Pediatric Asthma and Viral Infection | Archivos de Bronconeumología

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Luz Garcia-Garcia, Cristina Calvo Rey, Teresa del Rosal Rabes" "autores" => array:3 [ 0 => array:4 [ "nombre" => "M." "apellidos" => "Luz Garcia-Garcia" "email" => array:1 [ 0 => "marialuz.hso@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Cristina" "apellidos" => "Calvo Rey" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Teresa" "apellidos" => "del Rosal Rabes" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Pediatría, Hospital Universitario Severo Ochoa, Leganés, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Pediatría, Hospital Universitario La Paz, Leganés, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Asma y virus en el niño" ] ] "textoCompleto" => "IntroductionAsthma is a chronic inflammatory disease of the airways characterized by bronchial hyperresponsiveness to a wide variety of stimuli, recurrent episodes of wheezing, respiratory distress, and cough, associated with reversible airway obstruction. Asthma is one of the most prevalent chronic diseases worldwide, affecting more than 155 million individuals, so the impact of asthma is severe, and incidence is growing, particularly in developed countries.<a class="elsevierStyleCrossRefs" href="#bib0335">1,2</a>Respiratory viruses are one of the most common causes of asthma exacerbations in both adults and children.<a class="elsevierStyleCrossRefs" href="#bib0345">3–6</a> Furthermore, increasing evidence is emerging to suggest that viral respiratory infections in early life are related with the medium and long-term development of asthma.<a class="elsevierStyleCrossRefs" href="#bib0365">7,8</a>This article aims first to review the role of viruses as precipitating factors for asthma, and then to summarize the current state of knowledge on their role in asthma exacerbations.Respiratory Viruses as Precipitating Factors for AsthmaViral bronchiolitis is a common feature in the clinical histories of children who go on to develop wheezing and asthma during childhood. The term bronchiolitis has been in use since 1940, but it has several different interpretations, and there is no general agreement on its definition. In this review, we will use the standard criteria of McConnochie, who describes bronchiolitis as the first acute episode of wheezing, preceded by a respiratory syndrome of rhinorrhea, cough, and tachypnea, occurring with or without fever, in children younger than 2 years of age.<a class="elsevierStyleCrossRef" href="#bib0375">9</a>Bronchiolitis is the most common acute lower respiratory tract infection in children younger than 1 year, and accounts for 18% of all pediatric admissions.<a class="elsevierStyleCrossRef" href="#bib0380">10</a> Respiratory syncytial virus (RSV) is the causative agent in approximately 70%–80% of cases, followed by rhinovirus, adenovirus, human metapneumovirus (HMPV), and human bocavirus (HBoV).<a class="elsevierStyleCrossRefs" href="#bib0385">11,12</a> The most common respiratory viruses are listed in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Studies reporting global analyses of all patients with a history of bronchiolitis, irrespective of the causative agent, reveal a prevalence of recurrent wheezing that ranges from 75% in the first 2 years of life, 47%–59% between the ages of 2 and 4, and 25%–43% between 4 and 6 years,<a class="elsevierStyleCrossRefs" href="#bib0395">13–16</a> showing a clear trend to diminish with age. Only 2 prospective studies included a long-term follow-up of children hospitalized for bronchiolitis, irrespective of the causative virus. They found a prevalence of asthma at the age of 17–20 years of 41%–43% in patients with a history of bronchiolitis, compared to a rate of 11%–15% in controls; between 25 and 30 years of age, prevalence was 35%, with significant impact on health-related quality of life.<a class="elsevierStyleCrossRefs" href="#bib0415">17,18</a> These data suggest that recurrent wheezing occurs frequently in children after an episode of bronchiolitis, and also that respiratory symptoms frequently recur in young adults after a long symptom-free period during childhood and adolescence. This changes the previously held notion of a relatively good prognosis for early childhood wheezing, and indicates that the risk of asthma and lung function changes can persist until adulthood.<a class="elsevierStyleCrossRefs" href="#bib0425">19,20</a>RSV was the first virus to be associated with the development of asthma in children, although in recent years, other viruses, such as rhinovirus or the more recently described HMPB and HBoV, have also been studied in this context.Respiratory Syncytial VirusRSV is an RNA virus from the Paramyxoviridae family that often causes lower respiratory tract infections in infants and small children.<a class="elsevierStyleCrossRef" href="#bib0435">21</a>In 1959, Wittig and Glaser<a class="elsevierStyleCrossRef" href="#bib0440">22</a> first described the epidemiological association between viral bronchiolitis in childhood and the subsequent development of recurrent wheezing and/or asthma. Since then, numerous studies have evaluated this relationship, although the different methodologies employed made it difficult to draw conclusions that definitively proved this association. However, more recently, several prospective studies, now considered seminal,<a class="elsevierStyleCrossRefs" href="#bib0445">23–27</a> showed that a history of bronchiolitis caused by RSV is an independent risk factor for the development of recurrent wheezing and medically-diagnosed asthma. Of these authors, Sigurs et al.<a class="elsevierStyleCrossRef" href="#bib0465">27</a> performed the longest follow-up to date, with subjects reaching the age of 18 years in the last follow-up time point. The initial cohort consisted of 47 infants aged <1 year hospitalized with severe RSV bronchiolitis and 93 age- and gender-matched controls. Children who had been admitted for bronchiolitis had a higher prevalence of asthma/recurrent wheezing and allergic sensitizations at the ages of 3, 7 and 13 years, compared to the control group. At the age of 18, the bronchiolitis group maintained a significantly higher prevalence of asthma (39% vs 9%), allergic rhinoconjunctivitis (43% vs 17%), and perennial allergen sensitization (41% vs 14%). Moreover, at the age of 18, the bronchiolitis group had poorer lung function (FEV1, FEV1/FVC) than the control group, irrespective of whether they had concomitant asthma or not. They also had more prevalent bronchial hyperresponsiveness and bronchodilator response. Finally, the authors reported that the only 2 risk factors independently related with the diagnosis of asthma at 18 years of age were a history of severe RSV bronchiolitis and presence of allergic rhinoconjunctivitis. These results show that severe RSV bronchiolitis in the early months of life is associated with the development of asthma, bronchial hyperresponsiveness and allergic sensitization, and suggest that this association continues until adulthood.The results of another reference follow-up study, Tucson Children's Respiratory Study, show that RSV bronchiolitis is an independent risk factor for the development of asthma up to the age of 11 years, but the association disappears after the age of 13.<a class="elsevierStyleCrossRef" href="#bib0450">24</a> This difference in the long-term prognosis may be related with varying severity of the acute episode, since in the Sigurs study, all patients needed to be hospitalized, while the Tucson cohort included mostly outpatients. The authors also observed a greater risk of asthma among children who used more healthcare resources during the acute bronchiolitis episode.<a class="elsevierStyleCrossRef" href="#bib0470">28</a>The RSV Bronchiolitis in Early Life (RBEL) study also supports the association between severe RSV bronchiolitis and subsequent development of asthma<a class="elsevierStyleCrossRef" href="#bib0475">29</a>: of the 206 infants admitted for RSV bronchiolitis, approximately 50% had been diagnosed with asthma by the age of 7 years.RhinovirusAlthough RSV is without doubt the most common virus in the etiology of acute infantile bronchiolitis, the use of molecular diagnostic techniques – primarily polymerase chain reaction (PCR) – has established that other respiratory viruses, such as rhinovirus, are also associated with bronchiolitis, and probably with the development of asthma.