Asthma is a disease characterized by hyperresponsiveness of bronchi to various stimuli as well as changes in airway resistance, lung volumes, and inspiratory and expiratory flow rates, with symptoms of cough, wheezing, dyspnea, or shortness of breath. In 1991, a National Institutes of Health Expert Panel suggested that asthma was a disease characterized by (a) airway obstruction that is reversible—partially or completely, (b) airway inflammation, and (c) airway hyperresponsiveness (1). In 1997, the Expert Panel 2 report described asthma as follows:

“Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli. Reversibility of airflow limitation may be incomplete in some patients with asthma” (2).

The NIH Expert Panel 3 Report of 2007 confirmed this working definition (3). Asthma has been described by other designations, including allergic bronchitis, asthmatic bronchitis, allergic asthma, atopic asthma, nonallergic asthma, cough equivalent asthma (4), and cardiac asthma (5,6). A central feature of asthma from a physiologic viewpoint is bronchial hyperresponsiveness to stimuli such as histamine or methacholine, a characteristic not shared by patients without asthma. In population screening, such nonspecific hyperresponsiveness has been reported as sensitive but not specific. Surprisingly, in a study of children 7 to 10 years of age, 48% of those with a diagnosis of asthma did not have bronchial hyperresponsiveness (7). Asthma is characterized by wide variations of resistance to airflow on expiration (and inspiration) with remarkable transient increases in certain lung volumes, such as residual volume, functional residual capacity, and total lung capacity.

Asthma is considered, for most patients, a reversible obstructive airway disease as compared with chronic obstructive pulmonary disease (COPD). Many patients with asthma experience symptom-free periods of days, weeks, months, or years in between episodes, whereas chronic symptoms and fixed dyspnea characterize COPD. When daily symptoms of cough, wheezing, and dyspnea have been present for months in a patient with asthma, bronchodilator nonresponsiveness may be present. However, appropriate anti-inflammatory therapy reduces symptoms and improves the quality of life along with improvement in pulmonary function status.

Immunoglobulin E (IgE)-mediated bronchoconstriction can be demonstrated in many patients with asthma, but not all cases of asthma are “allergic.” It is thought that about 80% of patients have allergic asthma. In the Inner-City Asthma Study of children ages 5 to 11 years, 94% of children reacted to at least one allergen (8). Some evidence does exist for IgE
antibodies to respiratory syncytial virus (RSV) (9) and parainfluenza virus (10); however, not all studies are consistent with such a mechanistic explanation of antiviral IgE-mediated asthma. Perhaps, RSV infection allows for T_H2 polarization of the immune response and reduced antiviral IFNγ production (11). Serologic tests and nasopharyngeal or sputum cultures were positive for viruses in 23 of 29 (80%) adult patients who reported a recent respiratory tract infection and were hospitalized for asthma (12). Influenza A and rhinovirus were found most often. In children, viral infections (RSV in infants younger than 2 years of age and rhinovirus in children 2 to 16 years of age) were associated with acute wheezing episodes resulting in emergency department treatment or hospitalization (12). It is likely that other viruses or bacteria will be identified as causative of exacerbations of asthma, with use of increasingly sophisticated molecular techniques.

The sudden onset of wheezing dyspnea that occurs within 3 hours of ingestion of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) (13) is not an IgE-mediated reaction but represents alterations of arachidonic acid metabolism, such as blockage of the cyclooxygenase pathway with shunting of arachidonic acid into the lipoxygenase pathway. Potent lipoxygenase pathway products, such as leukotriene D4 (LTD₄), cause acute bronchoconstriction in aspirin- and NSAID-sensitive patients (13–15). Patients with aspirin exacerbated respiratory disease (aspirin intolerant asthma) have a “knock in” condition in that there is increased LTC₄ synthase in bronchial and nasal mucosa and elevated urinary concentrations of LTE₄, a metabolite of LTD₄, even at baseline (13,15). The concentrations of LTE₄ rise significantly after ingestion of aspirin or a NSAID in susceptible patients (13–15).

Many patients with asthma may have symptoms precipitated by nonspecific, non–IgE-mediated triggers, such as cold air, air pollutants including ozone (16) and fine particles (<2.5 µm in diameter) (16), exercise, crying or laughing, and changes in barometric pressure. Fortunately, pharmacologic therapy can minimize the effects of these nonspecific triggers. Psychological stress such as from post traumatic stress disorder (17) and violence and sexual or physical abuse (18) also are associated with asthma.

Genetic and environmental factors are important in terms of development of asthma, but the effects of heredity are much greater (19). Heritability of asthma ranges from 30% to 87% (19,20). In a study of 4,910 4-year-old twins, heredity accounted for 68% and the shared environment accounted for 13% (19). Nonshared environmental factors contributed 19% (19). The authors concluded that “rearing environment, family diet, and air pollutants seem to play a minor role” (19). If the approximate population prevalence for an allergic-type disease in a child is 20%, then having 1 parent with allergies increases the prevalence to 50% (21). If both parents are allergic, there is a 66% chance of the child developing an allergic condition (21). In twin studies, the concordance for asthma in monozygotic twins reared together was similar to that for twins reared apart (22,23). In addition, in a study of 5,864 twins who were evaluated from infancy to age 25 years, the cumulative incidence of asthma was 6% in males and 5.4% in females. If one twin developed asthma, the relative risk of the co-twin developing asthma was 17.9 for identical twins, compared with 2.3 for fraternal twins (23). More than 80% of cases of asthma began by 15 years of age, when nearly all of the study subjects lived in the same home environment (23). These data support a strong genetic effect on development of asthma. Methacholine responsiveness, total serum IgE concentration, and immediate skin test reactivity have been found to be more concordant in monozygotic twins than in dizygotic twins (24), which supports a genetic influence over an environmental influence. Both factors should be considered as contributory, and production of specific antiallergen IgE appears to be affected by environmental and local allergic exposures in the genetically susceptible subject. In Table 19.1, there are some examples of candidate genes for asthma or immunologic aspects involved with asthma (25). Single nucleotide polymorphisms (SNPs) have been associated with asthma (26), and it is likely that more will be identified and then replicated. Examples of SNPs that are associated with asthma include IL4RR551 and IL13+2044GA as they are associated with “Gain of
function” or enhanced biologic activity of IL-4 and IL-13, respectively (26).

