Faculty Perspectives: Prevalence, Burden, Epidemiology, and Pathophysiology of Asthma
Asthma Epidemiology, Burden, and PathophysiologyAsthma is a chronic inflammatory disorder of the airways characterized by airflow obstruction, heightened bronchial response, and underlying inflammation. 1,2 The acute manifestations of the disorder, often called “asthma attacks,” are periodic, recurrent episodes caused by chronically hyperactive and inflamed airways, leading to airflow obstruction.2 For most patients, asthma onset begins in childhood, with patterns of inflammation and disease persistence determined by early, recognizable risk factors, including parental history of asthma and atopy (a genetic predisposition toward allergic hypersensitivity reactions).3,4 During an acute exacerbation, individuals may experience wheezing, coughing, chest tightness, chest pain, or shortness of breath. The severity of asthma attacks varies from mild to moderate to severe. In extreme cases, attacks may be life-threatening and require immediate medical attention.1,2,5 There is no known cure for asthma.6 However, it can be controlled with appropriate medical care, and by avoiding exposures (particularly environmental exposures that may trigger an attack), exacerbations can be lessened and severe exacerbations should be rare.7
Epidemiology and Risk FactorsAsthma is a significant public health issue, affecting about 300 million people worldwide.8 In 2009, it was estimated that 1 in 12 people (approximately 25 million) had asthma in the United States alone.9 Asthma prevalence has been on the rise, increasing from 3.1% in 1980 to 5.5% in 1996 and 7.3% in 2001 to 8.4% in 2010.10 Race and ethnicity may play a role in asthma prevalence, as evidenced by data from 2001 through 2010. Higher rates of asthma were observed among blacks than whites and Hispanics, whereas Hispanics had lower rates than either group (Figure 1).10 In addition to race/ethnicity, asthma prevalence varies by a number of modifiable and nonmodifiable risk factors, including weight, tobacco use, age, socioeconomic status, and geography.11 Overall, it is more prevalent in children than adults. In terms of gender, asthma is more prevalent in women than men; however, among children, boys have a higher prevalence (11.3%) than girls (7.9%). Not surprisingly, the prevalence of asthma is higher among families living in poverty compared with those who have incomes above the federal poverty level.1 Asthma prevalence also varies from state to state, as shown by Behavioral Risk Factor Surveillance System data (Figure 2).12 Obesity has been receiving increasing attention as a risk factor for asthma. In a study published last year, Zhang and colleagues reported a high prevalence of asthma among obese (10.2%, 95% confidence interval [CI], 10.0-10.3) and morbidly obese (18.2%, 95% CI, 17.7-18.7) persons, concluding that the ongoing obesity epidemic could be contributing to an increased prevalence of asthma among adults in some states.11
Economic Burden of AsthmaIn 2007, the total societal cost of asthma was estimated at $56 billion. Most of this total ($50.1 billion) was attributed to medical expenses, whereas loss of productivity resulting from missed schooldays or workdays and premature death accounted for the remainder.13 By 2008, working adults who experienced 1 or more asthma attacks during the previous 12 months missed a combined total of 14.2 million days of work due to asthma.1 In 2010, asthma accounted for 3404 deaths; 439,400 hospitalizations; 1.8 million emergency department visits; and 14.2 million physician office visits.14 It was estimated that from 2002 to 2007, the value of productivity loss attributable to asthma was $2.03 billion because of morbidity and $2.37 billion because of mortality, per year. In addition, asthma was responsible for incremental direct medical costs of $3259 per person per year.13 In terms of healthcare utilization, asthma is responsible for an estimated 15.0 million outpatient visits per year.15
PathophysiologyAlthough the root causes of the inflammatory process leading to asthma are yet to be fully explained, the development of asthma appears to involve the interaction between genetic and environmental factors that take place at a critical point in the development of the immune system.2,16 The pathophysiology of asthma is complex and involves mechanisms of adaptive and nonadaptive immunity that result in airway inflammation, intermittent airflow obstruction, and bronchial hyperresponsiveness.2,17 Evidence indicates that patterns of inflammation vary according to phenotypic differences, which are identifiable clusters of demographic, clinical, or pathophysiological characteristics, including allergic asthma, nonallergic asthma, late-onset asthma, asthma with fixed airflow limitation, and asthma with obesity.3 Although some phenotype-guided treatments are available for patients with severe asthma, thus far, phenotypes have not correlated strongly with specific pathological processes or treatment responses.3 In allergic asthma—the most common form of the disease—T helper type 2 (TH2) lymphocytes produce interleukin (IL)-4, IL-5, IL-9, and IL-13 in response to airborne allergens. These cytokines regulate the allergen- specific synthesis of immunoglobulin E (IgE) from B cells, promote the growth and differentiation of mast cells and eosinophils and the recruitment and activation of basophils, and directly cause airway hyperreactivity, a hallmark characteristic of asthma.17,18
