Introduction
Asthma is a common disease whose prevalence has increased throughout the world for several decades. For many years the major focus of asthma investigations and treatment was on allergic mechanisms. More recently, studies of the epidemiology, natural history, and pathogenesis have clearly demonstrated that asthma is a heterogeneous disease, with multiple etiologies and contributing cofactors, complex pathobiologic mechanisms, and different molecular phenotypes. Understanding these differences is critical for developing therapeutic strategies that will be effective for the various phenotypes of asthma.
Epidemiology
Asthma is common and its prevalence has been steadily increasing over time. In the United States, the prevalence and severity of asthma are highest in certain vulnerable populations including children, people living below the poverty level, and specific minority groups (Puerto Ricans and black, non-Hispanic Americans). Although a family history of allergy is the strongest risk factor for asthma, early life infections are important cofactors in at least two ways. On one hand, the increasing prevalence of asthma may relate to the success of domestic hygiene in reducing the rate of exposure to bacterial products or changing the commensal microbiome in early childhood, which would otherwise consolidate antibacterial rather than allergic immune responses. On the other hand, viral respiratory infections in early childhood are thought to increase the risk for wheezing illnesses and asthma over time. A range of other exposures have been identified as risk factors for asthma, including intrauterine exposures, prematurity, breastfeeding, diet (especially vitamin intake), stress, exposure to other children, obesity, air pollution, antibiotic use, acetaminophen use, and occupational exposures. Ultimately, the natural history of asthma is heterogeneous; however, certain general patterns are common and the type of asthma that predominates in those who have their onset in childhood, teen years, and adult years may differ.
Methods
For studies of the epidemiology of asthma, definition of asthma remains a critical issue. Options for case definition by questionnaire include assessment of asthma symptoms, use of asthma medications, self-report of asthma, and report of physician-diagnosed asthma. These questionnaire data may be complemented by lung function testing or measurement of bronchial hyperresponsiveness. In general, self-report of asthma symptoms yields higher prevalence estimates than report of asthma diagnosis.
Prevalence
In the United States, the overall prevalence of asthma has risen inexorably between 1980 and 2011, even after accounting for changes in the definition of current asthma in National Health Interview Survey (NHIS) questionnaires ( Fig. 41-1 ). Since 2001 the estimate of asthma prevalence has been based on the following questions, “Have you ever been told by a doctor or other health professional that you had asthma?” to estimate lifetime prevalence and then “Do you still have asthma?” to estimate current prevalence. In 2012, overall lifetime prevalence of asthma was 13.0% and current prevalence of asthma was 8.3%.
In addition to being a common diagnosis across the entire U.S. population, there are marked and persistent differences in asthma prevalence across specific subgroups of the U.S. population, making asthma extremely common in certain vulnerable populations ( Fig. 41-2 ). In 2012, current asthma prevalence was very high in black non-Hispanics (11.9%), those of Puerto Rican heritage (18.8%), and among those living below the poverty threshold (12.4%). Current asthma prevalence also was higher among children (9.3%) than adults (8.0%) and among females (9.5%) than males (7.0%) overall, although the female-to-male balance changes over development with asthma less common in females than males during childhood (age younger than 18, 8.6% vs. 10%, respectively) but more common in females than males during adulthood (age 18 or older, 9.8% vs. 6%, respectively). These imbalances in prevalence among males and females, adults and children, ethnic groups, and poverty levels have not changed since 2001.
Internationally, the prevalence of asthma varies dramatically, with particularly high rates in specific, developed countries including the United Kingdom, New Zealand, Australia, the United States, and Canada ( Fig. 41-3 ). Furthermore, as in the United States, the international prevalence is increasing over time. Two large multinational studies have systematically assessed the worldwide prevalence of asthma in adults and children. The International Study of Asthma and Allergies in Childhood (ISAAC) study used a physician diagnosis and the presence of asthma-like symptoms in a validated questionnaire. In its first iteration, ISAAC Phase I studied 156 centers in 56 countries cross-sectionally during the period 1992-1996. This study confirmed the great variability in asthma prevalence that was inferred from the smaller studies that preceded it, with more than a 20-fold difference in prevalence between centers. However, it also found that some low- and middle-income countries had a prevalence of asthma symptoms that was similar to those in Western, developed countries. Thus the geographic trends are not absolute. ISAAC confirmed the overall increase in asthma prevalence on repeated evaluation from its Phase I period (1992-1996) to its Phase III period (2000-2003). However, these time trends in asthma symptom prevalence showed different regional patterns. With the exception of India, all of the countries with very low symptom prevalence rates at first evaluation reported increases in prevalence. However, in English-language developed countries, in which asthma prevalence was already high, there was little further increase. The European Community Respiratory Health Survey (ECRHS) used a questionnaire with seven questions relating to the 12-month prevalence of symptoms of asthma and studied representative samples of 20- to 44-year-old men and women in 48 centers, predominantly in Western Europe. Although the ECRHS included data from fewer countries than ISAAC and did not distill the broader set of questions into simple overall prevalence data, there was relatively good agreement between ISAAC and the ECHRS with respect to the prevalence of asthma symptoms across the 17 countries that both studies sampled.
Mortality
Death from asthma was once thought to be so uncommon as to prompt Osler’s adage that “the asthmatic pants into old age” ; nonetheless, data from the World Health Organization suggest there are 250,000 asthma-related deaths each year worldwide. Although asthma mortality has historically increased in parallel with asthma prevalence in many countries, the countries with the highest rates of death in the WHO report were not necessarily those with the highest prevalences, suggesting that poor access to care and essential medications are additional contributing factors to mortality. In specific instances, certain medications have also been suspected of contributing to asthma mortality. The event that initially attracted attention to asthma mortality was a dramatic, abrupt increase in asthma deaths in the 1960s, especially in the British Isles, Australia, New Zealand, and Norway. In these countries, asthma mortality increased twofold to tenfold in less than 5 years. This increase was attributed to use of a high-dose preparation of a highly potent, nonselective inhaled β-agonist, isoproterenol, and mortality fell following the preparation’s withdrawal. A second, even more dramatic increase in asthma mortality in New Zealand in the 1970s was again attributed to sales of a unique β-agonist, fenoterol.
In the United States, asthma mortality has been assessed over time using the Mortality Component of the National Vital Statistics System. These data indicate an increase in asthma mortality from 14.4 per 1 million population in 1980 to 21.9 per 1 million in 1995. Since 1995, asthma mortality in the United States appears to have decreased to 17.2 per 1 million persons in 1999, and decreased further to 15 per 1 million persons in 2009. However, as is true for asthma prevalence, asthma mortality disproportionately affects black Americans (38.7 per 1 million persons in 1999) and those of Puerto Rican heritage (40.1 per 1 million). It is not known whether high mortality among black and Puerto Rican Americans relates solely to societal factors, such as access to health care, insurance coverage, and access to medication or asthma education, or whether specific environmental or genetic influences differentially affect these ethnic groups.