The onset of early childhood asthma has been associated with smoking in utero (27) and parental smoking (28). For development of severe asthma in children, cigarette smoking by grandparents also has been identified (29). However, once asthma begins, evidence exists for increased childhood respiratory symptoms from passive smoking (30,31) and added deficits in lung function when there had been in utero smoking (32).

Environmental factors, such as viral infections, have been associated with development of IgE antibodies. Frick et al. (33) demonstrated development of antiallergen IgE in association with increasing antiviral antibodies in a prospective study of high-risk infants whose parents both had allergic diseases. Croup in early childhood has been associated with subsequent development of asthma (34–36), as have RSV, influenza, parainfluenza virus, and metapneumovirus infections (37–39). When infections occur in an at- risk infant, defined when the mother, father, or sibling has asthma, there is a greater incidence of wheezing (35). This association is magnified if there is concomitant parental smoking or sensitization to dust mites (35). These findings demonstrate the overlap between family history, allergic sensitization, and respiratory infections on development of asthma.

Indoor allergen exposures from house dust mites (40), cats (41), and cockroaches (42) have been associated with the development of childhood asthma. New-onset asthma in older men (aged 61 years or older) was associated with detectable serum IgE antibodies to cat allergen but not dust mites, ragweed, or mouse urinary antigen (43). In this study, IgE antibodies to dog dander and cockroach excreta were not measured.

Environmental factors can predispose to development of asthma but also can be associated with a reduced risk of asthma. The concept is that there are beneficial effects of microbes in the home that do not cause any recognizable infection or illness (28,44). The “protective” home environments consist of stables and dairy farms that are part of the family home, which is an L-shape. The home and barn are attached. This observation has been associated with the “hygiene hypothesis” and the purported beneficial effects of certain infections that would shift the T_H1/T_H2 paradigm toward T_H1. Absence of such exposures would permit asthma or atopy. Some specific protective factors have been identified and include small scale pig farming (<10 pigs/farm) but not sheep farming, raw milk consumption, a child’s involvement in frequent haying and staying in animal sheds (45). There remains some controversy about the “hygiene hypothesis” and development of asthma or atopy, but the microbe-rich environments seem to be protective against development of asthma by altering the predominant cytokines generated by CD4⁺ lymphocytes and interactions with innate immunity and its Toll-like receptors (TLRs) (45). A process that favors asthma includes generation of the helper T-cell subset T_H2, which is central to IgE production, as opposed to T_H1, which would diminish an “atopic” pattern and contribute to a classic delayed-type hypersensitivity response (type IVa₁). In a study of 867 children in Japan who had received Bacille Calmette Guérin (BCG) immunization after birth and at 6 and 12 years of age, the presence of and induration of tuberculosis skin tests were studied in relation to the emergence of atopy (asthma, rhinitis, and atopic dermatitis) (46). By age 12 years, 58% of the children had developed positive (≥10 mm in duration) responses to tuberculin testing, and 36% of children had reported atopic symptoms (46). Asthma symptoms and atopy were associated negatively with positive tuberculin responses, and presence of tuberculin reactivity was associated with remission from asthma by years 6 or 12 (46). The data raised the possibility that the T_H1 response produced by BCG immunization resulted in increases in the T_H1 cytokines, interferon-γ (IFN-γ), and interleukin-12 (IL-12) and decreases in incidence of asthma, possibly even inducing remissions of atopy. In addition, there were reduced quantities of the T_H2 cytokines IL-4, IL-13, and IL-10, compared with the BCG nonresponders, who had more atopy and asthma. Alternatively, these data might be interpreted that children likely to become atopic have a reduced ability to develop T_H1 memory lymphocytes after BCG immunization or, by analogy, reduced response to measles vaccination (47). The latter stems from data revealing less atopy when there was a previous episode of measles (47). These studies and the association between RSV and other viral infections and childhood asthma suggest that the critical link may be the predominance of the T_H1 cytokines and protective innate immune responses. The latter may be specific such as for TLR 5 for people exposed to pigs and TLRs 6 and 8 for people working with silage (45). The notion that asthma is “an epidemic in the absence of infection” has been suggested (48) and demonstrates how complex asthma and the identification of its origins are.

The effects of air pollution on the early development of asthma remain under investigation although the effects of air pollution from ozone and small particles have been associated with hospitalizations for acute severe asthma (49).

The cause of asthma remains unknown, although asthma is considered a very complex, heterogeneous, inflammatory disease (50, 51) or syndrome. Some important pathologic findings include a patchy loss of bronchial epithelium, usually associated with eosinophil infiltration (52–54), neutrophilic infiltration (55), lymphocyte infiltration (52), mast cell degranulation (52),
contraction and hypertrophy of bronchial smooth muscles, bronchial mucosa edema and increased blood flow (56), bronchial gland hyperplasia, hypersecretion of thick bronchial mucus, and basement membrane thickening (52,57). Collagen synthesis may result from stimulation or injury to airway epithelial cells (58). A key cell is the myofibroblast, which is a hybrid cell of fibroblast and smooth muscle cell origins. These cells produce types III and I collagen (58). Epithelial cells obtained during bronchoalveolar lavage (BAL) from patients with asthma have been found to be much less viable than in subjects without asthma (59). However, the epithelial cells from patients with asthma produced much more (a) fibronectin, a glycoprotein involved with cell attachment, cell growth, and chemotaxis; and (b) 15- hydroxyeicosatetraenoic acid (15-HETE), a metabolite of arachidonic acid (59). The increased metabolic activity of epithelial cells appears to contribute to airway damage and remodeling. There is subepithelial “fibrosis” that is composed of collagen types I, II, and V, which contributes to the basement membrane thickening of asthma.

