Although the causes of asthma are unknown, researchers do know that environmental and genetic factors contribute to its onset.
Since the mid 1980s, asthma rates in the United States have risen to epidemic levels: An estimated 14.9 million people had asthma in 1995, including more than 5 million children under 17 years old.1-3 Between 1980 and 1993, the overall death rate for asthma increased 57% (from 12.8 to 20.1 deaths per million of population). For those 17 years old and younger, the death rate increased 67% (from 1.8 to 3 deaths per million).1,3 The direct and indirect economic costs associated with asthma, including hospital costs, lost productivity, and an estimated 10 million missed school days, are staggering.4,5
The cause of asthma is unknown, but there is evidence that many factors are involved. Genetic factors contribute to family prevalence and are related to conditions such as rhinitis and allergy. Environmental factors may be protective or disease promoting, depending on exposure, timing of the exposure, genetic interactions, infection, drug interactions, viral exposure, and ongoing insult. Dietary changes over the past 2 to 3 decades may be contributing through alterations in biochemical pathways, including oxygen-radical scavenging, leukotriene production, and other proinflammatory pathways. A lack of exercise results in less time being devoted to mechanical stretching of the airways and to promotion of good airway muscle tone through enhancement of an efficient smooth-muscle contractile process. Occupational exposures to various chemicals, dusts, gases, molds, pollens, and other respiratory irritants also contribute to airway reactivity and inflammation.
Asthma presents many challenges to clinicians and researchers. Of all childhood asthma cases, 80% show onset by 3 years of age. This parallels atopy (the presence of allergic rhinitis or eczema) and/or a positive skin-prick test.6 Asthma and atopy represent a complex syndrome with an abundance of clinical phenotypes in children and adults, following a pattern of remission and relapse.
Asthma is best defined as a chronic disease characterized by inflammation of the airways and bronchial hyperresponsiveness. It typically presents as a variable degree of airway obstruction that is generally reversible. Physiologically, bronchial hyperresponsiveness is demonstrated as decreased airflow or increased resistance in the airways following bronchoprovocation testing using methacholine, histamine, or another challenge agent. Bronchoprovocation using an allergen induces an early-phase airway narrowing mediated by immunoglobulin E (IgE). This is followed by a latephase IgE-mediated reaction with airflow limitation that is sustained for 4 to 8 hours after the challenge.
Pathologic examination of the airways in patients with asthma reveals lung hyperinflation, smooth-muscle hypertrophy, thickening of the lamina reticularis, mucosal edema, epithelial-cell sloughing, cilia-cell disruption, and mucus-gland hypersecretion.7 Microscopic examination reveals increased numbers of eosinophils, neutrophils, lymphocytes, and plasma cells in bronchial tissues, with increased bronchial secretions and mucus. Leukocytes are initially recruited from the bloodstream to the airway through activated CD4 T-lymphocytes, which also trigger the release of inflammatory mediators from eosinophils, mast cells, and lymphocytes. In addition, activated helper T-lymphocytes8-14 (TH1 and TH2) produce elevated levels of interleukins (IL)4-6,10,13; IL-2 receptor15 levels are elevated in children with asthma. In turn, the interaction of the interleukins generates signals that switch immunoglobulin M antibodies to IgE antibodies. The cross-linkage of the two IgE molecules by the allergen causes mast cells to degranulate, thereby releasing histamine, leukotrienes, and other mediators that give rise to ongoing airway inflammation and airway narrowing. Cytokines generated by activated mast cells add to the ongoing insult and cause inflammation to persist. These continuing insults lead to more chronic changes, including lung injury with airway remodeling.
In many individuals, asthma is first recognized in infancy or early childhood. Both environmental factors (viruses, cold air, exercise, cigarette smoke, respiratory allergens, and various occupational exposures) and a genetic factor (atopy) contribute to its evolution.16 To comprehend fully the mechanisms responsible for the many variants of asthma, it is essential to identify triggers that initiate, intensify, and modulate asthma. Further, it is necessary to discriminate between genetic and environmental triggers and to evaluate each pathways part in the onset and evolution of asthma.
