1. Infectious triggers of asthma Joseph E. Crea, D.O.President, Crea Healthcare Partnering, Inc.MedcoLiberty Lake, WASeptember 15, 2011

2. Disclosure Information I have the following financial relationships to disclose: Honorarium and expenses paid by: Medco Health Solutions, Inc. through Business Services International, Inc. I have no other financial relationships to disclose. I will not discuss any investigational drugs. I will not discuss any off label uses.

3. Objectives: Pharmacists Contrast the ‘‘Hygiene Hypothesis’’ and ‘‘Hit-and-Run Hypothesis’’ as they relate to the development of asthma and atopy. Summarize the evidence. Compare viral-induced wheezing (VIW) and classic childhood asthma. Discuss the epidemiology, diagnosis, treatment, clinical course, and sequelae of respiratory syncytial virus (RSV) infections in the pediatric population. Describe how to identify the potential infectious agents responsible for asthma exacerbations. Summarize the difference between viral and atypical bacterial triggers as it relates to asthma chronicity. Delineate and discuss the advantages and disadvantages for the various treatments for the infectious triggers of asthma.

4. Objectives: Pharmacy Technicians Discuss the obstacles to clinically effective treatments for “the common cold.” Discuss the two phenotypes of wheezing. Delineate the various medications used for treatment in the infectious triggers of asthma. Describe the advantages and disadvantages between classes of antivirals. Explain the concerns with the various formulations of steroids in the treatment of asthma or atopy. Summarize the interactions between infectious agents and atopic status.

5. Asthma triggers Most asthma episodes are precipitated by factors other than allergen exposure. Infection has been implicated as the most common precipitant of asthma exacerbations. Many asthma episodes are preceded by upper respiratory tract (URI) symptoms and may last several days to weeks. Allergen-induced asthma exacerbations often lead to rapid onset of symptoms with recovery within 24 hours.

6. Mechanisms? Proposed mechanisms for viral infections provoking asthma: Direct extension of URIs to the lower respiratory tract where virus exert direct effects on airway cells. Increased production of IL-10 by monocytes during acute and convalescent phases. IL-10 may have a direct effect on airway smooth muscle and the regulation of airway tone. Generating changes in patterns of pro-inflammatory cytokine production that facilitates virus persistence or latency . Poorly understood. Indirect effects on airway responsiveness independent of direct epithelial damage and inflammation.

8. Phenotypes of wheezing Phenotypes Viral-induced wheeze (VIW)characterized by: Acute viral URI Brief episodes of lower respiratory symptoms Decreased pulmonary function Longer asymptomatic periods with normal pulmonary in-between Outgrow symptoms by age 6 May continue into adulthood Less severe symptoms, Negative methacholine challenge Normal pulmonary functions Classic childhood asthma characterized by: Chronic symptoms Atopy The inability to reliably differentiate between VIW and asthma complicates: Evaluation of the influence of viral infections on exacerbations of wheezing. Implications in determining efficacy of therapies.

9. Phenotypes of wheezing International guidelines for the management of asthma, but not for VIW. Because most acute exacerbations of asthma are induced by viral infections, one would presume that the current treatment for chronic asthma would be efficacious in preventing VIW. RSV-associated wheezing does not consistently respond to medications often used to treat asthma exacerbations.

10. Phenotypes of wheezing Several treatment approaches have been investigated in an attempt to reduce the morbidity associated with VIW. Short course of oral corticosteroid at onset of URI Reductions in the frequencies of wheezing, emergency room visits, and hospitalizations Unblinded Parent-initiated oral corticosteroids at onset of URI No difference Double-blinded, placebo-controlled Thus early use of oral corticosteroids is unclear. Further investigation is required.

11. Epidemiology of RTIs Respiratory tract infections (RTIs) are the most common cause of acute illness in adults and children. URIs constitute the majority of these illnesses. Adults typically experience two to four URIs per year. Children may have up to 12 URIs per year.