Risk Factors
Allergy
The strongest risk factor for asthma is a family history of atopy. This increases the risk of developing allergic rhinitis by fivefold and the risk of asthma by threefold to fourfold. In children 3 to 14 years old, both positive skin tests and increases in total serum IgE are strongly associated with asthma. Serum IgE also correlates strongly with bronchial hyperresponsiveness. In adults, the odds of having asthma increase with the number of positive skin tests to common allergens.
Because much allergic asthma is associated with sensitivity to allergens of the indoor environment and because Western styles of housing favor greater exposure to indoor allergens, initial attention focused on increased exposure to these allergens in infancy and early childhood as a primary cause of the rise in asthma. Specific allergens of interest have included house dust mite, dog and cat dander, and cockroach allergen, especially in the inner city. These and other observations strongly support the conclusion that allergen controls should be valuable in the treatment or prevention of asthma. However, even after more than 50 individual studies of allergen control, the conclusions drawn from those studies via meta-analyses and expert review have been at odds and hotly debated.
“Hygiene Hypothesis.”
One compelling hypothesis for the cause of the increase in asthma and allergies in Westernized countries is the “hygiene hypothesis.” This holds that the rise in allergies in children is an unintended consequence of the success of domestic hygiene in reducing the rate of infections or exposure to bacterial products in early childhood. This hypothesis was put forward to explain the inverse relationship between hay fever and family size. The hypothesis was cited later when children raised in West Germany were found to have significantly higher rates of asthma and hay fever than did those raised in communist East Germany despite its more severe pollution from heavy industrialization and coal burning. In these studies, children who lived on farms had a lower prevalence of hay fever and asthma than their peers who did not live in an agricultural environment. The reduction in risk was stronger for children whose families were running the farm on a full-time basis, and stronger yet if the farm included livestock. Factors related to environmental influences, such as increased exposure to bacterial compounds in stables, may prevent the development of allergic disorders in children. Continual long-term exposure to stables until age 5 was associated with very low rates of asthma (0.8%), hay fever (0.8%), and atopic sensitization (8.2%). Follow-up studies of the protective effects of farm life have yielded fascinating findings. One study showed that endotoxin levels in samples of dust from the children’s homes, regarded as a marker of environmental exposure to microbial products, were inversely related to the presence of hay fever, atopic asthma, and atopic sensitization. Another study employing two cohorts found that children who lived on farms had lower prevalences of asthma and atopy and were exposed to a greater variety of environmental microorganisms than the children in the reference groups and that the diversity of microbial exposure was inversely related to the risk of asthma.
Human Microbiome
One potential link between changes in hygiene and allergic disease is the effect that “improved” hygiene may have on our indigenous microbiota and the role this microbiota may play in shaping our immune system. The biologic model most commonly cited to explain this association is that early-life exposure to factors that promote Th1 immunity are necessary to blunt exuberant type 2 T helper (Th2) immunity. Animal studies provide some support for this model. However, the results of human trials designed to treat or prevent asthma and allergy through “probiotic” live bacteria administration have thus far been mixed. Thus additional studies will be required to determine whether clinically relevant interventions that leverage the proposed role of the human microbiome in shaping allergic responses can be fashioned.
Respiratory Viral Infections
In parallel with, and distinct from, the emergence of the “Hygiene Hypothesis,” there has been significant progress in documenting and understanding the role that viral respiratory tract infections play in the development of asthma. A population-based study reported that a history of bronchiolitis or croup in early childhood was a predictor of increased bronchial responsiveness and of atopy in later years. In a prospective, longitudinal study of children born to allergic parents, upper respiratory infections (URIs) were noted 1 to 2 months before the onset of allergic sensitization. Children who have lower respiratory tract infections (LRIs) caused by respiratory syncytial virus (RSV) are at a threefold to fourfold risk of subsequent wheezing during the early school years. Surprisingly, the presence of rhinovirus during wheezing episodes is an even stronger predictor of subsequent asthma. In some studies, the association between viral LRIs and subsequent asthma depends on concurrent atopic disease, suggesting that an interaction between atopic predisposition and LRI at an early developmental stage may be critically important.
One factor that complicates the relationship between early wheezing with LRIs and the risk of subsequent asthma is that longitudinal studies of the natural history of wheezing illnesses have identified inconsistent relationships between early wheezing phenotypes and the ultimate development of asthma. The natural history of asthma is discussed in more detail in the next section of this chapter, but, briefly, some children who have wheezing illnesses before age 3 continue to wheeze at age 6. However, not all children fit this “persistent-wheezer” pattern. Similarly, there are children who wheeze at age 6 who never had wheezing illnesses before age 3. Thus a propensity for wheezing can be transient and the causes may be different at different ages. For example, factors associated with wheezing before age 3 include small airway caliber and maternal smoking, whereas factors associated with wheezing after age 3 include elevated serum IgE and a maternal history of asthma. Furthermore, it is possible that viral LRIs do not induce asthma but rather unmask a predisposition to predominant Th2-like responses already present at the time of the infection and which manifest later as asthma. The recent availability of specific therapies for the treatment and prevention of RSV infection in early childhood may provide the tools for future studies to test whether viral LRIs actually cause persistent wheezing and asthma.
Atypical Bacterial Infections
Although typical bacterial infections are not thought to cause asthma, at least two bacterial causes of “atypical” pneumonia have been implicated in the development of chronic wheezing illnesses , Chlamydia pneumoniae and Mycoplasma pneumoniae . Both commonly infect the airway epithelium, can become chronic, and stimulate local inflammatory reactions. There is some polymerase chain reaction (PCR) evidence that M. pneumoniae or C. pneumoniae is more common in the airway of patients with chronic stable asthma compared with healthy controls and that their presence is associated with an increase in tissue mast cells. Other studies have found that these atypical infections are associated with asthma exacerbations. Both organisms are sensitive to macrolide antibiotics, and several studies have evaluated the utility of macrolides in patients with chronic asthma with variable results. A randomized trial of clarithromycin for the treatment of suboptimally controlled asthma showed no improvement in asthma control, whether or not M. pneumoniae or C. pneumoniae was detected by PCR in endobronchial biopsies. Another study showed that azithromycin did not reduce exacerbations overall in severe asthma, but a prespecified subgroup analysis showed improvement in the group with noneosinophilic asthma by sputum analysis. This result leaves open the question as to whether any beneficial effect of macrolides is mediated by antibacterial or anti-inflammatory activity of these drugs.
Air Pollution
Although it is widely accepted that air pollution can exacerbate preexisting asthma, it has been more difficult to demonstrate that air pollution can contribute to the development of asthma. In principle, exposure of the lung to air pollution could increase local oxidative stress, induce or modify local inflammation, enhance sensitization to allergens, impair lung development, or injure small airways. However, epidemiologic evidence for an association between ambient levels of air pollutants and prevalent or incident asthma has yielded mixed results. Nonetheless, several recent studies focused specifically on asthma incidence and prevalence by proximity to heavy automobile traffic and suggested that exposure to respirable particulate matter and NO 2 in this setting are both associated with the future development of asthma.
