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The Increase in Allergic Respiratory Diseases
opinions/hypothesis The Increase in Allergic Respiratory Diseases Survival of the Fittest? Arthur E. Varner, MD
The prevalence of allergic respiratory diseases, asthma and allergic rhinoconjunctivitis, has increased since the advent of industrialization. The inverse relationship between the number of infections early in life and atopy has been interpreted as the “hygiene hypothesis.” That is, many infections early in life promote the development of T helper type 1 cytokines, while fewer infections early in life favor the development of T helper type 2 (Th2) cytokines and atopy. An alternate interpretation of the same data, that atopy is protective against infections early in life, is rarely considered. With epidemiologic, historical, and immunologic data, I suggest that human evolution has favored individuals with an atopic predisposition. Th2 immune responses promote parity, and ensure successful pregnancy and term birth; provide the infant protection against infections and the inflammation induced by common pathogens in the first years of life until the immune system matures; and protect young adults exposed to viral respiratory pathogens. These traits are of particular value with the advent of industrialization, especially so in the era prior to the development of antibiotics. This theory contradicts the assumption that there is no biological or evolutionary advantage for allergic disease to exist in humans and has significant implications for our current and future treatments of allergic diseases. (CHEST 2002; 121:1308 –1316) Key words: allergic rhinoconjunctivitis; asthma; atopy; eosinophils; evolution; IgE; influenza; nitric oxide; T helper type 1/T helper type 2; viral infection Abbreviations: IL ⫽ interleukin; LRI ⫽ lower respiratory tract illness; NO ⫽ nitric oxide; RSV ⫽ respiratory syncytial virus; Th1 ⫽ T helper type 1; Th2 ⫽ T helper type 2; URI ⫽ upper respiratory tract illness
prevalence of allergic respiratory diseases, T heasthma and allergic rhinoconjunctivitis, has increased dramatically since the advent of industrialization. Many hypotheses exist to explain this phenomena: better hygiene, fewer severe infections early in life due to treatment with antibiotics and vaccinations, the loss of some protective effect found in rural lifestyle, environmental pollution, and changes in dietary habits.1,2 All have merit and data to support their role, but the underlying theme is that the environment is changing to promote allergic disease. One assumption in all of these theories is *From Allergy Diagnostic, Beachwood, OH. Manuscript received August 27, 2001; revision accepted October 10, 2001. Correspondence to: Arthur E. Varner, MD, Allergy Diagnostic, 23250 Mercantile Rd, Beachwood, OH 44122; e-mail: Wiscart@ aol.com 1308
that the immune system of atopic individuals, characterized by the ability to produce T helper type 2 (Th2) type cytokines, large amounts of total as well as antigen-specific IgE in response to environmental exposures, tissue eosinophilia, and increased exhaled nitric oxide (NO),3–5 is of no advantage to the host. More specifically, there is no biological or evolutionary reason for allergic disease to exist in humans. I will suggest, however, with epidemiologic, historical, and immunologic data, that atopy and allergic respiratory disease exist today because they have been beneficial to survival in the past. Birth It is widely accepted that early in life, atopy is more prevalent in first-born children as well as male infants and children.6 None of the hypotheses preOpinions/Hypothesis
sented to date explain both observations. It is thought that an intrauterine Th2 environment is necessary to prevent maternal rejection of the fetus.7 The first-born child, as opposed to subsequent children, and perhaps male fetuses more so than female fetuses, are foreign to the mother’s innate immune response. To prevent T helper type 1 (Th1)-mediated rejection, the inherent ability of the mother’s and fetus’s immune systems to mount a protective Th2 response promotes successful pregnancy. Furthermore, delaying delivery until term would also best ensure the infant’s survival by promoting maturation of organ systems and transfer of protective maternal antibodies. The onset of labor is associated with an increase in cyclo-oxygenase-2 production of prostaglandin E2.8,9 Th2 cytokines inhibit cyclooxygenase-2 activity10 and permit the pregnancy to continue until term. Observations confirm atopy to be less common in premature infants as opposed to infants born at term or later11,12 and for parity to be increased in atopic as opposed to nonatopic mothers.13 Certainly, evolution would favor women with a greater ability not only to have children but also those more likely to have infants born at full gestation with the greatest chance for survival in the first year of life. This may explain why the ability to mount a Th2 response is good for survival during the course of human evolution. It does not explain, however, why atopy is more prevalent today.
Early Life The major causes of premature mortality in the recent past were infant mortality and childhood infectious diseases, including diarrhea and enteritis, pneumonia and influenza, tuberculosis, and diphtheria.14 Common wisdom suggests that a Th1 response is needed to control infections. However, perhaps reflecting the persistence of the Th2-type immunity required for in utero survival and term birth, all infants possess an immune response skewed toward a Th2 phenotype15 as well as a relative eosinophilia.16 In atopic infants, as opposed to nonatopic infants, this Th2 cytokine profile persists in the first year of life.17 Intuitively, this Th2-type response would seem to put the child at risk for infections; however, this may also be protective against some of the common infectious agents encountered early in life. It is accepted that a Th2 response is protective against enteric parasitic organisms, but surprisingly atopy itself may also confer protection.18 –21 This may have been of great benefit in the past, but with industrialization and better sanitation, respiratory, as opposed to enteric, infectious agents became the more common pathogens. Is there any evidence that atopy prevents respiratory infections? www.chestjournal.org
Supporting the hygiene hypothesis, Ball et al22 and Illi et al23 presented data suggesting that frequent respiratory infections early in life prevent the development of atopy and allergic respiratory disease. The converse explanation for their findings, that the predisposition to develop atopy prevents infections, is rarely considered. Prior to the development of antibiotics, the infant’s innate immune response would be required not only to defend against infection but also to minimize host damage to ensure survival.24 Most allergists tend to neglect that Th2 cytokines are also anti-inflammatory in many situations.21,24,25 From the same cohort of children, Halonen et al26 demonstrates that infants with elevated cord serum IgE levels had fewer lower respiratory tract illnesses (LRI) in the first 6 months of life and suggests that IgE antibodies may have a protective function in infants. He has also demonstrated that children with nonwheezing LRI were more acutely ill and more likely to have decreased levels of total serum IgE at 9 months of age.27 This suggests the atopic phenotype may attenuate the severity of the inflammatory response to common viral respiratory pathogens. Von Mutuis et al28 present similar data demonstrating an inverse relationship between total serum IgE and number of fever episodes during the first years of life. School-age children with atopic asthma were significantly less likely to suffer from fever episodes and needed fewer courses of antibiotics than nonatopic asthmatic children. In the atopic asthmatic children, both atopy and bronchial hyperresponsiveness independently were inversely related to fever and antibiotic use, suggesting allergic inflammation in the upper and lower airway reduces the severity of illness associated with common childhood respiratory viral pathogens. In accordance, Van Schaik et al29 and Garofolo et al30 provide data suggesting that young children with a Th2-type cytokine profile in nasal secretions were more likely to have a simple upper respiratory tract illness (URI) than a LRI. Preliminary data from the Childhood Origins of Asthma study31 demonstrate that decreased production of the Th2 cytokine interleukin-13 by phytohemagglutinin-stimulated cord blood mononuclear cells is a risk factor for lower respiratory tract symptoms and wheezing with respiratory syncytial virus (RSV) infection in the first year of life. Taken together in this different perspective, a Th2 response may reduce the frequency or severity (URI as opposed to LRI) of viral respiratory infection early in life and thus confer a survival advantage to the atopic infant and child, particularly in the early industrialization and preantibiotic era. CHEST / 121 / 4 / APRIL, 2002
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Industrialization and Migration Thus far, I have proposed that the propensity to develop a Th2 response and atopy may enhance survival by minimizing the inflammatory response to “danger” in the intrauterine and extrauterine environment early in life. As early as 1873, Blackley32 noted hay fever to be more prevalent in the educated and wealthy, as opposed to those in the lower socioeconomic class, despite the greater exposure to allergens of the latter: “As civilization and education advance, the disorder will become more common than at the present time.” Thus, the hygiene hypothesis has been considered a cause for the increase in atopic disease since the first recognition of the illness. The observation that children of farmers have less allergic disease than urban children has now directed the hygiene theory to search for some protective factor that is lost in modern living.33 By definition, the children of farmers have not been exposed to other environments. Thus, is the factor protecting rural children unique to their environment, such as endotoxin, or does tolerance develop through highdose exposure to local allergens? Against conventional wisdom, early life exposure to high levels of animal and pollen allergens has been associated with reduced allergen-specific sensitization, suggesting that immune tolerance can develop naturally.34 –36 Clinically, most allergists have the experience of seeing patients of all ages who develop allergic disease soon after moving to a new environment. This observation has been noted in 1930 in adult workers from the East moving to rural mining towns in California,37 in 1959 in immigrants migrating to an urban city,38 and more recently in children and adults of numerous ethnic groups migrating to new, and generally more Western, environments.39 Thus, those with an atopic predispostion become sensitized to the allergens present in their environment, as opposed to exposure to allergens causing atopy. This observation could explain why the prevalence of allergic disease is generally similar in different areas of the United States as well as the association of childhood asthma with different dominant allergens in different regions (ie, cockroach in poor urban areas, dust mite in the Southeast, and animal dander in cold, dry climates). It may also explain the initial observation by Blackley.32 That is, the educated in 1873 were those most likely to migrate to a new environment with different allergens or previously encountered allergens but at a different intensity of exposure. The rise of cities, improvement in transportation, and increasing frequency of migration and travel simply exposed the atopic nature of the human immune response. This suggests that by the late 1310
1800s, evolutionary forces had favored an immature and mature human immune system with the capacity to innately respond to new environments and antigens with a Th2-type immune response. As with infants and children, could the development of allergic inflammation protect adults against new respiratory pathogens until specific immunity was acquired?
