Are inhaled corticosteroids effective in asthma exacerbations? Evidentia praxis

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(1) Hepatitis B vaccine (HB). – Doses of hexavalent vaccine at ages 2, 4 and 11 months. Children of HBsAg-positive mothers or mothers of unknown serologic status will also be given one dose of monovalent HB vaccine at birth, in addition to 0.5mL of hepatitis B immune globulin (HBIG) if maternal HBsAg-positive status is confirmed. Infants vaccinated at birth will adhere to the routine schedule for year 1 of life, and thus will receive 4 doses of HB vaccine. Unvaccinated children and adolescents should be given 3 doses of monovalent vaccine on a 0, 1 and 6-month schedule. (2) Diphtheria, tetanus and acellular pertussis vaccine (DTaP/Tdap). – 5 doses: primary vaccination with 2 doses, at 2 and 4 months, of DTaP (hexavalent) vaccine; booster at 11 months (third dose) with DTaP (hexavalent) vaccine; at 6 years (fourth dose) with the standard load vaccine (DTaP-IPV), preferable to the low diphtheria and pertussis antigen load vaccine (Tdap-IPV), and at 12–14 years (fifth dose) with Tdap. (3) Inactivated poliovirus vaccine (IPV). – 4 doses: primary vaccination with 2 doses, at 2 and 4 months, and booster doses at 11 months (with hexavalent) and 6 years (with DTaP-IPV or Tdap-IPV). (4) Haemophilus influenzae type b conjugate vaccine (Hib). – 3 doses: primary vaccination at 2 and 4 months and booster dose at 11 months (with hexavalent). (5) Pneumococcal conjugate vaccine (PCV). – 3 doses: the first two at 2 and 4 months, with a booster dose starting at 11 months of age. The vaccine recommended in Spain by the CAV-AEP continues to be the PCV13. (6) Rotavirus vaccine (RV). – 2 or 3 doses of rotavirus vaccine: at 2 and 3–4 months with the monovalent vaccine or at 2, 3 and 4 months or 2, 4 and 5–6 months with the pentavalent vaccine. It is very important to start vaccination between 6 and 12 weeks of life in order to minimise risks, and to complete it before 24 weeks for the monovalent vaccine or 32 weeks for the pentavalent vaccine. Doses must be given at least 4 weeks apart. Both vaccines may be given at the same time as any other vaccine. (7) Meningococcal B vaccine (MenB). – 4CMenB. 3 doses: start at age 2 months, with a primary series of 2 doses at least 2 months apart and a booster starting at age 12 months and at least 6 months after the last dose in the primary series. It can be administered at the same time as other vaccines in the schedule, although this could increase fever, so another option is to administer it 1 or 2 weeks apart from other injectable inactivated vaccines, up to age 12 months, to minimise potential reactogenicity. The separation by 1–2 weeks is not necessary for the MenACWY, MMR, varicella and rotavirus vaccines. Vaccination is also recommended at any age in risk groups: anatomic or functional asplenia, complement component deficiency, treatment with eculizumab or ravulizumab, haematopoietic stem cell transplant recipients, infection by HIV, prior episode of IMD caused by any serogroup, and contacts of an index case of IMD caused by serogroup B in the context of an outbreak. (8) Meningococcal C conjugate vaccine (MenC) and meningococcal ACWY conjugate vaccine (MenACWY). – 1 dose of conjugate MenC-TT at age 4 months. The CAV-AEP recommends 1 dose of the MenACWY conjugate vaccine at age 12 months and 12–14 years, and a progressive catch-up vaccination schedule to be completed by age 18 years. In ACs where vaccination with MenACWY is not included in the routine schedule, if parents choose not to administer the MenACWY vaccine at 12 months, the MenC-TT vaccine funded by the regional government must be administered instead. Administration of the MenACWY vaccine is still particularly recommended in children and adolescents that are to live in countries where the vaccine is administered at this age (United States, Canada, Argentina, United Kingdom, Austria, Greece, Netherlands, Italy and Switzerland) and for children with risk factors for IMD: anatomic or functional asplenia, complement component deficiency, treatment with eculizumab or ravulizumab, hematopoietic stem cell transplant recipients, HIV infection, prior episode of IMD caused by any serogroup, and contacts of an index case of IMD caused by serogroup A, C, W or Y in the context of an outbreak. Individuals traveling to Mecca for religious reasons and to the African meningitis belt