12. Economics of RTIs RTIs are a major cause of visits to primary care physicians. Associated with significant work and school absenteeism. Estimated 150 million lost workdays annually. $40 billion annually in the United States

13. Epidemiology of asthma Asthma is a chronic inflammatory lung disease that affects an estimated 23 million Americans (16 million adults). 12 million experience an asthma attack every year. Several factors influence the development and severity of asthma: Atopy Environmental exposures Genetic predisposition Gene–environment interactions Stress Obesity Diet Socioeconomic status Infection

14. Economics of asthma Unadjusted total medical expenditures for all adults with a reported ICD-9 code for asthma was $90.8 billion (2008 US dollars). Total medical expenditures attributable to adult asthma was calculated to be $18 billion (2008 US dollars) annually

15. Role of infectious agents The role of infectious agents in the development of asthma is complex. Causal (‘‘Hit-and-Run Hypothesis’’) Protective (‘‘Hygiene Hypothesis’’)

16. The ‘‘Hit-and-Run Hypothesis’’ Infections may be a cause for the onset and persistence of asthma. A pathogen promotes dysregulation of the immune system. Leads to prolonged inflammatory responses even after the pathogen has been cleared.

17. The ‘‘Hit-and-Run Hypothesis’’ Viral infections with a propensity for lower airway during infancy have been associated with chronic lower respiratory tract symptoms and asthma. RSV bronchiolitis is a significant independent risk factor for subsequent frequent wheezing. Could be explained in part by viral persistence. Hypothesized that asthmatics have increased susceptibility to viral infections. Some researchers have found an increased incidence of viral infections in asthmatic children when compared with non-asthmatics. Could be explained by the increased expression of ICAM-1 receptor for Rhinovirus. This finding was not confirmed in adults. Asthma did not significantly increase the risk of infection with rhinovirus in cohabitating couples consisting of an atopic asthmatic and a healthy non-atopic, non-asthmatic (OR = 1.15).

18. The ‘‘Hit-and-Run Hypothesis’’

19. The ‘‘Hygiene Hypothesis’’ An inverse relationship between infection and allergy was hypothesized because it was observed that increased family size and the age of day care entry, often associated with more frequent infections in early childhood, had an inverse relationship with the prevalence of asthma. One potential explanation for this pattern is that at birth there is a predominant TH2 response, and, as exposure to infections occurs, there is a gradual shift toward a TH1-dominant response. As TH1, which regulates response to viral infection, is impaired, a TH2 response predominates, favoring the development of allergy. In vivo studies have shown that asthmatics exposed to viral infections lack the capacity to mount a strong TH1 response.

20. Immunopathology and Mechanism of disease Viruses typically enter the body through contact with mucosal surfaces. The cell-specific distribution of viral receptors determines the viral tropism. Once the viral particles are internalized, nucleic acids are released, and transcription and production of viral proteins starts. The viral genome is replicated, and virions are released, propagating the infection. The immune system is activated through several mechanisms when a viral infection is noted: Cell surface receptors Viral proteins interact with intracellular proteins activating the host cell Activation of epithelial cells lead to production of: Cytokines (interferon-a, -b) Chemokines (IL-8; RANTES; MIP-1, -2, -3; MCP-3)

22. Immunopathology and Mechanism of disease One of the earliest responses to viral infection is the production of interferons (IFNs) by different cell types. IFN-a is produced by leukocytes IFN-b is produced by fibroblasts IFN-g is produced by Th1 cells and natural killer (NK) cells. Interferons Transcribe of genes; two with direct antiviral activity (MHC class I and II) Activate antiviral effector cells NK cells T-lymphocytes Macrophages Inflammatory process from viral infections are mainly TH1 with a predominance of interferons, especially INF-g. Atopy has a predominance of TH2 cytokines. However,different viral agents promote increased cytokine-mediated inflammation through direct induction of specific cytokines, which may explain why certain pathogens are more strongly associated with asthma exacerbation.

24. Interactions between infectious agents and allergy The effect of atopic status on the rate of viral infection is unclear. Evidence exists suggesting no difference between the rate of viral infection between atopic and non-atopic. There is an increased risk of acute wheezing when atopy is combined with viral infection when compared with atopy or viral infection alone. Infants with a family history of atopy seem more likely to develop bronchiolitis with a higher rate of hospitalization. Even if asthmatics do not experience more frequent infections than non-asthmatics, it is possible that asthmatics have a higher incidence of symptoms when experiencing viral infections. During rhinoviral infection, there is a greater incidence of symptoms in asthmatics compared with non-asthmatics. Asthmatics experienced seroconversion to Influenza A virus at the time of asthma exacerbation even in the absence of signs of respiratory infection.

