Asthma: Epidemiology, Pathophysiology, and Risk Factors

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Chapter 38 Asthma

Epidemiology, Pathophysiology, and Risk Factors

Borja G. Cosio, Jaime Rodríguez Rosado, Federico Fiorentino Rossi

Asthma has been described throughout time, beginning with ancient Egyptians. The Georg Ebers Papyrus, found in Egypt in the 1870s, contains prescriptions written in hieroglyphics for more than 700 treatments for the disorder. The inhalation of fumes extracted from the heating of herbs in bricks was one of the remedies available. The term asthma comes from the Greek word aazein, meaning “to pant, or breathe with the mouth open.” Between the 1930s and 1950s, asthma was considered to be a psychosomatic illness. During the 1960s, the emergence of the inflammation theory refuted a psychological origin and proved that asthma is a physical disease. Nonetheless, an association between psychological conditions (e.g., anxiety, depression) and difficult-to-treat asthma has been recognized since that time.

Nowadays, asthma is defined as a chronic inflammatory process characterized by reversible and variable airflow obstruction due to bronchial responsiveness secondary to multiple external stimuli in which genetic factors interact with environmental factors. The Global Initiative for Asthma (GINA) gives an operational description of asthma, as follows:

. . . a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated with airway hyperresponsiveness that leads to 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 within the lung that is often reversible either spontaneously or with treatment.

At present, much research is directed at elucidation of the underlying causes of asthma, which remain unknown. The risk for development of asthma is supported by evidence for a mixture of genetic, environmental, and lifestyle factors. Asthma does not respect age or gender, affecting both children and adults from kindergarten and school through work to retirement. For the moment, there is no cure for this condition, so preventive strategies are being effectively applied at the community level to prevent onset of the condition and to control worsening of asthma symptoms in the future. Nevertheless, some of these approaches have failed to reach the entire spectrum of the community population, for various reasons, such as limited access to information, personal beliefs, religious practices, and ethnicity within emigrational cohorts. Moreover, clinical practice guidelines and their distribution are basic for acute asthma diagnosis, treatment, and control.

Epidemiology

The World Health Organization (WHO) estimates that 300 million people have asthma worldwide, producing significant morbidity and interfering with daily activities and quality of life. During the year 2009, 250,000 people died from this condition in low- to middle-income countries. Furthermore, asthma is the most frequent chronic respiratory condition among children worldwide, and its prevalence is increasing. The Centers for Disease Control and Prevention (CDC) has estimated a significant rise in asthmatic patients of 12.3% since 2001 in the United States. Statistical figures for 2009 show that 24.6 million people had asthma, compared with 20.3 million at the beginning of the decade. This increase has come with a cost to society of $56 billion dollars in medical expenses and lost productivity. No clear explanation for this increased prevalence, however, has emerged, especially in view of the overall reduction in smoking and in second-hand smoke exposure with the implementation of laws banning smoking. The same situation is described outside the United States. From a metaanalysis of data obtained through routine statistics and population surveys, Anderson and co-workers concluded that asthma prevalence increased in the United Kingdom from 1955 to 2004.

Despite a large number of research studies, the reasons for why some people develop asthma and others do not and why asthma has emerged as a public health problem in some populations earlier than in others are not well understand. The main problem in focusing on the epidemiology of asthma is to address a proper operational definition in an attempt to unify the large conclusions of many epidemiologic studies from different areas of the world. The need to derive a practical and tangible definition of asthma for use in large-scale questionnaire-based epidemiologic research has led to a focus on asthma symptoms and their highly subjective expressions as part of the results. In questionnaire surveys, the presence of asthma often is defined on the basis of responses to questions about symptoms of wheeze in the past weeks or months, “wheeze ever,” and doctor-diagnosed asthma. This approach has been shown to have good short-term repeatability but may lack specificity, particularly in children, because other causes of wheezing illness, such as viral infection, may be misdiagnosed as asthma. With a focus on symptoms, the most common clinical presentation is one of breathlessness, wheezing, chest tightness, and cough, especially at night, coexisting with asymptomatic periods. Because of the nonspecificity and variability inherent in personal perception of respiratory difficulty, implementation of vital patient educational programs and pharmacologic treatment of asthma symptoms may be delayed. Clinical symptoms vary from one person to another, so a severe asthma exacerbation that necessitates urgent medical attention may not be recognized at first, and consequent delay in getting required treatment may lead to a poorer outcome.