The Flu of 1918 In the preantibiotic era, as industrialization and urbanization progressed and population centers grew, respiratory infections such as tuberculosis and influenza were responsible for much mortality. Epidemics of influenza were described more frequently in historical records with the rise of cities and were associated with much morbidity but little mortality except for the very young and the very old.40 Pandemics, however, in which no one was protected with acquired immunity as the virus was completely foreign to the human immune system, were associated with significant mortality, particularly in previously healthy young adults.41 The influenza pandemic of 1918, also known as the Spanish flu or Spanish Lady, is a neglected episode in the medical historical record, lost in the fury of World War I.42 A brush with disaster with the avian influenza A H5N1 virus that caused the Hong Kong flu of 199743 and work by Reid and Taubenberger44 in discovering the genetic code of the flu of 1918 revived interest. Both the virus of 1918 and the Hong Kong flu of 1997 were much more lethal than the usual influenza viruses. “City dwellers acquire some degree of immunity because they live in an atmosphere bearing infections. Country boys are more highly susceptible,” American epidemiologist Victor Vaughn remarked in 1918.45,46 In Cape Town in 1919, Duncan M. MacRae47 noted, “Further, 6 white patients with asthma and chronic bronchitis all contracted influenza and recovered without any complications.” Historical records and pathologic reports on the victims of influenza viruses in which no acquired immunity exists describe an infection with the typical acute onset of symptoms, including headache, coryza, fever, chills, and myalgias. Unlike epidemic influenza, where mortality is delayed and associated with secondary bacterial pneumonia, pandemic influenza is associated with early mortality and rapid onset of respiratory compromise with a systemic inflammatory response, changes consistent with a reactive hemophagocytic syndrome and hypercytokinemia of the Th1 type.48 –52 As no one had protective immunity against the virus in 1918, Vaughn’s obserOpinions/Hypothesis
vation suggests a protective effect of the immune response of atopic urban, as opposed to nonatopic rural,33 dwellers just as protection was observed in asthmatics in Cape Town. A recent study examining the effects of inhaled lipopolysaccharide on pulmonary and systemic responses demonstrated a reduced systemic response (fever, neutrophilia, and rise in serum acute-phase protein) in atopic individuals as opposed to nonatopic individuals.53 Thus, it is possible that the propensity to develop, or the presence of, allergic Th2-type inflammation could temper the severity of the innate Th1-type immune response in the lung to an unknown virus, prevent excessive systemic inflammation, and indeed be protective. Mortality data regarding the flu pandemic of 1918 reveal greater mortality in healthy young people as opposed to the normal excess of mortality seen in the young and old in a typical influenza epidemic.54 Even more curious, in various age, gender, ethnic, social, and occupational groups, there appears to be a consistent inverse relationship between the groups with excessive flu mortality rates in 1918 and allergic disease and asthma today (Table 1).42,46,54 – 65 If one assumes the immunologic genotypes and phenotypes of these groups have been stable over the last 80 years, this would suggest a protective effect of atopy against a respiratory viral infection never before encountered by humans and reflect a potential survival advantage in young adults and their offspring. Antiviral Mechanisms of Allergic Inflammation What are the potential mechanisms by which allergic inflammation would protect against infecTable 1—Inverse Relation Between Excessive Influenza Mortality in 1918 and Allergy/Asthma Today
Groups
Influenza Mortality 1918
Male subjects ⬍ 14 yr old Female subjects ⬍ 14 yr old Male subjects aged 20–54 yr Female subjects aged 20–54 yr American Indians American Eskimos Urban soldiers Rural soldiers African Americans Puerto Rican soldiers Immigrants from Western Europe Immigrants from Eastern Europe Cordite and gas works employees
2 1 1 2 1 1 2 1 2 2 2 1 2
*1 ⫽ increased; 2 ⫽ decreased . www.chestjournal.org
Prevalence Asthma/ Allergy Reference Today No. 1 2 2 1 2 2 1 2 1 1 1 2 1
54 54 54 54 55,56 42p241,57 33,46 33,46 58 59–61 42p227,62 42p227,62 63–65
tions? Most data suggest that Th1 responses are required for viral clearance but Th1 cytokines such as interferon-␥ can also enhance the inflammatory response.66 Allergic airway responses are characterized by Th2 cytokines, increased production of total and allergen-specific IgE, tissue eosinophilia, and elevated exhaled NO in the lower airway, and are thought to be ineffective against viral infection and perhaps even detrimental.67– 69 However, Avila et al69 demonstrated the opposite with experimental rhinovirus infection in atopic individuals. Allergic individuals primed with allergen to induce active allergic inflammation of the nasal mucosa prior to infection experienced a delay in the onset, a reduction in severity, and a shorter duration of cold symptoms as compared to those not primed with allergen. Total cell counts, neutrophils, and IL-6 and IL-8 levels in nasal lavage samples were all reduced in those primed with allergen. As the host response to infection,70 not the virus itself, reflects the severity of cold symptoms, allergic inflammation was “protective.”71 Indeed the number of eosinophils, the hallmark inflammatory cell representing allergic inflammation, was inversely correlated to the severity of symptoms. Th2 Cytokines Little data exist to suggest that Th2 cytokines themselves are antiviral, but their anti-inflammatory properties appear to modulate the host response to virus. Levels of IL-8, a potent neutrophil chemoattractant, are directly related to the severity of symptoms observed with respiratory viral infections in the upper and lower airway.72–74 Th2 cytokines such as IL-4 and IL-13 can inhibit IL-8 production by airway epithelial cells and airway smooth-muscle cells when stimulated with ragweed75 and inflammatory cytokines.76,77 Specifically in regards to RSV infection in infants and children, a predominant Th2 response in nasopharyngeal secretions29,30 as well as in stimulated peripheral blood cells has been associated with simple URI as opposed to bronchiolitis or pneumonia.78 Macrophage inflammatory protein-1, which has been associated with more severe RSV infections,30 is inhibited by Th2 cytokines.79 IgE As stated by Halonen et al,26 there is no known antiviral effect mediated by IgE. Th2 cytokines, primarily IL-4 and IL-13, regulate IgE production. Thus, a lack of IgE may reflect the inability to produce such cytokines. A familial syndrome of recurrent sinopulmonary viral and bacterial infections and subsequent lung function impairment has CHEST / 121 / 4 / APRIL, 2002
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been described in patients with decreased or no measurable serum IgE but without other demonstrable immune deficits.80 At the other extreme, in patients with hyperimmunoglobulin E and recurrent infections (Job’s) syndrome, the incidence of infection at mucosal surfaces and adjacent lymph nodes correlated inversely with serum anti-Staphylococcus aureus IgE and total serum IgE.81 This suggests a beneficial antibacterial effect of IgE itself or, more likely, the cytokine response that favors IgE production promotes appropriate resolution of inflammation induced by viral respiratory infection.
rhinovirus infection and cytokine production in respiratory epithelial cells.91,92 NO may have other beneficial effects on respiratory infection by a variety of pathogens including bacteria93 and mycobacteria.94 Indeed the highest levels of NO in the human body are found in the paranasal sinuses,95 which is a rare site for tuberculosis infection.96 Perhaps it is possible that the inverse relationship between tuberculosis and allergic disease may not be secondary to the immunomodulatory effects of tuberculosis infection, but rather the protective effect of airway NO on infection itself.97,98
Eosinophils
Implications for Treatment of Allergic Disease
In the study by Avila et al,69 eosinophils appeared to be responsible for the antiviral effect in rhinovirus infection. Reports by Domachowske et al82– 84 demonstrated antiviral effects of eosinophil products in vitro against RSV. In an animal model of viral infection, Adamko et al85 demonstrated in vivo the antiviral effect of eosinophils against parainfluenza virus. If infection in the first few months of life is an important determinant of subsequent atopy,22,23 it is interesting to note the antiviral effect of eosinophils is effective against the most common pediatric respiratory viral pathogens: rhinovirus, RSV, and parainfluenza virus. In infants at high risk for allergic disease, elevated levels of eosinophil cationic protein and eosinophil protein X have been demonstrated in nasal lavage fluid obtained in the first month of life.86 The presence of activated eosinophils in the upper airway of these children may reflect atopy as well as protection against viral infection (runny nose) in the first year of life.23 In regards to influenza virus and the seemingly protective effect of atopy against the flu of 1918, airway eosinophils may be required for this protection. In this regard it is of interest to note that inhaled corticosteroids used in the treatment of asthma not only reduce Th2 cytokines,87 airway eosinophilia, and exhaled NO, but also increase the risk for influenza and viral infection.88 This natural resistance to influenza may also be inferred by the lack of data regarding the efficacy of influenza vaccination in preventing infection in patients with asthma,89 as opposed to other forms of nonallergic chronic obstructive lung disease.90
If indeed atopy and allergic respiratory disease confer some survival advantage, are our current treatments appropriate? Inhaled corticosteroids are the primary treatment for persistent asthma and rhinitis and are thought to suppress Th2-like inflammation but not Th1 responses.87 Yet, nondiscriminate suppression of Th2 responses leads to a reduction in eosinophils, anti-inflammatory Th2 cytokines,99 and exhaled NO, and thus may enhance susceptibility to or severity of viral infection. Indeed, inhaled steroids are less effective against viral-induced wheezing than other triggers of asthma exacerbations100 and increase adverse sequelae of viral infection, such as otitis media in children, when used in the upper airway.101 Even avoidance measures34 –36,68,69 and other treatments for symptoms such as sneezing and coughing102–103 may be detrimental if indeed symptoms of active allergic inflammation are beneficial, much like the protective “weep and sweep” response observed with GI parasitic infections. Perhaps treatment such as allergen-specific immunotherapy, which can provide symptom control,104 the potential for long-term remission,104 and possible prevention of the development of new allergen sensitivities and asthma,105–109 would be more appropriate. This form of treatment, whether its mechanism of action is the induction of specific immune tolerance or shifting the immune response to specific allergens from Th2 to Th1, avoids global and nonspecific suppression of allergic and Th2-type inflammatory mechanisms that may be of benefit to the atopic individual when faced with viral infection.88,101,109