<a class="elsevierStyleCrossRefs" href="#bib0480">30,31</a> Indeed, several recent studies have shown that the risk of children hospitalized for bronchiolitis presenting asthma at 6 and 11 years is higher among those who were RSV-negative than those who were RSV-positive.<a class="elsevierStyleCrossRefs" href="#bib0490">32,33</a>Rhinovirus is an RNA virus from the Picornaviridae family, first isolated in 1950. It comprises a large RNA family of more than 100 serotypes, originally divided into 2 species, A and B, and now with the recent addition of the C type.<a class="elsevierStyleCrossRef" href="#bib0500">34</a>Studies published in recent years suggest that rhinovirus infections involve a greater risk for the development of asthma than RSV-associated infections. In the Childhood Origins of Asthma (COAST) study, which followed a cohort of 289 newborns with high risk of developing asthma, lower respiratory tract infection associated with rhinovirus was the main risk factor for presenting recurrent wheezing at 3 and 6 years of life, with an odds ratio of 10 for rhinovirus bronchiolitis compared to 2.6 for RSV bronchiolitis.<a class="elsevierStyleCrossRefs" href="#bib0505">35,36</a> Moreover, children with rhinovirus-associated wheezing in the first 3 years of life had worse lung function values (FEV1, FEV0.5, FEF25–75) than those with other viruses or those who never presented wheezing.<a class="elsevierStyleCrossRef" href="#bib0515">37</a> Midulla et al.<a class="elsevierStyleCrossRef" href="#bib0520">38</a> confirmed the role of rhinovirus bronchiolitis as one of the main risk factors for the development of asthma at the age of 6 years.The COAST study also showed that, in the case of rhinovirus, the risk of developing asthma is not limited to severe infection. In fact, only 1% of children with rhinovirus bronchiolitis included in the study needed to be hospitalized, demonstrating that even mild rhinovirus infections are associated with a greater long-term risk of asthma.Finally, another cohort study with a follow-up of 15–18 years showed that the risk of asthma in adolescence is greater in children hospitalized due to rhinovirus bronchiolitis, compared to RSV bronchiolitis. This study also found that the risk of asthma is greater in children whose initial episode of bronchiolitis occurred in seasons other than winter, when the predominant virus is not RSV.<a class="elsevierStyleCrossRef" href="#bib0525">39</a>Human MetapneumovirusHMPV is a paramyxovirus, discovered in 2001 and identified throughout the world as a common cause of acute respiratory infection, particularly in infants and small children.<a class="elsevierStyleCrossRef" href="#bib0530">40</a> The clinical features of acute HMPV infection are similar to those caused by RSV, and can manifest as mild upper respiratory tract infections, pneumonia or severe bronchiolitis requiring hospital admission. The similarity of the clinical symptoms with those of RSV has led to speculation that HMPV infections may also be associated with the development of asthma in the long term. To date, the medium-term progress of children admitted for HMPV bronchiolitis has been examined in only 1 study that reported a similar rate of recurrent wheezing to that seen in children admitted for RSV bronchiolitis: 5-fold the rate of the control group in both cases.<a class="elsevierStyleCrossRef" href="#bib0535">41</a>Human BocavirusHBoV is a DNA virus belonging to the Parvoviridae family. It was first identified in 2005 in respiratory samples from children with lower respiratory tract infections.<a class="elsevierStyleCrossRef" href="#bib0540">42</a> Since then, numerous studies have investigated its prevalence and its role in respiratory infections, but to date, only 1 has examined its possible role in the development of asthma: the study in question reported that 50% of children admitted for HBoV bronchiolitis had asthma by the age of 5–7 years.<a class="elsevierStyleCrossRef" href="#bib0545">43</a>The high rate of HBoV co-infection with other respiratory viruses, and its tendency to infect older children confounds the study of the real role of early HBoV infections in the development of asthma.The Bronchiolitis–Asthma Relationship: Cause or Coincidence?As discussed above, a wide body of evidence relates viral respiratory infections with the subsequent development of asthma, but it remains unclear if severe bronchiolitis is the real cause of asthma, or if it is a marker of susceptibility, identifying children with a predisposition for developing asthma.A prospective, multicenter study recently conducted in Europe, the United States, and Canada,<a class="elsevierStyleCrossRef" href="#bib0550">44</a> appears to support the causative role of RSV, after an 80% reduction was observed in recurrent wheezing in the medium term among premature babies with a family history of asthma and/or atopy who received prophylaxis with palivizumab, a monoclonal antibody used for preventing RSV infection. Curiously, the protective effect was only observed in children with a history of atopy, suggesting that RSV may have a causative role in the pathogenesis of recurrent wheezing, but only in patients with no genetic predisposition for atopy.The possible causative role of viral bronchiolitis was questioned by an epidemiological study performed in monozygotic twins, discordant for severe RSV bronchiolitis in infancy. The authors found no difference in the frequency of asthma, lung function or nitric oxide levels at the age of 7 years between twin siblings with a history or no history of hospitalization due to bronchiolitis.<a class="elsevierStyleCrossRef" href="#bib0555">45</a>Finally, another 2 recent studies support the hypothesis that early viral infections are markers of atopic predisposition, rather than the cause of asthma. One of these was the Danish Copenhagen Prospective Study of Asthma in Childhood, which followed a cohort of newborns with asthmatic mothers. Investigators measured lung function and response to methacholine of infants at 1 month of life, before any respiratory symptom had been observed. They found at this time point that children who subsequently developed severe bronchiolitis already had bronchial hyperresponsiveness as a precursor to bronchiolitis.<a class="elsevierStyleCrossRef" href="#bib0560">46</a> These results are supported by the recent COAST study, which identified allergic sensitization in the first year of life as a significant risk factor for virus-associated wheezing, while wheezing associated with respiratory infection does not increase the risk of developing allergic sensitization.<a class="elsevierStyleCrossRef" href="#bib0565">47</a>It seems likely that the 2 hypotheses – bronchiolitis as a cause or as a marker of asthma – are not mutually exclusive, and that the pathogenic mechanisms of rhinovirus and RSV infections differ. RSV characteristically produces a cytopathic effect in the airway, affecting children younger than 3 months, frequently requires hospitalization and occurs in epidemic outbreaks during the winter months.<a class="elsevierStyleCrossRef" href="#bib0570">48</a> In contrast, rhinovirus outbreaks occur throughout the year and affect older children who are generally treated as outpatients, and who often have a family history of asthma or atopy.<a class="elsevierStyleCrossRefs" href="#bib0365">7,49</a> These differences have led to the hypothesis of 2 different mechanisms: rhinovirus bronchiolitis may be more a marker of predisposition to asthma and atopy, while RSV bronchiolitis may have a greater causative role, particularly in severe cases requiring hospitalization.<a class="elsevierStyleCrossRefs" href="#bib0580">50,51</a>Respiratory Viruses Triggering Asthmatic ExacerbationsThe role of respiratory viruses as precipitants of asthma attacks in adults and children was identified over 30 years ago. In the early studies, in which viral diagnosis was not based on molecular methods, some viral activity was detected in between 10% and 25% of asthma attacks.