during the dry season should also receive the MenACWY vaccine. (9) Measles, mumps and rubella vaccine (MMR). – 2 MMR vaccine. The first at age 12 months and the second at age 3–4 years. The tetravalent MMRV vaccine may be administered for the second dose. Susceptible patients outside the specified ages will be vaccinated with 2 doses of MMR at least 1 month apart. (10) Varicella vaccine (Var). – 2 doses: the first at age 15 months (age 12 months is also acceptable) and the second at age 3–4 years. The tetravalent vaccine (MMRV) may be used for the second dose. Susceptible patients outside the specified ages will be vaccinated with 2 doses of monovalent Var vaccine at least 1 month apart. (11) Human papillomavirus vaccine (HPV). – Universal routine vaccination of all girls and boys, at age 12 years, to prevent HPV-related oncological diseases. All 3 HPV vaccines are authorised for use in male individuals, although there is little evidence on the use of the HPV2 vaccine in this sex. Administration of 2 doses at age 12 years. The vaccination schedule depends on the vaccine used: for the tetravalent vaccine, a 2-dose series (at 0 and 6 months) between ages 9 and 13 years and a 3-dose series (at 0, 2 and 6 months) in those aged ≥14 years; for the 2-valent and 9-valent vaccines, a 2-dose series (at 0 and 6 months) between ages 9 and 14 years and a 3-dose series (at 0, 1–2 [depending on the vaccine used] and 6 months) in those aged ≥15 years. The HPV vaccine may be administered at the same time as the MenC, MenACWY, hepatitis A and B and Tdap vaccines. There are no data on its coadministration with the varicella vaccine, although it should not cause any problems." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Francisco José Álvarez García, María José Cilleruelo Ortega, Javier Álvarez Aldeán, María Garcés-Sánchez, Nuria García Sánchez, Elisa Garrote Llanos, Ángel Hernández Merino, Antonio Iofrío de Arce, Abián Montesdeoca Melián, María Luisa Navarro Gómez, Jesús Ruiz-Contreras" "autores" => array:12 [ 0 => array:2 [ "nombre" => "Francisco José" "apellidos" => "Álvarez García" ] 1 => array:2 [ "nombre" => "María José" "apellidos" => "Cilleruelo Ortega" ] 2 => array:2 [ "nombre" => "Javier" "apellidos" => "Álvarez Aldeán" ] 3 => array:2 [ "nombre" => "María" "apellidos" => "Garcés-Sánchez" ] 4 => array:2 [ "nombre" => "Nuria" "apellidos" => "García Sánchez" ] 5 => array:2 [ "nombre" => "Elisa" "apellidos" => "Garrote Llanos" ] 6 => array:2 [ "nombre" => "Ángel" "apellidos" => "Hernández Merino" ] 7 => array:2 [ "nombre" => "Antonio" "apellidos" => "Iofrío de Arce" ] 8 => array:2 [ "nombre" => "Abián" "apellidos" => "Montesdeoca Melián" ] 9 => array:2 [ "nombre" => "María Luisa" "apellidos" => "Navarro Gómez" ] 10 => array:2 [ "nombre" => "Jesús" "apellidos" => "Ruiz-Contreras" ] 11 => array:1 [ "colaborador" => "on behalf of the Vaccine Advisory Committee of the Spanish Pediatric Association (CAV-AEP)" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S1695403320304409" "doi" => "10.1016/j.anpedi.2020.10.002" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1695403320304409?idApp=UINPBA00005H" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2341287920302180?idApp=UINPBA00005H" "url" => "/23412879/0000009400000001/v1_202101160808/S2341287920302180/v1_202101160808/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "Special Article" "titulo" => "Are inhaled corticosteroids effective in asthma exacerbations? Evidentia praxis" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "54.e1" "paginaFinal" => "54.e6" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Carlos Ochoa Sangrador, Álvaro Gimeno Díaz de Atauri, María Victoria Martínez Rubio" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Carlos" "apellidos" => "Ochoa Sangrador" "email" => array:1 [ 0 => "cochoas2@gmail.com" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Álvaro Gimeno" "apellidos" => "Díaz de Atauri" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 2 => array:3 [ "nombre" => "María Victoria" "apellidos" => "Martínez Rubio" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Servicio de Pediatría, Hospital Virgen de la Concha, Zamora, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Comité de Pediatría Basada en la Evidencia de la Asociación Española de Pediatría y de la Asociación Española de Pediatría de Atención Primaria, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Pediatría, Hospital 12 de