Asthma is a syndrome characterized by airflow obstruction that varies markedly, both spontaneously and with treatment. Asthmatics harbor a special type of inflammation in the airways that makes them more responsive than nonasthmatics to a wide range of triggers, leading to excessive narrowing with consequent reduced airflow and symptomatic wheezing and dyspnea. Narrowing of the airways is usually reversible, but in some patients with chronic asthma there may be an element of irreversible airflow obstruction. The increasing global prevalence of asthma, the large burden it now imposes on patients, and the high health care costs have led to extensive research into its mechanisms and treatment.
Asthma is one of the most common chronic diseases globally and currently affects approximately 300 million people worldwide. The prevalence of asthma has risen in affluent countries over the last 30 years but now appears to have stabilized, with approximately 10–12% of adults and 15% of children affected by the disease. In developing countries where the prevalence of asthma had been much lower, there is a rising prevalence, which is associated with increased urbanization. The prevalence of atopy and other allergic diseases has also increased over the same time, suggesting that the reasons for the increase are likely to be systemic rather than confined to the lungs. Most patients with asthma in affluent countries are atopic, with allergic sensitization to the house dust mite Dermatophagoides pteronyssinus and other environmental allergens, such as animal fur and pollens.
Asthma can present at any age, with a peak age of 3 years. In childhood, twice as many males as females are asthmatic, but by adulthood the sex ratio has equalized. Long-term studies that have followed children until they reach the age of 40 years suggest that many with asthma become asymptomatic during adolescence but that asthma returns in some during adult life, particularly in those with persistent symptoms and severe asthma. Adults with asthma, including those with onset during adulthood, rarely become permanently asymptomatic. The severity of asthma does not vary significantly within a given patient; those with mild asthma rarely progress to more severe disease, whereas those with severe asthma usually have severe disease at the onset.
Deaths from asthma are uncommon, and in many affluent countries have been steadily declining over the last decade. A rise in asthma mortality seen in several countries during the 1960s was associated with increased use of short-acting inhaled β2-adrenergic agonists (as rescue therapy), but there is now compelling evidence that the more widespread use of inhaled corticosteroids (ICS) in patients with persistent asthma is responsible for the decrease in mortality in recent years. Major risk factors for asthma deaths are poorly controlled disease with frequent use of bronchodilator inhalers, lack of or poor compliance with ICS therapy, and previous admissions to hospital with near-fatal asthma.
It has proved difficult to agree on a definition of asthma, but there is good agreement on the description of the clinical syndrome and disease pathology. Until the etiologic mechanisms of the disease are better understood, it will be difficult to provide an accurate definition.
RISK FACTORS AND TRIGGERS
Asthma is a heterogeneous disease with interplay between genetic and environmental factors. Several risk factors that predispose to asthma have been identified (Table 309-1). These should be distinguished from triggers, which are environmental factors that worsen asthma in a patient with established disease.
Atopy is the major risk factor for asthma, and nonatopic individuals have a very low risk of developing asthma. Patients with asthma commonly suffer from other atopic diseases, particularly allergic rhinitis, which may be found in over 80% of asthmatic patients, and atopic dermatitis (eczema). Atopy may be found in 40–50% of the population in affluent countries, with only a proportion of atopic individuals becoming asthmatic. This observation suggests that some other environmental or genetic factor(s) predispose to the development of asthma in atopic individuals. The allergens that lead to sensitization are usually proteins that have protease activity, and the most common allergens are derived from house dust mites, cat and dog fur, cockroaches (in inner cities), grass and tree pollens, and rodents (in laboratory workers). Atopy is due to the genetically determined production of specific IgE antibody, with many patients showing a family history of allergic diseases.
TABLE 309-1Risk Factors and Triggers Involved in Asthma ||Download (.pdf) TABLE 309-1 Risk Factors and Triggers Involved in Asthma
|Endogenous Factors ||Environmental Factors |
|Genetic predisposition ||Indoor allergens |
|Atopy ||Outdoor allergens |
|Airway hyperresponsiveness ||Occupational sensitizers |
|Gender ||Passive smoking |
|Ethnicity ||Respiratory infections |
|Obesity ||Diet |
|Early viral infections ||Acetaminophen (paracetamol) |
|Triggers || |
|Allergens || |
|Upper respiratory tract viral infections || |
|Exercise and hyperventilation || |
|Cold air || |
|Sulfur dioxide and irritant gases || |
|Drugs (β blockers, aspirin) || |
|Stress || |
|Irritants (household sprays, paint fumes) || |
The familial association of asthma and a high degree of concordance for asthma in identical twins indicate a genetic predisposition to the disease; however, whether or not the genes predisposing to asthma are similar or in addition to those predisposing to atopy is not yet clear. It now seems likely that different genes may also contribute to asthma specifically, and there is increasing evidence that the severity of asthma is also genetically determined. Genetic screens with classical linkage analysis and single-nucleotide polymorphisms of various candidate genes indicate that asthma is polygenic, with each gene identified having a small effect that is often not replicated in different populations. This observation suggests that the interaction of many genes is important, and these may differ in different populations. The most consistent findings have been associations with polymorphisms of genes on chromosome 5q, including the T helper 2 (TH2) cells interleukin (IL)-4, IL-5, IL-9, and IL-13, which are associated with atopy. There is increasing evidence for a complex interaction between genetic polymorphisms and environmental factors that will require very large population studies to unravel. Novel genes that have been associated with asthma, including ADAM-33, and DPP-10, have also been identified by positional cloning, but their function in disease pathogenesis is not yet clear. Recent genome-wide association studies have identified further novel genes, such as ORMDL3, although their functional role is not yet clear. Genetic polymorphisms may also be important in determining the response to asthma therapy. For example, the Arg-Gly-16 variant in the β2-receptor has been associated with reduced response to β2-agonists, and repeats of an Sp1 recognition sequence in the promoter region of 5-lipoxygenase may affect the response to antileukotrienes. However, these effects are small and inconsistent and do not yet have any implications for asthma therapy.
It is likely that environmental factors in early life determine which atopic individuals become asthmatic. The increasing prevalence of asthma, particularly in developing countries, over the last few decades also indicates the importance of environmental mechanisms interacting with a genetic predisposition.
Although viral infections (especially rhinovirus) are common triggers of asthma exacerbations, it is uncertain whether they play a role in etiology. There is some association between respiratory syncytial virus infection in infancy and the development of asthma, but the specific pathogenesis is difficult to elucidate because this infection is very common in children. Atypical bacteria, such as Mycoplasma and Chlamydophila, have been implicated in the mechanism of severe asthma, but thus far, the evidence is not very convincing of a true association.
The observation that allergic sensitization and asthma were less common in children with older siblings first suggested that lower levels of infection may be a factor in affluent societies that increase the risks of asthma. This “hygiene hypothesis” proposes that lack of infections in early childhood preserves the TH2 cell bias at birth, whereas exposure to infections and endotoxin results in a shift toward a predominant protective TH1 immune response. Children brought up on farms who are exposed to a high level of endotoxin are less likely to develop allergic sensitization than children raised on dairy farms. Intestinal parasite infection, such as hookworm, may also be associated with a reduced risk of asthma. Although there is considerable epidemiologic support for the hygiene hypothesis, it cannot account for the parallel increase in TH1-driven diseases such as diabetes mellitus over the same period.
The role of dietary factors is controversial. Observational studies have shown that diets low in antioxidants such as vitamin C and vitamin A, magnesium, selenium, and omega-3 polyunsaturated fats (fish oil) or high in sodium and omega-6 polyunsaturated fats are associated with an increased risk of asthma. Vitamin D deficiency may also predispose to the development of asthma. However, interventional studies with supplementary diets have not supported an important role for these dietary factors. Obesity is also an independent risk factor for asthma, particularly in women, but the mechanisms are thus far unknown.
Air pollutants, such as sulfur dioxide, ozone, and diesel particulates, may trigger asthma symptoms, but the role of different air pollutants in the etiology of the disease is much less certain. Most evidence argues against an important role for air pollution because asthma is no more prevalent in cities with a high ambient level of traffic pollution than in rural areas with low levels of pollution. Asthma had a much lower prevalence in East Germany compared to West Germany despite a much higher level of air pollution, but since reunification, these differences have decreased as eastern Germany has become more affluent. Indoor air pollution may be more important with exposure to nitrogen oxides from cooking stoves and exposure to passive cigarette smoke. There is some evidence that maternal smoking is a risk factor for asthma, but it is difficult to dissociate this association from an increased risk of respiratory infections.
