Medco CE- Infectious Triggers of Asthma

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  • This hypothesis suggests that the immune system is immature at birth; in support of this concept, experimental evidence shows that Th1-like interferon (IFN) responses are depressed in cells from umbilical cord blood [55]. According to the theory, each infection would provide a stimulus for the development or activation of Th1-like immune responses. This repetitive stimulation would lead to the development of balanced Th1-like and Th2-like cytokine responses and, as a result, to a low risk of developing allergies. In the absence of exposure to infectious diseases in infancy, the immune system is skewed toward Th2-like responses, and on exposure to environmental allergens, the risk of allergic sensitization would be increased. Presently, the evidence most strongly supports a reduction in the incidence of allergic sensitization in individuals from large families, particularly the youngest in the family (birth order effect), and in those living in a less affluent environment [56]. These relationships are stronger for allergic sensitization than for asthma [57,58]. Whether the effects of being in a large family result from increased exposure to infectious diseases. There is better evidence that repeated exposure to infectious diseases during early infancy in settings such as day care centers may reduce the risk of allergen sensitization. The route of infection may be important in determining long-term effects on allergies and asthma. For example, RSV bronchiolitis seems to be a risk factor for the development of asthma but in most studies does not promote allergic sensitization. In contrast, infections acquired by oro-fecal transmission (e.g., hepatitis A), are associated with lower rates of allergy and asthma [65]. These findings suggest that foodborne and fecal-oral rather than respiratory tract transmission of infection may be a more likely determinant of the risk of allergic sensitization during childhood.Other epidemiologic and biologic factors that have been considered to influence the development of allergic sensitization or asthma include early exposure to a farming lifestyle [66,67], alterations in bacterial flora of the gut [68], and increased antibiotic usage [69]. Furthermore, it has recently been demonstrated that high levels of exposure to endotoxin in the home, as occurs in farmhouses and homes with furred pets, is associated with reduced rates of allergy and an enhanced number of IFN-producing cells in peripheral blood. Collectively, these studies suggest that exposure to microbes, in addition to infections per se, may affect immune development to reduce the risk of atopy and asthma. This concept has led to efforts to use oral administration of probiotics (live cultures of Lactobacillus) to try to reduce the incidence of atopic diseases, and early results look promising.
  • Effects of viral infections on airway hyper-responsiveness Information derived from animal models, as well as clinical studies of natural or experimentally induced viral infections, indicate that viruses can enhance airway hyper-responsiveness, which is one of the key features of asthma [136]. Clinical studies have generally shown that viral infections cause mild increases in airway responsiveness during the time of peak cold symptoms and that these changes can sometimes last for several weeks. A heightened sensitivity to inhaled irritants and greater maximum bronchoconstriction in response to these stimuli have been observed. The mechanism of virus-induced airway responsiveness is likely to be multifactorial, and contributing factors are likely to include impairment in the inactivation of tachykinins, virus effects on nitric oxide production, and virus-induced changes in neural control of the airway [137].
  • InflammationEpithelial cellsThe epithelial cell serves as the host cell for viral replication and also helps to initiate antiviral responses. Damage to the epithelial cells can disturb airway physiology through a number of different pathways. For example, epithelial edema and shedding together with mucus production can cause airway obstruction and wheezing. Virus-induced epithelial damage can also increase the permeability of the mucosal layer [76,77], perhaps facilitating allergen contact with immune cells and leaving neural elements exposed.The processes associated with viral replication trigger both innate and adaptive immune responses within the epithelial cell. Virus attachment to cell surface receptors may initiate some immune responses. For example, RSV infection activates signaling pathways in airway epithelial cells through the surface molecule toll-like receptor 4 (TLR-4) [78]. There is also evidence of receptor-independent pathways for virus activation of epithelial cells, such as the generation of oxidative stress [79].Replication of viral RNA can also stimulate antiviral responses in epithelial cells. Double-stranded RNA (dsRNA) that is synthesized in virus-infected cells can bind to cell surface receptors and also directly activates intracellular enzymes, such as the dsRNA-dependent protein kinase (PKR) and 2–5 oligoadenylate synthase, which are important components of the innate antiviral immune response [80]. Through this mechanism, viral replication induces innate antiviral activity through the generation of nitric oxide, activation of RNase L, and inhibition of protein synthesis within infected cells. In addition, dsRNA generated during viral infections promotes the activation of chemokine genes such as interleukin (IL)-8 and RANTES (Regulated by Activation, Normal T cell Expressed and Secreted), which recruit inflammatory cells into the airway [81]. Thus, host cell recognition of dsRNA is an important pathway for the initiation of multiple and antiviral and proinflammatory pathways within the cell.Granulocytes and mononuclear cellsDuring natural infection, the initial inoculum that transmits the illness is assumed to be quite small; however, viral titers in respiratory secretions can attain 106 infectious units/mL, even after dilution by nasal lavage [82]. At this point, it is likely that mononuclear cells are activated by these high titers of virus. As a result, monocytes, macrophages, and, presumably, dendritic cells secrete proinflammatory cytokines such as IL-1, IL-8, tumor necrosis factor-alpha (TNF-a), IL-10, and IFN-a [83–85]. These cytokines activate other cells in the environment and are potent inducers of adhesion molecules. Together with chemokines generated by epithelial cells, this response provides a potent stimulus for inflammatory cell recruitment.Acute respiratory viral