Chapter 281: Asthma

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. Asthma is a heterogeneous disease with several phenotypes recognized, but thus far these do not correspond well to specific pathogenic mechanisms (endotypes) or responses to therapy. 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 ~300 million people worldwide, with ~250,000 deaths annually. 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 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 relatively 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.

Asthma is a heterogeneous disease with interplay between genetic and environmental factors. Several risk factors that predispose to asthma have been identified (Table 281-1). These should be distinguished from triggers, which are environmental factors that worsen asthma in a patient with established asthma.

Atopy

Atopy is the major risk factor for asthma, and non-atopic 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 >80% of asthmatic patients, and atopic dermatitis (eczema). Atopy may be found in 40–50% of the population in affluent countries, but 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.

Genetic Predisposition

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 (T_H2) 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 ORMDL3, 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.

Epigenetic Mechanisms

There is increasing evidence that epigenetic mechanisms may be important, particularly in the early development of asthma. DNA methylation and histone modification patterns may be influenced by diet, cigarette smoke exposure, and air pollution, and may affect genes involved in the pathogenesis of asthma. These epigenetic changes may occur in the fetus as a result of maternal environmental exposure.

Infections

Although viral infections (especially Rhinovirus) 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. 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. Living in damp houses with exposure to mold spores is now recognized to be a risk factor, and removal of these factors may improve asthma.

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 T_H2 cell bias at birth, whereas exposure to infections and endotoxin results in a shift toward a predominant protective T_H1 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. While there is considerable epidemiologic support for the hygiene hypothesis, it cannot account for the parallel increase in T_H1-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. 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 not yet clear.

Air Pollution

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 not yet clear. 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. There is increasing evidence that exposure to road traffic pollution is associated with increased asthma symptoms, with the main culprits being diesel particulates and nitrogen dioxide. Indoor air pollution is also 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.

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 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. Cleaners commonly develop occupational asthma owing to exposure to aerosols of cleaning liquids. Occupational asthma may be suspected when symptoms improve during weekends and holidays.

Obesity

Asthma occurs more frequently in obese people (BMI >30 kg/m²) and is often more difficult to control. Although mechanical factors may contribute, it may also be linked to the pro-inflammatory adipokines and reduced anti-inflammatory adipokines that are released from fat cells.

Other Factors

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.

Intrinsic Asthma

A minority of asthmatic patients (~10%) have negative skin tests to common inhalant allergens and normal serum concentrations of IgE. These patients, with non-atopic 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. Type-2 innate lymphoid cells (ILC2) may drive the eosinophilic inflammation in these non-allergic patients.

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 (preventive) therapy.

Allergens

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, an 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).

Virus Infections

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.

Pharmacologic Agents

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 beta blockers need to be avoided and even selective β, 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 non-asthmatics. Aspirin may worsen asthma in some patients (aspirin-sensitive asthma is discussed 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 fluid 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 β₂-agonists and antileukotrienes, but is best prevented by regular treatment with ICS, 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 and Diet

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.

Air Pollution

Increased ambient levels of sulfur dioxide, ozone, diesel particulates 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, thus, early detection and avoidance are important.

Hormones

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. Although acid reflux might trigger reflex bronchoconstriction, it rarely causes asthma symptoms, and antireflux therapy usually fails to reduce asthma symptoms in most patients.

Stress

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.

Pathology

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 (often termed 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. 281-1). 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), non-atopic (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.

Airway Inflammation

There is inflammation in the respiratory mucosa from the trachea to terminal bronchioles, but with a predominance in the bronchi (cartilaginous airways), but it is still uncertain how inflammatory cells interact and how inflammation translates into the symptoms of asthma (Fig. 281-2). 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. 281-3).

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 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 (Fc_εRII). 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 T_H2 cell differentiation and require cytokines such as IL-12 and tumor necrosis factor α (TNF-α), to promote the normally preponderant T_H1 response. The cytokine thymic stromal lymphopoietin (TSLP) released from epithelial cells in asthmatic patients instructs dendritic cells to release chemokines that attract T_H2 cells into the airways.

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 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.

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 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.