25. Viral infections and asthma exacerbation Seasonal pattern of distribution of viral infections and asthma exacerbations: Strong relationship was found between the seasonal incidence of asthma and viral infection. Strongest with severe cases requiring hospitalization. Viral infections were the major identifiable risk factor for autumnal asthma exacerbations. No correlation with pollen and spore counts.

26. Viral infections and asthma exacerbation

28. Atypical organisms Atypical organisms are involved as well. Mycoplasma pneumoniae Chlamydia pneumoniae RTIs with atypical organisms: May be the initial insult for development of asthma. Precipitate a significant proportion of acute episodes of wheezing. Contribute to the severity and persistence of asthma.

29. Viruses

33. Rhinovirus Human rhinovirus (RV) causes nearly half of all upper respiratory illnesses. Initially believed to be limited to the upper airways, but lower airway epithelial RV infection has been demonstrated. RV infection can enhance the immediate and late-phase responses to allergens. Potentially augments inflammation precipitating asthma exacerbations.

34. Rhinovirus Associated with declines in lung function in asthmatics within 2 days after development of a RV infection. Can lead to profound exacerbation of asthma Responsible for the majority of hospitalizations for childhood asthma. Less so in adults RV infection augments airway hyper-responsiveness 4 days after experimental RV infection. Hyper-responsiveness was accompanied by: Increase in nasal interleukin (IL)-8 in the RV-infected group at days 2 and 9; Increase in nasal IL-8 at day 2 correlated significantly with the change in airway responsiveness at day 4. More pronounced in those with a severe cold.

36. Produced a greater disease burden value than influenza or respiratory syncytial virus.

37. Associated with less severe lower respiratory tract symptoms than other viruses in asthmatic school-age children by PEF (56 L/min vs. 85.5 L/min).Implicated in more than 40% of LRTIs of elderly adult patients. 25% of these received antibiotics.

38. Discussion of Disease burden value

41. Adenovirus Demonstrated during acute asthma episodes, but substantially less frequently than for Rhinovirus and Coronavirus. The rate of adenoviral infection declines with age until 9 years and then it increases. Exception is serotype 7 Rate increases with age. Frequently associated with wheezing. 58.3% of non-asthmatic children under age 2 admitted to a PICU with acute LRTI due to Adenovirus. Mortality rate was 16.7% Mostly with serotype 7.

43. Adenovirus Latentadenoviral infection may have a role in the genesis of asthma. Adenoviral shedding may be prolonged (up to 906 days). Found in 78.4% of asymptomatic asthmatic children vs. 5% of healthy controls.

44. Adenovirus Study: Recovered from BAL in children with asthma 12 months or more after an acute infection. BAL performed in 34 children (mean age of 5 years) with unfavorable responses to standard corticosteroid and bronchodilator therapy. Adenoviral antigens detected in 94% of subjects. Repeat studies done on 8 subjects within 1 year showed that 6 were positive on two occasions and 3 on a third as well. Cultures of the BAL fluid were positive for Adenovirus in all cultures performed indicating that the virus was still capable of replication. Similar studies performed in control patients without persistent asthma failed to detect evidence of adenovirus.

45. Respiratory syncytial virus (RSV) Infects almost 100% of children by age 2. The most common cause of bronchiolitis and pneumonia in infants. RSV serves as a trigger for exacerbations of asthma and other chronic lung diseases.

48. Respiratory syncytial virus (RSV) RSV bronchiolitis is a significant independent risk factor for subsequent frequent wheezing, although this effect seems to decrease with age and may be dependent upon the severity of infection. Infants who experience severe RSV bronchiolitis have increased frequencies of wheeze and asthma later in life. Children admitted for bronchiolitis found that the post-bronchiolitis group had a significantly higher frequency of bronchial obstructive symptoms 2 to 10 years later. PFTs showed diminished FEV1 or increased bronchial reactivity compared with healthy controls. By 7.5 years of age, the cumulative prevalence of asthma was 30% in the RSV group vs. 3% in the control group. Current asthma was present in 23% of the RSV group versus 2% of the control group.