When bronchial biopsy samples were obtained from 14 patients who had asthma for 1 year or less, increases in numbers of mast cells, eosinophils, lymphocytes, and macrophages were found in the epithelium (60). Deeper in the lamina propria, eosinophils, lymphocytes, macrophages, and plasma cells were present, suggesting that patients with mild asthma, who had not received anti-inflammatory therapy, had marked cellular infiltration in the bronchial mucosa (60).

Human bronchial epithelium from patients with asthma express Fas ligand (Fas L) and Fas on eosinophils and T lymphocytes (61). Activation of Fas by Fas L induces apoptosis. Biopsy samples from patients, who had not received inhaled corticosteroids, had reduced numbers of apoptotic eosinophils and reduced expression Fas L and Bcl-2, which help regulate apoptosis. Conversely, inhaled corticosteroid–treated patients had fewer eosinophils and increased numbers of apoptotic eosinophils (61). In a study of BAL of 12 newly diagnosed and untreated patients with asthma, reduced expression of messenger RNA (mRNA) for both Fas and the Fas receptor (CD95) on CD3⁺ T lymphocytes was found (62). These findings are consistent with a persisting inflammatory cell infiltrate that characterizes asthma and offers the possibility of targeted anti-inflammatory therapy.

Some physiologic characteristics of asthma include bronchial hyperresponsiveness to stimuli such as histamine (63), methacholine (64), or LTD₄ (65) and at least a 12% improvement in forced expiratory volume in 1 second (FEV₁) after inhalation of a β₂-adrenergic agonist, unless the patient is experiencing acute severe asthma (status asthmaticus) or has had severe, ineffectively treated airway obstruction. There are large changes in lung compliance, depending on severity of the disease.

On a cellular level, during acute episodes of asthma, there are activated or hypodense eosinophils present in increased numbers (66–68) and hyperadhesive eosinophils in the sense of increased binding to VCAM and ICAM (69). Eosinophil products such as major basic protein (MBP) can be identified in sputum (67) and in areas where bronchial epithelium has been denuded (68). Eosinophil cationic protein has been identified in areas of denuded bronchial epithelium. This cationic protein has been reported to be even more cytotoxic than MBP (70). Mast cells in the bronchial lumen and submucosa are activated, and their many cell products are released, whether preformed or synthesized de novo. Mast cells are found to be in close proximity to smooth muscle and their interactions are being investigated regarding the ability of smooth muscle to stretch maximally (71). Indeed, it has been suggested that the mast cells infiltrate smooth muscle causing “mast cell myositis” (71). Macrophages, lymphocytes, and epithelial cells participate as well and when epithelial cells are damaged, the production of the protective PGE₂ is reduced. Epithelial cells are able to produce many different effector molecules.

Evidence supports neuroimmunologic abnormalities in asthma, such as the lack of the bronchodilating nonadrenergic noncholinergic (NANC) vasoactive intestinal peptide (VIP) in lung sections from patients with asthma (72) and reduced concentrations of VIP during acute exacerbations of asthma (73). There are increased concentrations of IgG autoantibodies that catalyze the hydrolysis of VIP in women whose asthma became more difficult to control during pregnancy (73). Substance P concentrations in induced sputum have been reported to be markedly elevated, compared with that in controls (74). The concentrations of the tachykinin, neurokinin A, is elevated in bronchoalveolar lavage fluid from patients with asthma compared to normal (75), and the potent vasodilator, calcitonin gene-related peptide, has been detected during late asthmatic reactions (76).

The free radical nitric oxide is detectable in expired air in patients with asthma, and its concentration increases further after allergen challenge (77). Inhaled corticosteroids, such as fluticasone, result in about a 60% reduction in exhaled nitric oxide (eNO) within 6 weeks (78). It has been hypothesized that management of asthma could be improved by using the biomarker, eNO. Nevertheless, when asthma management compared the use of the National Asthma Education and Prevention Program Expert Panel (NAEPP) guidelines combined with measurement of eNO to the guidelines alone, there was no meaningful difference in control of asthma (79). A free radical generated from arachidonic acid, 8-isoprostane, is increased in asthma and reflects ongoing oxidative stress (80). There are progressively greater amounts in expired air as asthma severity increases from mild-to-severe (80).

In addition to the above-described features of asthma, asthma is heterogeneous in its clinical presentations (phenotypes) and responses to pharmacologic treatment. Patients vary in their responses to β₂ adrenergic
agonists (81), inhaled corticosteroids (82), leukotriene antagonists (83), and oral corticosteroids (84).

These findings demonstrate some but not all of the complexities of asthma, which decades ago was considered a psychological condition. Asthma is not a psychological disorder. Nevertheless, the burden of asthma as a chronic disease, especially when the patient has experienced repeated hospitalizations or emergency department visits, may result in psychological disturbances or abnormal coping styles that coexist with asthma (17,18,85–88).

Asthma affects more than 22 million people in the United States, as of 2005, consisting of 6.5 million children and 15.7 million adults (89). It is estimated that 32.6 million people have at one time been diagnosed with asthma (89). The World Allergy Organization (WAO) has estimated that 300 million people worldwide have asthma, of which half are in developing countries (90). In the United States, using a random digit dialing system, the estimated prevalence of asthma was 8.4% of adults at least 18 years of age (91). The range by various counties across the country was 3% to 13.8% (91). Puerto Rican responders had a prevalence of asthma 80% to 140% higher than non-Hispanic whites (89,91). Native Americans and Alaskan Natives had prevalence rates 40% greater than non-Hispanic whites (89). Acute asthma is the most common childhood medical emergency (92). Disturbingly, the rate of emergency department visits for asthma was 350% higher in black people than in white people (89). Hospitalizations in black people were 240% greater (89). Often, adults and children requiring acute treatment of asthma have not received or are not using optimal anti-inflammatory therapy. In children in the United States, the attack rate (episode in the past 12 months) was 5.9% for boys and 4.5% among girls (89). Morbidity from asthma remains a major issue in that children, ages 5 to 17 years, missed 12.8 million days of school in 2003 and adults, ages 18 years and older, missed 10.1 million work days (89). The rate for hospitalizations for asthma based on the population has remained unchanged during the period from 1980 to 2004 (93) despite vast increments in the knowledge of asthma.

