1. 10/7/2015Moustapha Mounib1 بسم الله الرحمن الرحيم

2. 10/7/2015Moustapha Mounib2 Virus-Induced Asthma Attacks Moustapha Mounib, FCCP Consultant of Chest Diseases Military Medical Academy

3. 10/7/2015Moustapha Mounib3 Introduction Asthma is a disease of attacks and remissions. The cause of an attack can often be identified by carefully taking a history. Common causes of asthma attacks include inhaled irritants, inhaled allergens, and viral infections of the respiratory tract.

4. 10/7/2015Moustapha Mounib4 Numerous studies have demonstrated viral infections at the time of acute asthma attacks. Methods used include serologic testing, viral culture, and, most recently, reverse transcription-polymerase chain reaction to detect viral RNA; the viruses associated with asthma attacks are RNA viruses. In children and adults, the most common viruses in this setting are rhinoviruses (a picornavirus that is the usual cause of the common cold), followed by influenza, parainfluenza, respiratory synvytial virus (RSV), and coronaviruses.

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6. 10/7/2015Moustapha Mounib6 In contrast, the role of bacterial infections in acute asthma is far from established. Evidence linking acute infection with common respiratory bacteria is weak, and although such bacteria may be found in the airway with increased frequency in patients with airway disease, an increase during acute exacerbations of asthma has been difficult to demonstrate.

7. 10/7/2015Moustapha Mounib7 Possible exceptions to this rule are mycoplasma and chlamydia. These infections have been implicated in some studies of both acute and chronic asthma, and treatment of chlamydia has been associated with improvement in some series. However, controlled trials have not yet been conducted, and the possibility that these organisms are important contributors to acute asthma, although provocative, cannot yet be viewed as established.

8. 10/7/2015Moustapha Mounib8 Mechanisms Of Virus-Induced Asthma Attacks

9. 10/7/2015Moustapha Mounib9 Virus-Induced Airway Inflammation Airway epithelial cells produce a variety of inflammatory mediators in response to viral infection (Table)

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11. 10/7/2015Moustapha Mounib11 Viruses can also enter macrophages and replicate in them, which may result in the production of a wide range of inflammatory mediators, overlaping many of those produced by the epithelium.

12. 10/7/2015Moustapha Mounib12 Viral infections also potentiate the response to subsequent inhaled allergens in terms of inflammatory response and bronchoconstriction. Similarly, allergic responses in dust mite- sensitized mice are potentiated by repeated RSV infections. IgE production can be potentiated by viral infection, which may also contribute to maintaining asthmatic airway inflammation and potentiating the response to allergens.

13. 10/7/2015Moustapha Mounib13 Virus-Induced Impairement in Inactivation of Tachykinins and Histamine The effects of a variety of mediators in the airways are increased during viral infections. Included among these mediators are tachykinins, a group of peptide transmitters produced in sensory nerves. They cause bronchoconstriction, increase vascular permeability that leads to airway edema, stimulate gland secretion, and cause migration of leukocytes into the airways.

14. 10/7/2015Moustapha Mounib14 During viral infection these effects are potentiated because of loss of activity of neural endopeptidase, an enzyme in the airways that degrades and inactivates tachykinins. Changes in tachykinin expression and neurokinin receptors (which mediate the response to tachykinins) in the airways may also contribute.

15. 10/7/2015Moustapha Mounib15 The airway response to histamine is also potentiated. Although this response is largely due to increased reflex bronchoconstriction, viral infections also decrease the activity of the enzyme histamine N- methyltransferase, which normally inactivate histamine.

16. 10/7/2015Moustapha Mounib16 Nitric Oxide Production Because of the multiple effects of nitric oxide, the net effect of virus-induced changes in nitric oxide production is difficult to predict. Some studies suggest that nitric oxide contributes to tissue damage in the virus-infected lung, whereas others suggest that defective production of nitric oxide contributes to bronchoconstriction. Nitric oxide suppresses rhinovirus replication and the production of proinflammatory cytokines in airway epithelial cells.