infections are often accompanied by neutrophilia in airway secretions, and products of neutrophil activation are probably involved in obstructing the airway and causing lower airway symptoms [86,87]. Of particular interest is evidence that activated neutrophils, through the release of the potent secretagogue elastase, can increase goblet cell secretion of mucus [88]. In addition, changes in IL-8 levels in nasal secretions have been related to respiratory symptoms and virus-induced increases in airway hyper-responsiveness [89,90]. These findings suggest that neutrophils and neutrophil activation products contribute to airway obstruction and symptoms during viral infections and exacerbations of asthma. Lymphocytes are recruited into the upper and lower airways during the early stages of a viral respiratory infection, and it is assumed that innate and adaptive immune responses serve to limit the extent of infection and to clear virus-infected epithelial cells. This process is consistent with reports of severe viral lower respiratory infections in immunocompromised patients [91].For RSV, the G (attachment) and F (fusion) proteins are the major surface glycoproteins against which neutralizing antibody is directed. In both murine [92] and human [93] in vitro experiments, it has been noted that the G protein elicits a predominant Th2 immune response, whereas the F protein and infectious RSV produce a predominant Th1 response. This property of the G protein has led to speculation that this may be a mechanism by which RSV promotes allergen sensitization. In murine models, RSV infections are associated with the development of airway hyper-responsiveness [94] and an augmented allergic airway response [95]. Some [96], but not all [97], investigators have demonstrated that these alterations are related to increased production of the Th2-like cytokine IL-13 in the airway.These and other animal models of respiratory viral infection suggest that cellular immune responses and patterns of cytokine production may be related to the outcome of respiratory infections. This same concept has been tested in a limited number of studies involving humans. For example, reduced peripheral blood mononuclear cell production of IFN-g both during and months following RSV infection has been observed in only those children who develop subsequent asthma [98]. In contrast, concentrations of IFN-g in upper airway secretions are increased during episodes of viral-induced wheezing compared with upper respiratory infections [99].Additional information has been obtained by evaluating immune responses in volunteers inoculated with a strain of RV. In these studies, strong IFN-g responses to virus in blood mononuclear cells were associated with reduced viral shedding [100]. In addition, stronger Th1-like response in sputum cells (higher IFNg/IL-5 mRNA ratio) during induced colds was associated with milder cold symptoms and also with more rapid clearance of the virus [82]. There is evidence that production of IFN-g in response to viruses may be impaired in asthma [101]. Together, these experimental findings suggest that the impaired cellular immune responses to respiratory viruses, and reduced IFN-g production in particular, could promote more severe clinical manifestations of viral respiratory infections in asthma.
  • Effects of allergySeveral studies have addressed the possibility that allergic individuals may have impaired antiviral responses and, as a result, develop more severe manifestations of viral respiratory infections, particularly in relationship to airway obstruction and wheezing. In infants, several studies have evaluated whether allergy, atopic dermatitis, or a family history of allergy increase the risk of acute bronchiolitis during RSV epidemics [102–106]; however, these studies have yielded conflicting results. In addition, it seems unlikely that infections with RSV in infancy cause allergy [6,106], although this possibility, too, is a matter of controversy [107].Despite these uncertainties, more convincing evidence implicates respiratory allergy as a risk factor for wheezing with common cold infections later in childhood. In studies conducted in an emergency department, risk factors for developing acute wheezing episodes were ascertained [25,108]. Individual risk factors for developing wheezing included detection of a respiratory virus, most commonly RV, positive allergen-specific IgE as detected by radioallergosorbent testing (RAST), and evidence of eosinophilic inflammation. Viral infections and allergic inflammation synergistically enhanced the risk of wheezing [25]. Furthermore, other studies have shown that experimental inoculation with RV is more likely to increase airway responsiveness in allergic individuals than in non-allergic individuals [109]. Finally, the risk of hospitalization among virus-infected individuals is increased in patients who are both sensitized and exposed to respiratory allergens [29]. Considered together, these findings provide strong evidence that individuals with either respiratory allergies or eosinophilic airway inflammation have an increased risk for wheezing with viral infections.Viral infections may interact with allergic inflammation to promote airway dysfunction through several mechanisms [110]. First, it has been suggested that viruses capable of infecting lower airway epithelium may lead to enhanced absorption of aeroallergens across the airway wall predisposing to subsequent sensitization [111,112]. Second, viral infections may lead to mast cell mediator release within the airway, resulting in the development of bronchospasm and the ingress of eosinophils [113–118]. Third, airway resident and inflammatory cell generation of various cytokines (TNF-1b, IL-1-, IL-1b IL-6) [119–122], chemokines (macrophage inflammatory protein [MIP]-1a, RANTES, monocyte chemotactic protein [MCP]-1, IL-8) [123,124], leukotrienes [99], and adhesion molecules (intercellular adhesion molecule-1 [ICAM-1]) [119] may further increase the ongoing inflammatory response.Studies have been performed using bronchoscopy and experimental viral inoculation to try to understand RV-induced inflammation in the lower airway and interactions with allergen-induced inflammation. These studies have demonstrated that RV infections can enhance lower airway histamine responses and eosinophil recruitment in response to allergen challenge [125,126]. In addition, during a RV infection, study subjects had enhanced immediate responses to allergen and were more likely to have a late asthmatic response after allergen challenge [127]. These findings suggest that RV can enhance both the immediate and the late-phase response to allergen.