Other Early-Life Factors
Other early-life factors that influence the risk of asthma are exposures in utero, perinatally and in early childhood. Intrauterine risk factors include growth rates (both high and low), dietary vitamins D and E deficiency, exposure to microbial products, parental smoking, and parental stress. Perinatal risk factors associated with asthma include prematurity and chorioamnionitis. Finally, early childhood risk factors associated with asthma include a shorter period of breastfeeding, obesity, absence of older siblings or daycare attendance, bacterial colonization of the airways in early childhood, antibiotic use, and acetaminophen use.
Occupational Exposures
Finally, occupational exposures constitute an important risk factor for a specific subset of patients. Asthma induced by occupational exposures accounts for up to 17% of all adult-onset asthma. A full description of the occupational exposures that can cause asthma is beyond the scope of this chapter because the known exposures number in the hundreds. However, in general, occupational asthma can either result from immunologically mediated sensitization to occupational agents (i.e., sensitizer-induced occupational asthma) or from exposure to high concentrations of irritant compounds (i.e., irritant-induced occupational asthma) (see Chapter 72 ).
Natural History
The natural history of asthma is heterogeneous with different patients following different disease courses. In general, symptoms can begin at any age, although the type of asthma that predominates in those who have their onset in childhood, teen years, and adult years may differ. Over time, the symptoms of asthma can remit in any given patient, especially in childhood. Alternatively, the symptoms and the finding of airflow obstruction can persist or even worsen progressively in some patients. Other patients can be apparently well at most times but suffer from periodic worsening or exacerbations. From a population-based perspective, a relatively small but important subgroup of patients with asthma can suffer significant morbidity and some are at risk for dying from asthma.
Neonatal Period
A predisposition to asthma may begin as early as the neonatal period. The immunologic milieu at the fetal-maternal interface is skewed toward a Th2 phenotype, and this immune bias is carried into neonatal life. Unless the pattern of immune response in the airways is “re-programmed” toward a Th1 pattern, the infant may have a prolonged high-risk window for allergic sensitization to aeroallergens.
Childhood
Patterns of wheezing in early childhood have been intensively studied in longitudinal cohorts. The Tucson Children’s Respiratory Health Study found that 48% of children had at least one wheezing illness at some point in the first 6 years of life, 34% had at least one wheezing illness before age 3 (defined as early wheezing), and approximately half of these children continued to have at least one wheezing illness at age 6. In the remainder of children with wheezing episodes before age 3, these episodes were transient and resolved before age 6. Finally, approximately 15% of children presented with late-onset wheezing, defined as wheezing illnesses with onset at age 6. As described earlier, most of the early wheezing illnesses (before age 3) can be ascribed to viral respiratory infections such as RSV or rhinovirus and do not necessarily reflect atopy. In addition, transient early wheeze was associated with maternal smoking. However, wheezing at age 6, whether “persistent” or “late-onset,” was associated with atopy. Furthermore, children who had either “persistent” or “late-onset” wheezing at age 6 were more likely to go on to wheeze later in life and be diagnosed with asthma. The risk for persistence rather than remission after age 6 appears to be associated with severity of airflow obstruction and the degree of allergen sensitization. The British Avon Longitudinal Study of Parents and Children provided some additional detail to the categories of childhood wheezing illnesses by defining “intermediate-onset wheeze” (defined as onset of symptoms after 18 months) and “early prolonged wheeze” (defined as onset in the first year of life but remission at 69 months).
Atopic or Allergic March
The terms “atopic march” and “allergic march” are synonyms that refer to a characteristic pattern of atopic disease development during infancy and childhood. The most common pattern begins with atopic dermatitis or eczema in the first year of life, sometimes associated with food intolerance or food allergy, followed by rhinoconjunctivitis, and/or wheezing illnesses that are ultimately diagnosed as asthma. Thus the natural history of atopic disease, more generally, may follow a specific pattern of organ-specific development, which suggests a stereotyped set of underlying cellular and molecular mechanisms.
Teenage Years
After puberty, the demographics of patients with prevalent asthma switches from a male predominance to a female predominance, which suggests a change in the nature of incident cases of asthma. One straightforward inference would be that some incident cases of asthma in girls during teenage years relate specifically to hormonal factors. This is a compelling hypothesis and there are some data that provide clues to potential mechanisms, but specific hypotheses are difficult to test and establish in clinical studies. Nonetheless, these observations invite speculation that the onset of asthma in specific phases of life may reflect different underlying biologic underpinning or different endotypes of asthma.
Remission
Long-term follow-up of a population-based birth cohort of more than 1000 children born in Dunedin, New Zealand over a 12-month period in 1972-1973 who were evaluated annually to age 26 has provided a clear picture of the natural history of the disease. Just over half the children (51%) reported wheezing at more than one assessment, confirming the high prevalence of asthma in New Zealand. Wheezing persisted until adulthood in 15%, whereas wheezing appeared and remitted in 27%. This remission was often unsustained, however, for wheezing recurred by age 26 in nearly half of those in whom it had remitted. This finding echoes the findings of 15 earlier studies of the natural history of asthma, showing that about 50% of adults who recall having childhood asthma continue to have symptoms. Risk factors associated with greater likelihood of persistence of asthma into adulthood include sensitization to house dust mites, lower FEV 1 , airway hyperresponsiveness, female gender, and smoking at the age of 21 years. Whether “spontaneous remission” truly reflects disappearance of the eosinophilic, lymphocytic bronchial inflammation of asthma has been questioned. Even in patients with complete absence of symptoms while taking no asthma medications for at least 12 months, the fraction of nitric oxide in exhaled gas is elevated, airway responsiveness is increased, and bronchial biopsies show increases in eosinophils, T cells, mast cells, and increased subepithelial fibrosis.
Progressive Airflow Obstruction
Longitudinal studies have shown that people with asthma have greater rates of decline in pulmonary function than healthy nonsmokers, and asthmatic smokers have greater rates of decline than healthy smokers. Furthermore, many nonsmoking asthmatics have severe, irreversible airflow obstruction. The progressive narrowing of the airways in chronic asthma is hypothesized to result from the deposition of collagen and growth of vessels, smooth muscle, secretory cells, and glands, presumably mediated by the products of inflammatory cells activated in the airways. Nonetheless, it is not possible to prove that this “airway remodeling” is the cause of progressive airflow obstruction in asthma.
Adulthood
Because many adults with chronic asthma had the onset of symptoms during childhood, understanding the biologic events underlying the development and the prevention of asthma during childhood will likely make a significant impact on the prevalence of asthma in adults as well. However, even though many adults with asthma had asthma during childhood, adult asthma is particularly heterogeneous. The female predominance in asthma prevalence that first appears in teenage years continues in adult asthma, suggesting that a significant proportion of adults with asthma share the common underlying factors of teenage-onset asthma. Finally, asthma symptoms can begin de novo in an adult. Some of these patients have clear-cut atopy, but others have more predominantly nonatopic features. In some instances, the onset of wheezing is attributed to a specific acute respiratory illness that became persistent. In others, it is possible that atopy and wheezing illnesses as a child were modest and subclinical.
