- Email: [email protected]
Asthma in the elderly: What we do not know yet but should find out
Preface
Asthma in the elderly: What we do not know yet but should find out Charles E. Reed, MD
Rochester, Minn
‘‘The cause is hidden. The effect is visible to all.’’—Ovid Asthma in the elderly is an extraordinarily complex disease. This conference brings together the present knowledge on diagnosis, epidemiology, and management, but there are still many unanswered questions, particularly about pathogenesis. The network of intercellular and intracellular signaling pathways involved in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD) and the relationship between these airway diseases are exceedingly complex. Elderly asthmatic patients who smoked often have both diseases, and they often have additional lung diseases, particularly bronchiectasis with segmental fibrosis. The pathogenesis of asthma itself, however, is presumably similar to that seen in younger adults, except for agerelated changes in the immune response.1,2 The purpose of this address is to suggest particular areas for future research into the pathogenesis, diagnosis, and management of asthma in the elderly. The National Asthma Education and Prevention Program’s Expert Panel Report 3 stresses that gene-environment interactions are important to the expression of asthma.3 Thus consideration of environmental exposures should help provide answers. However, the conventional allergenic and viral agents described in the National Asthma Education and Prevention Program report do not fully answer these questions in mature adults, which is often ‘‘intrinsic’’ (ie, cause unknown) rather than ‘‘allergic.’’ However, agents that activate innate immune inflammation provide a profitable basis for future investigation. Innate immune responses are generally considered to be directed against bacteria and viruses activated through Toll-like receptors (TLRs). The more important of the 12 identified TLRs are TLR-2, which is stimulated by lipoproteins and fungal glucans; TLR-4, which is stimulated by gram-negative endotoxin; and TLR-9, which is stimulated by viral and bacterial DNA, especially CpG.4 Recently, a second form of innate immunity directed against multicellular organisms (ie, helminths, arthropods, and molds) has come into consideration, which is activated through protease-activated receptors (PARs), especially PAR-1 and PAR-2.3,4 PARs are present on all cells, except neutrophils. They were first investigated for their role in wound healing. Endogenous proteases from the coagulation cascade From the Department of Medicine, Mayo Medical School. Publication of this article was supported by the National Institute on Aging. Disclosure of potential conflict of interest: C. E. Reed has declared that he has no conflict of interest. Received for publication April 26, 2011; revised June 20, 2011; accepted for publication June 27, 2011. Reprint requests: Charles E. Reed, MD, 9193 Bald Eagle Rd, PO Box 158, Boulder Junction, WI 54512. E-mail: [email protected]. J Allergy Clin Immunol 2011;128:S1-3. 0091-6749/$36.00 Ó 2011 American Academy of Allergy, Asthma & Immunology doi:10.1016/j.jaci.2011.06.049
stimulate a tissue response that includes production of cytokines, chemokines, and adhesion molecules. Their stimulation results in attraction and activation of eosinophils and neutrophils, degranulation of eosinophils and mast cells, increased response of afferent neurons, smooth muscle contraction, angiogenesis, and fibrosis. More recently, exogenous proteases from parasites, insects, mites, and molds have been found to have the same effects5,6 and also can cause production of IgE to antigens that otherwise would not cause this effect. Some of these exogenous proteases can activate many of these cellular responses through pathways other than PARs. Table I is a brief summary of these forms of innate immunity. Thus a key area for future research will be investigation of innate immune mechanisms in the pathogenesis of asthma, what I will call the innate immune hypothesis. One important point to consider is that these agonists can come from 2 distinctly different environmental sources: directly from organisms growing in the respiratory tract and indirectly from airborne dust particles resulting from organisms growing in the home or workplace. Another important point is that these 2 forms of innate immunity can be present at the same time and interact. Although exposure to environments high in endotoxin reduces the frequency of asthma in infants (the hygiene hypothesis), occupational exposure to endotoxin is a major cause of COPD in adults. Endotoxin stimulation of TLRs also can make asthma more severe.7-9 Some unanswered questions about pathogenesis are as follows: d
d