  • How do common cold infections disturb lower airway physiology?Rhinovirus has traditionally been considered to be an upper airway pathogen because of its association with common cold symptoms and the observation that RV replicates best at 33 to 35C, which approximates temperatures in the upper airway. There is evidence to indicate that lower airway temperatures may also be conducive to RV replication. Lower airway temperatures have been directly mapped using a bronchoscope equipped with a thermister [128]. During quiet breathing of air at room temperature, airway temperatures are generally lower than 35C down to the level of fourth generation bronchi. Moreover, RV seems to replicate equally well in cultured epithelial cells derived from either upper or lower airway epithelium [129]. Finally, although RV has been difficult to culture from the lower airway, it has been detected in lower airway cells and secretions both by reverse transcription polymerase chain reaction (RT-PCR) and in situ hybridization of mucosal biopsies after experimental inoculation [130,131]. These findings establish that RV can replicate in the lower airway epithelium at temperatures found in the large airway of the lung. This concept is further supported by evidence that RV infections can produce lower airway inflammation, including increased neutrophils in bronchial lavage fluid [132], influx of T cells and eosinophils into lower airway epithelium [133], and enhanced epithelial expression of ICAM-1 [134].Remaining challenges include determining how much virus is present in the lower airway and establishing whether viral replication in the lower airway is a sufficient stimulus to provoke exacerbations of asthma. Alternate mechanisms to explain the link between colds and increased asthma include virus-induced systemic immune activation, the existence of reflex bronchospasm triggered by upper airway inflammation, and the aspiration of inflammatory cells and mediators that are generated in the upper airway [135].
  • The relationship between viral infections and wheezing illnesses in older children and adults has been clarified by the advent of sensitive diagnostic tests, based on PCR, for picornaviruses such as Rhinovirus (RV). With the development of these more sensitive diagnostic tools, information linking common cold infections with exacerbations of asthma has come from a number of sources. Prospective studies of persons with asthma have demonstrated that up to 85% of exacerbations of asthma in children and nearly half of such episodes in adults are caused by viral infections [22]. Although many respiratory viruses can provoke acute asthma symptoms, RV is most often detected, especially during the spring and fall RV seasons. In fact, the spring and fall peaks in hospitalizations caused by asthma closely coincide with patterns of RV isolation within the community [23]. Influenza and RSV are somewhat more likely to trigger acute asthma symptoms in the wintertime but seem to account for a smaller fraction of asthma flares. Furthermore, RV infections are frequently detected in children over the age of 2 years who present to emergency departments with acute wheezing [24,25] and in adults account for approximately one half of asthma-related acute care visits [26]. Together, these studies provide evidence of a strong relationship between viral infections, particularly those caused by RV, and acute exacerbations of asthma.Individuals with asthma do not necessarily have more colds, and neither the severity nor duration of virus-induced upper respiratory symptoms is enhanced by respiratory allergies or asthma [27,28]. In contrast to findings in the upper airway, a prospective study of colds in couples consisting of one asthmatic and one non-asthmatic individual demonstrated that colds cause greater duration and severity of lower respiratory symptoms in persons with asthma [28]. These findings suggest that there are fundamental differences in the lower airway effects of respiratory viral infections related to asthma. Although viral infections alone can promote lower airway symptoms, there is evidence that viral infections may exert synergistic effects with other known triggers for asthma. For example, the effects of colds on asthma may be amplified by exposure to allergens [29] and possibly by exposure to greater levels of air pollutants [30].In addition to provoking asthma, RV infections can also increase lower airway obstruction in individuals with other chronic airway diseases (e.g., chronic obstructive lung disease, cystic fibrosis) [31,32], and in infants [33] and elderly persons [34]. Thus, common cold viruses that produce relatively mild illnesses in most people can cause severe pulmonary problems in selected individuals.
  • One additional mechanism implicated in the pathogenesis of chronic asthmatic symptoms is latent Adenovirus infection [13]. A latent infection occurs when a virus incorporates itself into the host cell DNA and continues to express viral genes periodically. Respiratory disease caused by adenoviruses can be followed by latent infection that persists for many years [20]. A Slovenic study demonstrated that 94% of children with steroid-resistant asthma had detectable Adenovirus antigens, compared with 0% of controls [21]. In adults both with and without asthma, as many as 50% of the individuals tested showed evidence of adenoviral infection [15]. Although these preliminary results are intriguing, additional studies are needed to establish the causality and the specificity of these observations to asthma pathogenesis and to define the immunoinflammatory mechanisms contributing to these associations in adult and pediatric patients.
  • Recently, additional insight into these areas has been provided by the results of an 11-year prospective study involving 880 children who were enrolled at birth, followed for the development of lower respiratory tract illnesses in the first 3 years of life and then evaluated for the presence or absence of physician-diagnosed asthma or a history of current wheezing at ages 6 and 11 years [5]. Respiratory syncytial virus bronchiolitis increased the risk for both frequent episodes of wheezing (> 3/year) and infrequent episodes of wheezing (< 3/year); however, the risk decreased gradually with age and was not significant by age 13 years [6]. A decrease in the frequency of wheezing with increasing age following documented RSV infections has been observed by other investigators as well [7,8]. These data suggest that, although RSV infections contribute substantially to the expression of the asthmatic phenotype, other cofactors (e.g., genetic, environmental, developmental) also seem to contribute, either in the initial expression or the modification of the phenotype over time.
  • Thus far the most comprehensive evaluation of the role of both Chlamydia and Mycoplasma infections in chronic asthma was recently reported by Martin et al [15]. This group of investigators evaluated 55 adult patients with chronic asthma (percent of predicted forced expiratory volume at 1 second [FEV1] = 69.3 ± 2.1%) and 11 controls for infection with Mycoplasma, Chlamydia, and viruses. Fifty-six percent of the asthmatic patients had a positive polymerase chain reaction (PCR) assay for Mycoplasma (n = 25) or Chlamydia (n = 7), which were mainly found in lavage fluid or biopsy samples. Only 1 of 11 control subjects had a positive PCR for Mycoplasma. Cultures for both organisms were negative in all patients,and serologic confirmation correlated poorly with PCR results. Although these intriguing findings suggest that these organisms may play a role in the pathophysiology of asthma in some patients, the specificity of these findings to asthma and the phenotypic and genotypic characteristics of the at-risk patient need further delineation.