Asthma in the Elderly
If asthma is present in an adult, it will often remain as that adult ages. Surprisingly, new-onset asthma can also arise in the elderly. One retrospective cohort study of residents of Rochester, Minnesota reported that the incidence of new-onset asthma after age 65 was 95/100,000. In this age group, misdiagnosis of asthma (often as COPD) and undertreatment appear to be common. Furthermore, elderly patients with asthma are more likely than younger patients to have fixed airway obstruction. Mortality rates from asthma appear to be higher in the elderly because NHIS data from 2001-2003 indicate that the age-adjusted rate of mortality was 10.5 per 100,000 among people older than 65. All other adult age groups had asthma-specific mortality rates less than 2.2 per 100,000. However, these NHIS data appear to contrast with those of the Rochester, Minnesota retrospective cohort study described earlier, which found no difference in mortality between elderly patients with asthma and similarly aged historical control subjects. The term “intrinsic asthma,” often used to describe nonatopic reversible bronchoconstriction, has traditionally been associated with asthma in the elderly, and more than 60% of elderly patients in one study reported the first onset of asthma symptoms following a URI. However, at least one study has shown positive skin reactivity to one or more common allergens in almost two thirds of elderly asthmatic patients.
Molecular and Cellular Basis of Asthma
Type 2 immune responses in the lower airway are the central immunologic abnormality in asthma. Type 1 and type 2 immune responses differ in how they are induced and by the types of effector cells and molecules they employ. For example, type 1 immune responses are mounted against intracellular bacteria, viruses, and protozoa and are mediated by Th1 CD4 + cells, cytotoxic CD8 + T cells, and IgG antibodies. Type 1 responses can also be inappropriately mounted against self-antigens, and this is one mechanism of autoimmune disease. In contrast, type 2 immune responses usually arise in response to helminth and parasite infections and are mediated by Th2 CD4 + cells and IgE. Type 2 responses can also be inappropriately mounted against innocuous environmental antigens resulting in allergy. Th2 CD4 + cells are characterized by high expression of the transacting T-cell–specific transcription factor GATA-3 and by secretion of type 2 cytokines ( interleukin [IL]-4, IL-5, IL-9, and IL-13). An excess of type 2 cytokines in the lower airway will promote IgE-mediated hypersensitivity, activate epithelial cells, mediate inflammatory cell influx to the airway, and cause remodeling responses in the epithelium and subepithelial matrix. This cascade of inflammatory events downstream of type 2 cytokines explains much of the pathology underlying the key clinical features of asthma (airway hyperresponsiveness, airflow obstruction, and mucus secretion).
Initiation of Allergic Lower Airway Responses and Asthma
An accepted view now is that environmental stimuli in early childhood activate airway epithelial cells to initiate allergic airway responses and asthma in children who are susceptible because they have preexisting atopy, specific genetic risk factors, and other less well-understood vulnerabilities. How atopy and viral airway infections interact to initiate type 2 immune responses is incompletely understood. It has been postulated that communication between cells in the airway epithelium and cells in the underlying mesenchyme/submucosa is a fundamental mechanism of asthma. ( Fig. 41-4 ). Environmental stimuli that can activate epithelial cells include oxidants (cigarette smoke, car exhaust pollutants), aeroallergens, and microbial infections, especially viruses. Airway epithelial cells express multiple pattern recognition receptors to detect and respond to danger signals, such as pathogen-associated molecular patterns (“PAMPs”) on microbes or damage-associated molecular patterns (“DAMPs”) released by endogenous cells during periods of inflammation or cellular stress. Other pattern recognition receptors on airway epithelial cells include Toll-like receptors (TLRs) and receptors for alarmins, such as uric acid and adenosine triphosphate, which are endogenous molecules that signal damage. Activation of pattern recognition receptors on airway epithelial cells can trigger release of a variety of cytokines, chemokines, antimicrobial peptides, lipid mediators, nitric oxide, and reactive oxygen species. These inflammatory mediators have multiple consequences, including recruitment of circulating leukocytes to the airway, regulation of airway tone, regulation of airway secretions, and promotion of antimicrobial and antiviral activity. The release of epithelial cytokines, particularly IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), appears to be the key upstream event that initiates type 2 immune responses and the allergic inflammatory environment in asthma. Specifically, IL-25, IL-33, and TSLP released from epithelial cells by allergenic stimuli target resident hematopoietic cells to induce the influx of inflammatory cells and the activation and mobilization of dendritic cells. Dendritic cells are specialized immune cells that use the class 2 major histocompatibility complex (MHC) system to mediate T helper cell responses to foreign proteins such as aeroallergens. Dendritic cells are required for the differentiation of naive T cells into T helper subsets including Th2 cells. Immature dendritic cells from the bone marrow home to the airway under the influence of epithelial cell signals. Once in the airway mucosa, dendritic cell projections interdigitate between epithelial cells and form tight junctions with them, maintaining the integrity of the epithelial barrier. In this location, dendritic cells sample inhaled antigens, process them to linear peptides, and present them on their cell surface as part of the class II MHC heterodimer complex. Epithelial cytokines, especially TSLP, promote mobilization of dendritic cells to local draining lymph nodes, where they activate naive CD4 + T cells to an IL-4–competent state. These IL-4–competent T cells in lymph nodes migrate to B-cell zones, where they differentiate into T follicular helper (T FH ) cells. In addition, they move to the circulation to complete maturation as Th2 cells (see Fig. 41-4 ). Whereas IL-4–secreting developing T FH cells in parafollicular B-cell areas and germinal centers mediate IgE switching in B cells, Th2 cells that migrate to the airway epithelium and the subepithelial mucosa secrete IL-5 and IL-13 to mediate the characteristic pathologic features of asthma, including eosinophilic inflammation and remodeling changes in the epithelium and submucosa.
The aeroallergens of relevance to asthma such as pollens, house dust mite proteins, and proteins from furred animals are considered innocuous and should induce immune tolerance when inhaled. The breach in tolerance that takes place in asthmatic airways is incompletely understood. Some aeroallergens have physical properties that allow them to be aerosolized and reach conducting airways. Some also have protease activity that equips them to penetrate airway mucus barriers. Still others have molecular mimicry properties that trigger innate pattern recognition receptors on airway epithelial cells and other antigen-presenting cells. For example, house dust mite allergens have a papain-like cysteine protease and a lipid-binding MD-2 molecular mimetic capable of augmenting TLR4 signaling, while many other allergens contain chitin, which induces a leukotriene-mediated infiltrate of eosinophils and basophils and drives alternative activation of macrophages.
Breach in tolerance may also involve cooperative pathologic behavior between epithelial cells and dendritic cells. In mouse models, dendritic cells do not always recognize inhaled allergens. Rather, activated epithelial cells use a pattern recognition molecule such as TLR4 to sample allergens such as house dust mite protein and then orchestrate dendritic cell responses (recruitment, activation, lymph node migration) that lead to sensitization. These findings provide a framework for how an environmental stimulus might direct epithelial and dendritic cell responses in the airway toward allergic responses. Normal tolerance in the airway may also be breached because T regulatory cell (Treg) function is compromised. Tregs may induce peripheral tolerance to allergens through direct interactions with dendritic cells or competition with naive T cells for growth and differentiation factors. Another possible mechanism is that Tregs characteristically secrete IL-10 and transforming growth factor (TGF)-β, cytokines that have multiple activities relevant to tolerance, including synthesis of noninflammatory IgG4 and IgA isotypes and regulatory effects on T cells and dendritic cells. Although specific evidence for Treg cell dysfunction in asthma is lacking, the central role of Treg cells in controlling immune responses is well recognized in human disease.
