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American Lung Association/American Thoracic Society International Conference
Day 3 - April 27, 1999

The Role of Infections in Asthma

Homer A. Boushey, MD

Researchers have suspected for some time that viral and bacterial infections can play a role not only in asthma exacerbations but perhaps even in pathogenesis. New research outlined Tuesday provided additional insights for those pursuing these theories.

Monica Kraft and co-workers at National Jewish Medical and Research Center in Denver reported important new research suggesting that chronic airway infection with Mycoplasma pneumoniae or Chlamydia pneumoniae might be a common aggravating—or possibly even causal—but treatable factor in asthma[1,2]. Thompson et al, from Albuquerque, NM, presented their complementary study of Mycoplasma infection of BALB/c mice, showing that this strain, with a Th2 bias in its pattern of lymphocyte-mediated immune responses, clears the infection poorly and develops chronic inflammation and airway hyperreactivity[3].

Several other posters reported on how the nature of an infecting virus and the timing of its infection of the respiratory tract might alter the risks of acquiring asthma. Perhaps the most innovative and important of these was presented by Yamada and colleagues from Vancouver[4]. They showed that persistent or latent infection with adenovirus, lately proposed as a contributor to the pathogenesis of chronic obstructive pulmonary disease (COPD), might induce steroid resistance in a guinea-pig model of asthma.

Other work looked at the mechanism by which the viruses responsible for common colds cause asthma exacerbations. These studies showed again that while naturally acquired or experimentally induced viral respiratory infections cause some changes in the function of the lower airways, the changes do not seem greater in asthmatics than in healthy subjects. They also seem trivial compared with the profound changes in function seen routinely in the asthma exacerbations associated with cold symptoms in clinical practice.

A surprising exception to this theme was reported by Cates of the Cochrance Study Group in London[5]. His analysis of large, randomized controlled trials of the efficacy and side effects of live, attenuated influenza vaccination in asthmatic patients failed to confirm any protective effect against asthma exacerbation due to influenza infection. In fact, influenza vaccination might even carry a small additional risk of asthma exacerbation.

The Impact of Viral Infections

Most asthma, especially in children, appears to involve allergic inflammation of the airway mucosa. But clinicians have long suspected that viral infection of the respiratory tract might be important not only as a cause of asthma exacerbations but perhaps also as a cause or contributor to the pathogenesis of asthma itself.

The first suspicion—a viral role in exacerbations—was confirmed by studies exploiting the power of the polymerase chain reaction (PCR) in detecting even small quantities of viral DNA. The addition of this method to the usual viral culture of nasal secretions obtained from children and adults presenting with asthma exacerbations revealed the presence of a common cold virus in up to 80% of all attacks of asthma. Approximately half of the isolates were rhinovirus, the most common cause of the common cold[6,7].

The second suspicion—the role of these viruses in pathogenesis—has not been confirmed (some evidence even suggests that viral infections of the upper airway during infancy reduce the risk of acquiring asthma)[8,9], but childhood infection with respiratory syncitial virus has been reported to increase the risk of later wheezing and dyspnea by more than two-fold[10].

Until recently, bacterial pathogens were not suspected as important contributors to asthma, except by a handful of epidemiologic investigators who noted a strong association between serologic evidence of infection with C pneumoniae and asthma[11,12]. Again, the application of PCR has had dramatic effects on the conception of asthma. Kraft and her colleagues reported identifying a dramatically and significantly higher rate of M pneumoniae in samples of bronchial mucosa obtained from patients with moderate-severe asthma than in samples from healthy controls[13].

Chronic "Atypical" Bronchitis and Asthma

Research into the influence of infection on the acquisition and course of asthma has accelerated, and will doubtlessly be accelerated further by the findings reported Tuesday. Again, the most revolutionary work was presented by Kraft and her colleagues[1,2]. This group has now analyzed 39 subjects with asthma and 11 controls for the presence of M pneumoniae and C pneumoniae in the upper and lower airways by PCR and culture of bronchoalveolar lavage fluid, bronchial biopsy, and naso/oropharyngeal swabs. They also obtained blood samples for serologic testing for evidence of prior infection. M pneumoniae was detected by PCR in 20/39 asthmatics vs only 2/11 controls, a highly significant difference. C pneumoniae was detected by PCR in 7/39 asthmatics vs 0/11 controls. All cultures were negative for both organisms; no subject had positive serology for M pneumoniae, but 18 asthmatics and one healthy subject had positive serology for C pneumoniae.

