The effects of viral & atypical infections in asthmatics

1. The effects of viral & atypical infectionsin asthmatics İ.Kıvılcım Oğuzülgen Gazi University School of Medicine Dept. of Pulmonary Medicine, Ankara

2. The aim of this presentation is to provide an update about the effect of respiratory infections caused by either viruses or atypical bacteria on asthma.

3. Atypical and viral infections in asthma exacerbations Lieberman D et al. Am J Respir Crit Care Med 2003; 167:406-10.

4. Asthma & Viral infections

5. Asthma and viral infections • Clinical and epidemiological observarions strongly link viral infections with acute worsening of asthma in as many as 80% of cases in children and 60% in adults. Tan WC. Curr Opin Pulm Med 2005; 11:21-6.

6. Spectrum of viruses detected by PCR in asthma attacks Tan WC et al. Am J Med 2003;115:272-7.

7. Link between asthma and viral infections URT/LRT symptoms + PEFR 108 school age children Microbiological samples The seasonal patterns of upper respiratory infections correlated strongly with hospital admissions for asthma (r = 0.72; p < 0.0001). This relationship was stronger for pediatric (r = 0.68; p < 0.0001) than for adult admissions (r = 0.53; p < 0.01). Upper respiratory viral infections are strongly associated in time with hospital admissions for asthma in children and adults. Johnston SL et al. Am J Respir Crit Care Med. 1996;154:654-60.

8. Link between asthma and viral infections 138 adult asthmatics (19-46 yr) Mean wheese duration 19.6 yr • Colds were reported in 80% (223/280) of episodes with symptoms of wheeze, chest tightness, or breathlessness, and 89% (223/250) of colds were associated with asthma symptoms. Relation between symptomatic colds and asthma exacerbations Nicholson KG et al. BMJ 1993;307:982-6.

9. Link between asthma and viral infections Pathogen found 0 20 40 60 80 100 120 No pathogen found Decrease in peak expiratory flow (l/min) Days after onset of symptoms 1 3 6 9 12 14 Mean daily decrease in PEFR for episodes with objective evidence of asthma exacerbations Nicholson KG et al. BMJ 1993;307:982-6.

10. Link between asthma and viral infections Patients recorded symptom scores for asthma and peak expiratory flow rate daily for 11 months 31 atopic asthmatics (15-56 yr) Microbiological samples (every 4 wk & as soon as possible after the onset of worsening asthma or symptoms suggesting a respiratory tract infection) 30 viral infection 60% asthma exacerbation 178 asthma exacerbation 10% viral RTI 28 severe exacerbation 36% viral RTI Baesly R et al. Thorax 1988;43:679-83.

11. Link between asthma and viral infections • Rhinovirus was detected in 10.1% of asthmatics and 8.5% of healthy participants. • Frequency, severity, or duration of URT infections were similar. • Symptoms of LRT associated with RV infection were significantly more severe (p=0.001) and longer-lasting in participants with asthma than in healthy participants (p=0.005). Healthy control Atopic asthma 76 couples Daily URT and LRT symptoms & PEFR records & Nasal aspirates for rhinovirus (every 2 wk) Corne JM et al. Lancet 2002;359:831-4.

12. Asthma and Rhinovirus • During the following periods of childhood and adolescence,as well as in adults, about 60% of the viral,upperrespiratory tract infections involved inasthma exacerbations, are caused by Rhinovirus. Pelaia G et al. Respir Med 2006;100:775-84.

13. Effects of RV to lower respiratory tract 125 100 75 50 25 0 Baseline URI Recovery * PD20 (Cumulative Breath Units) FEV1 *,** * * *p<0.05 Compared to baseline **p<0.05 Compared to URI * * Histamin (Pre-antigen) Antigen Histamin (Post-antigen) • In 10 experimentally infected (with RV) patients with allergic rhinitis, comparison of the airway response to histamine and ragweeg antigen at baseline, during an acute RV illness, and 4 wk later at recovery. Lemanske RF Jr et al. J Clin Invest 1989;83:1-10.

14. Effects of RV to lower respiratory tract Normal Allergic Rhinitis 125 100 75 50 25 0 125 100 75 50 25 0 BAL Eosinophils (Milions) Pre Infection Acute Infection Post Infection Pre Infection Acute Infection Post Infection • BAL eosinopils before, 48 hr after and 4 weeks after segmental antigen challenge in subjects with experimentally infected with rhinovirus 16 Calhoun WJ et al. J Clin Invest 1994;94:2200-8.