Airway InflammationIn asthma, the mechanism of inflammation varies from acute to subacute to chronic.19 Most patients have chronic inflammation, which persists over many years. In addition to ongoing chronic inflammation, patients may also experience acute inflammatory episodes, or exacerbations, of asthma.19,20 Airway inflammation is characterized by varying degrees of mucus hypersecretion, desquamation of the epithelium, smooth muscle hyperplasia, and airway remodeling.19 The degree of airway hyperresponsiveness is usually correlated with the clinical severity of asthma.21 Chronic inflammation of the airways is associated with increased bronchial hyperresponsiveness, which leads to bronchospasm and typical symptoms of wheezing, shortness of breath, and coughing following exposure to triggers such as allergens, environmental irritants, or viruses. In some patients with chronic asthma, airflow limitation may be only partially reversible because of airway remodeling, which is characterized by hypertrophy and hyperplasia of smooth muscle, subepithelial fibrosis, injury to epithelial cells, and angiogenesis.2 Several cell types are involved in the inflammatory process, including mast cells, macrophages, eosinophils, epithelial cells, endothelial cells, and activated T lymphocytes. Patients with asthma have elevated numbers of mast cells in the smooth muscle lining the airways. Mast cells play a role in initiating the acute bronchoconstrictor responses to allergens and other stimuli,20 and are thought to be an important contributor in cases of severe asthma. A greater proportion of chymase-positive mast cells in the airways and increased prostaglandin D2 levels have been identified as important predictors of severe asthma.22 Macrophages are thought to be activated by IgE receptors present on allergenic cells and cell components, and may both increase and decrease inflammation, depending on the stimulus.20 Eosinophils are also thought to play a central role in asthma pathophysiology. The presence of elevated eosinophil counts are linked to airway hyperresponsiveness. In animal studies, activated eosinophils have shown direct inflammatory changes in the airway.20 Enhanced eosinophilic activity is mediated by TH2 cells, which activates vascular cell adhesion molecule- 1 to facilitate the preferential movement of circulating eosinophils to the airways.20,23 Structural cells of the airways, including epithelial and endothelial cells, are thought to be an important source of inflammatory mediators, such as cytokines and lipid mediators. Moreover, epithelial cells may have a key role in translating inhaled environmental signals into an airway inflammatory response.20 Neutrophils may also be involved in patients with certain asthma phenotypes. Elevated neutrophil activity has been found in patients with sudden-onset, fatal asthma exacerbations, in cases of occupational asthma, and in patients who smoke tobacco. However, it has not been determined whether neutrophils have a causative role in these fatal exacerbations.2,20,24 Two additional cell types, invariant natural killer T (iNKT) cells and innate lymphoid cells (ILCs), have been found to produce cytokines that mediate the inflammatory process in asthma, independently of adaptive immunity and conventional antigens. Although the specific roles of iNKT cells and ILCs in immunity are still being defined, these cells respond to environmental triggers important in clinical asthma and may function independently and in conjunction with adaptive immunity to shape immunity environmental triggers, including specific allergens, microbes, and foods.17
Airflow ObstructionAirflow obstruction can be caused by a variety of changes, including bronchoconstriction, edema, mucus plug formation, and airway remodeling (Figure 3).25 Acute bronchoconstriction, which is the primary manifestation of the early asthmatic response, takes place when IgE-dependent mediators are released upon exposure to airbound allergens. Airway edema, which typically occurs 6 to 24 hours following an allergen challenge, constitutes late asthmatic response. Chronic mucus plug formation, which consists of serum proteins and cell debris that accumulate in the airways, may take weeks to resolve. The structural changes associated with chronic inflammation may limit the reversibility of airway obstruction, resulting in permanent tissue impairment.26 Airway obstruction causes resistance to airflow and decreased expiratory flow rates. Over time, patients may experience irreversible decline in lung function because of persistent, chronic pathology that results in thickening of airway walls.26
