What Determines Asthma Phenotype?
Respiratory Infections and Asthma

JO A. DOUGLASS and ROBYN E. O'HEHIR

Department of Allergy, Asthma, and Clinical Immunology, Alfred Hospital and Monash University, Prahran, Australia

	INTRODUCTION

TOP INTRODUCTION INFECTIONS AND ATOPY THE ROLE OF VIRAL... ACUTE EXACERBATIONS OF ASTHMA THE ROLE OF BACTERIAL... THE ROLE OF OBLIGATE... THE ROLE OF PARASITIC... CONCLUSIONS IMPORTANT QUESTIONS REFERENCES

The increase in recognition and understanding of asthma as an immune-mediated disease has provided greater insights into both the etiology and pathology of the disorder. Because infections have profound effects on the immune system, orchestrating changes in humoral and cell-mediated responses, they influence both the pathogenesis of asthma and its ongoing status. Data regarding respiratory tract and systemic infections have increased our understanding of both the underlying immune genesis of asthma and the acute inflammatory airway changes that occur during asthma. This review deals with both these aspects of respiratory infections.

	INFECTIONS AND ATOPY

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The atopic state is one of the most important predictors of the presence and persistence of asthma. Examination of the consequences and influences of infections on the determination of atopy are relevant to the role of infections in asthma.

In the intrauterine environment the fetus is exposed to maternally ingested antigens. It has been proven from studies of cord blood cells that primary sensitization to environmental antigens may occur in utero (1). Moreover, in fetal life placentally derived helper T cell type 2 (Th2)-trophic factors, particularly interleukin 4 (IL-4), are responsible for generalized immune deviation to Th2 responses likely to generate an allergic humoral response (2). However, acquisition of the atopic state requires further immune stimulation during infancy. It is during early extrauterine life that the immune system may be most influenced by exposure to infectious agents.

In a seminal study, Shirakawa and colleagues reported that children who had been exposed to Mycobacterium tuberculosis in the first 12 yr of life had lower IgE levels, lower serum Th2 cytokine profiles, and a lower prevalence of the allergic diseases of asthma, rhinitis, and eczema compared with their peers who had not been exposed (3). However, no individuals were identified in this study with clear evidence of M. tuberculosis infection and nearly all children were vaccinated early in life with BCG. Consequently, an alternative explanation of these data may be that individuals who are to develop atopy have a lowered capacity to develop Th1 memory to BCG vaccination. Controversially, however, immunization soon after birth with the BCG vaccine, a common procedure in some countries, does not appear to confer protection against the development of atopy and atopic disease (4).

The observed protection from atopic disease conferred by exposure to M. tuberculosis has been attributed to the ability of M. tuberculosis infection to drive Th1 cellular responses. Other systemic infections also appear to confer such protection. Italian adult military recruits with serological evidence of past hepatitis A infection had a lower prevalence of atopy and allergic disease (5) and a similar relationship has been reported by Shaheen and coworkers concerning past infection with measles virus (6). This protection has been attributed to the propensity of viral infections to deviate the immune response toward a Th1 cytokine profile. However, a conflicting interpretation of the study by Shaheen and coworkers might be that measles vaccination is associated with an increased prevalence of atopy.

Interestingly, having three or more older siblings is an equivalent protective factor from allergic disease and atopy as a positive hepatitis A serology, suggesting that a multitude of infections acquired from older siblings may be protective in preventing the development of atopy. Several other epidemiological studies have also concluded that the presence of multiple older siblings is protective against the development of asthma and atopy (7).

Not all studies of this nature have correlated a history of infections early in life with a protective effect of sibship. Bodner and co-workers found that exposure to a larger number of infections before the age of 3 yr correlated with an increased odds ratio for asthma (8). However, most retrospective studies have supported an inverse relationship between respiratory infections in the first 3 yr of life and atopic disease, which is consistent with the hypothesis that exposure of the immune system to infective agents at this time skews the cytokine profile of T cell populations toward a Th1 phenotype. Further evidence may be gained from studies in Australian Aboriginal communities in which children have a low prevalence of asthma but an extremely high prevalence of chronic purulent upper respiratory tract disorders, suggesting a causative association (9).