For many countries, the prevalence of “clinical asthma” is greater than the 10.9% reported for the United States (94). For example, Scotland (18.4%), England (15.3), Australia (14.7%), Canada (14.1%), Peru (13.0%), and Brazil (11.4%) had higher rates than the United States (94). “Clinical asthma” in children was reported as 50% of the prevalence data for self-reported wheezing in the past 12 months (94). For adults, the rate for “clinical asthma” was from “breathlessness and wheeze” which was 50% of those reporting current wheeze (94).

Mortality from asthma appears to be decreasing somewhat in that there were 4,055 deaths in 2003, of which 195 were in children (89). There was a disproportionate increase in deaths in Puerto Ricans and black people (89). About 0.5% of hospitalizations for asthma are associated with a death from asthma, ranging from 0.3% in black people to 0.6% in white people more than 5 years of age (95). About one-third of deaths from asthma occur in the hospital (95). In the same study, the typical hospitalization for asthma was 2.7 days with hospital charges of $9,078 in year 2000 (95). Overall, in light of the unchanged per population rate of hospitalizations for asthma from 1980 to 2004 (93), the daunting challenge remains to reduce the number of hospitalizations (and deaths) from asthma.

Intermittent respiratory symptoms may exist for years before the actual diagnosis of asthma is made in patients older than 40 years of age. The diagnosis of asthma may be more likely made in women and nonsmokers, whereas men may be labeled as having chronic bronchitis, when in fact they do not have chronic sputum production for 3 months each year for 2 consecutive years. Asthma may have its onset in the geriatric population and medication nonadherence is found frequently (96). Asthma may begin during or after an upper respiratory tract infection. The prevalence of asthma was found to be 7% or greater, and all cause deaths, but not asthma specifically, have been reported to be increased in geriatric patients with asthma as compared to control patients without asthma (97).

Asthma morbidity can be enormous from a personal and family perspective as well as from the societal aspect. The number of hospitalizations in the United States for asthma increased almost fourfold from 1965 to 1983, with absolute numbers growing from 127,000 to 459,000 per year (98). This number has been stable from 1980 to 2004 based on per population calculation (93). The number of days of school missed from asthma is excessive, as is work absenteeism or presenteeism (present but not fully productive).

Asthma was thought to be related to occupational causes in 2% of the 6 million people with asthma in the United States in 1960. As of 2000, it was estimated that 5% to 15% of newly diagnosed asthma in working adults is caused by an occupational exposure (99). The 2008 Consensus Statement of the American College of Chest Physicians reported that 10% to 15% of asthma cases are related to occupational exposures (100). Terminology includes “work-related asthma” which consists of occupational asthma (de novo asthma or return of previously quiescent asthma) or work-exacerbated asthma (100).

The asthma death rate is over 4,000 annually in the United States (89) which reflects a decline in absolute numbers despite greater U.S. population. The number of fatalities from asthma increased in the United States from 0.8 deaths per 100,000 general population in 1977
to 2.0 in 1989 and still 2.0 in 1997 (101). By 2003, the rate had declined to 1.4 per 100,000 population (89). The fatality rate among Puerto Ricans (4.4/100,000), black people (3.2/100,000 population), American Indians (1.7/100,000 population), and Alaskan natives (2.0/100,000 population) remains higher than among white people (1.2/100,000 population) (89).

A disturbing finding was reported in a study of asthmatics conducted in the Detroit area. Black patients received or filled fewer prescriptions for inhaled corticosteroids and were less likely to be referred to an asthma specialist than Caucasians in the managed care setting in which the study took place. (102) All the patients in this study were enrolled in the same large health maintenance organization; thus, factors such as insurance type or access to medications would not explain the discrepancy in care for black patients as compared to Caucasians.

The costs of asthma include direct costs of medications, hospitalizations, and physician charges in addition to indirect costs for time lost from work (absenteeism) and loss of worker productivity (presenteeism). Some 20% of the patients used 80% of the resources ($2,584, compared with $140 per patient) (103). Some patients have been labeled as the “$100,000 asthmatic patients” because of repeated hospitalization and emergency department visits (104). Emotional costs of asthma are great for the sufferer and the family if asthma is managed ineffectively or if the patient refuses to adhere to appropriate medical advice.

The death of a family member or friend from asthma is shocking; the person may be young, and the fatal attack may not have been anticipated by others or even the patient. It must be kept in mind that with current understanding and treatment of asthma, nearly all fatalities should be avoidable, and asthma need not be a fatal disease. More than half of the deaths from asthma occur outside of the hospital. This observation has led some physicians to conclude that emergency medical services should be improved or even that every patient with asthma should receive a prescription for an albuterol metered-dose inhaler (MDI). One cannot dispute such an argument about emergency services, but it is advisable for the physician managing the patient with asthma to have an emergency plan (action plan) available for the patient or family so that asthma is not managed from a crisis orientation but rather on a preventive basis. Further, an education program or patient instructions can identify what patients should do when their medications are not effective, such as with a change in the level of control or for an exacerbation of asthma.

The central function of the lungs is gas exchange with delivery into the blood stream of oxygen and removal of carbon dioxide. The lung is an immunologic organ and has endocrine and drug-metabolizing properties that affect respiration. The lung consists of an alveolar network with capillaries passing near and through alveolar walls and progressively larger intrapulmonary airways, including membranous bronchioles (1 mm or smaller noncartilaginous airways) and larger cartilaginous bronchi and upper airways. Inspired air must reach the gas exchange network of alveoli. The first 16 airway divisions of the lung are considered the conducting zone, whereas subsequent divisions from 17 to 23 are considered transitional and respiratory zones. The conducting zone consists of trachea, bronchi, bronchioles, and terminal bronchioles and produces what is measured as airway resistance. The terminal bronchioles as a rule have diameters as small as 0.5 mm. Respiratory bronchioles, alveolar ducts, and sacs comprise the transitional and respiratory zones (105) and are the sites of gas exchange.