49. Respiratory syncytial virus (RSV)

50. Respiratory syncytial virus (RSV) However, the duration of the effect of RSV infection on asthma-related symptoms appears to be limited. In a prospective study of 1246 children enrolled at birth, 207 developed an RSV LTRI not requiring hospitalization during the first 3 years of life. When compared with a control group of children with no LRTI documented during the first 3 years of life, the group with mild RSV LRTI had a substantially increased risk of frequent wheezing at 6 years of age (OR = 4.3). The risk for frequent wheeze remained significantly increased at 11 years of age (OR = 2.4) Pre-bronchodilator FEV1 but not post-bronchodilator FEV1 was significantly lower in the RSV group. By age 13 years, there were no significant between-group differences in terms of increased risk for frequent or infrequent wheezing.

51. Respiratory syncytial virus (RSV) Similar to adenoviral infection, the persistence of RSV may underlie the sequelae of severe RSV disease. Infection may lead to alteration in the patterns of local interferon, chemokine, and cytokine production potentially leading to chronic inflammation. The age at first viral infection may direct the pattern of disease later in life by generating a memory response to RSV, which may direct other antigens in the lung toward an allergic response. Mice infected with RSV at different ages (1, 7, 28, or 56 days) demonstrated stronger responses in the youngest group when reinfected at 12 weeks of age.

53. Parainfluenza virus The Parainfluenza viruses (PIV) cause a spectrum of respiratory illness similar to RSV but result in fewer hospitalizations. Most illnesses are limited to the upper respiratory tract. 15% involve the lower respiratory tract. Only 2.8 of every 1000 children with PIV LRTIs require hospitalization. 14% of episodes of increased symptoms or decreased PEF in school-aged children. More frequent and severe wheezing correlated with elevated levels of IgE antibodyto RSV or PIV in nasal secretions of children with bronchiolitis due to RSV or PIV.

54. Human metapneumovirus Human metapneumovirus (hMPV) was identified in 2001 in respiratory samples from children with respiratory disease in the Netherlands. Clinical symptoms are diverse and may consist of upper or lower respiratory tract symptoms ranging from otitis media to bronchiolitis, croup, pneumonia, and possibly exacerbations of asthma. hMPV is responsible worldwide for community-acquired acute RTIs. Mean age of illness of 11.6 months Male predominance (male/female ratio 1.8:1). The broad epidemic seasonality and genetic variability suggest that there may be more than one serotype of hMPV.

57. Atypical organisms

58. M. pneumoniaeand C. pneumoniae Most present with malaise, gradual onset shortness-of-breath, and wheezing. Symptoms typically resolve after treatment with macrolide antibiotics or oral corticosteroids. Infections with these organisms can persist for months. Infections with decreased expiratory flow rates and increased airway hyper-responsiveness in previously healthy adults associated with the onset of asthma symptoms.

60. M. pneumoniaeand C. pneumoniae The most comprehensive evaluation of the role of M. pneumoniae and C. pneumoniae infections in patients with chronic asthma evaluated 55 adult patients with chronic asthma and 11 control subjects by using PCR, culture, and serology to detect M. pneumoniae species, C. pneumoniae species, and viruses from nasopharynx, lung, and blood. Fifty-six percent of the asthmatic patients were PCR-positive for M. pneumoniae (n = 25) or C. pneumoniae (n = 7). Mainly found in BAL fluid or biopsy samples. Only 1 of 11 control subjects was positive. Cultures for these organisms were negative in all patients. A distinguishing feature between PCR-positive and PCR-negative patients was a significantly greater number of tissue mast cells in the group of patients who were PCR positive.

62. M. pneumoniaeand C. pneumoniae Atypical infectious organisms linked to asthma exacerbations. In a serologically based prospective study, 100 adult patients hospitalized with exacerbations of asthma were compared with hospitalized surgical patients with no history of lung disease at any time or URI in the month before admission. In the asthmatic group 18 M. pneumoniae Only 8 as the sole infectious agent Difficult to ascertain the culpability of M. pneumoniae as the cause of hospitalization 11 Influenza A 8 C. pneumoniae 6 Adenovirus 5 Influenza B, Legionella spp. 3 PIV-1, S. pneumoniae, 2 RSV, PIV-2 1 PIV-3 In the control group, only 3 with M. pneumoniae.