Inhaled allergens are common triggers of asthma symptoms and have also been implicated in allergic sensitization. Exposure to house dust mites in early childhood is a risk factor for allergic sensitization and asthma, but rigorous allergen avoidance has not shown any evidence for a reduced risk of developing asthma. The increase in house dust mites in centrally heated poorly ventilated homes with fitted carpets has been implicated in the increasing prevalence of asthma in affluent countries. Domestic pets, particularly cats, have also been associated with allergic sensitization, but early exposure to cats in the home may be protective through the induction of tolerance.
Occupational asthma is relatively common and may affect up to 10% of young adults. Over 300 sensitizing agents have been identified. Chemicals such as toluene diisocyanate and trimellitic anhydride, may lead to sensitization independent of atopy. Individuals may also be exposed to allergens in the workplace such as small animal allergens in laboratory workers and fungal amylase in wheat flour in bakers. Occupational asthma may be suspected when symptoms improve during weekends and holidays.
Asthma occurs more frequently in obese people (body mass index >30 kg/m2) and is often more difficult to control. Although mechanical factors may contribute, it may also be linked to the proinflammatory adipokines and reduced anti-inflammatory adipokines that are released from fat stores.
Several other factors have been implicated in the etiology of asthma, including lower maternal age, duration of breast-feeding, prematurity and low birthweight, and inactivity, but are unlikely to contribute to the recent global increase in asthma prevalence. There is also an association with acetaminophen (paracetamol) consumption in childhood, which may be linked to increased oxidative stress.
A minority of asthmatic patients (approximately 10%) have negative skin tests to common inhalant allergens and normal serum concentrations of IgE. These patients, with nonatopic or intrinsic asthma, usually show later onset of disease (adult-onset asthma), commonly have concomitant nasal polyps, and may be aspirin-sensitive. They usually have more severe, persistent asthma. Little is understood about mechanism, but the immunopathology in bronchial biopsies and sputum appears to be identical to that found in atopic asthma. There is recent evidence for increased local production of IgE in the airways, suggesting that there may be common IgE-mediated mechanisms; staphylococcal enterotoxins, which serve as “superantigens,” have been implicated.
Several stimuli trigger airway narrowing, wheezing, and dyspnea in asthmatic patients. Although a previous view held that these stimuli should be avoided, the triggering of asthma by these stimuli is now seen as evidence for poor control and an indicator of the need to increase controller (preventive) therapy.
Inhaled allergens activate mast cells with bound IgE directly leading to the immediate release of bronchoconstrictor mediators, resulting in the early response that is reversed by bronchodilators. Often, experimental allergen challenge is followed by a late response when there is airway edema and an acute inflammatory response with increased eosinophils and neutrophils that are not very reversible with bronchodilators. The most common allergens to trigger asthma are Dermatophagoides species, and environmental exposure leads to low-grade chronic symptoms that are perennial. Other perennial allergens are derived from cats and other domestic pets, as well as cockroaches. Other allergens, including grass pollen, ragweed, tree pollen, and fungal spores, are seasonal. Pollens usually cause allergic rhinitis rather than asthma, but in thunderstorms, the pollen grains are disrupted and the particles that may be released can trigger severe asthma exacerbations (thunderstorm asthma).
Upper respiratory tract virus infections such as rhinovirus, respiratory syncytial virus, and coronavirus are the most common triggers of acute severe exacerbations and may invade epithelial cells of the lower as well as the upper airways. The mechanism whereby these viruses cause exacerbations is poorly understood, but there is an increase in airway inflammation with increased numbers of eosinophils and neutrophils. There is evidence for reduced production of type I interferons by epithelial cells from asthmatic patients, resulting in increased susceptibility to these viral infections and a greater inflammatory response.
Several drugs may trigger asthma. Beta-adrenergic blockers commonly acutely worsen asthma, and their use may be fatal. The mechanisms are not clear, but are likely mediated through increased cholinergic bronchoconstriction. All β blockers need to be avoided, and even selective β2 blockers or topical application (e.g., timolol eye drops) may be dangerous. Angiotensin-converting enzyme inhibitors are theoretically detrimental as they inhibit breakdown of kinins, which are bronchoconstrictors; however, they rarely worsen asthma, and the characteristic cough is no more frequent in asthmatics than in nonasthmatics. Aspirin may worsen asthma in some patients (aspirin-sensitive asthma is discussed below under “Special Considerations”).
Exercise is a common trigger of asthma, particularly in children. The mechanism is linked to hyperventilation, which results in increased osmolality in airway lining fluid and triggers mast cell mediator release, resulting in bronchoconstriction. Exercise-induced asthma (EIA) typically begins after exercise has ended and resolves spontaneously within about 30 min. EIA is worse in cold, dry climates than in hot, humid conditions. It is, therefore, more common in sports activities such as cross-country running in cold weather, overland skiing, and ice hockey than in swimming. It may be prevented by prior administration of β2-agonists and antileukotrienes, but is best prevented by regular treatment with ICSs, which reduce the population of surface mast cells required for this response.
Cold air and hyperventilation may trigger asthma through the same mechanisms as exercise. Laughter may also be a trigger. Many patients report worsening of asthma in hot weather and when the weather changes. Some asthmatics become worse when exposed to strong smells or perfumes, but the mechanism of this response is uncertain.
There is little evidence that allergic reactions to food lead to increased asthma symptoms, despite the belief of many patients that their symptoms are triggered by particular food constituents. Exclusion diets are usually unsuccessful at reducing the frequency of episodes. Some foods such as shellfish and nuts may induce anaphylactic reactions that may include wheezing. Patients with aspirin-induced asthma may benefit from a salicylate-free diet, but these are difficult to maintain. Certain food additives may trigger asthma. Metabisulfite, which is used as a food preservative, may trigger asthma through the release of sulfur dioxide gas in the stomach. Tartrazine, a yellow food-coloring agent, was believed to be a trigger for asthma, but there is little convincing evidence for this.
Increased ambient levels of sulfur dioxide, ozone, and nitrogen oxides are associated with increased asthma symptoms.
Several substances found in the workplace may act as sensitizing agents, as discussed above, but may also act as triggers of asthma symptoms. Occupational asthma is characteristically associated with symptoms at work with relief on weekends and holidays. If removed from exposure within the first 6 months of symptoms, there is usually complete recovery. More persistent symptoms lead to irreversible airway changes, and thus, early detection and avoidance are important.
Some women show premenstrual worsening of asthma, which can occasionally be very severe. The mechanisms are not completely understood, but are related to a fall in progesterone and in severe cases may be improved by treatment with high doses of progesterone or gonadotropin-releasing factors. Thyrotoxicosis and hypothyroidism can both worsen asthma, although the mechanisms are uncertain.
Gastroesophageal reflux is common in asthmatic patients because it is increased by bronchodilators. Although acid reflux might trigger reflex bronchoconstriction, it rarely causes asthma symptoms, and antireflux therapy usually fails to reduce asthma symptoms in most patients.
Many asthmatics report worsening of symptoms with stress. Psychological factors can induce bronchoconstriction through cholinergic reflex pathways. Paradoxically, very severe stress such as bereavement usually does not worsen, and may even improve, asthma symptoms.
Asthma is associated with a specific chronic inflammation of the mucosa of the lower airways. One of the main aims of treatment is to reduce this inflammation.
The pathology of asthma has been revealed through examining the lungs of patients who have died of asthma and from bronchial biopsies. The airway mucosa is infiltrated with activated eosinophils and T lymphocytes, and there is activation of mucosal mast cells. The degree of inflammation is poorly related to disease severity and may even be found in atopic patients without asthma symptoms. This inflammation is usually reduced by treatment with ICS. There are also structural changes in the airways (described as remodeling). A characteristic finding is thickening of the basement membrane due to subepithelial collagen deposition. This feature is also found in patients with eosinophilic bronchitis presenting as cough who do not have asthma and is, therefore, likely to be a marker of eosinophilic inflammation in the airway as eosinophils release fibrogenic mediators. The epithelium is often shed or friable, with reduced attachments to the airway wall and increased numbers of epithelial cells in the lumen. The airway wall itself may be thickened and edematous, particularly in fatal asthma. Another common finding in fatal asthma is occlusion of the airway lumen by a mucous plug, which is comprised of mucous glycoproteins secreted from goblet cells and plasma proteins from leaky bronchial vessels (Fig. 309-1). There is also vasodilation and increased numbers of blood vessels (angiogenesis). Direct observation by bronchoscopy indicates that the airways may be narrowed, erythematous, and edematous. The pathology of asthma is remarkably uniform in different phenotypes of asthma, including atopic (extrinsic), nonatopic (intrinsic), occupational, aspirin-sensitive, and pediatric asthma. These pathologic changes are found in all airways, but do not extend to the lung parenchyma; peripheral airway inflammation is found particularly in patients with severe asthma. The involvement of airways may be patchy, and this is consistent with bronchographic findings of uneven narrowing of the airways.