<a class="elsevierStyleCrossRef" href="#bib0590">52</a> In contrast, in recent years, the use of PCR techniques has revealed that the proportion of asthma exacerbations associated with viruses is much higher, up to 63%, according to Khetsuriani et al.,<a class="elsevierStyleCrossRef" href="#bib0595">53</a> up to 80%, according to Johnston et al.,<a class="elsevierStyleCrossRef" href="#bib0345">3</a> or even up to 95%, according to Allander et al.<a class="elsevierStyleCrossRef" href="#bib0600">54</a> At least 1 respiratory virus was identified in 71% of patients included in a Spanish study of children hospitalized for an asthma exacerbation.<a class="elsevierStyleCrossRef" href="#bib0355">5</a>Although practically all respiratory viruses, including the newly identified HMPV and HBoV, have been associated with asthma exacerbations, the agents most commonly detected in infants and schoolchildren are rhinovirus and RSV.<a class="elsevierStyleCrossRefs" href="#bib0355">5,55</a> In fact, a recent cohort study in 263 infants suggests that rhinovirus is the most common pathogen in the first year of life and the most important precipitant of wheezing in infants.<a class="elsevierStyleCrossRef" href="#bib0610">56</a>In children of school age, Johnston et al.<a class="elsevierStyleCrossRef" href="#bib0345">3</a> found that 80% of asthma exacerbations in asthmatic children aged 9–11 years were associated with viral respiratory infection, of which two thirds were caused by rhinovirus. Asthma exacerbations among pre-school- and school-age children tend to follow a seasonal pattern, and in temperate climates, the maximum incidence occurs in the month of September, coinciding with the beginning of the school year, and in Spring.<a class="elsevierStyleCrossRef" href="#bib0615">57</a> This pattern coincides almost exactly with the peaks of maximum circulation of rhinovirus in the community, suggesting a causal relationship between this virus and asthma exacerbations.The frequency of detecting respiratory viruses in adults with asthma exacerbations ranges between 41% and 78%, according to the results of a recent meta-analysis.<a class="elsevierStyleCrossRef" href="#bib0620">58</a> Although rhinovirus is also most common in this age group,<a class="elsevierStyleCrossRef" href="#bib0625">59</a> other viruses, such as RSV, HMPV, or influenza virus appear to play an important role in asthma exacerbations in adults in clinical practice.<a class="elsevierStyleCrossRef" href="#bib0630">60</a>Moreover, viral infections can act in synergy with other stimuli, such as exposure to allergens in allergic individuals<a class="elsevierStyleCrossRefs" href="#bib0635">61,62</a> or exposure to high levels of environmental contaminants,<a class="elsevierStyleCrossRef" href="#bib0645">63</a> increasing the risk of asthma exacerbations.Pathogenic Mechanism of the Viral Respiratory Infection–Asthma Exacerbation AssociationViral respiratory infections affect the lung in many ways, acting on epithelial cells and antigen-presenting cells. After it recognizes the viral infection, the immune system stimulates the production of cytokines, such as interleukins (IL) IL-25 and IL-33 and thymic stromal lymphopoietin (TSLP), in the epithelial cells of the airway. These cytokines induce the TH2 immune response to airborne allergens in the lungs. The production of certain cytokines, such as IL4, IL5, and IL13, by the TH2 cells subsequently increases eosinophil and mast cell recruitment, causing inflammation of the airway, cell metaplasia, and bronchoconstriction.<a class="elsevierStyleCrossRef" href="#bib0650">64</a>However, not all individuals who contract a respiratory virus infection suffer an asthma exacerbation, so the possibility that certain risk factors increase susceptibility to present wheezing after viral infection has been explored. Studies conducted by Wark et al.<a class="elsevierStyleCrossRef" href="#bib0655">65</a> and Contoli et al.<a class="elsevierStyleCrossRef" href="#bib0660">66</a> suggest that the absence of an efficient innate immune response, manifested by low interferon levels in the epithelial cells of asthma patients, may assist viral replication, leading to an exaggerated asthmatic response.It seems highly likely that an altered immune response to viral infections in genetically predisposed subjects are the major factors involved in the virus–asthma relationship.Conflict of InterestsThe authors declare that they have no conflict of interests." "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres631380" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec644209" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres631381" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec644210" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Respiratory Viruses as Precipitating Factors for Asthma" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Respiratory Syncytial Virus" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Rhinovirus" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Human Metapneumovirus" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Human Bocavirus" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "The Bronchiolitis–Asthma Relationship: Cause or Coincidence?" ] ] ] 6 => array:3 [ "identificador" => "sec0040" "titulo" => "Respiratory Viruses Triggering Asthmatic Exacerbations" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Pathogenic Mechanism of the Viral Respiratory Infection–Asthma Exacerbation Association" ] ] ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflict of Interests" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-10-09" "fechaAceptado" => "2015-11-09" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec644209" "palabras" => array:7 [ 0 => "Bronchiolitis" 1 => "Asthma" 2 => "Respiratory viruses" 3 => "Respiratory syncytial virus" 4 => "Rhinovirus" 5 => "Human bocavirus" 6 => "Human metapneumovirus" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec644210" "palabras" => array:7 [ 0 => "Bronquiolitis" 1 => "Asma" 2 => "Virus respiratorios" 3 => "Virus respiratorio sincitial" 4 => "Rinovirus" 5 => "Bocavirus humano" 6 => "Metapneumovirus humano" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Respiratory viral infections, particularly respiratory syncytial virus (RSV) and rhinovirus, are the most importance risk factors for the onset of wheezing in infants and small children. Bronchiolitis is the most common acute respiratory infection in children under 1 year of age, and the most common cause of hospitalization in this age group. RSV accounts for approximately 70% of all these cases, followed by rhinovirus, adenovirus, metapneumovirus and bocavirus. The association between bronchiolitis caused by RSV and the development of recurrent wheezing and/or asthma was first described more than 40 years ago, but it is still unclear whether bronchiolitis causes chronic respiratory symptoms, or if it is a marker for children with a genetic predisposition for developing asthma in the medium or long term. In any case, sufficient evidence is available to corroborate the existence of this association, which is particularly strong when the causative agent of bronchiolitis is rhinovirus.The pathogenic role of respiratory viruses as triggers for exacerbations in asthmatic patients has not been fully characterized. However, it is clear that respiratory viruses, and in particular rhinovirus, are the most common causes of exacerbation in children, and some type of respiratory virus has been identified in over 90% of children hospitalized for an episode of wheezing. Changes in the immune response to viral infections in genetically predisposed individuals are very likely to be the main factors involved in the association between viral infection and asthma." