ASTHMA

Asthma: Introduction

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.

Prevalence

Asthma is one of the most common chronic diseases globally and currently affects ~300 million people. The prevalence of asthma has risen in affluent countries over the last 30 years but now appears to have stabilized, with ~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 incidence that appears to be 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. This epidemiologic observation suggests that there is a maximum number of individuals in the community who are liable to be affected by asthma, likely by genetic predisposition. Most patients with asthma in affluent countries are atopic, with allergic sensitization to the house dust mite Dermatophagoides pteronyssinus and other environmental allergens.

Asthma is both common and frequently complicated by the effects of smoking on the lungs; hence, it is difficult to be certain about the natural history of the disease in adults. 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. The commonly held belief that children "grow out of their asthma" is justified to some extent. 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 children 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 have been steadily declining in many affluent countries over the last decade. A rise in asthma mortality seen in several countries during the 1960s was associated with increased use of short-acting 2-adrenergic agonists (as rescue therapy), but there is now compelling evidence that the more widespread use of inhaled corticosteroids (ICSs) 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 corticosteroid therapy, and previous admissions to the 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.

Etiology

Asthma is a heterogeneous disease with interplay between genetic and environmental factors. Several risk factors have been implicated (Table 248-1).

Table 248-1 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?
Early viral infections?
Triggers
Allergens
Upper respiratory tract viral infections
Exercise and hyperventilation
Cold air
Sulfur dioxide
Drugs ( blockers, aspirin)
Stress
Irritants (household sprays, paint fumes)




Atopy

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 commonest allergens are derived from house dust mites, cat and dog fur, cockroaches, 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.

Intrinsic Asthma

A minority of asthmatic patients (approximately 10%) have negative skin test 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.

Infections

Although viral infections are common as 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, as this infection is very common in children. More recently, atypical bacteria such as Mycoplasma and Chlamydia have been implicated in the mechanism of severe asthma, but thus far evidence of a true association is not very convincing.

Genetic Considerations

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 of 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, DPP-10, and GPRA, have also been identified by positional cloning, but their function in disease pathogenesis is thus far obscure. Genetic polymorphisms may also be important in determining the response to asthma therapy. For example, the Arg-Gly-16 variant in the 2-receptor is associated with reduced response to 2-agonists, and repeats of an Sp1 recognition sequence in the promoter region of 5-lipoxygenase may affect the response to antileukotrienes.

Environmental Factors

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.

Hygiene Hypothesis

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 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 may also be associated with a reduced risk of asthma. While 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.

Diet

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 polyunsaturates are associated with an increased risk of asthma. However, interventional studies 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 Pollution

There is no doubt that 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 as 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 from an increased risk of respiratory infections.

Allergens

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 Exposure

Occupational asthma is relatively common and may affect up to 10% of young adults. Over 200 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.

Other Factors

Several other factors have been implicated in the etiology of asthma, including lower maternal age, duration of breast-feeding, prematurity and low birth weight, and inactivity, but are unlikely to contribute to the recent global increase in asthma prevalence. There is also an association with acetaminophen (paracetamol) consumption, which remains unexplained.

Pathogenesis

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.

Pathology

The pathology of asthma has been revealed through examining the lungs at autopsy in patients who have died of asthma and from bronchial biopsies in patients with usually mild asthma. 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 be found in atopic patients without asthma symptoms. The inflammation is reduced by treatment with ICSs. 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; it is therefore likely to be a marker of eosinophilic inflammation in the airway, as eosinophils release fibrogenic factors. 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 composed of mucus glycoproteins secreted from goblet cells and plasma proteins from leaky bronchial vessels (Fig. 248-1). There is also vasodilatation and increased numbers of blood vessels (angiogenesis). Direct observation by bronchoscopy indicates that the airways may be narrowed, reddened, and edematous. The pathology of asthma is remarkably uniform in different types of asthma, including atopic, nonatopic, occupational, aspirin-sensitive, and pediatric asthma. These pathologic changes are found in all airways but do not extend to the lung parenchyma; small 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.