	THE ROLE OF VIRAL INFECTIONS AND ASTHMA

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Pathology of Viral Infections

Viral infections of the respiratory tract primarily target the bronchial epithelium where the nature of the virus determines the degree of damage to and denudation of the epithelium. For some viruses, such as rhinovirus, infection is not generally associated with epithelial denudation, although there is clear evidence of mucosal infiltration by lymphocytes and eosinophils. Conversely, respiratory syncytial virus (RSV) infection is associated with widespread epithelial denudation, as is influenza virus infection. Loss of airway epithelial integrity may lead to increased exposure and activation of the airway neural pathways contributing to bronchoconstriction. In addition, loss of epithelial integrity is likely to affect airway wall nitric oxide secretion, an important agent regulating airway smooth muscle tone (10).

The bronchial epithelium is a major source of the proinflammatory cytokines that are induced on viral infection. Interleukin 8 has been demonstrated to be released within 24 h of infection of epithelial cell lines with RSV (11) and rhinovirus (12), while other cytokines including IL-6 (13), granulocyte-macrophage colony-stimulating factor (GM-CSF) (13), RANTES (14), and IL-10 (15) have also been detected after viral infection. Secretion of RANTES and GM-CSF may be particularly important in the generation of eosinophilic inflammation, because of the roles of these cytokines in eosinophil maturation and cell movement.

Other airway cells are involved in the pathology of viral infections. Vascular endothelium and airway epithelium may be stimulated by the virally induced cytokine milieu to increase adhesion of molecule expression, facilitating inflammatory cell infiltration. In particular, nonspecific T cell recruitment occurs to the lungs in viral infection. Natural killer cells and CD8⁺ T cells both secrete large amounts of interferon  (IFN-) in response to viral infections, and lyse infected cells. Interferon  secretion from lymphocytes caused by viral infections may also enhance eosinophil secretion of superoxide and basophil histamine release, both events classically associated with allergic inflammation (16). In contrast, CD4⁺ T cells are not directly cytotoxic for viruses but do secrete critical cytokines. Secretion of IL-4 has been shown to delay viral clearance (17) and some virus infections, in particular RSV, appear to promote a Th2-dominant cytokine profile from antigen-specific T cells and, therefore, promote eosinophilia (18).

Respiratory Syncytial Virus Infections

Respiratory syncytial virus (RSV) infects most children in the first 2 yr of life, and some evidence has suggested that this specific viral infection is a seminal event in the pathogenesis of asthma. Initial follow-up studies of children admitted to hospital in the first year of life with bronchiolitis revealed a higher subsequent prevalence of asthma compared with control children (19). Subsequent larger studies have not confirmed such a relationship (20), and point to other etiologies for wheezing in children in early life. Other studies suggest that atopy may become manifest soon after exposure to RSV in the first year of life, although this effect disappears at later times during childhood (21). Increased IgE to RSV in children who wheezed after RSV infection has also been reported (22), although subsequent reports have suggested this property is not unique to RSV infections (23). Finally, pathology of RSV infection in the lungs causes both neutrophilic and eosinophilic cellular inflammation (24). Undoubtedly, RSV infection causes some degree of bronchial hyperreactivity, but the duration of this effect and its underlying persistence may be related to factors independent of the infection, such as atopy.

Immunological studies suggest that RSV promotes secretion of a Th2-like cytokine profile from antigen-specific T cells. Schwarze and coworkers (25) have shown that RSV infection enhances bronchial hyperresponsiveness to methacholine in a murine model of asthma. Cytokine production from bronchial lymph nodes at this stage was of predominantly Th1 type, but challenge with ovalbumin after RSV infection led to a predominance of Th2-type cytokines and subsequent eosinophilic inflammation. The eosinophilic infiltration could be blocked by administered anti-IL-5 antibody. This study points to a particular effect of RSV infection on the immune response, favoring a virally induced Th2 dominance that primes the immune system for allergic inflammatory responses (26). Even more recent studies from this group point to the pivotal role of the CD8⁺ T cell in stimulating eosinophilic inflammation in this animal model, suggesting that CD4⁺ T cell regulation is not solely responsible for the unique inflammatory processes observed with RSV infection (27).

In childhood, epidemiological evidence points to the presence of two distinct wheezing syndromes. Only one-third of children who develop wheeze in the first 3 yr of life will have recurrent wheeze after the age of 6 yr (20). The group of patients who grow out of wheeze by 6 yr of age have normal IgE levels and are more likely to have mothers who smoke, whereas persistent wheezers have higher IgE levels and a family history of asthma. Persistent wheezers have evidence even at this early stage of significantly elevated IgE during infections and during the convalescent phase of infections while peripheral blood eosinophil counts are lower in the group of transient wheezers during infective episodes (28). The role of eosinophilic inflammation in response to viral lower respiratory tract infections is supported by the finding of elevated serum eosinophil cationic protein in children who go on to have persistent wheeze (29). Direct evidence of airway cellular inflammation also exists in persistently wheezing children who have higher eosinophil and mast cell bronchoalveolar lavage cell counts (30).