Histopathology of a small airway in fatal asthma. The lumen is occluded with a mucous plug, there is goblet cell metaplasia, and the airway wall is thickened, with an increase in basement membrane thickness and airway smooth muscle. (Courtesy of Dr. J. Hogg, University of British Colombia.)
There is inflammation in the respiratory mucosa from the trachea to terminal bronchioles, but with a predominance in the bronchi (cartilaginous airways); however, it is still uncertain as to how inflammatory cells interact and how inflammation translates into the symptoms of asthma (Fig. 309-2). There is good evidence that the specific pattern of airway inflammation in asthma is associated with airway hyperresponsiveness (AHR), the physiologic abnormality of asthma, which is correlated with variable airflow obstruction. The pattern of inflammation in asthma is characteristic of allergic diseases, with similar inflammatory cells seen in the nasal mucosa in rhinitis. However, an indistinguishable pattern of inflammation is found in intrinsic asthma, and this may reflect local rather than systemic IgE production. Although most attention has focused on the acute inflammatory changes seen in asthma, this is a chronic condition, with inflammation persisting over many years in most patients. The mechanisms involved in persistence of inflammation in asthma are still poorly understood. Superimposed on this chronic inflammatory state are acute inflammatory episodes, which correspond to exacerbations of asthma. Although the common pattern of inflammation in asthma is characterized by eosinophil infiltration, some patients with severe asthma show a neutrophilic pattern of inflammation that is less sensitive to corticosteroids. However, many inflammatory cells are involved in asthma with no key cell that is predominant (Fig. 309-3).
Inflammation in the airways of asthmatic patients leads to airway hyperresponsiveness and symptoms. So2, sulfur dioxide.
The pathophysiology of asthma is complex with participation of several interacting inflammatory cells, which result in acute and chronic inflammatory effects on the airway.
Mast cells are important in initiating the acute bronchoconstrictor responses to allergens and several other indirectly acting stimuli, such as exercise and hyperventilation (via osmolality changes), as well as fog. Activated mucosal mast cells are found at the airway surface in asthma patients and also in the airway smooth-muscle layer, whereas this is not seen in normal subjects or patients with eosinophilic bronchitis. Mast cells are activated by allergens through an IgE-dependent mechanism, and binding of specific IgE to mast cells renders them more sensitive to activation by physical stimuli such as osmolality. The importance of IgE in the pathophysiology of asthma has been highlighted by clinical studies with humanized anti-IgE antibodies, which inhibit IgE-mediated effects, reduce asthma symptoms, and reduce exacerbations. There are, however, uncertainties about the role of mast cells in more chronic allergic inflammatory events. Mast cells release several bronchoconstrictor mediators, including histamine, prostaglandin D2, and cysteinyl-leukotrienes, but also several cytokines, chemokines, growth factors, and neurotrophins.
Macrophages and dendritic cells
Macrophages, which are derived from blood monocytes, may traffic into the airways in asthma and may be activated by allergens via low-affinity IgE receptors (FcεRII). Macrophages have the capacity to initiate a type of inflammatory response via the release of a certain pattern of cytokines, but these cells also release anti-inflammatory mediators (e.g., IL-10), and thus, their roles in asthma are uncertain. Dendritic cells are specialized macrophage-like cells in the airway epithelium, which are the major antigen-presenting cells. Dendritic cells take up allergens, process them to peptides, and migrate to local lymph nodes where they present the allergenic peptides to uncommitted T lymphocytes to program the production of allergen-specific T cells. Immature dendritic cells in the respiratory tract promote TH2 cell differentiation and require cytokines, such as IL-12 and tumor necrosis factor α (TNF-α), to promote the normally preponderant TH1 response. The cytokine thymic stromal lymphopoietin (TSLP) released from epithelial cells in asthmatic patients instructs dendritic cells to release chemokines that attract TH2 cells into the airways.
Eosinophil infiltration is a characteristic feature of asthmatic airways. Allergen inhalation results in a marked increase in activated eosinophils in the airways at the time of the late reaction. Eosinophils are linked to the development of AHR through the release of basic proteins and oxygen-derived free radicals. Eosinophil recruitment involves adhesion of eosinophils to vascular endothelial cells in the airway circulation due to interaction between adhesion molecules, migration into the submucosa under the direction of chemokines, and their subsequent activation and prolonged survival. Blocking antibodies to IL-5 causes a profound and prolonged reduction in circulating and sputum eosinophils, but is not associated with reduced AHR or asthma symptoms, although in selected patients with steroid-resistant airway eosinophils, there is a reduction in exacerbations. Eosinophils may be important in release of growth factors involved in airway remodeling and in exacerbations but probably not in AHR.
Increased numbers of activated neutrophils are found in sputum and airways of some patients with severe asthma and during exacerbations, although there is a proportion of patients even with mild or moderate asthma who have a predominance of neutrophils. The roles of neutrophils in asthma that are resistant to the anti-inflammatory effects of corticosteroids are currently unknown.
T lymphocytes play a very important role in coordinating the inflammatory response in asthma through the release of specific patterns of cytokines, resulting in the recruitment and survival of eosinophils and in the maintenance of a mast cell population in the airways. The naïve immune system and the immune system of asthmatics are skewed to express the TH2 phenotype, whereas in normal airways, TH1 cells predominate. TH2 cells, through the release of IL-5, are associated with eosinophilic inflammation and, through the release of IL-4 and IL-13, are associated with increased IgE formation. Recently, bronchial biopsies have demonstrated a preponderance of natural killer CD4+ T lymphocytes that express high levels of IL-4. Regulatory T cells play an important role in determining the expression of other T cells, and there is evidence for a reduction in a certain subset of regulatory T cells (CD4+CD25+) in asthma that is associated with increased TH2 cells. Recently, innate T cells (ILC2) without T cell receptors have been identified that release TH2 cytokines and are regulated by epithelial cytokines, such as IL-25 and IL-33.
Structural cells of the airways, including epithelial cells, fibroblasts, and airway smooth-muscle cells, are also important sources of inflammatory mediators, such as cytokines and lipid mediators, in asthma. Indeed, because structural cells far outnumber inflammatory cells, they may become the major sources of mediators driving chronic inflammation in asthmatic airways. In addition, epithelial cells may have key roles in translating inhaled environmental signals into an airway inflammatory response and are probably major target cells for ICS.
Multiple inflammatory mediators have been implicated in asthma, and they may have a variety of effects on the airways that account for the pathologic features of asthma (Fig. 309-4). Mediators such as histamine, prostaglandin D2, and cysteinyl-leukotrienes contract airway smooth muscle, increase microvascular leakage, increase airway mucus secretion, and attract other inflammatory cells. Because each mediator has many effects, the role of individual mediators in the pathophysiology of asthma is not yet clear. Although the multiplicity of mediators makes it unlikely that preventing the synthesis or action of a single mediator will have a major impact in clinical asthma, recent clinical studies with antileukotrienes suggest that cysteinyl-leukotrienes have clinically important effects.
Many cells and mediators are involved in asthma and lead to several effects on the airways. AHR, airway hyperresponsiveness; PAF, platelet-activating factor.
Multiple cytokines regulate the chronic inflammation of asthma. The TH2 cytokines IL-4, IL-5, and IL-13 mediate allergic inflammation, whereas proinflammatory cytokines, such as TNF-α and IL-1β, amplify the inflammatory response and play a role in more severe disease. TSLP is an upstream cytokine released from epithelial cells of asthmatics that orchestrates the release of chemokines that selectively attract TH2 cells. Some cytokines such as IL-10 and IL-12 are anti-inflammatory and may be deficient in asthma.