  • Wheezing infantsOne of the biggest challenges in treating infants who present with wheezing is to try to differentiate RSV bronchiolitis from wheezing that is caused by early-onset asthma. This differentiation is important, because bronchodilators produce at best only modest short-term improvements in clinical features of mild or moderately severe bronchiolitis and do not affect the rate or duration of hospitalization [138]. Given the high costs and uncertain benefit of this therapy, bronchodilators are not recommended for routine management of first-time wheezers.A meta-analysis of studies involving therapy of bronchiolitis with either oral or parenteral corticosteroids concluded that this approach produced modest benefits [139]. Of 12 relevant publications, 6 met the selection criteria and had relevant data available. Corticosteroid therapy (prednisone, prednisolone, methylprednisone, hydrocortisone, dexamethasone given orally, intramuscularly, or intravenously in dose ranges of 0.6 to 6.3 mg/kg/day of prednisone equivalents) was associated with a statistically significant reduction in clinical symptom scores and length of hospital stay (0.4 day difference). The analysis suggested that corticosteroid treatment might have its greatest effects in more severe cases, and that clinical benefits are noticeable in the first 24 hours.Several placebo-controlled trials [140–149] have addressed the question as to whether corticosteroid treatment can prevent respiratory sequelae after RSV bronchiolitis [8]. Seven of 10 of these trials did not show any long-term effects (follow-up time from 6 months to 5 years) on postbronchiolitic wheezing, the development of various wheezing phenotypes (transient, persistent, or late onset), or a subsequent diagnosis of asthma. In the three trials that did show some benefit, the positive effects observed were mainly over shorter time intervals following infection.Because elevated levels of leukotrienes have been reported in respiratory tract secretions of infants who develop recurrent wheezing following RSV bronchiolitis [150,151], the effect of a leukotriene receptor antagonist in modulating these developments recently has been evaluated. In a prospective, placebo-controlled trial, a 28-day treatment course of montelukast significantly reduced lower respiratory tract symptoms in infants who were hospitalized for RSV bronchiolitis [152]. These preliminary observations suggest a potential role of this class of compounds in improving short-term symptom control and also in preventing long-term lower respiratory tract sequelae.
  • Medco CE- Infectious Triggers of Asthma

    1. 1. Infectious triggers of asthma<br />Joseph E. Crea, D.O.President, Crea Healthcare Partnering, Inc.MedcoLiberty Lake, WASeptember 15, 2011<br />
    2. 2. Disclosure Information<br />I have the following financial relationships to disclose:<br />Honorarium and expenses paid by: <br />Medco Health Solutions, Inc. <br />through <br />Business Services International, Inc.<br />I have no other financial relationships to disclose.<br />I will not discuss any investigational drugs.<br />I will not discuss any off label uses.<br />
    3. 3. Objectives: Pharmacists<br />Contrast the ‘‘Hygiene Hypothesis’’ and ‘‘Hit-and-Run Hypothesis’’ as they relate to the development of asthma and atopy. Summarize the evidence.<br />Compare viral-induced wheezing (VIW) and classic childhood asthma.<br />Discuss the epidemiology, diagnosis, treatment, clinical course, and sequelae of respiratory syncytial virus (RSV) infections in the pediatric population.<br />Describe how to identify the potential infectious agents responsible for asthma exacerbations.<br />Summarize the difference between viral and atypical bacterial triggers as it relates to asthma chronicity. <br />Delineate and discuss the advantages and disadvantages for the various treatments for the infectious triggers of asthma.<br />
    4. 4. Objectives: Pharmacy Technicians<br />Discuss the obstacles to clinically effective treatments for “the common cold.”<br />Discuss the two phenotypes of wheezing. <br />Delineate the various medications used for treatment in the infectious triggers of asthma.<br />Describe the advantages and disadvantages between classes of antivirals.<br />Explain the concerns with the various formulations of steroids in the treatment of asthma or atopy.<br />Summarize the interactions between infectious agents and atopic status.<br />
    5. 5. Asthma triggers<br />Most asthma episodes are precipitated by factors other than allergen exposure. <br />Infection has been implicated as the most common precipitant of asthma exacerbations.<br />Many asthma episodes are preceded by upper respiratory tract (URI) symptoms and may last several days to weeks. <br />Allergen-induced asthma exacerbations often lead to rapid onset of symptoms with recovery within 24 hours.<br />
    6. 6. Mechanisms?<br />Proposed mechanisms for viral infections provoking asthma: <br />Direct extension of URIs to the lower respiratory tract where virus exert direct effects on airway cells. <br />Increased production of IL-10 by monocytes during acute and convalescent phases.<br />IL-10 may have a direct effect on airway smooth muscle and the regulation of airway tone.<br />Generating changes in patterns of pro-inflammatory cytokine production that facilitates virus persistence or latency . <br />Poorly understood.<br />Indirect effects on airway responsiveness independent of direct epithelial damage and inflammation.<br />
    7. 7.