15. Effects of RV to lower respiratory tract Normal Allergic Rhinitis 50 40 30 20 10 0 50 40 30 20 10 0 BAL TNFα (ng/ml) Pre Infection Acute Infection Post Infection Pre Infection Acute Infection Post Infection • BAL TNF α concentrations before, 48 hr after and 4 weeks after segmental antigen challenge in subjects with experimentally infected with rhinovirus 16 Calhoun WJ et al. J Clin Invest 1994;94:2200-8.

16. Mechanisms of RV-asthma interaction • NF-кB • IL-4 RV • ICAM-1 • IL-16 IL-8 IL-6 • FGF-2, Eotaksin, RANTES Pelaia G et al. Respir Med 2006;100:775-84.

17. Mechanisms of RV-asthma interaction • Exacerbation of asthma symtoms • Increase in bronchial hyper-responsiveness • Structural changes responsible for airway remodelling RV Pelaia G et al. Respir Med 2006;100:775-84.

18. Asthma and influenza & parainfluenza viruses • The airway immune inflammation occurring in manyasthmatic patients can be further amplified byacute viral infections caused by influenza viruses. • Influenza viruses often exacerbate respiratory symptomsand bronchial responsiveness to allergic stimuli. Pelaia G et al. Respir Med 2006;100:775-84.

19. Mechanisms of influenza-asthma interaction ACh M2 • IL-8. RANTES, MIP1-α ACh Pelaia G et al. Respir Med 2006;100:775-84.

20. Mechanisms of influensa-asthma interaction • Enhance celluler response to allergen sensitization • Exaggeration of reflex parasympathetic bronchoconstriction Pelaia G et al. Respir Med 2006;100:775-84.

21. Mechanisms of parainfluenza-asthma interaction • TGF-β NO Pelaia G et al. Respir Med 2006;100:775-84.

22. Mechanisms of parainfluenza-asthma interaction • Increase in bronchial hyper-responsiveness • Bronchiolar fibrosis • Structural changes responsible for airway remodelling Pelaia G et al. Respir Med 2006;100:775-84.

23. Conlusions: Viruses & Asthma • The importance of common respiratory viruses, especiallythe rhinovirus, in the pathogenesis of exacerbationsof asthma is well recognized. • There is now evidence that viral respiratory tractinfections affect existing asthma by increasing the intensity of (allergic) inflammation.There is good clinical andepidemiologic evidence that a synergistic effect with pre-existing allergen sensitization occurs.

24. Conlusions: Viruses & Asthma • Currently, there is no effective method for the prevention of these virus-provoked asthma attacks.

25. Atypical infections & Asthma

26. Rate of atypical infections in asthma exacerbations Lieberman D et al. Am J Respir Crit Care Med 2003; 167:406-10.

27. Rate of atypical infections in stable asthma 50 Mycoplasma Chlamydia 56 30 % of subjects 45 10 13 0 9 Asthma Control Asthma Total Asthma Control • Percent of subjects with positive PCR results for Mycoplasma and Chlamydia species amongasthmatic patients and normal control subjects. Martin RJ et al. J Allergy Clin Immunol 2001;107:595-601.

28. It is not known whether M. pneumoniae or C. pneumoniae were allowed to persist after an infection, or were present prior to the development of asthma. There is evidence to support both possibilities, the effects of infection with this organism can persist for months, resulting in decreased expiratory flow rates, and increased airway hyperresponsiveness in normal individuals. Kraft M et al. Chest 2002; 121:1782-88.

29. Proposed biological mechanisms • 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 cells may also lead to inflammation —possibly thereby increasing asthma severity—and tissue damage with airway remodelling. Johnston SL et al. Am J Respir Crit Care Med 2005; 172:1079-89.

30. Mechanisms of Chlamydia-asthma interaction Hsp60 Ag NF-кB TNF-α, IL-1β, IL-8 IL-6 Pelaia G et al. Respir Med 2006;100:775-84.

31. Mechanisms of Chlamydia-asthma interaction • Increase airway susceptibility to other environmental stimuli such as allergens and viruses thereby accelerate asthma progression • Structural changes responsible for airway remodelling • Contributes to asthma severity Pelaia G et al. Respir Med 2006;100:775-84.

32. Mechanisms of Mycoplasma-asthma interaction IgE B cell TNF-α, IL-1β, IL-8,IL-4, IL-5, IL-6, RANTES, TGF- β Pelaia G et al. Respir Med 2006;100:775-84.

