American College of Chest Physicians, American College of Emergency
Physicians, American College of Physicians, American Heart Association, American Thoracic Society, Arkansas
Medical Society, New York Academy of Medicine, New York Academy of Sciences, and Society for Academic
Emergency Medicine
Helen M Hollingsworth, MD Director, Adult Asthma and Allergy Services, Associate Professor, Department of Internal
Medicine, Division of Pulmonary and Critical Care, Boston Medical Center
Helen M Hollingsworth, MD is a member of the following medical societies: American Academy of Allergy Asthma and
Immunology, American College of Chest Physicians, American Thoracic Society, and Massachusetts Medical Society
Robert E O'Connor, MD, MPH Professor and Chair, Department of Emergency Medicine, University of Virginia Health
System
Robert E O'Connor, MD, MPH is a member of the following medical societies: American Academy of Emergency
Medicine, American College of Emergency Physicians, American College of Physician Executives, American Heart
Association, American Medical Association, Medical Society of Delaware, National Association of EMS Physicians,
Society for Academic Emergency Medicine, and Wilderness Medical Society
20/11/18 12.32
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of
Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
References
1. [Guideline] National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the
Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol. 2007 Nov. 120 (5 Suppl):S94-138.
[Medline].
2. Busse WW, Calhoun WF, Sedgwick JD. Mechanism of airway inflammation in asthma. Am Rev Respir Dis. 1993 Jun. 147(6
Pt 2):S20-4. [Medline].
3. Horwitz RJ, Busse WW. Inflammation and asthma. Clin Chest Med. 1995 Dec. 16(4):583-602. [Medline].
4. Murray JF, Nadel JA. Structure of the lungs relative to their principal function. Textbook of Respiratory Medicine. WB
Saunders Co; 1988. 15-20.
5. Balzar S, Fajt ML, Comhair SA, Erzurum SC, Bleecker E, Busse WW, et al. Mast cell phenotype, location, and activation in
severe asthma: data from the severe asthma research program. Am J Respir Crit Care Med. 2011 Feb 1. 183(3):299-309.
[Medline]. [Full Text].
6. Gauvreau GM, Boulet LP, Cockcroft DW, et al. Effects of Interleukin-13 Blockade on Allergen-induced Airway Responses in
Mild Atopic Asthma. Am J Respir Crit Care Med. 2011 Apr 15. 183(8):1007-14. [Medline].
7. Anderson WJ, Watson L. Asthma and the hygiene hypothesis. N Engl J Med. 2001 May 24. 344(21):1643-4. [Medline].
8. Brooks C, Pearce N, Douwes J. The hygiene hypothesis in allergy and asthma: an update. Curr Opin Allergy Clin Immunol.
2013 Feb. 13 (1):70-7. [Medline].
9. Sears MR. Consequences of long-term inflammation. The natural history of asthma. Clin Chest Med. 2000 Jun. 21(2):315-
29. [Medline].
10. Camargo CA Jr, Weiss ST, Zhang S, Willett WC, Speizer FE. Prospective study of body mass index, weight change, and risk
of adult-onset asthma in women. Arch Intern Med. 1999 Nov 22. 159(21):2582-8. [Medline].
11. Henderson WR Jr. Role of leukotrienes in asthma. Ann Allergy. 1994 Mar. 72(3):272-8. [Medline].
12. Beasley RW, Clayton TO, Crane J, Lai CK, Montefort SR, Mutius E, et al. Acetaminophen use and risk of asthma,
rhinoconjunctivitis, and eczema in adolescents: international study of asthma and allergies in childhood phase three. Am J
Respir Crit Care Med. 2011 Jan 15. 183(2):171-8. [Medline].
13. Comert S, Karakaya G. Kalyoncu AF. Aspirin desensitization treatment for the management of aspirin-exacerbated
respiratory disease. J Respir Res. 2016. 2:24-7.
14. Harding SM, Guzzo MR, Richter JE. The prevalence of gastroesophageal reflux in asthma patients without reflux symptoms.
Am J Respir Crit Care Med. 2000 Jul. 162(1):34-9. [Medline].
15. Tarlo SM, Balmes J, Balkissoon R, Beach J, Beckett W, Bernstein D, et al. Diagnosis and management of work-related