63. M. pneumoniaeand C. pneumoniae A study of 71 children with acute wheezing and 80 age-matched healthy children detected M. pneumoniae in 22.5% and C. pneumoniae in 15.5% of children with wheezing compared with 7.5% and 2.5%, respectively, in healthy control subjects. When the children who were infected with either organism were treated with clarithromycin, improvement in the course of the disease was observed, further supporting the role of these atypical organisms in the exacerbation of asthma. Acute M. pneumoniae infection was confirmed in 50% and C. pneumoniae in 8.3% of patients experiencing their first wheezing episode. Confirmed in French series, where M. pneumoniae infection was found in 20% and C. pneumoniae infection was found in 3.4% of children during an acute asthma exacerbation. Further studies are needed to confirm the association between infection and asthma exacerbation, to determine the prevalence with acute exacerbations of asthma, and if these organisms modify the severity of the exacerbation or the response to therapy.

65. Treatments

66. Treatments No clinically effective treatment for the common cold. Treatment for viral RTIs remains symptomatic. Major obstacles for treatment: Wide variety of organisms Rapid rate of mutation leads to resistance Delivery, expense, and efficacy of drugs. The relative treatment efficacies in the setting of RTIs depend upon the wheezing phenotype and probably the timing of the therapy. Involvement of inflammatory pathways suggests that antiviral and anti-inflammatory therapies have potential roles (possibly in combination) after onset of symptoms. As the mechanisms of viral-induced wheezing and asthma are elucidated, new forms of treatment may emerge. Currently, prophylaxis (i.e. hygiene, vaccination, antivirals) offers the best hope of disease control.

67. Vaccination Mainstay of prophylaxis against infections. With the exception of the influenza vaccine, development for respiratory viruses has been slow and disappointing. Influenza vaccine contains three strains (two A and one B) of inactivated virus Whole-cell influenza vaccine is no longer available One or two are modified yearly based upon predictions of the upcoming viral strains. Produced in embryonated hen eggs Highly immunogenic, conferring protection in 70% to 80% of recipients with minimal adverse effects. Current vaccines consist of subvirion (prepared by disrupting the lipid membrane) or purified surface antigen. Safe and recommended for asthmatics, but efficacy in question FluMist® (live attenuated, cold-adapted, trivalent, intranasal influenza vaccine ) is contraindicated in asthmatics. Vaccinated children tended to have shorter exacerbations (by approximately 3 days) than non-vaccinated children.

68. Intranasal influenza vaccine Description: Intranasal influenza vaccine live is the first FDA-approved influenza vaccine administered as a nasal spray. The vaccine is a liquid, trivalent, cold-adapted vaccine (CAIV-T) and contains live, attenuated influenza viruses. Thus, an adjuvant to enhance antigen immunogenicity is not needed. Intranasal administration stimulates localized mucosal antibody formation. Full immune response requires only 2 weeks, so even as the flu season progresses through February, patients may still receive immunization.Mechanism of Action: Intranasal influenza vaccine imparts immunity against the influenza virus by stimulating production of antibodies that are specific to the disease. Influenza strain-specific serum antibodies to the vaccine have been demonstrated. The intranasal route of administration also stimulates localized mucosal antibody formation and may enhance cytotoxic T-cell formation. In general, patients who receive the vaccine will be immune only to those strains of the virus from which the vaccine was prepared. Indications: Intranasal The vaccine is only indicated for patients 2—49 years of age. The intranasal influenza vaccine may be inappropriate for use in patients with a history of asthma or reactive airways disease. Patients > 6 months to 2 years and older than 49 should receive the inactivated vaccine IM. WARNING: Intranasal Patients should not receive the intranasal influenza vaccine if they have experienced egg hypersensitivity or chick embryo protein hypersensitivity. Live vaccines are contraindicated for use by patients with severe combined immunodeficiency disease (SCID). Pregnancy: Category C

69. Antivirals Target virus directly to decrease number thereby reducing the inflammatory process. Only approved respiratory antiviral therapies are for: Influenza A (amantadine and rimantadine) Influenza A and B (zanamivir and oseltamivir) RSV (ribavirin).