The incidence of asthma is greatest in children but remains at about 1 per 1000 throughout adult life. However, the prevalence of asthma remains the same at about 4%. Therefore as many adults recover from asthma as eventually have it. Why? The known explanations are less severe disease and less allergen exposure (eg, occupational allergy). Innate immune hypothesis: Reduced environmental exposure to endotoxins and proteases that perpetuate the disease. Why do many elderly asthmatic patients have irreversible obstruction, even at the time of onset? In addition to airway remodeling, there are at least 3 coexisting diseases to consider: COPD, bronchiectasis, and segmental fibrosis. Innate immune hypothesis: Occupational exposure to airborne endotoxin can cause COPD, and therefore years of exposure to airborne endotoxin and proteases at home or work might well be responsible for the combined development and persistence of asthma and COPD. Of course, many elderly asthmatic patients smoked cigarettes, and endotoxin is one of the many noxious components of cigarette smoke. Gram-negative bacteria grow in drying tobacco as they do in stored grain, cotton, and other sources of occupational endotoxin exposures. In addition, as Hogg5 has shown, chronic adenovirus infection of the respiratory epithelium is necessary for COPD to develop in cigarette smokers. Adenovirus might stimulate TLR-9 through viral DNA, and S1
S2 REED
J ALLERGY CLIN IMMUNOL SEPTEMBER 2011
TABLE I. Innate immunity and lung disease TH1 like
TH2 like
Endogenous agonists
Fibronectin, heparin, hyaluronic acid, fibrinogen, and b-defensin
PAR-1: thrombin and mast cell chymase PAR-2: trypsin, airway trypsin-like protease, and mast cell tryptase
Exogenous agonists
Endotoxin, bacterial and viral RNA and DNA, and fungal b(1-3) glycans TLRs, especially TLR-2, TLR-4, and TLR-9 Viruses, bacteria, and molds Macrophages/monocytes, lymphocytes, and epithelial cells TNF-a, IFN-g, IL-6, IL-10, and IL-12 IL-8 ICAM-1 Neutrophils Neutrophils IgG Epithelial cell damage, loss of alveolar elastic tissue, and goblet cell hyperplasia
Serine and cysteine proteases and fungal b(1-3) glycans PARs, especially PAR-2 Helminths, arthropods, and molds Epithelial cells, mast cells, and lymphocytes
Receptors Organisms Primary responding cells Cytokines generated Chemokines generated Adhesion molecules generated Leukocytes attracted Granulocytes activated Increased immunoglobulin production Tissue effects
Lung diseases Environmental airborne sources Mucosal sources
Bronchitis and emphysema Occupations, contaminated HVAC, water-damaged buildings, and pets Pseudomonas aeruginosa and adenovirus DNA
IL-4, IL-5, IL-6, IL-9, and IL-13 IL-8 and eotaxins ICAM-1 and VCAM-1 Eosinophils, monocytes, lymphocytes, and neutrophils Eosinophils, basophils, and mast cells IgE Disruption of tight junctions between epithelial cells, basement membrane collagen production, smooth muscle hypertrophy, bronchial gland hypertrophy, angiogenesis, and increased nociception Asthma Digestive proteases from mites, fungi, cockroaches, and mice feces Fungi (bacteria, viruses?)
ICAM-1, Intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion molecule 1.
d
d
local colonization by bacteria (eg, Pseudomonas species) or fungi (eg, Aspergillus species) might cause these irreversible conditions. What is the ‘‘cause’’ of intrinsic asthma? Although allergic asthma might have persisted from childhood or youth in some cases, most elderly asthmatic patients had the disease in middle age or later.6,7 Also, intrinsic asthma does not have the familial clustering seen in cases of allergic asthma, and therefore the gene-environment interactions must be different. Innate immune hypotheses: (1) Asthma often begins in adults after an acute respiratory tract infection. Could the infection have become chronic, as Hogg5 has described for adenovirus in patients who have COPD from smoking?10 (2) Colonization by fungi is known to cause bronchopulmonary aspergillosis, and Alternaria species and other molds have been implicated in the pathogenesis of nasal polyps.8 These organisms grow by secreting digestive enzymes, including proteases that stimulate PAR-2. Could asthma result from this TH2-like innate immunity stimulated by fungi that have germinated on the mucous membrane? (3) Could it result from long-term exposure to airborne digestive proteases excreted by organisms, such as mites and molds, that thrive in locations of high humidity or from cockroaches and mice in dirty houses Why is the obstruction in patients with severe asthma complete in some segments and only partial in others? The pathology consists of mucus plugs and extensive hypertrophy of the submucosal glands. Innate immune hypothesis: Local colonization by bacteria or fungi with stimulation of PARs. Years ago, when I was establishing the criteria for the diagnosis of allergic bronchopulmonary aspergillosis, I found that sputum cultures were more than 90% sensitive but only 60% specific. The culture was positive in many patients with asthma severe enough to produce a sample but
