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Translating Basic Research Into Clinical Practice |

Asthma and Atypical Bacterial Infection* FREE TO VIEW

E. Rand Sutherland, MD, MPH, FCCP; Richard J. Martin, MD, FCCP
Author and Funding Information

*From the National Jewish Medical and Research Center, Denver, CO.

Correspondence to: E. Rand Sutherland, MD, MPH, FCCP, National Jewish Medical and Research Center, Department of Medicine, 1400 Jackson St, J220, Denver, CO 80206; e-mail: sutherlande@njc.org



Chest. 2007;132(6):1962-1966. doi:10.1378/chest.06-2415
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A growing body of basic and clinical science implicates the atypical bacterial pathogens Mycoplasma pneumoniae and Chlamydophila (formerly Chlamydia) pneumoniae as potentially important factors in asthma, although their exact contribution to asthma development and/or persistence remains to be determined. Evidence from human studies links both M pneumoniae and C pneumoniae to new-onset wheezing, exacerbations of prevalent asthma, and long-term decrements in lung function, suggesting that these organisms can play an important role in the natural history of asthma. Furthermore, animal models of acute and chronic infection with these organisms indicate that they have the ability to modulate allergic sensitization and pulmonary physiologic and immune response to allergen challenge. These findings raise the possibility that, in at least some individuals with asthma, antibiotic therapy might have a role in long-term treatment. While antibiotics do not currently have a defined role in the treatment of stable patients with chronic asthma, there is emerging evidence that asthma symptoms and biomarkers of airway inflammation can improve when patients who have atypical bacterial infection as a cofactor in their asthma are treated with macrolide antibiotics. Ongoing research into the importance of atypical pathogens in asthma will further elucidate whether these infections are important in disease development or whether their prevalence is increased in asthmatic subjects due to chronic airway inflammation or other, yet unidentified, predisposing factors. Current studies will further define the role of macrolide antibiotics in the treatment of stable patients with asthma, ultimately determining whether these therapeutic agents have a place in asthma management.

Figures in this Article

Infection of the lower respiratory tract with the atypical bacteria Mycoplasma pneumoniae and Chlamydophila pneumoniae has emerged as an important clinical issue in stable patients with chronic asthma. While the exact contribution of atypical bacterial infection to asthma pathogenesis and phenotype remains to be determined, a growing body of both basic and clinical science implicates these pathogens as potentially important factors in asthma. However, the challenges faced in elucidating the relationship between atypical bacterial infection and asthma remain numerous. Robust animal models of chronic atypical bacterial infection are still being developed, many of the methods of detecting atypical bacteria in humans are either insensitive or nonspecific, and reliable detection typically requires invasive diagnostic procedures such as endobronchial biopsy. Furthermore, since asthma is a clinical syndrome that likely is influenced by a host of intrinsic and acquired factors, determining the importance of infectious agents relative to other risk factors in the pathogenesis and prognosis of asthma continues to pose a challenge.

M pneumoniae, which is a common cause of atypical pneumonia and tracheobronchitis,1attaches to ciliated airway epithelial cells by means of a terminal organelle, infecting the cell and causing epithelial damage and ciliary dysfunction.2 Evidence linking M pneumoniae to new-onset wheezing, exacerbations of prevalent asthma, and long-term decrements in lung function suggest that this organism can play an important role in asthma.

Although sporadic case reports3have suggested that antecedent Mycoplasma infection can be associated with the subsequent development of asthma, a stronger and perhaps more clinically relevant association is the importance of M pneumoniae as a precipitant of exacerbations in asthmatic subjects. One example of this is the report by Lieberman and colleagues4 of a prospective study of atypical bacterial infections in patients hospitalized with acute asthma exacerbation that demonstrated serologic evidence of acute M pneumoniae infection in 18% of patients with an asthma exacerbation, compared with a prevalence of 3% in a matched control group (p = 0.0006). In an earlier series5 of children with preexisting asthma, M pneumoniae infection was similarly seen in 7 of 40 episodes (18%) of acute exacerbation.