The ability to understand asthma fully is confounded by the large number of potential environmental triggers, as well as the complex, chronic nature of the disease process. Recently, researchers have begun to focus on the environment and on how exposure to environmental triggers may influence asthma. This area of research supports the belief that asthma is the result of allergen (environmental) exposure. While only limited data are available, some research17-23 suggests that exposure to specific agents or biological materials may be protective, especially if exposure occurs at critical points in development. Conversely, evidence also exists that casts doubt on this hypothesized protective effect.24,25 Recently, urban versus farm/rural studies have been published in an attempt to identify differences in asthma prevalence and severity.24 The emerging hygiene hypothesis offers an explanation for the distribution of the disease in time and place. The hygiene hypothesis postulates that there is an inverse relationship between the infectious burden in early life and the development of atopy and asthma. Irrefutable evidence for this hypothesis is lacking,26,27 and other hypotheses exist. Data from several countries, however, support the position that farm/rural dwellers may be protected from childhood and adult asthma, as well as other allergic processes.
A general consensus suggests that allergy plays a major role in the pathogenesis of childhood asthma.28-30 By 6 years of age, children who wheeze present with significantly more positive skin tests for aeroallergens than those who never wheeze.28-30 Indoor allergens are known to elevate the risk for asthma, and sensitization to other allergens (cats, dogs, and molds) is associated with asthma in some communities.31-33 Paradoxically, some cross-sectional studies31-32 suggest that increased exposure to cats and dogs may be associated with reduced sensitization and a lower incidence of pet allergy and asthma. Other studies,34 however, have failed to verify a protective effect associated with early exposure. Studies35,36 from developing countries have demonstrated less association between sensitization to indoor allergens and asthma, suggesting that the timing, type, and kinetics of allergen exposure may account for some of the geographical variances in asthma and allergy prevalence.
Anderson37 and Von Mutius et al38 found a lower prevalence of asthma in children who have frequent respiratory infections and pneumonias. Matricardi et al39 and Martinez and Holt40 found that military students who were seropositive for hepatitis A (an indicator of poor hygiene) presented with a significantly lower prevalence of allergic sensitization and atopic disease (including asthma) than their peers without antibodies to hepatitis A. These data suggest a protective effect for increased exposure to infections in infancy. The hygiene hypothesis associates early exposure to environmental triggers with a protective effect. Some suggest that reduced exposure to environmental influences (infections) that produce a TH1-type immune response has given rise to persistent fetal immune responses that are TH2 skewed.40 In turn, this process may increase susceptibility to allergic disease. The childhood transition from the fetal TH2 cytokine phenotype to the adult TH1 cytokine phenotype is influenced by both environmental and genetic factors. Thus, maturation of the immune response in the newborn is thought to be significantly influenced by microbial and/or endotoxin (environmental) exposure, and differences may well exist between urban and rural dwellers.
Epidemiological studies17-21,41 suggest that exposure to a farming environment confers protection from atopy and allergic diseases, including asthma. Moreover, exposure to farm animals has been documented42 as closely linked to the noted protective effects. While the protective mechanism is yet to be identified, the role of a TH1-type response or induction of immune tolerance has been implicated. Further evidence suggests that children,19,21,42,43 adolescents,44,45 and adults reared on farms exhibit a relationship between sensitization and atopic diseases. One explanation for the suggested protective effect of being brought up on a farm focuses on exposure to immunomodulating agents such as bacteria or their endotoxins. Gram-positive and gram-negative bacteria, together with endotoxins, have been measured at high concentrations in stables and other confinement buildings on farms.46-48 Other vectors also exist for bacterial/endotoxin exposure on farms.18 Bacterial/endotoxin exposure is associated with high TH1-cell immune activity through production of tumor necrosis factor-a, interferon-g, IL-10, IL-12, and IL-18. High TH1-cell immune activity in response to allergen challenge makes activation of IgE less likely, thereby reducing the risks of atopic sensitization and asthma.