Figure 248-1




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.)



Inflammation

There is inflammation in the respiratory mucosa from trachea to terminal bronchioles, but with a predominance in the bronchi (cartilaginous airways). Considerable research has identified the major cellular components of inflammation, but it is still uncertain how inflammatory cells interact and how inflammation translates into the symptoms of asthma (Fig. 248-2). There is good evidence that the specific pattern of airway inflammation in asthma is associated with airway hyperresponsiveness (AHR), the physiologic abnormality of asthma that 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, although 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. Many inflammatory cells are known to be involved in asthma, with no predominant key cell (Fig. 248-3).

Figure 248-2




Inflammation in the airways of asthmatic patients leads to airway hyperresponsiveness and symptoms.



Figure 248-3




The pathophysiology of asthma is complex, with participation of several interacting inflammatory cells, resulting in acute and chronic inflammatory effects on the airway.



Mast Cells

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 or thermal changes), as well as fog. In biopsies from asthmatic patients, mast cells are localized to the airway smooth muscle layer; they are not found in normal subjects or in patients with eosinophilic cough. 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. 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 prevent 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 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 (FcRII). 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, such as IL-10, and thus their role in asthma is 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 TNF-, to promote the normally preponderant TH1 response.

Eosinophils

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 airway hyperresponsiveness 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 cause a profound and prolonged reduction in circulating and sputum eosinophils, but they are not associated with reduced AHR or asthma symptoms, thus questioning the pivotal role of eosinophils in asthma. Furthermore, eosinophilic inflammation is also found in patients with chronic cough who do not have any clinical features of asthma or AHR. Increasing evidence suggests that eosinophils may be more important in release of growth factors involved in airway remodeling than in AHR.

Neutrophils

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 that have a predominance of neutrophils. The role of neutrophils in asthma, which are resistant to the anti-inflammatory effects of corticosteroids, is currently unknown.

T Lymphocytes

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, which 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, which is associated with increased TH2 cells.

Structural Cells

Structural cells of the airways, including epithelial cells, fibroblasts and airway smooth-muscle cells, are also an important source of inflammatory mediators, such as cytokines and lipid mediators, in asthma. Indeed, because structural cells far outnumber inflammatory cells, they may become the major source of mediators driving chronic inflammation in asthmatic airways. In addition, epithelial cells may have a key role in translating inhaled environmental signals into an airway inflammatory response, and are probably a major target cell for ICSs.

Inflammatory Mediators

Many different mediators have been implicated in asthma, and they may have a variety of effects on the airways that could account for the pathologic features of asthma (Fig. 248-4). Mediators such as histamine, prostaglandins, 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 a clinically important effect.

Figure 248-4




Many cells and mediators are involved in asthma and lead to several effects on the airways.



Cytokines

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 tumor necrosis factor (TNF-) and IL-1, amplify the inflammatory response and play a role in more severe disease. Thymic stromal lymphopoietin is an upstream cytokine released from epithelial cells of asthmatics that orchestrates the release of chemokines, which selectively attract TH2 cells. Some cytokines, such as IL-10 and IL-12, are anti-inflammatory and may be deficient in asthma.

Chemokines

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. 248-5).

Figure 248-5




Chemokines in asthma. Tumor necrosis factor (TNF-) and other triggers of airway epithelial cells release thymus and activation-regulated chemokine (TARC, CCL17) and macrophage-derived chemokine (MDC, CCL22) from epithelial cells, which attract TH2 cells via activation of their CCR4 receptors. These promote eosinophilic inflammation directly through the release of interleukin 5 (IL-5) and indirectly via the release of IL-4 and IL-13, which induce eotaxin (CCL11) formation in airway epithelial cells.



Oxidative Stress

There is increased oxidative stress in asthma as 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

Nitric oxide (NO) is produced by several cells in the airway by NO synthases, 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. Exhaled NO is increasingly used in the diagnosis and monitoring of asthmatic inflammation, although it is not used routinely in clinical practice.

