(See also Wheezing and Asthma in Infants and Young Children Wheezing and Asthma in Infants and Young Children Wheezing is a relatively high-pitched whistling noise produced by movement of air through narrowed or compressed small airways. It is common in the first few years of life and is typically caused... read more .)
More than 25 million people in the US are affected. Asthma is one of the most common chronic diseases of childhood, affecting about 6 million children in the US. It also occurs more frequently in non-Hispanic Blacks and Puerto Ricans.
In the US, about 10,000 deaths occur annually as a result of asthma, and the mortality rate is declining (1 Epidemiology references Asthma is a disease of diffuse airway inflammation caused by a variety of triggering stimuli resulting in partially or completely reversible bronchoconstriction. Symptoms and signs include dyspnea... read more ). However, the death rate is 2 to 3 times higher for Blacks than for Whites. The mortality rate is higher for adults than children and is especially high in adults over 65. Asthma is among the leading causes of hospitalization in children and is a leading cause of school absenteeism (2 Epidemiology references Asthma is a disease of diffuse airway inflammation caused by a variety of triggering stimuli resulting in partially or completely reversible bronchoconstriction. Symptoms and signs include dyspnea... read more ). Asthma is estimated to cost the US $56 billion/year in medical care and lost productivity (3 Epidemiology references Asthma is a disease of diffuse airway inflammation caused by a variety of triggering stimuli resulting in partially or completely reversible bronchoconstriction. Symptoms and signs include dyspnea... read more ).
The increase in asthma prevalence has been mirrored by an increase in obesity. Because of this association, obesity is now considered an important modifiable risk factor for asthma. Obesity often precedes the diagnosis of asthma. Key mediators implicated by observational and cross-sectional studies include leptin, adipokines, and serum Il-6. However, underlying mechanisms are not yet known. Multiple studies have shown decreases in asthma severity and exacerbations after weight loss (4 Epidemiology references Asthma is a disease of diffuse airway inflammation caused by a variety of triggering stimuli resulting in partially or completely reversible bronchoconstriction. Symptoms and signs include dyspnea... read more ).
1. Pate CA, Zahrn HS, Qin X, et al: Asthma Surveillance — United States, 2006–2018. MMWR Surveill Summ 70(No. SS-5):1–32, 2021. doi: 10.15585/mmwr.ss7005a1
2. Centers for Disease Control and Prevention: CDC Healthy Schools: Asthma. Updated June 14, 2021. Accessed January 21, 2022.
3. Allergy and Asthma Foundation of America: Cost of asthma on society. Accessed January 21, 2022. https://www.aafa.org/cost-of-asthma-on-society
4. Peters U, Dixon AE, Forno E: Obesity and asthma. J Allergy Clin Immunol 141(4):1169–1179, 2018. doi: 10.1016/j.jaci.2018.02.004
Etiology of Asthma
Development of asthma is multifactorial and depends on the interactions among multiple susceptibility genes and environmental factors.
More than 100 asthma susceptibility genes have been reported. Many are thought to involve the broad category of T-helper cells type 2 (TH2) and may play a role in inflammation. Examples include the FCER1B gene, which encodes the beta chain of the high-affinity IgE receptor; the genes encoding certain interleukins (IL) such as IL-4, IL-13, and the IL-4 receptor; genes responsible for innate immunity (HLA-DRB1, HLA-DQB1, CD14); and genes participating in cellular inflammation (eg, genes encoding granulocyte-monocyte colony-stimulating factor [GM-CSF] and tumor necrosis factor-alpha [TNF-α]). Also, the ADAM33 gene may stimulate airway smooth muscle and fibroblast proliferation and remodeling; it was the first asthma risk locus found with whole-genome family linkage studies.
More recently, the most replicated is at the chromosome 17q21 locus. This locus contains the ORMDL3 gene, which is an allergen and cytokine (IL-4/IL-13)–inducible gene implicated in epithelial cell remodeling and sphingolipid metabolism to affect bronchial hyperreactivity.
Environmental risk factors for asthma may include the following:
Evidence clearly implicates household allergens (eg, dust mite, cockroach, pet) and other environmental allergens in disease development in older children and adults. Diets low in vitamins C and E and in omega–3 fatty acids have been linked to asthma; however, several studies supporting dietary influence are limited by sample size or did not account for differences in socioeconomic, environmental, and demographic factors. Dietary supplementation with these substances does not appear to prevent asthma. Asthma has also been linked to perinatal factors, such as young maternal age, poor maternal nutrition, prematurity, low birthweight, and lack of breastfeeding.
On the other hand, endotoxin exposure early in life can induce tolerance and may be protective. Air pollution is not definitively linked to disease development, although it may trigger exacerbations. The role of childhood exposure to cigarette smoke is controversial, with some studies finding a contributory and some a protective effect.
Genetic and environmental components may interact. Infants may be born with a predisposition toward proallergic and proinflammatory type 2 (T2) immune responses(immune responses related to T-helper 2 cells). The proinflammatory T2 response is characterized by growth and activation of eosinophils and IgE production. Asthma with this pattern of inflammation has often been referred to as eosinophilic asthma. Early childhood exposure to bacterial and viral infections and endotoxins may shift the body to T-helper cells type 1 (TH1) responses, which suppresses TH2 cells and induce tolerance. Type 1 (T1) responses are characterized by a proliferation of type 1 T-helper cells. Trends toward smaller families with fewer children, cleaner indoor environments, and early use of vaccinations and antibiotics may deprive children of these T2-suppressing, tolerance-inducing exposures and may partly explain the continuous increase in asthma prevalence in higher income countries (the hygiene hypothesis).