asthma: American College Of Chest Physicians Consensus Statement. Chest. 2008 Sep. 134(3 Suppl):1S-41S. [Medline].
16. Lemanske RF Jr, Jackson DJ, Gangnon RE, Evans MD, Li Z, Shult PA, et al. Rhinovirus illnesses during infancy predict
subsequent childhood wheezing. J Allergy Clin Immunol. 2005 Sep. 116(3):571-7. [Medline].
17. Bizzintino J, Lee WM, Laing IA, Vang F, Pappas T, Zhang G, et al. Association between human rhinovirus C and severity of
acute asthma in children. Eur Respir J. 2011 May. 37(5):1037-42. [Medline]. [Full Text].
18. Martin RJ, Kraft M, Chu HW, Berns EA, Cassell GH. A link between chronic asthma and chronic infection. J Allergy Clin
Immunol. 2001 Apr. 107(4):595-601. [Medline].
19. Hamilos DL. Gastroesophageal reflux and sinusitis in asthma. Clin Chest Med. 1995 Dec. 16(4):683-97. [Medline].
20. McFadden ER Jr. Exercise-induced airway obstruction. Clin Chest Med. 1995 Dec. 16(4):671-82. [Medline].
20/11/18 12.32
21. Randolph C. Exercise-induced asthma: update on pathophysiology, clinical diagnosis, and treatment. Curr Probl Pediatr.
1997 Feb. 27(2):53-77. [Medline].
22. Ito S, Noguchi E, Shibasaki M, Yamakawa-Kobayashi K, Watanabe H, Arinami T. Evidence for an association between
plasma platelet-activating factor acetylhydrolase deficiency and increased risk of childhood atopic asthma. J Hum Genet.
2002. 47(2):99-101. [Medline].
23. Bousquet J, Jeffery PK, Busse WW, Johnson M, Vignola AM. Asthma. From bronchoconstriction to airways inflammation and
remodeling. Am J Respir Crit Care Med. 2000 May. 161(5):1720-45. [Medline].
24. Zucker, M. Asthma phenotype, genotype may guide future therapies. Available at
http://www.pulmonaryreviews.com/jun03/pr_jun03_phenotype.html. Accessed: June 8, 2003.
25. Drazen JM, Yandava CN, Dube L, Szczerback N, Hippensteel R, Pillari A, et al. Pharmacogenetic association between
ALOX5 promoter genotype and the response to anti-asthma treatment. Nat Genet. 1999 Jun. 22(2):168-70. [Medline].
26. Thompson EE, Pan L, Ostrovnaya I, Weiss LA, Gern JE, Lemanske RF Jr, et al. Integrin beta 3 genotype influences asthma
and allergy phenotypes in the first 6 years of life. J Allergy Clin Immunol. 2007 Jun. 119(6):1423-9. [Medline].
27. Wechsler ME, Lehman E, Lazarus SC, Lemanske RF Jr, Boushey HA, Deykin A, et al. beta-Adrenergic receptor
polymorphisms and response to salmeterol. Am J Respir Crit Care Med. 2006 Mar 1. 173(5):519-26. [Medline]. [Full Text].
28. Cottrell L, Neal WA, Ice C, Perez MK, Piedimonte G. Metabolic abnormalities in children with asthma. Am J Respir Crit Care
Med. 2011 Feb 15. 183(4):441-8. [Medline]. [Full Text].
29. Juel CT, Ali Z, Nilas L, Ulrik CS. Asthma and obesity: does weight loss improve asthma control? a systematic review. J
Asthma Allergy. 2012. 5:21-6. [Medline].
30. Sonnenschein-van der Voort AM, Jaddoe VW, Raat H, Moll HA, Hofman A, de Jongste JC, et al. Fetal and infant growth and
asthma symptoms in preschool children: the generation R study. Am J Respir Crit Care Med. 2012 Apr 1. 185(7):731-7.
[Medline].
31. Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald M, et al. Global strategy for asthma management and
prevention: GINA executive summary. Eur Respir J. 2008 Jan. 31(1):143-78. [Medline]. [Full Text].
32. Zhang Y, McConnell R, Gilliland F, Berhane K. Ethnic differences in the effect of asthma on pulmonary function in children.
Am J Respir Crit Care Med. 2011 Mar 1. 183(5):596-603. [Medline]. [Full Text].
33. Burrows B, Barbee RA, Cline MG, Knudson RJ, Lebowitz MD. Characteristics of asthma among elderly adults in a sample of
the general population. Chest. 1991 Oct. 100(4):935-42. [Medline].
34. Martin AJ, Landau LI, Phelan PD. Lung function in young adults who had asthma in childhood. Am Rev Respir Dis. 1980
Oct. 122(4):609-16. [Medline].
35. Sly RM. Changing asthma mortality. Ann Allergy. 1994 Sep. 73(3):259-68. [Medline].