Transcription Factors

Proinflammatory transcription factors, such as nuclear factor B (NFB) and activator protein 1 (AP-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.

Effects of Inflammation

The chronic inflammatory response has several effects on the target cells of the airways, resulting in the characteristic pathophysiologic changes associated with asthma. Asthma may be regarded as a disease with continuous inflammation and repair proceeding simultaneously. Important advances continue to be made in our understanding of these changes, but despite these new insights, the relationship between chronic inflammatory processes and asthma symptoms is often not clear.

Airway Epithelium

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 allergen exposure, 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 normally degrade 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.

Fibrosis

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 it is associated with eosinophil infiltration, presumably through the release of profibrotic mediators, such as transforming growth factor . 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.

Airway Smooth Muscle

There is still debate about the role of abnormalities in airway smooth muscle is asthmatic airways. In vitro airway smooth muscle from asthmatic patients usually shows no increased responsiveness to constrictors. Reduced responsiveness to -agonists has also been reported in post-mortem or surgically removed bronchi from asthmatics, although the number of -receptors is not reduced, suggesting that -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 or endothelin 1, released from inflammatory or epithelial cells.

Vascular Responses

There is increased airway mucosal blood flow in asthma. The bronchial circulation may play an important role in regulating airway caliber, since an increase in the vascular volume may contribute to airway narrowing. Increased airway blood flow may be important in removing inflammatory mediators from the airway and may play a role in the development of exercise-induced asthma. 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.

Mucus Hypersecretion

Increased mucus secretion contributes to the viscid mucus plugs that occlude asthmatic airways, particularly in fatal asthma. There is evidence for hyperplasia of submucosal glands that are confined to large airways and of increased numbers of epithelial goblet cells. IL-4 and IL-13 induce mucus hypersecretion in experimental models of asthma.

Neural Effects

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 peripheral tissues, may cause proliferation and sensitization of airway sensory nerves. Airway nerves may also release neurotransmitters, such as substance P, which have inflammatory effects.

Airway Remodeling

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. This observation suggests that the accelerated decline in lung function occurs in a smaller proportion of asthmatics, and these are usually patients with more severe disease. There is debate about whether the early use of ICSs may reduce the decline in lung function. The characteristic structural changes are increased airway smooth muscle, fibrosis, angiogenesis, and mucus hyperplasia.

Asthma Triggers

Several stimuli trigger airway narrowing, wheezing, and dyspnea in asthmatic patients. While the previous view held that these should be avoided, it is now seen as evidence for poor control and an indicator of the need to increase controller therapy.

Allergens

Inhaled allergens are able to activate mast cells with bound IgE directly leading to the immediate release of bronchoconstrictor mediators, resulting in the early response 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 is not very reversible with bronchodilators. The most common allergen to trigger asthma is Dermatophagoides sp., and environmental exposure leads to low-grade chronic symptoms that are perennial. 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).

Virus Infections

Upper respiratory tract virus infections, such as rhinovirus, respiratory syncytial virus, and coronavirus, are the commonest triggers of acute severe exacerbations. 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.

Pharmacologic Agents

Several drugs may trigger asthma. -adrenergic blockers commonly worsen asthma, and their use may be fatal. The mechanisms are not clear but are mediated through increased cholinergic bronchoconstriction. All beta blockers need to be avoided, and even selective 2 blocker 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 nonasthmatics. Aspirin may worsen asthma in some patients (aspirin-sensitive asthma is discussed below under "Special Considerations").

Exercise

Exercise is a common trigger of asthma, particularly in children. The mechanism is linked to hyperventilation, which results in increased osmolality in airway lining fluids and triggers mast cell mediator release, resulting in bronchoconstriction. Exercise-induced asthma (EIA) typically begins after exercise has ended and recovers spontaneously within about 30 min. EIA is worse in cold, dry climates than in hot, humid conditions. It is therefore more common in sports such as cross-country running in cold weather, overland skiing, and ice hockey than in swimming. It may be prevented by prior administration of 2-agonists and antileukotrienes, but is best prevented by regular treatment with inhaled glucocorticoids, which reduce the population of surface mast cells required for this response.