Conclusion NO Exhaled NO is elevated in patients with asthma and atopy.3–5 NO has been demonstrated to inhibit 1312
This hypothesis regarding the increase in respiratory allergic disease differs from others in one important respect—there may indeed be a reason for this trend, the evolutionary advantage of atopy. Opinions/Hypothesis
Allergic and Th2 immune responses ensure parity, successful pregnancy, and term birth; provide the infant protection against infections and the inflammation induced by common pathogens in the first years of life until the immune system matures; and protect young adults exposed to new respiratory pathogens such as the flu of 1918. These traits are of particular value with the advent of industrialization, improved transportation and increased migration, and the development of dense population centers with exposures to new allergens as well as respiratory pathogens. The greatest effect of this survival advantage would have manifest during the early industrialization era prior to the development of antibiotics. Consistent with an evolutionary advantage, this protective effect is greatest during the first several decades of life and may become negligible against the chronic illnesses of later life such as cardiovascular disease and cancer.110,111 This review is contrary to current belief, though never substantiated71 and somewhat paradoxical in the sense of the hygiene hypothesis, that atopic patients experience more frequent and severe infections. It certainly does not explain the mechanism of viral-induced asthma exacerbations, but many other forces are driving the increase in symptomatic allergic respiratory disease in modern societies, particularly asthma, which has become somewhat dissociated from atopy.1,2,112–114 Current treatments for allergic rhinoconjunctivitis and asthma control symptoms but are not curative and may even enhance progression of the diseases115–119 and possibly increase morbidity associated with viral infection.69,88,101 Ongoing investigations such as the Childhood Origins of Asthma study will help to define immunologic phenotypes present at birth and the interaction between viral infection, atopy, and asthma. Results of this study and the thoughts presented in this review should be considered before embracing methods to enhance Th1 and suppress Th2 immune responses as treatments for allergic diseases.120 –124
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References 1 Seaton A, Godden DJ, Brown K. Increase in asthma: a more toxic environment or a more susceptible population? Thorax 1994; 49:171–174 2 Strannegard O, Strannegard I-L. The causes of the increasing prevalence of allergy: is atopy a microbial deprivation disorder? Allergy 2001; 56:91–102 3 Franklin PJ, Taplin R, Stick SM. A community health study of exhaled nitric oxide in healthy children. Am J Respir Crit Care Med 1999; 159:69 –73 4 Ho L-P, Wood FT, Robson A, et al. Atopy influences exhaled nitric oxide in adult asthmatics. Chest 2000; 118: 1327–1331 5 Moody A, Fergusson W, Wells A, et al. Increased nitric www.chestjournal.org
23 24 25
26
oxide production in the respiratory tract in asymptomatic Pacific Islanders: an association with skin prick reactivity to house dust mite. J Allergy Clin Immunol 2000; 105:895– 899 Strachan DP. Hay fever, hygiene, and household size. BMJ 1989; 299:1259 –1260 Wegmann TG, Lin H, Guilbert L, et al. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today 1993; 14:353–356 Kniss DA, Iams JD. Regulation of parturition update: endocrine and paracrine effectors of term and preterm labor. Clin Perinatol 1998; 25:819 – 836 Gordon MC, Samuels P. Indomethacin. Clin Obstet Gynecol 1995; 38:697–705 Varner AE. The cyclooxygenase-2 theory of atopy and asthma. Pediatr Asthma Allergy Immunol 1999; 13:43–50 Pekkanen J, Xu B, Jarvelin M-R. Gestational age and occurrence of atopy at age 31: a prospective birth cohort study in Finland. Clin Exp Allergy 2001; 31:95–102 Siltanen M, Kajosaari M, Pohjavuori M, et al. Prematurity at birth reduces the long-term risk of atopy. J Allergy Clin Immunol 2001; 107:229 –234 Nilsson L, Kjellman NI, Lofman O, et al. Parity among atopic and non-atopic mothers. Pediatr Allergy Immunol 1997; 3:134 –136 Centers for Disease Control and Prevention. Achievements in Public Health, 1999: control of infectious diseases. MMWR Morb Mortal Wkly Rep 1999; 48:621– 629 Prescott SL, Macaubas C, Holt BJ, et al. Transplacental priming of the human immune system to environmental allergens: universal skewing of initial T cell responses toward the Th2 cytokine profile. J Immunol 1998; 160:4730 – 4737 Camitta BM. The anemias. In: Behrman RE, Kliegman RM, Arvin AM, eds. Nelson textbook of pediatrics. 15th ed. Philadelphia, PA: W.B. Saunders, 1996; 1379 Prescott SL, Macaubas C, Smallacombe T, et al. Development of allergen-specific T-cell memory in atopic and normal children. Lancet 1999; 353:196 –200 Lynch NR, Hagel IA, Palenque ME, et al. Relationship between helminthic infection and IgE response in atopic and nonatopic children in a tropical environment. J Allergy Clin Immunol 1998; 101:217–221 Openshaw PJM, O’Donnell DR. Asthma and the common cold: can viruses imitate worms? Thorax 1994; 49:101–103 McSharry C, Xia Y, Holland CV, et al. Natural immunity to Ascaris lumbricoides associated with immunoglobulin E antibody to ABA-1 allergen and inflammation indicators in children. Infect Immun 1999; 67:484 – 489 Finkelman FD, Urban JF. The other side of the coin: the protective role of Th2 cytokines. J Allergy Clin Immunol 2001; 107:772–780 Ball TM, Castro-Rodriguez JA, Griffith KA, et al. Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N Engl J Med 2000; 343:538 –543 Illi S, von Mutuis E, Lau S, et al. Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study. BMJ 2001; 322:390 –395 Spellberg B, Edwards JE Jr. Type 1/type 2 immunity in infectious diseases. Clin Infect Dis 2001; 32:76 –102 Van Roon JAG, Lafeber FPJG, Bijlsma JWJ. Synergistic activity of interleukin-4 and interleukin-10 in suppression of inflammation and joint destruction in rheumatoid arthritis. Arthritis Rheum 2001; 44:3–12 Halonen M, Stern D, Taussig LM, et al. The predictive relationship between serum IgE levels at birth and subsequent incidences of lower respiratory illnesses and eczema in infants. Am Rev Respir Dis 1992; 146:866 – 870 CHEST / 121 / 4 / APRIL, 2002
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27 Martinez FD, Stern DA, Wright AL, et al. Association of non-wheezing lower respiratory tract illnesses in early life with persistently diminished serum IgE levels. Thorax 1995; 50:1067–1072 28 Von Mutuis E, Illi S, Hirsch T, et al. Frequency of infections and risk of asthma, atopy and airway hyperresponsiveness in children. Eur Respir J 1999; 14:4 –11 29 Van Schaik S, Tristam DA, Nagpal IS, et al. Increased production of IFN-␥ and cysteinyl leukotrienes in virusinduced wheezing. J Allergy Clin Immunol 1999; 103:630 – 636 30 Garofalo RP, Patti J, Hintz KA, et al. Macrophage inflammatory protein-1 (not T helper type 2 cytokines) is associated with severe forms of respiratory syncytial bronchiolitis. J Infect Dis 2001; 184:292–399 31 Brooks GD, Anklam KS, Roberg KA, et al. Reduced newborn mononuclear cell production of interleukin-5 (IL-5) and interleukin-13 (IL-13) is associated with wheezing in the first year of life [abstract]. J Allergy Clin Immunol 2001; 107:S65 32 Blackley C. Experimental researches on catarrhus aestivus. London, UK: Bailliere, Tindall and Cox, 1873 33 Von Ehrenstein OS, von Mutuis E, Illi S, et al. Reduced risk of hay fever and asthma among children of farmers. Clin Exp Allergy 2000; 30:187–193 34 Platts-Mills T, Vaughn J, Squillace S, et al. Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross sectional study. Lancet 2001; 357:752–756 35 Nilsson L, Bjorksten B, Hattevig G, et al. Season of birth as predictor of atopic manifestations. Arch Dis Child 1997; 76:341–344 36 Hesselmar B, Aberg N, Aberg B, et al. Does early exposure to cat or dog protect against later allergy development? Clin Exp Allergy 1999; 29:611– 617 37 Piness G, Miller H. An unusual opportunity to make an allergic study of an entire community with the etiology and results of treatment. J Allergy 1930; 1:117–123 38 Fine AJ, Abram LE. The period of sensitization in immigrant hay fever patients. J Allergy 1960; 31:375–380 39 Leung R. Asthma, allergy and atopy in South-East Asian immigrants in Australia. Aust N Z J Med 1994; 24:255–257 40 Patterson KD. Pandemic influenza 1700 –1900: a study in historical epidemiology. Totowa, NJ: Rowman and Littlefield, 1986 41 Simonsen L, Clarke MJ, Schonberger LB, et al. Pandemic versus epidemic influenza mortality: a pattern of changing age distribution. J Infect Dis 1998; 178:53– 60 42 Crosby AW. America’s forgotten pandemic: the influenza of 1918. Cambridge UK: Cambridge University Press, 1989 43 Yuen KY, Chan PKS, Peiris M, et al. Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet 1998; 351:467– 471 44 Reid AH, Taubenberger JK. The flu and other influenza pandemics: “over there” and back again. Lab Invest 1999; 79:95–101 45 Iezzoni L. Influenza 1918: the worst epidemic in American history. New York, NY: TV Books, LLC, 1999; 79 46 Love AG, Davenport CB. Immunity of city-bred recruits. Arch Intern Med 1919; 24:129 –153 47 MacRae DM. Influenza and chronic lung disease. Lancet 1919; 281 48 To K-F, Chan PKS, Chan K-F, et al. Pathology of fatal human infection associated with avian influenza A H5N1 virus. J Med Virol 2001; 63:242–246 49 Kimura K, Adlakha A, Simon PM. Fatal case of swine 1314
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influenza virus in an immunocompetent host. Mayo Clin Proc 1998; 73:243–245 Bone RC. Immunologic dissonance: a continuing evolution in our understanding of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS). Ann Intern Med 1996; 125:680 – 687 Tsuda H. Hemophagocytic syndrome (HPS) in children and adults. Int J Hematol 1997; 65:215–226 Akashi K, Hayashi S, Gondo H, et al. Involvement of interferon-␥ and macrophage colony-stimulating factor in the pathogenesis of haemophagocytic lymphohistiocytosis in adults. Br J Haematol 1994; 87:243–250 Michel O, Dentener M, Corazza F, et al. Healthy subjects express differences in clinical responses to inhaled lipopolysaccharide that are related with inflammation and with atopy. J Allergy Clin Immunol 2001; 107:797– 804 Collins SD. Age and sex incidence of influenza and pneumonia morbidity and mortality in the epidemic of 1928 –29 with comparative data for the epidemic of 1918 –19. Public Health Rep 1931; 46:33 Influenza among American Indians. Public Health Rep 1919; 34:1008 –1009 Rhoades ER. The major respiratory diseases of American Indians. Am Rev Respir Dis 1990; 141:595– 600 Herxheimer H, Schaefer O. Asthma in Canadian Eskimos [letter]. N Engl J Med 1974; 291:1419 Frankel LK, Dublin LI. Influenza mortality among wage earners and the families: a preliminary statement of results. Am J Public Health 19:731–742 Office of the Surgeon General Medical Department, US Army. 1919, 9; 94 Beckett WS, Belanger K, Gent JF, et al. Asthma among Puerto Rican Hispanics: a multi-ethnic comparison study of risk factors. Am J Respir Crit Care Med 1996; 154:894 – 899 Ledogar RJ, Penchaszadeh A, Garden CCI, et al. Asthma and Latino cultures: different prevalence reported among groups sharing the same environment. Am J Public Health 2000; 90:929 –935 Beasley R, Keil U, von Mutuis E, et al, for the NISAAC Steering Committee. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis and atopic eczema: ISAAC. Lancet 1998; 351:1225–1232 Gregor A. A note on the epidemiology of influenza among workers in gas works, in a cordite factory, and in a tin mine. BMJ 1919; 242–243 Park J-K, Kim Y-K, Lee S-R, et al. Repeated exposure to low levels of sulfur dioxide (SO2) enhances the development of ovalbumin-induced asthmatic reactions in guinea pigs. Ann Allergy Asthma Immunol 2001; 86:62– 67 Balmes JR, Fine JM, Christian D, et al. Acidity potentiates bronchoconstriction induced by hypoosmolar aerosols. Am Rev Respir Dis 1988; 138:35–39 Van Schaik SM, Obot N, Enhorning G, et al. Role of interferon ␥ in the pathogenesis of primary respiratory syncytial virus infection in BALB/c mice. J Med Virol 2000; 62:257–266 Busse WW. The relationship between viral infections and onset of allergic diseases and asthma. Clin Exp Allergy 1989; 19:1–9 Bardin PG, Fraenkel DJ, Sanderson G, et al. Amplified rhinovirus colds in atopic subjects. Clin Exp Allergy 1994; 24:457– 464 Avila PC, Abisheganaden JA, Wong H, et al. Effects of allergic inflammation of the nasal mucosa on the severity of rhinovirus 16 cold. J Allergy Clin Immunol 2000; 105:923– 932 Hendley JO. Editorial comment: the host response, not the Opinions/Hypothesis