Chemokines are involved in attracting inflammatory cells from the bronchial circulation into the airways. Eotaxin (CCL11) is selectively attractant to eosinophils via CCR3 and is expressed by epithelial cells of asthmatics, whereas CCL17 (TARC) and CCL22 (MDC) from epithelial cells attract TH2 cells via CCR4 (Fig. 309-5).
T lymphocytes in asthma. Allergen interacts with dendritic cells and releases thymus stimulated lymphopoeitin (TSLP), which stimulates activated dendritic cells to release the chemokines CCL17 and CCL22, which attract T helper 2 (TH2) lymphocytes. Allergens and viral infection may release interleukin (IL)-25 and -33, which recruit and activate type 2 innate lymphoid cells (ILC2). Both TH2 and ILC2 cells release IL-5 and epithelial cells release CCL11 (eotaxin), which together lead to recruitment of eosinophils into the airways.
Activated inflammatory cells such as macrophages and eosinophils produce reactive oxygen species. Evidence for increased oxidative stress in asthma is provided by the increased concentrations of 8-isoprostane (a product of oxidized arachidonic acid) in exhaled breath condensates and increased ethane (a product of lipid peroxidation) in the expired air of asthmatic patients. Increased oxidative stress is related to disease severity, may amplify the inflammatory response, and may reduce responsiveness to corticosteroids.
Nitric oxide (NO) is produced by NO synthases in several cells in the airway, particularly airway epithelial cells and macrophages. The level of NO in the expired air of patients with asthma is higher than normal and is related to the eosinophilic inflammation. Increased NO may contribute to the bronchial vasodilation observed in asthma. Fractional exhaled NO (FENO) is increasingly used in the diagnosis and monitoring of asthmatic inflammation, although it is not yet used routinely in clinical practice.
Proinflammatory transcription factors, such as nuclear factor-κB (NF-κB) and activator protein-1, are activated in asthmatic airways and orchestrate the expression of multiple inflammatory genes. More specific transcription factors that are involved include nuclear factor of activated T cells and GATA-3, which regulate the expression of TH2 cytokines in T cells.
The chronic inflammatory response has several effects on the target cells of the airways, resulting in the characteristic pathophysiologic and remodeling changes associated with asthma. Asthma may be regarded as a disease with continuous inflammation and repair proceeding simultaneously, although the relationship between chronic inflammatory processes and asthma symptoms is often obscure.
Airway epithelial shedding may be important in contributing to AHR and may explain how several mechanisms, such as ozone exposure, virus infections, chemical sensitizers, and allergens (usually proteases), can lead to its development, as all of these stimuli may lead to epithelial disruption. Epithelial damage may contribute to AHR in a number of ways, including loss of its barrier function to allow penetration of allergens; loss of enzymes (such as neutral endopeptidase) that degrade certain peptide inflammatory mediators; loss of a relaxant factor (so called epithelial-derived relaxant factor); and exposure of sensory nerves, which may lead to reflex neural effects on the airway.
In all asthmatic patients, the basement membrane is apparently thickened due to subepithelial fibrosis with deposition of types III and V collagen below the true basement membrane and is associated with eosinophil infiltration, presumably through the release of profibrotic mediators such as transforming growth factor-β. Mechanical manipulations can alter the phenotype of airway epithelial cells in a profibrotic fashion. In more severe patients, there is also fibrosis within the airway wall, which may contribute to irreversible narrowing of the airways.
In vitro airway smooth muscle from asthmatic patients usually shows no increased responsiveness to constrictors. Reduced responsiveness to β-agonists has also been reported in postmortem or surgically removed bronchi from asthmatics, although the number of β-receptors is not reduced, suggesting that β-receptors have been uncoupled. These abnormalities of airway smooth muscle may be secondary to the chronic inflammatory process. Inflammatory mediators may modulate the ion channels that serve to regulate the resting membrane potential of airway smooth-muscle cells, thus altering the level of excitability of these cells. In asthmatic airways there is also a characteristic hypertrophy and hyperplasia of airway smooth muscle, which is presumably the result of stimulation of airway smooth-muscle cells by various growth factors such as platelet-derived growth factor (PDGF) or endothelin-1 released from inflammatory or epithelial cells.
There is increased airway mucosal blood flow in asthma, which may contribute to airway narrowing. There is an increase in the number of blood vessels in asthmatic airways as a result of angiogenesis in response to growth factors, particularly vascular endothelial growth factor. Microvascular leakage from postcapillary venules in response to inflammatory mediators is observed in asthma, resulting in airway edema and plasma exudation into the airway lumen.
Increased mucus secretion contributes to the viscid mucous plugs that occlude asthmatic airways, particularly in fatal asthma. There is hyperplasia of submucosal glands that are confined to large airways and of increased numbers of epithelial goblet cells. IL-13 induces mucus hypersecretion in experimental models of asthma.
Various defects in autonomic neural control may contribute to AHR in asthma, but these are likely to be secondary to the disease, rather than primary defects. Cholinergic pathways, through the release of acetylcholine acting on muscarinic receptors, cause bronchoconstriction and may be activated reflexly in asthma. Inflammatory mediators may activate sensory nerves, resulting in reflex cholinergic bronchoconstriction or release of inflammatory neuropeptides. Inflammatory products may also sensitize sensory nerve endings in the airway epithelium such that the nerves become hyperalgesic. Neurotrophins, which may be released from various cell types in airways, including epithelial cells and mast cells, may cause proliferation and sensitization of airway sensory nerves. Airway nerves may also release neurotransmitters, such as substance P, which have inflammatory effects.
Several changes in the structure of the airway are characteristically found in asthma, and these may lead to irreversible narrowing of the airways. Population studies have shown a greater decline in lung function over time than in normal subjects; however, most patients with asthma preserve normal or near-normal lung function throughout life if appropriately treated.
The accelerated decline in lung function occurs in a smaller proportion of asthmatics, and these are usually patients with more severe disease. There is some evidence that the early use of ICS may reduce the decline in lung function. The characteristic structural changes are increased airway smooth muscle, fibrosis, angiogenesis, and mucus hyperplasia.
Limitation of airflow is due mainly to bronchoconstriction, but airway edema, vascular congestion, and luminal occlusion with exudate may contribute. This results in a reduction in forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity (FVC) ratio, and peak expiratory flow (PEF), as well as an increase in airway resistance. Early closure of peripheral airway results in lung hyperinflation (air trapping) and increased residual volume, particularly during acute exacerbations and in severe persistent asthma. In more severe asthma, reduced ventilation and increased pulmonary blood flow result in mismatching of ventilation and perfusion and in bronchial hyperemia. Ventilatory failure is very uncommon, even in patients with severe asthma, and arterial PCO2 tends to be low due to increased ventilation.
AHR is the characteristic physiologic abnormality of asthma and describes the excessive bronchoconstrictor response to multiple inhaled triggers that would have no effect on normal airways. The increase in AHR is linked to the frequency of asthma symptoms, and, thus, an important aim of therapy is to reduce AHR. Increased bronchoconstrictor responsiveness is seen with direct bronchoconstrictors such as histamine and methacholine, which contract airway smooth muscle, but is characteristically also seen with many indirect stimuli, which release bronchoconstrictors from mast cells or activate sensory nerves. Most of the triggers for asthma symptoms appear to act indirectly, including allergens, exercise, hyperventilation, fog (via mast cell activation), irritant dusts, and sulfur dioxide (via a cholinergic reflex).
CLINICAL FEATURES AND DIAGNOSIS
The characteristic symptoms of asthma are wheezing, dyspnea, and coughing, which are variable, both spontaneously and with therapy. Symptoms may be worse at night, and patients typically awake in the early morning hours. Patients may report difficulty in filling their lungs with air. There is increased mucus production in some patients, with typically tenacious mucus that is difficult to expectorate. There may be increased ventilation and use of accessory muscles of ventilation. Prodromal symptoms may precede an attack, with itching under the chin, discomfort between the scapulae, or inexplicable fear (impending doom).
Typical physical signs are inspiratory, and to a greater extent expiratory, rhonchi throughout the chest, and there may be hyperinflation. Some patients, particularly children, may present with a predominant nonproductive cough (cough-variant asthma). There may be no abnormal physical findings when asthma is under control.
The diagnosis of asthma is usually apparent from the symptoms of variable and intermittent airways obstruction, but must be confirmed by objective measurements of lung function.