Octubre, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Centro de Salud Los Fresnos, Torrejón de Ardoz, Madrid, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "¿Son eficaces los corticoides inhalados en las exacerbaciones asmáticas? Evidentia praxis" ] ] "textoCompleto" => "Clinical scenarioBoy aged 10 years with a diagnosis of asthma treated with low-dose inhaled corticosteroids (ICSs) for the past 6 months. Under this regimen, he needed salbutamol for rescue in the context of physical activity in one isolated episode 2 months prior. The boy presents to your office after being treated in the emergency department for an exacerbation for which he received a prescription for salbutamol and oral corticosteroids. You verify that his inhaler technique is correct and that he seems to adhere properly to treatment with ICSs.In the latest guideline of the Global Initiative for Asthma (GINA) of 2019,<a class="elsevierStyleCrossRef" href="#bib0005">1</a> you have read that in adolescents treated with ICSs, in the presence of symptoms indicative of worsening asthma, increasing the ICS dose to 4 times the usual is effective, but that in children with good adherence to treatment, increasing the dose to 5 times the usual is not. You have also read that in patients in maintenance treatment with ICS-formoterol, the GINA recommends increasing the dose as needed to up to a maximum of 72 μg/day of formoterol (single maintenance and reliever therapy [SMART]). It also recommends as-needed combination ICS-formoterol therapy in patients with very sporadic symptoms of asthma without maintenance therapy with ICSs and/or before physical activity in patients with exercise-induced bronchoconstriction.The GINA advises including these recommendations in the asthma action plan provided to the patients/family. You also see that for the management of asthmatic exacerbations in children aged more than 5 years at the primary care or emergency care levels, the GINA recommends use of short-acting beta2 agonists (SABAs) and systemic corticosteroids (SCSs), although in patients that do not receive SCSs, high-dose ICSs could be effective. However, neither the updated GINA strategy of 2019<a class="elsevierStyleCrossRef" href="#bib0010">2</a> nor the 2020 Spanish guideline (Guía Española para el Manejo del Asma [GEMA])<a class="elsevierStyleCrossRef" href="#bib0015">3</a> contemplate replacing SCSs by high-dose ICSs during an exacerbation, although they do contemplate maintenance of ongoing high-dose ICS therapy or its initial prescription, especially in exacerbations of moderate severity.You decide to revise the action plan for potential future exacerbations.Literature search and analysis of evidenceFocused clinical question (PICO strategy)PatientChildren/adolescents with asthma (age 3−18 years; excluding studies exclusively on subjects aged >16 years or that do not present separate data for individuals under 18 years), not receiving controller therapy or in treatment with low/medium-dose ICS, alone or in combination with a long-acting beta2 agonist (LABA).<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">a)With symptoms of acute exacerbation at home.</li><li class="elsevierStyleListItem" id="lsti0010">b)With exacerbation managed in unscheduled visit or emergency department.</li></ul>Intervention<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0015">a)High-dose ICS + SABA or formoterol as needed.</li><li class="elsevierStyleListItem" id="lsti0020">b)Increased dose of ICS + SABA or formoterol.</li></ul>ComparisonPlacebo + SABA or formoterol as needed.OutcomeAsthma exacerbation requiring SCS therapy and/or hospital admission.Question: in children or adolescents with asthma that exhibit features of exacerbation, does the use of inhaled corticosteroids (newly prescribed, or with an increased dose) reduce the risk of exacerbations requiring systemic corticosteroid therapy and/or hospital admission?Literature searchWe did a literature search for randomised controlled trials (RCTs) and systematic reviews (SRs) in MEDLINE (PubMed), EMBASE, Web of Science (WoS), CENTRAL and CINAHL on February 25, 2020, without any date or language restrictions. The initial selection of articles was made by reading the abstracts, with 2 reviewers each reading all abstracts and a third reviewer resolving any disagreement between them regarding the articles to be selected. After this initial selection, 2 reviewers read the full text