In addition to causing a decrement in pulmonary function during acute infection, M pneumoniae might also be associated with the long-term impairment of pulmonary function in both asthmatic subjects and nonasthmatic subjects. In a series of 108 children with lower respiratory tract infection caused by M pneumoniae (detected by increased complement fixation titers), 40% of subjects presented with wheezing as an initial clinical finding, and at both three months and three years of age there were decrements in FVC (93.1% vs 100.8% of predicted, p < 0.01) and forced expiratory volume in one second (FEV1) (94.5% vs 100.6% of predicted, p < 0.02) in infected nonasthmatic subjects compared to control subjects.6The reported strength of this association is variable, however, as a separate series of 50 chil-dren evaluated 1.5 to 9.5 years after clinical and radiographic recovery from M pneumoniae pneumonia did not demonstrate persistent reductions in FVC or FEV1.7 A report by Kim and colleagues suggested a potential anatomic substrate for impaired lung function after acute M pneumoniae pneumonia, in that high-resolution chest CT scanning performed in 37 children at a mean interval of 1.5 years after the episode of pneumonia demonstrated findings such as bronchial wall thickening, mosaic perfusion and air trapping, features which were not seen in a control population of 17 children with Mycoplasma upper airway infection.8

C pneumoniae, also classified as an “atypical” bacterial pathogen, is a common cause of bronchitis and atypical pneumonia, may result in chronic infections,9and like M pneumoniae has been associated with subsequent wheezing illness. C pneumoniae also causes exacerbations of preexisting asthma, as reported in case series such as that of Allegra and colleagues, where in a cohort of seventy adults presenting with asthma exacerbation, 10% were shown by serology to be acutely infected with C pneumoniae.10 In a community-based cohort of 365 patients with lower respiratory tract illness, 47% of patients with acute C pneumoniae infection were found to wheeze during the course of the infection, with a statistically-significant dose-response relationship between the level of C pneumoniae IgG titer and prevalence of wheezing in the cohort. There was also an association of C pneumoniae antibody titers and subsequent development of “asthmatic bronchitis” after the acute illness, which was seen in 32% of cases (odds ratio = 7.2, 95% CI = 2.2–23.4).11

In 2001, Martin and colleagues12 published the first systematic evaluation of Mycoplasma and Chlamydophila infection in the upper and lower airways of adults with chronic, stable asthma. The investigators evaluated 55 stable asthmatic subjects and 11 healthy control subjects for the presence of M pneumoniae and C pneumoniae, performing serology, cultures, and polymerase chain reaction (PCR) for these organisms on specimens obtained from the nasopharynx and oropharynx, BAL, and endobronchial biopsy. M pneumoniae or C pneumoniae was detected by PCR in 56.4% of asthmatic subjects compared with 9% of control subjects (p = 0.02). Culture findings for both organisms were negative in all subjects. A total of 18 asthmatic subjects and 1 healthy control subject had serologic results that were positive for C pneumoniae. Of the 18 asthmatic subjects, 10 had positive results by IgG criteria and 5 had positive results by IgM criteria, with 3 of the subjects demonstrating both positive IgG and positive IgM criteria. However, only seven subjects had PCR results that were positive for C pneumoniae; of these, only three subjects had serologic results that were positive for C pneumoniae. On the basis of these data, the authors concluded that a majority of stable adults with chronic asthma are chronically infected with M pneumoniae, with a significantly greater frequency than nonasthmatic subjects, and that serologic evaluation does not reliably indicate lower airway PCR status.,12 At this time, more study is needed to evaluate whether Mycoplasma or Chlamydophila infection is a pathogenic factor in asthma or merely an epiphenomenon that is somehow related to the enhanced airway inflammation seen in subjects with chronic asthma.

Mycoplasma species have been used to study respiratory tract infection in laboratory animals, including mice, leading to insights into mechanisms by which atypical bacteria lead to airway inflammation and responsiveness. Although M pneumoniae is not a natural mouse pathogen, Wubbel and colleagues13 demonstrated that the intranasal introduction of M pneumoniae into BALB/c mice results in acute respiratory tract infection, based on positive broth culture data from fluid specimens from BAL performed up to 15 days following infection. Murine infection with M pneumoniae also results in an active immunologic response, with 62% of animals demonstrating enzyme-linked immunosorbent assay evidence of M pneumoniae-specific IgM production, and 97% of animals demonstrating positive immunoblots for M pneumoniae. Many animals also demonstrated histologic evidence of airway epithelial disruption following M pneumoniae infection.,13

