2153Asthma CHAPTER 287

Fungi and Allergic Airway Mycoses One to 2% of patients with

asthma may have an IgE-mediated sensitization to colonization of the

airway by fungi, with the most common fungus causing such a reaction being Aspergillus fumigatus. So-called allergic bronchopulmonary

aspergillosis (ABPA) is characterized by a type 2 airway inflammatory

response to aspergillus with IgE >1000 IU/mL, eosinophils >500/μL,

positive skin test to Aspergillus, and specific IgE and IgG antibodies to

Aspergillus. Patients may have intermittent mucus plugging and central bronchiectasis. Up to two-thirds of patients will grow Aspergillus

from the sputum. Treatment involves systemic antifungal treatment

with itraconazole or voriconazole and oral corticosteroids.

Exercise-Induced Symptoms in Elite Athletes Exerciseinduced airway narrowing in elite athletes undertaking extreme exercise

in strenuous condition. These athletes may have little, or no, airway

hyperreactivity or asthma risk factors. The condition may involve additional mechanisms including direct epithelial injury. Such a syndrome

has also been reported in swimmers possibly related to pool chlorination.

■ TRIGGERS OF AIRWAY NARROWING

The risk factors and exposures reviewed above lead to increased airway reactivity and a propensity to react to factors that trigger airway

narrowing (see Fig. 287-1). Almost all asthmatics can identify triggers

that will make their asthma worse. These triggers are listed in Table

287-2. Many of them overlap with the risk factors and etiologic factors reviewed above. In some cases, elimination of these triggers may

dramatically reduce the impairment caused by asthma. In a minority,

abatement can lead to “remission” so that these patients no longer

require asthma medications and do not experience bronchospasm

with their daily activities and routines. While acute exposures to these

triggers generally cause short-lived bronchospasm, the bronchospasm

may be severe enough that treatment for an exacerbation is required.

Chronic exposure may lead to permanent deterioration in asthma

control, although this does not appear to be true for exercise or stress.

It should be noted that evidence suggests that severe asthma exacerbations (those requiring systemic corticosteroids) may, in and of

themselves, accelerate lung function decline.

Allergens In patients with sensitization to particular allergens

through production of allergen-specific IgE, exposure to those allergens by inhalation can result in activation of mast cells and basophils

with acute production of bronchoactive mediators (see Fig. 287-3). Such

exposure can produce immediate bronchospasm (early response)

and a late response (2–24 h after exposure) with bronchial narrowing

and inflammation. These mechanisms can account for reactions to

inhalation of pollens, mold, or dust; insects (especially cockroaches);

animals; occupational materials; seasonal worsening of asthma; and

so-called “thunderstorm asthma.” Chronic exposure may lead to persistent symptoms. While food allergies can produce bronchospasm

through anaphylaxis, food allergies are generally not etiologically

linked to asthma.

Irritants Many asthmatics report increased symptoms on exposure

to strong odors, smoke, combustion products, cleaning fluids, or perfumes. In general, the effects are short-lived, although chronic exposure

(see “Occupational Exposures” above) and large-quantity exposures

(see discussion of RADS above) can lead to long-lasting or permanent

symptoms.

Viral Infections Most asthmatics report that asthma exacerbations can be triggered by upper respiratory infections. The inflammation that occurs may be neutrophilic as well as eosinophilic. There is

some evidence that IgE generation may reduce production of interferon, possibly predisposing to the effects of upper respiratory viruses.

Increased airway reactivity after viral infections generally persists

for 4–6 weeks but, in some cases, may be associated with permanent

changes and impairment.

Exercise and Cold/Dry Air Exercise may be a trigger to asthmatic bronchoconstriction in patients with asthma. Hyperventilation

that occurs with exercise dries the airway lining, changing the tonicity

of lining cells and causing release of bronchoconstrictive mediators.

This effect is more prominent the lower the moisture content of the

air, and since cold air has a lower absolute moisture content, the lower

the temperature of the inspired air, the less exercise is required to

induce bronchoconstriction. In addition, cold air may produce airway

edema during airway wall rewarming. At routine levels of exercise,

these effects are short-lived.

Air Pollution Increased rates of exacerbations have been associated with increased ambient ozone, sulfur dioxide, and nitrogen

dioxide, among other air pollutants.

Drugs Beta blockers may trigger bronchospasm even when used

solely in ophthalmic preparations. While the more selective beta

blockers are safe for most asthmatics, beta blocker use may be a

cause of difficult-to-control asthma. Aspirin may precipitate bronchospasm in those with aspirin-exacerbated respiratory disease (see

“Special Considerations”). Angiotensin-converting enzyme (ACE)

inhibitors (and to a lesser extent angiotensin receptor blockers) may

cause cough.

Occupational Exposures In addition to RADS (see above), episodic and/or recurrent exposures to workplace irritants and/or substances to which one has become sensitized can produce symptoms.

These symptoms are usually reduced when patients are away from

such exposures on weekends or vacation.

Stress Asthmatics may report increased symptoms with stress. The

mechanisms are poorly understood.

Hormonal Factors A small proportion of women report a regular increase in perimenstrual symptoms, and symptoms may worsen

during perimenopause. This may be related to rapid fluctuations in

estrogen levels. Pregnancy can precipitate worsening of asthma in

approximately one-third of pregnant patients.

