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Department of Respiratory Medicine, National Heart and Lung Institute and Wright Fleming Institute of Infection and Immunity, Imperial College London, London, United Kingdom; National Jewish Medical and Research Center, and University of Colorado, Denver, Colorado
ABSTRACT
The potential role of atypical bacterial infection in the pathogenesis of asthma is a subject of continuing debate. There is an increasing body of literature concerning the association between the atypical bacteria Chlamydophila pneumoniae and Mycoplasma pneumoniae and asthma pathogenesis; however, many studies investigating such a link have been uncontrolled and have provided conflicting evidence, in part due to the difficulty in accurately diagnosing infection with these atypical pathogens. This article reviews the evidence for an association between atypical bacterial respiratory pathogens and the pathogenesis of asthma, and discusses the biological mechanisms that could account for such a link. The possible role of antibacterial therapy in the management of asthma and the need for well-designed studies to investigate this is also discussed.
Key Words: asthma Chlamydophila pneumoniae ketolides macrolides Mycoplasma pneumoniae
Until the 1970s, many physicians considered infection to be a causative factor in asthma (1); however, this belief was later supplanted by the premise that asthma is a noninfectious condition with inflammation as its root cause (2). Interest in the potential role of infection in asthma reemerged during the 1990s, when the importance of viral infections as precipitants of the majority of asthma exacerbations was demonstrated (3, 4). Assertions that bacterial infections may have a role in the pathogenesis of asthma—both acute and chronic—are much more controversial (5). Of bacterial respiratory pathogens, the atypical bacteria Chlamydophila (previously Chlamydia) pneumoniae and Mycoplasma pneumoniae are most commonly implicated in each of these contexts.
This article examines the evidence for an association between atypical bacterial respiratory pathogens and the pathogenesis of asthma, and discusses the need for well-designed studies to investigate the possible role of antibacterial therapy in the management of stable asthma, new- or late-onset asthma, and acute asthma exacerbations.
CHLAMYDOPHILA PNEUMONIAE AND MYCOPLASMA PNEUMONIAE
C. pneumoniae is a ubiquitous obligate intracellular bacterium, which is entirely dependent on energy produced by the host for its replication within the host cell cytoplasm, where the bacteria form characteristic intracellular inclusions (6). C. pneumoniae is a common pathogen globally (7–9). More than 50% of adults in the United States and many other countries show serologic evidence of past infection with C. pneumoniae. C. pneumoniae infection is less common in young children, but rises sharply during school-age years. Although estimates vary, the organism has been implicated in approximately 10% of cases of community-acquired pneumonia and 5% of cases of sinusitis and bronchitis. C. pneumoniae appears to have a propensity to cause chronic infections, and is associated with ciliary dysfunction and epithelial damage in bronchial cells (10, 11).
Unlike C. pneumoniae, M. pneumoniae is an extracellular pathogen that attaches to and destroys ciliated epithelial cells of the respiratory tract mucosa. M. pneumoniae is implicated in community-acquired respiratory tract infections in children and adults, including pneumonia, interstitial pneumonitis, bronchitis, bronchiolitis, and pharyngitis (12–15).
DETECTION OF ATYPICAL ORGANISMS
Investigation of the potential association between C. pneumoniae and M. pneumoniae and asthma is greatly hampered by the lack of standardized, sensitive, and specific methods for the detection of these atypical respiratory pathogens (16, 17). A second major barrier is the difficulty (in both practical and ethical terms) in sampling the lower respiratory tract in representative populations of patients with asthma and control subjects.
Culture is a very insensitive diagnostic technique, given the fastidiousness of these pathogens. Consequently, serologic tests for the presence of antibodies against these pathogens have been most commonly used as a diagnostic approach. The microimmunofluorescence (MIF) test is the only serologic method currently recommended for routine diagnosis of C. pneumoniae (17) and is the most frequently used detection method across studies undertaken to investigate the association between asthma and C. pneumoniae. Use of the MIF test allows definition of criteria for serologic evidence of acute infection (defined by a fourfold rise in IgG between acute and convalescent samples or an acute IgM titer 1:16) or past exposure (indicated by an IgG titer 1:16) (17). However, it should be noted that the quality of commercially available MIF kits varies and interpretation of results is subjective, making comparisons across laboratories and studies problematic. Although a number of alternative serologic assays for detection of C. pneumoniae have been described in the literature, their use is not currently recommended because of a lack of commercial availability and/or peer-reviewed evaluation of specificity (17, 18).