Pietsch and colleagues14 studied the inflammatory response of BALB/c mice during acute primary and secondary infection with M pneumoniae. Following infection, the investigators evaluated in vivo cytokine gene expression in the spleens and lungs of these animals.,14 During the acute phase of infection, the authors found elevated expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, and interferon (IFN)-γ. IL-2 and IL-2 receptor gene expression was seen only during reinfection. The expression of cytokines also varied over the course of the infection. IL-2 messenger RNA levels fell over the first 24 h of infection and were not detectable after 24 h; IL-10 messenger RNA levels rose over this same period. Furthermore, during reinfection with M pneumoniae, messenger RNA levels of IL-6 and TNF-α were 10-fold higher than those seen during acute infection. IFN-γ messenger RNA levels were 50-fold higher following reinfection than with acute infection.,14

To investigate the relationship between the timing of Mycoplasma infection, allergic sensitization, and subsequent pulmonary physiologic and immune response, Chu and colleagues15 investigated the effect of experimental M pneumoniae infection both before and after ovalbumin sensitization and challenge on airway hyperresponsiveness (AHR), lung inflammation, and protein levels of T-helper (Th) type 1 and Th2 cytokines in BALB/c mice. When experimental Mycoplasma infection was instituted 3 days prior to ovalbumin sensitization and challenge, this sequence resulted in reduced AHR, a reduction in lung inflammatory cell influx, and induced a predominantly Th1 response with increases in the ratio of IFN-γ to the Th2 cytokine IL-4 in BAL fluid (Fig 1 ). Inoculation and infection with M pneumoniae 48 h after ovalbumin challenge initially caused a temporary reduction in AHR, followed by augmented AHR (Fig 2 ), lung inflammation score, and BAL fluid IL-4 concentration with a concomitant reduction in BAL fluid IFN-γ concentration. The authors,15 concluded that Mycoplasma infection can modulate physiologic and inflammatory responses to allergic airway inflammation and that their findings with regard to the timing of infection vs allergic sensitization supported the “hygiene hypothesis” of asthma, in which protection against asthma and/or allergic diseases occurs in those persons experiencing infections early in life (ie, prior to allergen sensitization).

Although the data cited above suggest that Mycoplasma could modulate events occurring early in the development of asthma, questions remain about what effect chronic infection might have on the airways over the long term. In a series of mouse experiments in which animals with experimental M pneumoniae infections were observed for up to 56 days, Chu and colleagues16 investigated whether infection could lead to alterations in airway collagen deposition. In mice in which infection was preceded by allergic sensitization and challenge, an increase in airway wall collagen deposition (Fig 3 ) was observed at 42 days, but not at 14 days, after infection, a finding that was accompanied by increased lung expression of TGF-β1 messenger RNA and protein (as evaluated by immunohistochemistry). In allergen-naïve mice, Mycoplasma infection did not alter airway wall collagen. Although these findings require further investigation, this study suggested that Mycoplasma infection could, over the long term, modulate airway collagen deposition, and thereby possibly airway fibrosis and remodeling.,16

Although no animal reservoir has been implicated in the transmission of C pneumoniae,17 animal models of C pneumoniae have been successfully established in mice, rabbits, and monkeys. Kuo and colleagues,17have demonstrated homogeneous infection in mice following nasal inoculation with C pneumoniae, with the occurrence of interstitial pneumonitis on the third day after inoculation, the occurrence of parenchymal pneumonia on the fifth day following inoculation, and the occurrence of a strong antibody response, which peaked 3 to 4 weeks following intranasal inoculation. These pathologic changes were observed for several weeks after the acute infection.18 Furthermore, C pneumoniae DNA can be detected in lungs by PCR and in situ DNA hybridization, even after the organism can no longer be cultured from the lungs.19C pneumoniae also appears to establish chronic latent infection in mice; if immunosuppressive medications such as corticosteroids are administered after recovery from the primary infection, C pneumoniae can once again be cultured from lung tissue within 14 days following immunosuppression.20