36. Moorman JE, Rudd RA, Johnson CA, King M, Minor P, Bailey C, et al. National surveillance for asthma--United States, 1980-
2004. MMWR Surveill Summ. 2007 Oct 19. 56(8):1-54. [Medline].
37. National Heart, Lung, and Blood Institute Chartbook on Cardiovascular, Lung, and BloodDiseases, U.S. Department of
Health and Human Services, et al. 2009. Available at http://www.nhlbi.nih.gov/resources/docs/2009_ChartBook.pdf.
38. Bailey WC, Richards JM Jr, Brooks CM, Soong SJ, Windsor RA, Manzella BA. A randomized trial to improve self-
management practices of adults with asthma. Arch Intern Med. 1990 Aug. 150(8):1664-8. [Medline].
39. Ignacio-Garcia JM, Gonzalez-Santos P. Asthma self-management education program by home monitoring of peak expiratory
flow. Am J Respir Crit Care Med. 1995 Feb. 151(2 Pt 1):353-9. [Medline].
40. Kotses H, Bernstein IL, Bernstein DI, Reynolds RV, Korbee L, Wigal JK, et al. A self-management program for adult asthma.
Part I: Development and evaluation. J Allergy Clin Immunol. 1995 Feb. 95(2):529-40. [Medline].
41. Nathan RA, Sorkness CA, Kosinski M, Schatz M, Li JT, Marcus P, et al. Development of the asthma control test: a survey for
assessing asthma control. J Allergy Clin Immunol. 2004 Jan. 113(1):59-65. [Medline].
42. Coffman JM, Cabana MD, Yelin EH. Do school-based asthma education programs improve self-management and health
outcomes?. Pediatrics. 2009 Aug. 124(2):729-42. [Medline]. [Full Text].
43. [Guideline] Management of Asthma Working Group. VA/DoD clinical practice guideline for management of asthma in children
20/11/18 12.32
and adults. Washington (DC): Department of Veteran Affairs, Department of Defense; 2009. [Full Text].
44. Font-Ribera L, Villanueva CM, Nieuwenhuijsen MJ, et al. Swimming pool attendance, asthma, allergies, and lung function in
the Avon Longitudinal Study of Parents and Children cohort. Am J Respir Crit Care Med. 2011 Mar 1. 183(5):582-8.
[Medline]. [Full Text].
45. Shao W, Chung T, Berdon WE, Mellins RB, Griscom NT, Ruzal-Shapiro C, et al. Fluoroscopic diagnosis of laryngeal asthma
(paradoxical vocal cord motion). AJR Am J Roentgenol. 1995 Nov. 165(5):1229-31. [Medline].
46. Morris MJ, Deal LE, Bean DR, Grbach VX, Morgan JA. Vocal cord dysfunction in patients with exertional dyspnea. Chest.
1999 Dec. 116(6):1676-82. [Medline].
47. Nastasi KJ, Howard DA, Raby RB, Lew DB, Blaiss MS. Airway fluoroscopic diagnosis of vocal cord dysfunction syndrome.
Ann Allergy Asthma Immunol. 1997 Jun. 78(6):586-8. [Medline].
48. Wynn SR, O'Connell EJ, Frigas E, Payne WS, Sachs MI. Exercise-induced "asthma" as a presentation of bronchial
carcinoid. Ann Allergy. 1986 Aug. 57(2):139-41. [Medline].
49. Rolfe LM, Rayner CF. A wheezy man with a bony abnormality. Postgrad Med J. 1999 Aug. 75(886):503-4. [Medline]. [Full
Text].
50. Tucker GF Jr. Pulmonary migraine. Ann Otol Rhinol Laryngol. 1977 Sep-Oct. 86(5 Pt 1):671-6. [Medline].
51. Isselbacher KJ. Harrison's Principles of Internal Medicine. Braunwald E, Wilson JD, et al. Heart failure. 13th. McGraw-Hill;
1994. 1001.
52. Kim YW, Han SK, Shim YS, Kim KY, Han YC, Seo JW, et al. The first report of diffuse panbronchiolitis in Korea: five case
reports. Intern Med. 1992 May. 31(5):695-701. [Medline].
53. Bevelaqua F, Schicchi JS, Haas F, Axen K, Levin N. Aortic arch anomaly presenting as exercise-induced asthma. Am Rev
Respir Dis. 1989 Sep. 140(3):805-8. [Medline].
54. Newman LJ, Platts-Mills TA, Phillips CD, Hazen KC, Gross CW. Chronic sinusitis. Relationship of computed tomographic
findings to allergy, asthma, and eosinophilia. JAMA. 1994 Feb 2. 271(5):363-7. [Medline].
55. Shapiro GG, Christie DL. Gastroesophageal reflux and asthma. Clin Rev Allergy. 1983 Mar. 1(1):39-56. [Medline].
56. Cuevas Hernández MM, Arias Hernández RM. [Pulmonary gammagraphy study in asthmatic children with gastroesophageal
reflux]. Rev Alerg Mex. 2008 Nov-Dec. 55(6):229-33. [Medline].