A further limitation of serologic testing methods is the high prevalence of antibodies to C. pneumoniae in the general population. In conjunction with the short duration of the initial antibody response (3–5 yr), the evidence of seroconversion in the majority of adults suggests that chronic infection and reinfection are common (9). The high frequency of asymptomatic carriage among healthy individuals makes it difficult to detect significant case-control differences. Furthermore, such serologic methods do not reliably indicate the timing of infection, so differentiating previous infection from acute infection, chronic infection/colonization, or reactivation of chronic infection is extremely difficult. In addition, serology cannot determine the precise localization of infection (e.g., upper or lower airways) and cross-reactivity with other Chlamydia spp. may also occur (15).
Laboratory diagnosis of M. pneumoniae infection is also problematic (13, 16). Traditionally, M. pneumoniae serology was determined using complement fixation. However, this test lacks specificity and is unable to differentiate between the antibody classes, resulting in difficulty in differentiating acute from chronic or previous infections. ELISA has largely replaced complement fixation as the means of immunoglobulin detection and several ELISA kits are now commercially available (16, 19). IgM tests can effectively indicate recent or current M. pneumoniae infection, especially in children (20). However, IgM levels are not always raised on infection or reinfection in adults. Hence, the separate detection of IgM and IgG by ELISA facilitates a more accurate diagnosis (16, 19). An elevated titer of IgG of more than 1:80 is frequently interpreted as evidence of acute infection, whereas low levels of M. pneumoniae IgG can indicate either the early stage of acute infection or a past illness. Ideally, a second sample should be examined after 2 to 3 wk, when a fourfold or greater increase of the IgG titer is interpreted as evidence of acute infection (16).
New molecular diagnostic methods that target pathogen DNA, such as polymerase chain reaction (PCR), may facilitate the detection of both C. pneumoniae and M. pneumoniae. Unlike culture, PCR testing can detect both organisms rendered nonviable during transport and organisms that are noncultivable in persistent infection; however, this attribute also limits the clinical utility of PCR, as it cannot distinguish between viable and nonviable organisms after antibacterial treatment (18). It may be possible to overcome this by using reverse transcriptase–PCR, which can identify metabolic activity via the detection of messenger RNA (21); however, this new method is not yet well validated. Although PCR is widely used for the rapid diagnosis of C. pneumoniae and M. pneumoniae in research settings, methods are typically laboratory-specific and may use a variety of clinical source materials (e.g., peripheral blood or respiratory secretions). Although there are four PCR assays for C. pneumoniae that fulfill validation criteria laid down by the Centers for Disease Control and Prevention, these are not yet available as standardized commercial tests (17, 22). In contrast, kits for the PCR detection of M. pneumoniae are commercially available.
CLINICAL STUDIES
This article analyzes controlled observational studies investigating the association between C. pneumoniae and M. pneumoniae infection and the pathogenesis of asthma (Table 1; References 23–57 appear in Table 1).
Chronic Stable Asthma
Of the 19 studies that investigated C. pneumoniae and/or M. pneumoniae in chronic stable asthma, 15 supported a relationship between infection with these pathogens and asthma (Table 1). The majority of these studies used serologic methods to identify infection. It is notable that 2 of the 15 studies that reported an association failed to demonstrate significant differences between patients with asthma and control subjects with conventional serologic markers of C. pneumoniae infection, but significant differences were observed in the prevalence of antibodies to C. pneumoniae heat-shock proteins (HSPs) (34, 37). Elevated concentrations of C-reactive protein (an indicator of inflammation) related to C. pneumoniae antibody titers were also seen in one of these studies (37), indicating that airway inflammation may be directly linked to C. pneumoniae infection, at least in some patients with asthma. Both studies that addressed the presence of infection in the airways using PCR methods supported an association between M. pneumoniae and C. pneumoniae in chronic asthma (39, 40); however, it should be noted that 18 subjects from the first study were also included in the second. A further study used a reverse transcriptase–PCR method for C. pneumoniae alone—developed to enable detection of replicating organisms—and also reported increased detection of this organism in patients with asthma compared with control subjects (36).