The structures of bronchi and trachea are similar, with cartilaginous rings surrounding the bronchi completely until the bronchi enter the lungs, at which point there are cartilage plates that surround the bronchi. When bronchioles are about 1 mm in diameter, the cartilage plates are not present. Smooth muscle surrounds bronchi and is present until the end of the respiratory bronchioles.

The lining mucous membrane of the trachea and bronchi is composed of pseudostratified ciliated columnar epithelium (Fig. 19.1). Goblet cells are mucin-secreting epithelial cells and are present in airways until their disappearance at the level of terminal bronchioles. In the terminal bronchioles, the epithelium becomes that of cuboidal cells with some cilia, Clara (secretory) cells, and goblet cells until the level of respiratory bronchioles, where the epithelium becomes alveolar in type. Mucus consists of a superficial gel phase composed of glycoproteins and a sol phase consisting of isotonic fluid in contact with the mucous membrane cells. The cilia move in the sol phase proximally to help remove luminal material (debris, cells, mucus) by the ciliary “mucus escalator.” Other cells such as mast cells, alveolar macrophages, polymorphonuclear leukocyte lymphocytes, eosinophils, and airway smooth muscle cells contribute to lung pathology in different ways. Epithelial cells may be thought of in a constant state of “injury” and are not able to be “repaired” completely. There is loss of columnar epithelial cells and the tight junctions. Permeability is increased (106). Primary bronchial epithelial cells from subjects with asthma have been shown to replicate rhinovirus in vitro to several logs, whereas those of normal control subjects were resistant to infection. This resistance was a result of rapid induction of apoptosis and of interferon (IFN)-β in the normal cells, whereas these responses were deficient in asthmatic cells. These studies were recently extended to a novel family of three related proteins, the IFN-γs 1–3, production of which was also deficient in
vitro and related to asthma exacerbation severity in vivo. (106).

The bronchial wall is characterized by mucosa, lamina propria, smooth muscle, submucosa, submucosal glands, and then cartilaginous plates. Submucosal glands produce either mucous or serous material depending on their functional type. Mast cells can be identified in the bronchial lumen or between the basement membrane and epithelium. They are “microlocalized” to smooth muscle cells and mucosal glands (107). Mast cells have been recovered from BAL samples but are low in number in these samples (108). Mast cell heterogeneity has been recognized based on contents and functional properties. Briefly, mucosal mast cells are not recognized in a formalin-fixed specimen, but connective tissue mast cells are. Mucosal mast cells are present in the lung and contain tryptase but not chymase, whereas connective tissue mast cells contain tryptase and chymase (109). Mast cells participate in airway remodeling because they activate fibroblasts (109,110) and infiltrate and interact with smooth muscle cells (109,110) causing a “mast cell myositis” of the smooth muscle. Mast cell–derived tryptase is a mitogen for epithelial cells and stimulates synthesis of collagen (109). The mucosal mast cells are stimulated by IL-3, IL-4, and IL-9 (a growth factor for mast cells) (109). The sub-mucosal (connective tissue) mast cells are present in large and small airways and are thought to participate in localized fibrogenesis (109). These mast cells interact with stem cell factor (c-kit ligand) and smooth muscle cells (109). In addition to mast cell generation of histamine, prostaglandin D₂ (PGD₂), LTD₄, and tryptase, they secrete IL-4, which upregulates vascular cell adhesion molecule (VCAM) on vessel endothelial surfaces. Eosinophil entry into tissues is facilitated by VCAM. IL-4 also favors isotype switching within the nucleus to cause production of IgE antibodies. The mast cell has many effects, from mediator release and cytokine production to fibrogenic activity. Their interactions with smooth muscle cells are intriguing in the context of induced “myositis” of the smooth muscle (109).

Neutrophils have been recovered in induced sputum using 3.5% saline in an ultrasonic nebulizer (111) from patients with asthma. The numbers were increased in patients with severe asthma (53%) compared with moderate (49%) and mild (35%) asthma. Sputum from nonatopic, nonasthmatic subjects had 28% neutrophils (111). The concentrations of IL-8, which is chemoattractant for neutrophils and is an angiogenic cytokine, and of myeloperoxidase were increased in sputum from patients with moderate and severe asthma (111). Neutrophils have been identified in some (112) but not all (113) patients with sudden (<3 hours) death from asthma.

Macrophages serve as antimicrobial and pro-inflammatory cells and are accessory cells for presenting antigens. Macrophages are present in patients with asthma but are found in greater numbers in patients with chronic bronchitis. Macrophages have been detected during both early and late bronchial responses to allergens. These cells are metabolically active in that they can generate prostaglandins, leukotrienes, pro-inflammatory cytokines, chemokines, free radicals, and mucus secretagogues.

Increased numbers of eosinophils in bronchial biopsy specimens and sputum can be expected in patients with asthma. It has been estimated that for every 1 eosinophil in peripheral blood, there are 100 to 1,000 in the tissue. Patients with mild asthma have eosinophils detected in bronchial biopsy samples, and eosinophils can be found in postmortem histological sections (112,113). Eosinophils produce major basic protein, eosinophil cationic protein, eosinophil derived neurotoxin, eosinophil peroxidase, free radicals, leukotrienes, and T_H2 cytokines. Eosinophils are proinflammatory cells that participate in the pathogenesis of airway remodeling in patients with persistent asthma.