Reported prevalence rates for asthma are widely variable. Despite the difficulty in obtaining a consensus on epidemiologic data, several studies have shown that asthma prevalence is increasing worldwide, with at least 7% to 10% of the population affected. Inclusion of data obtained using nonstandardized methods (questionnaires versus definition agreement) in a majority of the epidemiologic studies to determine asthma prevalence underlies the notable differences in global rates published in contemporary literature. This particular finding has no significance for geographic distribution of asthma, rates for which remain very low in many rural villages, in contrast with data reported for Western populations. Pollution in industrialized civilizations acts like a silent predator on the susceptible airway, leading to asthma in persons with certain respiratory diseases. A “hygiene hypothesis” has been proposed to explain an increased risk in children for the development of asthma that may reflect reduced microbe exposure in early life.

In a morbidity and mortality report from the CDC for the period 2006 to 2008, asthma prevalence was estimated as 7.8% for the U.S. population (Table 38-1). Current asthma prevalence was higher among the multiracial (14.8%), Puerto Rican Hispanics (14.2%), and non-Hispanic blacks (9.5%) than among non-Hispanic whites (7.8%). Current asthma prevalence also was higher among children (9.3%) than among adults (7.3%), among females (8.6%) than among males (6.9%), and among the poor (11.2%) than among the near-poor (8.4%) and nonpoor (7.0%).

Table 38-1 Prevalence of Current Asthma Among Children and Adults by Sex, Race/Ethnicity, and Economic Status–Poverty Level*

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With respect to the worldwide variability in reported prevalence rates for asthma, different studies have examined the impact on asthma care in two of the most ethnically diverse nations, such as the United Kingdom and the United States. Emigrational cohorts of Mexican Hispanics have demonstrated a lower rate of asthma than that in U.S.-born Hispanics. Moreover, in a comparison of U.K.-born persons of the same ethnic group with those already settled after emigration, the second group demonstrated a lower rate of physician visits for asthmatic symptoms. Nevertheless, Westernization does not explain this variance, and the inequalities also may be influenced by differences in genetics, environmental risk factors, and social activities.

One of the main objectives of the European Community Respiratory Health Survey (ECRHS) was to estimate the variation in prevalence of asthma, asthma-like symptoms, atopic sensitization, and bronchial hyperreactivity, predominantly in Western Europe and many other countries (Figure 38-1). The highest rates in Europe were in the United Kingdom (15.2%), and the lowest were in Georgia (0.28%). Another important ongoing multicenter study, the International Study of Asthma and Allergies in Children (ISAAC), had as its main aim to determine the asthma prevalence in children. A comparative survey conducted in Canadian children between 2 and 7 years of age showed an asthma prevalence of 9.8% overall, with a 4.6% higher rate in boys than in girls (Figure 38-2). GINA embraced the results of both of these valuable studies in the Global Burden of Asthma report and estimated that by 2025, 400 million people around the world will have a diagnosis of asthma. In the same way, this increase in prevalence is directly related to the augmented rates of rhinitis, eczema, and other atopic disorders.

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Figure 38-1 Prevalence of asthma in Europe.

(Courtesy European Community Respiratory Health Survey I Centers. Available at: http://www.ecrhs.org/ECRHS%20I.htm.)

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Figure 38-2 Annual changes in worldwide prevalence of asthma symptoms among children 6 to 7 years of age and those 13 to 14 years of age, over a mean of 7 years after phase I of the International Study of Asthma and Allergies in Childhood (which in most participating countries was conducted between 1991 and 1993). Blue triangles, locations where prevalence was reduced by at least 1 standard error (SE) per year; green squares, locations where there was little change in prevalence (i.e., change of less than 1 SE per year); red triangles, locations where prevalence increased by at least 1 SE per year.

(From Subbarao P, Mandhane PJ, Sears MR: Asthma: epidemiology, etiology and risk factors, CMAJ 181:E181–E190, 2009.)