    8. 8. Phenotypes of wheezing<br />Phenotypes<br />Viral-induced wheeze (VIW)characterized by:<br />Acute viral URI<br />Brief episodes of lower respiratory symptoms<br />Decreased pulmonary function <br />Longer asymptomatic periods with normal pulmonary in-between <br />Outgrow symptoms by age 6<br />May continue into adulthood <br />Less severe symptoms, <br />Negative methacholine challenge <br />Normal pulmonary functions<br />Classic childhood asthma characterized by:<br />Chronic symptoms<br />Atopy<br />The inability to reliably differentiate between VIW and asthma complicates:<br />Evaluation of the influence of viral infections on exacerbations of wheezing. <br />Implications in determining efficacy of therapies.<br />
    9. 9. Phenotypes of wheezing<br />International guidelines for the management of asthma, but not for VIW. <br />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. <br />RSV-associated wheezing does not consistently respond to medications often used to treat asthma exacerbations.<br />
    10. 10. Phenotypes of wheezing<br />Several treatment approaches have been investigated in an attempt to reduce the morbidity associated with VIW.<br />Short course of oral corticosteroid at onset of URI<br />Reductions in the frequencies of wheezing, emergency room visits, and hospitalizations<br />Unblinded<br />Parent-initiated oral corticosteroids at onset of URI<br />No difference<br />Double-blinded, placebo-controlled<br />Thus early use of oral corticosteroids is unclear.<br />Further investigation is required.<br />
    11. 11. Epidemiology of RTIs<br />Respiratory tract infections (RTIs) are the most common cause of acute illness in adults and children.<br />URIs constitute the majority of these illnesses. <br />Adults typically experience two to four URIs per year.<br />Children may have up to 12 URIs per year. <br />
    12. 12. Economics of RTIs<br />RTIs are a major cause of visits to primary care physicians.<br />Associated with significant work and school absenteeism.<br />Estimated 150 million lost workdays annually.<br />$40 billion annually in the United States<br />
    13. 13. Epidemiology of asthma<br />Asthma is a chronic inflammatory lung disease that affects an estimated 23 million Americans (16 million adults).<br />12 million experience an asthma attack every year.<br />Several factors influence the development and severity of asthma:<br />Atopy<br />Environmental exposures<br />Genetic predisposition<br />Gene–environment interactions<br />Stress<br />Obesity<br />Diet<br />Socioeconomic status<br />Infection<br />
    14. 14. Economics of asthma<br />Unadjusted total medical expenditures for all adults with a reported ICD-9 code for asthma was $90.8 billion (2008 US dollars).<br />Total medical expenditures attributable to adult asthma was calculated to be $18 billion (2008 US dollars) annually<br />
    15. 15. Role of infectious agents<br />The role of infectious agents in the development of asthma is complex.<br />Causal (‘‘Hit-and-Run Hypothesis’’)<br />Protective (‘‘Hygiene Hypothesis’’)<br />
    16. 16. The ‘‘Hit-and-Run Hypothesis’’<br />Infections may be a cause for the onset and persistence of asthma. <br />A pathogen promotes dysregulation of the immune system.<br />Leads to prolonged inflammatory responses even after the pathogen has been cleared.<br />
    17. 17. The ‘‘Hit-and-Run Hypothesis’’<br />Viral infections with a propensity for lower airway during infancy have been associated with chronic lower respiratory tract symptoms and asthma.<br />RSV bronchiolitis is a significant independent risk factor for subsequent frequent wheezing. <br />Could be explained in part by viral persistence. <br />Hypothesized that asthmatics have increased susceptibility to viral infections. <br />Some researchers have found an increased incidence of viral infections in asthmatic children when compared with non-asthmatics.<br />Could be explained by the increased expression of ICAM-1 receptor for Rhinovirus. <br />This finding was not confirmed in adults.<br />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).<br />
    18. 18. The ‘‘Hit-and-Run Hypothesis’’<br />
    19. 19. The ‘‘Hygiene Hypothesis’’<br />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.<br />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. <br />As TH1, which regulates response to viral infection, is impaired, a TH2 response predominates, favoring the development of allergy. <br />In vivo studies have shown that asthmatics exposed to viral infections lack the capacity to mount a strong TH1 response.<br />
    20. 20. Immunopathology and Mechanism of disease<br />Viruses typically enter the body through contact with mucosal surfaces. <br />The cell-specific distribution of viral receptors determines the viral tropism.<br />Once the viral particles are internalized, nucleic acids are released, and transcription and production of viral proteins starts. <br />The viral genome is replicated, and virions are released, propagating the infection. <br />The immune system is activated through several mechanisms when a viral infection is noted: <br />Cell surface receptors<br />Viral proteins interact with intracellular proteins activating the host cell<br />Activation of epithelial cells lead to production of:<br />Cytokines (interferon-a, -b)<br />Chemokines (IL-8; RANTES; MIP-1, -2, -3; MCP-3)<br />
    21. 21.
    22. 22. Immunopathology and Mechanism of disease<br />One of the earliest responses to viral infection is the production of interferons (IFNs) by different cell types.<br />IFN-a is produced by leukocytes <br />IFN-b is produced by fibroblasts <br />IFN-g is produced by Th1 cells and natural killer (NK) cells.<br />Interferons<br />Transcribe of genes; two with direct antiviral activity (MHC class I and II)<br />Activate antiviral effector cells <br />NK cells <br />T-lymphocytes <br />Macrophages<br />Inflammatory process from viral infections are mainly TH1 with a predominance of interferons, especially INF-g.<br />Atopy has a predominance of TH2 cytokines. <br />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.<br />
    23. 23.