70. Antivirals Neuraminidase inhibitors (zanamivir and oseltamivir) have advantage over adamantanes (amantadine and rimantadine) because of broader spectrum (A and B). Inhibition of neuraminidase prevents cleavage of sialic acid from newly acquired membrane, leaving emerging virus inactive. Improve respiratory outcomes in asthma and acute influenza infections Added benefit of being effective in the prophylaxis against Influenza. Disadvantage is the specificity for Influenza and initiation of treatment must be within 48 hours of onset. The toxicity profile of ribavirin, approved for use in severe RSV infections, limits its clinical use except in settings of severe illness in immunocompromised hosts.

71. Amantadine Description: Amantadine is a synthetic antiviral agent. It was introduced as an agent for prophylaxis of seasonal influenza A and was later found to cause symptomatic improvement in parkinsonism. It is used for the prophylactic or symptomatic treatment of seasonal influenza A virus. Mechanism of Action: Amantadine appears to block the uncoating of the virus particle and subsequent release of viral nucleic acid into the host cell. This process is thought to be caused by interference with fusion of the virion coat to vacuolar membranes. To prevent a viral infection, the drug should be present before exposure to the virus, but, if given within 24—48 hours of onset of symptoms, the influenza may be less severe. Pharmacokinetics:Amantadine crosses the blood-brain barrier and the placenta; distributes into tears, saliva, and nasal secretions; and is excreted into breast milk. Ninety percent of amantadine is excreted in the urine via glomerular filtration and tubular secretion. The elimination half-life in adult patients with normal renal function is about 11—15 hours but can be as long as 7—10 days for those with severe renal impairment. Acidifying the urine increases the rate of excretion. Pregnancy: Category C

72. Rimantadine Description: It is indicated for the prophylaxis and treatment of seasonal influenza A virus infections in adults and for prophylaxis only in children. Rimantadine lacks the central nervous system effects seen with amantadine. Rimantadine achieves higher concentrations in respiratory secretions than amantadine, and has a more favorable side effect profile. Mechanism of Action: Amantadine appears to block the uncoating of the virus particle and subsequent release of viral nucleic acid into the host cell. This process is thought to be caused by interference with fusion of the virion coat to vacuolar membranes. To prevent a viral infection, the drug should be present before exposure to the virus, but, if given within 24—48 hours of onset of symptoms, the influenza may be less severe. Pharmacokinetics: Oral Route Protein binding is approximately 40% (albumin as the major binding protein), with extensive metabolism by the liver to three distinct hydroxylated metabolites and one conjugated metabolite. These metabolites and the parent drug account for 74 ± 10% (n=4) of a single 200 mg oral dose of rimantadine excreted in the urine over 72 hours. The half-life of rimantadine ranges from 13—65 hours. Urinary excretion of unchanged rimantadine accounts for less than 25% of the dose in healthy subjects. Pregnancy: Category C

73. Oseltamivir Description: Oseltamivir is an oral neuraminidase inhibitor. It is a prodrug that is metabolized to its active form, oseltamivir carboxylate. As opposed to amantadine and rimantadine that have activity against influenza A only, oseltamivir has activity against influenza A and B. Mechanism of Action: Oseltamivir is activated to oseltamivir carboxylate, which acts as a neuraminidase (sialidase) inhibitor. Oseltamivir carboxylate selectively inhibits the neuraminidases of influenza A and B, and does not significantly inhibit human lysosomal neuraminidase. This action promotes the spread of virus in the respiratory tract by several mechanisms. Oseltamivir carboxylate acts extracellularly and binds to an unoccupied area of influenza neuraminidase that results in competitive inhibition of the enzyme. Pharmacokinetics: Oral Route Oseltamivir is extensively converted to oseltamivir carboxylate by hepatic esterases; oseltamivir carboxylate is the active form of the drug. The binding of oseltamivir carboxylate to plasma proteins is low (3%). Oseltamivir has an elimination half-life of 1—3 hours, and > 90% of oseltamivir is eliminated by conversion to oseltamivir carboxylate. Oseltamivir carboxylate is not further metabolized and is eliminated in the urine. The elimination half-life of oseltamivir carboxylate is 6—10 hours. Oseltamivir carboxylate is more than 99% eliminated by renal excretion. The renal clearance of oseltamivir carboxylate exceeds the glomerular filtration rate, which suggests tubular secretion in addition to glomerular filtration. Pregnancy: Category C