■ COMORBIDITIES

Comorbidities may make asthma difficult to manage, and the common comorbidities are listed in Table 287-3.

Obesity Obese adults with asthma have more severe asthma symptoms than lean adults and are two to four times more likely to be hospitalized with an asthma exacerbation. Nonrandomized studies have

shown an improvement and significant reduction in exacerbations

after bariatric surgery.

TABLE 287-3 Differential Diagnosis and Comorbidities That May Make

Asthma Difficult to Control

Differential Diagnosis of Diseases with Overlapping Symptoms That

Can Present with Obstructive Pulmonary Function Tests

1. Heart failure

2. Chronic obstructive pulmonary disease (COPD)

3. α1

 antitrypsin deficiency

4. Airway obstruction from mass or foreign body

5. Inducible laryngeal dysfunction (vocal cord dysfunction)

6. Bronchiolitis obliterans

7. Bronchiectasis

8. Tracheobronchomalacia

Comorbidities That Can Make Asthma Difficult to Control

1. Chronic rhinosinusitis +/– nasal polyposis

2. Obesity

3. Gastroesophageal reflux disease

4. Inducible laryngeal dysfunction (vocal cord dysfunction)

5. COPD

6. Anxiety/depression

7. Obstructive sleep apnea

2154 PART 7 Disorders of the Respiratory System

Gastroesophageal Reflux Disease The presence of gastroesophageal reflux disease (GERD) predicts poor quality of life and is an

independent predictor of asthma exacerbations. Treatment of symptomatic reflux disease has been shown to produce modest improvements in airway function, symptoms, and exacerbation frequency.

Treatment of asymptomatic patients has not shown a benefit.

Rhinosinusitis And/Or Nasal Polyposis Rhinosinusitis may

be a manifestation of the eosinophilic inflammation in the lower airway in asthma. In addition, poorly controlled rhinosinusitis is believed

to aggravate asthma by several potential mechanisms including inflammatory and irritant effects of the secretions on the lower airway, neural

reflexes, and production of inflammatory mediators and cells that

produce systemic inflammation. Treatment with intranasal corticosteroids has been shown to decrease airway reactivity and emergency

department visits and hospitalizations. Evidence for the benefit of

surgical therapy is inconclusive. There is increasing evidence that biologics targeted at type 2 inflammation may also be particularly useful

for asthma associated with rhinosinusitis and polyposis in particular.

Nasal polyposis is rare in children, and its presence in adults with

asthma should raise suspicions of aspirin-exacerbated respiratory disease (see “Special Considerations”).

Vocal Cord Dysfunction Now known as inducible laryngeal

obstruction, vocal cord dysfunction involves inappropriate narrowing

of the larynx, producing resistance to airflow. It can complicate asthma

and mimic it. It is more commonly seen in women and patients with

anxiety and depression. Definitive diagnosis involves laryngoscopy

during symptomatic episodes or during induced obstruction.

Chronic Obstructive Pulmonary Disease (COPD) See

“Asthma-COPD Overlap” under “Special Considerations.”

Anxiety/Depression Increased rates of asthma exacerbations

occur in asthmatics with anxiety, depression, or chronic stress. Some

patients may be unable to distinguish anxiety attacks from asthma.

DIAGNOSIS AND EVALUATION

■ APPROACH

A presumptive diagnosis of asthma can usually be made based on a

compatible history of recurrent wheezing, shortness of breath, chest

tightness, or cough related to common bronchoconstrictor precipitants when appropriate components of the differential diagnosis have

been considered and/or eliminated. In some cases, a therapeutic trial

of low-dose inhaled corticosteroid (ICS) may be considered. In all but

the mildest cases, the diagnosis should be confirmed with pulmonary

function testing or demonstration of airway hyperresponsiveness.

Unfortunately, the diagnosis may be difficult to confirm after initiation of therapy since airway obstruction and hyperresponsiveness may

be mitigated with therapy. A trial of tapering medications may be necessary. Studies have shown that more than one-third of patients with a

physician diagnosis of asthma do not meet the criteria for the diagnosis.

Adjunctive evaluation, as outlined below, should be undertaken to

identify precipitating factors and underlying mechanisms that may

be amenable to specific therapies (e.g., allergen avoidance). Cases

that require more than a daily moderate-dose ICS combined with

a long-acting β2

-agonist (LABA) (together known as ICS/LABA)

should undergo more formal evaluation to assess comorbidities that

may make asthma difficult to control and a reassessment of any

possible confounding diagnoses that may mimic asthma symptoms

(see Table 287-3).

■ PRIMARY ASSESSMENT TOOLS FOR

ESTABLISHING A DIAGNOSIS

History Patients with asthma most commonly complain of episodes of wheezing, shortness of breath, chest tightness, mucus production, or cough upon exposure to triggers listed in Table 287-2.