Viral infections are among the most important of the environmental stimuli that are implicated in asthma initiation. Airway epithelial cells are considered active sentinels and master coordinators of antiviral responses in the lung. Airway epithelial cells are primed to produce interferon (IFN) and express hundreds of IFN-stimulated genes (ISGs) in response to viral infection. STAT1 is a key regulator of ISG expression, and ISGs encode proteins that inhibit viral production directly or indirectly by activating immune cells and killing infected host cells. Because the functional level of antiviral responses correlates with the degree of host protection, it is possible that a deficiency of IFN makes some people susceptible to virus-initiated or virus-exacerbated asthma. Data from mouse models suggest that a deficiency of IFN signaling in airway epithelial cells compromises host defense against respiratory viruses, and data from these models and epidemiologic studies show that more severe viral infections are more likely to lead to asthma. Although some studies have shown a deficiency in IFN-β and IFN-λ production in response to rhinovirus infection in asthmatic airway epithelial cells, it is not yet established that a defect in IFN-dependent control of viral replication is a mechanism of asthma initiation or exacerbation.
Atopy, Asthma, and Other Allergic Diseases
Studies of the childhood origins of asthma reveal a sequence in which atopy arises first, followed by viral airway infections and then the onset of asthma. Atopic illnesses in childhood include allergic rhinitis, atopic dermatitis, eosinophilic esophagitis, and asthma. Many children only develop one of these atopic diseases, which raises the possibility that atopy represents one hit along a multihit continuum with different hits resulting in different atopic diseases. For example, atopy combined with filaggrin mutations may be required to cause atopic eczema. In this instance, filaggrin dysfunction may alter the skin epithelial barrier in ways that promote eczema. Atopy combined with mutations in TSLP may cause eosinophilic esophagitis. In this instance, TSLP dysfunction in esophageal epithelial cells may interact with T cells, basophils, or innate lymphoid cells to initiate eosinophilic esophageal disease. Whereas genetic studies clearly point to mutations in the filaggrin and TSLP genes as susceptibility factors for eczema and eosinophilic esophagitis, respectively, the genetic pointers in asthma are toward IL-33 and its receptor (ST2, suppression of tumorigenicity 2). Thus atopy may be the core pathologic abnormality in a variety of allergic diseases, but each of these atopic diseases may require an additional and specific genetic susceptibility to confer organ-specific risk of disease.
IL-33/ST2 Axis in Asthma
IL-33 is an epithelial cell cytokine that is considered a key mediator of type 2 immune responses in asthma. IL-33 is classified as a member of the IL-1 family of cytokines because it has an IL-1–type cytokine-signaling domain in its C terminal region. Unlike other members of the IL-1 cytokine family, IL-33 is active in its full-length form, although protease digestion of specific N terminal regions can increase its activity. IL-33 triggers biologic responses in effector cells by assembling a heterotrimeric signaling complex with two receptor chains that comprise a high-affinity primary receptor called IL1RL1 (better known as ST2) and a low-affinity coreceptor called IL-1RAcP. In the airway, IL-33 localizes mainly to the nuclei of epithelial basal cells, and this unusual cellular location reflects its dual roles. One role that depends on its nuclear localization is as a repressor of gene transcription; a second (better understood) role depends on its extracellular secretion and activity as a cytokine. The principal cytokine activity of IL-33 is to promote Th2 inflammation through release of Th2 cytokines by ST2-bearing cells. ST2 is expressed on a wide range of innate and adaptive immune cells, including CD4 + T cells, mast cells, basophils, and innate lymphoid type 2 (ILC2) cells. ILC2 cells are recently characterized lineage negative IL-25R + lymphoid cells. Although CD4 + T cells are the dominant source of Th2 cytokines in the airway, the ILC2 cell is increasingly recognized as a rare but potentially important cellular source.
The emphasis on IL-33 as a key epithelial cell mediator of type 2 immune responses in asthma stems from multiple genome-wide association studies (GWASs) that have consistently found associations between asthma and genetic polymorphisms at the IL-33 locus and the ST2 locus. The ST2 gene locus encodes the full-length ST2 receptor (ST2L) and the short soluble form of ST2 (sST2) that acts as a potent negative regulator of extracellular IL-33 activity. Interestingly, genetic polymorphisms in ST2 are associated with low levels of circulating sST2 and high numbers of peripheral blood eosinophils, so a relative deficiency in sST2 may be a mechanism of Th2-type inflammation. Thus the IL-33/ST2 axis in asthma is a complex signaling system in which regulation of IL-33, ST2L, and sST2 all contribute to net effects on type 2 immune responses in the airway. The genetic defects in IL-33 and ST2 identified in GWAS studies are presumed to result in net positive IL-33 activity. To date, the specific functional consequences of genetic mutations in IL-33 and ST2 are poorly understood, but additional mechanistic studies should clarify how these genetic abnormalities promote airway Th2 inflammation to cause asthma.
Mechanisms of Persistence of Asthma
As described earlier, the initiation of asthma involves the development of type 2 immune responses to inhaled allergen in young children who have a family and personal history of atopy and who frequently have a history of respiratory tract infection. The mechanisms of persistent type 2 immune responses in asthma are not well understood. One possibility is that aberrant immune programs become fixed because they are established during critical time windows in early life when the immune system is plastic. In this window, it may be that epithelial cells are particularly susceptible to epigenetic changes that lead to persistent changes in cell behavior. Epigenetic changes include DNA methylation or post-translational modification of the amino acid tails of histones by acetylation, phosphorylation, methylation, sumoylation, or ubiquitylation. Because epigenetic changes persist in dividing cells, they provide a mechanism by which environmental factors can cause stable alterations in phenotype without changes in genotype. Most epigenetic changes take place prenatally and shortly after birth, which would coincide with the specific time periods when individuals are most susceptible to environmental exposures that induce asthma. Although the epigenetic hypothesis is attractive, there is little direct evidence for it yet in asthma.
Inflammatory Mechanisms in Chronic Asthma
Current concepts hold that upstream events in the airway epithelium involving master regulators such as IL-33 result in increased activity of type 2 cytokines in the airway, secreted mainly by CD4 + T cells, and driving a cascade of downstream events, including IgE-mediated hypersensitivity, activation of airway epithelial cells, chemoattraction of effector cells (mast cells, eosinophils, and basophils), and remodeling of the epithelium and subepithelial matrix ( Fig. 41-5 ).