Physical Factors

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.

Food

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 food yellow-coloring agent, was believed to be a trigger for asthma, but there is little convincing evidence for this.

Air Pollution

Increased ambient levels of sulfur dioxide, ozone, and nitrogen oxides are associated with increased asthma symptoms.

Occupational Factors

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 therefore early detection and avoidance are important.

Hormonal Factors

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

Gastroesophageal reflux is common in asthmatic patients as it is increased by bronchodilators. While acid reflux might trigger reflex bronchoconstriction, it rarely causes asthma symptoms, and anti-reflux therapy fails to reduce asthma symptoms in most patients.

Stress

Many asthmatics report worsening of symptoms with stress. There is no doubt that 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.

Pathophysiology

Limitation of airflow is due mainly to bronchoconstriction, but airway edema, vascular congestion, and luminal occlusion with exudate may also contribute. This results in a reduction in forced expiratory volume in 1 s (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. 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 PaCO2 tends to be low due to increased ventilation.

Airway Hyperresponsiveness

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; 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 it is characteristically also seen with many indirect stimuli, which release bronchoconstrictors from mast cells or activate sensory neural reflexes. 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 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 great 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.

Diagnosis

The diagnosis of asthma is usually apparent from the symptoms of variable and intermittent airways obstruction, but is usually confirmed by objective measurements of lung function.

Lung Function Tests

Simple spirometry confirms airflow limitation with a reduced FEV1, FEV1/FVC ratio, and PEF. Reversibility is demonstrated by a >12% or 200 mL increase in FEV1 15 min after an inhaled short-acting 2-agonist or, in some patients, by a 2- to 4-week trial of oral glucocorticoids (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.

Airway Responsiveness

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 post-exercise 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.

Hematologic Tests

Blood tests are not usually helpful. Total serum IgE and specific IgE to inhaled allergens (RAST) may be measured in some patients.

Imaging

Chest roentgenography is usually normal but may show hyperinflated lungs in more severe patients. In exacerbations, there may be evidence of a pneumothorax. Lung shadowing usually indicates pneumonia or eosinophilic infiltrates in patients with bronchopulmonary aspergillosis. High-resolution 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 Tests

Skin prick tests to common inhalant allergens 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.

Differential Diagnosis

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, which 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.

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 oral corticosteroids; these patients probably have both diseases concomitantly.

Asthma: Treatment

The treatment of asthma is straightforward and the majority of patients are now managed by internists with effective and safe therapies. There are several aims of therapy (Table 248-2). 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.

Table 248-2 Aims of Asthma Therapy



Minimal (ideally no) chronic symptoms, including nocturnal
Minimal (infrequent) exacerbations
No emergency visits
Minimal (ideally no) use of as-required 2-agonist

No limitations on activities, including exercise
PEF circadian variation <20%
(Near) normal PEF
Minimal (or no) adverse effects from medicine



Note: PEF, peak expiratory flow.


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 bronchodilator in current use: 2-adrenergic agonists, anticholinergics, and theophylline; of these, 2-agonists are by far the most effective.

B2-Agonists

2-Agonists activate 2-adrenergic receptors, which are widely expressed in the airways. 2-Receptors are coupled through a stimulatory G protein to adenylyl cyclase, resulting in increased intracellular cyclic AMP, which relaxes smooth-muscle cells and inhibits certain inflammatory cells.

Mode of Action

The primary action of 2-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 non-bronchodilator effects that may be clinically useful, including inhibition of mast cell mediator release, reduction in plasma exudation, and inhibition of sensory nerve activation (Table 248-3). Inflammatory cells express small numbers of 2-receptors, but these are rapidly downregulated with 2-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.