Symptoms may be worse on arising in the morning. Some may

have nocturnal symptoms alone. However, such patients should be

evaluated for postnasal drip or GERD if that is their sole presenting

symptom. Patients frequently complain of symptoms with rapid

changes of temperature or humidity. Exercise-induced symptoms are

common with increased sensitivity to cold air. As compared to cardiac

sources of dyspnea, exercise symptoms tend to develop more slowly

after initiation of exercise and tend to resolve more slowly unless a β2

-agonist is administered after the onset of symptoms. A careful exposure

history should be obtained for home (e.g., pets, molds, dust, direct

or secondhand smoke), work (work environment and exposure to

occupational sensitizers), and recreational (e.g., hobbies, recreational

inhalants) exposures. Allergen-sensitized patients may complain of

symptoms on exposure to known allergens such as animals and may

complain of increased symptoms during specific pollen seasons. Up to

two-thirds of patients with asthma will be atopic (as opposed to half

of the U.S. population), and almost half will have a history of rhinitis,

with many complaining of intermittent sinusitis. In patients with

adult-onset asthma, a careful occupational history should be obtained

and a history of reactions to nonsteroidal anti-inflammatory drugs

(NSAIDs) or use of new medications, such as beta blockers (including ophthalmic preparations) and ACE inhibitors (due to potential

cough), should be elicited.

Physical Examination In between acute attacks, physical findings may be normal. Many patients will have evidence of allergic

rhinitis with pale nasal mucus membranes. Five percent or more

of patients may have nasal polyps, with increased frequency in

those with more severe asthma and aspirin-exacerbated respiratory

disease. Some patients will have wheezing on expiration (less so on

inspiration). During an acute asthma attack, patients present with

tachypnea and tachycardia, and use of accessory muscles can be

observed. Wheezing, with a prolonged expiratory phase, is common

during attacks, but as the severity of airway obstruction progresses,

the chest may become “silent” with loss of breath sounds.

Pulmonary Function Tests Effective reduction of the airway

lumen in asthma produces increased resistance to airflow, which can be

detected as a reduction in expiratory airflow during forced expiratory

maneuvers. The peak expiratory flow rate (PEFR), forced expiratory

volume in 1 s (FEV1

), and the FEV1

/forced vital capacity (FVC) ratio

are reduced below the lower limit of normal. The flow-volume loop

may show a characteristic scalloping (see Chap. 286). These findings

may not be present during acute attacks or on therapy (especially

after recent use of bronchodilators). Reversibility is defined as a ≥12%

increase in the FEV1

 and an absolute increase of ≥200 mL at least

15 min after administration of a β2

-agonist or after several weeks of

corticosteroid therapy. Diurnal peak flow variability of >20% has also

been proposed as an indicator of reversible airways disease, but it is less

reliable due to difficulties with quality control and variability of home

assessments. Lung volumes and diffusing capacity should be normal in

uncomplicated asthma.

Assessment of Airway Responsiveness In cases where pulmonary function tests are nonconfirmatory and the diagnosis remains in

doubt, testing to demonstrate increased reactivity to provocative stimuli in the laboratory can be undertaken. Methacholine, a cholinergic

agonist, inhaled in increasing concentrations is most commonly used.

A provocative dose producing a 20% drop in FEV1

 (PD20) is calculated,

with a value ≤400 μg indicative of airway reactivity. Mannitol is used

as well, and occasionally, hypertonic saline may be used. Challenge

with exercise and/or cold, dry air can be performed, with a positive

response recorded if there is a ≥10% drop in FEV1

 from baseline. In

the case of suspected environmental/occupational exposures, specific

allergen challenges may be undertaken in highly specialized labs.

■ ADJUNCTIVE ASSESSMENT TOOLS

Eosinophil Counts A large proportion of asthma patients not

treated with oral or high-dose ICSs will have eosinophil counts

≥300 cells/μL. Eosinophil counts correlate with severity of disease

in population studies. Their presence in patients with severe asthma

indicates a likelihood that the patient would respond to medications

2155Asthma CHAPTER 287

targeted at type 2 inflammation. Extremely elevated levels should

prompt consideration of eosinophilic granulomatosis with polyangiitis

or primary eosinophilic disorders.

IgE, Skin Tests, and Radioallergosorbent Tests Total serum

IgE levels are useful in considering whether patients with severe

asthma would be eligible for anti-IgE therapy. Levels >1000 IU/mL

should prompt consideration of ABPA. Skin tests, or their in vitro

counterparts that detect IgE directed at specific antigens (radioallergosorbent test [RAST]), can be useful in confirming atopy and

suggesting allergic rhinitis, which can complicate asthma management. Allergy investigations may be useful, when correlated with a

history of reactions, in identifying environmental exposures that may

be aggravating asthma.

Exhaled Nitric Oxide Fraction of exhaled nitric oxide (FeNO)

in exhaled breath is an approximate indicator of eosinophilic inflammation in the airways. It is easily suppressed by ICSs and, thus, can be

used to assess adherence in patients in whom it was initially elevated.

Elevated levels (>35–40 ppb) in untreated patients are indicative of

eosinophilic inflammation. Levels >20–25 ppb in patients with severe

asthma on moderate- to high-dose ICS indicate either poor adherence

or persistent type 2 inflammation despite therapy.

■ ADDITIONAL EVALUATION IN SEVERE/POORLY

RESPONSIVE ASTHMA

In patients with poorly responsive asthma, additional evaluations for

comorbidities (see Table 287-3) may be necessary, including sinus

radiographic studies (even in those who have no symptoms of sinus

disease) and esophageal studies in those who have symptoms of reflux.