Further evidence to suggest causal relationships between the presence of organisms and disease pathogenesis would be provided by identification of dose–response relationships between the two. This has been observed in the study of Huittinen and coworkers (31), where C. pneumoniae HSP60 IgA antibodies were significantly inversely associated with pulmonary function, as measured by FEV1 (r = –0.23, p = 0.04), suggesting an association with the severity of pulmonary obstruction. A similar dose–response relationship was observed in an uncontrolled study by Black and colleagues (58), where an inverse association between IgG antibodies to C. pneumoniae and percent-predicted FEV1 was observed in subjects with asthma who had elevated IgG and/or IgA (p = 0.04). In this group, IgA antibodies were also associated with a higher daytime asthma symptom score (p = 0.04). Patients with elevated levels of both IgA and IgG were significantly more likely to require high-dose (as opposed to low-dose) inhaled corticosteroids (odds ratio, 4.44; p = 0.0001). Higher titers of antibodies to C. pneumoniae thus appeared to be associated with several markers of asthma severity (58). Additional evidence showing that C. pneumoniae is associated with a greater rate of decline of airway obstruction in patients with late-onset asthma is discussed below (59).
There are limited data concerning the influence of atopic status on the effects of C. pneumoniae infection (42, 60). One controlled study in Finland found that elevated IgG levels were significantly associated with asthma, particularly long-standing asthma (42). Analysis by atopic status revealed that C. pneumoniae infection was most strongly related to the risk of long-standing, nonatopic asthma (odds ratio, 6.0). However, a population-based study in Italy found a significant association between C. pneumoniae seropositivity and atopy in young adults (odds ratio, 1.73; p = 0.05) (60).
The weight of evidence, including the high proportion of studies suggesting an association between C. pneumoniae and/or M. pneumoniae infection and chronic stable asthma, and the dose–response relationships discussed above do appear to support a significant relationship.
Late-Onset or New-Onset Asthma
Of the six studies that investigated C. pneumoniae and/or M. pneumoniae in late-onset asthma, three supported a relationship between infection with these pathogens and asthma (Table 1). One of these found that significantly more patients with serologic evidence of exposure to C. pneumoniae developed asthma after respiratory illness and revealed a dose–response relationship between exposure and the prevalence of asthmatic bronchitis (23). The two other positive studies found higher levels of C. pneumoniae–specific antibodies in patients with asthma compared with healthy control subjects (statistical analyses for these differences were not presented for one of the studies) (43, 46). Interesting data from a cross-sectional study of patients with severe, late-onset, nonatopic asthma point to a possible deleterious effect of C. pneumoniae on fixed airway obstruction (59). In this study, patients with IgG antibodies showed a fourfold greater estimated decline in post-bronchodilator FEV1/FVC (percent predicted) as compared with patients without elevated titers of IgG (2.3 vs. 0.5% predicted/yr of asthma duration, p = 0.001).
In contrast, a study of newly diagnosed asthma in children showed no difference in C. pneumoniae serology between asthmatic and control groups, regardless of the serologic method used (MIF or enzyme immunoassay; Table 1) (47). Overall, there is insufficient evidence to determine whether there is a link between C. pneumoniae or M. pneumoniae and late-onset or new-onset asthma, as these conflicting data neither support nor refute such an association.
Acute Asthma
Of the 12 studies that investigated C. pneumoniae and/or M. pneumoniae in acute asthma, 9 supported a relationship between infection with these pathogens and asthma (Table 1). In one of the largest studies undertaken to date, rates of infection with atypical pathogens—including C. pneumoniae and M. pneumoniae—in 100 adults hospitalized for acute exacerbation of bronchial asthma were compared with 100 nonasthmatic control subjects (54). Paired sera were tested using MIF or enzyme immunoassay methods to establish serologic diagnosis. Only infection with M. pneumoniae was found to be significantly associated with hospitalization for acute exacerbation of asthma, with evidence of acute infection with this pathogen in 18% of patients with asthma compared with only 3% of the control group (p = 0.0006). The rate of acute infection with C. pneumoniae was not found to differ significantly between the two patient groups (8 vs. 6%).
