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Virusinduced wheezing and asthma Dr. Hala al refai Damascus Hospital • Viral respiratory infections, particularly with respiratory syncytial virus (RSV) • and human rhinovirus (HRV), are the most common causes of wheezing in infants and young children • and are common triggers of asthma exacerbations in patients with preexisting asthma • In addition, • wheezing with viral illnesses in infants and young children is associated with an increased risk of childhood asthma PATHOGENESIS • Viral respiratory infections interact with host factors to promote virus induced wheezing and asthma exacerbations • Respiratory symptoms with viral infections • probably result from virus induced damage of the airway epithelium, followed by airway inflammation in a predisposed individual. • Immune responses triggered by viral respiratory tract infections include • enhanced allergic inflammation, increased granulocyte recruitment, promotion of cytokine production • Respiratory viruses, such as influenza and RSV cause cytopathic damage to airway epithelium and these changes can affect the function of the epithelium and airway smooth muscle. • In addition, disturbing the integrity of the epithelial layer may enhance mucosal permeability and increase exposure of inflammatory and antigen presenting cells to allergens • Rhinoviruses, in contrast to other respiratory viruses, do not damage the epithelium. • However, rhinovirus and other respiratory viruses can activate epithelial cells to upregulate the expression of ICAM1 receptors, enhancing replication of HRV. • They also induce epithelial cells to secrete a wide variety of chemokines and cytokines, including interleukin (IL)6, IL8 (CXCL8), IL11, • and RANTES (CCL5), a chemo attractant for eosinophils, monocytes, and T cells • Respiratory viral infection and replication activate innate and adaptive antiviral immune responses, resulting in proinflammatory cytokine and chemokine production and the recruitment of inflammatory cells to the airway. • Rhinovirus has shown few cytopathic effects on airway epithelium or other tissues in contrast to other respiratory viruses, such as RSV and influenza • These observations raise the possibility that rhinovirus can induce and promote airway inflammation by its interaction with airway cells and the subsequent stimulation of cytokine production • Experimental infections with rhinovirus lead to increased airway responsiveness, enhanced inflammatory responses, a higher likelihood for the development of the late allergic reaction, and eosinophil recruitment to the airway following antigen challenge. • Two studies found increased airway responsiveness to histamine and augmentation of both the • immediate and late phase responses to inhaled allergen following experimental rhinovirus infection in patients with allergic rhinitis • In one of these reports, rhinovirus infection enhanced the allergic inflammatory reaction in the lower airway, as demonstrated by increased recruitment of eosinophils to the airway following segmental antigen challenge • Increased submucosal lymphocytes and epithelial eosinophils are demonstrated on biopsy of the lower airway during rhinovirus colds that are associated with increased airway responsiveness to histamine • Granulocytes — Neutrophils are the principal cells recruited to the airways during the acute phase of a viral infection and are also recruited to the lower airways during experimental rhinovirus infection • During acute viral illness, HRV infected adults with asthma have increased recruitment of neutrophils compared with HRV infected adults without asthma • This response is, in part, regulated by IL8 • (CXCL8) and leukotriene B4 (LTB4) • Macrophages and monocytes — Airway macrophages are the predominant airway cell and are probably involved in host responses to respiratory viruses. • Nasal secretions obtained during upper respiratory tractinfections contain • IL1, • tumor necrosis factor (TNF)alpha, • and IL8 • These cytokines are important in the development of acute symptoms, such as fever and myalgia. • In addition, these mediators can stimulate epithelial cells to express adhesion molecules • Parasympathetic hyper responsiveness In animal studies, other mechanisms have been identified to explain changes in airway function during viral respiratory infections. • Two studies in guinea pigs and rats • found that viral respiratory infections impair inhibitory M2 muscarinic receptor function, producing • parasympathetic hyper responsiveness that leads to broncho constriction • Increased IgE • One study demonstrated increases in IgE levels in subjects with allergic rhinitis, • but not in subjects with nonallergic rhinitis after experimental rhinovirus infection • Other investigators • have shown that RSV and parainfluenza virus can stimulate total IgE and virusspecific IgE in children • The development of virusspecific IgE levels correlates with the probability of recurrent episodes