Epithelial cells are shed especially in patients with severe asthma but also in patients with mild asthma. There are a vast number functions and interactions of epithelial cells (114). In addition to being antimicrobial, one of many actions is to produce neutral endopeptidase, which degrades substance P. The loss of functioning epithelium could lead to potentiated effects of this neuropeptide. Similarly, epithelial cells generate smooth muscle–relaxing factors that could be decreased in amount as epithelium is denuded. Epithelial cell fluid obtained during BAL was analyzed for a gelatinase, which is in the family of matrix metalloproteinases (115). Mechanically ventilated patients with asthma were found to have very high quantities of a 92-kDa gelatinase, compared with patients with mild asthma and with ventilated, nonasthmatic subjects (115). This enzyme may damage collagen and elastin and the subepithelial basal lamina region (115). Increased permeability could result because of epithelial cell shedding and alterations of types IV and V collagens that are present in this basement membrane region (115). In this study, mechanically ventilated patients had increased numbers of eosinophils and neutrophils, compared with nonventilated patients with mild asthma (115). There was no difference in numbers of epithelial cells in BAL between patients with mild asthma and the mechanically ventilated patients with asthma, but both groups had twice the percentage as the nonasthmatic subjects, emphasizing that epithelial cell denudation occurs in mild as well as severe asthma.

From a pathophysiologic perspective, the changes that occur in asthma are multiple, diverse, and complex. Further, some of the abnormalities, such as bronchial hyperresponsiveness and mucus obstruction of bronchi, can be present when patients do not have symptoms. Major pathophysiologic abnormalities in asthma are (a) widespread smooth muscle contraction, (b) mucus hypersecretion, (c) mucosal and submucosal edema, (d) bronchial hyperresponsiveness, and (e) inflammation of airways. Obstruction to airflow during expiration and inspiration results in greater limitation during expiration. Hypertrophy and even hyperplasia of smooth muscle have been recognized in asthma. Smooth muscle contraction occurs in large and or small bronchi. The concept of “airway remodeling” includes inflammation, mucus hypersecretion, subepithelial fibrosis, airway smooth muscle hypertrophy and angiogenesis (3).

Bronchial challenge of patients with asthma by inhalation of histamine demonstrated two abnormal responses compared with patients without asthma (118). First, the patients with asthma have increased sensitivity to histamine (or methacholine) because a smaller-than-normal dose of agonist is usually necessary to produce a 20% decline in FEV₁. Second, the maximal response to the agonist in asthma is increased over that which occurs in nonasthmatic, nonrhinitic subjects. In fact, the maximal bronchoconstrictive response (reduction of FEV₁) that occurs in the nonasthmatic, nonrhinitis subject, if one occurs at all, reaches a plateau beyond which increases in agonist produce no further bronchoconstriction. In contrast, were it possible (and safe) to give a patient with asthma increasing amounts of an agonist such as histamine, or methacholine, increasing bronchoconstriction would occur. In an analysis of 146 patients with mild asthma who had undergone bronchial provocation challenge with histamine, two patterns were identified (119). The first was the decline of FEV₁ and FEV₁/FVC without a change in FVC at the dose of histamine causing a 20% decline in FEV₁ (PC₂₀). The second pattern, detected at the time of the PC₂₀ response, had reductions in FVC and FEV₁ but not FEV₁/FVC. It was concluded that the latter subjects experienced excessive bronchoconstriction (119). The authors identified a clinical connection in that there was a moderate correlation between the percentage decline in FVC at the PC₂₀ and patients necessitating prescriptions for oral corticosteroids (but not β₂-adrenergic agonists) (119). In the patients who develop a declining FVC and FEV₁ after bronchoprovocation challenge, there is a concurrent increase in residual volume, which is detrimental if it continues. In summary from these findings, the ease of bronchoconstriction (PC₂₀) is one parameter, but the extent of bronchoconstriction (drop in FVC), when the patient has reached the PC₂₀, correlated with need for oral corticosteroids.

Hypersecretion of bronchial mucus may be limited or extensive in patients with asthma. Autopsy studies of patients who died from asthma after having symptoms for days or weeks classically reveal extensive mucus
plugging of airways. Large and small airways are filled with viscid mucus that is so thick that the plugs must be cut for examination (120). Reid (120) has described this pattern as consistent with endobronchial mucus suffocation. Other patients have mild amounts of mucus, suggesting that perhaps the fatal asthma episode occurred suddenly (over hours) and that severe bronchial obstruction from smooth muscle contraction contributed to the patient’s death. A virtual absence of mucus plugging, called empty airways or sudden asphyxic asthma, has been reported (120,121). Desquamation of bronchial epithelium can be identified on histological examination (122) or when a patient coughs up clumps of desquamated epithelial cells (creola bodies). Bronchial mucus contains eosinophils, which may be observed in expectorated sputum. Charcot-Leyden crystals (lysophospholipase) are derived from eosinophils and appear as dipyramidal hexagons or needles in sputum. Viscid mucus plugs, when expectorated, can form a cast of the bronchi and are called Curschmann’s spirals.

In clinically active asthma, mucus hypersecretion is reduced or eliminated after treatment with systemic and then inhaled corticosteroids. Mucus from patients with asthma has tightly bound glycoprotein and oligosaccharide, compared with mucus from patients with chronic bronchitis (123). It remains unknown why the mucus of patients with asthma is so tenacious compared to patients with cystic fibrosis or chronic bronchitis.

The bronchial mucosa is edematous, as is the submucosa, and both are infiltrated with mast cells, activated eosinophils, and CD4⁺ T_H2 lymphocytes (3). Neutrophils can be a manifestation of severe asthma (3). Macrophages and epithelium both amplify the inflammatory responses of asthma (3). Venous dilation, plasma leakage and proliferation of new vessels occur along with the cellular infiltration (3). In addition to its presence on mast cells, basophils, and eosinophils, IgE has been identified in bronchial glands, epithelium, and basement membrane. Because plasma cell staining for IgE was not increased in number, it has been thought that IgE is not produced locally. However, because the lung is recognized as an immunologic organ, further work may show that IgE is produced in the lung.