By contrast, a similar large study of 160 patients with asthma with "acute bronchitis" and 88 control subjects reported increased detection of IgG to C. pneumoniae HSP10 in the patients with asthma (51). M. pneumoniae was not investigated in that study.
The high proportion of studies that have reported a link between acute exacerbations of asthma and C. pneumoniae and/or M. pneumoniae infection suggests that these pathogens may play a significant role in such exacerbations.
PROPOSED BIOLOGICAL MECHANISMS
A number of biological mechanisms have been proposed that may explain the possible role of these atypical pathogens in the pathogenesis of airway inflammation (61, 62). Research to date has largely concentrated on C. pneumoniae, with less information available concerning the possible biologic effects of M. pneumoniae infection.
Bacterial infection of resident airway cells, such as epithelial cells or macrophages, produces a cascade of cytokines that recruit and activate immune cells involved in bacterial destruction. However, these immune cells may also lead to inflammation and tissue damage (63). C. pneumoniae infection has been shown to induce secretion of cytokines, including tumor necrosis factor (TNF-) and interleukin 8 (IL-8), and reactive oxygen species from peripheral blood mononuclear cells (64) and alveolar macrophages (65). It also appears to activate TNF-, IL-8, IFN-, and nuclear factor–B (NF-B) in airway epithelial (66, 67) and vascular endothelial cells (68). NF-B activates genes encoding a wide range of proinflammatory cytokines (69). Animal models of asthma show NF-B activity to be correlated with both the degree of lung dysfunction and the course of disease. For example, Bureau and colleagues (70) found that high levels of bronchial NF-B activity correlated with acute airway obstruction during exacerbations and residual lung dysfunction 3 wk after exacerbations in horses with heaves, a naturally occurring disorder that parallels asthma in humans.
C. pneumoniae infection induces the production of IL-6, IFN-, and basic fibroblast growth factor (bFGF) in human bronchial smooth muscle cells in vitro (71, 72). Because IFN- and bFGF mediate smooth muscle cell proliferation, these data provide a mechanism by which C. pneumoniae infection might contribute to airway remodeling, as well as chronic inflammation, in patients with asthma. C. pneumoniae also increases the production of matrix metalloproteinases (MMPs) by human vascular smooth muscle cells (73). MMPs have been linked with airway remodeling in asthma (74); thus, if the same occurred with bronchial smooth muscle, the link between C. pneumoniae and airway remodeling would become stronger. Inflammatory responses initiated by certain C. pneumoniae–specific stress-response proteins—particularly HSP60 and HSP10—appear to play a role in the pathogenesis of chronic asthma (28, 31, 34, 37) or exacerbations of asthma (51). HSP60 induces TNF- production in a concentration- and time-dependent manner (75), and also induces MMP production by macrophages (75).
It has recently been proposed that C. pneumoniae might modulate epithelial cell apoptosis by upregulating both proapoptosis and antiapoptosis genes. As yet it is unknown how this upregulation modulates apoptosis during C. pneumoniae infection, but it has been suggested that C. pneumoniae–induced inhibition of apoptosis increases the longevity of the host cell, enhancing the survival of C. pneumoniae in patients with chronic asthma (76). In vitro, phagocytosed C. pneumoniae also survive and inhibit apoptosis in polymorphonuclear neutrophils via effects mediated by IL-8 and chlamydial LPS (77). The pathophysiologic role of apoptosis inhibition by C. pneumoniae in asthma remains unclear; however, recent data indicate that impaired apoptosis increases susceptibility to respiratory virus infection (78). If C. pneumoniae were shown to inhibit apoptotic responses to virus infection, this would provide a neat link between C. pneumoniae and the pathogenesis of asthma exacerbations.