Antibiotics do not currently play a major role in the treatment of chronic asthma in stable patients. There is emerging evidence, however, that symptoms and markers of airway inflammation may improve when patients who have atypical bacterial infection as a cofactor in their asthma are treated with macrolide antibiotics. In a double-blind protocol, Kraft and colleagues21 treated 55 stable asthmatic subjects with chronic asthma with clarithromycin (500 mg po bid) for 6 weeks. At the end of the treatment course, there was a significant improvement in FEV1 in those who were PCR-positive on endobronchial biopsy for either M pneumoniae or C pneumoniae, a clinical finding that was accompanied by a reduction of TNF-α, IL-5, and IL-12 messenger RNA expression in BAL fluid, and of TNF-α messenger RNA expression in airway epithelial cells in these subjects.,21 The observation that PCR positivity appeared to predict the response to macrolide antibiotic therapy was made post hoc, however, and the Asthma Clinical Research Network is currently conducting a PCR-stratified, prospective study (the Macrolides In Asthma trial [Clinicaltrials.gov identifier NCT00318708]) to explore further the importance of PCR positivity in determining the response to macrolide antibiotic therapy.

Pilot studies focusing on macrolide antibiotic treatment of subjects with chronic asthma who have positive serology for C pneumoniae have been performed. In an open-label trial of 48 adults with stable persistent asthma published in 1995, Hahn22 reported significant clinical improvement or complete remission of asthma symptoms after 3 to 9 weeks of antibiotic therapy. In this study,22the majority of subjects received therapy with azithromycin, although other antibiotics were used as well. In a follow-up study, Hahn et al23 conducted a community-based randomized, placebo-controlled trial of azithromycin (600 mg po for 3 days, followed by 600 mg each week for 5 weeks) in subjects with persistent asthma. Macrolide antibiotic therapy did not result in a significant improvement as determined by the Asthma Quality of Life Questionnaire, but there was a treatment-related improvement in asthma symptoms.23As noted previously, the diagnosis of C pneumoniae in study participants was based on serology alone, and only baseline serum IgA was associated with a positive treatment response. A similarly modest effect was observed in a 6-week treatment trial of roxithromycin in 232 subjects with chronic asthma and serologic evidence (IgG titer, ≥ 1:64; or IgA titer, ≥ 1:16) of C pneumoniae infection. Although numerically small, statistically significant increases in morning and evening peak flow rates were observed, these findings were not sustained at 3 and 6 months following the end of treatment.24

Guidelines have historically recommended against the use of antibiotics in acute exacerbations of asthma,25a recommendation made on the basis of two controlled clinical trials that failed to show a clinical benefit of adding nonmacrolide antibiotics to usual care for acute asthma exacerbation. An additional contribution to this literature occurred in 2006 with the publication of a controlled trial26 of telithromycin (a ketolide antibiotic) added to usual care for exacerbated asthma in a group of patients, of whom approximately 61% had serologic evidence of Mycoplasma or Chlamydophila infection. Although the investigators reported a decrease in asthma symptom scores with telithromycin therapy vs placebo at the end of the 10-day treatment period, there was no effect on lung function.26

Mounting evidence from both animal and human studies suggests that atypical bacterial infection is an important acquired factor in the pathogenesis and clinical expression of asthma. Ongoing research into the importance of atypical pathogens in asthma will elucidate questions about whether these infections are important in disease development and/or whether their prevalence is increased in asthmatic subjects due to chronic airway inflammation or other, yet unidentified, predisposing factors. Current studies will further define the role of macrolide antibiotics in the treatment of stable asthma patients, ultimately determining whether these therapeutic agents have a place in the management of stable patients with asthma.

Abbreviations: AHR = airway hyperresponsiveness; IFN = interferon; IL = interleukin; PCR = polymerase chain reaction; Th = T helper; TNF = tumor necrosis factor

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Figure Jump LinkFigure 1. Cytokine measurement in the BAL fluid of mice infected with M pneumoniae (MP) or treated with saline solution followed by ovalbumin sensitization and challenge. The median (interquartile range) of BAL fluid IFN-γ protein concentration (left, A), BAL fluid IL-4 protein concentration (center, B), and BAL fluid IFN-γ protein/IL-4 protein ratio (right, C) are shown.15Grahic Jump Location
Figure Jump LinkFigure 2. Airway resistance (RL) 3, 7, 14, and 21 days after inoculation with saline solution (white line) or M pneumoniae (red line) in 4-week-old BALB/c mice previously sensitized to and challenged with ovalbumin. Base = baseline; sal = saline; * = p < 0.05 for comparison at a given methacholine concentration.Grahic Jump Location
Figure Jump LinkFigure 3. Cross-sectional view (×200) of airway collagen deposition (arrowheads) in allergen-sensitized and challenged animals 42 days after intratracheal inoculation with saline solution (left, a) or M pneumoniae (right, b). Images courtesy of Hong Wei Chu, MD, National Jewish Medical and Research Center, Denver, CO.Grahic Jump Location
Baseman, JB, Tully, JG (1997) Mycoplasmas: sophisticated, reemerging, and burdened by their notoriety.Emerg Infect Dis3,21-32. [PubMed] [CrossRef]
 