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Las infecciones por virus respiratorios, especialmente virus respiratorio sincitial (VRS) y rinovirus, suponen el mayor factor de riesgo para la aparición de episodios de sibilancias en lactantes y niños pequeños. La bronquiolitis es la infección respiratoria aguda de vías respiratorias inferiores más común en menores de un año y constituye la causa más frecuente de hospitalización en este grupo de edad. El VRS causa aproximadamente el 70% de todas ellas, seguido por rinovirus, adenovirus, metapneumovirus o bocavirus. La asociación entre bronquiolitis por VRS y desarrollo de sibilancias recurrentes y/o asma ha sido descrita hace más de 4 décadas, aunque en la actualidad se desconoce con exactitud si la bronquiolitis es la causa de los síntomas respiratorios crónicos o si, más bien, es un marcador que señala a los niños con predisposición genética a desarrollar asma a medio o largo plazo. En cualquier caso, existe evidencia suficiente como para afirmar que esta asociación existe y que es especialmente intensa si el agente asociado a la bronquiolitis es el rinovirus.El papel patogénico de los virus respiratorios como desencadenantes de exacerbaciones en el paciente asmático no está totalmente aclarado, pero sin duda los virus respiratorios, y en especial el rinovirus, son el desencadenante más frecuente de exacerbaciones asmáticas en los niños, llegando a identificarse algún virus respiratorio hasta en el 90% de los niños hospitalizados por un episodio de sibilancias. Muy probablemente, las alteraciones en la respuesta inmune frente a las infecciones virales en sujetos genéticamente predispuestos sean los principales implicados en la asociación virus-asma." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Luz Garcia-Garcia M, Calvo Rey C, del Rosal Rabes T. Asma y virus en el niño. Arch Bronconeumol. 2016;52:269–273." ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Species \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Family \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Genus \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Subgroups \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Syncytial respiratory virus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Paramyxoviridae \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pneumovirus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RNA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">A, B \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Parainfluenza 1, 3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Paramyxoviridae \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Respirovirus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RNA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1, 3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Parainfluenza 2, 4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Paramyxoviridae \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rubulavirus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RNA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2, 4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Metapneumovirus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Paramyxoviridae \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Metapneumovirus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RNA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1–4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Influenza \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Orthomyxoviridae \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ortomixovirus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RNA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">A, B, C \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rhinovirus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Picornaviridae \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rhinovirus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RNA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">A, B, C \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Adenovirus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Adenoviridae \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mastadenovirus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DNA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">A to F \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Human bocavirus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Parvoviridae \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bocavirus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DNA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1, 2, 3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Coronavirus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Coronaviridae \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Coronavirus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RNA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">I, II \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1035937.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Classification of Respiratory Viruses." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:66 [ 0 => array:3 [ "identificador" => "bib0335" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Asthma in the United States: burden and current theories" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "S.C. 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Pediatric Asthma and Viral Infection

Asma y virus en el niño

M. Luz Garcia-Garciaa,

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marialuz.hso@gmail.com

Corresponding author.

, Cristina Calvo Reya, Teresa del Rosal Rabesb

a Servicio de Pediatría, Hospital Universitario Severo Ochoa, Leganés, Madrid, Spain

b Servicio de Pediatría, Hospital Universitario La Paz, Leganés, Madrid, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Asthma is a chronic inflammatory disease of the airways characterized by bronchial hyperresponsiveness to a wide variety of stimuli&#44; recurrent episodes of wheezing&#44; respiratory distress&#44; and cough&#44; associated with reversible airway obstruction&#46; Asthma is one of the most prevalent chronic diseases worldwide&#44; affecting more than 155 million individuals&#44; so the impact of asthma is severe&#44; and incidence is growing&#44; particularly in developed countries&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Respiratory viruses are one of the most common causes of asthma exacerbations in both adults and children&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">3&#8211;6</span></a> Furthermore&#44; increasing evidence is emerging to suggest that viral respiratory infections in early life are related with the medium and long-term development of asthma&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">7&#44;8</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">This article aims first to review the role of viruses as precipitating factors for asthma&#44; and then to summarize the current state of knowledge on their role in asthma exacerbations&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Respiratory Viruses as Precipitating Factors for Asthma</span><p id="par0020" class="elsevierStylePara elsevierViewall">Viral bronchiolitis is a common feature in the clinical histories of children who go on to develop wheezing and asthma during childhood&#46; The term bronchiolitis has been in use since 1940&#44; but it has several different interpretations&#44; and there is no general agreement on its definition&#46; In this review&#44; we will use the standard criteria of McConnochie&#44; who describes bronchiolitis as the first acute episode of wheezing&#44; preceded by a respiratory syndrome of rhinorrhea&#44; cough&#44; and tachypnea&#44; occurring with or without fever&#44; in children younger than 2 years of age&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">9</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Bronchiolitis is the most common acute lower respiratory tract infection in children younger than 1 year&#44; and accounts for 18&#37; of all pediatric admissions&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">10</span></a> Respiratory syncytial virus &#40;RSV&#41; is the causative agent in approximately 70&#37;&#8211;80&#37; of cases&#44; followed by rhinovirus&#44; adenovirus&#44; human metapneumovirus &#40;HMPV&#41;&#44; and human bocavirus &#40;HBoV&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">11&#44;12</span></a> The most common respiratory viruses are listed in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Studies reporting global analyses of all patients with a history of bronchiolitis&#44; irrespective of the causative agent&#44; reveal a prevalence of recurrent wheezing that ranges from 75&#37; in the first 2 years of life&#44; 47&#37;&#8211;59&#37; between the ages of 2 and 4&#44; and 25&#37;&#8211;43&#37; between 4 and 6 