M. pneumoniae infection induces the secretion of IL-8 and TNF- by human lung epithelial cells in vitro (79). It was demonstrated over a decade ago that Mycoplasma pulmonis infection exacerbates neurogenic respiratory tract inflammation in rats (80). More recently, several studies have demonstrated that respiratory M. pneumoniae infection produces airway hyperreactivity and pulmonary inflammation in mice (81–83), perhaps in association with the suppression of IFN- (81). Evidence from a murine model of allergic asthma suggests that the effect of M. pneumoniae infection might depend on the timing of the infection relative to allergen sensitization and challenge, and on the acute or chronic phase of the infection (83). Recent clinical data show increased serum levels of IL-5 in children with wheezing and acute M. pneumoniae infection (53). Tissue biopsies in patients with asthma demonstrated that those with PCR evidence of C. pneumoniae or M. pneumoniae infection had a significantly greater mast cell tissue infiltration than those with negative PCR results, supporting a potential interaction between infection and allergen sensitization (40).
Thus, although there are relatively few data available, the body of evidence is sufficient to make a biologically plausible case that bronchial infection with atypical bacteria is likely to be associated with increased airway inflammation—possibly thereby increasing asthma severity—and with airway remodeling. These organisms are common causes of infection and clearly not all infected patients develop asthma. This suggests that certain individuals may be genetically predisposed to the chronic effects of atypical organisms on airway function, or be genetically susceptible to infection (78), rendering them more likely to be persistently infected. Few studies have investigated the nature of this susceptibility to date. However, Nagy and colleagues (35) found that the presence of variant mannose-binding lectin (MBL) alleles (as opposed to the normal MBL genotype) significantly increased the risk of asthma development among children infected with C. pneumoniae. This risk was highest in children with recurrent or chronic infection (odds ratio, 5.38; p = 0.01), as opposed to current infection. Further studies investigating genetic susceptibility to infection with, or the chronic effects of, C. pneumoniae and M. pneumoniae are clearly required.
THE POTENTIAL ROLE OF ANTIBACTERIAL THERAPY IN ASTHMA
A number of different antibacterial agents have in vitro activity against C. pneumoniae and M. pneumoniae, including tetracyclines, macrolides (e.g., erythromycin, roxithromycin, clarithromycin, and the azalide azithromycin), the newer quinolones, and the ketolide telithromycin (84, 85). Newer macrolides and azalides accumulate intracellularly, show good activity against atypical organisms, have few clinically significant interactions, and are well tolerated (86). Macrolides, tetracyclines, and the newer quinolones have all demonstrated clinical efficacy in acute bronchitis and pneumonia caused by atypical pathogens, although relapse of C. pneumoniae infection is common after traditional 7- to 10-d courses of therapy. Persistence of atypical organisms has also been documented after clinical cure (87). Clarithromycin, roxithromycin, and azithromycin have shown clinical benefit in patients with chronic stable asthma, as discussed below (88–94).
The ketolides are a new class of antibacterial agents related to the macrolides, but which have structural modifications that confer bactericidal activity. Telithromycin—the first ketolide to be approved for clinical use—is also known to accumulate in a number of cell types, including macrophages, epithelial cells, and neutrophils (95–97), making it well suited for the treatment of infections caused by intracellular organisms.
Immunomodulatory Effects of Antibacterial Agents
Some macrolides appear to exert immunomodulatory properties that are independent of their antibacterial activity (98, 99). These agents modulate the functions of inflammatory cells, including polymorphonuclear leukocytes, lymphocytes, and macrophages. Macrolides influence several pathways involved in the inflammatory process, including the migration of neutrophils, the oxidative burst in phagocytes, and the production of proinflammatory mediators and cytokines, and several of these agents have shown antiinflammatory effects. Macrolides inhibit the synthesis and/or secretion of proinflammatory cytokines (e.g., TNF-, IL-8, IL-6, IL-1), whereas their effects on antiinflammatory cytokines (IL-10, IL-4) are more variable (100). The most important molecular targets for the antiinflammatory effects of the macrolides in asthma appear to be the transcription factors activator protein-1 and NF-B (100). Fewer data are available concerning the antiinflammatory properties of ketolides, although telithromycin has demonstrated immunomodulatory effects both in vitro (101) and in vivo (102). Telithromycin has been shown to significantly inhibit secretion of IL-1 and TNF- in LPS-stimulated human monocytes (101), in addition to inhibiting IL-1, IL-6, and IL-10 secretion in a murine neutropenic thigh infection model (102).