Andersen, P Pathogenesis of lower respiratory tract infections due to Chlamydia, Mycoplasma, Legionella and viruses.Thorax1998;53,302-307. [PubMed]
 
Yano, T, Ichikawa, Y, Komatu, S, et al Association ofMycoplasma pneumoniaeantigen with initial onset of bronchial asthma.Am J Respir Crit Care Med1994;149,1348-1353. [PubMed]
 
Lieberman, D, Lieberman, D, Printz, S, et al Atypical pathogen infection in adults with acute exacerbation of bronchial asthma.Am J Respir Crit Care Med2003;167,406-410. [PubMed]
 
Berkovich, S, Millian, SJ, Snyder, RD The association of viral and Mycoplasma infections with recurrence of wheezing in the asthmatic child.Ann Allergy1970;28,43-49. [PubMed]
 
Sabato, AR, Martin, AJ, Marmion, BP, et al Mycoplasma pneumoniae: acute illness, antibiotics, and subsequent pulmonary function.Arch Dis Child1984;59,1034-1037. [PubMed]
 
Mok, JY, Waugh, PR, Simpson, H Mycoplasma pneumoniaeinfection: a follow-up study of 50 children with respiratory illness.Arch Dis Child1979;54,506-511. [PubMed]
 
Kim, CK, Chung, CY, Kim, JS, et al Late abnormal findings on high-resolution computed tomography after Mycoplasma pneumonia.Pediatrics2000;105,372-378. [PubMed]
 
Grayston, JT, Kuo, CC, Wang, SP, et al A newChlamydia psittacistrain, TWAR, isolated in acute respiratory tract infections:N Engl J Med1986;315,161-168. [PubMed]
 
Allegra, L, Blasi, F, Centanni, S, et al Acute exacerbations of asthma in adults: role ofChlamydia pneumoniaeinfection.Eur Respir J1994;7,2165-2168. [PubMed]
 
Hahn, DL, Dodge, RW, Golubjatnikov, R Association ofChlamydia pneumoniae(strain TWAR) infection with wheezing, asthmatic bronchitis, and adult-onset asthma.JAMA1991;266,225-230. [PubMed]
 
Martin, RJ, Kraft, M, Chu, HW, et al A link between chronic asthma and chronic infection.J Allergy Clin Immunol2001;107,595-601. [PubMed]
 
Wubbel, L, Jafri, HS, Olsen, K, et al Mycoplasma pneumoniaepneumonia in a mouse model.J Infect Dis1998;178,1526-1529. [PubMed]
 
Pietsch, K, Ehlers, S, Jacobs, E Cytokine gene expression in the lungs of BALB/c mice during primary and secondary intranasal infection withMycoplasma pneumoniae.Microbiology1994;140,2043-2048. [PubMed]
 
Chu, HW, Honour, JM, Rawlinson, CA, et al Effects of respiratoryMycoplasma pneumoniaeinfection on allergen-induced bronchial hyperresponsiveness and lung inflammation in mice.Infect Immun2003;71,1520-1526. [PubMed]
 
Chu, HW, Rino, JG, Wexler, RB, et al Mycoplasma pneumoniaeinfection increases airway collagen deposition in a murine model of allergic airway inflammation.Am J Physiol Lung Cell Mol Physiol2005;289,L125-133. [PubMed]
 
Kuo, CC, Jackson, LA, Campbell, LA, et al Chlamydia pneumoniae(TWAR).Clin Microbiol Rev1995;8,451-461. [PubMed]
 
Kishimoto, T Studies onChlamydia pneumoniae, strain TWAR, infection: I. Experimental infection ofC pneumoniaein mice and serum antibodies against TWAR by MFA.Kansenshogaku Zasshi1990;64,124-131. [PubMed]
 