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77
78
79
80 81
82
83
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86
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virus, causes the symptoms of the common cold. Clin Infect Dis 1998; 26:847– 848 Busse WW, Gern JE. Do allergies protect against the effects of a rhinovirus cold? J Allergy Clin Immunol 2000; 105:889 – 891 Turner RB, Weingand KW, Yeh C-H, et al. Association between interleukin-8 concentration in nasal secretions and severity of symptoms of experimental rhinovirus colds. Clin Infect Dis 1998; 26:840 – 846 Hull J, Thomsom A, Kwiatkowski D. Association of respiratory syncytial virus bronchiolitis with the interleukin 8 gene region in UK families. Thorax 2000; 55:1023–1027 Bont L, Heijnen CJ, Kavelaars A, et al. Peripheral blood cytokine responses and disease severity in respiratory syncytial virus bronchiolitis. Eur Respir J 1999; 14:144 –149 Chen W, Hunninghake GW. Effects of ragweed and Th-2 cytokines on the secretion of IL-8 in human airway epithelial cells. Exp Lung Res 2000; 26:229 –239 Fujisawa T, Kato Y, Atsuta J, et al. Chemokine production by the BEAS-2B human bronchial epithelial cells: differential regulation of eotaxin, IL-8, and RANTES by TH2- and TH1-derived cytokines. J Allergy Clin Immunol 2000; 105: 126 –133 John M, Au B-T, Jose PJ, et al. Expression and release of interleukin-8 by human airway smooth muscle cells: inhibition by Th-2 cytokines and corticosteroids. Am J Respir Cell Mol Biol 1998; 18:84 –90 Bendelja K, Gagro A, Bace A, et al. Predominant type-2 response in infants with respiratory syncytial virus (RSV) infection demonstrated by cytokine flow cytometry. Clin Exp Immunol 2000; 121:332–338 Berkman N, John M, Roesems G, et al. Interleukin-13 inhibits macrophage inflammatory protein-1␣ production from human alveolar macrophages and monocytes. Am J Respir Cell Mol Biol 1996; 15:382–389 Schoettler JJ, Schleissner LA, Heiner DC. Familial IgE deficiency associated with sinopulmonary disease. Chest 1989; 96:516 –521 Dreskin SC, Goldsmith PK, Gallin JI. Immunoglobulins in the hyperimmunoglobulin E and recurrent infection (Job’s) syndrome: deficiency of anti-Staphylococcus aureus immunoglobulin A. J Clin Invest 1985; 75:26 –34 Domachowske JB, Dyer KD, Adams AG, et al. Eosinophil cationic protein/RNase 3 is another A-family ribonuclease with direct antiviral activity. Nucleic Acids Res 1998; 26: 3358 –3363 Domachowske JB, Bonville CA, Dyer KD, et al. Evolution of antiviral activity in the ribonuclease A gene superfamily: evidence for a specific interaction between eosinophilderived neurotoxin (EDN/RNase 2) and respiratory syncytial virus. Nucleic Acids Res 1998; 26:5327–5332 Rosenberg HF, Domachowske JB. Eosinophils, ribonucleases and host defense: solving the puzzle. Immunol Res 1999; 20:261–274 Adamko DJ, Yost BL, Gleich GJ, et al. Ovalbumin sensitization changes the inflammatory response to subsequent Parainfluenza infection: eosinophils mediate airway hyperresponsiveness, M2 muscarinic receptor dysfunction, and antiviral effects. J Exp Med 1999; 190:1465–1477 Halmerbauer G, Gartner C, Koller D, et al. Eosinophil cationic protein and eosinophil protein X in the nasal lavage of children during the first 4 weeks of life. Allergy 2000; 55:1121–1126 Umland SP, Nahrebne DK, Razac S, et al. The inhibitory effects of topically active glucocorticoids on IL-4, IL-5, and interferon-␥ production by cultured primary CD4⫹ T cells. J Allergy Clin Immunol 1997; 100:511–519
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88 Physicians desk reference. 55th ed. Montvale, NJ: Medical Economics Company, 2001 89 Cates CJ, Jefferson TO, Bara AI, et al. Vaccines for preventing influenza in people with asthma (Cochrane Review). Cochrane Database Syst Rev 2000; 4:CD000364 90 Poole PJ, Chacko E, Wood-Baker RW, et al. Influenza vaccine for patients with chronic obstructive pulmonary disease (Cochrane Review). Cochrane Database Syst Rev 2000; 4:CD002733 91 Sanders SP, Siekierski ES, Porter JD, et al. Nitric oxide inhibits rhinovirus-induced cytokine production and viral replication in a human respiratory epithelial cell line. J Virol 1998; 72:934 –942 92 Sanders SP. Asthma, viruses, and nitric oxide. Proc Soc Exp Biol Med 1999; 220:123–132 93 Fang FC. Mechanisms of nitric oxide-related antimicrobial activity. J Clin Invest 1997; 99:2818 –2825 94 MacMicking JD, North RJ, LaCourse R, et al. Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc Natl Acad Sci U S A 1997; 94:5243–5248 95 Lundberg JO, Farkas-Szallasi T, Weitzberg E, et al. High nitric oxide production in human paranasal sinuses. Nat Med 1995; 1:370 –373 96 Myerson MC. Tuberculosis of the ear, nose, and throat. Springfield, IL: C.C. Thomas, 1944 97 Shirakawa T, Enomoto T, Shimazu S, et al. The inverse association between tuberculin responses and atopic disorder. Science 1997; 275:77–79 98 Von Mutuis E, Pearce N, Beasley R, et al. International patterns of tuberculosis and the prevalence of asthma, rhinitis, and eczema. Thorax 2000; 55:449 – 453 99 Kita H, Jorgensen RK, Reed CE, et al. Mechanism of topical glucocorticoid treatment of hay fever: IL-5 and eosinophil activation during natural allergen exposure are suppressed, but IL-4, IL-6, and IgE antibody production are unaffected. J Allergy Clin Immunol 2000; 106:521–529 100 McKean M, Ducharme F. Inhaled steroids for episodic viral wheeze of childhood. Cochrane Database Syst Rev 2000; 2:CD001107 101 Ruohola A, Heikkinen T, Waris M, et al. Intranasal fluticasone propionate does not prevent acute otitis media during viral upper respiratory infection in children. J Allergy Clin Immunol 2000; 106:467– 471 102 Gwaltney JM Jr, Hendley JO, Phillips CD, et al. Nose blowing propels nasal fluid into the paranasal sinuses. Clin Infect Dis 2000; 30:387–391 103 Van Ganse E, Van der Linden P, Leufkens HGM, et al. Antiallergic and antitussive medications: extent of use and relationship to asthma exacerbations. Therapie 1996; 51: 373–377 104 Durham SR, Walker SM, Varga EM, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med 1999; 341:468 – 475 105 Des Roches A, Paradis L, Menardo JL, et al. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract: VI. Specific immunotherapy prevents the onset of new sensitizations in children. J Allergy Clin Immunol 1997; 99:450 – 453 106 Purello-D’Ambrosio F, Gangemi S, Merendino RA, et al. Prevention of new sensitizations in monosensitized subjects submitted to specific immunotherapy or not: a retrospective study. Clin Exp Allergy 2001; 31:1295–1302 107 Grembiale RD, Camporota L, Naty S, et al. Effects of specific immunotherapy in allergic rhinitis individuals with bronchial hyperresponsiveness. Am J Respir Crit Care Med 2000; 162:2048 –2052 108 Walker SM, Pajno GB, Lima MT, et al. Grass pollen CHEST / 121 / 4 / APRIL, 2002
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immunotherapy for seasonal rhinitis and asthma: a randomized, controlled trial. J Allergy Clin Immunol 2001; 107: 87–93 Parker RA, Hartman EE. A 48-year-old man with recurrent sinusitis, 1 year later [letter]. JAMA 2001; 286:2594 Gergen PJ, Turkeltaub PC, Sempos CT. Is allergen skin test reactivity a predictor of mortality? Findings from a national cohort. Clin Exp Allergy 2000; 30:1717–1723 Hospers JJ, Rijcken B, Schouten JP, et al. Eosinophilia and positive skin tests predict cardiovascular mortality in a general population sample followed for 30 years. Am J Epidemiol 1999; 150:482– 491 Varner AE, Busse WW, Lemanske RF Jr. Hypothesis: decreased use of pediatric aspirin has contributed to the increasing prevalence of childhood asthma. Ann Allergy Asthma Immunol 1998; 81:347–351 Newson RB, Shaheen SO, Chinn S, et al. Paracetamol sales and atopic disease in children and adults: an ecological analysis. Eur Respir J 2000; 16:817– 823 Kuehni CE, Davis A, Brooke AM, et al. Are all wheezing disorders in very young (preschool) children increasing in prevalence? Lancet 2001; 357:1821–1825 Gauvreau GM, Jordana M, Watson RM, et al. Effect of regular inhaled albuterol on allergen-induced late responses and sputum eosinophils in asthmatic subjects. Am J Respir Crit Care Med 1997; 156:1738 –1745 Fedyk ER, Adawi A, Looney RJ, et al. Regulation of IgE and cytokine production by cAMP: implications for extrinsic asthma. Clin Immunol Immunopathol 1996; 81:101–113
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117 The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000; 343:1054 –1063 118 Salvi SS, Babu KS, Holgate ST. Glucocorticoids enhance IgE synthesis: are we heading towards new paradigms? Clin Exp Allergy 2000; 30:1499 –1505 119 Barnes PJ. Corticosteroids, IgE, and atopy. J Clin Invest 2001; 107:265–266 120 Hansen G, Berry G, DeKruyff RH, et al. Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation. J Clin Invest 1999; 103:175–183 121 Magone MT, Whitcup SM, Fukushima A, et al. The role of IL-12 in the induction of late-phase cellular infiltration in a murine model of allergic conjunctivitis. J Allergy Clin Immunol 2000; 105:299 –308 122 Bryan SA, O’Connor BJ, Matti S, et al. Effects of recombinant human interleukin-12 on eosinophils, airway hyperresponsiveness, and the late asthmatic response. Lancet 2000; 356:2149 –2153 123 Arkwright PD, David TJ. Intradermal administration of a killed Mycobacterium vaccae suspension (SRL 172) is associated with improvement in atopic dermatitis in children with moderate-to-severe disease. J Allergy Clin Immunol 2001; 107:531–534 124 Storm van Lleeuwen W, Varekamp H. On the tuberculin treatment of bronchial asthma and hay fever. Lancet 1921; 1366 –1369
Opinions/Hypothesis