of each of these articles to decide whether they would be included in the systematic review. We completed the search by reviewing the bibliography of the articles in the final selection.The search strategy used in PubMed was: («Asthma» [MeSH] OR «Respiratory Sounds» [MeSH] OR «Bronchial Spasm» [MeSH] OR «Bronchoconstriction» [MeSH]) AND («Disease Progression» [MeSH] OR «Exacerbation» OR «acute» OR «attack» OR «Reliever therapy») AND («Administration, Inhalation» [Mesh] OR «Inhalation» OR «Inhaled» OR «nebulized» OR «SMART» OR «Single inhaler» OR «reliever therapy») AND («Steroids»[ MeSH] OR «Steroids» OR «Corticosteroids» OR «formoterol») AND («child» [MeSH Terms] OR «child» OR «children» OR «adolescent» [MeSH Terms] OR «adolescent») AND (systematic[sb] OR Clinical Trial [ptyp]). For the other databases, we used an adaptation of this strategy (Appendix B of Supplemental material).We assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE),<a class="elsevierStyleCrossRef" href="#bib0020">4</a> the risk of bias in RCTs with the Risk of Bias (RoB) tool of the Cochrane Collaboration, the consistency of the results, the direct relationship with the clinical scenario, the precision, the effect size, the dose-response relationship, publication bias, the control of confounding factors, the importance of the endpoint and the cost-benefit ratio.We made tables summarizing the evidence obtained from the data retrieved from the reviewed studies. In the case of SRs that did not include separate analyses for the paediatric population, we estimated composite effect sizes, comparing 2 interventions by means of the systematic review software of the Cochrane Collaboration (Review Manager 5.3) and more than 2 interventions with the Excel-based Bayesian network meta-analysis macro NetMetaXL and WinBUGS 1.4.3. We used random effects models for paired meta-analysis and Bayesian inference with weakly informative priors.ResultsThe searches yielded 627 references, excluding duplicates, out of which we selected 50 for reading of the full text, to which we added another 5 identified through the review of the references of those 50. The final qualitative review included 22 articles (Appendix B of Supplemental material). Table S1 (Appendix B of Supplemental material) summarises the characteristics and results of 5 systematic reviews<a class="elsevierStyleCrossRefs" href="#bib0025">5–9</a> and one meta-analysis of the paediatric studies included in one of those reviews.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> We did not summarise the findings of one narrative review<a class="elsevierStyleCrossRef" href="#bib0055">11</a> and one systematic review<a class="elsevierStyleCrossRef" href="#bib0060">12</a> because they included RCTs that we had already evaluated separately or that were included in other reviews.Table S2 (Appendix B of Supplemental material) summarises the characteristics and results of the 16 RCTs<a class="elsevierStyleCrossRefs" href="#bib0065">13–28</a> with information that supplemented the information obtained from SRs, either because the trial was not included in the reviews or because it provided data for specific paediatric age subgroups that was not included in the review. For 2 RCTs, we analysed the data but did not take them into account because the controls were assigned to controller therapy with ICSs as an alternative to rescue therapy with ICSs<a class="elsevierStyleCrossRefs" href="#bib0070">14,28</a>; 2 RCTs included in the SRs made the same comparison.<a class="elsevierStyleCrossRefs" href="#bib0095">19,29</a> Another 5 RCTs could not be included in the composite analysis of SRs because they did not analyse the primary outcomes analysed in the reviews,<a class="elsevierStyleCrossRefs" href="#bib0080">16,18,26</a> because the sample consisted of hospitalised preschool-age children<a class="elsevierStyleCrossRef" href="#bib0115">23</a> or because they had a cross-sectional design<a class="elsevierStyleCrossRef" href="#bib0135">27</a>; the direction of effect in these studies, however, was consistent with the findings of the SR.