In relation to mortality, asthma accounts for an estimated 250,000 annual deaths worldwide. Statistical data show large differences between countries, and asthma death rates do not parallel prevalence rates (Figure 38-3). Mortality seems to be high in countries where access to essential drugs is low. According to the WHO, many asthma-related deaths are preventable, being a result of suboptimal long-term medical care and delay in obtaining help during the final, fatal attack. In many areas of the world, people with asthma do not have access to basic asthma medications and health care. Nations with the highest death rates are those in which controller medications are not available. In many countries, deaths due to asthma have declined recently as a result of better asthma management. Considerable evidence points to an overall trend of decreasing mortality. For instance, mortality rates in Australia registered by the Australian Institute of Health and Welfare decreased by approximately 70% between 1989 and 2006. Persons older than 65 years of age and people of lower socioeconomic status were at higher risk for dying from asthma, mainly secondary to respiratory infections during winter. Overall, asthma-related mortality in Australia remains uncommon, accounting for 402 (0.30%) in the year 2006 of all deaths (Australian Centre for Asthma Monitoring: Asthma in Australia 2008, AIHW Asthma Series no. 3, Cat. no. ACM 14, Canberra, Australian Institute of Health and Welfare, 2008) (Figure 38-4).

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Figure 38-3 World map of asthma case-fatality rates: asthma deaths per 100,000 people with asthma in the 5- to 34-year-old age group.

(From Masoli M, Fabian D, Holt S, Beasley R; Global Initiative for Asthma [GINA] Program: The global burden of asthma: executive summary of the GINA Dissemination Committee Report, Allergy 59:469–478, 2004.)

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Figure 38-4 Changes in prevalence of diagnosed asthma (A) and asthma symptoms (B) over time among children and young adults.

(From Eder W, Ege MJ, von Mutius E: The asthma epidemic, N Engl J Med 355:2226–2235, 2006.)

It is worth emphasizing that many of the deaths secondary to asthma are preventable, and that the high economic costs attributable to this disease can be diminished. The elevated prevalence and mortality rates are associated with not inconsideable consumption of health-related resources, placing an additional economic load on health care services.

Pathogenesis

Asthma is an inflammatory disorder of the airways in which multiple mediators and several types of inflammatory cells are involved. This pattern of inflammation is strongly associated with airway hyperresponsiveness and classic asthma symptoms of wheezing, breathlessness, chest tightness, and coughing.

A genetic predisposition to develop specific immunoglobulin E (IgE) antibodies directed against common environmental allergens, or atopy, is the strongest identifiable risk factor for the development of asthma. Intrinsic abnormalities in airway smooth muscle and airway remodeling in response to injury and inflammation add to the effects of airway inflammation in creating the clinical presentation of asthma (Figure 38-5).

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Figure 38-5 Natural history of asthma.

(From Szefler SJ: The natural history of asthma and early intervention, J Allergy Clin Immunol 109:S550, 2002. Adapted from Holgate ST: The cellular and mediator basis of asthma in relation to natural history, Lancet 350[Suppl 2]:5–9, 1997.)

Airway Inflammation in Asthma

Despite the highly heterogeneous clinical expression of asthma, the presence of airway inflammation remains a consistent feature. Although airway inflammation in asthma is persistent even though symptoms are episodic, no clear relationship between the severity of asthma and the intensity of inflammation has been discovered. The inflammation affects all airways, including in most patients the upper respiratory tract and nose, but its pathophysiologic effects are most pronounced in medium-sized bronchi. The pattern of inflammation in the airways appears to be essentially the same in all clinical forms of asthma, whether allergic, nonallergic, or aspirin-induced, and at all ages.