Bronchial HyperresponsivenessBronchial hyperresponsiveness is an exaggerated reponse to stimuli, leading to excessive bronchial narrowing.27 Although it is recognized as an important feature in asthma, it does not occur in all patients with the disease.28 Moreover, bronchial hyperresponsiveness is not specific to asthma, and may also be caused by endogenous pathologies such as chronic obstructive pulmonary disease (COPD), viral respiratory infection, and cystic fibrosis as well as exogenous stimuli, including atopy, tobacco smoking, smoke inhalation, and near-drowning.27 Although the precise biochemical mechanisms have not been fully elucidated, the pathogenesis of bronchial hyperresponsiveness depends on the underlying pathological process. As a result, there are important differences in the pathogenesis of bronchial hyperresponsiveness in patients with asthma, COPD, or allergic rhinitis.29 Bronchial hyperresponsiveness is associated with the influx of inflammatory cells.28 In asthma, epithelial shedding and subsequent loss of barrier function can contribute to bronchial hyperresponsiveness by allowing allergens to penetrate the epithelial barrier. Epithelial damage also results in the loss of enzymes that break down inflammatory mediators, which may exacerbate the inflammatory process.30 The precise pathological mechanisms involved in bronchial hyperresponsiveness are currently being explored. Researchers have found that the TH2 cytokines IL-4, IL-5, and IL-13 are each associated with worsening of bronchial hyperresponsiveness in animal models. Specific interventions to block each of these cytokines in humans with asthma may warrant further investigation.28
SummaryOverall, it appears that the development of asthma involves an interaction between host factors (particularly genetics) and environmental exposures that occur at a crucial point in the development of the immune system.2,16 Atopy, the genetic predisposition for the development of an IgE-mediated response to common airborne allergens, such as mites, animal dander, pollen, mold, and fungi, is the strongest identifiable predisposing factor for developing asthma. In addition, viral respiratory infections are one of the most important causes of exacerbations of asthma and may also contribute to the development of the disease.31 A variety of other factors have also been linked to asthma or airway hyperreactivity, including exercise, chronic comorbid conditions (eg, gastroesophageal reflux disease and obesity), aspirin or other nonsteroidal anti-inflammatory drugs, beta-blockers, emotional hypersensitivity, tobacco smoke, occupational exposure (eg, cold air, chemical irritants, or air pollution), and stress.31,32 The interaction of the pathophysiological features of asthma determines the clinical manifestations and disease severity, as well as the response to treatment.2 Although the critical role of airway inflammation in asthma pathology is clear, considerable variations exist in patterns of inflammation, which suggests that phenotypic differences may influence treatment responses. Further research is warranted regarding the potential clinical utility of a targeted approach to treatment based on the asthma phenotype profile.2,3 However, since it is a central feature of asthma, mitigating inflammation remains a primary target of treatment. Although current therapeutic approaches are effective in controlling symptoms, reducing airflow limitation, and preventing exacerbations, they do not appear to prevent progression of the underlying disease severity.31 As inflammatory and genetic factors become better understood at the cellular and molecular levels, new therapeutic approaches may be developed that will allow even greater specificity, to tailor treatment to the individual patient’s needs and circumstances.33 Emerging research that seeks to identify more targeted therapies for asthma will be discussed in more detail in the next issue of this series.
- Akinbami LJ, Moorman JE, Liu X. Asthma Prevalence, Health Care Use, and Mortality: United States, 2005–2009. National health statistics reports; no 32. Hyattsville, MD: National Center for Health Statistics; 2011.
- Expert Panel Report 3 (EPR-3)—Summary Report 2007. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. NIH Publication No. 08-5846. Bethesda, MD: US Department of Health & Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program; 2007.
- Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention 2014. www.ginasthma.org. Accessed November 7, 2014.
- Merck Manuals Web site. Overview of allergy and atopy. www.merckmanuals.com/professional/immunology_allergic_disorders/allergic_autoimmune_and_other_hypersensitivity_disorders/overview_of_allergy_and_atopy.html. Accessed November 7, 2014.
- Data from the CDC National Asthma Control Program. Asthma’s impact on the nation. www.cdc.gov/asthma/impacts_nation/asthmafactsheet.pdf. Accessed November 7, 2014.
- US Department of Health & Human Services. National Institutes of Health; National Heart, Lung, and Blood Institute. How is asthma treated and controlled? www.nhlbi.nih.gov/health/health-topics/topics/asthma/treatment.html. Accessed November 7, 2014.
- Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Revised 2006. www.ginasthma.org. Accessed November 7, 2014.
- Masoli M, Fabian D, Holt S, Beasley R, for the Global Initiative for Asthma (GINA) Program. The global burden of asthma: executive summary of the GINA Dissemination Committee Report. Allergy. 2004;59:469-478.
- CDC Web site. Vital signs. www.cdc.gov/vitalsigns. Accessed November 7, 2014.
- CDC. National Center for Environmental Health. Asthma prevalence in the United States [PowerPoint]. June 2014.
- Zhang X, Morrison-Carpenter T, Holt JB, Callahan DB. Trends in adult current asthma prevalence and contributing risk factors in the United States by state: 2000–2009. BMC Public Health. 2013;13:1156.