In patients with nonreversible disease, many obtain a serum α1

 antitrypsin level. Additionally, the following evaluations may be of utility in

poorly responsive asthma.

Chest Radiography Chest CT can be useful to assess for the presence of bronchiectasis and other structural abnormalities that could

produce airway obstruction. New image analysis tools are being used

in the research setting to assess airway properties such as airway wall

thickness, airway diameter, and evidence of air trapping.

Sputum Induced sputum may be used in more specialized centers

to help characterize type 2 and non–type 2 inflammation by detection

of eosinophils and neutrophils, respectively. In severe asthma, there is

some evidence that some patients may have localized persistent eosinophilic airway inflammation despite lack of peripheral eosinophils on

blood analysis.

TREATMENT

Asthma

GOALS OF ASTHMA THERAPY AND ASSESSMENT

OF CONTROL

Goals of asthma therapy in terms of achieving control of symptoms

and reducing risk (as reflected in frequency of asthma exacerbations) are listed in Table 287-4. The therapeutic agents used in

treatment are discussed below, and an integrated approach to care

is discussed subsequently.

A comprehensive treatment approach involves avoiding and

reducing asthma triggers and, if necessary, the adjunctive use of

medications. Asthma medications are primarily divided into those

that relax smooth muscle and produce a fairly rapid relief of acute

symptoms and those that target inflammation or mediator production. The former medications are commonly referred to as reliever

medications, and the latter are known as controller medications.

REDUCING TRIGGERS

Mitigation As shown in Tables 287-1 and 287-2, triggers and

exposures can cause asthma and make it difficult to control. In

TABLE 287-4 Goals of Asthma Therapy

1. Reduction in symptom frequency to ≤2 times/week

2. Reduction of nighttime awakenings to ≤2 times/month

3. Reduction of reliever use to ≤2 times a week (except before exercise)

4. No more than 1 exacerbation/year

5. Optimization of lung function

6. Maintenance of normal daily activities

7. Satisfaction with asthma care with minimal or no side effects of treatment

the case of those with occupational exposures, removal from the

offending environment may sometimes result in complete resolution of symptoms or significant improvement. Secondhand smoke

exposure and frequent exposure to combustion products of cannabis are remediable environmental exposures as well. The removal

of pets that are clearly associated with symptoms can reduce symptoms. Pest control at home and in the school in those with evidence

of IgE-mediated sensitivity (skin test or IgE RAST) may also be

beneficial. The effect of dust or mold control in reducing asthma

symptoms has been more variable. There is moderate evidence that

dust control (impermeable mattress and pillowcase covers) in those

patients with symptoms and sensitization may be effective in reducing symptoms only when conducted as part of a comprehensive

allergen mitigation strategy.

Allergen Immunotherapy Allergen immunotherapy reduces IgEmediated reactions to the allergens administered. It clearly reduces

the symptoms of allergic rhinitis and thus may be helpful in reducing this comorbidity. The evidence for its effectiveness in isolated

asthma in those who are sensitized and have clinical symptoms is

variable. Due to the risk of anaphylaxis, guidelines generally recommend immunotherapy only in patients whose asthma is under

control and who have mild to moderate asthma. The evidence base

for the effectiveness of sublingual allergen immunotherapy in the

treatment of asthma is not substantial.

Vaccination Respiratory infections are a major cause of asthma

exacerbations. Patients with asthma are strongly advised to receive

both types of currently available pneumococcal vaccines and yearly

influenza vaccines. COVID-19 vaccination is advised, as well.

MEDICATIONS

Bronchodilators Bronchodilators relax airway smooth muscle.

There are three major classes of bronchodilators, β2

-agonists,

anticholinergics, and theophylline.

a2

-Agonists Available in inhaled or oral form, these agents activate β2

-receptors present on airway smooth muscle. Such receptors

are also present on mast cells, but they contribute little to the efficacy of these agents in asthma. β2

-receptors are G protein–coupled

receptors that activate adenyl cyclase to produce cyclic AMP, which

results in relaxation of smooth muscle.

Use β2

-Agonists are primarily used in inhaled forms to provide

relief of bronchospasm or to reduce the degree of bronchospasm

anticipated in response to exercise or other provocative stimuli.

Regular use has been associated with tachyphylaxis of the bronchoprotective effect and possible increased airway reactivity. This

may be more common in patients with a polymorphism at the 16th

amino acid position of the β2

-receptor. Frequent short-acting β-2

agonist use has been associated with increased asthma mortality

resulting in decreased enthusiasm for use in isolation without

inhaled corticosteroids.

Short-Acting a2

-Agonists Albuterol (also known as salbutamol) is the most commonly used agent. Bronchodilation begins

within 3–5 min of inhalation, and effects generally last 4–6 h.

It is most commonly administered by metered-dose inhaler.

Solutions for nebulization are also used, especially for relief of

bronchospasm in children. Oral forms are available but are not

commonly used.