<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> presents evaluation of the quality of analysed evidence using the GRADE classification. Figs. S1–S5 and Tables S3 and S4 in Appendix B (Supplemental material) present the meta-analyses performed by our group to complete the overall analysis, which included 13 RCTs, the results of which are summarised in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>CommentaryMost reviews analyse the efficacy of ICSs, as newly prescribed treatment or in increased doses relative to the onset of exacerbation features, compared to placebo or to maintenance of the baseline dose of ICS. Two analysed the SMART approach compared to controller ICS therapy, alone or combined with a LABA.<a class="elsevierStyleCrossRefs" href="#bib0035">7,10</a> One review analysed the efficacy of ICS as reliever medication in asthma exacerbations diagnosed at the emergency department<a class="elsevierStyleCrossRef" href="#bib0030">6</a> compared to placebo or systemic steroid therapy. In studies in which bronchodilators were not part of the intervention, all patients could receive SABA as needed.The primary endpoints were usually exacerbation, defined as the need of treatment with SCSs and, in some studies, the need for emergency care or hospital admission. In analyses of the management of asthma exacerbations in the emergency setting, the primary endpoint was the need for hospital admission.<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> presents evaluation of the quality of analysed evidence using the GRADE classification. It details the comparisons made in the studies and the outcome measures. All these measures were considered “relevant” from a clinical perspective, but not of critical importance. We found that the quality of the evidence was low or very low, save for the evidence on the comparison of ICSs versus placebo for management of asthma exacerbations in the emergency care setting and the comparison of increased-dose ICS therapy compared to maintaining the current dose of controller ICS therapy at the onset of symptoms, which was considered of moderate quality.We could establish a theoretical hierarchy of clinical scenarios based on the baseline risk. The lowest risk would correspond to patients not taking controller treatment that start to develop symptoms, in which case we would want to know whether ICS therapy would be effective in an exacerbation. The next level would correspond to patients receiving ICSs for maintenance therapy, in who we would consider whether or not to increase the dose at the beginning of an exacerbation. The highest level would correspond to patients receiving an ICS-LABA combination for maintenance therapy, in who we would consider whether to keep using this combination or use a SABA for rescue therapy. We investigated the recommendations that would apply to these 3 scenarios to include them in the asthma action plan provided to parents.Another scenario that we could not include in this theoretical hierarchy was the treatment of asthma exacerbations in the emergency department. Simply put, these patients have already reached the outcome that interventions in the previous scenarios attempt to prevent, regardless of the fact that their baseline risk was not the same. In this subset of patients, we could establish a particular risk hierarchy based on the compared treatments, from lower to higher steps of treatment, in increasing order, ICSs versus placebo, ICSs versus SCSs and, lastly, ICSs and SCSs versus SCSs alone. On the other hand, the interventions and outcome measures analysed in this scenario, unlike the previous scenarios, take place in the short-term. Information from these studies provides direct evidence to guide the development of protocols for management in the emergency care setting, although it could serve as indirect evidence for other scenarios.There is evidence of low-quality that in patients with persistent asthma that are not under maintenance therapy, the use of ICSs for a week at the onset of exacerbation symptoms reduces the risk of requiring SCSs; this evidence is imprecise and indirect (preschool-age children), so estimates of the effect size based on it would be undependable. There is also evidence of moderate quality that in patients undergoing maintenance therapy with ICSs, increasing the dose to double or even 5-fold when symptoms develop does not reduce the risk of exacerbation requiring SCSs (weak recommendation against treatment). The observed effect may reflect differences in outcomes between patients that receive corticosteroids versus those that do not, without a dose-dependent effect associated to dose increases, but we do not know whether this is a short-term effect or a cumulative effect of repeated doses. On the other hand, we did