Reactive airways dysfunction syndrome (RADS) and irritant-induced asthma
Reactive airways dysfunction syndrome (RADS) is the rapid onset (minutes to hours, but not > 24 hours) of an asthma-like syndrome Occupational Asthma that
Develops in people with no history of asthma
Occurs following a single, specific inhalation exposure to a significant amount of an irritating gas or particulate
Persists for ≥ 3 months
Numerous substances have been implicated, including chlorine gas, nitrogen oxide, and volatile organic compounds (eg, from paints, solvents, adhesives). The exposure event is usually obvious to the patient, particularly when symptoms begin almost immediately.
Irritant-induced asthma refers to a similar, persistent asthma-like response following multiple or chronic inhalational exposure to high levels of similar irritants. Manifestations are sometimes more insidious, and thus the connection to the inhalational exposure is clear only in retrospect.
RADS and chronic irritant-induced asthma have many clinical similarities to asthma (eg, wheezing, dyspnea, cough, presence of airflow limitation, bronchial hyperresponsiveness) and respond significantly to bronchodilators and often corticosteroids. Unlike in asthma, the reaction to the inhaled substance is not thought to be an IgE-mediated allergy; low-level exposures do not cause RADS or irritant-induced asthma. However, repeated exposure to the initiating agent may trigger additional symptoms.
Pathophysiology of Asthma
Airway edema and inflammation
In patients with asthma, TH2 cells and other cell types—notably, eosinophils and mast cells, but also other CD4+ subtypes and neutrophils—form an extensive inflammatory infiltrate in the airway epithelium and smooth muscle, leading to airway remodeling (ie, desquamation, subepithelial fibrosis, angiogenesis, smooth muscle hypertrophy). Hypertrophy of smooth muscle narrows the airways and increases reactivity to allergens, infections, irritants, parasympathetic stimulation (which causes release of proinflammatory neuropeptides, such as substance P, neurokinin A, and calcitonin gene-related peptide), and other triggers of bronchoconstriction.
Additional contributors to airway hyperreactivity include loss of inhibitors of bronchoconstriction (epithelium-derived relaxing factor, prostaglandin E2) and loss of other substances called endopeptidases that metabolize endogenous bronchoconstrictors. Mucus plugging and peripheral blood eosinophilia are additional classic findings in asthma and may be epiphenomena of airway inflammation. However, not all patients with asthma have eosinophilia.
Common triggers of an asthma exacerbation include
Environmental and occupational allergens (numerous)
Cold, dry air
Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs)
Infectious triggers in young children include respiratory syncytial virus Respiratory Syncytial Virus (RSV) and Human Metapneumovirus Infections Respiratory syncytial virus and human metapneumovirus infections cause seasonal lower respiratory tract disease, particularly in infants and young children. Disease may be asymptomatic, mild... read more , rhinovirus, and parainfluenza virus infection. In older children and adults, upper respiratory infections (particularly with rhinovirus) and pneumonia are common infectious triggers. Exercise can be a trigger, especially in cold or dry environments, and cold air alone can also trigger symptoms. Inhaled irritants, such as air pollution, cigarette smoke, perfumes, and cleaning products can also trigger symptoms in patients with asthma. (Inhaled irritants that trigger asthma exacerbations do so by inducing a T2 response, in contrast to what happens in reactive airways dysfunction syndrome and chronic irritant-induced asthma.) Emotions such as anxiety, anger, and excitement sometimes trigger exacerbations.
Aspirin is a trigger in up to 30% of patients with severe asthma and in < 10% of all patients with asthma. Aspirin-sensitive asthma is typically accompanied by nasal polyps with nasal and sinus congestion, which is a condition also known as Samter's triad (asthma, nasal polyps, and sensitivity to aspirin and NSAIDs).
GERD is a common trigger among some patients with asthma, possibly via esophageal acid-induced reflex bronchoconstriction or by microaspiration of acid. However, treatment of asymptomatic GERD (eg, with proton pump inhibitors) does not seem to improve asthma control.
Allergic rhinitis often coexists with asthma; it is unclear whether the two are different manifestations of the same allergic process or whether rhinitis is a discrete asthma trigger.
In the presence of triggers, there is reversible airway narrowing and uneven lung ventilation. In lung regions distal to narrowed airways, relative perfusion exceeds relative ventilation; thus, alveolar oxygen tensions fall and alveolar carbon dioxide tensions rise. Usually, such regional hypoxia and hypercarbia trigger compensatory pulmonary vasoconstriction to match regional ventilation and perfusion; however, these compensatory mechanisms fail during an asthma exacerbation due to the vasodilatory effects of prostaglandins that are upregulated during an exacerbation. Most patients can compensate by hyperventilating, but in severe exacerbations, diffuse bronchoconstriction causes severe gas trapping, and the respiratory muscles are put at a marked mechanical disadvantage so that the work of breathing increases. Under these conditions, hypoxemia worsens and PaCO2 rises. Respiratory acidosis Respiratory Acidosis Respiratory acidosis is primary increase in carbon dioxide partial pressure (Pco2) with or without compensatory increase in bicarbonate (HCO3−); pH is usually low but may be near... read more and metabolic acidosis Metabolic Acidosis Metabolic acidosis is primary reduction in bicarbonate (HCO3−), typically with compensatory reduction in carbon dioxide partial pressure (Pco2); pH may be markedly low or slightly... read more may result and, if left untreated, cause respiratory and cardiac arrest.