57. Bacci E, Cianchetti S, Bartoli M, Dente FL, Di Franco A, Vagaggini B, et al. Low sputum eosinophils predict the lack of
response to beclomethasone in symptomatic asthmatic patients. Chest. 2006 Mar. 129(3):565-72. [Medline].
58. Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, et al. Asthma exacerbations and sputum
eosinophil counts: a randomised controlled trial. Lancet. 2002 Nov 30. 360(9347):1715-21. [Medline].
59. Matsumoto H. Serum periostin: a novel biomarker for asthma management. Allergol Int. 2014 Jun. 63 (2):153-60. [Medline].
60. Woods AQ, Lynch DA. Asthma: an imaging update. Radiol Clin North Am. 2009 Mar. 47(2):317-29. [Medline].
61. Teel GS, Engeler CE, Tashijian JH, duCret RP. Imaging of small airways disease. Radiographics. 1996 Jan. 16(1):27-41.
[Medline].
62. Enright PL, Lebowitz MD, Cockroft DW. Physiologic measures: pulmonary function tests. Asthma outcome. Am J Respir Crit
Care Med. 1994 Feb. 149(2 Pt 2):S9-18; discussion S19-20. [Medline].
63. Ali SS, O'Connell C, Kass L, Graff G. Single-breath counting: a pilot study of a novel technique for measuring pulmonary
function in children. Am J Emerg Med. 2011 Jan. 29(1):33-6. [Medline].
64. Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG. Guidelines for methacholine and exercise challenge
testing-1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999.
Am J Respir Crit Care Med. 2000 Jan. 161(1):309-29. [Medline].
65. Anderson SD, Charlton B, Weiler JM, Nichols S, Spector SL, Pearlman DS, et al. Comparison of mannitol and methacholine
to predict exercise-induced bronchoconstriction and a clinical diagnosis of asthma. Respir Res. 2009 Jan 23. 10:4. [Medline].
66. Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment in
chronic asthma. N Engl J Med. 2005 May 26. 352(21):2163-73. [Medline].
20/11/18 12.32
67. Rossi OV, Lähde S, Laitinen J, Huhti E. Contribution of chest and paranasal sinus radiographs to the management of acute
asthma. Int Arch Allergy Immunol. 1994 Sep. 105(1):96-100. [Medline].
68. Pratter MR, Curley FJ, Dubois J, Irwin RS. Cause and evaluation of chronic dyspnea in a pulmonary disease clinic. Arch
Intern Med. 1989 Oct. 149(10):2277-82. [Medline].
69. Irwin RS. Chronic cough due to gastroesophageal reflux disease: ACCP evidence-based clinical practice guidelines. Chest.
2006 Jan. 129(1 Suppl):80S-94S. [Medline].
70. Aras G, Kanmaz D, Kadakal F, Purisa S, Sonmez K, Tuncay E, et al. Gastroesophageal reflux disease in our asthma
patients: the presence of dysphagia can influence pulmonary function. Multidiscip Respir Med. 2012 Dec 17. 7 (1):53.
[Medline].
71. Price D, Musgrave SD, Shepstone L, et al. Leukotriene antagonists as first-line or add-on asthma-controller therapy. N Engl J
Med. 2011 May 5. 364(18):1695-707. [Medline].
72. Chauhan BF, Ducharme FM. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent
and/or chronic asthma in adults and children. Cochrane Database Syst Rev. 2012 May 16. 5:CD002314. [Medline].
73. Bruzzese JM, Sheares BJ, Vincent EJ, et al. Effects of a School-based Intervention for Urban Adolescents with Asthma: A
Controlled Trial. Am J Respir Crit Care Med. 2011 Apr 15. 183(8):998-1006. [Medline]. [Full Text].
74. Scott M, Roberts G, Kurukulaaratchy RJ, Matthews S, Nove A, Arshad SH. Multifaceted allergen avoidance during infancy
reduces asthma during childhood with the effect persisting until age 18 years. Thorax. 2012 Dec. 67(12):1046-51. [Medline].
75. McCormack MC, Breysse PN, Matsui EC, et al. Indoor particulate matter increases asthma morbidity in children with non-
atopic and atopic asthma. Ann Allergy Asthma Immunol. 2011 Apr. 106(4):308-15. [Medline].
76. Tung KY, Tsai CH, Lee YL. Microsomal epoxide hydroxylase genotypes/diplotypes, traffic air pollution, and childhood asthma.
Chest. 2011 Apr. 139(4):839-48. [Medline].