17. 10/7/2015Moustapha Mounib17 Virus-induced Changes in Neural Control of the Airways Viral infections increase vagally mediated reflex bronchoconstriction. They may also potentiate responses to tachykinins and cause defective airway relaxation.

18. 10/7/2015Moustapha Mounib18 In the airways, the dominant neural control is provided by cholinergic fibers in the vagus nerves. Increased cholinergic reflex bronchoconstriction has been demonstrated in humans with naturally ocurring viral infections. Animal studies clearly demonstrate increases in the efferent part of the reflex.

19. 10/7/2015Moustapha Mounib19 Release of acetylcholine from vagal nerve endings is limited by M2 muscarinic receptors on the airway nerves. Acetylcholine released from parasympathetic fibers stimulates smooth muscle contraction and bronchoconstriction by binding to M3 receptors on the smooth muscle. However, at the same time, released acetylcholine feeds back onto inhibitory M2 receptors on the nerve endings themselves. Binding of acetylcholine to these inhibitory autoreceptors provides negative feedback, decreasing further release of acetylcholine.

20. 10/7/2015Moustapha Mounib20 Viruses and interferons produced in response to viral infection downregulate the expression of the M2 receptors gene. Animal studies demonstrate that the inhibitory M2 receptors lose function during viral infections, which eliminates the normal negative feedback inhibition of acetylcholine release and increases vagally mediated bronchoconstriction. This loss of function can be reversed by corticosteroids, which increase M2 receptor gene expression and function.

21. 10/7/2015Moustapha Mounib21 M2 receptor dysfunction may also occur via eosinophil-dependent mechanisms. In patients who have died from severe asthma, eosinophils are found clustered along the airway nerves. These eosinophils release major basic protein, which binds to M2 receptors, blocking their function.

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23. 10/7/2015Moustapha Mounib23 Studies in experimental animals demonstrate that viral infection can activate eosinophils to cause M2 receptor dysfuntion and bronchoconstriction via this mechanism. The mechanism by which viruses activate eosinophils is not well understood, but experimental studies suggest that CD8 T lymphocytes are involved.

24. 10/7/2015Moustapha Mounib24 Airway parasympathetic neurons express eotaxin, which attract eosinophils. These neurons also express intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule. Expression of ICAM-1 is inhibited by dexamethasone, which also prevents the influx of eosinophils into the airway nerves and dysfuntion of the M2 receptor.

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26. 10/7/2015Moustapha Mounib26 The eosinophil may also be beneficial in virus- infected airways, exerting a substantial antiviral effect. Preliminary studies suggest that the antiviral effects of eosinophils are mediated via the production of hypobromous acid. It has also been suggested that production of ribonucleases by eosinophils may participate in the antiviral effect by degrading viral RNA. Thus, both T H 1-type cytokines (interferon  ) and T H 2 -type cytokines (leading to eosinophilia) can participate in virus-induced M2 receptor dysfunction.

27. 10/7/2015Moustapha Mounib27 Studies suggest that sensitization to a nonviral antigen or possibly a background of atopy, as is present in many patients with asthma, may predispose patients to the latter pathway in which eosinophils are activated by viral infections. In contrast, in the absence of an atopic background, viruses lead to production of interferons that can downregulate M2 receptor expression and function. Because levels of interferon  are increased in the airways of patients with atopic asthma, this mechanism may also apply in these patients.

28. 10/7/2015Moustapha Mounib28 Implications For Treatment

29. 10/7/2015Moustapha Mounib29 Anticholinergic Bronchodilators Anticholinergic therapy offers modest benefits in stable asthma, but acute exacerbations of asthma appear to respond more favorably when anticholinergics are added to b-agonists than when b-agonists are used alone. Thus, a National Institutes of Health Expert Panel Report recommends anticholinergics in addition to  -agonists for the initial treatment of severe asthma attacks and for patients admitted to the hospital with acute asthma. Controlled studies show that emergency treatment of acute asthma attacks with anticholinergics in addition to  - agonists decreases the hospitalization rate in adults and children. The benefit of anticholinergic treatment is greatest in those with more severe attacks.