Kaukoranta-Tolvanen, SE, Laurila, AL, Saikku, P, et al ExperimentalChlamydia pneumoniaeinfection in mice: effect of reinfection and passive immunization.Microb Pathog1995;18,279-288. [PubMed]
 
Malinverni, R, Kuo, CC, Campbell, LA, et al Reactivation ofChlamydia pneumoniaelung infection in mice by cortisone.J Infect Dis1995;172,593-594. [PubMed]
 
Kraft, M, Cassell, GH, Pak, J, et al Mycoplasma pneumoniaeandChlamydia pneumoniaein asthma: effect of clarithromycin.Chest2002;121,1782-1788. [PubMed]
 
Hahn, DL Treatment ofChlamydia pneumoniaeinfection in adult asthma: a before-after trial.J Fam Pract1995;41,345-351. [PubMed]
 
Hahn, DL, Plane, MB, Mahdi, OS, et al Secondary outcomes of a pilot randomized trial of azithromycin treatment for asthma.PLoS Clin Trials2006;1,e11. [PubMed]
 
Black, PN, Blasi, F, Jenkins, CR, et al Trial of roxithromycin in subjects with asthma and serological evidence of infection withChlamydia pneumoniae.Am J Respir Crit Care Med2001;164,536-541. [PubMed]
 
National Heart, Lung, and Blood Institute... Expert panel report: guidelines for the diagnosis and management of asthma; update on selected topics 2002. 2002; National Heart, Lung and Blood Institute. Bethesda, MD: NHLBI Publication No. 02–5074.
 
Johnston, SL, Blasi, F, Black, PN, et al The effect of telithromycin in acute exacerbations of asthma.N Engl J Med2006;354,1589-1600. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Cytokine measurement in the BAL fluid of mice infected with M pneumoniae (MP) or treated with saline solution followed by ovalbumin sensitization and challenge. The median (interquartile range) of BAL fluid IFN-γ protein concentration (left, A), BAL fluid IL-4 protein concentration (center, B), and BAL fluid IFN-γ protein/IL-4 protein ratio (right, C) are shown.15Grahic Jump Location
Figure Jump LinkFigure 2. Airway resistance (RL) 3, 7, 14, and 21 days after inoculation with saline solution (white line) or M pneumoniae (red line) in 4-week-old BALB/c mice previously sensitized to and challenged with ovalbumin. Base = baseline; sal = saline; * = p < 0.05 for comparison at a given methacholine concentration.Grahic Jump Location
Figure Jump LinkFigure 3. Cross-sectional view (×200) of airway collagen deposition (arrowheads) in allergen-sensitized and challenged animals 42 days after intratracheal inoculation with saline solution (left, a) or M pneumoniae (right, b). Images courtesy of Hong Wei Chu, MD, National Jewish Medical and Research Center, Denver, CO.Grahic Jump Location

Tables

References

Baseman, JB, Tully, JG (1997) Mycoplasmas: sophisticated, reemerging, and burdened by their notoriety.Emerg Infect Dis3,21-32. [PubMed] [CrossRef]
 
Andersen, P Pathogenesis of lower respiratory tract infections due to Chlamydia, Mycoplasma, Legionella and viruses.Thorax1998;53,302-307. [PubMed]
 
Yano, T, Ichikawa, Y, Komatu, S, et al Association ofMycoplasma pneumoniaeantigen with initial onset of bronchial asthma.Am J Respir Crit Care Med1994;149,1348-1353. [PubMed]
 
Lieberman, D, Lieberman, D, Printz, S, et al Atypical pathogen infection in adults with acute exacerbation of bronchial asthma.Am J Respir Crit Care Med2003;167,406-410. [PubMed]
 
Berkovich, S, Millian, SJ, Snyder, RD The association of viral and Mycoplasma infections with recurrence of wheezing in the asthmatic child.Ann Allergy1970;28,43-49. [PubMed]
 
Sabato, AR, Martin, AJ, Marmion, BP, et al Mycoplasma pneumoniae: acute illness, antibiotics, and subsequent pulmonary function.Arch Dis Child1984;59,1034-1037. [PubMed]
 
Mok, JY, Waugh, PR, Simpson, H Mycoplasma pneumoniaeinfection: a follow-up study of 50 children with respiratory illness.Arch Dis Child1979;54,506-511. [PubMed]
 