77. Sheikh A, Hurwitz B, Shehata Y. House dust mite avoidance measures for perennial allergic rhinitis. Cochrane Database
Syst Rev. 2007 Jan 24. CD001563. [Medline].
78. Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2003. CD001186.
[Medline].
79. Abramson MJ, Puy RM, Weiner JM. Is allergen immunotherapy effective in asthma? A meta-analysis of randomized
controlled trials. Am J Respir Crit Care Med. 1995 Apr. 151(4):969-74. [Medline].
80. Bruggenjurgen B, Reinhold T, Brehler R, Laake E, Wiese G, Machate U, et al. Cost-effectiveness of specific subcutaneous
immunotherapy in patients with allergic rhinitis and allergic asthma. Ann Allergy Asthma Immunol. 2008 Sep. 101(3):316-24.
[Medline].
81. Marcus P. Incorporating anti-IgE (omalizumab) therapy into pulmonary medicine practice: practice management implications.
Chest. 2006 Feb. 129(2):466-74. [Medline].
82. Busse WW, Morgan WJ, Gergen PJ, et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N
Engl J Med. 2011 Mar 17. 364(11):1005-15. [Medline]. [Full Text].
83. Hanania NA, Alpan O, Hamilos DL, et al. Omalizumab in severe allergic asthma inadequately controlled with standard
therapy: a randomized trial. Ann Intern Med. 2011 May 3. 154(9):573-82. [Medline].
84. Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. Mepolizumab treatment in patients with severe
eosinophilic asthma. N Engl J Med. 2014 Sep 25. 371 (13):1198-207. [Medline]. [Full Text].
85. Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al. Oral glucocorticoid-sparing effect of
mepolizumab in eosinophilic asthma. N Engl J Med. 2014 Sep 25. 371 (13):1189-97. [Medline]. [Full Text].
86. Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma
(DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012 Aug 18. 380 (9842):651-9. [Medline].
87. Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, et al. Reslizumab for inadequately controlled
asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-
controlled, phase 3 trials. Lancet Respir Med. 2015 May. 3 (5):355-66. [Medline].
88. Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and safety of benralizumab for
patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO):
20/11/18 12.32
a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016 Oct 29. 388 (10056):2115-2127. [Medline].
89. FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, et al. Benralizumab, an anti-interleukin-5 receptor α
monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a
randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016 Oct 29. 388 (10056):2128-2141. [Medline].
90. Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, et al. Oral Glucocorticoid-Sparing Effect of Benralizumab in
Severe Asthma. N Engl J Med. 2017 Jun 22. 376 (25):2448-2458. [Medline].
91. Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, et al. Dupilumab Efficacy and Safety in Moderate-to-Severe
Uncontrolled Asthma. N Engl J Med. 2018 Jun 28. 378 (26):2486-2496. [Medline].
92. Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, et al. Efficacy and Safety of Dupilumab in Glucocorticoid-
Dependent Severe Asthma. N Engl J Med. 2018 Jun 28. 378 (26):2475-2485. [Medline].
93. Castro M, Rubin AS, Laviolette M, Fiterman J, De Andrade Lima M, Shah PL, et al. Effectiveness and safety of bronchial
thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J
Respir Crit Care Med. 2010 Jan 15. 181(2):116-24. [Medline].
94. Keller D. Bronchial Thermoplasty Benefits Asthma Sufferers Long Term. Medscape Medical News. Available at
http://www.medscape.com/viewarticle/804695. Accessed: June 4, 2013.
95. Wechsler ME, Laviolette M, Rubin AS, Fiterman J, Lapa E Silva JR, Shah PL, et al. Bronchial thermoplasty: Long-term safety
and effectiveness in patients with severe persistent asthma. J Allergy Clin Immunol. 2013 Aug 30. [Medline].
96. Boggs W. Bronchial Thermoplasty Effective for Severe Persistent Asthma. Medscape [serial online]. Available at