Classification of Asthma
Unlike hypertension (eg, in which one parameter [blood pressure] defines the severity of the disorder and the efficacy of treatment), asthma causes a number of clinical and testing abnormalities. Also, unlike most types of hypertension, asthma manifestations typically wax and wane. Thus, monitoring (and studying) asthma requires a consistent terminology and defined benchmarks.
The term status asthmaticus describes severe, intense, prolonged bronchospasm that is resistant to treatment.
Severity is the intrinsic intensity of the disease process (ie, how bad it is—see table Classification of Asthma Severity Classification of Asthma Severity* ). Severity can usually be assessed directly only before treatment is started, because patients who have responded well to treatment by definition have few symptoms. Asthma severity is categorized as
It is important to remember that the severity category does not predict how serious an exacerbation a patient may have. For example, a patient who has mild asthma with long periods of no or mild symptoms and normal pulmonary function may have a severe, life-threatening exacerbation.
Control is the degree to which symptoms, impairments, and risks are minimized by treatment. Control is the parameter assessed in patients receiving treatment. The goal is for all patients to have well-controlled asthma regardless of disease severity. Control is classified as
Not well controlled
Very poorly controlled
Severity and control are assessed in terms of patient impairment and risk (see tables Classification of Asthma Severity Classification of Asthma Severity* and Classification of Asthma Control Classification of Asthma Control*,† ).
Impairment refers to the frequency and intensity of patients' symptoms and functional limitations (see table Classification of Asthma Severity Classification of Asthma Severity* ). Impairment is assessed using similar criteria to severity, but differs from severity by its emphasis on symptoms and functional limitations rather than the intrinsic intensity of the disease process. Lung function or physiologic, objective impairment can be measured by spirometry, mainly forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC), which correlate strongly with subjective components of asthma control that includes symptoms and clinical features such as
How often symptoms are experienced
How often the patient awakens at night
How often the patient uses a short-acting beta-2 agonist for symptom relief
How often asthma interferes with normal activity
Risk refers to the likelihood of future exacerbations or decline in lung function and the risk of adverse drug effects. Risk is assessed by long-term trends in spirometry and clinical features such as
Frequency of need for oral corticosteroids
Need for hospitalization
Need for intensive care unit (ICU) admission
Need for intubation
Symptoms and Signs of Asthma
Patients with mild asthma are typically asymptomatic between exacerbations. Patients with more severe disease and those with exacerbations experience dyspnea, chest tightness, audible wheezing, and coughing. Coughing may be the only symptom in some patients (cough-variant asthma). Symptoms can follow a circadian rhythm and worsen during sleep, often around 4 AM. Many patients with more severe disease waken during the night (nocturnal asthma).
Signs include wheezing, pulsus paradoxus Pulsus paradoxus Complete examination of all systems is essential to detect peripheral and systemic effects of cardiac disorders and evidence of noncardiac disorders that might affect the heart. Examination... read more (ie, a fall of systolic blood pressure [BP] > 10 mm Hg during inspiration), tachypnea, tachycardia, and visible efforts to breathe (use of neck and suprasternal [accessory] muscles, upright posture, pursed lips, speech limited by dyspnea). When severe, the expiratory phase of respiration is prolonged, with an inspiratory:expiratory ratio of at least 1:3. Wheezes can be present through both phases or just on expiration, but patients with severe bronchoconstriction may have no audible wheezing because of markedly limited airflow.
Patients with a severe exacerbation and impending respiratory failure typically have some combination of altered consciousness, cyanosis, pulsus paradoxus > 15 mm Hg, oxygen saturation < 90%, and PaCO2 > 45 mm Hg. Chest x-ray reveals hyperinflation often and pneumothorax Pneumothorax Pneumothorax is air in the pleural space causing partial or complete lung collapse. Pneumothorax can occur spontaneously or result from trauma or medical procedures. Diagnosis is based on clinical... read more or pneumomediastinum Pneumomediastinum Pneumomediastinum is air in mediastinal interstices. The main causes of pneumomediastinum are Alveolar rupture with dissection of air into the interstitium of the lung with translocation to... read more rarely.
Symptoms and signs disappear between exacerbations, although soft wheezes may be audible during forced expiration at rest, or after exercise, in some asymptomatic patients. Hyperinflation of the lungs may alter the chest wall in patients with long-standing uncontrolled asthma, causing a barrel-shaped thorax.
All symptoms and signs are nonspecific, are reversible with timely treatment, and typically are brought on by exposure to one or more triggers.
Diagnosis of Asthma
Pulmonary function testing
Diagnosis is based on history and physical examination and is confirmed with pulmonary function tests. Diagnosis of causes and the exclusion of other disorders that cause wheezing are important. Asthma and chronic obstructive pulmonary disease Chronic Obstructive Pulmonary Disease (COPD) Chronic obstructive pulmonary disease (COPD) is airflow limitation caused by an inflammatory response to inhaled toxins, often cigarette smoke. Alpha-1 antitrypsin deficiency and various occupational... read more (COPD) are sometimes easily confused; they cause similar symptoms and produce similar results on pulmonary function tests but differ in important biologic ways that are not always clinically apparent. The T2, or allergic inflammation, is most commonly characterized by elevated exhaled nitric oxide (FeNO), blood eosinophil counts, and serum IgE and is the most commonly recognized asthma subgroup. The T1 cell-mediated immunity is associated with elevated interferon-gamma, tumor necrosis factor, and neutrophilic inflammation that have traditionally been associated with COPD but can occur in asthma subgroups not driven by T2 inflammation. These biologic mechanisms are not exclusive to either disease and can overlap between asthma and COPD.