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 T_H2 phenotype, whereas in normal airways T_H1 cells predominate. T_H2 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. Natural killer CD4⁺ T lymphocytes that express high levels of IL-4 have been described in some studies. Regulatory T cells (Treg) play an important role in determining the expression of other T cells, and there is evidence for a reduction in a certain subset of Tregs (CD4⁺CD25⁺) that express the transcription factor FOXP3 in asthma that is associated with increased T_H2 cells. Recently innate T cells (ILC2) without T cell receptors have been identified that release T_H2 cytokines and are regulated by epithelial cytokines such as IL-25 and IL-33 and may be predominant in non-allergic asthma.

Structural Cells

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.

Inflammatory Mediators

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. 281-4). Mast cell-derived 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.

Cytokines

Multiple cytokines regulate the chronic inflammation of asthma. The T_H2 cytokines IL-4, IL-5, IL-9, 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 T_H2 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 T_H2 cells via CCR4 (Fig. 281-5).

Oxidative Stress

Activated inflammatory cells such as macrophages, eosinophils, and neutrophils 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, it may amplify the inflammatory response, and may reduce responsiveness to corticosteroids.

Nitric Oxide

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 (F_ENO) is increasingly used in the diagnosis and monitoring of asthmatic inflammation, although it is not yet used routinely in clinical practice.

Transcription Factors

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 T_H2 cytokines in T_H2 and ILC2 cells.

Effects of Inflammation

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 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 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/neprilysin) that degrade certain peptide inflammatory mediators like bradykinin; 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 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.

Airway Smooth Muscle

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. Airway smooth-muscle cells from asthmatic patients also release multiple inflammatory mediators, particularly cytokines and chemokines.

Vascular Responses

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.

Mucus Hypersecretion

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.

Neural Regulation

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 may 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 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 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.

Physiology

Limitation of airflow is due mainly to bronchoconstriction (from mast cell mediators), 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 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, 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).

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.

Lung Function Tests

Simple spirometry confirms airflow limitation with a reduced FEV₁, FEV₁/FVC ratio, and PEF (Fig. 281-6). Reversibility is demonstrated by a >12% and 200-mL increase in FEV₁ 15 min after an inhaled short-acting β₂-agonist (SABA; such as inhaled albuterol 400 μg) or in some patients by a 2–4 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, measured by carbon monoxide transfer, is usually normal, but there may be a small increase 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 (radioallergosorbent test [RAST]) may be measured in some patients.

Imaging

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 (BPA). 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 (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.

Exhaled NO

Fractional exhaled nitric oxide (F_ENO) is now being used as a noninvasive test to measure eosinophilic 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.

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 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 cord dysfunction may mimic asthma and is thought to be a hysterical conversion syndrome.

Eosinophilic pneumonias and systemic vasculitis, including Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis) 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 15% of COPD patients have features of asthma, with increased sputum eosinophils and a response to OCS; these patients probably have both diseases concomitantly.

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 hypoxemia, and is usually low due to hyperventilation. A normal or rising 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.

Refractory Asthma

Although most patients with asthma are easily controlled with appropriate medication, a small proportion of patients (~5%) are difficult to control despite maximal inhaled therapy. It is important to check adherence to therapy and inhaler technique. 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.

Mechanisms

The most common reason for poor control of asthma is poor adherence 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. Adherence with ICS is difficult to monitor as there are no useful plasma measurements that can be made but measuring F_ENO may identify the problem. Compliance may be improved by giving the ICS as a combination with a LABA that gives symptom relief. Adherence 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 T_H1 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.

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 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.

Brittle Asthma

Some patients show chaotic variations in lung function despite taking appropriate therapy. Some show a persistent pattern of variability and may require OCS or, at times, continuous infusion of β₂-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.

Aspirin-Sensitive Asthma

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 those 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 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 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.

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 as poor control may have adverse effects on fetal development. Adherence may be a problem as 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 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 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. LABA and theophylline appear to overcome some of the steroid resistance; so, ICS-LABA combination therapy and low dose theophylline 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.

Surgery

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. Anti-IgE therapy may also be useful to reduce the need for OCS.

Although asthma and COPD are distinct syndromes with different clinical presentations and underlying inflammatory mechanisms, some patients with asthma have features of COPD (for example, asthmatics who smoke and severe asthmatics with irreversible airflow limitation) and some patients with COPD have features of asthma with more reversibility and increased airway and blood eosinophils. This may represent the coincidence of two common diseases, or these may be distinct phenotypes. ACO patients tend to have more symptoms and exacerbations. They may benefit from triple therapy with ICS, LABA, and LAMA.