http://www.medscape.com/viewarticle/811113. Accessed: September 30, 2013.
97. O'Byrne PM, Pedersen S, Carlsson LG, et al. Risks of pneumonia in patients with asthma taking inhaled corticosteroids. Am
J Respir Crit Care Med. 2011 Mar 1. 183(5):589-95. [Medline].
98. Dhuper S, Chandra A, Ahmed A, et al. Efficacy and cost comparisons of bronchodilatator administration between metered
dose inhalers with disposable spacers and nebulizers for acute asthma treatment. J Emerg Med. 2011 Mar. 40(3):247-55.
[Medline].
99. Rowe BH, Keller JL, Oxman AD. Effectiveness of steroid therapy in acute exacerbations of asthma: a meta-analysis. Am J
Emerg Med. 1992 Jul. 10(4):301-10. [Medline].
100. Rowe BH, Edmonds ML, Spooner CH, Diner B, Camargo CA Jr. Corticosteroid therapy for acute asthma. Respir Med. 2004
Apr. 98(4):275-84. [Medline].
101. Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl
J Med. 2000 Oct 12. 343(15):1064-9. [Medline].
102. Tastepe AI, Kuzucu A, Demircan S, Liman ST, Demirag F. Surgical treatment of tracheal hamartoma. Scand Cardiovasc J.
1998. 32(4):239-41. [Medline].
103. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. Long-term inhaled corticosteroids in
preschool children at high risk for asthma. N Engl J Med. 2006 May 11. 354(19):1985-97. [Medline].
104. van den Berge M, ten Hacken NH, Cohen J, Douma WR, Postma DS. Small airway disease in asthma and COPD: clinical
implications. Chest. 2011 Feb. 139(2):412-23. [Medline].
105. Kingston HG, Hirshman CA. Perioperative management of the patient with asthma. Anesth Analg. 1984 Sep. 63(9):844-55.
[Medline].
106. [Guideline] Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2016. Global Initiative for
Asthma (GINA). Available at http://www.ginasthma.org. 2016; Accessed: May 9, 2016.
107. Scott HA, Gibson PG, Garg ML, Pretto JJ, Morgan PJ, Callister R, et al. Dietary restriction and exercise improve airway
inflammation and clinical outcomes in overweight and obese asthma: a randomized trial. Clin Exp Allergy. 2013 Jan. 43
(1):36-49. [Medline].
108. [Guideline] Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on
definition, evaluation and treatment of severe asthma. Eur Respir J. 2014 Feb. 43 (2):343-73. [Medline].
109. Berridge MS, Lee Z, Heald DL. Pulmonary distribution and kinetics of inhaled [11C]triamcinolone acetonide. J Nucl Med.
2000 Oct. 41(10):1603-11. [Medline].
20/11/18 12.32
110. Nelson HS. Advair: combination treatment with fluticasone propionate/salmeterol in the treatment of asthma. J Allergy Clin
Immunol. 2001 Feb. 107(2):398-416. [Medline].
111. [Guideline] Parsons JP, Hallstrand TS, Mastronarde JG, Kaminsky DA, Rundell KW, Hull JH, et al. An official American
Thoracic Society clinical practice guideline: exercise-induced bronchoconstriction. Am J Respir Crit Care Med. 2013 May 1.
187 (9):1016-27. [Medline].
112. Tantisira KG, Lasky-Su J, Harada M, et al. Genomewide association between GLCCI1 and response to glucocorticoid
therapy in asthma. N Engl J Med. 2011 Sep 29. 365(13):1173-83. [Medline].
113. Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R, Ameredes BT, et al. Tiotropium bromide step-up therapy for
adults with uncontrolled asthma. N Engl J Med. 2010 Oct 28. 363(18):1715-26. [Medline]. [Full Text].
114. Kerstjens HA, Engel M, Dahl R, Paggiaro P, Beck E, Vandewalker M, et al. Tiotropium in Asthma Poorly Controlled with
Standard Combination Therapy. N Engl J Med. 2012 Sep 2. [Medline].
115. Rank MA, Liesinger JT, Ziegenfuss JY, Branda ME, Lim KG, Yawn BP, et al. The impact of asthma medication guidelines on
asthma controller use and on asthma exacerbation rates comparing 1997-1998 and 2004-2005. Ann Allergy Asthma
Immunol. 2012 Jan. 108(1):9-13. [Medline].
116. Brooks M. FDA Oks New Maintenance Asthma Treatment Arnuity Ellipta. Medscape Medical News. Available at
http://www.medscape.com/viewarticle/830213. Accessed: August 23, 2014.