Kim, CK, Chung, CY, Kim, JS, et al Late abnormal findings on high-resolution computed tomography after Mycoplasma pneumonia.Pediatrics2000;105,372-378. [PubMed]
 
Grayston, JT, Kuo, CC, Wang, SP, et al A newChlamydia psittacistrain, TWAR, isolated in acute respiratory tract infections:N Engl J Med1986;315,161-168. [PubMed]
 
Allegra, L, Blasi, F, Centanni, S, et al Acute exacerbations of asthma in adults: role ofChlamydia pneumoniaeinfection.Eur Respir J1994;7,2165-2168. [PubMed]
 
Hahn, DL, Dodge, RW, Golubjatnikov, R Association ofChlamydia pneumoniae(strain TWAR) infection with wheezing, asthmatic bronchitis, and adult-onset asthma.JAMA1991;266,225-230. [PubMed]
 
Martin, RJ, Kraft, M, Chu, HW, et al A link between chronic asthma and chronic infection.J Allergy Clin Immunol2001;107,595-601. [PubMed]
 
Wubbel, L, Jafri, HS, Olsen, K, et al Mycoplasma pneumoniaepneumonia in a mouse model.J Infect Dis1998;178,1526-1529. [PubMed]
 
Pietsch, K, Ehlers, S, Jacobs, E Cytokine gene expression in the lungs of BALB/c mice during primary and secondary intranasal infection withMycoplasma pneumoniae.Microbiology1994;140,2043-2048. [PubMed]
 
Chu, HW, Honour, JM, Rawlinson, CA, et al Effects of respiratoryMycoplasma pneumoniaeinfection on allergen-induced bronchial hyperresponsiveness and lung inflammation in mice.Infect Immun2003;71,1520-1526. [PubMed]
 
Chu, HW, Rino, JG, Wexler, RB, et al Mycoplasma pneumoniaeinfection increases airway collagen deposition in a murine model of allergic airway inflammation.Am J Physiol Lung Cell Mol Physiol2005;289,L125-133. [PubMed]
 
Kuo, CC, Jackson, LA, Campbell, LA, et al Chlamydia pneumoniae(TWAR).Clin Microbiol Rev1995;8,451-461. [PubMed]
 
Kishimoto, T Studies onChlamydia pneumoniae, strain TWAR, infection: I. Experimental infection ofC pneumoniaein mice and serum antibodies against TWAR by MFA.Kansenshogaku Zasshi1990;64,124-131. [PubMed]
 
Kaukoranta-Tolvanen, SE, Laurila, AL, Saikku, P, et al ExperimentalChlamydia pneumoniaeinfection in mice: effect of reinfection and passive immunization.Microb Pathog1995;18,279-288. [PubMed]
 
Malinverni, R, Kuo, CC, Campbell, LA, et al Reactivation ofChlamydia pneumoniaelung infection in mice by cortisone.J Infect Dis1995;172,593-594. [PubMed]
 
Kraft, M, Cassell, GH, Pak, J, et al Mycoplasma pneumoniaeandChlamydia pneumoniaein asthma: effect of clarithromycin.Chest2002;121,1782-1788. [PubMed]
 
Hahn, DL Treatment ofChlamydia pneumoniaeinfection in adult asthma: a before-after trial.J Fam Pract1995;41,345-351. [PubMed]
 
Hahn, DL, Plane, MB, Mahdi, OS, et al Secondary outcomes of a pilot randomized trial of azithromycin treatment for asthma.PLoS Clin Trials2006;1,e11. [PubMed]
 
Black, PN, Blasi, F, Jenkins, CR, et al Trial of roxithromycin in subjects with asthma and serological evidence of infection withChlamydia pneumoniae.Am J Respir Crit Care Med2001;164,536-541. [PubMed]
 
National Heart, Lung, and Blood Institute... Expert panel report: guidelines for the diagnosis and management of asthma; update on selected topics 2002. 2002; National Heart, Lung and Blood Institute. Bethesda, MD: NHLBI Publication No. 02–5074.
 
Johnston, SL, Blasi, F, Black, PN, et al The effect of telithromycin in acute exacerbations of asthma.N Engl J Med2006;354,1589-1600. [PubMed]
 
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