who did not have bronchiectasis or high IgE levels to Aspergillus species. In conclusion, testing these hypotheses will require many studies to correlate gene-environment interactions of these complex intercellular and intracellular pathways. It is not yet known why only a few patients have disease in response to exposure to these agents. There are several hints about genes. PAR-2 expression is increased in bronchial epithelial cells of asthmatic patients, but it is not known whether this increase is present before or after the disease develops.9 Variations in the expression of CD14, the molecule that binds endotoxin to the cell membrane, have been described.10,11 The role of endogenous protease inhibitors, not only a1-antitrypsin but also other secretory protease inhibitors, is likely to be important. More information is needed about colonization of the respiratory tract by bacteria, such as Pseudomonas species, and fungi, such as Alternaria and Aspergillus species, and their production of agonists of innate immunity. Also, aggressive treatment of these infections needs to be evaluated. Studies are needed that correlate quantitative assays of the environment with clinical status. Standardized methods for measurement of endotoxin are available. Assays for serine and cysteine proteases are also available but have not yet been standardized and adapted for environmental studies. Sample collection methods need evaluation, too. Theoretically, airborne concentrations would be most relevant, but should the sample be collected in the room for 24 hours or in a personal sampler? Some particles, such as mite allergens, settle so fast that settled dust samples actually correlate with disease better than air samples. Similar information about size and settling rate is needed for particles that stimulate innate immunity. Furthermore, methods of collecting the dust and expressing the results need evaluation. What is the best apparatus? Is the molecule
J ALLERGY CLIN IMMUNOL VOLUME 128, NUMBER 3
uniformly distributed in the building, and if not, where should the sample be collected? Should the results be expressed as the concentration per gram of dust or the concentration per square meter of area sampled? A particularly difficult issue is that it is likely that fairly low levels of exposure over a period of many years, rather than brief heavy exposure, is the basis of the chronic disease. After standardized methods of sampling have been shown to correlate with the onset, persistence, and relapse of asthma, control methods need to be devised and evaluated. Some of these agents, particularly gram-negative bacteria and molds, are related to dampness and water damage, and therefore the environment should be checked and corrected. Other agents occur in dry buildings. Control of mites and cockroaches is effective in patients with specific IgE. Is it also effective for other asthmatic patients? Ultimately, widespread clinical laboratory availability of assays for endotoxin and proteases in the environment could be as helpful in patient care as currently available assays for IgE antibodies. Such assays for mite, cockroach, and several occupational allergens have established levels that elicit symptoms and have helped control exposure.
REED S3
REFERENCES 1. Busse PJ, Mathur SK. Age-related changes in immune function: effect on airway inflammation. J Allergy Clin Immunol 2010;126:690-9. 2. Reed CE. Asthma in the elderly: diagnosis and management. J Allergy Clin Immunol 2010;126:681-7. 3. Expert Panel Report 3 (EPR-3): guidelines for the diagnosis and management of asthma—summary report 2007. J Allergy Clin Immunol 2007;120(suppl):S94-S138. 4. Schroder NW, Arditi M. The role of innate immunity in the pathogenesis of asthma: evidence for the involvement of Toll-like receptor signaling. J Endotoxin Res 2007;13:305-12. 5. Hogg JC. Role of latent viral infections in chronic obstructive pulmonary disease and asthma. Am J Respir Crit Care Med 2001;164(suppl):S71-5. 6. Reed CE. The natural history of asthma in adults: the problem of irreversibility. J Allergy Clin Immunol 1999;103:539-47. 7. Bauer BA, Reed CE, Yunginger JW, Wollan PC, Silverstein MD. Incidence and outcomes of asthma in the elderly. A population-based study in Rochester, Minnesota. Chest 1997;111:303-10. 8. Ponikau JU, Sherris DA, Kephart GM, Adolphson C, Kita H. The role of ubiquitous airborne fungi in chronic rhinosinusitis. Curr Allergy Asthma Rep 2005;5:472-6. 9. Knight DA, Lim S, Scaffidi AK, Roche N, Chung KF, Stewart GA, et al. Proteaseactivated receptors in human airways: upregulation of PAR-2 in respiratory epithelium from patients with asthma. J Allergy Clin Immunol 2001;108:797-803. 10. Martinez FD. CD14, endotoxin, and asthma risk: actions and interactions. Proc Am Thorac Soc 2007;4:221-5. 11. Yang IA, Fong KM, Holgate ST, Holloway JW. The role of Toll-like receptors and related receptors of the innate immune system in asthma. Curr Opin Allergy Clin Immunol 2006;6:23-8.