Asthma-COPD overlap (ACO) is being increasingly recognized as a unique entity that presents with persistent airflow obstruction and several features of both asthma and COPD. Key features include fixed airway obstruction not responsive to bronchodilators, significant exposure to tobacco smoking or pollutants, and traditional asthma features, including blood or sputum eosinophilia and reversible airflow obstruction. ACO represents an important subset of patients with asthma (15 to 35%) and COPD (10 to 40%) that might respond to drugs not typically indicated for the disorder corresponding to the patient's main diagnosis (eg, prescribing roflimulast/azithromycin in an patient diagnosed with asthma or T2 biologic therapies in a patient diagnosed with COPD.
Asthma that is difficult to control or refractory to commonly used controller therapies should be further evaluated for alternative causes of episodic wheezing, cough, and dyspnea such as allergic bronchopulmonary aspergillosis Allergic Bronchopulmonary Aspergillosis (ABPA) Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to Aspergillus species (generally A. fumigatus) that occurs almost exclusively in patients with asthma... read more , bronchiectasis Bronchiectasis Bronchiectasis is dilation and destruction of larger bronchi caused by chronic infection and inflammation. Common causes are cystic fibrosis, immune defects, and recurrent infections, though... read more , asthma-COPD overlap, alpha-1 antitrypsin deficiency Alpha-1 Antitrypsin Deficiency Alpha-1 antitrypsin deficiency is congenital lack of a primary lung antiprotease, alpha-1 antitrypsin, which leads to increased protease-mediated tissue destruction and emphysema in adults.... read more , cystic fibrosis Cystic Fibrosis Cystic fibrosis is an inherited disease of the exocrine glands affecting primarily the gastrointestinal and respiratory systems. It leads to chronic lung disease, exocrine pancreatic insufficiency... read more , or vocal cord dysfunction Vocal Cord Dysfunction Vocal cord dysfunction involves paradoxical or dysfunctional movement of the vocal cords and is defined as adduction of the true vocal cords on inspiration and abduction on expiration; it causes... read more .
Pulmonary function tests
Patients suspected of having asthma should undergo pulmonary function testing Overview of Tests of Pulmonary Function Pulmonary function tests provide measures of airflow, lung volumes, gas exchange, response to bronchodilators, and respiratory muscle function. Basic pulmonary function tests available in the... read more to confirm and quantify the severity and reversibility of airway obstruction. Pulmonary function data quality is effort-dependent and requires patient education before the test. If it is safe to do so, bronchodilators should be stopped before the test: 8 hours for short-acting beta-2 agonists, such as albuterol; 24 hours for ipratropium; 12 to 48 hours for theophylline; 48 hours for long-acting beta-2 agonists, such as salmeterol and formoterol; and 1 week for tiotropium.
Spirometry Airflow, Lung Volumes, and Flow-Volume Loop Airflow and lung volume measurements can be used to differentiate obstructive from restrictive pulmonary disorders, to characterize severity, and to measure responses to therapy. Measurements... read more should be done before and after inhalation of a short-acting bronchodilator. Signs of airflow limitation before bronchodilator inhalation include reduced FEV1 and a reduced FEV1/FVC ratio. The FVC may also be decreased because of gas trapping, such that lung volume measurements may show an increase in the residual volume, the functional residual capacity, or both. An improvement in FEV1 of > 12% or an increase ≥ 10% of predicted FEV1 in response to bronchodilator treatment confirms reversible airway obstruction, although absence of this finding should not preclude a therapeutic trial of long-acting bronchodilators.
Flow-volume loops Airflow, Lung Volumes, and Flow-Volume Loop Airflow and lung volume measurements can be used to differentiate obstructive from restrictive pulmonary disorders, to characterize severity, and to measure responses to therapy. Measurements... read more should also be reviewed to diagnose vocal cord dysfunction, a common cause of upper airway obstruction that mimics asthma. However, it should be noted that vocal cord dysfunction is intermittent, and normal flow-volume loops do not exclude this condition.
Provocative testing, in which inhaled methacholine (or alternatives, such as inhaled histamine, adenosine, or bradykinin, or exercise testing) is used to provoke bronchoconstriction, is indicated for patients suspected of having asthma who have normal findings on spirometry and flow-volume testing and for patients suspected of having cough-variant asthma, provided there are no contraindications. Contraindications include FEV1 1 L or < 50% predicted, recent myocardial infarction or stroke, and severe hypertension (systolic BP > 200 mm Hg; diastolic BP > 100 mm Hg). A decline in FEV1 of > 20% on a provocative testing protocol is relatively specific for the diagnosis of asthma. However, FEV1 may decline in response to drugs used in provocative testing in other disorders, such as COPD. If FEV1 decreases by < 20% by the end of the testing protocol, asthma is less likely to be present.
Other tests may be helpful in some circumstances:
Diffusing capacity for carbon monoxide (DLCO)
Exhaled nitric oxide (FeNO)
DLCO testing can help distinguish asthma from COPD. Values are normal or elevated in asthma and usually reduced in COPD, particularly in patients with emphysema.