Table 248-3 Effects of -Adrenergic Agonists on Airways



Relaxation of airway smooth muscle (proximal and distal airways)
Inhibition of mast cell mediator release
Inhibition of plasma exudation and airway edema
Increased mucociliary clearance
Increased mucus secretion
Decreased cough
No effect on chronic inflammation




Clinical Use

2-Agonists are usually given by inhalation to reduce side effects. Short-acting 2-agonists (SABAs), such as albuterol and terbutaline, have a duration of action of 3–6 hours. They have a rapid onset of bronchodilation and are therefore used as needed for symptom relief. Increased use of SABAs 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 2-agonists (LABAs) include salmeterol and formoterol, both of which have a duration of action over 12 hours and are given twice daily. LABAs have replaced the regular use of SABAs, but LABAs should not be given in the absence of ICS therapy as 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 2-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 a clinical problem.

Tolerance

Tolerance is a potential problem with any agonist given chronically, but while there is downregulation of 2-receptors, this does not reduce the bronchodilator response as 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 2-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 SABAs 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 LABAs is related to the lack of use of concomitant ICS, as the LABA therapy does not deal with 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.

Anti-Cholinergics

Muscarinic receptor antagonists, such as ipratropium bromide, prevent cholinergic nerve–induced bronchoconstriction and mucus secretion. They are much less effective than 2-agonists in asthma therapy as they inhibit only the cholinergic reflex component of bronchoconstriction, whereas 2-agonists prevent all bronchoconstrictor mechanisms. Anticholinergics are therefore only used as an additional bronchodilator in patients with asthma that is not controlled on other inhaled medications. High doses may be given by nebulizer in treating acute severe asthma but should only be given following 2-agonists since they have a slower onset of bronchodilation.

Side effects are not usually a problem as 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 as it was inexpensive. It has now fallen out of favor as side effects are common and inhaled 2-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 bronchodilation 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. There is evidence that theophylline activates the key nuclear enzyme histone deacetylase-2, which is a critical mechanism for switching off activated inflammatory genes.

Clinical Use

Oral theophylline is usually given as a slow-release preparation once or twice daily as 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 ICSs and are particularly useful in patients with severe asthma. Indeed, withdrawal of theophylline from these patients may result in marked deterioration in asthma control. The drug is well tolerated at low doses. Intravenous aminophylline (a soluble salt of theophylline) was used for the treatment of severe asthma but has now been largely supplemented by inhaled SABAs, which are more effective and have fewer side effects. Aminophylline is occasionally used (via slow intravenous infusion) in patients with severe exacerbations that are refractory to high-dose SABAs.

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—nausea, vomiting, and headaches—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 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 248-4).

Table 248-4 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




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 the number of inflammatory cells and their activation in the airways. ICSs reduce eosinophils in the airways and sputum, and 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 factors NFB and AP-1, but an important mechanism is recruitment of histone deacetylase-2 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 2-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 ICSs appears to prevent irreversible changes in airway function that occur with chronic asthma. Withdrawal of ICSs 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 an 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 ICSs have minimal systemic effects (Fig. 248-6). 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 ICSs reduces the number of courses of oral corticosteroids that are needed and thus reduces systemic exposure to ICSs.

Figure 248-6




Pharmacokinetics of inhaled corticosteroids.



Systemic Corticosteroids

Corticosteroids are used intravenously (hydrocortisone or methylprednisolone) for the treatment of acute severe asthma, although several studies now show that oral corticosteroids are as effective and easier to administer. A course of oral corticosteroids (usually prednisone or prednisolone 30–45 mg od 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 oral corticosteroids; the lowest dose necessary to maintaining 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 oral corticosteroids, 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 and zafirlukast, block cys-LT1-receptors and provide modest clinical benefit in asthma. They are less effective than ICSs 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 inhaled corticosteroids (although they are less effective than LABAs). 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 4 times daily by inhalation). They are very safe, and though they were popular in the treatment of childhood asthma, low doses of ICSs are now preferred as they are more effective and have a proven safety profile.