Inflammatory Cells

Studies using bronchoalveolar lavage and bronchial biopsies have demonstrated that a variety of cells and mediators are involved, with IgE and mast cells implicated in the acute response and eosinophils and eosinophil granule proteins in the late response, with T cells, particularly TH2 cells, orchestrating these responses through their production of cytokines such as the interleukins IL-4, IL-5, IL-9, and IL-13. Stromal and epithelial cells also are involved in the inflammatory response, as shown by the ability of these cells to respond to TH2 cytokines with the production of chemokines that initiate and perpetuate tissue inflammatory reactions. As a result, a pathogenetic construct for atopic asthma (and possibly other forms of asthma) has been proposed in which (1) TH2 cells play a central role in the recognition of antigens and the initiation and perpetuation of inflammation; (2) eosinophils are important proinflammatory and epithelium-damaging cells; and (3) a variety of cells, including mast cells, epithelial cells, basophils, fibroblasts, smooth muscle cells, and macrophages, contribute through the secretion of cytokines that generate tissue inflammation or influence TH2 lymphocyte or eosinophil function.

Implicit in the “inflammation theory” of asthma is the belief that inflammation is both necessary and sufficient to account for the complex features of asthma. Although inflammation is undoubtedly a cornerstone of asthma, it is now clear that the asthmatic response is more complex. Also clear from pathologic investigations is that structural alterations exist in the asthmatic airway. Mathematical modeling studies have provided evidence that these alterations contribute to the symptoms and physiologic dysregulation seen in asthma. As a result, it has been proposed that the chronic inflammation that is characteristic of the asthmatic airway leads to a remodeling response, and that the structural alterations induced by this response play an important role in generating the manifestations of the disorder. This conceptual evolution predicts that an enhanced understanding of asthma pathogenesis can be expected when asthma is studied in the context of paradigms of injury and wound healing, as well as the traditional paradigms relevant to the interface of inflammation and airway physiology. It also suggests that studies utilizing this new perspective will identify novel targets against which therapies can be directed and will help to elucidate the biologic basis for the patient-to-patient variability encountered in clinical practice.

Inflammatory Mediators

More than 100 different mediators are now recognized to be involved in asthma and to mediate the complex inflammatory response in the airways. Chemokines are expressed mainly in airway epithelial cells and are important in the recruitment of inflammatory cells into the airways. Eotaxin is relatively selective for eosinophils, whereas macrophage-derived chemokines (MDCs) recruit TH2 cells.

Cytokines such as IL-1β and TNF-α, which amplify the inflammatory response, and granulocyte-macrophage colony-stimulating factor (GM-CSF), which prolongs eosinophil survival in the airways, orchestrate the inflammatory response in asthma and determine its severity. TH2-derived cytokines include IL-5, which is required for eosinophil differentiation and survival; IL-4, which is important for TH2 cell differentiation; and IL-13, needed for IgE formation.

Cysteinyl leukotrienes are potent bronchoconstrictors that act as proinflammatory mediators mainly derived from mast cells and eosinophils. Their inhibition has been associated with an improvement in lung function and asthma symptoms.

The prostaglandin PGD2 is a bronchoconstrictor derived predominantly from mast cells and is involved in TH2 cell recruitment to the airways.

Histamine is released from mast cells and contributes to bronchoconstriction and to the inflammatory response.

Nitric oxide (NO) has been associated with the presence of eosinophilic inflammation in asthma. It is produced predominantly from the action of inducible nitric oxide synthase (iNOS) in airway epithelial cells. Exhaled NO concentration is increasingly being used to diagnose asthma in the context of a compatible clinical history and to monitor the effectiveness of asthma treatment.

Pathophysiology

Airway narrowing is the final common pathway leading to symptoms and physiologic changes in asthma. As discussed next, several factors contribute to the development of airway narrowing in asthma (Figure 38-6).

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Figure 38-6 Pathobiology of asthma.

(From Barnes PJ: New drugs for asthma, Nat Rev Drug Discov 3:831–844, 2004.)

Bronchoconstriction

Bronchoconstriction is an abnormal contraction of airway smooth muscle that was presumed to be due to an intrinsic abnormality in the airway myocytes. Nervous system dysfunction with cholinergic and/or tachykinin excess also was proposed as an important pathogenic process. Autonomic dysfunction decreases in response to β-agonist and increases in response to α-agonist activity.

Airway Edema

Airway edema is due to increased microvascular leakage occurring in response to inflammatory mediators. This pathomechanism may be particularly important during acute exacerbations.

Airway Remodeling
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