    24. 24. Interactions between infectious agents and allergy<br />The effect of atopic status on the rate of viral infection is unclear.<br />Evidence exists suggesting no difference between the rate of viral infection between atopic and non-atopic. <br />There is an increased risk of acute wheezing when atopy is combined with viral infection when compared with atopy or viral infection alone.<br />Infants with a family history of atopy seem more likely to develop bronchiolitis with a higher rate of hospitalization.<br />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. <br />During rhinoviral infection, there is a greater incidence of symptoms in asthmatics compared with non-asthmatics. <br />Asthmatics experienced seroconversion to Influenza A virus at the time of asthma exacerbation even in the absence of signs of respiratory infection.<br />
    25. 25. Viral infections and asthma exacerbation<br />Seasonal pattern of distribution of viral infections and asthma exacerbations:<br />Strong relationship was found between the seasonal incidence of asthma and viral infection.<br />Strongest with severe cases requiring hospitalization. <br />Viral infections were the major identifiable risk factor for autumnal asthma exacerbations.<br />No correlation with pollen and spore counts.<br />
    26. 26. Viral infections and asthma exacerbation<br />
    27. 27.
    28. 28. Atypical organisms<br />Atypical organisms are involved as well.<br />Mycoplasma pneumoniae<br />Chlamydia pneumoniae<br />RTIs with atypical organisms:<br />May be the initial insult for development of asthma.<br />Precipitate a significant proportion of acute episodes of wheezing.<br />Contribute to the severity and persistence of asthma.<br />
    29. 29. Viruses<br />
    30. 30.
    31. 31.
    32. 32.
    33. 33. Rhinovirus<br />Human rhinovirus (RV) causes nearly half of all upper respiratory illnesses.<br />Initially believed to be limited to the upper airways, but lower airway epithelial RV infection has been demonstrated. <br />RV infection can enhance the immediate and late-phase responses to allergens.<br />Potentially augments inflammation precipitating asthma exacerbations.<br />
    34. 34. Rhinovirus<br />Associated with declines in lung function in asthmatics within 2 days after development of a RV infection. <br />Can lead to profound exacerbation of asthma<br />Responsible for the majority of hospitalizations for childhood asthma.<br />Less so in adults <br />RV infection augments airway hyper-responsiveness 4 days after experimental RV infection.<br />Hyper-responsiveness was accompanied by:<br />Increase in nasal interleukin (IL)-8 in the RV-infected group at days 2 and 9;<br />Increase in nasal IL-8 at day 2 correlated significantly with the change in airway responsiveness at day 4.<br />More pronounced in those with a severe cold. <br />
    35. 35. Coronavirus<br /><ul><li>Coronavirus is the second most common virus associated with asthma episodes.
    36. 36. Produced a greater disease burden value than influenza or respiratory syncytial virus.
    37. 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).</li></ul>Implicated in more than 40% of LRTIs of elderly adult patients.<br />25% of these received antibiotics. <br />
    38. 38. Discussion of Disease burden value<br />
    39. 39. Influenza virus<br />Influenza virus triggers asthma exacerbations in all age groups. <br /><ul><li>Asthmatics more susceptible to death associated with influenza infections.</li></ul>Asian pandemic (1957)<br />Fifteen of 20 asthmatic children (ages 8 to 12) had decreases in FEV1 >20% from baseline at onset of symptoms. <br />One decreased during the incubation period. <br />FEV1 decreased maximally on the second day of illness by an average of 30%. <br />Improvement began on the third day.<br />FEV1 returned to within 10% of normal between the seventh and tenth day.<br />
    40. 40.
    41. 41. Adenovirus<br />Demonstrated during acute asthma episodes, but substantially less frequently than for Rhinovirus and Coronavirus. <br />The rate of adenoviral infection declines with age until 9 years and then it increases. <br />Exception is serotype 7<br />Rate increases with age. <br />Frequently associated with wheezing.<br />58.3% of non-asthmatic children under age 2 admitted to a PICU with acute LRTI due to Adenovirus. <br />Mortality rate was 16.7%<br />Mostly with serotype 7. <br />
    42. 42.
    43. 43. Adenovirus<br />Latentadenoviral infection may have a role in the genesis of asthma.<br />Adenoviral shedding may be prolonged (up to 906 days).<br />Found in 78.4% of asymptomatic asthmatic children vs. 5% of healthy controls. <br />
    44. 44. Adenovirus<br />Study:<br />Recovered from BAL in children with asthma 12 months or more after an acute infection. <br />BAL performed in 34 children (mean age of 5 years) with unfavorable responses to standard corticosteroid and bronchodilator therapy. <br />Adenoviral antigens detected in 94% of subjects. <br />Repeat studies done on 8 subjects within 1 year showed that 6 were positive on two occasions and 3 on a third as well.<br />Cultures of the BAL fluid were positive for Adenovirus in all cultures performed indicating that the virus was still capable of replication. <br />Similar studies performed in control patients without persistent asthma failed to detect evidence of adenovirus.<br />
    45. 45. Respiratory syncytial virus (RSV)<br />Infects almost 100% of children by age 2.<br />The most common cause of bronchiolitis and pneumonia in infants.<br />RSV serves as a trigger for exacerbations of asthma and other chronic lung diseases.<br />
    46. 46.
    47. 47.