Such properties might be expected to be of potential clinical utility in patients with inflammatory airway diseases. Indeed, use of macrolides for the treatment of diffuse panbronchiolitis has led to dramatic improvements in pulmonary function and survival in patients (99, 100). Diffuse panbronchiolitis is a chronic inflammatory airway disorder of unknown etiology, which primarily occurs in East Asia. In 1984, the 5-yr survival rate for diffuse panbronchiolitis was only 26%. However, patient prognosis has improved dramatically since the introduction of long-term, low-dose erythromycin therapy, with 10-yr survival rates reaching 94% in 1998 (103). Available data suggest that the bacteriostatic activity of macrolides may not be a significant factor for their clinical efficacy in diffuse panbronchiolitis, with clinical benefits seen at macrolide dosages providing peak tissue levels well below the minimum inhibitory concentrations of major respiratory pathogens (104). Similarly, clinical improvement has been observed in the absence of bacterial eradication, as well as in patients superinfected with macrolide-resistant pathogens (104).
CLINICAL TRIALS OF ANTIBACTERIAL THERAPY IN ASTHMA
Although observations in uncontrolled settings suggest that antibacterial treatment in patients with asthma may be of clinical benefit (48, 88), there are few well-controlled studies to confirm these data.
Chronic Stable Asthma
A Cochrane review of macrolide usage in chronic asthma has recently become available (89). Of an initial 95 studies, 20 were potentially eligible for consideration, of which only 5 (357 patients) met the entry criteria (randomized placebo-controlled study of macrolide therapy of > 4-wk duration). There was an overall positive effect on symptoms and eosinophilic markers of inflammation with macrolide therapy. However, the small numbers of patients evaluated and the varying study designs clearly limit the ability to extrapolate these findings to recommendations for routine clinical care.
Only one of the studies took bacterial infection into account, although this was the largest study, contributing 232 of the 357 subjects. The Chlamydia pneumoniae, Asthma, Roxithromycin, Multinational (CARM) study found 6 wk of treatment with roxithromycin to be associated with a statistically significant improvement of lung function but not of asthma symptoms (90). Adult patients with stable chronic asthma and serologic evidence of C. pneumoniae infection (IgG antibodies to C. pneumoniae 1:64 and/or IgA antibodies 1:16) participated in this multicenter, randomized, double-blind, placebo-controlled trial. Subjects received roxithromycin 150 mg twice daily or placebo for 6 wk and were monitored for 6 mo. A significantly greater increase in peak expiratory flow from baseline levels (difference between groups 12 L/min) was seen in roxithromycin-treated patients at 6 wk (p = 0.02), although this benefit was no longer apparent at the 3- and 6-mo follow-up visits. The authors suggested that this might have been because of suppression—rather than eradication—of C. pneumoniae. It is important to note that the serologic methods used in this study were not able to determine whether C. pneumoniae infection was present in the airways, and M. pneumoniae was not investigated at all.
A randomized, placebo-controlled study published after the completion of the Cochrane review evaluated the effect of treatment with clarithromycin 500 mg twice daily for 6 wk in 55 patients with chronic stable asthma, 56% of whom had M. pneumoniae or C. pneumoniae infection in the airways, as demonstrated by PCR (91). Treatment with clarithromycin was only associated with significant improvements in lung function (FEV1) in patients with documented atypical infection, with no changes seen in patients who were PCR-negative. Although the subgroup analyses may not have been adequately powered, this may suggest that the beneficial effects of clarithromycin were at least in part caused by antimicrobial activity, although atypical organisms were found to persist in the airways of seven patients after treatment. Treatment with clarithromycin was also associated with reductions in expression of TNF-, IL-5, and IL-12 mRNA. This may indicate immunomodulatory activity; however, it is also possible that a decrease in organism load contributed to decreased cytokine expression.
The full publication of additional studies of antibacterial therapy in chronic asthma is awaited with interest (93, 94).