30. 10/7/2015Moustapha Mounib30 Steroids Treatment with steroids is a standard therapy for asthma attacks. Although many mechanisms are likely to contribute to the beneficial effects of steroids, it is likely to be significant that steroids can reverse the effects viruses and interferons on M2 receptor gene expression and that they can increase M2 receptor expression and function.

31. 10/7/2015Moustapha Mounib31 Treatment and Prevention of Viral Infections Because viruses may precipitate asthma attacks, prevention or treatment of viral infections is advisable in patients with asthma. Unfortunately, among the the viruses commonly implicated in asthma attacks, effective vaccination is available only for influenza.

32. 10/7/2015Moustapha Mounib32 Influenza Patients with asthma should receive flu shots, although an overall decrease in asthma attacks in patients receiving flu shots has been difficult to demonstrate, probably because less than 10% of asthma attacks are caused by influenza. Treatment and prevention of influenza infection with neuraminidase inhibitors may also be advisable, although again a reduction in asthma attacks has yet to be demonstrated.

33. 10/7/2015Moustapha Mounib33 Respiratory Syncytial Virus The association of RSV infection with asthma attacks in older children and adults suggests that treatment and prevention of RSV infections might also be beneficial in patients with asthma. However, neither a vaccine nor an effective treatment is available for this virus. Treatment with humanized monoclonal antibodies(palivizumab) is costly and has not been evaluated in older patients or in those with asthma. The antiviral medication ribavirin has been used to treat these infections in infants and children, but a beneficial effect has been difficult to demonstrate.

34. 10/7/2015Moustapha Mounib34 Parainfluenza and Coronavirus Parainfluenza virus and coronaviruses are common causes of upper respiratory tract infections. In patients with asthma, they may precipitate attacks. Neither treatments nor vaccines are available.

35. 10/7/2015Moustapha Mounib35 Rhinovirus Rhinovirus infections are the predominant cause of the common cold and of virus-induced asthma attacks. Unfortunately, it has not yet been possible to develop a vaccine. There are more than 100 serotypes of rhinovirus. Immunity follows infection with each one; however, because they are all immunologiclly distinct, antibodies to a very wide range of antigens would be required to confer immunity to all rhinoviruses. Both a soluble form of ICAM- 1 and the compound pleconaril can interfere with rhinovirus binding and may hold promise for treating infection.

36. 10/7/2015Moustapha Mounib36 Antibiotics Conventional bacteria are probably not major causes of asthma attacks. For this reason, antibacterial treatment cannot be viewed as standard care during asthma attacks unless there is definite evidence of a bacterial infection. The role of treatment for mycoplasmal and chlamydial infections in acute and chronic asthma awaits controlled clinical trials.

37. 10/7/2015Moustapha Mounib37 CONCLUSIONS

38. 10/7/2015Moustapha Mounib38 According to the data reviewed here, the following can be recommended: 1-The management of acute asthma should include anticholinergic bronchodilators in addition to  - agonists and steroids. 2-Routine use of antibiotics is probably not justified. 3- Prevention of viral infections by using vaccination as well as antiviral medications as they become available is likely to be advisable in patients with asthma.

39. 10/7/2015Moustapha Mounib39 4-As neurokinin receptor antagonists are develoloped, they may be particularly effective in this group of patients because tachykinin- mediated responses are potentiated. 5- The long list of known virus-induced proinflammatory mediators may suggest new therapeutic directions as antagonists of thes mediators become available.

40. 10/7/2015Moustapha Mounib40 Thank you.