Simple spirometry confirms airflow limitation with a reduced FEV1, FEV1/FVC ratio, and PEF (Fig. 309-6). Reversibility is demonstrated by a >12% and 200-mL increase in FEV1 15 min after an inhaled short-acting β2-agonist or in some patients by a 2- to 4-week trial of oral corticosteroids (OCS) (prednisone or prednisolone 30–40 mg daily). Measurements of PEF twice daily may confirm the diurnal variations in airflow obstruction. Flow-volume loops show reduced peak flow and reduced maximum expiratory flow. Further lung function tests are rarely necessary, but whole-body plethysmography shows increased airway resistance and may show increased total lung capacity and residual volume. Gas diffusion is usually normal, but there may be a small increase in gas transfer in some patients.
Spirometry and flow-volume loop in asthmatic compared to normal subject. There is a reduction in forced expiratory volume in 1 second (FEV1) but less reduction in forced vital capacity (FVC), giving a reduced FEV1/FVC ratio (<70%). The flow-volume loop shows reduced peak expiratory flow and a typical scalloped appearance indicating widespread airflow obstruction.
The increased AHR is normally measured by methacholine or histamine challenge with calculation of the provocative concentration that reduces FEV1 by 20% (PC20). This is rarely useful in clinical practice, but can be used in the differential diagnosis of chronic cough and when the diagnosis is in doubt in the setting of normal pulmonary function tests. Occasionally exercise testing is done to demonstrate the postexercise bronchoconstriction if there is a predominant history of EIA. Allergen challenge is rarely necessary and should only be undertaken by a specialist if specific occupational agents are to be identified.
Blood tests are not usually helpful. Total serum IgE and specific IgE to inhaled allergens (radioallergosorbent test [RAST]) may be measured in some patients.
Chest roentgenography is usually normal but in more severe patients may show hyperinflated lungs. In exacerbations, there may be evidence of a pneumothorax. Lung shadowing usually indicates pneumonia or eosinophilic infiltrates in patients with bronchopulmonary aspergillosis. High-resolution computed tomography (CT) may show areas of bronchiectasis in patients with severe asthma, and there may be thickening of the bronchial walls, but these changes are not diagnostic of asthma.
Skin prick tests to common inhalant allergens (house dust mite, cat fur, grass pollen) are positive in allergic asthma and negative in intrinsic asthma, but are not helpful in diagnosis. Positive skin responses may be useful in persuading patients to undertake allergen avoidance measures.
FENO is now being used as a noninvasive test to measure airway inflammation. The typically elevated levels in asthma are reduced by ICS, so this may be a test of compliance with therapy. It may also be useful in demonstrating insufficient anti-inflammatory therapy and may be useful in down-titrating ICS. However, studies in unselected patients have not convincingly demonstrated improved clinical outcomes, and it may be necessary to select patients who are poorly controlled.
It is usually not difficult to differentiate asthma from other conditions that cause wheezing and dyspnea. Upper airway obstruction by a tumor or laryngeal edema can mimic severe asthma, but patients typically present with stridor localized to large airways. The diagnosis is confirmed by a flow-volume loop that shows a reduction in inspiratory as well as expiratory flow, and bronchoscopy to demonstrate the site of upper airway narrowing. Persistent wheezing in a specific area of the chest may indicate endobronchial obstruction with a foreign body. Left ventricular failure may mimic the wheezing of asthma, but basilar crackles are present in contrast to asthma. Vocal chord dysfunction may mimic asthma and is thought to be an hysterical conversion syndrome.
Eosinophilic pneumonias and systemic vasculitis, including Churg-Strauss syndrome and polyarteritis nodosa, may be associated with wheezing. Chronic obstructive pulmonary disease (COPD) is usually easy to differentiate from asthma as symptoms show less variability, never completely remit, and show much less (or no) reversibility to bronchodilators. Approximately 10% of COPD patients have features of asthma, with increased sputum eosinophils and a response to OCSs; these patients probably have both diseases concomitantly.
The treatment of asthma is straightforward, and the majority of patients are now managed by internists and family doctors with effective and safe therapies. There are several aims of therapy (Table 309-2). Most emphasis has been placed on drug therapy, but several nonpharmacologic approaches have also been used. The main drugs for asthma can be divided into bronchodilators, which give rapid relief of symptoms mainly through relaxation of airway smooth muscle, and controllers, which inhibit the underlying inflammatory process. BRONCHODILATOR THERAPIES
Bronchodilators act primarily on airway smooth muscle to reverse the bronchoconstriction of asthma. This gives rapid relief of symptoms but has little or no effect on the underlying inflammatory process. Thus, bronchodilators are not sufficient to control asthma in patients with persistent symptoms. There are three classes of bronchodilators in current use: β2-adrenergic agonists, anticholinergics, and theophylline; of these, β2-agonists are by far the most effective. β2-Agonists
β2-Agonists activate β2-adrenergic receptors, which are widely expressed in the airways. β2-Receptors are coupled through a stimulatory G protein to adenylyl cyclase, resulting in increased intracellular cyclic adenosine monophosphate (AMP), which relaxes smooth-muscle cells and inhibits certain inflammatory cells, particularly mast cells. Mode of Action
The primary action of β2-agonists is to relax airway smooth-muscle cells of all airways, where they act as functional antagonists, reversing and preventing contraction of airway smooth-muscle cells by all known bronchoconstrictors. This generalized action is likely to account for their great efficacy as bronchodilators in asthma. There are also additional nonbronchodilator effects that may be clinically useful, including inhibition of mast cell mediator release, reduction in plasma exudation, and inhibition of sensory nerve activation. Inflammatory cells express small numbers of β2-receptors, but these are rapidly downregulated with β2-agonist activation so that, in contrast to corticosteroids, there are no effects on inflammatory cells in the airways and there is no reduction in AHR. Clinical Use
β2-Agonists are usually given by inhalation to reduce side effects. Short-acting β2-agonists (SABAs) such as albuterol and terbutaline have a duration of action of 3–6 h. They have a rapid onset of bronchodilatation and are, therefore, used as needed for symptom relief. Increased use of SABA indicates that asthma is not controlled. They are also useful in preventing EIA if taken prior to exercise. SABAs are used in high doses by nebulizer or via a metered-dose inhaler with a spacer. Long-acting β2-agonists (LABAs) include salmeterol and formoterol, both of which have a duration of action over 12 h and are given twice daily by inhalation; indacaterol is given once daily. LABAs have replaced the regular use of SABAs, but LABAs should not be given in the absence of ICS therapy because they do not control the underlying inflammation. They do, however, improve asthma control and reduce exacerbations when added to ICS, which allows asthma to be controlled at lower doses of corticosteroids. This observation has led to the widespread use of fixed-combination inhalers that contain a corticosteroid and a LABA, which have proved to be highly effective in the control of asthma. Side Effects
Adverse effects are not usually a problem with β2-agonists when given by inhalation. The most common side effects are muscle tremor and palpitations, which are seen more commonly in elderly patients. There is a small fall in plasma potassium due to increased uptake by skeletal muscle cells, but this effect does not usually cause any clinical problem. Tolerance
Tolerance is a potential problem with any agonist given chronically, but although there is downregulation of β2-receptors, this does not reduce the bronchodilator response because there is a large receptor reserve in airway smooth-muscle cells. By contrast, mast cells become rapidly tolerant, but their tolerance may be prevented by concomitant administration of ICS. Safety
The safety of β2-agonists has been an important issue. There is an association between asthma mortality and the amount of SABA used, but careful analysis demonstrates that the increased use of rescue SABA reflects poor asthma control, which is a risk factor for asthma death. The slight excess in mortality that has been associated with the use of LABA is related to the lack of use of concomitant ICS, as the LABA therapy fails to suppress the underlying inflammation. This highlights the importance of always using an ICS when LABAs are given, which is most conveniently achieved by using a combination inhaler. Anticholinergics
Muscarinic receptor antagonists such as ipratropium bromide prevent cholinergic nerve-induced bronchoconstriction and mucus secretion. They are less effective than β2-agonists in asthma therapy because they inhibit only the cholinergic reflex component of bronchoconstriction, whereas β2-agonists prevent all bronchoconstrictor mechanisms. Anticholinergics, including once-daily tiotropium bromide, may be used as an additional bronchodilator in patients with asthma that is not controlled by ICS and LABA combinations. High doses may be given by nebulizer in treating acute severe asthma but should only be given following β2-agonists, because they have a slower onset of bronchodilatation.