Asthma in the elderly: What we do not know yet but should find out Charles E. Reed, MD
Rochester, Minn
‘‘The cause is hidden. The effect is visible to all.’’—Ovid Asthma in the elderly is an extraordinarily complex disease. This conference brings together the present knowledge on diagnosis, epidemiology, and management, but there are still many unanswered questions, particularly about pathogenesis. The network of intercellular and intracellular signaling pathways involved in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD) and the relationship between these airway diseases are exceedingly complex. Elderly asthmatic patients who smoked often have both diseases, and they often have additional lung diseases, particularly bronchiectasis with segmental fibrosis. The pathogenesis of asthma itself, however, is presumably similar to that seen in younger adults, except for agerelated changes in the immune response.1,2 The purpose of this address is to suggest particular areas for future research into the pathogenesis, diagnosis, and management of asthma in the elderly. The National Asthma Education and Prevention Program’s Expert Panel Report 3 stresses that gene-environment interactions are important to the expression of asthma.3 Thus consideration of environmental exposures should help provide answers. However, the conventional allergenic and viral agents described in the National Asthma Education and Prevention Program report do not fully answer these questions in mature adults, which is often ‘‘intrinsic’’ (ie, cause unknown) rather than ‘‘allergic.’’ However, agents that activate innate immune inflammation provide a profitable basis for future investigation. Innate immune responses are generally considered to be directed against bacteria and viruses activated through Toll-like receptors (TLRs). The more important of the 12 identified TLRs are TLR-2, which is stimulated by lipoproteins and fungal glucans; TLR-4, which is stimulated by gram-negative endotoxin; and TLR-9, which is stimulated by viral and bacterial DNA, especially CpG.4 Recently, a second form of innate immunity directed against multicellular organisms (ie, helminths, arthropods, and molds) has come into consideration, which is activated through protease-activated receptors (PARs), especially PAR-1 and PAR-2.3,4 PARs are present on all cells, except neutrophils. They were first investigated for their role in wound healing. Endogenous proteases from the coagulation cascade From the Department of Medicine, Mayo Medical School. Publication of this article was supported by the National Institute on Aging. Disclosure of potential conflict of interest: C. E. Reed has declared that he has no conflict of interest. Received for publication April 26, 2011; revised June 20, 2011; accepted for publication June 27, 2011. Reprint requests: Charles E. Reed, MD, 9193 Bald Eagle Rd, PO Box 158, Boulder Junction, WI 54512. E-mail: [email protected]. J Allergy Clin Immunol 2011;128:S1-3. 0091-6749/$36.00 Ó 2011 American Academy of Allergy, Asthma & Immunology doi:10.1016/j.jaci.2011.06.049
stimulate a tissue response that includes production of cytokines, chemokines, and adhesion molecules. Their stimulation results in attraction and activation of eosinophils and neutrophils, degranulation of eosinophils and mast cells, increased response of afferent neurons, smooth muscle contraction, angiogenesis, and fibrosis. More recently, exogenous proteases from parasites, insects, mites, and molds have been found to have the same effects5,6 and also can cause production of IgE to antigens that otherwise would not cause this effect. Some of these exogenous proteases can activate many of these cellular responses through pathways other than PARs. Table I is a brief summary of these forms of innate immunity. Thus a key area for future research will be investigation of innate immune mechanisms in the pathogenesis of asthma, what I will call the innate immune hypothesis. One important point to consider is that these agonists can come from 2 distinctly different environmental sources: directly from organisms growing in the respiratory tract and indirectly from airborne dust particles resulting from organisms growing in the home or workplace. Another important point is that these 2 forms of innate immunity can be present at the same time and interact. Although exposure to environments high in endotoxin reduces the frequency of asthma in infants (the hygiene hypothesis), occupational exposure to endotoxin is a major cause of COPD in adults. Endotoxin stimulation of TLRs also can make asthma more severe.7-9 Some unanswered questions about pathogenesis are as follows: d
d