CD4 + T Cells
CD4 + T lymphocyte subsets are categorized on the basis of their cellular functions and capacity to secrete specific cytokines. CD4 + Th2 lymphocytes evolved to mediate type 2 immune responses to helminths and parasites, but they are also central to mechanisms of atopy and asthma. IL-4 is the most potent Th2 polarizing factor, and Th2 cells secrete IL-4, IL-5, IL-9, and IL-13. There is evidence in human asthma for an excess of CD4 + Th2 lymphocytes in the airway. Lavage fluid from asthmatic subjects has increased numbers of T cells expressing mRNA for IL-4 and IL-5 (but not IFN-γ). Subsequent studies have confirmed either an excess of Th2 lymphocytes or increases in Th2 cytokine transcripts, protein, or activity in the airway. CD4 + Th2 cells are not the sole source of Th2 cytokines because mast cells, basophils, and ILC2 cells also secrete these cytokines, but they do appear to be the dominant source in chronic established disease. CD4 + Th2 cells are CCR4 + and are responsive to CCL17 (also called thymus and activation-regulated chemokine, TARC), which is an epithelial cell-derived chemokine important for Th2 cell accumulation in the airway (see Fig. 41-5 ). CD4 + Th2 cells also display multiple other receptors, including CRTH2, ST2, TSLPR, and IL17BR, which means that they can also respond to PGD2, IL-33, TSLP, and IL-25, respectively. IL-5 from Th2 cells promotes tissue eosinophilia, whereas IL-9 promotes mast cell hyperplasia, and IL-13 causes epithelial cell activation, as described earlier.
IgE-Mediated Hypersensitivity
As described previously, the production of allergen-specific IgE requires that allergens are taken up by dendritic cells or other antigen-presenting cells, which, in the presence of IL-4, present the processed antigens to naive T cells to direct them toward a Th2 cell phenotype. IL-4 also induces isotype switching in B cells, resulting in IgE production. Notably, the IL-4–producing cells that interact with B cells in secondary lymphoid organs are T FH cells, and not Th2 cells. IgE has two IgE receptors—FcεRI and FcεRII. FcεRI is a high-affinity receptor found on mast cells and basophils. FcεRII (CD23) is a low-affinity receptor found on epithelial cells, B cells, and myeloid cells. Antigen-induced aggregation of IgE bound to FcεRI stimulates mast cells to release diverse biologically active products. Preformed products in cytoplasmic granules include histamine, serotonin, tryptase, chymase, carboxypeptidase A3, and proteoglycans (heparin and/or chondroitin sulfates). Other products are synthesized de novo and include lipid-derived mediators (PGD2, LTB4, LTC4, LTD4, and LTE4) and Th2 cytokines. Mediators are released within minutes of antigen exposure, and the aggregate response to mediators released shortly after antigen- and IgE-induced mast cell degranulation is called an immediate-hypersensitivity (“early-phase”) reaction. This reaction includes airway smooth muscle contraction, heightened bronchovascular permeability, and increases in mucin secretion. The physiologic consequence is a decrease in airflow but can include hypotension and anaphylaxis if the immediate hypersensitivity response is systemic. Although the inflammation and functional changes associated with early-phase responses resolve within 1 to 3 hours, a second (“late-phase”) reaction can develop in some asthmatics, typically beginning 2 to 6 hours after exposure and lasting for 24 to 48 hours. Late-phase responders are often studied in proof-of-concept studies of novel controller medications for asthma because a drug’s ability to inhibit late-phase responses to inhaled allergen is a good predictor of its efficacy in improving asthma control outcomes. For example, omalizumab is a recombinant humanized monoclonal antibody directed against IgE. In early proof of concept studies, omalizumab was shown to inhibit both early and late phase responses. In subsequent clinical trials it was shown to decrease exacerbation rates in asthmatics.
Activation of Airway Epithelial Cells
Unbiased studies of gene expression in airway epithelial cells show a gene profile consistent with IL-13 activation. Gene transcripts for IL-13 in the airway epithelium itself are sparse but are more easily detectable in submucosal tissue or in sputum cells. Thus the cellular source of the IL-13 is the cells in the submucosa or in the supramucosal mucus layer. These IL-13–producing cells comprise mainly CD4 + T cells, but ILC2 cells and mast cells likely contribute as well. IL-13 has many effects on airway epithelial cells. Genes upregulated include eotaxins (especially eotaxin-3, also called CCL26), CCL17 (TARC), and stem cell factor, which provide chemotactic or survival signals for eosinophils, CD4 + Th2 cells, and mast cells, respectively. Also upregulated are inducible nitric oxide synthase (iNOS), periostin, and some mucin genes. iNOS catalyzes the production of NO from l -arginine, and exhaled NO can therefore be used as a biomarker of IL-13 activation of the airway epithelium. Because iNOS is a steroid-sensitive gene, exhaled NO levels are typically low in asthmatic patients taking corticosteroid medications. Periostin is a secreted protein of the fascilin family that interacts with integrins, TGF-β, and matrix proteins to initiate a variety of biologic effects including cell proliferation and migration, Treg cell regulation, and modulation of the biomechanical properties of collagen. Although periostin gene expression is high in airway epithelial cells, periostin protein does not immunolocalize to airway epithelial cells, because it is rapidly secreted in a basal direction. This rapid secretion from epithelial cells explains why periostin immunolocalizes to the subepithelial matrix, where it is proposed to bind and stiffen collagen. In this location, periostin is also accessible to the systemic circulation via the subepithelial bronchial venous plexus. Periostin is therefore a useful blood-based biomarker of airway epithelial cell activation by IL-13. The biologic consequence of periostin upregulation in asthma is uncertain. Although in vitro studies show that periostin potently upregulates TGF-β in epithelial cells to induce epithelial mesenchymal transition (EMT), there is little evidence that EMT takes place in vivo in asthma. Mice deficient in periostin have exaggerated responses to inhaled allergen, suggesting that periostin has protective functions in the airway, perhaps through its regulation of TGF-β and Treg cell function. Multiple other proteins in the airway epithelium are dysregulated by IL-13, including mucin genes. An overarching principle, though, is that, although epithelial-derived cytokines such as IL-33 are important for initiating and perhaps perpetuating asthma, activation of epithelial cells by IL-13 is an important amplification mechanism in the pathophysiology of asthma (see Fig. 41-5 ).
Eosinophils
An increase in the number of eosinophils in the airway is a pathologic hallmark of asthma. Peripheral blood eosinophilia is frequent as well. Airway eosinophilia is associated with worse measures of lung function, including airway hyperresponsiveness. Drugs that suppress airway eosinophilia, including corticosteroids, anti-IgE, and anti-IL-5, are all consistently effective in reducing asthma exacerbation rates. Eosinophils are thought to alter lung function in asthma via the activity of potent cytoplasmic granule proteins and through their capacity to secrete cytokines. Eosinophil granule proteins include major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPX), and eosinophil-derived neurotoxin (EDN). MBP is cytotoxic against helminths and can disrupt the integrity of lipid bilayers in mammalian cells. It is also an antagonist of the airway M2 muscarinic receptors that normally provide negative feedback to limit neurotransmission and bronchoconstriction. ECP and EDN have ribonuclease activities that mediate neurotoxic effects, and both proteins have antiviral activity ; EPX is a peroxidase that generates reactive oxidants and radical species. The overall effects of eosinophil granule proteins could be to promote nerve-mediated bronchoconstriction and activate epithelial cells. The role of eosinophil cytokines, which include TGF-α and TGF-β, may be to mediate mechanisms of airway mucin secretion and fibrosis, respectively.