74. Zanamivir Description: Zanamivir is a neuraminidase inhibitor anti-viral agent administered via oral inhalation. It was the first agent of this type to be approved in the US. Zanamivir was chemically designed using knowledge of the crystal structure of influenza virus surface proteins. Zanamivir exhibits activity against both influenza A and B. Mechanism of Action: Oseltamivir is activated to oseltamivir carboxylate, which acts as a neuraminidase (sialidase) inhibitor. Oseltamivir carboxylate selectively inhibits the neuraminidases of influenza A and B. This action promotes the spread of virus in the respiratory tract by several mechanisms. Oseltamivir carboxylate acts extracellularly and binds to an unoccupied area of influenza neuraminidase that results in competitive inhibition of the enzyme. Topical application via inhalation of the powder into the lungs provides a high drug concentration at the site of infection and may potentiate its antiviral effects and reduce the risk of resistance. Pharmacokinetics: Inhalation Route The peak serum concentrations ranged from 17—142 ng/ml within 1—2 hours following inhalation of a 10 mg dose. Zanamivir administered via a Diskhaler resulted in deposition of 13.2% of the dose in the lungs and 77.6% of the dose in the oropharynx in adults and adolescents. The total inhaled dose is excreted within 24 hours. Children under 7 years of age do not produce proper peak inspiratory flow rates needed for the proper use of the Diskhaler device, which limits the systemic absorption and clinical efficacy of zanamivir. Pregnancy: Category C

75. Ribavirin Description: Ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a synthetic guanosine analog with antiviral activity that has been shown to be active against many DNA and RNA viruses. Mechanism of Action:Ribavirin is phosphorylated intracellularly to mono-, di-, and triphosphate metabolites, which disrupt cellular purine metabolism by inhibiting inosine monophosphate dehydrogenase decreasing guanosine triphosphate. Ribavirin also increases the production of antiviral cytokines, such as interleukin (IL)—2, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma, by Type 1 CD4 and CD8 T-cells. Type 1 T-cells are responsible for cell-mediated immunity, especially helper T-cell-mediated cytotoxic T-cell response to viral pathogens. Pharmacokinetics:Inhalation RoutePeak concentrations in respiratory tract secretions are generally achieved at the end of the inhalation period and are greater than plasma concentrations. Following inhalation, the elimination half-life is about 9.5 hours and appears to take place in a biphasic manner. WARNING: The primary clinical toxicity of Ribavirin is hemolytic anemia. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to Ribavirin.

76. Antibiotics Antibiotic use is appropriate only if there is evidence of bacterial infection contributing to asthma exacerbations. Macrolide antibiotics Have antiviral effects in vitro against rhinoviruses (not confirmed in vivo). Have anti-inflammatory effects. Asthmatic patients infected with M. pneumoniae or C. pneumoniae may benefit from prolonged treatment with clarithromycin as evidenced by: Significant improvement in FEV1 Methacholine responsiveness Improvement in airway hyper-responsiveness Mechanism unknown, but may due to: Treatment of occult or chronic infection Interference with steroid metabolism Anti-inflammatory properties

77. Corticosteroids The repeated use of systemic corticosteroids remains a clinical concern. Because of the safety profile of inhaled corticosteroids (ICS), their use in the management of VIW has been explored. Lack of efficacy in the regular use of ICS in patients with mild VIW. ICS used episodically for VIW in children not using them as maintenance may decrease the rate of oral corticosteroid requirement. The common clinical practice of doubling the dose of ICS at the onset of an asthma exacerbation has been shown to be ineffective; however, quadruplingthe ICS dose (in adults) has been effective. These data suggest that corticosteroids, taken orally or inhaled, may be used as treatment and preventive therapy for asthma exacerbations in the setting of RTIs.

79. CysLTs may play a role in the pathophysiology of VIW as well.CysLTs are detectable in the blood, urine, nasal secretions, sputum, and BAL fluid of patients with chronic asthma. Elevated cysLTs have been detected in respiratory secretion of children with VIW at levels similar to asthmatics. CysLTs are not fully suppressed by inhaled corticosteroids; therefore, leukotriene receptor antagonists may be of clinical benefit in VIW.