Side effects are not usually a problem because there is little or no systemic absorption. The most common side effect is dry mouth; in elderly patients, urinary retention and glaucoma may also be observed. Theophylline
Theophylline was widely prescribed as an oral bronchodilator several years ago, especially because it was inexpensive. It has now fallen out of favor because side effects are common and inhaled β2-agonists are much more effective as bronchodilators. The bronchodilator effect is due to inhibition of phosphodiesterases in airway smooth-muscle cells, which increases cyclic AMP, but doses required for bronchodilatation commonly cause side effects that are mediated mainly by phosphodiesterase inhibition. There is increasing evidence that theophylline at lower doses has anti-inflammatory effects, and these are likely to be mediated through different molecular mechanisms. Theophylline activates the key nuclear enzyme histone deacetylase-2 (HDAC2), which is a critical mechanism for switching off activated inflammatory genes and may, therefore, reduce corticosteroid insensitivity in severe asthma. Clinical Use
Oral theophylline is usually given as a slow-release preparation once or twice daily because this gives more stable plasma concentrations than normal theophylline tablets. It may be used as an additional bronchodilator in patients with severe asthma when plasma concentrations of 10–20 mg/L are required, although these concentrations are often associated with side effects. Low doses of theophylline, giving plasma concentrations of 5–10 mg/L, have additive effects to ICS and are particularly useful in patients with severe asthma. Indeed, withdrawal of theophylline from these patients may result in marked deterioration in asthma control. At low doses, the drug is well tolerated. IV aminophylline (a soluble salt of theophylline) was used for the treatment of severe asthma but has now been largely replaced by high doses of inhaled SABA, which are more effective and have fewer side effects. Aminophylline is occasionally used (via slow IV infusion) in patients with severe exacerbations that are refractory to SABA. Side Effects
Oral theophylline is well absorbed and is largely inactivated in the liver. Side effects are related to plasma concentrations; measurement of plasma theophylline may be useful in determining the correct dose. The most common side effects are nausea, vomiting, and headaches and are due to phosphodiesterase inhibition. Diuresis and palpitations may also occur, and at high concentrations, cardiac arrhythmias, epileptic seizures, and death may occur due to adenosine A1-receptor antagonism. Theophylline side effects are related to plasma concentration and are rarely observed at plasma concentrations below 10 mg/L. Theophylline is metabolized by CYP450 in the liver, and thus, plasma concentrations may be elevated by drugs that block CYP450 such as erythromycin and allopurinol. Other drugs may also reduce clearance by other mechanisms leading to increased plasma concentrations (Table 309-3). CONTROLLER THERAPIES Inhaled Corticosteroids
ICSs are by far the most effective controllers for asthma, and their early use has revolutionized asthma therapy. Mode of Action
ICSs are the most effective anti-inflammatory agents used in asthma therapy, reducing inflammatory cell numbers and their activation in the airways. ICSs reduce eosinophils in the airways and sputum and the numbers of activated T lymphocytes and surface mast cells in the airway mucosa. These effects may account for the reduction in AHR that is seen with chronic ICS therapy.
The molecular mechanism of action of corticosteroids involves several effects on the inflammatory process. The major effect of corticosteroids is to switch off the transcription of multiple activated genes that encode inflammatory proteins such as cytokines, chemokines, adhesion molecules, and inflammatory enzymes. This effect involves several mechanisms, including inhibition of the transcription factor NF-κB, but an important mechanism is recruitment of HDAC2 to the inflammatory gene complex, which reverses the histone acetylation associated with increased gene transcription. Corticosteroids also activate anti-inflammatory genes, such as mitogen-activated protein (MAP) kinase phosphatase-1, and increase the expression of β2-receptors. Most of the metabolic and endocrine side effects of corticosteroids are also mediated through transcriptional activation. Clinical Use
ICSs are by far the most effective controllers in the management of asthma and are beneficial in treating asthma of any severity and age. ICSs are usually given twice daily, but some may be effective once daily in mildly symptomatic patients. ICSs rapidly improve the symptoms of asthma, and lung function improves over several days. They are effective in preventing asthma symptoms, such as EIA and nocturnal exacerbations, but also prevent severe exacerbations. ICSs reduce AHR, but maximal improvement may take several months of therapy. Early treatment with ICS appears to prevent irreversible changes in airway function that occur with chronic asthma. Withdrawal of ICS results in slow deterioration of asthma control, indicating that they suppress inflammation and symptoms, but do not cure the underlying condition. ICSs are now given as first-line therapy for patients with persistent asthma, but if they do not control symptoms at low doses, it is usual to add a LABA as the next step. Side Effects
Local side effects include hoarseness (dysphonia) and oral candidiasis, which may be reduced with the use of a large-volume spacer device. There has been concern about systemic side effects from lung absorption, but many studies have demonstrated that ICS have minimal systemic effects (Fig. 309-7). At the highest recommended doses, there may be some suppression of plasma and urinary cortisol concentrations, but there is no convincing evidence that long-term treatment leads to impaired growth in children or to osteoporosis in adults. Indeed effective control of asthma with ICS reduces the number of courses of OCS that are needed and, thus, reduces systemic exposure to ICS. Systemic Corticosteroids
Corticosteroids are used intravenously (hydrocortisone or methylprednisolone) for the treatment of acute severe asthma, although several studies now show that OCSs are as effective and easier to administer. A course of OCS (usually prednisone or prednisolone 30–45 mg once daily for 5–10 days) is used to treat acute exacerbations of asthma; no tapering of the dose is needed. Approximately 1% of asthma patients may require maintenance treatment with OCS; the lowest dose necessary to maintain control needs to be determined. Systemic side effects, including truncal obesity, bruising, osteoporosis, diabetes, hypertension, gastric ulceration, proximal myopathy, depression, and cataracts, may be a major problem, and steroid-sparing therapies may be considered if side effects are a significant problem. If patients require maintenance treatment with OCS, it is important to monitor bone density so that preventive treatment with bisphosphonates or estrogen in postmenopausal women may be initiated if bone density is low. Intramuscular triamcinolone acetonide is a depot preparation that is occasionally used in noncompliant patients, but proximal myopathy is a major problem with this therapy. Antileukotrienes
Cysteinyl-leukotrienes are potent bronchoconstrictors, cause microvascular leakage, and increase eosinophilic inflammation through the activation of cys-LT1-receptors. These inflammatory mediators are produced predominantly by mast cells and, to a lesser extent, eosinophils in asthma. Antileukotrienes, such as montelukast, block cys-LT1-receptors and provide modest clinical benefit in asthma. They are less effective than ICS in controlling asthma and have less effect on airway inflammation, but are useful as an add-on therapy in some patients not controlled with low doses of ICS, although less effective than LABA. They are given orally once or twice daily and are well tolerated. Some patients show a better response than others to antileukotrienes, but this has not been convincingly linked to any genomic differences in the leukotriene pathway. Cromones
Cromolyn sodium and nedocromil sodium are asthma controller drugs that appear to inhibit mast cell and sensory nerve activation and are, therefore, effective in blocking trigger-induced asthma such as EIA and allergen- and sulfur dioxide–induced symptoms. Cromones have relatively little benefit in the long-term control of asthma due to their short duration of action (at least four times daily by inhalation). They are very safe and were popular in the treatment of childhood asthma, although now low doses of ICS are preferred because they are more effective and have a proven safety profile. Steroid-Sparing Therapies
Various immunomodulatory treatments have been used to reduce the requirement for OCS in patients with severe asthma who have serious side effects with this therapy. Methotrexate, cyclosporin A, azathioprine, gold, and IV gamma globulin have all been used as steroid-sparing therapies, but none of these treatments has any long-term benefit, and each is associated with a relatively high risk of side effects. Anti-IgE
Omalizumab is a blocking antibody that neutralizes circulating IgE without binding to cell-bound IgE and, thus, inhibits IgE-mediated reactions. This treatment has been shown to reduce the number of exacerbations in patients with severe asthma and may improve asthma control. However, the treatment is very expensive and is only suitable for highly selected patients who are not controlled on maximal doses of inhaler therapy and have a circulating IgE within a specified range. Patients should be given a 3- to 4-month trial of therapy to show objective benefit. Omalizumab is usually given as a subcutaneous injection every 2–4 weeks and appears not to have significant side effects, although anaphylaxis is very occasionally seen. Immunotherapy