The mechanism of bronchial hyperresponsiveness in asthma is unknown but is perhaps the central abnormality physiologically. Bronchial hyperresponsiveness occurs in patients with asthma to agonists, such as histamine, methacholine, leukotriene D₄, allergens, platelet-activating factor (PAF), PGD₂ (short-lived response), adenosine monophosphate, and mannitol. Bronchial hyperresponsiveness is sensitive for asthma if one considers a maximum dose of methacholine of 8 mg/mL, which is necessary to cause a decline in FEV₁ of 20%. Patients with active symptomatic asthma often experience such a decline in FEV₁ when the dose of methacholine is 2 mg/mL or less. However, bronchial hyperresponsiveness is not specific for asthma because it occurs in patients who have disease other than asthma (Table 19.3).

Bronchial hyperresponsiveness is measured physiologically by reductions in expiratory flow rates, FEV₁, or decreases in specific conductance. Nevertheless, hyperresponsiveness consists of bronchoconstriction, hypersecretion, and hyperemia (mucosal edema). It has been easier to measure airway caliber by changes in FEV₁ than to measure changes in bronchial gland secretion, cellular infiltration, or blood vessels (dilation and increased permeability) that also contribute to hyperresponsiveness and cause airways obstruction. Indeed, there has yet to be an “inflammamometer” for asthma. The bronchial responsiveness detected after challenge with histamine or methacholine measures bronchial sensitivity or ease of bronchoconstriction (119). As stated, an additional finding in some patients with asthma is excessive bronchoconstriction, which can be attributable to associated increases in residual volume and possibly more rapid clinical deterioration (119).

Often, on opening the thorax of a patient who has died from status asthmaticus, the lungs are hyperinflated and do not collapse (Fig. 19.2). Mucus plugging and obstruction of bronchi and bronchioles are present. In some cases, complicating factors, such as atelectasis or acute pneumonia, are identified. On histological examination, there is a patchy loss of bronchial epithelium with desquamation and denudation of mucosal epithelium. Eosinophils are present in areas of absent epithelium, and immunologic staining has revealed evidence of eosinophil MBP at sites of bronchial epithelium desquamation. Activated (EG2-positive) eosinophils are
present in the mucosa, submucosa, and connective tissue. Other histological findings include hyperplasia of bronchial mucus glands, bronchial mucosal edema, smooth muscle hypertrophy, and basement membrane thickening (Fig. 19.3). The latter occurs from the remodeling process from collagen deposition (types I, III, and IV), immunoglobulin deposition and cellular infiltrates as evidence of inflammation. The mucus plugs typically contain eosinophils. Occasionally, bronchial epithelium is denuded, but histologic studies do not identify eosinophils. In some cases, neutrophils have been present (112). Other mechanisms of lung damage are present but not understood completely. Similarly, although many autopsy examinations reveal the classic pattern of mucus plugging (Fig. 19.4) of large and smaller bronchi and bronchioles leading to mucus suffocation or asphyxia as the terminal asthmatic event, some autopsies reveal empty bronchi (113,120,121). Eosinophils have been identified in such cases in airways or in basement membranes, but a gross mechanical explanation, analogous to mucus suffocation, is not present. A third morphologic pattern of patients dying from asthma is that of mild-to-moderate mucus plugging (120).

Some patients dying from asthma have evidence of myocardial contraction band necrosis, which is different from myocardial necrosis associated with infarction. Contraction bands are present in necrotic myocardial smooth muscle cell bands in asthma and curiously the cells are thought to die in tetanic contraction whereas in cases of fatal myocardial infarction, cells die in relaxation.

In patients who experience acute severe asthma but do not die from it, it can be expected that when the patient presents with an FEV₁ of 50% of predicted value, there may be a 10-fold increase in inspiratory muscle work. Pleural pressure becomes more negative, so that as inspiration occurs, the patient is able to apply sufficient radial traction on the airways to maintain their patency. Air can get in more easily than it can be expired, which results in progressively breathing at higher and higher lung volumes. The residual volume (RV) increases several-fold, and functional residual capacity (FRC) expands as well. Expiratory flow rates decrease in large and small airways. The lung hyperinflation is not distributed evenly, and some areas of the lung have a high or low ventilation-perfusion ratio (V/Q). Overall, the hypoxemia that results from acute severe asthma occurs from reduced V/Q, not from shunting of blood. The lung hyperinflation also results in “dynamic autopeep” as the patient attempts to maintain airway caliber by applying some endogenous positive airway pressure.

There is no evidence of chest wall (inspiratory muscle) weakness in patients with asthma. Nevertheless, some patients who have received prolonged courses of daily or twice-daily prednisone or who have been mechanically ventilated with muscle relaxants and corticosteroids can be those who have respiratory muscle fatigue.

After successful treatment of an attack of acute severe asthma, the increases in lung volume may remain present for 6 weeks. The changes are primarily in RV and FRC. Small airways may remain obstructed for weeks or months; in some patients, they do not become normal again. At the same time, it can be expected that the patient has no sensation of dyspnea within 1 week of treatment of acute severe asthma
despite increases in RV and reduced small airways caliber. This divergence between symptom recognition in asthma and physiologic measurements has been demonstrated in ambulatory patients who did not have acute severe asthma (status asthmaticus) (124). When patients with an FEV₁ percentage of 60% were studied, 31% overestimated and 17% underestimated the extent of airway obstruction (124). Some patients reported fewer symptoms despite no improvement in FEV₁ or peak expiratory flow rate (PEFR). The reduction in trapped gas in the lung can result in symptom reduction even without improvement in expiratory flow rates.

Asthma pathophysiology includes poor or impaired symptom perception in some patients and in management of asthma, increased symptom perception in others (125,126). There may be poor sensitivity or discrimination (recognizing improvement or worsening status) (125). Dyspnea has been classified into either (a) inspiratory difficulty, (b) chest tightness, (c) unsatisfied inspiration, or (d) work (126). In Table 19.4, factors that alter the perception of dyspnea in asthma are presented. As the exacerbation of asthma becomes worse, the reduction in inspiratory capacity is associated with increases in functional residual capacity (hyperinflation) and increasing dyspnea (126).