The prevalence of allergic respiratory diseases, asthma and allergic rhinoconjunctivitis, has increased since the advent of industrialization. The inverse relationship between the number of infections early in life and atopy has been interpreted as the “hygiene hypothesis.” That is, many infections early in life promote the development of T helper type 1 cytokines, while fewer infections early in life favor the development of T helper type 2 (Th2) cytokines and atopy. An alternate interpretation of the same data, that atopy is protective against infections early in life, is rarely considered. With epidemiologic, historical, and immunologic data, I suggest that human evolution has favored individuals with an atopic predisposition. Th2 immune responses promote parity, and ensure successful pregnancy and term birth; provide the infant protection against infections and the inflammation induced by common pathogens in the first years of life until the immune system matures; and protect young adults exposed to viral respiratory pathogens. These traits are of particular value with the advent of industrialization, especially so in the era prior to the development of antibiotics. This theory contradicts the assumption that there is no biological or evolutionary advantage for allergic disease to exist in humans and has significant implications for our current and future treatments of allergic diseases. (CHEST 2002; 121:1308 –1316) Key words: allergic rhinoconjunctivitis; asthma; atopy; eosinophils; evolution; IgE; influenza; nitric oxide; T helper type 1/T helper type 2; viral infection Abbreviations: IL ⫽ interleukin; LRI ⫽ lower respiratory tract illness; NO ⫽ nitric oxide; RSV ⫽ respiratory syncytial virus; Th1 ⫽ T helper type 1; Th2 ⫽ T helper type 2; URI ⫽ upper respiratory tract illness
prevalence of allergic respiratory diseases, T heasthma and allergic rhinoconjunctivitis, has increased dramatically since the advent of industrialization. Many hypotheses exist to explain this phenomena: better hygiene, fewer severe infections early in life due to treatment with antibiotics and vaccinations, the loss of some protective effect found in rural lifestyle, environmental pollution, and changes in dietary habits.1,2 All have merit and data to support their role, but the underlying theme is that the environment is changing to promote allergic disease. One assumption in all of these theories is *From Allergy Diagnostic, Beachwood, OH. Manuscript received August 27, 2001; revision accepted October 10, 2001. Correspondence to: Arthur E. Varner, MD, Allergy Diagnostic, 23250 Mercantile Rd, Beachwood, OH 44122; e-mail: Wiscart@ aol.com 1308
that the immune system of atopic individuals, characterized by the ability to produce T helper type 2 (Th2) type cytokines, large amounts of total as well as antigen-specific IgE in response to environmental exposures, tissue eosinophilia, and increased exhaled nitric oxide (NO),3–5 is of no advantage to the host. More specifically, there is no biological or evolutionary reason for allergic disease to exist in humans. I will suggest, however, with epidemiologic, historical, and immunologic data, that atopy and allergic respiratory disease exist today because they have been beneficial to survival in the past. Birth It is widely accepted that early in life, atopy is more prevalent in first-born children as well as male infants and children.6 None of the hypotheses preOpinions/Hypothesis
sented to date explain both observations. It is thought that an intrauterine Th2 environment is necessary to prevent maternal rejection of the fetus.7 The first-born child, as opposed to subsequent children, and perhaps male fetuses more so than female fetuses, are foreign to the mother’s innate immune response. To prevent T helper type 1 (Th1)-mediated rejection, the inherent ability of the mother’s and fetus’s immune systems to mount a protective Th2 response promotes successful pregnancy. Furthermore, delaying delivery until term would also best ensure the infant’s survival by promoting maturation of organ systems and transfer of protective maternal antibodies. The onset of labor is associated with an increase in cyclo-oxygenase-2 production of prostaglandin E2.8,9 Th2 cytokines inhibit cyclooxygenase-2 activity10 and permit the pregnancy to continue until term. Observations confirm atopy to be less common in premature infants as opposed to infants born at term or later11,12 and for parity to be increased in atopic as opposed to nonatopic mothers.13 Certainly, evolution would favor women with a greater ability not only to have children but also those more likely to have infants born at full gestation with the greatest chance for survival in the first year of life. This may explain why the ability to mount a Th2 response is good for survival during the course of human evolution. It does not explain, however, why atopy is more prevalent today.
Early Life The major causes of premature mortality in the recent past were infant mortality and childhood infectious diseases, including diarrhea and enteritis, pneumonia and influenza, tuberculosis, and diphtheria.14 Common wisdom suggests that a Th1 response is needed to control infections. However, perhaps reflecting the persistence of the Th2-type immunity required for in utero survival and term birth, all infants possess an immune response skewed toward a Th2 phenotype15 as well as a relative eosinophilia.16 In atopic infants, as opposed to nonatopic infants, this Th2 cytokine profile persists in the first year of life.17 Intuitively, this Th2-type response would seem to put the child at risk for infections; however, this may also be protective against some of the common infectious agents encountered early in life. It is accepted that a Th2 response is protective against enteric parasitic organisms, but surprisingly atopy itself may also confer protection.18 –21 This may have been of great benefit in the past, but with industrialization and better sanitation, respiratory, as opposed to enteric, infectious agents became the more common pathogens. Is there any evidence that atopy prevents respiratory infections? www.chestjournal.org
Supporting the hygiene hypothesis, Ball et al22 and Illi et al23 presented data suggesting that frequent respiratory infections early in life prevent the development of atopy and allergic respiratory disease. The converse explanation for their findings, that the predisposition to develop atopy prevents infections, is rarely considered. Prior to the development of antibiotics, the infant’s innate immune response would be required not only to defend against infection but also to minimize host damage to ensure survival.24 Most allergists tend to neglect that Th2 cytokines are also anti-inflammatory in many situations.21,24,25 From the same cohort of children, Halonen et al26 demonstrates that infants with elevated cord serum IgE levels had fewer lower respiratory tract illnesses (LRI) in the first 6 months of life and suggests that IgE antibodies may have a protective function in infants. He has also demonstrated that children with nonwheezing LRI were more acutely ill and more likely to have decreased levels of total serum IgE at 9 months of age.27 This suggests the atopic phenotype may attenuate the severity of the inflammatory response to common viral respiratory pathogens. Von Mutuis et al28 present similar data demonstrating an inverse relationship between total serum IgE and number of fever episodes during the first years of life. School-age children with atopic asthma were significantly less likely to suffer from fever episodes and needed fewer courses of antibiotics than nonatopic asthmatic children. In the atopic asthmatic children, both atopy and bronchial hyperresponsiveness independently were inversely related to fever and antibiotic use, suggesting allergic inflammation in the upper and lower airway reduces the severity of illness associated with common childhood respiratory viral pathogens. In accordance, Van Schaik et al29 and Garofolo et al30 provide data suggesting that young children with a Th2-type cytokine profile in nasal secretions were more likely to have a simple upper respiratory tract illness (URI) than a LRI. Preliminary data from the Childhood Origins of Asthma study31 demonstrate that decreased production of the Th2 cytokine interleukin-13 by phytohemagglutinin-stimulated cord blood mononuclear cells is a risk factor for lower respiratory tract symptoms and wheezing with respiratory syncytial virus (RSV) infection in the first year of life. Taken together in this different perspective, a Th2 response may reduce the frequency or severity (URI as opposed to LRI) of viral respiratory infection early in life and thus confer a survival advantage to the atopic infant and child, particularly in the early industrialization and preantibiotic era. CHEST / 121 / 4 / APRIL, 2002
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Industrialization and Migration Thus far, I have proposed that the propensity to develop a Th2 response and atopy may enhance survival by minimizing the inflammatory response to “danger” in the intrauterine and extrauterine environment early in life. As early as 1873, Blackley32 noted hay fever to be more prevalent in the educated and wealthy, as opposed to those in the lower socioeconomic class, despite the greater exposure to allergens of the latter: “As civilization and education advance, the disorder will become more common than at the present time.” Thus, the hygiene hypothesis has been considered a cause for the increase in atopic disease since the first recognition of the illness. The observation that children of farmers have less allergic disease than urban children has now directed the hygiene theory to search for some protective factor that is lost in modern living.33 By definition, the children of farmers have not been exposed to other environments. Thus, is the factor protecting rural children unique to their environment, such as endotoxin, or does tolerance develop through highdose exposure to local allergens? Against conventional wisdom, early life exposure to high levels of animal and pollen allergens has been associated with reduced allergen-specific sensitization, suggesting that immune tolerance can develop naturally.34 –36 Clinically, most allergists have the experience of seeing patients of all ages who develop allergic disease soon after moving to a new environment. This observation has been noted in 1930 in adult workers from the East moving to rural mining towns in California,37 in 1959 in immigrants migrating to an urban city,38 and more recently in children and adults of numerous ethnic groups migrating to new, and generally more Western, environments.39 Thus, those with an atopic predispostion become sensitized to the allergens present in their environment, as opposed to exposure to allergens causing atopy. This observation could explain why the prevalence of allergic disease is generally similar in different areas of the United States as well as the association of childhood asthma with different dominant allergens in different regions (ie, cockroach in poor urban areas, dust mite in the Southeast, and animal dander in cold, dry climates). It may also explain the initial observation by Blackley.32 That is, the educated in 1873 were those most likely to migrate to a new environment with different allergens or previously encountered allergens but at a different intensity of exposure. The rise of cities, improvement in transportation, and increasing frequency of migration and travel simply exposed the atopic nature of the human immune response. This suggests that by the late 1310
1800s, evolutionary forces had favored an immature and mature human immune system with the capacity to innately respond to new environments and antigens with a Th2-type immune response. As with infants and children, could the development of allergic inflammation protect adults against new respiratory pathogens until specific immunity was acquired?