2156 PART 7 Disorders of the Respiratory System

Long-Acting a2

-Agonists Salmeterol and formoterol are the two

available LABAs. They have an ~12-h duration of action. Formoterol has a quick onset comparable to the short-acting β2-agonists.

Salmeterol has a slower onset of action. These agents can be used

for prophylaxis of exercise-induced bronchospasm. In contrast to

their use in chronic obstructive pulmonary disease (COPD), these

agents are not recommended for use as monotherapy in the treatment of asthma. Their use in asthma is generally restricted to use in

combination with an ICS.

Ultra-Long-Acting a2

-Agonists These agents (indacaterol, olodaterol, and vilanterol) have a 24-h effect. They are only used in

combination with ICSs in the treatment of asthma.

Safety β2

-Agonists are fairly specific for the β2

-receptors, but

in some patients and especially at higher doses, they can produce tremor, tachycardia, palpitations, and hypertension. They

promote potassium reentry into cells, and at high doses, they can

produce hypokalemia. Type B (nonhypoxic) lactic acidosis can

also occur and is thought to be secondary to increased glycogenolysis and glycolysis and increased lipolysis, leading to a rise

in fatty acid levels, which can inhibit conversion of pyruvate to

acetyl-coenzyme A.

Increased asthma mortality was associated with highpotency β2

-agonists in Australia and New Zealand. Increased use

of β2

-agonists for relief of bronchospasm is a clear marker of poor

asthma control and has been associated with increased mortality.

Questions had been raised as to whether adding LABAs to ICS

might be associated with severe adverse asthma outcomes, but

several studies have not detected such outcomes in comparison to

maintaining the ICS dose.

Anticholinergics Cholinergic nerve–induced smooth-muscle

constriction plays a role in asthmatic bronchospasm. Anticholinergic medications can produce smooth-muscle relaxation by antagonizing this mechanism of airway narrowing. Agents that have been

developed for asthma have been pharmacologically designed to be

less systemically absorbed so as to minimize their systemic anticholinergic effects. The long-acting agents in this class are known as

long-acting muscarinic antagonists (LAMAs).

Use The short-acting agents in this class can be used alone for

acute bronchodilation. They appear to be somewhat less effective

than β2

-agonists and have a slower onset of action as well.

Safety Dry mouth may occur. At higher doses and in the elderly,

acute glaucoma and urinary retention have been reported. There

was a numerical (but not significant) difference in mortality in

African Americans treated with ICS/LAMA versus ICS/LABA for

asthma.

Theophylline Theophylline, an oral compound that increases

cyclic AMP levels by inhibiting phosphodiesterase, is now rarely

used for asthma due to its narrow therapeutic window, drug-drug

interactions, and reduced bronchodilation as compared to other

agents.

Controller (Anti-Inflammatory/Antimediator) Therapies So-called

“controller” therapies reduce asthma exacerbations and improve

long-term control, decreasing the need for intermittent use of

bronchodilator therapies. None of these therapies have yet been

shown to prevent progression of airway remodeling or the more

rapid decline in lung function that can occur in a subset of asthma

patients.

Corticosteroids Corticosteroids are particularly effective in

reducing type 2 inflammation and airway hyperresponsiveness.

Corticosteroids bind to a cytoplasmic glucocorticoid receptor to

form a complex that translocates to the nucleus. The complex binds

to positive and negative response elements that result in inhibition

of T-cell activation; eosinophil function, migration, and proliferation; and proinflammatory cytokine elaboration and activation of

nuclear factor-κB. It also attaches to other transcription factors,

resulting in deactivation of other proinflammatory pathways.

Use Corticosteroids reduce airway hyperresponsiveness, improve

airway function, prevent asthma exacerbations, and improve asthma

symptoms. Corticosteroid use by inhalation (ICSs) minimizes systemic toxicity and represents a cornerstone of asthma treatment.

ICS and ICS/LABA ICSs are the cornerstone of asthma therapy.

They take advantage of the pleiotropic effects of corticosteroids

to produce salutary impact at levels of systemic effect considerably lower than oral corticosteroids. Their use is associated with

decreased asthma mortality. They are generally used regularly twice

a day as first-line therapy for all forms of persistent asthma. Doses

are increased, and they are combined with LABAs to control asthma

of increasing severity. European guidelines now recommend their

intermittent use even in intermittent asthma. Combining them with

LABAs permits effective control at lower ICS dose. Longer-acting

preparations permitting once-a-day use are available. Their effects

can be noticeable in several days, but continued improvement may

occur over months of therapy, with the majority of improvement

evident within the first month of regular use. Adherence to regular therapy is generally poor, with as few as 25% of total annual

prescriptions being refilled. Very high doses are sometimes used to

reduce oral corticosteroid requirements. Not all patients respond to

ICS. Increasing evidence suggests that the most responsive patients

are those with significant type 2–mediated asthma.

Oral Corticosteroids Chronic oral corticosteroids (OCSs) at the

lowest doses possible (due to side effects) are used in patients who

cannot achieve acceptable asthma control without them. Alternate-day dosing may be preferred, and pneumocystis pneumonia

prophylaxis should be administered for those maintained on a daily

prednisone dose of ≥20 mg. OCSs are also used to treat asthma

exacerbations, frequently at a dose of 40–60 mg/d of prednisone or

equivalent for 1–2 weeks. Since they are well absorbed, they may

also be used for managing hospitalized patients.