The patency of bronchi and bronchioles is a function of many factors. There is the overriding loss of airway distensibility will less elastic recoil pressures (127). Bronchomotor patency is affected by mediators secreted by mast cells, the autonomic nervous system, the nonadrenergic noncholinergic nervous system, circulating humoral substances, the respiratory epithelium, smooth muscle cells, and effects of cellular infiltration and glandular secretions (Tables 19.5 and 19.6). Even this list is oversimplified because asthma must be considered a very complex condition in terms of airway caliber and tone.

Mediator release caused by mast cell activation results in acute and late bronchial smooth muscle contraction, cellular infiltration, and mucus production. Autonomic nervous stimulation contributes through vagal stimulation. The neurotransmitter for postganglionic parasympathetic nerves is acetylcholine, which causes smooth muscle contraction. Norepinephrine is the neurotransmitter for postganglionic sympathetic nerves. However, there appears to be little if any significant smooth muscle relaxation through stimulation of postganglionic sympathetic nerves. Exogenously administered epinephrine can produce smooth muscle relaxation. Circulating endogenous epinephrine apparently does not serve to produce relaxation of smooth muscles. Sensory nerves in the respiratory epithelium are stimulated and lead to release of a host of neuropeptides that may be potent bronchoconstrictors or bronchodilators. Respiratory epithelium itself may contain bronchi-relaxing factors that may become unavailable when epithelium is denuded. Tables 19.5 and 19.6 list some chemical mediators derived from mast cells and cytokines and neuropeptides that may contribute to pathogenesis of asthma.

Although much attention has been directed at understanding the contribution of IgE and mast cell activation in asthma, triggering or actual regulation of some of the allergic inflammation of asthma may occur because of other cells in lungs of patients. Low-affinity IgE receptors (FcεR II) are present on macrophages, eosinophils, monocytes, B lymphocytes, and platelets. These cells, as well as mast cells in the bronchial mucosa or lumen, can be activated in the absence of classic IgE-mediated asthma.

Bronchial biopsy specimens from patients with asthma demonstrate mucosal mast cells in various stages of activation in patients with and without symptoms. Mast cell hyperreleasibility may occur in asthma, in that bronchoalveolar mast cells recovered during lavage contain and release greater quantities of histamine when stimulated by allergen or anti-IgE in vitro.

Eosinophils are thought to contribute to proinflammatory effects by secretion of damaging cell products, such as MBP, that can result in bronchial epithelial denudation, exposing sensory nerves, and leading to smooth muscle contraction. Eosinophils are proinflammatory in that they cause eosinophil and neutrophil chemotaxis, which produces positive feedback in terms of leukotriene and PAF production from attracted and newly activated eosinophils. The latter can be demonstrated by activation markers such as EG2 and reduced density on centrifugation, so called hypodense eosinophils.

On a cellular level, the control of airway tone is influenced by even more fundamental factors, including IL-1, IL-2, IL-3, IL-4, IL-6, IL-10, IL-12, IL-16, and IFN-γ, among others, that influence lymphocyte development and proliferation. IL-3 and IL-5 are eosinophil growth factors. IL-8, detected in bronchial epithelium, binds to secretory IgA and serves to chemoattract eosinophils that generate PAF and LTC₄. IL-8 is also a potent chemotactic substance for neutrophils.

During an acute attack of asthma, there is an increase in inspiratory efforts, which apply greater radial traction to airways. Patients with asthma have great ability to generate increases in inspiratory pressures. Unfortunately, patients who have experienced nearly fatal attacks of asthma have blunted perception of dyspnea and impaired ventilatory responses to hypoxia (128).

Patients with persistent severe asthma have been divided into eosinophil-positive (and macrophage-positive) and eosinophil-negative categories based on results on bronchial biopsy findings (129). Both subgroups of patients were prednisone-dependent (average, 28 mg daily) and had asthma for about 20 years
(129). The residual volume measurements were about 200% of predicted and FEV₁ percentage was 56% of predicted in eosinophil-positive and 42% of predicted in eosinophil-negative patients (129). The ratio of the FVC to slow vital capacity was 88%, indicating more airway collapsibility in eosinophil-positive patients, compared with 97% in eosinophil-negative patients. Perhaps the former patients who had somewhat higher FEV₁ percentages had more loss of elastic recoil in their lungs, so that their airways collapsed more easily (129). On biopsy assessments, sub-basement membrane thickening was higher in these eosinophil-predominant patients than in eosinophil-negative patients. These findings were associated with eosinophil-predominant patients with severe asthma having an increased number of CD3⁺ lymphocytes and activated eosinophils (EG2⁺) in biopsy samples and an increased quantity of β-tryptase in BAL. It is likely that the cellular inflammation and cell products participate in control or perturbation of airway tone, and continued investigations of the many aspects of allergic inflammation should help clarify this difficult issue.

Some types of asthma with an emphasis on etiology are listed in Table 19.7. It is helpful to categorize the type of asthma because treatment programs vary depending on the type of asthma present. Some patients have more than one type of asthma. The NAEPP Report 3 suggests assessing signs and symptoms of asthma in association with spirometry (3). Asthma severity is classified as intermittent (most of the time, implying mild asthma) or persistent (mild, moderate, or severe). In Table 19.8, a version of this classification system is presented. It can be helpful to determine that patients have “moderate persistent allergic asthma” and use the classifications from Tables 19.7 and 19.8 together when applicable.

Asthma in children may be classified by age of onset and persistence of wheezing. (Chapter 20). Designations include “transient early wheeze” (wheezing with lower respiratory tract illnesses before age 3 years but not thereafter), “late-onset wheeze” (wheezing beginning at or after age 6 years), and “persistent wheeze” (wheeze with lower respiratory tract illnesses before age 3 years and wheeze at age 6 years) (157).

In adults, another approach is that of grouping of patients with asthma into clusters using pre-specified variables including induced sputum eosinophil numbers (158). For example, some patients are classified as “concordant disease” because there is a match between symptoms and eosinophilic inflammation, whereas others are either “discordant symptoms” (excessive symptoms with little sputum eosinophilia that could
characterize obese subjects or hypervigilant people) or “discordant inflammation” (few symptoms but high levels of sputum eosinophilia) (158).