The Flu of 1918 In the preantibiotic era, as industrialization and urbanization progressed and population centers grew, respiratory infections such as tuberculosis and influenza were responsible for much mortality. Epidemics of influenza were described more frequently in historical records with the rise of cities and were associated with much morbidity but little mortality except for the very young and the very old.40 Pandemics, however, in which no one was protected with acquired immunity as the virus was completely foreign to the human immune system, were associated with significant mortality, particularly in previously healthy young adults.41 The influenza pandemic of 1918, also known as the Spanish flu or Spanish Lady, is a neglected episode in the medical historical record, lost in the fury of World War I.42 A brush with disaster with the avian influenza A H5N1 virus that caused the Hong Kong flu of 199743 and work by Reid and Taubenberger44 in discovering the genetic code of the flu of 1918 revived interest. Both the virus of 1918 and the Hong Kong flu of 1997 were much more lethal than the usual influenza viruses. “City dwellers acquire some degree of immunity because they live in an atmosphere bearing infections. Country boys are more highly susceptible,” American epidemiologist Victor Vaughn remarked in 1918.45,46 In Cape Town in 1919, Duncan M. MacRae47 noted, “Further, 6 white patients with asthma and chronic bronchitis all contracted influenza and recovered without any complications.” Historical records and pathologic reports on the victims of influenza viruses in which no acquired immunity exists describe an infection with the typical acute onset of symptoms, including headache, coryza, fever, chills, and myalgias. Unlike epidemic influenza, where mortality is delayed and associated with secondary bacterial pneumonia, pandemic influenza is associated with early mortality and rapid onset of respiratory compromise with a systemic inflammatory response, changes consistent with a reactive hemophagocytic syndrome and hypercytokinemia of the Th1 type.48 –52 As no one had protective immunity against the virus in 1918, Vaughn’s obserOpinions/Hypothesis
vation suggests a protective effect of the immune response of atopic urban, as opposed to nonatopic rural,33 dwellers just as protection was observed in asthmatics in Cape Town. A recent study examining the effects of inhaled lipopolysaccharide on pulmonary and systemic responses demonstrated a reduced systemic response (fever, neutrophilia, and rise in serum acute-phase protein) in atopic individuals as opposed to nonatopic individuals.53 Thus, it is possible that the propensity to develop, or the presence of, allergic Th2-type inflammation could temper the severity of the innate Th1-type immune response in the lung to an unknown virus, prevent excessive systemic inflammation, and indeed be protective. Mortality data regarding the flu pandemic of 1918 reveal greater mortality in healthy young people as opposed to the normal excess of mortality seen in the young and old in a typical influenza epidemic.54 Even more curious, in various age, gender, ethnic, social, and occupational groups, there appears to be a consistent inverse relationship between the groups with excessive flu mortality rates in 1918 and allergic disease and asthma today (Table 1).42,46,54 – 65 If one assumes the immunologic genotypes and phenotypes of these groups have been stable over the last 80 years, this would suggest a protective effect of atopy against a respiratory viral infection never before encountered by humans and reflect a potential survival advantage in young adults and their offspring. Antiviral Mechanisms of Allergic Inflammation What are the potential mechanisms by which allergic inflammation would protect against infecTable 1—Inverse Relation Between Excessive Influenza Mortality in 1918 and Allergy/Asthma Today
Groups
Influenza Mortality 1918
Male subjects ⬍ 14 yr old Female subjects ⬍ 14 yr old Male subjects aged 20–54 yr Female subjects aged 20–54 yr American Indians American Eskimos Urban soldiers Rural soldiers African Americans Puerto Rican soldiers Immigrants from Western Europe Immigrants from Eastern Europe Cordite and gas works employees
2 1 1 2 1 1 2 1 2 2 2 1 2
*1 ⫽ increased; 2 ⫽ decreased . www.chestjournal.org
Prevalence Asthma/ Allergy Reference Today No. 1 2 2 1 2 2 1 2 1 1 1 2 1
54 54 54 54 55,56 42p241,57 33,46 33,46 58 59–61 42p227,62 42p227,62 63–65
tions? Most data suggest that Th1 responses are required for viral clearance but Th1 cytokines such as interferon-␥ can also enhance the inflammatory response.66 Allergic airway responses are characterized by Th2 cytokines, increased production of total and allergen-specific IgE, tissue eosinophilia, and elevated exhaled NO in the lower airway, and are thought to be ineffective against viral infection and perhaps even detrimental.67– 69 However, Avila et al69 demonstrated the opposite with experimental rhinovirus infection in atopic individuals. Allergic individuals primed with allergen to induce active allergic inflammation of the nasal mucosa prior to infection experienced a delay in the onset, a reduction in severity, and a shorter duration of cold symptoms as compared to those not primed with allergen. Total cell counts, neutrophils, and IL-6 and IL-8 levels in nasal lavage samples were all reduced in those primed with allergen. As the host response to infection,70 not the virus itself, reflects the severity of cold symptoms, allergic inflammation was “protective.”71 Indeed the number of eosinophils, the hallmark inflammatory cell representing allergic inflammation, was inversely correlated to the severity of symptoms. Th2 Cytokines Little data exist to suggest that Th2 cytokines themselves are antiviral, but their anti-inflammatory properties appear to modulate the host response to virus. Levels of IL-8, a potent neutrophil chemoattractant, are directly related to the severity of symptoms observed with respiratory viral infections in the upper and lower airway.72–74 Th2 cytokines such as IL-4 and IL-13 can inhibit IL-8 production by airway epithelial cells and airway smooth-muscle cells when stimulated with ragweed75 and inflammatory cytokines.76,77 Specifically in regards to RSV infection in infants and children, a predominant Th2 response in nasopharyngeal secretions29,30 as well as in stimulated peripheral blood cells has been associated with simple URI as opposed to bronchiolitis or pneumonia.78 Macrophage inflammatory protein-1, which has been associated with more severe RSV infections,30 is inhibited by Th2 cytokines.79 IgE As stated by Halonen et al,26 there is no known antiviral effect mediated by IgE. Th2 cytokines, primarily IL-4 and IL-13, regulate IgE production. Thus, a lack of IgE may reflect the inability to produce such cytokines. A familial syndrome of recurrent sinopulmonary viral and bacterial infections and subsequent lung function impairment has CHEST / 121 / 4 / APRIL, 2002
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been described in patients with decreased or no measurable serum IgE but without other demonstrable immune deficits.80 At the other extreme, in patients with hyperimmunoglobulin E and recurrent infections (Job’s) syndrome, the incidence of infection at mucosal surfaces and adjacent lymph nodes correlated inversely with serum anti-Staphylococcus aureus IgE and total serum IgE.81 This suggests a beneficial antibacterial effect of IgE itself or, more likely, the cytokine response that favors IgE production promotes appropriate resolution of inflammation induced by viral respiratory infection.
rhinovirus infection and cytokine production in respiratory epithelial cells.91,92 NO may have other beneficial effects on respiratory infection by a variety of pathogens including bacteria93 and mycobacteria.94 Indeed the highest levels of NO in the human body are found in the paranasal sinuses,95 which is a rare site for tuberculosis infection.96 Perhaps it is possible that the inverse relationship between tuberculosis and allergic disease may not be secondary to the immunomodulatory effects of tuberculosis infection, but rather the protective effect of airway NO on infection itself.97,98
Eosinophils
Implications for Treatment of Allergic Disease
In the study by Avila et al,69 eosinophils appeared to be responsible for the antiviral effect in rhinovirus infection. Reports by Domachowske et al82– 84 demonstrated antiviral effects of eosinophil products in vitro against RSV. In an animal model of viral infection, Adamko et al85 demonstrated in vivo the antiviral effect of eosinophils against parainfluenza virus. If infection in the first few months of life is an important determinant of subsequent atopy,22,23 it is interesting to note the antiviral effect of eosinophils is effective against the most common pediatric respiratory viral pathogens: rhinovirus, RSV, and parainfluenza virus. In infants at high risk for allergic disease, elevated levels of eosinophil cationic protein and eosinophil protein X have been demonstrated in nasal lavage fluid obtained in the first month of life.86 The presence of activated eosinophils in the upper airway of these children may reflect atopy as well as protection against viral infection (runny nose) in the first year of life.23 In regards to influenza virus and the seemingly protective effect of atopy against the flu of 1918, airway eosinophils may be required for this protection. In this regard it is of interest to note that inhaled corticosteroids used in the treatment of asthma not only reduce Th2 cytokines,87 airway eosinophilia, and exhaled NO, but also increase the risk for influenza and viral infection.88 This natural resistance to influenza may also be inferred by the lack of data regarding the efficacy of influenza vaccination in preventing infection in patients with asthma,89 as opposed to other forms of nonallergic chronic obstructive lung disease.90
If indeed atopy and allergic respiratory disease confer some survival advantage, are our current treatments appropriate? Inhaled corticosteroids are the primary treatment for persistent asthma and rhinitis and are thought to suppress Th2-like inflammation but not Th1 responses.87 Yet, nondiscriminate suppression of Th2 responses leads to a reduction in eosinophils, anti-inflammatory Th2 cytokines,99 and exhaled NO, and thus may enhance susceptibility to or severity of viral infection. Indeed, inhaled steroids are less effective against viral-induced wheezing than other triggers of asthma exacerbations100 and increase adverse sequelae of viral infection, such as otitis media in children, when used in the upper airway.101 Even avoidance measures34 –36,68,69 and other treatments for symptoms such as sneezing and coughing102–103 may be detrimental if indeed symptoms of active allergic inflammation are beneficial, much like the protective “weep and sweep” response observed with GI parasitic infections. Perhaps treatment such as allergen-specific immunotherapy, which can provide symptom control,104 the potential for long-term remission,104 and possible prevention of the development of new allergen sensitivities and asthma,105–109 would be more appropriate. This form of treatment, whether its mechanism of action is the induction of specific immune tolerance or shifting the immune response to specific allergens from Th2 to Th1, avoids global and nonspecific suppression of allergic and Th2-type inflammatory mechanisms that may be of benefit to the atopic individual when faced with viral infection.88,101,109