A chest x-ray may help exclude some causes of asthma or alternative diagnoses, such as heart failure Heart Failure (HF) Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular (LV) failure causes shortness of breath and fatigue, and right ventricular (RV) failure causes peripheral and abdominal... read more or pneumonia Overview of Pneumonia Pneumonia is acute inflammation of the lungs caused by infection. Initial diagnosis is usually based on chest x-ray and clinical findings. Causes, symptoms, treatment, preventive measures, and... read more . The chest x-ray in asthma is usually normal but may show hyperinflation or segmental atelectasis, a sign of mucous plugging. Infiltrates, especially those that come and go and that are associated with findings of central bronchiectasis, suggest allergic bronchopulmonary aspergillosis Allergic Bronchopulmonary Aspergillosis (ABPA) Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to Aspergillus species (generally A. fumigatus) that occurs almost exclusively in patients with asthma... read more .
Allergy testing may be indicated for children whose history suggests allergic triggers (particularly for allergic rhinitis Allergic Rhinitis Allergic rhinitis is seasonal or perennial itching, sneezing, rhinorrhea, nasal congestion, and sometimes conjunctivitis, caused by exposure to pollens or other allergens. Diagnosis is by history... read more ) because these children may benefit from immunotherapy. It should be considered for adults whose history indicates relief of symptoms with allergen avoidance and for those in whom a trial of therapeutic anti-IgE antibody therapy Other drugs Major drug classes commonly used in the treatment of asthma and asthma exacerbations include Bronchodilators (beta-2 agonists, anticholinergics) Corticosteroids Leukotriene modifiers Mast cell... read more is being considered. Skin testing and measurement of allergen-specific IgE Specific tests Allergic (including atopic) and other hypersensitivity disorders are inappropriate or exaggerated immune reactions to foreign antigens. Inappropriate immune reactions include those that are... read more via radioallergosorbent testing (RAST) can identify specific allergic triggers.
Blood tests may be done. Elevated blood eosinophils (> 400 cells/mcL [> 0.4 × 109 /L]) and elevated nonspecific IgE levels are suggestive but are neither sensitive nor specific for a diagnosis of allergic asthma. Furthermore, some studies have indicated that eosinophil levels may vary diurnally and with other factors (1 Diagnosis references Asthma is a disease of diffuse airway inflammation caused by a variety of triggering stimuli resulting in partially or completely reversible bronchoconstriction. Symptoms and signs include dyspnea... read more ). Generally, blood eosinophil levels are higher in the morning, and there may be falsely low eosinophil counts when samples are collected in the afternoon.
In patients ≥ 5 years, fractional exhaled nitric oxide (FeNO) may be used in the evaluation when the diagnosis of asthma is unclear, especially in children, and it can be used as a biomarker to monitor disease severity and therapeutic efficacy (2 Diagnosis references Asthma is a disease of diffuse airway inflammation caused by a variety of triggering stimuli resulting in partially or completely reversible bronchoconstriction. Symptoms and signs include dyspnea... read more ). FeNO levels > 50 ppb are consistent with allergic airways inflammation, supporting an asthma diagnosis. A level < 25 ppb is more consistent with an alternative diagnosis. Levels between 25 and 50 ppb are indeterminate.
Sputum evaluation for eosinophils is not commonly done; finding large numbers of eosinophils is suggestive of asthma but is neither sensitive nor specific.
Peak expiratory flow (PEF) measurements with inexpensive handheld flow meters are recommended for home monitoring of disease severity and for guiding therapy.
Evaluation of exacerbations
Patients with asthma with an acute exacerbation are evaluated based on clinical criteria but should sometimes also have certain tests:
Sometimes peak expiratory flow (PEF) measurement
The decision to treat an exacerbation is based primarily on an assessment of signs and symptoms. PEF measures can help establish the severity of an exacerbation but are most commonly used to monitor response to treatment in outpatients. PEF values are interpreted in light of the patient’s personal best, which may vary widely among patients who are equally well controlled. A 15 to 20% reduction from this baseline indicates a significant exacerbation. When baseline values are not known, the percent predicted PEF based on age, height, and sex may be used, but this is less accurate than a comparison to patient's personal best.
Although spirometry (eg, FEV1) more accurately reflects airflow than PEF, it is impractical in most urgent outpatient and emergency department settings. It may be used for office-based monitoring of treatment or when objective measures are required (eg, when an exacerbation appears to be more severe than perceived by the patient or is not recognized).
Chest x-ray is not necessary for most exacerbations but should be done in patients with symptoms or signs suggestive of pneumonia Overview of Pneumonia Pneumonia is acute inflammation of the lungs caused by infection. Initial diagnosis is usually based on chest x-ray and clinical findings. Causes, symptoms, treatment, preventive measures, and... read more , pneumothorax Pneumothorax Pneumothorax is air in the pleural space causing partial or complete lung collapse. Pneumothorax can occur spontaneously or result from trauma or medical procedures. Diagnosis is based on clinical... read more , or pneumomediastinum Pneumomediastinum Pneumomediastinum is air in mediastinal interstices. The main causes of pneumomediastinum are Alveolar rupture with dissection of air into the interstitium of the lung with translocation to... read more .
Arterial or venous blood gas measurements Arterial Blood Gas (ABG) Sampling Gas exchange is measured through several means, including Diffusing capacity for carbon monoxide Pulse oximetry Arterial blood gas sampling The diffusing capacity for carbon monoxide (DLCO)... read more should be done in patients with marked respiratory distress or symptoms and signs of impending respiratory failure Overview of Respiratory Failure Acute respiratory failure is a life-threatening impairment of oxygenation, carbon dioxide elimination, or both. Respiratory failure may occur because of impaired gas exchange, decreased ventilation... read more .