The incidence of asthma is greatest in children but remains at about 1 per 1000 throughout adult life. However, the prevalence of asthma remains the same at about 4%. Therefore as many adults recover from asthma as eventually have it. Why? The known explanations are less severe disease and less allergen exposure (eg, occupational allergy). Innate immune hypothesis: Reduced environmental exposure to endotoxins and proteases that perpetuate the disease. Why do many elderly asthmatic patients have irreversible obstruction, even at the time of onset? In addition to airway remodeling, there are at least 3 coexisting diseases to consider: COPD, bronchiectasis, and segmental fibrosis. Innate immune hypothesis: Occupational exposure to airborne endotoxin can cause COPD, and therefore years of exposure to airborne endotoxin and proteases at home or work might well be responsible for the combined development and persistence of asthma and COPD. Of course, many elderly asthmatic patients smoked cigarettes, and endotoxin is one of the many noxious components of cigarette smoke. Gram-negative bacteria grow in drying tobacco as they do in stored grain, cotton, and other sources of occupational endotoxin exposures. In addition, as Hogg5 has shown, chronic adenovirus infection of the respiratory epithelium is necessary for COPD to develop in cigarette smokers. Adenovirus might stimulate TLR-9 through viral DNA, and S1
S2 REED
J ALLERGY CLIN IMMUNOL SEPTEMBER 2011
TABLE I. Innate immunity and lung disease TH1 like
TH2 like
Endogenous agonists
Fibronectin, heparin, hyaluronic acid, fibrinogen, and b-defensin
PAR-1: thrombin and mast cell chymase PAR-2: trypsin, airway trypsin-like protease, and mast cell tryptase
Exogenous agonists
Endotoxin, bacterial and viral RNA and DNA, and fungal b(1-3) glycans TLRs, especially TLR-2, TLR-4, and TLR-9 Viruses, bacteria, and molds Macrophages/monocytes, lymphocytes, and epithelial cells TNF-a, IFN-g, IL-6, IL-10, and IL-12 IL-8 ICAM-1 Neutrophils Neutrophils IgG Epithelial cell damage, loss of alveolar elastic tissue, and goblet cell hyperplasia
Serine and cysteine proteases and fungal b(1-3) glycans PARs, especially PAR-2 Helminths, arthropods, and molds Epithelial cells, mast cells, and lymphocytes
Receptors Organisms Primary responding cells Cytokines generated Chemokines generated Adhesion molecules generated Leukocytes attracted Granulocytes activated Increased immunoglobulin production Tissue effects
Lung diseases Environmental airborne sources Mucosal sources
Bronchitis and emphysema Occupations, contaminated HVAC, water-damaged buildings, and pets Pseudomonas aeruginosa and adenovirus DNA
IL-4, IL-5, IL-6, IL-9, and IL-13 IL-8 and eotaxins ICAM-1 and VCAM-1 Eosinophils, monocytes, lymphocytes, and neutrophils Eosinophils, basophils, and mast cells IgE Disruption of tight junctions between epithelial cells, basement membrane collagen production, smooth muscle hypertrophy, bronchial gland hypertrophy, angiogenesis, and increased nociception Asthma Digestive proteases from mites, fungi, cockroaches, and mice feces Fungi (bacteria, viruses?)
ICAM-1, Intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion molecule 1.
d
d
local colonization by bacteria (eg, Pseudomonas species) or fungi (eg, Aspergillus species) might cause these irreversible conditions. What is the ‘‘cause’’ of intrinsic asthma? Although allergic asthma might have persisted from childhood or youth in some cases, most elderly asthmatic patients had the disease in middle age or later.6,7 Also, intrinsic asthma does not have the familial clustering seen in cases of allergic asthma, and therefore the gene-environment interactions must be different. Innate immune hypotheses: (1) Asthma often begins in adults after an acute respiratory tract infection. Could the infection have become chronic, as Hogg5 has described for adenovirus in patients who have COPD from smoking?10 (2) Colonization by fungi is known to cause bronchopulmonary aspergillosis, and Alternaria species and other molds have been implicated in the pathogenesis of nasal polyps.8 These organisms grow by secreting digestive enzymes, including proteases that stimulate PAR-2. Could asthma result from this TH2-like innate immunity stimulated by fungi that have germinated on the mucous membrane? (3) Could it result from long-term exposure to airborne digestive proteases excreted by organisms, such as mites and molds, that thrive in locations of high humidity or from cockroaches and mice in dirty houses Why is the obstruction in patients with severe asthma complete in some segments and only partial in others? The pathology consists of mucus plugs and extensive hypertrophy of the submucosal glands. Innate immune hypothesis: Local colonization by bacteria or fungi with stimulation of PARs. Years ago, when I was establishing the criteria for the diagnosis of allergic bronchopulmonary aspergillosis, I found that sputum cultures were more than 90% sensitive but only 60% specific. The culture was positive in many patients with asthma severe enough to produce a sample but