years&#44;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">13&#8211;16</span></a> showing a clear trend to diminish with age&#46; Only 2 prospective studies included a long-term follow-up of children hospitalized for bronchiolitis&#44; irrespective of the causative virus&#46; They found a prevalence of asthma at the age of 17&#8211;20 years of 41&#37;&#8211;43&#37; in patients with a history of bronchiolitis&#44; compared to a rate of 11&#37;&#8211;15&#37; in controls&#59; between 25 and 30 years of age&#44; prevalence was 35&#37;&#44; with significant impact on health-related quality of life&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">17&#44;18</span></a> These data suggest that recurrent wheezing occurs frequently in children after an episode of bronchiolitis&#44; and also that respiratory symptoms frequently recur in young adults after a long symptom-free period during childhood and adolescence&#46; This changes the previously held notion of a relatively good prognosis for early childhood wheezing&#44; and indicates that the risk of asthma and lung function changes can persist until adulthood&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">19&#44;20</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">RSV was the first virus to be associated with the development of asthma in children&#44; although in recent years&#44; other viruses&#44; such as rhinovirus or the more recently described HMPB and HBoV&#44; have also been studied in this context&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Respiratory Syncytial Virus</span><p id="par0040" class="elsevierStylePara elsevierViewall">RSV is an RNA virus from the <span class="elsevierStyleItalic">Paramyxoviridae</span> family that often causes lower respiratory tract infections in infants and small children&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">21</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In 1959&#44; Wittig and Glaser<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">22</span></a> first described the epidemiological association between viral bronchiolitis in childhood and the subsequent development of recurrent wheezing and&#47;or asthma&#46; Since then&#44; numerous studies have evaluated this relationship&#44; although the different methodologies employed made it difficult to draw conclusions that definitively proved this association&#46; However&#44; more recently&#44; several prospective studies&#44; now considered seminal&#44;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">23&#8211;27</span></a> showed that a history of bronchiolitis caused by RSV is an independent risk factor for the development of recurrent wheezing and medically-diagnosed asthma&#46; Of these authors&#44; Sigurs et al&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">27</span></a> performed the longest follow-up to date&#44; with subjects reaching the age of 18 years in the last follow-up time point&#46; The initial cohort consisted of 47 infants aged &#60;1 year hospitalized with severe RSV bronchiolitis and 93 age- and gender-matched controls&#46; Children who had been admitted for bronchiolitis had a higher prevalence of asthma&#47;recurrent wheezing and allergic sensitizations at the ages of 3&#44; 7 and 13 years&#44; compared to the control group&#46; At the age of 18&#44; the bronchiolitis group maintained a significantly higher prevalence of asthma &#40;39&#37; vs 9&#37;&#41;&#44; allergic rhinoconjunctivitis &#40;43&#37; vs 17&#37;&#41;&#44; and perennial allergen sensitization &#40;41&#37; vs 14&#37;&#41;&#46; Moreover&#44; at the age of 18&#44; the bronchiolitis group had poorer lung function &#40;FEV<span class="elsevierStyleInf">1</span>&#44; FEV<span class="elsevierStyleInf">1</span>&#47;FVC&#41; than the control group&#44; irrespective of whether they had concomitant asthma or not&#46; They also had more prevalent bronchial hyperresponsiveness and bronchodilator response&#46; Finally&#44; the authors reported that the only 2 risk factors independently related with the diagnosis of asthma at 18 years of age were a history of severe RSV bronchiolitis and presence of allergic rhinoconjunctivitis&#46; These results show that severe RSV bronchiolitis in the early months of life is associated with the development of asthma&#44; bronchial hyperresponsiveness and allergic sensitization&#44; and suggest that this association continues until adulthood&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The results of another reference follow-up study&#44; Tucson Children&#39;s Respiratory Study&#44; show that RSV bronchiolitis is an independent risk factor for the development of asthma up to the age of 11 years&#44; but the association disappears after the age of 13&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">24</span></a> This difference in the long-term prognosis may be related with varying severity of the acute episode&#44; since in the Sigurs study&#44; all patients needed to be hospitalized&#44; while the Tucson cohort included mostly outpatients&#46; The authors also observed a greater risk of asthma among children who used more healthcare resources during the acute bronchiolitis episode&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">28</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">The RSV Bronchiolitis in Early Life &#40;RBEL&#41; study also supports the association between severe RSV bronchiolitis and subsequent development of asthma<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">29</span></a>&#58; of the 206 infants admitted for RSV bronchiolitis&#44; approximately 50&#37; had been diagnosed with asthma by the age of 7 years&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Rhinovirus</span><p id="par0060" class="elsevierStylePara elsevierViewall">Although RSV is without doubt the most common virus in the etiology of acute infantile bronchiolitis&#44; the use of molecular diagnostic techniques &#8211; primarily polymerase chain reaction &#40;PCR&#41; &#8211; has established that other respiratory viruses&#44; such as rhinovirus&#44; are also associated with bronchiolitis&#44; and probably with the development of asthma&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">30&#44;31</span></a> Indeed&#44; several recent studies have shown that the risk of children hospitalized for bronchiolitis presenting asthma at 6 and 11 years is higher among those who were RSV-negative than those who were RSV-positive&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">32&#44;33</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Rhinovirus is an RNA virus from the <span class="elsevierStyleItalic">Picornaviridae</span> family&#44; first isolated in 1950&#46; It comprises a large RNA family of more than 100 serotypes&#44; originally divided into 2 species&#44; A and B&#44; and now with the recent addition of the C type&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">34</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Studies published in recent years suggest that rhinovirus infections involve a greater risk for the development of asthma than RSV-associated infections&#46; In the Childhood Origins of Asthma &#40;COAST&#41; study&#44; which followed a cohort of 289 newborns with high risk of developing asthma&#44; lower respiratory tract infection associated with rhinovirus was the main risk factor for presenting recurrent wheezing at 3 and 6 years of life&#44; with an odds ratio of 10 for rhinovirus bronchiolitis compared to 2&#46;6 for RSV bronchiolitis&#46;<a class="elsevierStyleCrossRefs" href="#bib0505"><span class="elsevierStyleSup">35&#44;36</span></a> Moreover&#44; children with rhinovirus-associated wheezing in the first 3 years of life had worse lung function values &#40;FEV<span class="elsevierStyleInf">1</span>&#44; FEV<span class="elsevierStyleInf">0&#46;5</span>&#44; FEF<span class="elsevierStyleInf">25&#8211;75</span>&#41; than those with other viruses or those who never presented wheezing&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">37</span></a> Midulla et al&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">38</span></a> confirmed the role of rhinovirus bronchiolitis as one of the main risk factors for the development of asthma at the age of 6 years&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">The COAST