Fractional exhaled nitric oxide measurement has been proposed as an adjunct in evaluation of asthma control in patients with confusing or unclear histories or clinical scenarios. No cut off values have been established; however, FeNO-based monitoring of treatment efficacy and compliance has resulted in significant reductions in exacerbation frequency. There are limited data concerning FeNO use in patients taking immunomodulatory drugs (2 Diagnosis references Asthma is a disease of diffuse airway inflammation caused by a variety of triggering stimuli resulting in partially or completely reversible bronchoconstriction. Symptoms and signs include dyspnea... read more ).
1. Gibson PG: Variability of blood eosinophils as a biomarker in asthma and COPD. Respirology 23(1):12–13, 2018. doi: 10.1111/resp.13200
2. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), Cloutier MM, Baptist AP, et al: 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol 146(6):1217–1270, 2020. doi: 10.1016/j.jaci.2020.10.003
Prognosis for Asthma
Asthma resolves in many children, but for as many as 1 in 4, wheezing persists into adulthood or relapse occurs in later years. Female sex, smoking, earlier age of onset, and sensitization to household dust mites, are risk factors for persistence and relapse.
Although a significant number of deaths each year are attributable to asthma, most of these deaths are preventable with treatment. Thus, the prognosis is good with adequate access and adherence to treatment. Risk factors for death include increasing requirements for oral corticosteroids before hospitalization, previous hospitalization for acute exacerbations, and lower peak expiratory flow values at presentation. Several studies show that use of inhaled corticosteroids decreases hospital admission and mortality rates.
Over time, the airways in some patients with asthma undergo permanent structural changes (remodeling) and develop to baseline airflow obstruction that is not completely reversible. Early aggressive use of anti-inflammatory drugs may help prevent this remodeling.
Treatment of Asthma
Control of triggers
Treatment of acute exacerbations
Treatment objectives are to minimize impairment and risk, including preventing exacerbations and minimizing chronic symptoms, including nocturnal awakenings; to minimize the need for emergency department visits or hospitalizations; to maintain baseline (normal) pulmonary function and activity levels; and to avoid adverse treatment effects.
Control of triggering factors
Triggering factors in some patients may be controlled with use of synthetic fiber pillows and impermeable mattress covers and frequent washing of bed sheets, pillowcases, and blankets in hot water. Ideally, upholstered furniture, soft toys, carpets, curtains, and pets should be removed, at least from the bedroom, to reduce dust mites and animal dander. Dehumidifiers should be used in basements and in other poorly aerated, damp rooms to reduce mold. Steam treatment of homes diminishes dust mite allergens. House cleaning and extermination to eliminate cockroach exposure are especially important. Although control of triggering factors is more difficult in urban environments, the importance of these measures is not diminished.
High-efficiency particulate air (HEPA) vacuums and filters may relieve symptoms, but no beneficial effects on pulmonary function and on the need for drugs have been observed.
Sulfite-sensitive patients should avoid sulfite-containing food (eg, certain wine and salad dressings).
Nonallergenic triggers, such as cigarette smoke, strong odors, irritant fumes, cold temperatures, and high humidity should also be avoided or controlled when possible. Limiting exposure to people with viral upper respiratory infections is also important. However, exercise-induced asthma is not treated with exercise avoidance because exercise is important for health reasons. Instead, a short-acting bronchodilator is given prophylactically before exercise and as needed during or after exercise (rescue inhaler); controller therapy (step 2 and above in Table Steps of Asthma Management Steps of Asthma Management* ) should be started if exercise-induced symptoms are not responsive to rescue inhalers or occur daily or more frequently.
Patients with aspirin-sensitive asthma can use acetaminophen, choline magnesium salicylate, or highly selective NSAIDs like celecoxib when they need a pain reliever.
Asthma is a relative contraindication to the use of nonselective beta-blockers (eg, propranolol, timolol, carvedilol, nadolol, sotalol), including topical formulations, but cardioselective drugs (eg, metoprolol, atenolol) probably have no adverse effects.
Major drug classes commonly used in the treatment of asthma and asthma exacerbations include
Bronchodilators (beta or beta-2 adrenergic receptor agonists Beta agonists Major drug classes commonly used in the treatment of asthma and asthma exacerbations include Bronchodilators (beta-2 agonists, anticholinergics) Corticosteroids Leukotriene modifiers Mast cell... read more , anticholinergics Anticholinergics (antimuscarinics) Major drug classes commonly used in the treatment of asthma and asthma exacerbations include Bronchodilators (beta-2 agonists, anticholinergics) Corticosteroids Leukotriene modifiers Mast cell... read more )
Drugs in these classes (see table Drug Treatment of Chronic Asthma Drug Treatment of Asthma* ) are inhaled, taken orally, or injected subcutaneously or intravenously; inhaled drugs come in aerosolized and powdered forms. Use of aerosolized forms with a spacer or holding chamber facilitates deposition of the drug in the airways rather than the pharynx; patients are advised to wash and dry their spacers after each use to prevent bacterial contamination. In addition, use of aerosolized forms requires coordination between actuation of the inhaler (drug delivery) and inhalation; powdered forms reduce the need for coordination, because drug is delivered only when the patient inhales. For details, see Drug Treatment of Asthma Drug Treatment of Asthma Major drug classes commonly used in the treatment of asthma and asthma exacerbations include Bronchodilators (beta-2 agonists, anticholinergics) Corticosteroids Leukotriene modifiers Mast cell... read more .