Intravenous Corticosteroids Intravenous preparations are frequently used in hospitalized patients. Patients are rapidly transitioned to OCS once their condition has stabilized.

Intramuscular Corticosteroids In high-risk, poorly adherent

patients, intramuscular triamcinolone acetonide has been used to

achieve asthma control and reduce exacerbations.

Safety Chronic administration of systemic corticosteroids is

associated with a plethora of side effects including diabetes, osteoporosis, cataracts and glaucoma, bruising, weight gain, truncal

obesity, hypertension, ulcers, depression, and accelerated cardiac

risk, among others. Appropriate monitoring and infectious (pneumocystis pneumonia prophylaxis for those treated chronically with

≥20 mg prednisone/d) and bone health prophylaxis are necessary.

Intermittent “bursts” of systemic corticosteroids to treat asthma

exacerbations are associated with reduced side effects, but observational studies have suggested that the cumulative dose over time is

associated with deleterious side effects.

ICSs have dramatically reduced side effects as compared to

OCSs. At higher doses, bruising occurs and osteoporosis can accelerate. There is a small increase in glaucoma and cataracts. Local

effects include thrush, which can be reduced by use of a spacer and

gargling. Hoarseness may be the result of a direct myopathic effect

on the vocal cords. Rare patients exhibit side effects even at moderate doses of ICS. Children may experience growth suppression.

Leukotriene Modifiers Agents that inhibit production of leukotrienes (zileuton, an inhibitor of 5-lipoxygenase) or the action of

leukotrienes at the CysLT1

 receptor (montelukast and zafirlukast)

are moderately effective in asthma.

They can improve airway function and reduce exacerbations but

not to the same degree as bronchodilators or ICS, respectively. They

are also effective in reducing symptoms of allergic rhinitis and, thus,

2157Asthma CHAPTER 287

can be used in patients with concomitant allergic rhinitis. Montelukast, in particular, is frequently used in children with mild asthma

due to concerns of ICS-related growth suppression. Montelukast

use may decrease due to safety warnings regarding depression with

this compound. Leukotriene modifiers are effective in preventing

exercise-induced bronchoconstriction without the tachyphylactic

effects that occur with regular use of LABAs. Leukotriene modifiers

are particularly effective in aspirin-exacerbated respiratory disease,

which is characterized by significant leukotriene overproduction.

They have also shown modest effect as add-on therapy in patients

poorly controlled on high-dose ICS/LABA.

CysLT1

 Antagonists Montelukast and zafirlukast are administered

orally once or twice daily, respectively. The onset of effect is rapid

(hours), with the majority of chronic effectiveness seen within

1 month.

5-Lipoxygenase Inhibition Zileuton in its extended form is

administered orally twice a day.

Safety Montelukast is well tolerated, but an association with

suicidal ideation has now resulted in a warning label from the U.S.

Food and Drug Administration. Zileuton increases liver function

tests (transaminases) in 3% of patients. Intermittent monitoring is

suggested. It inhibits CYP1A2, and appropriate dose adjustments of

concomitant medications may be necessary.

Cromolyn Sodium Cromolyn sodium is an inhaled agent

believed to stabilize mast cells. It is only available by nebulization

and must be administered two to four times a day. It is mildly to

modestly effective and appears to be helpful for exercise-induced

bronchospasm. It is used primarily in pediatrics in those concerned

about ICS side effects.

Anti-IgE Omalizumab, a monoclonal antibody to the Fc portion

of the IgE molecule, prevents the binding of IgE to mast cells and

basophils. Reduction in free IgE that can bind to effector cells blocks

antigen-related signaling, which is responsible for production or

release of many of the mediators and cytokines critical to asthma

pathobiology. In addition, through feedback mechanisms, reduction

in IgE production occurs as well. Anti-IgE has been shown to increase

interferon production in rhinovirus infections, decrease viralinduced asthma exacerbations, and reduce duration and peak viral

shedding. This effect is believed to be due to IgE’s ability to reduce

interferon γ production in response to viral infections.

Use In asthma, anti-IgE has been tested in patients with a

circulating IgE ≥30 IU/mL and a positive skin test or RAST to a

perennial allergen. It is generally used in patients not responsive

to moderate- to high-dose ICS/LABA. It reduces exacerbations by

25–50% and can reduce asthma symptoms but has minimal effect

on lung function. Anti-IgE is dosed based on body weight and circulating IgE and is administered subcutaneously every 2–4 weeks

depending on the calculated dose. In the United States, the maximum

dose is 300 mg every 2 weeks, which generally restricts the drug to

those with a body weight ≤150 kg. Most effects are generally seen

in 3–6 months. Retrospective studies have suggested that patients

with an exhaled nitric oxide approximately ≥20 ppb or circulating

eosinophils ≥260/μL have the greatest response as ascertained by

reduction in exacerbations. FeNO is slightly reduced by treatment,

but circulating IgE, as measured by available clinical tests, is not

affected since these tests measure total circulating IgE, not free IgE.

Safety The incidence of side effects is low. Anaphylaxis has been

reported in 0.2% of patients receiving the drug.