Asthma: Signs and Symptoms

Caricato da

Informazioni sul documento

Descrizione originale:

Titolo originale

Copyright

Formati disponibili

Condividi questo documento

Condividi o incorpora il documento

Opzioni di condivisione

Hai trovato utile questo documento?

Questo contenuto è inappropriato?

Copyright:

Formati disponibili

Asthma: Signs and Symptoms

Caricato da

Copyright:

Formati disponibili

20/11/18 12.

Signs and symptoms

Signs and symptoms of asthma include the following:

See Clinical Presentation for more detail.

Episodic symptoms of airflow obstruction are present

Airflow obstruction or symptoms are at least partially reversible

Exclusion of alternative diagnoses

See Workup for more detail.

See Treatment and Medication for more detail.

Airway hyperresponsiveness or bronchial hyperreactivity in asthma is an exaggerated response to numerous

Airway structure consists of the following:

A smooth-muscle matrix extending to the alveolar entrances

Predominantly fibrocartilaginous or fibroelastic-supporting connective tissue.

The pathophysiology of asthma is complex and involves the following components:

Intermittent airflow obstruction

The presence of airway hyperresponsiveness or bronchial hyperreactivity in asthma is an exaggerated response to

Viral respiratory tract infections

Gastroesophageal reflux disease

Chronic sinusitis or rhinitis

Aspirin or nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity, sulfite sensitivity

Use of beta-adrenergic receptor blockers (including ophthalmic preparations)

Environmental pollutants, tobacco smoke

Irritants (eg, household sprays, paint fumes)

Emotional factors or stress

Gastroesophageal reflux disease

Viral exposure in children

Exercise-induced asthma (EIA), or exercise-induced bronchoconstriction (EIB), is an asthma variant defined as a

Exposure to cold or dry air

Environmental pollutants (eg, sulfur, ozone)

level of bronchial hyperreactivity

Chronicity of asthma and symptomatic control

Duration and intensity of exercise

Allergen exposure in atopic individuals

Coexisting respiratory infection

The key points of education include the following:

Patient education should be integrated into every aspect of asthma care

Treatment goals should be developed for the patient and family.

A written, individualized, daily self-management plan should be developed.

A patient education video of an overview of asthma is provided below.

Whether symptoms are attributable to asthma

Whether findings support the likelihood of asthma (eg, family history)

Identification of possible precipitating factors

The patient’s exacerbation history is important with respect to the following:

Usual prodromal signs or symptoms

Number in the last year

Need for emergency department visits, hospitalizations, ICU admissions, intubations

Missed days from work or school or activity limitation

General manifestations of asthma

Episodic symptoms of airflow obstruction are present

Airflow obstruction or symptoms are at least partially reversible

Exclusion of alternative diagnoses.

Manifestations of an acute episode

Moderately severe episodes

Imminent respiratory arrest

The severity of asthma is classified as the following:

Vocal cord dysfunction or inducible laryngeal obstruction (ILO)

Tracheal and bronchial lesions

Congestive heart failure

Aortic arch anomalies

Other conditions and factors

long-term treatment with corticosteroids.

Chronic Obstructive Pulmonary Disease (COPD)