Steroid-Sparing Therapies

Various immunomodulatory treatments have been used to reduce the requirement for oral corticosteroids in patients with severe asthma who have serious side effects with this therapy. Methotrexate, cyclosporine, azathioprine, gold, and intravenous 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; it 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 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 3–4 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.

Immunotherapy

Specific immunotherapy using injected extracts of pollens or house dust mite 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, chiropraxy, 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 as current therapy with corticosteroids and 2-agonists is so effective in the majority of patients. There, however, is 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 a rather weak effect, presumably reflecting the fact that multiple mediators are involved. Antagonists of chemokine receptors, particularly CCR3, are in development and may be more effective. Novel anti-inflammatory treatments that are in clinical development include inhibitors of phosphodiesterase-4, NFB, p38 MAP kinase and phosphoinositide-3 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 are 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 248-2). 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.

Stepwise Therapy

For patients with mild, intermittent asthma, a short-acting 2-agonist is all that is required (Fig. 248-7). However, use of a reliever medication more than three times 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 g bid of beclomethasone dipropionate (BDP) or equivalent] and to decrease the dose if symptoms are controlled after 3 months. If symptoms are not controlled, an LABA should be added, most conveniently 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 LABAs. 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 oral corticosteroid 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.

Figure 248-7




Step-wise approach to asthma therapy according to the severity of asthma and ability to control symptoms. ICS, inhaled corticosteroid; LABA, long-acting 2-agonists; OCS, oral corticosteroid.



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 ICSs. 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 in adults and children and are recommended particularly in patients with unstable disease who have frequent exacerbations.

Acute Severe Asthma

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.

Clinical Features

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 hypoxia and PaCO2 is usually low due to hyperventilation. A normal or rising PaCO2 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.

Acute Severe Asthma: Treatment

A high concentration of oxygen should be given by face mask to achieve oxygen saturation of >90%. The mainstay of treatment is high doses of short-acting inhaled 2-agonists that are given either by nebulizer or via a metered dose inhaler with a spacer. In severely ill patients with impending respiratory failure, intravenous 2-agonists may be given. An inhaled anti-cholinergic may be added if there is not a satisfactory response to 2-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 has also been shown to be effective when added to inhaled 2-agonists, and is relatively well tolerated but is not routinely recommended. Prophylactic intubation may be indicated for impending respiratory failure, when the PaCO2 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 as they may depress ventilation. Antibiotics should not be used routinely unless there are signs of pneumonia.

Refractory Asthma

Although most patients with asthma are easily controlled with appropriate medication, a small proportion of patients (approximately 5% of asthmatics) are difficult to control despite maximal inhaled therapy. Some of these patients will require maintenance treatment with oral corticosteroids. 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.

Mechanisms

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 as there are no useful plasma measurements that can be made. Compliance may be improved by giving the ICS as a combination with an LABA that gives symptom relief. Compliance with oral corticosteroids 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. Gastroesophageal reflux is common among asthmatics due to bronchodilator therapy, but there is little evidence that it is a significant factor in worsening asthma, and treatment of the reflux is not usually effective at improving asthma symptoms. Some patients may have chronic infection with Mycoplasma pneumoniae or Chlamydophila pneumoniae and benefit from treatment with a macrolide antibiotic. Drugs such as -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.

Relatively little is known about the pathology of refractory asthma, as biopsy studies are more difficult in these patients. Some patients show the typical eosinophilic pattern of inflammation, whereas others have a predominantly neutrophilic pattern. There may be an increase in TH1 cells and CD8 lymphocytes compared to mild asthma and increased expression of TNF-. Structural changes in the airway, including fibrosis, angiogenesis, and airway smooth-muscle thickening, are more commonly seen in these patients.