Interventions designed to prevent asthma should be initiated at birth or shortly thereafter.30 Further, maternal smoking during pregnancy is associated with reduced pulmonary function in infants and children and should be avoided. There is a clear association between parental exposure to cigarette smoke and increased wheezing and asthma in children.49 Avoiding irritants (cleaning fluids, solvents, perfumes, chemicals, and countless others) known to trigger airway reactivity is recommended for those who are susceptible. Allergen avoidance can be effective in preventing asthma exacerbations or ameliorating asthma symptoms.49,50 To this end, reducing indoor allergen exposure during infancy and early childhood may decrease allergic sensitization and asthma. Conversely, early environmental exposures may be critical for the proper development of tolerance to ubiquitous nonpathogenic antigens. Identifying which environmental exposure(s) early in life afford some protective immunity should be the focus of further research. Sound nutritional practices, coupled with regular and interspersed intense exercise, will assist patients in controlling weight gain, toning muscle, enhancing cardiopulmonary physiology, promoting good immune function, and improving other physiological and biochemical processes. It may be vital for children to increase their exposure to specific infectious agents early in life and to limit their time in contact with others (such as dust mites). Future research should address these and other critical factors. In addition, interactions with environmental triggers, nutrition, alternative medical practices, medication use, and comorbid conditions should be considered.
Multiple genetic and environmental factors affect whether the clinical atopic or asthmatic phenotype is expressed in a given child. Understanding the immune response to allergens in early life will be a critical step in alleviating the burden of asthma globally. Insights gained from research focusing on the apparent benefits of growing up in a farm/rural environment suggest that exposure at critical developmental stages may have a more positive impact on asthma than was previously appreciated. These new insights may advance the understanding, treatment, and prevention of asthma.
Farm/rural living, the chronicity and severity of exposure, and treatment may impart a protective effect for some individuals, if they occur at the correct development stage and improve (or promote the maturation of) immunological function. Conversely, research may prove that the key factor is removal of specific asthma triggers, especially those encountered indoors. Through these and other efforts (such as avoiding smoking, optimizing nutrition, exercising regularly, and maintaining a clean home and work space), asthma prevalence and severity might be decreased.
Rick Carter, PhD, MBA, is chair and professor, Jiann-Ping Hsu School of Public Health, Georgia Southern University, Statesboro. Stuart H. Tedders, PhD, is assistant professor at the school and acting director of the universitys Center for Rural Health and Research. Anthony V. Parrillo, PhD, CHES, and Barry Joyner, PhD, are associate professors at the school. Brian Tiep, MD, is medical director, Respiratory Disease Management Institute, Pomona, Calif.
1. Mannino DM, Homa DM, Akinbami LJ, Moorman JE, Gwynn C, Redd SC. Surveillance for asthmaUnited States, 1960-1995. MMWR Surveill Summ. 1998;47(1):1-27.
2. National Heart, Lung and Blood Institute. Data Fact Sheet: Asthma Statistics. Bethesda, Md: National Institutes of Health; 1999.
3. National Asthma Education and Prevention Program Expert Panel. Expert Panel Report 2. Guidelines for the Diagnosis and Management of Asthma. Bethesda, Md: National Heart, Lung, and Blood Institute; 1997:1-86.
4. Smith DH, Malone DC, Lawson KA, Okamoto LJ, Battista C, Saunders WB. A national estimate of the economic costs of asthma. Am J Respir Crit Care Med. 1997;156(3 Pt 1):787-93.
5. Weiss KB, Gergen PJ, Hodgson TA. An economic evaluation of asthma in the United States. N Engl J Med. 1992;326(13):862-6.
6. Weiss ST. Environmental risk factors in childhood asthma. Clin Exp Allergy. 1998;28 Suppl 5:29-34.
7. Fishman AF, ed. Pulmonary Diseases and Disorders. New York: McGraw-Hill; 1988.
8. Wills-Karp M, Luyimbazi JX, Xu X, et al. Interleukin-13: central mediator of allergic asthma. Science. 1998;282(5397):2258-2261.