study also showed that&#44; in the case of rhinovirus&#44; the risk of developing asthma is not limited to severe infection&#46; In fact&#44; only 1&#37; of children with rhinovirus bronchiolitis included in the study needed to be hospitalized&#44; demonstrating that even mild rhinovirus infections are associated with a greater long-term risk of asthma&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Finally&#44; another cohort study with a follow-up of 15&#8211;18 years showed that the risk of asthma in adolescence is greater in children hospitalized due to rhinovirus bronchiolitis&#44; compared to RSV bronchiolitis&#46; This study also found that the risk of asthma is greater in children whose initial episode of bronchiolitis occurred in seasons other than winter&#44; when the predominant virus is not RSV&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">39</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Human Metapneumovirus</span><p id="par0085" class="elsevierStylePara elsevierViewall">HMPV is a paramyxovirus&#44; discovered in 2001 and identified throughout the world as a common cause of acute respiratory infection&#44; particularly in infants and small children&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">40</span></a> The clinical features of acute HMPV infection are similar to those caused by RSV&#44; and can manifest as mild upper respiratory tract infections&#44; pneumonia or severe bronchiolitis requiring hospital admission&#46; The similarity of the clinical symptoms with those of RSV has led to speculation that HMPV infections may also be associated with the development of asthma in the long term&#46; To date&#44; the medium-term progress of children admitted for HMPV bronchiolitis has been examined in only 1 study that reported a similar rate of recurrent wheezing to that seen in children admitted for RSV bronchiolitis&#58; 5-fold the rate of the control group in both cases&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">41</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Human Bocavirus</span><p id="par0090" class="elsevierStylePara elsevierViewall">HBoV is a DNA virus belonging to the <span class="elsevierStyleItalic">Parvoviridae</span> family&#46; It was first identified in 2005 in respiratory samples from children with lower respiratory tract infections&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">42</span></a> Since then&#44; numerous studies have investigated its prevalence and its role in respiratory infections&#44; but to date&#44; only 1 has examined its possible role in the development of asthma&#58; the study in question reported that 50&#37; of children admitted for HBoV bronchiolitis had asthma by the age of 5&#8211;7 years&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">43</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">The high rate of HBoV co-infection with other respiratory viruses&#44; and its tendency to infect older children confounds the study of the real role of early HBoV infections in the development of asthma&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">The Bronchiolitis&#8211;Asthma Relationship&#58; Cause or Coincidence&#63;</span><p id="par0100" class="elsevierStylePara elsevierViewall">As discussed above&#44; a wide body of evidence relates viral respiratory infections with the subsequent development of asthma&#44; but it remains unclear if severe bronchiolitis is the real cause of asthma&#44; or if it is a marker of susceptibility&#44; identifying children with a predisposition for developing asthma&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">A prospective&#44; multicenter study recently conducted in Europe&#44; the United States&#44; and Canada&#44;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">44</span></a> appears to support the causative role of RSV&#44; after an 80&#37; reduction was observed in recurrent wheezing in the medium term among premature babies with a family history of asthma and&#47;or atopy who received prophylaxis with palivizumab&#44; a monoclonal antibody used for preventing RSV infection&#46; Curiously&#44; the protective effect was only observed in children with a history of atopy&#44; suggesting that RSV may have a causative role in the pathogenesis of recurrent wheezing&#44; but only in patients with no genetic predisposition for atopy&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">The possible causative role of viral bronchiolitis was questioned by an epidemiological study performed in monozygotic twins&#44; discordant for severe RSV bronchiolitis in infancy&#46; The authors found no difference in the frequency of asthma&#44; lung function or nitric oxide levels at the age of 7 years between twin siblings with a history or no history of hospitalization due to bronchiolitis&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">45</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Finally&#44; another 2 recent studies support the hypothesis that early viral infections are markers of atopic predisposition&#44; rather than the cause of asthma&#46; One of these was the Danish Copenhagen Prospective Study of Asthma in Childhood&#44; which followed a cohort of newborns with asthmatic mothers&#46; Investigators measured lung function and response to methacholine of infants at 1 month of life&#44; before any respiratory symptom had been observed&#46; They found at this time point that children who subsequently developed severe bronchiolitis already had bronchial hyperresponsiveness as a precursor to bronchiolitis&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">46</span></a> These results are supported by the recent COAST study&#44; which identified allergic sensitization in the first year of life as a significant risk factor for virus-associated wheezing&#44; while wheezing associated with respiratory infection does not increase the risk of developing allergic sensitization&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">47</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">It seems likely that the 2 hypotheses &#8211; bronchiolitis as a cause or as a marker of asthma &#8211; are not mutually exclusive&#44; and that the pathogenic mechanisms of rhinovirus and RSV infections differ&#46; RSV characteristically produces a cytopathic effect in the airway&#44; affecting children younger than 3 months&#44; frequently requires hospitalization and occurs in epidemic outbreaks during the winter months&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">48</span></a> In contrast&#44; rhinovirus outbreaks occur throughout the year and affect older children who are generally treated as outpatients&#44; and who often have a family history of asthma or atopy&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">7&#44;49</span></a> These differences have led to the hypothesis of 2 different mechanisms&#58; rhinovirus bronchiolitis may be more a marker of predisposition to asthma and atopy&#44; while RSV bronchiolitis may have a greater causative role&#44; particularly in severe cases requiring hospitalization&#46;<a class="elsevierStyleCrossRefs" href="#bib0580"><span class="elsevierStyleSup">50&#44;51</span></a></p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Respiratory Viruses Triggering Asthmatic Exacerbations</span><p id="par0125" class="elsevierStylePara elsevierViewall">The role of respiratory viruses as precipitants of asthma attacks in adults and children was identified over 30 years ago&#46; In the early studies&#44; in which viral diagnosis was not based on molecular methods&#44; some viral activity was detected in between 10&#37; and 25&#37; of asthma attacks&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">52</span></a> In contrast&#44; in recent years&#44; the use of PCR techniques has revealed that the proportion of asthma exacerbations associated with viruses is much higher&#44; up to 63&#37;&#44; according to Khetsuriani et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">53</span></a> up to 80&#37;&#44; according to Johnston et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">3</span></a> or even up to 95&#37;&#44; according to Allander et al&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">54</span></a> At least 1 respiratory virus was identified in 71&#37; of patients included