of wheeze WHEEZING DUE TO VIRAL INFECTION • Studies have shown that viral infections trigger up to 85 % of asthma exacerbations in school aged children • and up to 50 % of exacerbations in adults • Children <2 years of age — A first episode of wheezing in association with a viral respiratory infection leads to an outpatient visit for about 15 % of all infants in the United States, • and 3 % are hospitalized with this presentation • Bronchiolitis, or inflammation of the bronchioles, is a clinical syndrome characterized by wheezing, tachypnea, and hyperinflation of the lungs • It is of • primary importance in infants and young children less than two years of age • RSV is the most common cause of bronchiolitis and wheezing in this age group. • examined the causative factors for acute wheezing in infants and children presenting to the emergency department • RSV was the most common infectious agent found in children less than two years of age, and the affected children were nonallergic • Rhinovirus is also a common cause of wheezing and bronchiolitis in infancy, although its prevalence in virus induced • wheezing is more significant in adults and children older than two years of age • The HRVC serotypes, in addition to HRVA • and HRVB, are associated with virusinduced • wheezing and asthma exacerbations in children • Metapneumovirus, another member of the Paramyxoviridae family, can cause upper and lower respiratory tract infection and wheezing in young children • Coronaviruses, bocaviruses, and influenza can also provoke wheezing DEVELOPMENT OF ASTHMA • Viral respiratory infections in infancy, particularly with RSV and HRV, are predictive of the development of asthma in later childhood • In addition, • the timing of birth and the subsequent exposure to peak bronchiolitis and RSV season may influence the development of asthma • Respiratory syncytial virus — In infants and children less than two years of age, respiratory infections with respiratory syncytial virus (RSV) are the most common cause of virusinduced wheezing. • Many of these children have decreased wheezing during viral infections as they grow older, although RSV infections are viewed as a potential contributor to the development of asthma • Those children that have persistent symptoms of asthma or that develop asthma after RSV infection usually have other asthma risk factors, such as a maternal history of asthma and elevated IgE levels • Rhinovirus (the common cold virus) influences the development of asthma • Studies have shown that infants who wheeze with rhinovirus infection have increased risk of recurrent wheeze and asthma at ages three, five, and six ASTHMA COMPLICATED BY VIRAL INFECTION • Viral respiratory infections are an important, • and probably the most common, cause of increased pulmonary symptoms in children and adults with preexisting asthma • Rhinovirus is the predominant pathogen identified in school aged children and adult patients with acute asthma exacerbations. • Infection with rhinovirus group C is associated with more severe disease in children admitted for asthma exacerbations • Asthma exacerbations — Viral upper respiratory infections (URIs or colds) are the most frequent cause of asthma exacerbations. SUMMARY • Viral respiratory infections, particularly with respiratory syncytial virus (RSV) and human rhinovirus (HRV), are the most common causes of wheezing in infants and young children and they have important influences on the development of asthma. • In addition, viral infections, most often with rhinovirus, are the most common causes of wheezing or increased symptoms in patients with preexisting asthma. • Respiratory viruses interact with host factors to promote virusinduced wheezing and asthma • exacerbations via a number of mechanisms including increased recruitment of inflammatory cells, promotion of cytokine production, enhancement of allergic inflammation, and augmented • airways Hyper responsiveness • Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and wheezing in children <2 years of age. • Exposure to tobacco smoke and reduced lung function are risk factors associated with virusinduced wheezing in this age group. • Wheezing with viral respiratory infections, particularly with RSV and HRV, are important predictors of the subsequent development of asthma. • However, it is unclear whether certain viral espiratory infections cause asthma or if wheezing with these infections is a predictor of childhood asthma. • Viral respiratory infections are an important, and probably the most common, cause of increase pulmonary symptoms in children and adults with preexisting asthma. • Rhinovirus is the predominant pathogen and the most frequent trigger of virusinduced asthma exacerbations in patients with asthma. • Patients with asthma do not appear to be more susceptible to rhinovirus infection than healthy controls. • However, they are at greater risk of developing more severe and prolonged lower respiratory tract symptoms with infection شكرا •