In summary, respiratory tract infections, which are usually viral in nature, are associated with the production of wheeze in children. A subgroup of these children develop markers of allergic inflammation during periods of wheeze at less than 3 yr of age and are likely to develop persistent wheeze independent of subsequent respiratory tract infection. The relationship between the infection and the development of asthma may be dependent on several factors including the causative organism, the severity of infection, and the time the infection occurs. The role of specific infections is likely to be elucidated by prospective cohort studies that are currently underway.

	ACUTE EXACERBATIONS OF ASTHMA

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In addition to predicting subsequent asthma, proven viral respiratory tract infections have been associated closely with asthma exacerbations in children. In a prospective study of Southampton schoolchildren with a history of wheeze, 85% had detectable virus in upper airway samples analyzed by polymerase chain reaction (PCR) for common viral genomes at the time of an acute wheezing episode or drop in peak flow (31). The major pathogen implicated was rhinovirus. Comparison of the pattern of hospital admissions for asthma with virus isolation showed a close correlation, suggesting a common etiology (32). In adults, 55% of emergency department presentations with asthma exacerbation were associated with detectable respiratory tract infection (33), with rhinovirus, coronaviruses, and influenza viruses most commonly detected.

Laboratory studies have also revealed the presence of respiratory tract viruses in the lower airways. Rhinovirus RNA can be detected in the lower airways of individuals after experimentally induced infection (34). This finding correlates with lower airway inflammatory changes involving increased submucosal lymphocytes together with increased eosinophils in individuals with experimentally induced rhinovirus infections. These changes persist into the recovery period, and an experimental correlate exists where IL-8 is released from an infected lower respiratory epithelial cell line in a persistent manner after infection independent of viral replication (35). These findings correlate functionally with increased bronchial hyperresponsiveness measured by methacholine challenge after experimental rhinovirus infection. Cheung and coworkers demonstrated increased methacholine responsiveness persisting for 15 d after rhinovirus infection (36). In a similar methodological study, airway hyperresponsiveness after rhinovirus infection was significantly greater in allergic as compared with nonallergic subjects (37).

	THE ROLE OF BACTERIAL INFECTIONS AND ATOPY AND/OR ASTHMA

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Exposure to particular microbes, especially in childhood, may determine whether genetically susceptible individuals develop allergic disease. Microbial infections are potent, highly Th1-selective stimuli for the adaptive immune system. Microbes are potent inducers of IL-12 secretion from dendritic cells, neutrophils, macrophages, and natural killer (NK) cells with subsequent enhancement of the Th1 cytokine pathway.

Commensal microorganisms that colonize the gastrointestinal tract during infancy provide the major stimulus for postnatal upregulation of Th1 function (38). In experimental models maintaining infant animals in a germ-free environment, the Th2 polarity of the fetal immune system can be maintained, with the germ-free animals resistant to tolerization or immune deviation to Th1 response on exposure to mucosally delivered antigens (39). These observations raise the possibility that postnatal gut colonization in humans may be causally implicated in the different prevalences of atopy encountered in the first world versus second world populations. Timing may be the most critical factor, with specific microbial stimuli before sensitization protecting against subsequent atopy and specific microbial stimulation after sensitization exacerbating the asthma phenotype.

A recent study identifying polymorphisms in the CD14 gene (encoding the high-affinity receptor for bacterial lipopolysaccharide) located on chromosome 5q adjacent to the Th2 cytokine gene cluster raises the hypothesis that CD14 may be associated with the intensity of the expressed atopic phenotype (40).

	THE ROLE OF OBLIGATE INTRACELLULAR BACTERIA

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Chlamydia

Airway infection with Chlamydia pneumoniae has been associated with chronic asthma in several studies. Chlamydia spp. are obligate intracellular pathogens that are similar to gram-negative bacteria but lack peptidoglycan. Infections with Chlamydia spp. can be detected serologically or by analysis of airway samples, especially by PCR. The association was first describe by Hahn and colleagues, who revealed that 9 of 19 adults with new onset of wheeze had serological evidence of recent infection with C. pneumoniae (41). Further studies have also shown an association of C. pneumoniae with adult asthma. In a study by Hahn and McDonald, 163 individuals with an acute wheezing illness or chronic asthma were evaluated serologically for the presence of C. pneumoniae infection. Twelve percent of patients (n = 20) were diagnosed with C. pneumoniae infection by serology. Ten of these patients wheezed for the first time and 6 of these developed chronic airways disease while the other half had a preexisting diagnosis of chronic asthma (42).