Late-Onset Asthma
To date, no controlled studies investigating antibiotics in the treatment of late-onset asthma have been published.
Acute Asthma
A recently published Cochrane review identified only two well-controlled studies of antibiotics in acute asthma (105), neither of which demonstrated any benefit in patients receiving the antibacterial therapy. However, it should be noted that the agents used—hetacillin and amoxicillin—are not active against atypical bacteria (105).
A multicenter, double-blind, randomized, placebo-controlled clinical study (TELICAST [TELIthromycin, Chlamydia, and ASThma]) assessed the efficacy of oral telithromycin 800 mg once daily for 10 d as a supplement to standard-of-care treatment for patients with acute exacerbations of asthma. Assessment of C. pneumoniae and/or M. pneumoniae infection by culture, serology, and PCR was included. Preliminary data for the first 35 enrolled patients showed 23 of 35 (65.7%) patients to have a positive C. pneumoniae IgM by ELISA and/or MIF, suggesting that C. pneumoniae infection may be a more common feature of asthma exacerbations than previously recognized (106). A further preliminary report indicated that telithromycin was associated with significant clinical benefit (107). Full publication of this study is awaited, however.
CONCLUSIONS
The etiology of asthma is complex, involving interactions between genetic susceptibility, allergen exposure, and environmental factors, such as respiratory tract infections, air pollution, and smoking. Infection has been implicated in a number of diseases that were previously believed to have a noninfectious etiology. The role of infection in asthma is complex and still not fully understood. Although viral infections are now well established as being associated with acute asthma exacerbations, there is increasing evidence from controlled studies to support an association between atypical bacterial infection—particularly with C. pneumoniae and M. pneumoniae—and both chronic stable asthma and acute exacerbations of asthma. There are inadequate data available for late-onset asthma to draw reliable conclusions. However, it is important to note that evidence for an association between atypical bacterial infection and asthma does not necessarily indicate a causative role for infection in the pathogenesis of asthma; rather, it could indicate an increased susceptibility to infection leading to increased frequency of detection. Although no data are currently available to support such an effect with atypical bacterial infection, there is evidence that patients with asthma are more susceptible to naturally occurring rhinovirus infection than individuals without asthma (108, 109). Perhaps the most likely scenario is that increased susceptibility to infection in asthma leads to increased atypical bacterial infection, which itself then plays a direct role in increasing airway inflammation contributing directly to the pathogenesis of asthma.
A number of criteria should be met before an organism is established as the cause of a disease, namely the following: recovery of the organism from diseased hosts, cultivation in host cells, production of a comparable disease in the original host species or a related one, and reisolation of the organism and detection of a specific immune response. To these can be added evidence of a dose–response relationship between organism load and disease severity and evidence of improvement in the disease on specific antiorganism therapy. For each asthma type (chronic stable, late-onset, and acute), the evidence to date includes recovery of the organism from diseased hosts and detection of a specific immune response. In chronic stable asthma, there is also some evidence of a link between organism load and disease severity, and we await convincing evidence of improvement in the disease after antibiotic therapy.
Two published studies suggest treatment with macrolides may be of clinical benefit in patients with asthma and evidence of C. pneumoniae or M. pneumoniae infection. However, much additional research is clearly required to confirm these early results, and if confirmed, to identify the patients most likely to benefit from therapy, the optimum agent(s), and the timing and duration of antibiotic therapy in this setting. To achieve this, there is an urgent need for much better diagnostic methods, in addition to further studies on pathogenesis. However, only placebo-controlled studies of therapy associated with definitive diagnostic testing will prove cause and effect. Such studies are urgently needed to inform treatment guidelines.
Acknowledgments
The authors thank Anne Le-Moigne-Amrani for statistical support.
FOOTNOTES
Supported by sanofi-aventis.
Conflict of Interest Statement: S.L.J. received consultant fees of less than $10,000 in the last 3 yr from Aventis/sanofi-aventis. R.J.M. received a total of $7,000 in consultant fees for the last 3 yr from Aventis/sanofi-aventis. He also received a total of $22,500 in research grant funding from Abbott.
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