This confirmation and extension of their previous report of a high rate of PCR identification of M pneumoniae in a small number of asthmatic subjects would have been important in itself. But Kraft et al made it even more important in a study of the effects of treatment with clarithromycin, a macrolide antibiotic active against both of these "atypical" bacteria[2].

In an on-going study of 26 patients treated with 500 mg of clarithromycin or placebo BID for 6 weeks, they found significant increases in FEV1 and significant reductions in tissue expression of IL-4 only in those whose bronchial biopsies were positive by PCR for M pneumoniae. These findings thus show an antibiotic, clarithromycin, to have a treatment effect previously demonstrated only with oral or inhaled corticosteroids—a reduction in the levels of a cytokine thought responsible for mediating allergic inflammation.

Mycoplasma Infection - From Man to Mouse

Data from epidemiologic and clinical studies of humans prompted Thompson and colleagues to study infections of mice with Mycoplasma pulmonis, a naturally occurring rodent pathogen whose effects resemble those of M pneumoniae in humans[3]. They infected Balb/c mice, a strain with an inborn bias to Th2 patterns of response to immunoprovocation. These mice did not clear the infection well, developing first an intense lymphocytic bronchitis, progressing to infiltration with neutrophils. Despite the influx of neutrophils, the cytokines identified were IL-4 and IL-5, indicating a Th2 response. Airway resistance and airway responsiveness both increased in the infected mice. As the authors noted, these findings are consistent with Kraft and colleagues' proposal of a role for chronic mycoplasma infection in asthma.

Other Airway Infections

Respiratory syncitial virus has also been linked to the development of allergic asthma in children. Schwarze and coworkers reported their study of the effects of acute RSV infection on subsequent airway sensitization in Balb/c mice[14]. They found that neutralizing IL-5 with a mononclonal antibody prevented airway sensitization to ovalbumin.

This result confirmed the importance of this cytokine by showing a loss of sensitization in Balb/c mice without the gene for IL-5 (IL-5 knock-out mice). When IL-5 was reconstituted during RSV infection, ovalbumin challenge again induced eosinophilic airway inflammation. The authors concluded that IL-5 is critical in mediating the effects of RSV infection on allergic airway sensitization.

Yamada et al's study compared the effects of budesonide in down-regulating eosinophilic airway inflammation in guinea pigs sensitized to ovalbumin[4]. Budesonide was effective, as expected, in control guinea pigs, but was ineffective in those that had been infected with adenovirus 5. These results extend a long theme of this research group's work, suggesting that latent infection with adenovirus may be important in the pathogenesis of COPD. Latent infection with adenovirus may also be important in the pathogenesis of steroid-resistant asthma.

Inhaled Corticosteroids in Virally Induced Asthma Exacerbations

Grunberg and colleagues from Leiden examined the effects of inhaled budesonide on markers of airway inflammation in bronchial biopsies obtained from asthmatic volunteers before and after inoculation with rhinovirus-16, a strain used in many centers to induce common colds[15]. Infection led to a modest increase in T-cell and mast-cell, but (surprisingly) not in eosinophil numbers in the bronchial mucosa. Budesonide treatment blocked the modest increase in mast cell numbers.

In the discussion of this poster, Sebastian Johnston noted that these data are quite consistent with the ineffectiveness of augmented inhaled corticosteroid treatment for virally-induced asthma exacerbations noted in clinical trials. Others at the session were impressed that the signs of rhinovirus-induced inflammation were small, echoing the theme that experimentally induced infections do not cause impressive worsening of asthma compared to the severity of cold-induced attacks seen regularly in clinical practice.

Do Natural Colds Rarely Cause Asthma Exacerbations?

In following markers of inflammation in induced-sputum and blood samples from 23 healthy subjects and 14 asthmatic subjects with naturally-acquired colds, Berlyne et al from Hamilton, Ontario found increases in the numbers of polymorphonuclear leukocytes in induced sputum samples[16]. The increases in the samples from healthy and asthmatic subjects did not differ, and even in the asthmatic subjects, sputum eosinophilia did not increase.

Why do Viral URIs Cause so Little Change in Airway Function?

Rob Lemanske, one of the sessions co-chairs, proposed possible reasons why the experimental studies have shown so little effect of viral infection on lower airway function in asthmatic and healthy subjects.