IL-5–Active Drugs Mepolizumab and reslizumab are monoclonal antibodies that bind to IL-5, and benralizumab binds to the IL-5

receptor. They rapidly (within a day) reduce circulating eosinophils.

Use In patients symptomatic on moderate- to high-dose ICS/

LABA, generally with two or more exacerbations that require OCS

per year and with an eosinophil count of ≥300/μL, IL-5–active drugs

reduce exacerbations by about half or more. FEV1

 and symptoms

improve moderately as well. In patients who are not on chronic

OCSs, these drugs are less effective in those with eosinophil counts

<300/μL. They are also effective in reducing the need for chronic

OCSs regardless of circulating eosinophil count (presumably due to

the fact that many of those patients have type 2 inflammation but

their circulating eosinophils have been suppressed by the systemic

OCS). FeNO and IgE are relatively unaffected by these drugs. Most

clinical effects are usually seen within 3–6 months.

Safety These drugs are associated with minimal side effects. Mepolizumab and benralizumab are approved for home administration.

Anti–IL-4/13 The IL-4 and IL-13 receptors are heterodimers that

share a common subunit, IL-4 receptor α. Dupilumab binds to this

subunit and, thus, blocks signaling through both receptors.

Use In addition to effectiveness in the phenotype of patients

who respond to anti–IL-5 therapies, poorly controlled patients on

moderate- to high-dose ICS/LABA with an FeNO of 20–25 ppb

also appear to respond to dupilumab even if their peripheral eosinophils are not elevated. Dupilumab reduces exacerbations by ≥50%,

decreases symptoms, and may produce more of an effect on FEV1

than anti–IL-5 drugs. It gradually reduces FeNO and IgE levels. Paradoxically, circulating eosinophil counts may initially temporarily

increase. Most effects are seen by 3–6 months of therapy.

Safety Side effects are minimal but cases of serious systemic eosinophilia associated with the reduction of oral corticosteroids have

been noted. This drug is also approved for home administration

and is also approved for atopic dermatitis.

Bronchial Thermoplasty, Alternative Therapies, and Therapies

Under Development • Bronchial Thermoplasty This procedure involves radiofrequency ablation of the airway smooth muscle in the major airways administered through a series of three

bronchoscopies for patients with severe asthma. There is some

evidence that it may reduce exacerbations in very select patients.

The procedure may be accompanied by significant morbidity, and

most guidelines do not recommend it other than in the context of

clinical trials or registries.

Alternative Therapies Alternative therapies such as acupuncture and yoga have not been shown to improve asthma in controlled

trials. Studies with placebo have demonstrated that there may be a

significant response to placebo.

Therapies in Development Trials are underway targeting

pathways and receptors shown in Fig. 287-3. Those in more

advanced stages of development include therapies targeting

TSLP, IL-33, and CRTH2

. Studies targeting IL-17 and TNF-α

have not shown efficacy, but it is unclear if they were appropriately targeted. Whether these interventions might prove useful

for particular endotypes of asthma is unclear. Proof-of-concept

studies targeting mast cells via inhibition of tyrosine kinase have

suggested efficacy in severe asthma.

APPROACH TO THE PATIENT

Asthma

U.S. (National Asthma Education and Prevention Program [NAEPP])

and World Health Organization (Global Initiative for Asthma

[GINA]) guidelines advise a symptomatic approach to asthma treatment assuming that appropriate measures have been taken to address

asthma triggers, exposures, and comorbidities enumerated in

Tables 287-2 and 287-3. Additionally, adherence and inhaler techniques need to be addressed. Poor adherence or poor inhaler technique has been identified as the cause of poor asthma control in up

to 50% of patients referred for poorly controlled asthma.

The stepwise approach to intensifying and reducing asthma therapy is outlined in Table 287-5. It involves “stepping” therapy up

or down based on assessment of whether asthma is controlled by

2158 PART 7 Disorders of the Respiratory System

TABLE 287-5 Step Therapy for the Treatment of Asthma Ages 12+ (modified from GINA and NAEPP)

Address exposures and comorbidities (see Tables 287-2 and 287-3)

Confirm inhaler technique and optimize adherence

Move up or down steps based on control (see Table 287-3)

STEP 1 STEP 2 STEP 3 STEP 4 STEP 5 STEP 6

Preferred regular

therapy

None Nonea

 or low-dose ICSb Low-dose ICS/

formoterol

Medium-dose

ICS/formoterol

Medium to high-dose

ICS/LABA, + add-on

LAMA

Anti-IgE or anti–IL-5

or anti–IL4-Rα; step 5

therapy as required

Alternative regular

therapy

None LTRA Medium-dose ICS High-dose ICS Anti-IgE or anti–IL-5

or anti–IL4-Rα

OCSc

Adjunctive therapy LTM and/or LAMA (especially LAMA at Step 5)

As-needed reliever

therapy

ICS/formoterol (low

dose) or SABAb

ICS/formoterol

(low dose), or PRN

concomitant ICS and

SABAb

 or SABAe

ICS/formoterol (low dose)d

a

If using as-needed ICS/formoterol or PRN concomitant ICS & SABA, this is an option. b

National Asthma Education and Prevention Program (NAEPP) recommendation. c

To

be avoided as much as possible. d

PRN ICS/formoterol only suggested for steps 3 and 4 by NAEPP. e

If using low-dose ICS as regular therapy.