Mast Cells
Mast cells have long been known to be central effector cells in asthma with multiple studies showing increases in mast cells in the airway mucosa and in airway secretions. The importance of the mast cell has been emphasized again recently by data from microarray studies in asthma and better understanding of IL-33/ST2 biology. Specifically, microarray studies in airway epithelial brushings show that mast cell genes are among the most highly upregulated genes in asthma. Immunolocalization studies confirm increased numbers of epithelial mast cells in asthma, characterized by high expression of tryptase and carboxypeptidase A3 and low expression of chymase. Other studies have emphasized the immunolocalization of mast cells to the submucosal airway smooth muscle, where they may contribute to airway smooth muscle hyperplasia and hyperresponsiveness. Mast cells constitutively express multiple cell surface receptors, including FcεRI and ST2. Cross-linking of FcεRI by IgE-antigen complexes leads to mast cell degranulation and release of multiple preformed and newly generated mediators. These IgE-mediated degranulation events are well known. ST2-mediated mast cell activation is less well appreciated but probably also important in the pathogenesis of asthma. Specifically, IL-33 binds ST2 on mast cells to enhance mast cell survival and provide a stimulus for secretion of IL-6, IL-8, and IL-13. IL-33–mediated activation of mast cells may be of particular importance in the pathophysiology of asthma exacerbations when IL-33 is released from epithelial cells as an alarmin. Indeed, mast cells may be a cellular source of the high levels of IL-6 and IL-8 detectable in airway secretions in acute severe asthma.
Basophils
Basophils are circulating granulocytes that respond to allergic stimuli by migrating and accumulating at sites of allergic inflammation. They contain cytoplasmic granules with similar histamine levels per cell as mast cells. In contrast, the amount of tryptase in basophils is less than 1% of that in mast cells. Cross-linking of the FcεRI by IgE-antigen complexes causes basophil degranulation and mediator release, particularly of histamine. In addition, epithelial cell cytokines, including IL-33 and TSLP, bind to ST2 or TSLPR on basophils to cause cytokine secretion, particularly of IL-4. Recently, a role for basophils in type 2 immune responses is being explored. For example, in a mouse model of eosinophilic esophagitis, basophils are required for eosinophilic and Th2 cytokine responses. Similar information about a central role for basophils in asthma is currently lacking.
Macrophages
Macrophages are abundant in the lung and they adopt different phenotypes on the basis of signals they encounter. Exposure to IFN-γ, TNF-α, or lipopolysaccharide drives differentiation of macrophages to a classically activated (M1) phenotype. This phenotype has important roles in host defense against intracellular pathogens. Although M1 macrophages have been implicated in nonatopic asthma and in some subtypes of severe asthma, alternatively activated (M2) macrophages are more usually associated with asthma. Type 2 immune responses drive lung macrophages toward an M2 phenotype that is characterized by upregulated expression of mannose receptors and transglutaminase 2 in man and mice and by upregulated expression of arginase-1, chitinase-3–like protein-3 (also known as Ym1), and resistin-like molecule-α (also known as FIZZ1) in mice only. Markers expressed by M2 macrophages have been found in asthma in some studies but not in others. Overall, airway macrophages have capacity to secrete a wide array of inflammatory mediators, but their role in asthma pathogenesis remains uncertain.
Products of Arachidonic Acid Metabolism—Leukotrienes, Prostaglandins, and Lipoxins
The cysteinyl leukotrienes (cys-LTs) are peptide-conjugated arachidonic acid–derived inflammatory mediators that are generated by eosinophils, basophils, mast cells, macrophages, and myeloid dendritic cells. Cys-LTs are generated in the lipid bilayer of the cell membrane when arachidonic acid is oxidized by 5-lipoxygenase in successive enzymatic conversions to generate leukotriene C 4 (LTC 4 ), LTD 4 , and LTE 4 . Cys-LTs activate at least two receptors on smooth muscle cells to induce muscle contraction and on endothelial cells to increase vascular permeability. Medications targeting this pathway include zileuton (a 5-lipoxygenase inhibitor) and montelukast and zafirlukast (selective antagonists of cys-LT 1 receptor) and are effective in asthma, especially in patients with aspirin sensitivity and Samter triad (aspirin sensitivity, nasal polyps, and asthma). When these patients ingest cyclooxygenase-1 inhibitors, such as aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), arachidonic acid metabolism is diverted away from prostanoid metabolites of arachidonate and toward excessive generation of cys-LTs. Consequently, urinary LTE 4 levels are especially high in aspirin-sensitive patients.
Prostaglandins are generated by metabolism of arachidonic acid by prostaglandin synthase enzymes and cyclooxygenase. Prostaglandin D 2 (PGD 2 ) is the prostanoid most relevant to asthma pathogenesis. Mast cells are the most important cellular source of PGD 2 , but Th2 cells, dendritic cells, and airway epithelial cells also produce PGD 2 at relatively low levels. There is good evidence that PGD 2 participates in airway responses to inhaled allergen in asthmatics. Allergen challenge in asthmatic patients leads to rapid and large increases in PGD 2 in bronchoalveolar lavage fluid, and PGD 2 inhalation challenge causes bronchoconstriction and airway eosinophilia. PGD 2 exerts its biologic effects via three receptors—DP1/DP, TP, and CRTH2/DP2—that are expressed collectively on hematopoietic cells, dendritic cells, epithelial cells, goblet cells, endothelial cells, and platelets. Small molecule inhibitors of CRTH2 are currently in clinical trials as treatments for asthma, atopic dermatitis, and allergic rhinitis.
Lipoxins (LXs) are enzyme-derived products of arachidonic acid and ω-3 fatty acids, with putative but less well-established roles in asthma. They are counter-regulatory lipid mediators that inhibit inflammation and are rapidly inactivated. Anti-inflammatory actions include inhibition of granulocyte activation and locomotion, promotion of monocyte-derived macrophage phagocytosis of apoptotic granulocytes, blockade of T lymphocyte cytokine release, and epithelial proinflammatory cytokine and chemokine release. LXA 4 also prevents prostaglandin D 2 -stimulated release of IL-13 from ILC2s.
Nerves and Nerve Receptors in Asthma
The lungs are highly innervated and peptidergic, cholinergic, adrenergic, and other neurogenic mediators and their receptors may modulate airway tone and airway inflammation. Adrenergic receptor agonists and cholinergic receptor antagonists are mainstays of current bronchodilator therapy for asthma. The term “neurogenic inflammation” refers to the inflammatory responses caused by tachykinins that activate specific receptors as part of the nonadrenergic noncholinergic (NANC) system. Excitatory NANC effects are mediated by release of tachykinins such as neurokinin A and substance P acting on NK 1 and NK 2 receptors. In general, NK 1 receptors mediate gland secretion, plasma extravasation, vasodilation, and leukocyte adhesion, whereas NK 2 receptors mediate contractions of airway smooth muscle. Inhibitory NANC effects are thought to be mediated principally by vasoactive intestinal peptide and nitric oxide. Evidence for the NANC system in asthma comes from studies showing that asthmatic subjects develop bronchoconstriction after inhaling neurokinin A or substance P. Although an NK 1 /NK 2 receptor antagonist protected against bradykinin-induced bronchoconstriction in asthmatic subjects, a selective NK 1 receptor antagonist did not protect against hypertonic saline-induced cough or bronchoconstriction.