Serologic evidence of C. pneumoniae infection has also been found in 8.9% of patients presenting with acute asthma, significantly greater than controls (43). However, these data are not supported uniformly and a study by Cook and co-workers found no association between acute C. pneumoniae infection in patients with acute asthma or control patients, but did find an association between severe chronic asthma and infection (44). Taken together the weight of evidence in adults would support a role for C. pneumoniae infection in adults with severe chronic asthma, but the evidence of precipitation of acute asthma is less persuasive.

In children C. pneumoniae infection was demonstrated in 23% of symptomatic episodes of airway infection and in 28% of an asymptomatic group of children with asthma (45). The detection of secretory (IgA) antibodies to C. pneumoniae in pharyngeal aspirates of children positively correlated with the number of exacerbations of asthma during the course of the study.

Trials of treatment for C. pneumoniae infection in asthma are currently underway. One report of an open-label study in community practice suggests that half of patients with chronic asthma benefit from treatment (46). Because of the clinical and cost implications, this finding will need confirmation by a blinded placebo-controlled study. Overall, the possible role of C. pneumoniae in the pathogenesis of asthma needs clarification.

Mycoplasma pneumoniae has also been found in association with chronic asthma in adults (47), but no such relationship has been found in children (45).

	THE ROLE OF PARASITIC INFECTIONS AND ASTHMA

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Helminthic infections induce an IL-4-dependent polyclonal IgE stimulation via potent induction of Th2 immunity. Higher total IgE levels after Ascaris sensitization are associated with allergen-specific IgE seropositivity, positive allergen skin prick tests, and higher prevalence of allergic rhinitis and asthma (48). These observations suggest that low-level contact with helminths enhances allergic reactivity but in the East German children studied did not lead to an increased prevalence of asthma (48).

	CONCLUSIONS

TOP INTRODUCTION INFECTIONS AND ATOPY THE ROLE OF VIRAL... ACUTE EXACERBATIONS OF ASTHMA THE ROLE OF BACTERIAL... THE ROLE OF OBLIGATE... THE ROLE OF PARASITIC... CONCLUSIONS IMPORTANT QUESTIONS REFERENCES

Infections may contribute to the pathogenesis of asthma both by the nature of the induced bronchial wall inflammation and by their longer-term effects on immune responses when acquired in infancy. The recent rise in asthma morbidity has been in part attributed to the lack of respiratory infections experienced by individuals living in the Western world. Early data suggest that the type of respiratory infection may play a critical role in determining whether a Th1 or Th2 cytokine profile is induced. Natural bacterial infections or vaccines, such as with M. tuberculosis, may act as adjuvants to induce a Th1 cytokine profile whereas some viral vaccines or natural viral infections, including RSV, favor a Th2 cytokine milieu. Vaccine trials to deviate the immune response from an "asthma" phenotype may be extremely important in future preventive strategies for asthma.

	IMPORTANT QUESTIONS

TOP INTRODUCTION INFECTIONS AND ATOPY THE ROLE OF VIRAL... ACUTE EXACERBATIONS OF ASTHMA THE ROLE OF BACTERIAL... THE ROLE OF OBLIGATE... THE ROLE OF PARASITIC... CONCLUSIONS IMPORTANT QUESTIONS REFERENCES

• What are the effects of infection on postnatal development of allergen-specific helper T lymphocyte memory in relation to timing, type, intensity, duration, frequency of infections, and immune status at time of infections?
• What is the effect of pathogenic infections versus commensal organisms?
• What are the underlying mechanisms for the above?
• Can the above information (once available) be harnessed for development of early intervention techniques?
• What is the role for therapy of acute infections in asthma (including Chlamydia): antivirals, antibiotics?

	Footnotes

Correspondence and requests for reprints should be addressed to R. E. O'Hehir, M.D., Ph.D., Department of Allergy, Asthma, and Clinical Immunology, Alfred Hospital and Monash University, P.O. Box 315, Prahran, Victoria 3181, Australia.

	References

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