in a Spanish study of children hospitalized for an asthma exacerbation&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">5</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Although practically all respiratory viruses&#44; including the newly identified HMPV and HBoV&#44; have been associated with asthma exacerbations&#44; the agents most commonly detected in infants and schoolchildren are rhinovirus and RSV&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">5&#44;55</span></a> In fact&#44; a recent cohort study in 263 infants suggests that rhinovirus is the most common pathogen in the first year of life and the most important precipitant of wheezing in infants&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">56</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">In children of school age&#44; Johnston et al&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">3</span></a> found that 80&#37; of asthma exacerbations in asthmatic children aged 9&#8211;11 years were associated with viral respiratory infection&#44; of which two thirds were caused by rhinovirus&#46; Asthma exacerbations among pre-school- and school-age children tend to follow a seasonal pattern&#44; and in temperate climates&#44; the maximum incidence occurs in the month of September&#44; coinciding with the beginning of the school year&#44; and in Spring&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">57</span></a> This pattern coincides almost exactly with the peaks of maximum circulation of rhinovirus in the community&#44; suggesting a causal relationship between this virus and asthma exacerbations&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">The frequency of detecting respiratory viruses in adults with asthma exacerbations ranges between 41&#37; and 78&#37;&#44; according to the results of a recent meta-analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">58</span></a> Although rhinovirus is also most common in this age group&#44;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">59</span></a> other viruses&#44; such as RSV&#44; HMPV&#44; or influenza virus appear to play an important role in asthma exacerbations in adults in clinical practice&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">60</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Moreover&#44; viral infections can act in synergy with other stimuli&#44; such as exposure to allergens in allergic individuals<a class="elsevierStyleCrossRefs" href="#bib0635"><span class="elsevierStyleSup">61&#44;62</span></a> or exposure to high levels of environmental contaminants&#44;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">63</span></a> increasing the risk of asthma exacerbations&#46;</p><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Pathogenic Mechanism of the Viral Respiratory Infection&#8211;Asthma Exacerbation Association</span><p id="par0150" class="elsevierStylePara elsevierViewall">Viral respiratory infections affect the lung in many ways&#44; acting on epithelial cells and antigen-presenting cells&#46; After it recognizes the viral infection&#44; the immune system stimulates the production of cytokines&#44; such as interleukins &#40;IL&#41; IL-25 and IL-33 and thymic stromal lymphopoietin &#40;TSLP&#41;&#44; in the epithelial cells of the airway&#46; These cytokines induce the TH2 immune response to airborne allergens in the lungs&#46; The production of certain cytokines&#44; such as IL4&#44; IL5&#44; and IL13&#44; by the TH2 cells subsequently increases eosinophil and mast cell recruitment&#44; causing inflammation of the airway&#44; cell metaplasia&#44; and bronchoconstriction&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">64</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">However&#44; not all individuals who contract a respiratory virus infection suffer an asthma exacerbation&#44; so the possibility that certain risk factors increase susceptibility to present wheezing after viral infection has been explored&#46; Studies conducted by Wark et al&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">65</span></a> and Contoli et al&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">66</span></a> suggest that the absence of an efficient innate immune response&#44; manifested by low interferon levels in the epithelial cells of asthma patients&#44; may assist viral replication&#44; leading to an exaggerated asthmatic response&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">It seems highly likely that an altered immune response to viral infections in genetically predisposed subjects are the major factors involved in the virus&#8211;asthma relationship&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflict of Interests</span><p id="par0165" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interests&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "Respiratory Viruses as Precipitating Factors for Asthma"
          "secciones" => array:5 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Respiratory Syncytial Virus"
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              "identificador" => "sec0020"
              "titulo" => "Rhinovirus"
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            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Human Metapneumovirus"
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            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Human Bocavirus"
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            4 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "The Bronchiolitis&#8211;Asthma Relationship&#58; Cause or Coincidence&#63;"
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          "identificador" => "sec0040"
          "titulo" => "Respiratory Viruses Triggering Asthmatic Exacerbations"
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              "identificador" => "sec0045"
              "titulo" => "Pathogenic Mechanism of the Viral Respiratory Infection&#8211;Asthma Exacerbation Association"
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          "titulo" => "Conflict of Interests"
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          "titulo" => "References"
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    "fechaRecibido" => "2014-10-09"
    "fechaAceptado" => "2015-11-09"
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          "clase" => "keyword"
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          "palabras" => array:7 [
            0 => "Bronchiolitis"
            1 => "Asthma"
            2 => "Respiratory viruses"
            3 => "Respiratory syncytial virus"
            4 => "Rhinovirus"
            5 => "Human bocavirus"
            6 => "Human metapneumovirus"
          ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec644210"
          "palabras" => array:7 [
            0 => "Bronquiolitis"
            1 => "Asma"
            2 => "Virus respiratorios"
            3 => "Virus respiratorio sincitial"
            4 => "Rinovirus"
            5 => "Bocavirus humano"
            6 => "Metapneumovirus humano"