Bronchial thermoplasty is a bronchoscopic technique in which heat is applied through a device that transfers localized controlled radiofrequency waves to the airways. The heat decreases the amount of airway smooth muscle remodeling (and thus the smooth muscle mass) that occurs with asthma. In clinical trials in patients with severe asthma not controlled with multiple therapies, there have been modest decreases in exacerbation frequency and improvement in asthma symptom control. However, some patients have experienced an immediate worsening of symptoms, sometimes requiring hospitalization immediately after the procedure. Expert recommendations are to avoid bronchial thermoplasty unless a patient places a low value on the potential for adverse outcomes and a high value on short-term potential benefits. If possible, bronchial thermoplasty should be done in centers where it is done routinely(1 Treatment reference Asthma is a disease of diffuse airway inflammation caused by a variety of triggering stimuli resulting in partially or completely reversible bronchoconstriction. Symptoms and signs include dyspnea... read more ).
Criteria for consideration of bronchial thermoplasty include severe asthma not controlled with inhaled corticosteroids and long-acting beta agonists, intermittent or continuous use of oral corticosteroids, FEV1 ≥ 50% of predicted, and no history of life-threatening exacerbations. Patients should understand the risk of post-procedure asthma exacerbation and need for hospitalization before proceeding with the procedure. The long-term efficacy and safety of bronchial thermoplasty is not known. There are no data in patients with > 3 exacerbations per year or an FEV1 < 50% of predicted because these patients were excluded from the clinical trials.
Monitoring response to treatment
Guidelines recommend office use of spirometry (FEV1, FEV1/FVC, FVC) to measure airflow limitation and assess impairment and risk. Spirometry should be repeated at least every 1 to 2 years in patients with asthma to monitor disease progression, and a step-up in therapy might be required if lung function declines or becomes impaired with evidence of increased airflow obstruction (see table Classification of Asthma Control Classification of Asthma Control*,† ). Outside the office, home peak expiratory flow (PEF) monitoring, in conjunction with patient symptom diaries and the use of an asthma action plan, is especially useful for charting disease progression and response to treatment in patients with moderate to severe persistent asthma. When asthma is quiescent, one PEF measurement in the morning suffices. Should PEF measurements fall to < 80% of the patient’s personal best, then twice/day monitoring to assess circadian variation is useful. Circadian variation of > 20% indicates airway instability and the need to re-evaluate the therapeutic regimen.
The importance of patient education cannot be overemphasized. Patients do better when they know more about asthma—what triggers an exacerbation, what drug to use when, proper inhaler technique, how to use a spacer with a metered-dose inhaler (MDI), and the importance of early use of corticosteroids in exacerbations. Every patient should have a written action plan for day-to-day management, especially for management of acute exacerbations, that is based on the patient’s best personal peak flow rather than on a predicted normal value. Such a plan leads to much better asthma control, largely attributable to improved adherence to therapies.
Treatment of acute asthma exacerbation
The goal of asthma exacerbation treatment is to relieve symptoms and return patients to their best lung function. Treatment includes
Inhaled bronchodilators (beta agonists and anticholinergics)
Usually systemic corticosteroids
Details of the treatment of acute asthma exacerbations Treatment of Acute Asthma Exacerbations The goal of asthma exacerbation treatment is to relieve symptoms and return patients to their best lung function. Treatment includes Inhaled bronchodilators ( beta-2 agonists and anticholinergics)... read more , including of severe attacks requiring hospitalization Hospitalization The goal of asthma exacerbation treatment is to relieve symptoms and return patients to their best lung function. Treatment includes Inhaled bronchodilators ( beta-2 agonists and anticholinergics)... read more , are discussed elsewhere.
Treatment of chronic asthma
Current asthma guidelines recommend treatment based on the severity classification. Continuing therapy is based on assessment of control (see table Classification of Asthma Control Classification of Asthma Control*,† ). Therapy is increased in a stepwise fashion (see table Steps of Asthma Management Steps of Asthma Management* ) until the best control of impairment and risk is achieved (step-up). Before therapy is stepped up, adherence, exposure to environmental factors (eg, trigger exposure), and presence of comorbid conditions (eg, obesity Obesity Obesity is excess body weight, defined as a body mass index (BMI) of ≥ 30 kg/m2. Complications include cardiovascular disorders (particularly in people with excess abdominal fat)... read more , allergic rhinitis Allergic Rhinitis Allergic rhinitis is seasonal or perennial itching, sneezing, rhinorrhea, nasal congestion, and sometimes conjunctivitis, caused by exposure to pollens or other allergens. Diagnosis is by history... read more , gastroesophageal reflux disease Gastroesophageal Reflux Disease (GERD) Incompetence of the lower esophageal sphincter allows reflux of gastric contents into the esophagus, causing burning pain. Prolonged reflux may lead to esophagitis, stricture, and rarely metaplasia... read more , chronic obstructive pulmonary disease Chronic Obstructive Pulmonary Disease (COPD) Chronic obstructive pulmonary disease (COPD) is airflow limitation caused by an inflammatory response to inhaled toxins, often cigarette smoke. Alpha-1 antitrypsin deficiency and various occupational... read more , obstructive sleep apnea Obstructive Sleep Apnea (OSA) Obstructive sleep apnea (OSA) consists of multiple episodes of partial or complete closure of the upper airway that occur during sleep and lead to breathing cessation (defined as a period of... read more , vocal cord dysfunction Vocal Cord Dysfunction Vocal cord dysfunction involves paradoxical or dysfunctional movement of the vocal cords and is defined as adduction of the true vocal cords on inspiration and abduction on expiration; it causes... read more , inhaled cocaine use) are reviewed. These factors should be addressed before increasing drug therapy. Once asthma has been well controlled for at least 3 months, drug therapy is reduced if possible to the minimum that maintains good control (step-down). For specific drugs and doses, see table Drug Treatment of Chronic Asthma Drug Treatment of Asthma* .