Specific immunotherapy using injected extracts of pollens or house dust mites has not been very effective in controlling asthma and may cause anaphylaxis. Side effects may be reduced by sublingual dosing. It is not recommended in most asthma treatment guidelines because of lack of evidence of clinical efficacy. Alternative Therapies
Nonpharmacologic treatments, including hypnosis, acupuncture, chiropraxis, breathing control, yoga, and speleotherapy, may be popular with some patients. However, placebo-controlled studies have shown that each of these treatments lacks efficacy and cannot be recommended. However, they are not detrimental and may be used as long as conventional pharmacologic therapy is continued. Future Therapies
It has proved very difficult to discover novel pharmaceutical therapies, particularly because current therapy with corticosteroids and β2-agonists is so effective in the majority of patients. There is, however, a need for the development of new therapies for patients with refractory asthma who have side effects with systemic corticosteroids. Antagonists of specific mediators have little or no benefit in asthma, apart from antileukotrienes, which have rather weak effects, presumably reflecting the fact that multiple mediators are involved. Blocking antibodies against IL-5 may reduce exacerbations in highly selected patients who have sputum eosinophils despite high doses of corticosteroids, whereas anti-TNF-α antibodies are not effective in severe asthma. Novel anti-inflammatory treatments that are in clinical development include inhibitors of phosphodiesterase-4, NF-κB, and p38 MAP kinase. However, these drugs, which act on signal transduction pathways common to many cells, are likely to have troublesome side effects, necessitating their delivery by inhalation. Safer and more effective immunotherapy using T cell peptide fragments of allergens or DNA vaccination is also being investigated. Bacterial products, such as CpG oligonucleotides that stimulate TH1 immunity or regulatory T cells, are also currently under evaluation. MANAGEMENT OF CHRONIC ASTHMA
There are several aims of chronic therapy in asthma (Table 309-2). It is important to establish the diagnosis objectively using spirometry or PEF measurements at home. Triggers that worsen asthma control, such as allergens or occupational agents, should be avoided, whereas triggers, such as exercise and fog, which result in transient symptoms, provide an indication that more controller therapy is needed. It is important to assess asthma control, determined by symptoms, night awakening, need for reliever inhalers, limitation of activity, and lung function (Table 309-4). Avoidance of side effects and expense of medications are also important. There are several validated questionnaires for quantifying asthma control, such as the Asthma Quality of Life Questionnaire (AQLQ) and Asthma Control Test (ACT). Stepwise Therapy
For patients with mild, intermittent asthma, a short-acting β2-agonist is all that is required (Fig. 309-8). However, use of a reliever medication more than twice a week indicates the need for regular controller therapy. The treatment of choice for all patients is an ICS given twice daily. It is usual to start with an intermediate dose (e.g., 200 μg bid of beclomethasone dipropionate [BDP]) or equivalent and to decrease the dose if symptoms are controlled after 3 months. If symptoms are not controlled, a LABA should be added, which is most conveniently given by switching to a combination inhaler. The dose of controller should be adjusted accordingly, as judged by the need for a rescue inhaler. Low doses of theophylline or an antileukotriene may also be considered as an add-on therapy, but these are less effective than LABA. In patients with severe asthma, low-dose oral theophylline is also helpful, and when there is irreversible airway narrowing, the long-acting anticholinergic tiotropium bromide may be tried. If asthma is not controlled despite the maximal recommended dose of inhaled therapy, it is important to check compliance and inhaler technique. In these patients, maintenance treatment with an OCS may be needed, and the lowest dose that maintains control should be used. Occasionally omalizumab may be tried in steroid-dependent asthmatics who are not well controlled. Once asthma is controlled, it is important to slowly decrease therapy in order to find the optimal dose to control symptoms. Education
Patients with asthma need to understand how to use their medications and the difference between reliever and controller therapies. Education may improve compliance, particularly with ICS. All patients should be taught how to use their inhalers correctly. In particular, they need to understand how to recognize worsening of asthma and how to step up therapy. Written action plans have been shown to reduce hospital admissions and morbidity rates in adults and children, and are recommended particularly in patients with unstable disease who have frequent exacerbations.
TABLE 309-2AIMS of Asthma Therapy ||Download (.pdf) TABLE 309-2 AIMS of Asthma Therapy
|• Minimal (ideally no) chronic symptoms, including nocturnal |
|• Minimal (infrequent) exacerbations |
|• No emergency visits |
|• Minimal (ideally no) use of a required β2-agonist |
|• No limitations on activities, including exercise |
|• Peak expiratory flow circadian variation <20% |
|• (Near) normal peak expiratory flow |
|• Minimal (or no) adverse effects from medicine |
TABLE 309-3Factors Affecting Clearance of Theophylline ||Download (.pdf) TABLE 309-3 Factors Affecting Clearance of Theophylline
|Increased Clearance |
|• Enzyme induction (rifampicin, phenobarbitone, ethanol) |
|• Smoking (tobacco, marijuana) |
|• High-protein, low-carbohydrate diet |
|• Barbecued meat |
|• Childhood |
|Decreased Clearance |
|• Enzyme inhibition (cimetidine, erythromycin, ciprofloxacin, allopurinol, zileuton, zafirlukast) |
|• Congestive heart failure |
|• Liver disease |
|• Pneumonia |
|• Viral infection and vaccination |
|• High-carbohydrate diet |
|• Old age |
TABLE 309-4Asthma Control ||Download (.pdf) TABLE 309-4 Asthma Control
|Characteristic ||Controlled (all of the following) ||Partly Controlled ||Uncontrolled |
|Daytime symptoms ||None (≤2/week) ||>2/week ||Three or more features of partly controlled |
|Limitation of activities ||None ||Any || |
|Nocturnal symptoms/awakening ||None ||Any || |
|Need for reliever/rescue treatment ||None (≤2/week) ||>2/week || |
|Lung function (PEF or FEV1) ||Normal ||<80% predicted or personal best (if known) || |
Pharmacokinetics of inhaled corticosteroids. GI, gastrointestinal; MDI, metered-dose inhaler.
Stepwise approach to asthma therapy according to the severity of asthma and ability to control symptoms. ICS, inhaled corticosteroids; LABA, long-acting β2-agonist; OCS, oral corticosteroid.
Exacerbations of asthma are feared by patients and may be life threatening. One of the main aims of controller therapy is to prevent exacerbations; in this respect, ICS and combination inhalers are very effective.
Patients are aware of increasing chest tightness, wheezing, and dyspnea that are often not or poorly relieved by their usual reliever inhaler. In severe exacerbations, patients may be so breathless that they are unable to complete sentences and may become cyanotic. Examination usually shows increased ventilation, hyperinflation, and tachycardia. Pulsus paradoxus may be present, but this is rarely a useful clinical sign. There is a marked fall in spirometric values and PEF. Arterial blood gases on air show hypoxemia, and PCO2 is usually low due to hyperventilation. A normal or rising PCO2 is an indication of impending respiratory failure and requires immediate monitoring and therapy. A chest roentgenogram is not usually informative but may show pneumonia or pneumothorax.
TREATMENT Acute Severe Asthma
A high concentration of oxygen should be given by face mask to achieve oxygen saturation of >90%. The mainstay of treatment are high doses of SABA given either by nebulizer or via a metered-dose inhaler with a spacer. In severely ill patients with impending respiratory failure, IV β2-agonists may be given. A nebulized anticholinergic may be added if there is not a satisfactory response to β2-agonists alone, as there are additive effects. In patients who are refractory to inhaled therapies, a slow infusion of aminophylline may be effective, but it is important to monitor blood levels, especially if patients have already been treated with oral theophylline. Magnesium sulfate given intravenously or by nebulizer is effective when added to inhaled β2-agonists, and is relatively well tolerated but is not routinely recommended. Prophylactic intubation may be indicated for impending respiratory failure, when the PCO2 is normal or rises. For patients with respiratory failure, it is necessary to intubate and institute ventilation. These patients may benefit from an anesthetic such as halothane if they have not responded to conventional bronchodilators. Sedatives should never be given because they may depress ventilation. Antibiotics should not be used routinely unless there are signs of pneumonia.
Although most patients with asthma are easily controlled with appropriate medication, a small proportion of patients (approximately 5–10% of asthmatics) are difficult to control despite maximal inhaled therapy. Some of these patients will require maintenance treatment with OCS. In managing these patients, it is important to investigate and correct any mechanisms that may be aggravating asthma. There are two major patterns of difficult asthma: some patients have persistent symptoms and poor lung function, despite appropriate therapy, whereas others may have normal or near-normal lung function but intermittent, severe (sometimes life-threatening) exacerbations.