who did not have bronchiectasis or high IgE levels to Aspergillus species. In conclusion, testing these hypotheses will require many studies to correlate gene-environment interactions of these complex intercellular and intracellular pathways. It is not yet known why only a few patients have disease in response to exposure to these agents. There are several hints about genes. PAR-2 expression is increased in bronchial epithelial cells of asthmatic patients, but it is not known whether this increase is present before or after the disease develops.9 Variations in the expression of CD14, the molecule that binds endotoxin to the cell membrane, have been described.10,11 The role of endogenous protease inhibitors, not only a1-antitrypsin but also other secretory protease inhibitors, is likely to be important. More information is needed about colonization of the respiratory tract by bacteria, such as Pseudomonas species, and fungi, such as Alternaria and Aspergillus species, and their production of agonists of innate immunity. Also, aggressive treatment of these infections needs to be evaluated. Studies are needed that correlate quantitative assays of the environment with clinical status. Standardized methods for measurement of endotoxin are available. Assays for serine and cysteine proteases are also available but have not yet been standardized and adapted for environmental studies. Sample collection methods need evaluation, too. Theoretically, airborne concentrations would be most relevant, but should the sample be collected in the room for 24 hours or in a personal sampler? Some particles, such as mite allergens, settle so fast that settled dust samples actually correlate with disease better than air samples. Similar information about size and settling rate is needed for particles that stimulate innate immunity. Furthermore, methods of collecting the dust and expressing the results need evaluation. What is the best apparatus? Is the molecule
J ALLERGY CLIN IMMUNOL VOLUME 128, NUMBER 3
uniformly distributed in the building, and if not, where should the sample be collected? Should the results be expressed as the concentration per gram of dust or the concentration per square meter of area sampled? A particularly difficult issue is that it is likely that fairly low levels of exposure over a period of many years, rather than brief heavy exposure, is the basis of the chronic disease. After standardized methods of sampling have been shown to correlate with the onset, persistence, and relapse of asthma, control methods need to be devised and evaluated. Some of these agents, particularly gram-negative bacteria and molds, are related to dampness and water damage, and therefore the environment should be checked and corrected. Other agents occur in dry buildings. Control of mites and cockroaches is effective in patients with specific IgE. Is it also effective for other asthmatic patients? Ultimately, widespread clinical laboratory availability of assays for endotoxin and proteases in the environment could be as helpful in patient care as currently available assays for IgE antibodies. Such assays for mite, cockroach, and several occupational allergens have established levels that elicit symptoms and have helped control exposure.
REED S3
REFERENCES 1. Busse PJ, Mathur SK. Age-related changes in immune function: effect on airway inflammation. J Allergy Clin Immunol 2010;126:690-9. 2. Reed CE. Asthma in the elderly: diagnosis and management. J Allergy Clin Immunol 2010;126:681-7. 3. Expert Panel Report 3 (EPR-3): guidelines for the diagnosis and management of asthma—summary report 2007. J Allergy Clin Immunol 2007;120(suppl):S94-S138. 4. Schroder NW, Arditi M. The role of innate immunity in the pathogenesis of asthma: evidence for the involvement of Toll-like receptor signaling. J Endotoxin Res 2007;13:305-12. 5. Hogg JC. Role of latent viral infections in chronic obstructive pulmonary disease and asthma. Am J Respir Crit Care Med 2001;164(suppl):S71-5. 6. Reed CE. The natural history of asthma in adults: the problem of irreversibility. J Allergy Clin Immunol 1999;103:539-47. 7. Bauer BA, Reed CE, Yunginger JW, Wollan PC, Silverstein MD. Incidence and outcomes of asthma in the elderly. A population-based study in Rochester, Minnesota. Chest 1997;111:303-10. 8. Ponikau JU, Sherris DA, Kephart GM, Adolphson C, Kita H. The role of ubiquitous airborne fungi in chronic rhinosinusitis. Curr Allergy Asthma Rep 2005;5:472-6. 9. Knight DA, Lim S, Scaffidi AK, Roche N, Chung KF, Stewart GA, et al. Proteaseactivated receptors in human airways: upregulation of PAR-2 in respiratory epithelium from patients with asthma. J Allergy Clin Immunol 2001;108:797-803. 10. Martinez FD. CD14, endotoxin, and asthma risk: actions and interactions. Proc Am Thorac Soc 2007;4:221-5. 11. Yang IA, Fong KM, Holgate ST, Holloway JW. The role of Toll-like receptors and related receptors of the innate immune system in asthma. Curr Opin Allergy Clin Immunol 2006;6:23-8.