80. Leukotriene receptor antagonists

81. Montelukast Description: Montelukast is an oral agent for the prophylaxis and chronic treatment of asthma and for the treatment of allergic rhinitis. It was the second leukotriene receptor antagonist to be approved in the US, after zafirlukast. Unlike zafirlukast, montelukast does not inhibit CYP2C9 or CYP3A4, and has not been found to affect the hepatic clearance of drugs metabolized by these enzymes. Leukotriene antagonists are considered an alternate, but not preferred, treatment to the use of inhaled corticosteroids (ICSs) for mild persistent asthma. Mechanism of Action: Montelukast is a potent and selective antagonist of leukotriene D4 (LTD4) at the cysteinyl leukotriene receptor, CysLT1, found in the human airway. Montelukast improves the signs and symptoms of asthma by inhibiting the physiologic actions of LTD4 at the CysLT1 receptor. Pharmacokinetics:Montelukast is more than 99% bound to plasma proteins. The drug has a small volume of distribution with minimal distribution across the blood-brain barrier. Montelukast undergoes extensive hepatic metabolism by hepatic microsomal isoenzymes CYP3A4 and CYP2C9. P450 isozymes are not inhibited. Plasma concentrations of metabolites of montelukast are undetectable at steady state. Montelukast and its metabolites are excreted almost exclusively via the bile. Mean elimination half-life is 2.7—5.5 hours in healthy young adults. Absorption of montelukast is rapid, with peak plasma concentrations occurring 3—4 hours after administration; all oral forms of montelukast may be taken without regard to meals.WARNING: Do not use as monotherapy. Pregnancy: Category B

82. Zafirlukast Description: Zafirlukast is an oral leukotriene receptor antagonist for the treatment of asthma. Leukotriene receptor antagonists primarily help to control the inflammatory process of asthma, thus helping to prevent asthma symptoms. Leukotriene antagonists are considered an alternate, but not preferred, treatment to the use of inhaled corticosteroids (ICSs) for mild persistent asthma. Mechanism of Action: Zafirlukast is a potent, selective, and long-acting leukotriene receptor antagonist that exhibits antiinflammatory properties and mild bronchodilator effects. Zafirlukast selectively inhibits the binding of leukotriene types D4 (LTD4), and E4 (LTE4) and is 1000 to 10,000-fold more selective for leukotriene receptors (CysLT) than for alpha-receptors, beta-receptors, histamine receptors, or others. Zafirlukast appears to exhibit similar anti-inflammatory activity to cromolyn or nedocromil, but less than that of inhaled corticosteroids. The time to onset of zafirlukast-induced bronchodilator response is longer than that of beta-agonists and it is also less pronounced. Pharmacokinetics:Zafirlukast is administered orally and has also been studied as an inhalation. Systemically, protein-binding is > 99% with minimal distribution across the blood-brain-barrier. Zafirlukast is extensively metabolized; the hydroxylated metabolites of zafirlukast are formed through the hepatic cytochrome P450 CYP2C9 isoenzyme. Zafirlukast inhibits the activity of cytochrome isoenzymes CYP3A4 and CYP2C9; therefore has significant drug-drug interactions. Hydroxylated metabolites are excreted in the feces. Urinary excretion accounts for 10% of a zafirlukast dose. The mean terminal elimination half-life in both normal controls and asthma patients is approximately 10 hours.[ Pregnancy: Category B

83. Summary Infections have been implicated in asthma exacerbations as well as the inception of asthma. Viruses and atypical infectious agents may induce asthma exacerbations and affect its chronicity thereafter. Further elucidation of the mechanisms underlying the interactions between infectious triggers and phenotypes of wheezing will lead to improvements in treatment and prevention.

84. Main references Gern, J E and Lemanske, Jr. R F. (2003). Infectious triggers of pediatric asthma. Pediatr Clin N Am 50:555–75. MacDowell, A L and Bacharier, L B. (2005). Infectious triggers of asthma. Immunol Allergy Clin N Am 25:45–66. Sullivan, P W et al. (2011). The burden of adult asthma in the United States: Evidence from the Medical Expenditure Panel Survey. J Allergy Clin Immunol 127:363-9.

85. Thank you! Any questions?