Conclusion NO Exhaled NO is elevated in patients with asthma and atopy.3–5 NO has been demonstrated to inhibit 1312
This hypothesis regarding the increase in respiratory allergic disease differs from others in one important respect—there may indeed be a reason for this trend, the evolutionary advantage of atopy. Opinions/Hypothesis
Allergic and Th2 immune responses ensure parity, successful pregnancy, and term birth; provide the infant protection against infections and the inflammation induced by common pathogens in the first years of life until the immune system matures; and protect young adults exposed to new respiratory pathogens such as the flu of 1918. These traits are of particular value with the advent of industrialization, improved transportation and increased migration, and the development of dense population centers with exposures to new allergens as well as respiratory pathogens. The greatest effect of this survival advantage would have manifest during the early industrialization era prior to the development of antibiotics. Consistent with an evolutionary advantage, this protective effect is greatest during the first several decades of life and may become negligible against the chronic illnesses of later life such as cardiovascular disease and cancer.110,111 This review is contrary to current belief, though never substantiated71 and somewhat paradoxical in the sense of the hygiene hypothesis, that atopic patients experience more frequent and severe infections. It certainly does not explain the mechanism of viral-induced asthma exacerbations, but many other forces are driving the increase in symptomatic allergic respiratory disease in modern societies, particularly asthma, which has become somewhat dissociated from atopy.1,2,112–114 Current treatments for allergic rhinoconjunctivitis and asthma control symptoms but are not curative and may even enhance progression of the diseases115–119 and possibly increase morbidity associated with viral infection.69,88,101 Ongoing investigations such as the Childhood Origins of Asthma study will help to define immunologic phenotypes present at birth and the interaction between viral infection, atopy, and asthma. Results of this study and the thoughts presented in this review should be considered before embracing methods to enhance Th1 and suppress Th2 immune responses as treatments for allergic diseases.120 –124
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References 1 Seaton A, Godden DJ, Brown K. Increase in asthma: a more toxic environment or a more susceptible population? Thorax 1994; 49:171–174 2 Strannegard O, Strannegard I-L. The causes of the increasing prevalence of allergy: is atopy a microbial deprivation disorder? Allergy 2001; 56:91–102 3 Franklin PJ, Taplin R, Stick SM. A community health study of exhaled nitric oxide in healthy children. Am J Respir Crit Care Med 1999; 159:69 –73 4 Ho L-P, Wood FT, Robson A, et al. Atopy influences exhaled nitric oxide in adult asthmatics. Chest 2000; 118: 1327–1331 5 Moody A, Fergusson W, Wells A, et al. Increased nitric www.chestjournal.org
23 24 25
26
oxide production in the respiratory tract in asymptomatic Pacific Islanders: an association with skin prick reactivity to house dust mite. J Allergy Clin Immunol 2000; 105:895– 899 Strachan DP. Hay fever, hygiene, and household size. BMJ 1989; 299:1259 –1260 Wegmann TG, Lin H, Guilbert L, et al. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today 1993; 14:353–356 Kniss DA, Iams JD. Regulation of parturition update: endocrine and paracrine effectors of term and preterm labor. Clin Perinatol 1998; 25:819 – 836 Gordon MC, Samuels P. Indomethacin. Clin Obstet Gynecol 1995; 38:697–705 Varner AE. The cyclooxygenase-2 theory of atopy and asthma. Pediatr Asthma Allergy Immunol 1999; 13:43–50 Pekkanen J, Xu B, Jarvelin M-R. Gestational age and occurrence of atopy at age 31: a prospective birth cohort study in Finland. Clin Exp Allergy 2001; 31:95–102 Siltanen M, Kajosaari M, Pohjavuori M, et al. Prematurity at birth reduces the long-term risk of atopy. J Allergy Clin Immunol 2001; 107:229 –234 Nilsson L, Kjellman NI, Lofman O, et al. Parity among atopic and non-atopic mothers. Pediatr Allergy Immunol 1997; 3:134 –136 Centers for Disease Control and Prevention. Achievements in Public Health, 1999: control of infectious diseases. MMWR Morb Mortal Wkly Rep 1999; 48:621– 629 Prescott SL, Macaubas C, Holt BJ, et al. Transplacental priming of the human immune system to environmental allergens: universal skewing of initial T cell responses toward the Th2 cytokine profile. J Immunol 1998; 160:4730 – 4737 Camitta BM. The anemias. In: Behrman RE, Kliegman RM, Arvin AM, eds. Nelson textbook of pediatrics. 15th ed. Philadelphia, PA: W.B. Saunders, 1996; 1379 Prescott SL, Macaubas C, Smallacombe T, et al. Development of allergen-specific T-cell memory in atopic and normal children. Lancet 1999; 353:196 –200 Lynch NR, Hagel IA, Palenque ME, et al. Relationship between helminthic infection and IgE response in atopic and nonatopic children in a tropical environment. J Allergy Clin Immunol 1998; 101:217–221 Openshaw PJM, O’Donnell DR. Asthma and the common cold: can viruses imitate worms? Thorax 1994; 49:101–103 McSharry C, Xia Y, Holland CV, et al. Natural immunity to Ascaris lumbricoides associated with immunoglobulin E antibody to ABA-1 allergen and inflammation indicators in children. Infect Immun 1999; 67:484 – 489 Finkelman FD, Urban JF. The other side of the coin: the protective role of Th2 cytokines. J Allergy Clin Immunol 2001; 107:772–780 Ball TM, Castro-Rodriguez JA, Griffith KA, et al. Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N Engl J Med 2000; 343:538 –543 Illi S, von Mutuis E, Lau S, et al. Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study. BMJ 2001; 322:390 –395 Spellberg B, Edwards JE Jr. Type 1/type 2 immunity in infectious diseases. Clin Infect Dis 2001; 32:76 –102 Van Roon JAG, Lafeber FPJG, Bijlsma JWJ. Synergistic activity of interleukin-4 and interleukin-10 in suppression of inflammation and joint destruction in rheumatoid arthritis. Arthritis Rheum 2001; 44:3–12 Halonen M, Stern D, Taussig LM, et al. The predictive relationship between serum IgE levels at birth and subsequent incidences of lower respiratory illnesses and eczema in infants. Am Rev Respir Dis 1992; 146:866 – 870 CHEST / 121 / 4 / APRIL, 2002
1313
27 Martinez FD, Stern DA, Wright AL, et al. Association of non-wheezing lower respiratory tract illnesses in early life with persistently diminished serum IgE levels. Thorax 1995; 50:1067–1072 28 Von Mutuis E, Illi S, Hirsch T, et al. Frequency of infections and risk of asthma, atopy and airway hyperresponsiveness in children. Eur Respir J 1999; 14:4 –11 29 Van Schaik S, Tristam DA, Nagpal IS, et al. Increased production of IFN-␥ and cysteinyl leukotrienes in virusinduced wheezing. J Allergy Clin Immunol 1999; 103:630 – 636 30 Garofalo RP, Patti J, Hintz KA, et al. Macrophage inflammatory protein-1 (not T helper type 2 cytokines) is associated with severe forms of respiratory syncytial bronchiolitis. J Infect Dis 2001; 184:292–399 31 Brooks GD, Anklam KS, Roberg KA, et al. Reduced newborn mononuclear cell production of interleukin-5 (IL-5) and interleukin-13 (IL-13) is associated with wheezing in the first year of life [abstract]. J Allergy Clin Immunol 2001; 107:S65 32 Blackley C. Experimental researches on catarrhus aestivus. London, UK: Bailliere, Tindall and Cox, 1873 33 Von Ehrenstein OS, von Mutuis E, Illi S, et al. Reduced risk of hay fever and asthma among children of farmers. Clin Exp Allergy 2000; 30:187–193 34 Platts-Mills T, Vaughn J, Squillace S, et al. Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross sectional study. Lancet 2001; 357:752–756 35 Nilsson L, Bjorksten B, Hattevig G, et al. Season of birth as predictor of atopic manifestations. Arch Dis Child 1997; 76:341–344 36 Hesselmar B, Aberg N, Aberg B, et al. Does early exposure to cat or dog protect against later allergy development? Clin Exp Allergy 1999; 29:611– 617 37 Piness G, Miller H. An unusual opportunity to make an allergic study of an entire community with the etiology and results of treatment. J Allergy 1930; 1:117–123 38 Fine AJ, Abram LE. The period of sensitization in immigrant hay fever patients. J Allergy 1960; 31:375–380 39 Leung R. Asthma, allergy and atopy in South-East Asian immigrants in Australia. Aust N Z J Med 1994; 24:255–257 40 Patterson KD. Pandemic influenza 1700 –1900: a study in historical epidemiology. Totowa, NJ: Rowman and Littlefield, 1986 41 Simonsen L, Clarke MJ, Schonberger LB, et al. Pandemic versus epidemic influenza mortality: a pattern of changing age distribution. J Infect Dis 1998; 178:53– 60 42 Crosby AW. America’s forgotten pandemic: the influenza of 1918. Cambridge UK: Cambridge University Press, 1989 43 Yuen KY, Chan PKS, Peiris M, et al. Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet 1998; 351:467– 471 44 Reid AH, Taubenberger JK. The flu and other influenza pandemics: “over there” and back again. Lab Invest 1999; 79:95–101 45 Iezzoni L. Influenza 1918: the worst epidemic in American history. New York, NY: TV Books, LLC, 1999; 79 46 Love AG, Davenport CB. Immunity of city-bred recruits. Arch Intern Med 1919; 24:129 –153 47 MacRae DM. Influenza and chronic lung disease. Lancet 1919; 281 48 To K-F, Chan PKS, Chan K-F, et al. Pathology of fatal human infection associated with avian influenza A H5N1 virus. J Med Virol 2001; 63:242–246 49 Kimura K, Adlakha A, Simon PM. Fatal case of swine 1314
50
51 52
53
54
55 56 57 58 59 60 61
62
63 64
65 66
67 68 69
70