9. Grunig G, Warmock M, Wakil AE, et al. Requirement for Il-13 independently of Il-14 in experimental asthma. Science. 1998;282(5397):2261-2263.
10. Hamid Q, Azzawi M, Ying S, et al. Expression of mRNA for interleukin-5 in mucosal bronchial biopsies from asthma. J Clin Invest. 1991;87(5):1541-1546.
11. Corrigan CJ, Kay AB. T Cells and eosinophils in the pathogenesis of asthma. Immunol Today. 1992;13(12):501-507.
12. Gerblich AA, Salik H, Schuyler MR. Dynamic T-cell changes in peripheral blood and bronchoalveolar lavage after antigen bronchoprovocation in asthmatics. Am Rev Respir Dis. 1991;143:533-537.
13. Robinson DS, Hamid Q, Ying S, et al. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med. 1992;326(5):298-304.
14. Chretien I, Pene J, Briere F, DeWaal Malefijt R, Rousset F, DeVries JE. Regulation of human IgE synthesis: human IgE synthesis in vitro is determined by the reciprocal antagonistic effects of interleukin 4 and interferon-gamma. Eur J Immunol. 1990;20(2):243-251.
15. Warner JO, Marguet C, Rao R, Roche WR, Pohunek P. Inflammatory mechanisms in childhood asthma. Clin Exp Allergy. 1998;28 Suppl 5:71-75.
16. Weiss ST. The origins of childhood asthma. Monaldi Arch Chest Dis. 1994;49(2):154-8.
17. Von Ehrenstein OS, Von Mutius E, Illi S, Baumann L, Bohm O, von Kries R. Reduced hay fever and asthma among children of farmers. Clin Exp Allergy. 2000;30(2):187-93.
18. Riedler J, Braun-Fahralander C, Eder C, et al. Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet. 2002;358 (9288):1129-1133.
19. Riedler J, Eder W, Oberfeld G, Schreuer M. Austrian children living on a farm have less hay fever, asthma and allergic sensitization. Clin Exp Allergy. 2000;30(2):153-7.
20. Gassner-Bachmann M, Wuthrich B. Farmers children suffer less from hay fever and asthma [in German}. Dtsch Med Wochenschr. 2000;125(31-32):924-31.
21. Downs SH, Marks GB, Mitakakis TZ, Leuppi JD, Car NG, Peat JK. Having lived on a farm and protection against allergic diseases in Australia. Clin Exp Allergy. 2001;31(4):570-5.
22. Filipiak B, Heinrich J, Schafer T, Ring J, Wichman HE. Farming, rural lifestyle and atopy in adults from southern GermanyResults From the MONICA/KORA Study, Augsburg. Clin Exp Allergy. 2001; 41(12):1829-1838.
23. Remes St, Pekkanen J, Soininen L, Kajosaari M, Husman T, Koivikko A. Does heredity modify the association between farming and allergy in children? Acta Paediatr. 2002;91(11):1163-9.
24. Chrischilles E, Ahrens R, Kuehl A, et al. Asthma prevalence and morbidity among rural Iowa school children. J Allergy Clin Immunol. 2004;113(1):66-71.
25. Wickens K, Lane JM, Fitzharris P, et al. Farm residence and exposures and the risk of allergic diseases in New Zealand children. Allergy. 2002;57(12):1094-1096.
26. Cullinan P, Newman Taylor A. Asthma: environmental and occupational factors. Br Med Bull. 2003;68:227-42. Review.
27. Von Hertzen LC. Puzzling associations between childhood infections and the later occurrence of asthma and atopy. Ann Med. 2000;32(6):397-400.
28. Boner AL, Bodini A, Piacentini GL. Environmental allergens and childhood asthma. Clin Exp Allergy. 1998;28 Suppl 5:76-81.
29. Morgan WJ, Martinez FD. Risk factors for developing wheezing and asthma in childhood. Pediatr Clin North Am. 1992;39(6):1185-1203. Review.