33. Mechanisms of Mycoplasma-asthma interaction • Trigger Th2-like cytokine responses, associated with elevated serum IgE concentrations • Causes inflammatory and structural changes Pelaia G et al. Respir Med 2006;100:775-84.

34. Mechanisms of Mycoplasma-asthma interaction • Airway collagen deposition in allergen sensitized animals 6 weeks after experimental model of Mycoplasma pneumonia infection (b) and control group (a) Sutherland ER et al. Chest 2007; 132:1962-6.

35. Mechanisms of Mycoplasma-asthma interaction • 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.

36. Antibiotics in the treatment of asthma • 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 antibiotics. Sutherland ER et al. Chest 2007; 132:1962-6. Johnston SL. J Allergy Clin Immunol 2006;117:1233-6

37. Antibiotics in the treatment of 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 azithromycin), the newer quinolones, and the ketolide telithromycin. Johnston SL et al. Am J Respir Crit Care Med 2005; 172:1079-89.

38. Effects of macrolides in asthma • Modulate the functions of inflammatory cells, including polymorphonuclear leukocytes, lymphocytes, and macrophages. • 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. • Inhibit the synthesis and/or secretion of proinflammatory cytokines (e.g., TNF-, IL-8, IL-6, IL-1). Their effects on antiinflammatory cytokines (IL-10, IL-4) are more variable. Johnston SL et al. Am J Respir Crit Care Med 2005; 172:1079-89.

39. Effects of macrolides in asthma • 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-кB. Johnston SL et al. Am J Respir Crit Care Med 2005; 172:1079-89.

40. Effect of clarithromycin in asthma 3.0 p=0.47 p=0.05 FEV 1 (L) 2.5 PCR + PCR - 2.0 Baseline Clarithromycin Baseline Clarithromycin • In 55 chronic stable asthmatics, M. pneumoniae or C. pneumoniae were present in the airways by PCR in 55% of the patients. In addition, treatment with clarithromycin improved the FEV1 and reduced airway tissue expression of IL-5, but only in the PCR-positive subjects. Kraft M et al. Chest 2002; 121:1782-88.

41. 7 studies recruiting a total of 416 participants • Findings from studies comparing macrolide treatment for at least 4 weeks in adult and pediatric patients treated forchronic asthma. • 4 studies showed a positive effect on symptoms of macrolides in different types of asthmatic patients. • There was no significant difference in FEV1 for either parallel or crossover trials. • However, therewere significant differences in eosinophilic inflammation and symptoms. • One large parallel group trial reported significant differencesin peak flow but these differences abated within six months of treatment. Richeldi L et al. Cochrane Database of Systematic Reviews 2005, Issue 4 . Updated 2007

42. Effects of ketolides in asthma • Fewer data are available concerning the antiinflammatory properties of ketolides, although telithromycin has demonstrated immunomodulatory effects both in vitro and in vivo. • Telithromycin has been shown to significantly inhibit secretion of IL-1 and TNF-α in human monocytes in vitro, and inhibit IL-1, IL-6, and IL-10 secretion in a murine model. Johnston SL et al. Am J Respir Crit Care Med 2005; 172:1079-89.

43. Telithromycine in asthma 278 adults with acute exacerbation of asthma (61%had microbiological evidence of Mycoplasma or Chlamydia infection) p=NS Change in FEV1 from baseline (L) 0.8 0.6 0.4 0.2 0.0 p=0.001 Telithromycine • Patients in the telithromycin group (n:126) had a significantly greater improvement in asthma symptoms during the 10-day treatment period but did not have an improvement in peak expiratory flow rates as measured in the morning at home.There was no relationship between bacteriologic status andthe response to asthma treatment. Placebo 0 11-14 28 42 Day Johnston SL et al. N Engl J Med 2006;354:1589-600.

44. Conclusions • Even though some clinical data indicate a positive effect of macrolides in asthmatic patients in the absence of relevant side effects, these data are insufficient to recommend the routine use of macrolides for control of asthma at present. • Current studies will further define the role of macrolide antibiotics in the treatment of stable asthma patients. Richeldi L et al. Cochrane Database of Systematic Reviews 2005, Issue 4.Updated 2007. Sutherland ER et al. Chest 2007; 132:1962-6

45. As a result, increasing evidence suggests atypical bacterial and viral infections contribute to exacerbation severity, as well as stable asthma, particularly severe asthma. Johnston SL. J Allergy Clin Immunol 2006;117:1233-6