Differential Diagnosis

Some patients who apparently have difficult-to-control asthma also have vocal cord dysfunction, resulting in wheezing or stridor. This symptom is thought to be an attention-seeking hysterical conversion syndrome and may lead to escalating doses of asthma therapy, with some patients taking high doses of oral corticosteroids. It may be recognized by the characteristic discrepancy between tests of forced expiration, such as FEV1 and PEF, and relatively normal airway resistance. Direct inspection by laryngoscopy may confirm adduction of the vocal cords at the time of symptoms. This condition is usually difficult to manage, but it is important that patients be weaned off oral and inhaled corticosteroids. Speech therapy is sometimes beneficial. Some patients with COPD may be diagnosed as asthmatic and may show the characteristic poor response to corticosteroids and bronchodilators, but this situation is complicated by the fact that some patients with COPD also have concomitant asthma.

Corticosteroid-Resistant Asthma

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 <1 in 1000 patients. It is defined by a failure to respond to a high dose of oral prednisone/prednisolone (40 mg od 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 oral corticosteroids (corticosteroid-dependent asthma). In all 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 excess of the transcription factor AP-1, an increase in the alternatively spliced form of the glucocorticoid receptor GR-, an abnormal pattern of histone acetylation in response to corticosteroids, a defect in IL-10 production, and a reduction in histone deacetylase 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 determined.

Brittle Asthma

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 2-agonists (type I 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 as 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.

Refractory Asthma: Treatment

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 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. There is some evidence that anti-TNF therapy may be effective, but this is controversial and very expensive. A few patients may benefit from infusions of 2-agonists. New therapies are needed for these patients, who currently consume a disproportionate amount of health care spending.

Special Considerations

Although asthma is usually straightforward to manage, there are some situations that may require additional investigation and different therapy.

Aspirin-Sensitive Asthma

A small proportion (approximately 1%) of asthmatics become worse with aspirin and other COX inhibitors, although this is much more commonly seen in severe patients and in those with frequent hospital admission. Aspirin-sensitive asthma is a well-defined subtype 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 irritation, facial flushing, and wheezing. There is a genetic predisposition to increased production of cysteinyl-leukotrienes with functional polymorphism of cys-leukotriene synthase. Asthma is triggered by COX inhibitors but is persistent even in their absence. All nonselective COX inhibitors should be avoided, but selective COX-2 inhibitors are apparently safe to use when an anti-inflammatory analgesic is needed. Aspirin-sensitive asthma responds to usual therapy with an 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 in the Elderly

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 2-agonists and more systemic side effects with ICSs. Comorbidities are more frequent in this age group, and interactions with drugs such as 2 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 oral corticosteroids may be very useful in documenting the steroid responsiveness of asthma.

Pregnancy

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 since poor control may have adverse effects on fetal development. Compliance may be a problem as there is often concern about the effects of anti-asthma 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 short-acting 2-agonists, ICSs, and theophylline; there is less safety information about newer classes of drugs such as LABAs, antileukotrienes, and anti-IgE. If an oral corticosteroid is needed, it is better to use prednisone rather than prednisolone as 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.

Cigarette Smoking

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, necessitating higher doses for asthma control. Smoking cessation improves lung function and reverses the steroid resistance; thus, vigorous smoking cessation strategies should be used. Some patients report a temporary worsening of asthma when they first stop smoking, which could be due to the loss of the bronchodilating effect of nitric oxide in cigarette smoke.

Surgery

If asthma is well-controlled, there is no contraindication to general anesthesia and intubation. Patients who are treated with oral corticosteroids will have adrenal suppression and should be treated with an increased dose of oral corticosteroid immediately prior to surgery. Patients with FEV1 <80% of their normal levels should also be given a boost of oral corticosteroids 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

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. As airways become blocked with mucoid plugs rich in eosinophils, 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 ICSs, but it is necessary to give a course of oral corticosteroids if there is any sign of worsening or pulmonary shadowing is found. Treatment with the oral antifungal itraconazole is beneficial in preventing exacerbations.