The most common reason for poor control of asthma is noncompliance with medication, particularly ICS. Compliance with ICS may be low because patients do not feel any immediate clinical benefit or may be concerned about side effects. Compliance with ICS is difficult to monitor because there are no useful plasma measurements that can be made, but measuring the fractional excretion of induced NO (FENO) may identify the problem. Compliance may be improved by giving the ICS as a combination with a LABA that gives symptom relief. Compliance with OCS may be measured by suppression of plasma cortisol and the expected concentration of prednisone/prednisolone in the plasma. There are several factors that may make asthma more difficult to control, including exposure to high, ambient levels of allergens or unidentified occupational agents. Severe rhinosinusitis may make asthma more difficult to control; upper airway disease should be vigorously treated. Drugs such as beta-adrenergic blockers, aspirin, and other cyclooxygenase (COX) inhibitors may worsen asthma. Some women develop severe premenstrual worsening of asthma, which is unresponsive to corticosteroids and requires treatment with progesterone or gonadotropin-releasing factors. Few systemic diseases make asthma more difficult to control, but hyper- and hypothyroidism may increase asthma symptoms and should be investigated if suspected.
Bronchial biopsy studies in refractory asthma may show the typical eosinophilic pattern of inflammation, whereas others have a predominantly neutrophilic pattern. There may be an increase in TH1 cells, TH17 cells, and CD8 lymphocytes compared to mild asthma and increased expression of TNF-α. Structural changes in the airway, including fibrosis, angiogenesis, and airway smooth-muscle thickening, are more commonly seen in these patients.
A few patients with asthma show a poor response to corticosteroid therapy and may have various molecular abnormalities that impair the anti-inflammatory action of corticosteroids. Complete resistance to corticosteroids is extremely uncommon and affects less than 1 in 1000 patients. It is defined by a failure to respond to a high dose of oral prednisone/prednisolone (40 mg once daily over 2 weeks), ideally with a 2-week run-in with matched placebo. More common is reduced responsiveness to corticosteroids where control of asthma requires OCS (corticosteroid-dependent asthma). In patients with poor responsiveness to corticosteroids, there is a reduction in the response of circulating monocytes and lymphocytes to the anti-inflammatory effects of corticosteroids in vitro and reduced skin blanching in response to topical corticosteroids. There are several mechanisms that have been described, including an increase in the alternatively spliced form of the glucocorticoid receptor (GR)-β, an abnormal pattern of histone acetylation in response to corticosteroids, a defect in IL-10 production, and a reduction in HDAC2 activity (as in COPD). These observations suggest that there are likely to be heterogeneous mechanisms for corticosteroid resistance; whether these mechanisms are genetically determined has yet to be decided.
Some patients show chaotic variations in lung function despite taking appropriate therapy. Some show a persistent pattern of variability and may require oral corticosteroids or, at times, continuous infusion of β2-agonists (type 1 brittle asthma), whereas others have generally normal or near-normal lung function but precipitous, unpredictable falls in lung function that may result in death (type 2 brittle asthma). These latter patients are difficult to manage because they do not respond well to corticosteroids, and the worsening of asthma does not reverse well with inhaled bronchodilators. The most effective therapy is subcutaneous epinephrine, which suggests that the worsening is likely to be a localized airway anaphylactic reaction with edema. In some of these patients, there may be allergy to specific foods. These patients should be taught to self-administer epinephrine and should carry a medical warning accordingly.
TREATMENT Refractory Asthma
Refractory asthma is difficult to control, by definition. It is important to check compliance and the correct use of inhalers and to identify and eliminate any underlying triggers. Low doses of theophylline may be helpful in some patients, and theophylline withdrawal has been found to worsen in many patients. Most of these patients will require maintenance treatment with oral corticosteroids, and the minimal dose that achieves satisfactory control should be determined by careful dose titration. Steroid-sparing therapies are rarely effective. In some patients with allergic asthma, omalizumab is effective, particularly when there are frequent exacerbations. Anti-TNF therapy is not effective in severe asthma and should not be used. A few patients may benefit from infusions of β2-agonists. New therapies are needed for these patients, who currently consume a disproportionate amount of health care spending.
A small proportion (1–5%) of asthmatics become worse with aspirin and other COX inhibitors, although this is much more commonly seen in severe cases and in patients with frequent hospital admission. Aspirin-sensitive asthma is a well-defined phenotype of asthma that is usually preceded by perennial rhinitis and nasal polyps in nonatopic patients with a late onset of the disease. Aspirin, even in small doses, characteristically provokes rhinorrhea, conjunctival injection, facial flushing, and wheezing. There is a genetic predisposition to increased production of cysteinyl-leukotrienes with functional polymorphism of cys-leukotriene C4 synthase. Asthma is triggered by COX inhibitors but is persistent even in their absence. All nonselective COX inhibitors should be avoided, but selective COX2 inhibitors are safe to use when an anti-inflammatory analgesic is needed. Aspirin-sensitive asthma responds to usual therapy with ICS. Although antileukotrienes should be effective in these patients, they are no more effective than in allergic asthma. Occasionally, aspirin desensitization is necessary, but this should only be undertaken in specialized centers.
Asthma may start at any age, including in elderly patients. The principles of management are the same as in other asthmatics, but side effects of therapy may be a problem, including muscle tremor with β2-agonists and more systemic side effects with ICS. Comorbidities are more frequent in this age group, and interactions with drugs such as β2-blockers, COX inhibitors, and agents that may affect theophylline metabolism need to be considered. COPD is more likely in elderly patients and may coexist with asthma. A trial of OCS may be very useful in documenting the steroid responsiveness of asthma.
Approximately one-third of asthmatic patients who are pregnant improve during the course of a pregnancy, one-third deteriorate, and one-third are unchanged. It is important to maintain good control of asthma because poor control may have adverse effects on fetal development. Compliance may be a problem because there is often concern about the effects of antiasthma medications on fetal development. The drugs that have been used for many years in asthma therapy have now been shown to be safe and without teratogenic potential. These drugs include SABA, ICS, and theophylline; there is less safety information about newer classes of drugs such as LABA, antileukotrienes, and anti-IgE. If an OCS is needed, it is better to use prednisone rather than prednisolone because it cannot be converted to the active prednisolone by the fetal liver, thus protecting the fetus from systemic effects of the corticosteroid. There is no contraindication to breast-feeding when patients are using these drugs.
Approximately 20% of asthmatics smoke, which may adversely affect asthma in several ways. Smoking asthmatics have more severe disease, more frequent hospital admissions, a faster decline in lung function, and a higher risk of death from asthma than nonsmoking asthmatics. There is evidence that smoking interferes with the anti-inflammatory actions of corticosteroids by reducing HDAC2, necessitating higher doses for asthma control. Smoking cessation improves lung function and reduces the steroid resistance, and thus, vigorous smoking cessation strategies should be used. Some patients report a temporary worsening of asthma when they first stop smoking, possibly due to the loss of the bronchodilating effect of NO in cigarette smoke.
If asthma is well controlled, there is no contraindication to general anesthesia and intubation. Patients who are treated with OCS will have adrenal suppression and should be treated with an increased dose of OCS immediately prior to surgery. Patients with FEV1 <80% of their normal levels should also be given a boost of OCS prior to surgery. High-maintenance doses of corticosteroids may be a contraindication to surgery because of increased risks of infection and delayed wound healing.
Bronchopulmonary aspergillosis (BPA) is uncommon and results from an allergic pulmonary reaction to inhaled spores of Aspergillus fumigatus and, occasionally, other Aspergillus species. A skin prick test to A. fumigatus is always positive, whereas serum Aspergillus precipitins are low or undetectable. Characteristically, there are fleeting eosinophilic infiltrates in the lungs, particularly in the upper lobes. Airways become blocked with mucoid plugs rich in eosinophils, and patients may cough up brown plugs and have hemoptysis. BPA may result in bronchiectasis, particularly affecting central airways, if not suppressed by corticosteroids. Asthma is controlled in the usual way by ICS, but it is necessary to give a course of OCS if any sign of worsening or pulmonary shadowing is found. Treatment with the oral antifungal itraconazole is beneficial in preventing exacerbations.