- CDC Web site. 2010 adult asthma data: prevalence, tables and maps. www.cdc.gov/asthma/brfss/2010/current/mapC1.htm. Accessed November 7, 2014.
- Barnett SB, Nurmagambetov TA. Costs of asthma in the United States: 2002- 2007. J Allergy Clin Immunol. 2011;127:145-152.
- CDC. Asthma Facts—CDC’s National Asthma Control Program Grantees. Atlanta, GA: US Department of Health & Human Services, Centers for Disease Control and Prevention; 2013.
- Dougherty RH , Fahy JV. Acute exacerbations of asthma: epidemiology, biology and the exacerbation-prone phenotype. Clin Exp Allergy. 2009;39:193-202.
- Subbarao P, Mandhane PJ, Sears MR. Asthma: epidemiology, etiology and risk factors. CMAJ. 2009;18:E181-E190.
- DeKruyff RH, Yu S, Kim HY, Umetsu DT. Innate immunity in the lung regulates the development of asthma. Immunol Rev. 2014;260:235-248.
- Kim HY, DeKruyff RH, Umetsu DT. The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nature Immunol. 2010;11:577-584.
- Busse WW, Calhoun WF, Sedgwick JD. Mechanism of airway inflammation in asthma. Am Rev Respir Dis. 1993;147:S20-S24.
- Barnes PJ. Pathophysiology of asthma. Eur Respir Mon. 2003:23;84-113.
- Olivenstein R, Taha R. Airway hyperresponsiveness. In: Hamid Q, Shannon J,Martin J, eds. Clinical Respiratory Physiology. Hamilton, Ont, Canada: BC Decker; 2005:709-719.
- Balzar S, Fajt ML, Comhair SAA, et al. Mast cell phenotype, location, and activation in severe asthma: data from the severe asthma research program. Am J Respir Crit Care Med. 2011;183:299-309.
- Johansson MW, Han S-T, Gunderson KA, et al. Platelet activation, P-selectin, and eosinophil β1-integrin activation in asthma. Am J Respir Crit Care Med. 2012;185:498-507.
- Lugogo NL, MacIntyre NR. Life-threatening asthma: pathophysiology and management. Respir Care. 2008;53:726-735.
- Doeing DC, Solway J. Airway smooth muscle in the pathophysiology and treatment of asthma. J Appl Physiol. 2013;114:834-843.
- Sears MR. Consequences of long-term inflammation. The natural history of asthma. Clin Chest Med. 2000;21:315-329.
- Law KW, Ng KK, Yuen KN, Ho CS. Detecting asthma and bronchial hyperresponsiveness in children. Hong Kong Med J. 2000;6:99-104.
- Grootendorst DC, Rabe KF. Mechanisms of bronchial hyperreactivity in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2004; 1:77-87.
- Antosova M, Strapkova A, Plevkova J. Bronchial hyperreactivity: pathogenesis and treatment options. Open J Molec Integr Physiol. 2011;1:43-51.
- Kaufman G. Asthma: pathophysiology, diagnosis and management. Nursing Standard. 2011;26:48-56.
- EPR 3—Full Report 2007. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. NIH Publication No. 07-4051. Bethesda, MD: US Department of Health & Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program; August 2007.
- World Health Organization Web site. Chronic respiratory disease. www.who.int/respiratory/asthma/causes/en/. Accessed November 7, 2014.
- Arron JR, Scheerens H, Matthews JG. Redefining approaches to asthma: developing targeted biologic therapies. Adv Pharmacol. 2013;66:1-49.
At Johns Hopkins Hospital, each specialist in my practice sees approximately 8 to 10 patients with nonmetastatic NSCLC per month, some of whom are not candidates for surgery based on physiologic parameters. In most cases, we follow the NCCN Guidelines or ASCO clinical practice guidelines in our management of patients with early-stage NSCLC, except in clinical scenarios where the patient may not fit into a particular category within the guidelines, or when we enroll a patient in a clinical trial. For example, we may determine that a neoadjuvant clinical study is appropriate for a patient with stage IB NSCLC, whereas this recommendation is not concordant with the NCCN Guidelines. There are also instances in which we apply recently published clinical study data when managing our patients—even before the NCCN Guidelines have been updated to reflect the most recent findings.
Lenvatinib (Figure) is an orally administered multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors1:VEGFR1 (FLT1)VEGFR2 (KDR)VEGFR3 (FLT4).Lenvatinib also inhibits other RTKs involved in tumor proliferation, including1:Fibroblast growth factor receptors 1, 2, 3, and 4The [ Read More ]