    48. 48. Respiratory syncytial virus (RSV)<br />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.<br />Infants who experience severe RSV bronchiolitis have increased frequencies of wheeze and asthma later in life. <br />Children admitted for bronchiolitis found that the post-bronchiolitis group had a significantly higher frequency of bronchial obstructive symptoms 2 to 10 years later.<br />PFTs showed diminished FEV1 or increased bronchial reactivity compared with healthy controls.<br />By 7.5 years of age, the cumulative prevalence of asthma was 30% in the RSV group vs. 3% in the control group.<br />Current asthma was present in 23% of the RSV group versus 2% of the control group. <br />
    49. 49. Respiratory syncytial virus (RSV)<br />
    50. 50. Respiratory syncytial virus (RSV)<br />However, the duration of the effect of RSV infection on asthma-related symptoms appears to be limited.<br />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. <br />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).<br />The risk for frequent wheeze remained significantly increased at 11 years of age (OR = 2.4)<br />Pre-bronchodilator FEV1 but not post-bronchodilator FEV1 was significantly lower in the RSV group. <br />By age 13 years, there were no significant between-group differences in terms of increased risk for frequent or infrequent wheezing. <br />
    51. 51. Respiratory syncytial virus (RSV)<br />Similar to adenoviral infection, the persistence of RSV may underlie the sequelae of severe RSV disease. <br />Infection may lead to alteration in the patterns of local interferon, chemokine, and cytokine production potentially leading to chronic inflammation. <br />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. <br />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.<br />
    52. 52.
    53. 53. Parainfluenza virus<br />The Parainfluenza viruses (PIV) cause a spectrum of respiratory illness similar to RSV but result in fewer hospitalizations. <br />Most illnesses are limited to the upper respiratory tract. <br />15% involve the lower respiratory tract.<br />Only 2.8 of every 1000 children with PIV LRTIs require hospitalization.<br />14% of episodes of increased symptoms or decreased PEF in school-aged children. <br />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.<br />
    54. 54. Human metapneumovirus<br />Human metapneumovirus (hMPV) was identified in 2001 in respiratory samples from children with respiratory disease in the Netherlands. <br />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. <br />hMPV is responsible worldwide for community-acquired acute RTIs. <br />Mean age of illness of 11.6 months <br />Male predominance (male/female ratio 1.8:1). <br />The broad epidemic seasonality and genetic variability suggest that there may be more than one serotype of hMPV.<br />
    55. 55.
    56. 56. Human metapneumovirus<br /><ul><li>More than half of otherwise healthy children with acute respiratory illness and evidence of hMPV experienced wheezing. </li></ul>6.4%-20% of previously healthy patients with no pathogen identified initially, subsequently found hMPV. <br />Bronchiolitis was the most common diagnosis (50%). <br />Co-infection with RSV and hMPV may augment the severity of bronchiolitis.<br />Conflicting reports linking hMPV infections and asthma exacerbations.<br />hMPV may be responsible for a portion of hospitalizations in children with infectious triggers of asthma unrelated to RSV infection. <br />
    57. 57. Atypical organisms<br />
    58. 58. M. pneumoniaeand C. pneumoniae<br />Most present with malaise, gradual onset shortness-of-breath, and wheezing.<br />Symptoms typically resolve after treatment with macrolide antibiotics or oral corticosteroids. <br />Infections with these organisms can persist for months.<br />Infections with decreased expiratory flow rates and increased airway hyper-responsiveness in previously healthy adults associated with the onset of asthma symptoms.<br />
    59. 59.
    60. 60. M. pneumoniaeand C. pneumoniae<br />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. <br />Fifty-six percent of the asthmatic patients were PCR-positive for M. pneumoniae (n = 25) or C. pneumoniae (n = 7).<br />Mainly found in BAL fluid or biopsy samples. <br />Only 1 of 11 control subjects was positive.<br />Cultures for these organisms were negative in all patients. <br />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.<br />
    61. 61.
    62. 62. M. pneumoniaeand C. pneumoniae<br />Atypical infectious organisms linked to asthma exacerbations. <br />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. <br />In the asthmatic group <br />18 M. pneumoniae<br />Only 8 as the sole infectious agent<br />Difficult to ascertain the culpability of M. pneumoniae as the cause of hospitalization<br />11 Influenza A<br />8 C. pneumoniae<br />6 Adenovirus<br />5 Influenza B, Legionella spp. <br />3 PIV-1, S. pneumoniae, <br />2 RSV, PIV-2 <br />1 PIV-3 <br />In the control group, only 3 with M. pneumoniae. <br />
    63. 63. M. pneumoniaeand C. pneumoniae<br />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. <br />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. <br />Acute M. pneumoniae infection was confirmed in 50% and C. pneumoniae in 8.3% of patients experiencing their first wheezing episode. <br />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. <br />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.<br />
    64. 64. Bacterial sinusitis<br />S/S of sinusitis in children overlap with many respiratory disorders.<br />Frequent comorbidities during acute exacerbations of asthma. <br />Children with bronchodilator-resistant asthma symptoms revealed substantial improvement in upper and lower respiratory symptoms post-treatment (may need antral lavage). <br />Most common pathogen is Moraxella catarrhalis.<br /><ul><li>Suggested mechanisms</li></ul>Hyper-responsiveness postnasal drip provokes acute lower airway symptoms.<br />Sinobronchial reflex<br />Pharyngobronchial reflex<br />Generalized inflammatory disorder of the respiratory mucosa<br />Cellular<br />Eosinophils <br />Mast cells <br />T cells<br />Mucosal thickening and epithelial cell damage <br />Increased histamine and leukotriene levels<br />
    65. 65. Treatments<br />
    66. 66. Treatments<br />No clinically effective treatment for the common cold. <br />Treatment for viral RTIs remains symptomatic.<br />Major obstacles for treatment:<br />Wide variety of organisms<br />Rapid rate of mutation leads to resistance<br />Delivery, expense, and efficacy of drugs. <br />The relative treatment efficacies in the setting of RTIs depend upon the wheezing phenotype and probably the timing of the therapy. <br />Involvement of inflammatory pathways suggests that antiviral and anti-inflammatory therapies have potential roles (possibly in combination) after onset of symptoms. <br />As the mechanisms of viral-induced wheezing and asthma are elucidated, new forms of treatment may emerge. <br />Currently, prophylaxis (i.e. hygiene, vaccination, antivirals) offers the best hope of disease control.<br />