Parasympathetic nerves innervate airway smooth muscle, and hyperresponsiveness of airway smooth muscle is a central pathophysiologic feature of asthma. However, this hyperresponsiveness is not due to increased responsiveness to muscarinic signaling in smooth muscle cells because airway smooth muscle isolated from asthmatics does not show increased sensitivity to muscarinic agonists. Parasympathetic nerves also innervate submucosal glands and regulate mucin secretion from submucosal gland cells. Notably, inflammatory cells in the airway all express muscarinic receptors, so these cells may be under parasympathetic nerve control. Relevant here is the fact that nerves produce and release inflammatory mediators and can contribute to the recruitment and activation of leukocytes. These leukocytes can then alter production and release of neurotransmitters from nerves. In this way, cross talk between airway nerves and leukocytes may help maintain chronic inflammation in asthma. All of this suggests that anticholinergic treatment should benefit patients with asthma and not just because of bronchodilator effects. Indeed, it is known that vagotomy decreases inflammation in the lungs of asthmatic patients and that treating patients with uncontrolled asthma with a long-acting anticholinergic drug (tiotropium bromide) improves asthma control.
Non–Type 2 Immune Responses in Asthma
So far this chapter has emphasized type 2 immune responses in asthma, and type 2 responses are indeed the immune responses typical of many patients with asthma. However, appreciation of the heterogeneous nature of asthma at both clinical and molecular levels is driving new research to uncover the disease mechanisms that operate in “Th2-low” subsets of asthma. For now, relatively little is known about the mechanisms of disease in these subsets of patients, but there has been interest in exploring whether some asthma subsets are driven by type 1 immune responses or by IL-17–mediated inflammatory mechanisms. The possibility that there is a subtype of asthma that is mediated by IL-17 inflammation (characterized by neutrophilia) has been of particular interest.
IL-17 in Asthma
The IL-17 cytokine family has members designated as IL-17A through IL-17F. CD4 + T cells that produce IL-17 are a distinct lineage (Th17 cells), but multiple other immune cell types also produce IL-17, including invariant natural killer T cells, CD8 + T cells, lymphoid tissue inducer (LTi)–like cells, and gamma delta T (γδT) cells. Possible pathogenic roles for IL-17 cytokines in the asthmatic airway include mediation of airway hyperresponsiveness and airway neutrophilia. Although data from mouse models show that IL-17A produced by Th17 cells contributes to allergen-induced airway hyperresponsiveness through direct effects on airway smooth muscle, there is only limited evidence of this mechanism in human asthma. Similarly, the evidence linking IL-17 to airway neutrophilia in asthma is limited. Ongoing clinical trials of IL-17 inhibitors in asthma should soon clarify the importance of IL-17 family members as cytokine mediators of asthma.
Neutrophils in Asthma
Neutrophils are abundant in airway secretions in both healthy and asthmatic subjects. Airway neutrophils are not elevated in mild or moderate asthma but are characteristically elevated in more severe asthma and asthma exacerbations. In addition, neutrophil numbers correlate inversely with measures of airflow in asthma. Whether this neutrophil association with low airflow is causal is not known, because specific neutrophil-directed treatments have not been used in asthma. Possible mechanisms by which neutrophils could lower lung function in asthma include neutrophil-mediated oxidative stress, neutrophil protease-mediated activation of airway epithelial cells, or neutrophil protease-mediated goblet cell degranulation. The proteases secreted by neutrophils include neutrophil elastase, cathepsin G, and matrix metalloproteinase, especially MMP9. Neutrophils may not always have a pathogenic role in asthma. For example, neutrophil numbers may increase markedly in the airways in acute severe asthma, where they may have a beneficial role. Specifically, it is postulated that neutrophil elastase may digest mucin polymers to promote mucus turnover, an important recovery step in acute asthma.
Airway and Gut Microbiome in Asthma
Multiple factors have increased interest in the airway and gut microbiome as drivers of altered immune responses in asthma. First, there are data in mouse models indicating that the intestinal microbiome is a key regulator of immune cell function in early life and data from children show that Bacteroides fragilis colonization at age 3 weeks is associated with increased risk of asthma. Second, there are epidemiologic data that children raised on farms have lower prevalence of asthma, an association thought likely to relate to farm-related microbial exposures that influence the host microbiome. And, third, analysis of the microbiome of airway secretions from asthmatics and controls shows that upper airway colonization in infants by Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis predicts later development of asthma. In addition, sequencing- and microarray-based analyses of lower airway biospecimens from asthmatics show abnormalities in the composition of bacterial microbiota, especially Proteobacteria (which include H. influenzae, Pseudomonas, Neisseria, Burkholderia species, and Enterobacteriaceae species. Notably, Proteobacterial species promote neutrophilic inflammation, and there is now great interest in whether specific microbial pathogens drive specific subtypes of asthma (such as neutrophilic asthma). Studies of the airway and gut microbiome in asthma are currently in their infancy, however, and ongoing research should reveal whether treatment with microbes can prevent asthma in some cases or if suppression of specific microbial species can improve asthma in established disease.
Mechanisms of Asthma Exacerbation
Asthma exacerbations represent acute-on-chronic worsening of airflow obstruction that is a consequence of worsening airway smooth muscle contraction, airway wall edema, and luminal obstruction with mucus. The mucus pathology is especially problematic in fatal and near fatal asthma (see later). Common upper respiratory tract viruses, especially rhinoviruses, are the most common and important cause of exacerbations in both children and adults. Susceptibility to acute reductions in airflow in asthmatics relates to airway mucosal remodeling. Changes in the epithelium to increase mucin stores, in airway smooth muscle to render it more hyperreactive, and in blood vessels to make them leakier render many asthmatics vulnerable to exaggerated airway responses to inhaled environmental insults, such as viruses, allergens, or pollutants. Asthmatic airways are hyperreactive in more ways than one—concentric smooth muscle contraction from hyperresponsiveness is one element, but mucosal edema from vascular permeability and excess mucus from mucin hypersecretion are others. The efficacy of corticosteroids in preventing exacerbations likely relates to their effects in not only reducing inflammatory cell numbers (especially eosinophils) but also improving pathologic changes in goblet cells, smooth muscle cells, and blood vessels.
Pathologic Changes in the Airway in Asthma
Asthma is characterized by structural changes in both the epithelium and the submucosa. These changes include abnormal deposition of collagen in the subepithelium (subepithelial fibrosis) and changes in structural cells such as goblet cells, submucosal gland cells, smooth muscle cells, and blood vessel cells ( Fig. 41-6 ).