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Respiratory viral infections&#44; particularly respiratory syncytial virus &#40;RSV&#41; and rhinovirus&#44; are the most importance risk factors for the onset of wheezing in infants and small children&#46; Bronchiolitis is the most common acute respiratory infection in children under 1 year of age&#44; and the most common cause of hospitalization in this age group&#46; RSV accounts for approximately 70&#37; of all these cases&#44; followed by rhinovirus&#44; adenovirus&#44; metapneumovirus and bocavirus&#46; The association between bronchiolitis caused by RSV and the development of recurrent wheezing and&#47;or asthma was first described more than 40 years ago&#44; but it is still unclear whether bronchiolitis causes chronic respiratory symptoms&#44; or if it is a marker for children with a genetic predisposition for developing asthma in the medium or long term&#46; In any case&#44; sufficient evidence is available to corroborate the existence of this association&#44; which is particularly strong when the causative agent of bronchiolitis is rhinovirus&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The pathogenic role of respiratory viruses as triggers for exacerbations in asthmatic patients has not been fully characterized&#46; However&#44; it is clear that respiratory viruses&#44; and in particular rhinovirus&#44; are the most common causes of exacerbation in children&#44; and some type of respiratory virus has been identified in over 90&#37; of children hospitalized for an episode of wheezing&#46; Changes in the immune response to viral infections in genetically predisposed individuals are very likely to be the main factors involved in the association between viral infection and asthma&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Las infecciones por virus respiratorios&#44; especialmente virus respiratorio sincitial &#40;VRS&#41; y rinovirus&#44; suponen el mayor factor de riesgo para la aparici&#243;n de episodios de sibilancias en lactantes y ni&#241;os peque&#241;os&#46; La bronquiolitis es la infecci&#243;n respiratoria aguda de v&#237;as respiratorias inferiores m&#225;s com&#250;n en menores de un a&#241;o y constituye la causa m&#225;s frecuente de hospitalizaci&#243;n en este grupo de edad&#46; El VRS causa aproximadamente el 70&#37; de todas ellas&#44; seguido por rinovirus&#44; adenovirus&#44; metapneumovirus o bocavirus&#46; La asociaci&#243;n entre bronquiolitis por VRS y desarrollo de sibilancias recurrentes y&#47;o asma ha sido descrita hace m&#225;s de 4 d&#233;cadas&#44; aunque en la actualidad se desconoce con exactitud si la bronquiolitis es la causa de los s&#237;ntomas respiratorios cr&#243;nicos o si&#44; m&#225;s bien&#44; es un marcador que se&#241;ala a los ni&#241;os con predisposici&#243;n gen&#233;tica a desarrollar asma a medio o largo plazo&#46; En cualquier caso&#44; existe evidencia suficiente como para afirmar que esta asociaci&#243;n existe y que es especialmente intensa si el agente asociado a la bronquiolitis es el rinovirus&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">El papel patog&#233;nico de los virus respiratorios como desencadenantes de exacerbaciones en el paciente asm&#225;tico no est&#225; totalmente aclarado&#44; pero sin duda los virus respiratorios&#44; y en especial el rinovirus&#44; son el desencadenante m&#225;s frecuente de exacerbaciones asm&#225;ticas en los ni&#241;os&#44; llegando a identificarse alg&#250;n virus respiratorio hasta en el 90&#37; de los ni&#241;os hospitalizados por un episodio de sibilancias&#46; Muy probablemente&#44; las alteraciones en la respuesta inmune frente a las infecciones virales en sujetos gen&#233;ticamente predispuestos sean los principales implicados en la asociaci&#243;n virus-asma&#46;</p></span>"
      ]
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    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Luz Garcia-Garcia M&#44; Calvo Rey C&#44; del Rosal Rabes T&#46; Asma y virus en el ni&#241;o&#46; Arch Bronconeumol&#46; 2016&#59;52&#58;269&#8211;273&#46;</p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Species&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Family&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Subgroups&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Syncytial respiratory virus&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&#44; B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Parainfluenza 1&#44; 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Paramyxoviridae</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Respirovirus</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RNA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44; 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Parainfluenza 2&#44; 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Paramyxoviridae</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RNA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Picornaviridae</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Rhinovirus</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RNA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&#44; B&#44; C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Adenovirus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Adenoviridae</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DNA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A to F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Human bocavirus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Parvoviridae</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Bocavirus</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DNA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44; 2&#44; 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Coronavirus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Coronaviridae</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RNA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&#44; II&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Classification of Respiratory Viruses&#46;</p>"
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      "titulo" => "References"
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        0 => array:2 [
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              "identificador" => "bib0335"
              "etiqueta" => "1"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Asthma in the United States&#58; burden and current theories"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "S&#46;C&#46; Redd"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Environ Health Perspect"
                        "fecha" => "2002"
                        "volumen" => "110"
                        "paginaInicial" => "557"
                        "paginaFinal" => "560"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12194886"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0340"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Epidemiology of asthma&#58; prevalence and burden of disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "S&#46; Croisant"
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                    ]
                  ]
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                      "doi" => "10.1007/978-1-4614-8603-9_2"
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Article information

ISSN: 15792129
Original language: English

DOI:10.1016/j.arbr.2016.03.010

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Year/Month	Html	Pdf	Total

2024 November	4	1	5
2024 October	46	32	78
2024 September	53	19	72
2024 August	81	36	117
2024 July	65	17	82
2024 June	93	44	137
2024 May	136	30	166
2024 April	71	37	108
2024 March	64	28	92
2024 February	45	29	74
2023 March	9	7	16
2023 February	59	17	76
2023 January	52	47	99
2022 December	83	46	129
2022 November	85	43	128
2022 October	83	50	133
2022 September	57	41	98
2022 August	73	36	109
2022 July	52	46	98
2022 June	53	43	96
2022 May	70	68	138
2022 April	55	39	94
2022 March	79	53	132
2022 February	68	39	107
2022 January	56	56	112
2021 December	54	37	91
2021 November	64	40	104
2021 October	67	60	127
2021 September	62	44	106
2021 August	54	49	103
2021 July	63	66	129
2021 June	160	48	208
2021 May	221	62	283
2021 April	272	78	350
2021 March	119	45	164
2021 February	65	35	100
2021 January	59	44	103
2020 December	65	31	96
2020 November	51	30	81
2020 October	67	16	83
2020 September	66	24	90
2020 August	55	28	83
2020 July	49	24	73
2020 June	57	17	74
2020 May	51	20	71
2020 April	121	32	153
2020 March	143	34	177
2020 February	108	55	163
2020 January	72	40	112
2019 December	80	33	113
2019 November	108	37	145
2019 October	86	36	122
2019 September	142	45	187
2019 August	88	41	129
2019 July	57	43	100
2019 June	151	57	208
2019 May	108	56	164
2019 April	117	61	178
2019 March	962	57	1019
2019 February	69	37	106
2019 January	146	36	182
2018 December	75	51	126
2018 November	201	61	262
2018 October	310	39	349
2018 September	204	34	238
2018 May	45	0	45
2018 April	161	18	179
2018 March	39	21	60
2018 February	30	12	42
2018 January	36	22	58
2017 December	27	9	36
2017 November	39	13	52
2017 October	35	19	54
2017 September	34	13	47
2017 August	36	22	58
2017 July	30	26	56
2017 June	38	26	64
2017 May	46	22	68
2017 April	62	39	101
2017 March	50	28	78
2017 February	51	18	69
2017 January	31	23	54
2016 December	46	25	71
2016 November	60	30	90
2016 October	63	54	117
2016 September	73	34	107
2016 August	61	21	82
2016 July	2	0	2

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