Abbreviations: ICS, inhaled corticosteroid; IL, interleukin; LABA, long-acting β-agonist; LAMA, long-acting muscarinic antagonist; LTM, leukotriene modifier; LTRA,

leukotriene receptor antagonist; OCS, oral corticosteroid; PRN, as needed; SABA, short-acting β-agonist.

the criteria listed in Table 287-4. Assuming comorbidities have

been addressed, adherence has been evaluated, education regarding

avoiding triggers has been performed, and inhaler technique is verified, the cornerstone of preferred therapy is the intensification of

ICS therapy in conjunction with the use of a LABA to achieve greater

control at lower ICS doses.

A major change in the stepwise approach, advocated for more

than two decades, has occurred. Evidence has accumulated that

as-needed ICS can be used instead of regular ICS in milder asthma

and that the trigger for such use could be patient perception of the

need to use a reliever inhaler. Since formoterol is a LABA with a

rapid onset, combination ICS/formoterol has been used as a single

agent in multiple studies: as needed without background therapy in

milder asthma, and as needed in addition to twice daily ICS/formoterol in more severe asthma. Since asthma mortality can occur

even in mild asthma (albeit at lower rates than more severe asthma),

GINA, as part of a comprehensive strategy of asthma management,

recommends ICS/formoterol be used as the reliever in all steps

of asthma severity, including intermittent asthma (Step 1). NAEPP

guidelines utilizing evidence-based studies recommend that ICS/

formoterol be used as the reliever medication in patients requiring

step 3 and 4 therapy (see Table 287-5) and that as-needed concomitant ICS and short-acting β-agonist (SABA) can be used as a therapy in step 2. For the sake of simplicity, an adapted GINA approach

is outlined in Table 287-5 with footnotes identifying the major

differences from the NAEPP. Leukotriene receptor antagonists

(LTRAs) are alternative medications in step 2, which may be used

in those concerned about the minimal ICS side effects. However,

recent warnings about suicidal ideation associated with montelukast may make this approach less appealing. Leukotriene modifiers

and long-acting anticholinergics are possible add-on (adjunctive)

therapies in those requiring step 4 and/or 5 therapies. Biologics are

incredibly effective in their specific endotypes (type 2 with exacerbations and specific biomarkers, as previously described), but their

high cost currently relegates them to step 5 therapy or beyond.

TREATMENT

Asthma Attacks

Asthma deteriorations of mild to moderate severity can be initially

treated with a β2

-agonist administered up to every 1 h. Increasing

the dose of ICSs by four- to fivefold may be helpful as well. If

patients fail to achieve adequate control and continue to require

β2

-agonists hourly for several hours, they should be referred for

urgent care. In the urgent care setting, PEFR or FEV1

 should be

assessed, and patients are usually treated with nebulized β2

-agonists

up to every 20 min. Those with PEFR >60% of predicted will frequently respond to β2

-agonists alone. If they fail to respond in 1–2 h,

intravenous corticosteroids should be administered. Supplemental

oxygen is usually administered to correct hypoxemia. An LTRA

and magnesium are sometimes given as well. Nebulized anticholinergics can be administered to produce additional bronchodilation.

Failure to achieve PEFR >60% or persistent severe tachypnea over

4–6 h should prompt consideration of admission to the hospital.

In-hospital treatment may include continuous bronchodilator nebulization. Noninvasive positive-pressure ventilation to assist with

respiratory exhaustion is sometimes used to prevent a need for

intubation, and helium-oxygen mixtures may be used to decrease

the work of breathing. Antibiotics should be administered only if

there are signs of infection.

Mechanical ventilation may be difficult in patients with status

asthmaticus due to high positive pressures in the setting of high

resistance to airflow due to airway obstruction. Most patients with

asthma attacks present with hypocapnia due to a high respiratory

rate. Normal or near-normal Pco2

 in a patient with asthma in

respiratory distress should raise concerns of impending respiratory

failure and need for mechanical ventilation. Mechanical ventilation

should aim for low respiratory rates and/or ventilation volumes to

decrease peak airway pressures. This can frequently be achieved by

“permissive hypercapnia”—allowing the Pco2

 to rise and, if necessary, temporarily correcting critical acidosis with administration

of fluids to increase the pH. Neuromuscular paralysis may sometimes be beneficial. Bronchoscopy to clear mucus plugs has been

described but may be dangerous in the setting of difficulties with

mechanical ventilation.

SPECIAL CONSIDERATIONS

■ HIGH-RISK ASTHMA PATIENTS

Three to four thousand people die from asthma in the United States

each year. Table 287-6 lists characteristics of patients at high risk for

asthma death. These characteristics should be considered in evaluating

and treating patients who present with asthma.

■ EXERCISE-INDUCED SYMPTOMS

In many cases, the degree of exercise intolerance may reflect poor

asthma control. Treatment involves step therapy of asthma as outlined

in Table 287-5. In other cases, however, asthma may be well controlled

in all other respects, but patients may report that they cannot undertake the level of exercise they desire. Some increase in exercise capacity