30. Wright AL, Taussig LM. Lessons from long term cohort studies. Childhood asthma. Eur Respir J. 1998;27:17s-22s.
31. Roost HP, Kunzli N, Schindler C. Role of current and childhood exposure to cat and atopic sensitization. J Allergy Clin Immunol. 1999;104(5):941-7.
32. Svanes C, Jarvis D, Chinn S, Burney P. Childhood environment and adult atopy: results from the European Community Respiratory Health Survey. J Allergy Clin Immunol. 1999;103(3 Pt 1):415-20.
33. Remes ST, Castro-Rodriguez JA, Holberg CJ, Martinez FD, Wright AL. Dog exposure in infancy decreases the subsequent risk of frequent wheeze but not atopy. J Allergy Clin Immunol. 2001;108(4):509-15.
34. Sporik R, Squillance S, Ingram J, Rakes G, Honsinger RW, Platts Mills TA. Mite, cat and cockroach exposure, allergen sensitization and asthma in children: a case control study of three schools. Thorax. 1999;54(8):675-80.
35. Yemaneberhan H, Bekele Z, Venn A, Lewis S, Parry E, Britton J. Prevalence of wheeze and asthma and relation to atopy in urban and rural Ethiopia. Lancet. 1997;350(9071):85-90.
36. Leung R, Ho P. Asthma, allergy, and atopy in three south-east Asian populations. Thorax. 1994;49(12):1205-10.
37. Anderson HR. The epidemiological and allergic features of asthma in the New Guinea highlands. Clin Allergy. 1974;4(2):171-83.
38. Von Mutius E, Martinez FD, Fritzsch C, Nicolai T, Roell G, Thiemann HH. Prevalence of asthma in two areas of West and East Germany. Am J Respir Crit Care Med. 1994;149(2 Pt 2):358-64.
39. Matricardi PM, Rosmini F, Ferrigno L, et al. Cross sectional retrospective study of prevalence of atopy among Italian military students with antibodies against hepatitis A virus. BMJ. 1997;314(7086):999-1003.
40. Martinez FD, Holt PG. Role of microbial burden in aetiology of allergy and asthma. Lancet. 1999;354 Suppl 2:SII12-15.
41. Braun-Fahrlander C. Allergic diseases in farmers children. Pediatr Allergy Immunol. 2000;11 Suppl 13:19-22.
42. Braun-Fahrlander C, Gassner M, Grize L, et al. Prevalence of hay fever and allergic sensitization in farmers children and their peers living in the same rural community. Clin Exp Allergy. 1999;29(1):28-34.
43. Celli BR. Pulmonary rehabilitation in patients with COPD. Am J Respir Crit Care Med. 1995;152(3):861-4.
44. Ernst P, Cormier Y. Relative scarcity of asthma and atopy among rural adolescents raised on a farm. Am J Respir Crit Care Med. 2000;161(15):1563-6.
45. Portengen L, Sigsgaard T, Omland O, Hjort C, Heederik D, Doekes G. Low prevalence of common atopy in young Danish farmers, association with both farm childhood and present working life as a farmer. Clin Exp Allergy. 2002;32:247-53.
46. Cormier Y, Israel-Assyag E, Racine G, et al. Farming practices and the respiratory health of swine confinement buildings. Eur Respir J. 2000;15(3):560-5.
47. Cormier Y, Tremblay G, Meriaux A, Brochu G, Lavoie J. Airborne microbial contents in two types of swine confinement buildings in Quebec. Am Ind Hyg Assoc J. 1990;51:304-309.
48. Heemerik D, Brouwer R, Biersteker K, et al. Relationship of airborne endotoxin and bacteria levels in pig farms with the lung function and respiratory symptoms of farmers. Int Arch Occup Environ Health. 1991;62(8):595-601.
49. Peat J, Bjorksten B. Primary and secondary prevention of allergic asthma. Eur Respir J Suppl. 1998;27:28s-34s.
50. Custovic A, Simpson A, Chapman MD, Woodcock A. Allergen avoidance in the treatment of asthma and atopic disorders. Thorax. 1998;53(1):63-72.