Exercise-induced asthma can generally be prevented by prophylactic inhalation of a short-acting beta-2 agonist or mast cell stabilizer before starting the exercise. If beta-2 agonists are not effective or if exercise-induced asthma causes symptoms daily or more frequently, the patient requires controller therapy.
The primary treatment for aspirin-sensitive asthma is avoidance of aspirin and other NSAIDs. Celecoxib does not appear to be a trigger. Leukotriene modifiers can blunt the response to NSAIDs. Alternatively, desensitization can be done in either the inpatient or outpatient clinic setting depending on the severity of aspirin sensitivity and asthma severity; desensitization has been successful in the majority of patients who are able to continue desensitization treatment for more than one year.
Multiple therapies are being developed to target specific components of the inflammatory cascade. Therapies directed at interleukin 6 (IL-6), thymic stromal lymphopoietin, tumor necrosis factor-alpha, other chemokines, and cytokines or their receptors are all under investigation or consideration as therapeutic targets.
1. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), Cloutier MM, Baptist AP, et al: 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol 146(6):1217–1270, 2020. doi: 10.1016/j.jaci.2020.10.003
Infants, children, and adolescents
Asthma is difficult to diagnose in infants; thus, under-recognition and undertreatment are common (see also Wheezing and Asthma in Infants and Young Children Wheezing and Asthma in Infants and Young Children Wheezing is a relatively high-pitched whistling noise produced by movement of air through narrowed or compressed small airways. It is common in the first few years of life and is typically caused... read more ). Empiric trials of inhaled bronchodilators and anti-inflammatory drugs may be helpful for both. Drugs may be given by nebulizer or metered-dose inhaler (MDI) with a holding chamber with or without a face mask. Infants and children < 5 years who require treatment > 2 times/week should be given daily anti-inflammatory therapy with inhaled corticosteroids (preferred), leukotriene receptor antagonists, or cromolyn.
Children > 5 years and adolescents with asthma can be treated similarly to adults except that long-acting muscarinic antagonists are not recommended. Also, zileuton should only be used in children ≥ 12 years. Children > 5 years of age and adolescents with asthma should be encouraged to maintain physical activities, exercise, and sports participation. Predicted norms for pulmonary function tests in adolescents are closer to childhood (not adult) standards. Adolescents and mature younger children should participate in developing their own asthma management plans and establishing their own goals for therapy to improve adherence. The action plan should be understood by teachers and school nurses to ensure reliable and prompt access to rescue drugs. Cromolyn and nedocromil are often tried in this group but are not as beneficial as inhaled corticosteroids. Long-acting drugs prevent the problems (eg, inconvenience, embarrassment) of having to take drugs at school.
About one third of women with asthma who become pregnant notice relief of symptoms, one third notice worsening (at times to a severe degree), and one third notice no change. Gastroesophageal reflux disease (GERD) may be an important contributor to symptomatic disease in pregnancy. Asthma control during pregnancy Asthma in Pregnancy The effect of pregnancy on asthma varies; deterioration is slightly more common than improvement, but most pregnant women do not have severe attacks. The effect of asthma on pregnancy also varies... read more is crucial because poorly controlled maternal disease can result in increased prenatal mortality, premature delivery, and low birth weight.
Asthma drugs have not been shown to have adverse fetal effects, but safety data are lacking. (See also guidelines from the National Asthma Education and Prevention Program, Managing Asthma During Pregnancy: Recommendations for Pharmacologic Treatment–Update 2004.) In general, uncontrolled asthma is more of a risk to mother and fetus than adverse effects due to asthma drugs. During pregnancy, normal blood PCO2 level is about 32 mm Hg. Therefore, carbon dioxide retention is probably occurring if PCO2 approaches 40 mm Hg.
Pearls & Pitfalls
Older patients have a high prevalence of other obstructive lung disease (eg, COPD Chronic Obstructive Pulmonary Disease (COPD) Chronic obstructive pulmonary disease (COPD) is airflow limitation caused by an inflammatory response to inhaled toxins, often cigarette smoke. Alpha-1 antitrypsin deficiency and various occupational... read more ), so it is important to determine the magnitude of the reversible component of airflow obstruction (eg, by a 2- to 3-week trial of inhaled corticosteroids or pulmonary function testing with bronchodilator challenge). Older patients may be more sensitive to adverse effects of beta-2 agonists and inhaled corticosteroids. Patients requiring inhaled corticosteroids, particularly those with risk factors for osteoporosis, may benefit from measures to preserve bone density (eg, calcium and vitamin D supplements, bisphosphonates).
Asthma triggers range from environmental allergens and respiratory irritants to infections, aspirin, exercise, emotion, and gastroesophageal reflux disease.
Consider asthma in patients who have unexplained persistent coughing, particularly at night.
If asthma is suspected, arrange pulmonary function testing, with methacholine provocation if necessary.
Educate patients on how to avoid triggers.
Control chronic asthma with drugs that modulate the allergic and immune response—usually inhaled corticosteroids—with other drugs (eg, long-acting bronchodilators, mast cell stabilizers, leukotriene inhibitors) added based on asthma severity.
Treat asthma aggressively during pregnancy.
The following are some English-language resources that may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), Cloutier MM, Baptist AP, et al: 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol 146(6):1217–1270, 2020. doi: 10.1016/j.jaci.2020.10.003