influenza virus in an immunocompetent host. Mayo Clin Proc 1998; 73:243–245 Bone RC. Immunologic dissonance: a continuing evolution in our understanding of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS). Ann Intern Med 1996; 125:680 – 687 Tsuda H. Hemophagocytic syndrome (HPS) in children and adults. Int J Hematol 1997; 65:215–226 Akashi K, Hayashi S, Gondo H, et al. Involvement of interferon-␥ and macrophage colony-stimulating factor in the pathogenesis of haemophagocytic lymphohistiocytosis in adults. Br J Haematol 1994; 87:243–250 Michel O, Dentener M, Corazza F, et al. Healthy subjects express differences in clinical responses to inhaled lipopolysaccharide that are related with inflammation and with atopy. J Allergy Clin Immunol 2001; 107:797– 804 Collins SD. Age and sex incidence of influenza and pneumonia morbidity and mortality in the epidemic of 1928 –29 with comparative data for the epidemic of 1918 –19. Public Health Rep 1931; 46:33 Influenza among American Indians. Public Health Rep 1919; 34:1008 –1009 Rhoades ER. The major respiratory diseases of American Indians. Am Rev Respir Dis 1990; 141:595– 600 Herxheimer H, Schaefer O. Asthma in Canadian Eskimos [letter]. N Engl J Med 1974; 291:1419 Frankel LK, Dublin LI. Influenza mortality among wage earners and the families: a preliminary statement of results. Am J Public Health 19:731–742 Office of the Surgeon General Medical Department, US Army. 1919, 9; 94 Beckett WS, Belanger K, Gent JF, et al. Asthma among Puerto Rican Hispanics: a multi-ethnic comparison study of risk factors. Am J Respir Crit Care Med 1996; 154:894 – 899 Ledogar RJ, Penchaszadeh A, Garden CCI, et al. Asthma and Latino cultures: different prevalence reported among groups sharing the same environment. Am J Public Health 2000; 90:929 –935 Beasley R, Keil U, von Mutuis E, et al, for the NISAAC Steering Committee. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis and atopic eczema: ISAAC. Lancet 1998; 351:1225–1232 Gregor A. A note on the epidemiology of influenza among workers in gas works, in a cordite factory, and in a tin mine. BMJ 1919; 242–243 Park J-K, Kim Y-K, Lee S-R, et al. Repeated exposure to low levels of sulfur dioxide (SO2) enhances the development of ovalbumin-induced asthmatic reactions in guinea pigs. Ann Allergy Asthma Immunol 2001; 86:62– 67 Balmes JR, Fine JM, Christian D, et al. Acidity potentiates bronchoconstriction induced by hypoosmolar aerosols. Am Rev Respir Dis 1988; 138:35–39 Van Schaik SM, Obot N, Enhorning G, et al. Role of interferon ␥ in the pathogenesis of primary respiratory syncytial virus infection in BALB/c mice. J Med Virol 2000; 62:257–266 Busse WW. The relationship between viral infections and onset of allergic diseases and asthma. Clin Exp Allergy 1989; 19:1–9 Bardin PG, Fraenkel DJ, Sanderson G, et al. Amplified rhinovirus colds in atopic subjects. Clin Exp Allergy 1994; 24:457– 464 Avila PC, Abisheganaden JA, Wong H, et al. Effects of allergic inflammation of the nasal mucosa on the severity of rhinovirus 16 cold. J Allergy Clin Immunol 2000; 105:923– 932 Hendley JO. Editorial comment: the host response, not the Opinions/Hypothesis
71
72
73 74 75 76
77
78
79
80 81
82
83
84 85
86
87
virus, causes the symptoms of the common cold. Clin Infect Dis 1998; 26:847– 848 Busse WW, Gern JE. Do allergies protect against the effects of a rhinovirus cold? J Allergy Clin Immunol 2000; 105:889 – 891 Turner RB, Weingand KW, Yeh C-H, et al. Association between interleukin-8 concentration in nasal secretions and severity of symptoms of experimental rhinovirus colds. Clin Infect Dis 1998; 26:840 – 846 Hull J, Thomsom A, Kwiatkowski D. Association of respiratory syncytial virus bronchiolitis with the interleukin 8 gene region in UK families. Thorax 2000; 55:1023–1027 Bont L, Heijnen CJ, Kavelaars A, et al. Peripheral blood cytokine responses and disease severity in respiratory syncytial virus bronchiolitis. Eur Respir J 1999; 14:144 –149 Chen W, Hunninghake GW. Effects of ragweed and Th-2 cytokines on the secretion of IL-8 in human airway epithelial cells. Exp Lung Res 2000; 26:229 –239 Fujisawa T, Kato Y, Atsuta J, et al. Chemokine production by the BEAS-2B human bronchial epithelial cells: differential regulation of eotaxin, IL-8, and RANTES by TH2- and TH1-derived cytokines. J Allergy Clin Immunol 2000; 105: 126 –133 John M, Au B-T, Jose PJ, et al. Expression and release of interleukin-8 by human airway smooth muscle cells: inhibition by Th-2 cytokines and corticosteroids. Am J Respir Cell Mol Biol 1998; 18:84 –90 Bendelja K, Gagro A, Bace A, et al. Predominant type-2 response in infants with respiratory syncytial virus (RSV) infection demonstrated by cytokine flow cytometry. Clin Exp Immunol 2000; 121:332–338 Berkman N, John M, Roesems G, et al. Interleukin-13 inhibits macrophage inflammatory protein-1␣ production from human alveolar macrophages and monocytes. Am J Respir Cell Mol Biol 1996; 15:382–389 Schoettler JJ, Schleissner LA, Heiner DC. Familial IgE deficiency associated with sinopulmonary disease. Chest 1989; 96:516 –521 Dreskin SC, Goldsmith PK, Gallin JI. Immunoglobulins in the hyperimmunoglobulin E and recurrent infection (Job’s) syndrome: deficiency of anti-Staphylococcus aureus immunoglobulin A. J Clin Invest 1985; 75:26 –34 Domachowske JB, Dyer KD, Adams AG, et al. Eosinophil cationic protein/RNase 3 is another A-family ribonuclease with direct antiviral activity. Nucleic Acids Res 1998; 26: 3358 –3363 Domachowske JB, Bonville CA, Dyer KD, et al. Evolution of antiviral activity in the ribonuclease A gene superfamily: evidence for a specific interaction between eosinophilderived neurotoxin (EDN/RNase 2) and respiratory syncytial virus. Nucleic Acids Res 1998; 26:5327–5332 Rosenberg HF, Domachowske JB. Eosinophils, ribonucleases and host defense: solving the puzzle. Immunol Res 1999; 20:261–274 Adamko DJ, Yost BL, Gleich GJ, et al. Ovalbumin sensitization changes the inflammatory response to subsequent Parainfluenza infection: eosinophils mediate airway hyperresponsiveness, M2 muscarinic receptor dysfunction, and antiviral effects. J Exp Med 1999; 190:1465–1477 Halmerbauer G, Gartner C, Koller D, et al. Eosinophil cationic protein and eosinophil protein X in the nasal lavage of children during the first 4 weeks of life. Allergy 2000; 55:1121–1126 Umland SP, Nahrebne DK, Razac S, et al. The inhibitory effects of topically active glucocorticoids on IL-4, IL-5, and interferon-␥ production by cultured primary CD4⫹ T cells. J Allergy Clin Immunol 1997; 100:511–519
www.chestjournal.org
88 Physicians desk reference. 55th ed. Montvale, NJ: Medical Economics Company, 2001 89 Cates CJ, Jefferson TO, Bara AI, et al. Vaccines for preventing influenza in people with asthma (Cochrane Review). Cochrane Database Syst Rev 2000; 4:CD000364 90 Poole PJ, Chacko E, Wood-Baker RW, et al. Influenza vaccine for patients with chronic obstructive pulmonary disease (Cochrane Review). Cochrane Database Syst Rev 2000; 4:CD002733 91 Sanders SP, Siekierski ES, Porter JD, et al. Nitric oxide inhibits rhinovirus-induced cytokine production and viral replication in a human respiratory epithelial cell line. J Virol 1998; 72:934 –942 92 Sanders SP. Asthma, viruses, and nitric oxide. Proc Soc Exp Biol Med 1999; 220:123–132 93 Fang FC. Mechanisms of nitric oxide-related antimicrobial activity. J Clin Invest 1997; 99:2818 –2825 94 MacMicking JD, North RJ, LaCourse R, et al. Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc Natl Acad Sci U S A 1997; 94:5243–5248 95 Lundberg JO, Farkas-Szallasi T, Weitzberg E, et al. High nitric oxide production in human paranasal sinuses. Nat Med 1995; 1:370 –373 96 Myerson MC. Tuberculosis of the ear, nose, and throat. Springfield, IL: C.C. Thomas, 1944 97 Shirakawa T, Enomoto T, Shimazu S, et al. The inverse association between tuberculin responses and atopic disorder. Science 1997; 275:77–79 98 Von Mutuis E, Pearce N, Beasley R, et al. International patterns of tuberculosis and the prevalence of asthma, rhinitis, and eczema. Thorax 2000; 55:449 – 453 99 Kita H, Jorgensen RK, Reed CE, et al. Mechanism of topical glucocorticoid treatment of hay fever: IL-5 and eosinophil activation during natural allergen exposure are suppressed, but IL-4, IL-6, and IgE antibody production are unaffected. J Allergy Clin Immunol 2000; 106:521–529 100 McKean M, Ducharme F. Inhaled steroids for episodic viral wheeze of childhood. Cochrane Database Syst Rev 2000; 2:CD001107 101 Ruohola A, Heikkinen T, Waris M, et al. Intranasal fluticasone propionate does not prevent acute otitis media during viral upper respiratory infection in children. J Allergy Clin Immunol 2000; 106:467– 471 102 Gwaltney JM Jr, Hendley JO, Phillips CD, et al. Nose blowing propels nasal fluid into the paranasal sinuses. Clin Infect Dis 2000; 30:387–391 103 Van Ganse E, Van der Linden P, Leufkens HGM, et al. Antiallergic and antitussive medications: extent of use and relationship to asthma exacerbations. Therapie 1996; 51: 373–377 104 Durham SR, Walker SM, Varga EM, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med 1999; 341:468 – 475 105 Des Roches A, Paradis L, Menardo JL, et al. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract: VI. Specific immunotherapy prevents the onset of new sensitizations in children. J Allergy Clin Immunol 1997; 99:450 – 453 106 Purello-D’Ambrosio F, Gangemi S, Merendino RA, et al. Prevention of new sensitizations in monosensitized subjects submitted to specific immunotherapy or not: a retrospective study. Clin Exp Allergy 2001; 31:1295–1302 107 Grembiale RD, Camporota L, Naty S, et al. Effects of specific immunotherapy in allergic rhinitis individuals with bronchial hyperresponsiveness. Am J Respir Crit Care Med 2000; 162:2048 –2052 108 Walker SM, Pajno GB, Lima MT, et al. Grass pollen CHEST / 121 / 4 / APRIL, 2002
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112
113 114 115
116
immunotherapy for seasonal rhinitis and asthma: a randomized, controlled trial. J Allergy Clin Immunol 2001; 107: 87–93 Parker RA, Hartman EE. A 48-year-old man with recurrent sinusitis, 1 year later [letter]. JAMA 2001; 286:2594 Gergen PJ, Turkeltaub PC, Sempos CT. Is allergen skin test reactivity a predictor of mortality? Findings from a national cohort. Clin Exp Allergy 2000; 30:1717–1723 Hospers JJ, Rijcken B, Schouten JP, et al. Eosinophilia and positive skin tests predict cardiovascular mortality in a general population sample followed for 30 years. Am J Epidemiol 1999; 150:482– 491 Varner AE, Busse WW, Lemanske RF Jr. Hypothesis: decreased use of pediatric aspirin has contributed to the increasing prevalence of childhood asthma. Ann Allergy Asthma Immunol 1998; 81:347–351 Newson RB, Shaheen SO, Chinn S, et al. Paracetamol sales and atopic disease in children and adults: an ecological analysis. Eur Respir J 2000; 16:817– 823 Kuehni CE, Davis A, Brooke AM, et al. Are all wheezing disorders in very young (preschool) children increasing in prevalence? Lancet 2001; 357:1821–1825 Gauvreau GM, Jordana M, Watson RM, et al. Effect of regular inhaled albuterol on allergen-induced late responses and sputum eosinophils in asthmatic subjects. Am J Respir Crit Care Med 1997; 156:1738 –1745 Fedyk ER, Adawi A, Looney RJ, et al. Regulation of IgE and cytokine production by cAMP: implications for extrinsic asthma. Clin Immunol Immunopathol 1996; 81:101–113
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117 The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000; 343:1054 –1063 118 Salvi SS, Babu KS, Holgate ST. Glucocorticoids enhance IgE synthesis: are we heading towards new paradigms? Clin Exp Allergy 2000; 30:1499 –1505 119 Barnes PJ. Corticosteroids, IgE, and atopy. J Clin Invest 2001; 107:265–266 120 Hansen G, Berry G, DeKruyff RH, et al. Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation. J Clin Invest 1999; 103:175–183 121 Magone MT, Whitcup SM, Fukushima A, et al. The role of IL-12 in the induction of late-phase cellular infiltration in a murine model of allergic conjunctivitis. J Allergy Clin Immunol 2000; 105:299 –308 122 Bryan SA, O’Connor BJ, Matti S, et al. Effects of recombinant human interleukin-12 on eosinophils, airway hyperresponsiveness, and the late asthmatic response. Lancet 2000; 356:2149 –2153 123 Arkwright PD, David TJ. Intradermal administration of a killed Mycobacterium vaccae suspension (SRL 172) is associated with improvement in atopic dermatitis in children with moderate-to-severe disease. J Allergy Clin Immunol 2001; 107:531–534 124 Storm van Lleeuwen W, Varekamp H. On the tuberculin treatment of bronchial asthma and hay fever. Lancet 1921; 1366 –1369
Opinions/Hypothesis