The suggestion that most resonated with the session's participants was that the >100 serotypes of rhinovirus may differ in their "asthmagenicity," and that even rhinovirus 16, the serotype most used in human studies, may have shifted genetically during passages in vitro. Another theory advanced by several participants is that only subjects with mild asthma have been enrolled in inoculation studies, and it may be those with severe asthma who are most prone to exacerbations with viral URIs (upper respiratory infections).

A third theory, advanced by Peter Sterk, from the University of Leiden, and Lemanske, is that the route of infection may be important. These researchers note that nasal inoculation, the route used by almost all studies, may have minimal effects on lower airway function, whereas direct deposition of the rhinovirus onto the airway mucosa, as from inhalation of aerosolized virus particles, might cause much greater lower inflammation.

As a final and possibly synthesizing theory, Donald MacDonald, University of California San Francisco, noted that murine studies have shown prior infection with Mycoplasma to greatly amplify the inflammatory response to subsequent infection with a respiratory virus.

References

  1. Kraft M, Cassell GH, Duffy LB, et al: Mycoplasma and chlamydia are present in the airways of chronic, stable asthmatics [Session C21]. ALA/ATS International Conference, San Diego, Ca, 1999.
  2. Kraft M, Hamid Q, Cassell GH, et al: Mycoplasma and chlamydia cause increased airway inflammation that is responsive to clarithromycin [Session C21]. ALA/ATS International Conference, San Diego, Ca, 1999.
  3. Thompson M, Middleton S, Wilder J, et al: Chronic mycoplasma pulmonis infection: determination of host immune response & airway hyperresponsiveness [Session C21]. ALA/ATS International Conference, San Diego, Ca, 1999.
  4. Yamada K, Elliott WM, Hayashi S, et al: The effect of latent adenoviral infection on steroid suppression of allergic lung inflammation in guinea pigs [Session C21]. ALA/ATS International Conference, San Diego, Ca, 1999.
  5. Cates CJ: Influenza vaccination in asthma: efficacy and side effects, (A systematic review) [Session C21]. ALA/ATS International Conference, San Diego, Ca, 1999.
  6. Pattemore PK, Johnston SL, Bardin PG: Viruses as precipitants of asthma symptoms. I Epidemiology. Clin Exper Allergy 22:325-336, 1992.
  7. Nicholson KG, Kent J, Ireland DC: Respiratory viruses and exacerbations of asthma in adults. Br Med J 307:982-996, 1993.
  8. Holt PG: Environmental factors and primary T-cell sensitisation to inhalant allergens in infancy: reappraisal of the role of infections and air pollution. Pedia Allergy Immunol 6:1-10, 1995.
  9. Holt PG, Yabuhara A, Prescott S, et al: Allergen recognition in the origin of asthma, in, Chadwick DJ, Cardew G (eds): The Rising Trends in Asthma/Ciba Foundation Symposium 206. John Wiley & Sons, Ltd., West Sussex, England 1997; 35-55.
  10. Weiss ST, Tager IB, Munoz A, et al: The relationship of respiratory infections in early childhood to the occurrence of increased levels of bronchial responsiveness and atopy. Am Rev Respir Dis 131:573-578, 1985.
  11. Hahn DL, Dodge RW, Golubjatnikov R: Association of chlamydia pneumoniae (strain TWAR) infection with wheezing, asthmatic bronchitis, and adult-onset asthma. JAMA 266(2):225-230, 1991.
  12. Emre U, Roblin PM, Gelling M, et al: The association of chlamydia pneumoniae infection and reactive airway disease in children. Arch Pediatr Adolesc Med 148:727-732, 1994.
  13. Kraft M, Cassell GH, Henson JE, et al: Detection of mycoplasma pneumoniae in the airways of adults with chronic asthma. Am J Respir Crit Care Med 158(3):998-1001, 1998.
  14. Schwarze J, Cieslewicz G, Joetham A, et al: The presence of interleukin-5 during acute RSV infection is critical for the development of airway hyperresponsiveness (AHR) following subsequent airway sensitization [Session C21]. ALA/ATS International Conference, San Diego, Ca, 1999.
  15. Grunberg K, Sharon RF, Sont JK, et al: Effects of inhaled steroids on rhinovirus 16-induced airways inflammation in asthma [Session C21]. ALA/ATS International Conference, San Diego, Ca, 1999.
  16. Berlyne GS, Hussack P, Efthimiadis AE, et al: Sputum and blood indices of inflammation over the course of natural colds in healthy and asthmatic subjects [Session C21]. ALA/ATS International Conference, San Diego, Ca, 1999.

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