    67. 67. Vaccination<br />Mainstay of prophylaxis against infections. <br />With the exception of the influenza vaccine, development for respiratory viruses has been slow and disappointing. <br />Influenza vaccine contains three strains (two A and one B) of inactivated virus<br />Whole-cell influenza vaccine is no longer available<br />One or two are modified yearly based upon predictions of the upcoming viral strains. <br />Produced in embryonated hen eggs <br />Highly immunogenic, conferring protection in 70% to 80% of recipients with minimal adverse effects. <br />Current vaccines consist of subvirion (prepared by disrupting the lipid membrane) or purified surface antigen. <br />Safe and recommended for asthmatics, but efficacy in question<br />FluMist® (live attenuated, cold-adapted, trivalent, intranasal influenza vaccine ) is contraindicated in asthmatics.<br />Vaccinated children tended to have shorter exacerbations (by approximately 3 days) than non-vaccinated children.<br />
    68. 68. Intranasal influenza vaccine<br />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.<br />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.<br />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).<br />Pregnancy: Category C<br />
    69. 69. Antivirals<br />Target virus directly to decrease number thereby reducing the inflammatory process. <br />Only approved respiratory antiviral therapies are for:<br />Influenza A (amantadine and rimantadine)<br />Influenza A and B (zanamivir and oseltamivir)<br />RSV (ribavirin). <br />
    70. 70. Antivirals<br />Neuraminidase inhibitors (zanamivir and oseltamivir) have advantage over adamantanes (amantadine and rimantadine) because of broader spectrum (A and B).<br />Inhibition of neuraminidase prevents cleavage of sialic acid from newly acquired membrane, leaving emerging virus inactive. <br />Improve respiratory outcomes in asthma and acute influenza infections <br />Added benefit of being effective in the prophylaxis against Influenza. <br />Disadvantage is the specificity for Influenza and initiation of treatment must be within 48 hours of onset. <br />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.<br />
    71. 71. Amantadine<br />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. <br />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.<br />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.<br />Pregnancy: Category C<br />
    72. 72. Rimantadine<br />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.<br />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.<br />Pharmacokinetics: Oral Route <br />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.<br />Pregnancy: Category C<br />
    73. 73. Oseltamivir<br />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.<br />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.<br />Pharmacokinetics: Oral Route <br />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.<br />Pregnancy: Category C<br />
    74. 74. Zanamivir<br />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.<br />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.<br />Pharmacokinetics: Inhalation Route <br />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.<br />Pregnancy: Category C<br />
    75. 75. Ribavirin<br />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. <br />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.<br />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.<br />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.<br />
    76. 76. Antibiotics<br />Antibiotic use is appropriate only if there is evidence of bacterial infection contributing to asthma exacerbations.<br />Macrolide antibiotics <br />Have antiviral effects in vitro against rhinoviruses (not confirmed in vivo).<br />Have anti-inflammatory effects. <br />Asthmatic patients infected with M. pneumoniae or C. pneumoniae may benefit from prolonged treatment with clarithromycin as evidenced by:<br />Significant improvement in FEV1<br />Methacholine responsiveness<br />Improvement in airway hyper-responsiveness <br />Mechanism unknown, but may due to:<br />Treatment of occult or chronic infection<br />Interference with steroid metabolism<br />Anti-inflammatory properties<br />
    77. 77. Corticosteroids<br />The repeated use of systemic corticosteroids remains a clinical concern. <br />Because of the safety profile of inhaled corticosteroids (ICS), their use in the management of VIW has been explored. <br />Lack of efficacy in the regular use of ICS in patients with mild VIW. <br />ICS used episodically for VIW in children not using them as maintenance may decrease the rate of oral corticosteroid requirement.<br />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.<br />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.<br />
    78. 78. Leukotriene receptor antagonists<br /><ul><li>Cysteinyl leukotrienes (cysLTs) have been identified as important mediators in the pathophysiology of asthma.
    79. 79. CysLTs may play a role in the pathophysiology of VIW as well.</li></ul>CysLTs are detectable in the blood, urine, nasal secretions, sputum, and BAL fluid of patients with chronic asthma.<br />Elevated cysLTs have been detected in respiratory secretion of children with VIW at levels similar to asthmatics.<br />CysLTs are not fully suppressed by inhaled corticosteroids; therefore, leukotriene receptor antagonists may be of clinical benefit in VIW.<br />
    80. 80. Leukotriene receptor antagonists<br />
    81. 81. Montelukast<br />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.<br />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. <br />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.<br />Pregnancy: Category B<br />
    82. 82. Zafirlukast<br />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.<br />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.<br />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.[<br />Pregnancy: Category B<br />
    83. 83. Summary<br />Infections have been implicated in asthma exacerbations as well as the inception of asthma. <br />Viruses and atypical infectious agents may induce asthma exacerbations and affect its chronicity thereafter. <br />Further elucidation of the mechanisms underlying the interactions between infectious triggers and phenotypes of wheezing will lead to improvements in treatment and prevention. <br />
    84. 84. Main references<br />Gern, J E and Lemanske, Jr. R F. (2003). Infectious triggers of pediatric asthma. Pediatr Clin N Am 50:555–75.<br />MacDowell, A L and Bacharier, L B. (2005). Infectious triggers of asthma. Immunol Allergy Clin N Am 25:45–66.<br />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.<br />
    85. 85. Thank you!<br />Any questions?<br />

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