not find sufficient evidence in support of intermittent ICS therapy as an alternative to maintenance ICS therapy in patients that experience exacerbations. It is worth noting that the 4 RCTs that compared these 2 regimens (2 in school-age children<a class="elsevierStyleCrossRefs" href="#bib0070">14,19</a> and 2 in preschool-age children<a class="elsevierStyleCrossRefs" href="#bib0140">28,29</a>) did not find significant differences, although the direction of effect supported controller ICS therapy.There is low-quality evidence that in paediatric patients aged 12−17 years with persistent asthma, SMART (budesonide/formoterol for maintenance and rescue) compared to ICSs for controller therapy and SABA (terbutaline) for rescue reduces the risk of severe exacerbation, with 7 patients needing treatment to prevent 1 severe exacerbation. There is no evidence of SMART being better compared to ICS-LABA combination for maintenance and a SABA (terbutaline) or formoterol for rescue in this subset of patients. Although the outcomes of SMART in adults support its efficacy, the evidence available for the paediatric age group suggests that in patients receiving combination therapy, the benefits would be much smaller compared to patients receiving ICSs alone for maintenance. It should be taken into account that SMART is contemplated in patients that are already receiving combination therapy for maintenance, and thus the evidence on its efficacy would not apply to patients managed with ICS therapy alone, unless the decision is made to step up the treatment. It is also important to take into account the high cost of combination therapy compared to the use of a SABA for rescue therapy (combination therapy costs between 8 and 40 times the usual cost of SABAs). Therefore, SMART is an option to consider in patients under maintenance therapy with ICS-formoterol (weak recommendation in favour).Last of all, there is evidence of moderate quality that in patients under 18 years that present to the emergency department with asthma exacerbations, the use of ICSs compared to placebo reduce the risk of hospital admission, with 9 patients requiring treatment to prevent 1 hospitalization. In the same scenario, ICSs have not been proven to perform better than SCSs (low-quality evidence), while there is evidence of very low quality suggesting that ICSs combined with SCSs very lightly reduce the risk of admission compared to use of SCSs alone, with 19 patients needing to be treated to avoid 1 hospitalization. It is unclear whether this evidence applies to patients that start to develop features of an exacerbation managed at the primary care level, although this could be an option in patients currently not treated with ICSs and in who SCSs have never been prescribed before, especially if the possibility of continuing treatment with ICSs as controller therapy is being considered (weak recommendation in favour).Interestingly, although we presented the results according to the theoretical risk hierarchy, if we consider the baseline risk of control groups we do not find the expected trend, which may be explained by the fact that the greater the risk, the higher the step of treatment that control groups are receiving.Resolution of the clinical scenarioTaking into account all the available information, we had to revise the action plan for our patient, including a personalised rescue therapy plan that would depend on the controller therapy we decided to recommend. We needed to decide whether the patient required step-up treatment with addition of an antileukotriene, increase of the ICS to a medium dose or a combination of ICS-LABA. While the patient had a recent exacerbation, resorting to a use LABA seemed unwarranted given the concerns that have been raised about the safety of these drugs in children aged less than 12 years. We also decided against adding a leukotriene due to the reports of neuropsychiatric adverse events.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> Therefore, we tried to identify barriers to adherence and develop strategies to overcome them, or, if we concluded that adherence was not the problem, to increase ICS therapy to a medium dose.As for the action plan in case the patient starts to develop symptoms of an exacerbation, there were two possible options: to recommend a SABA as rescue therapy or to use a combination of ICS-SABA or ICS-formoterol. From what we gathered, in patients already receiving ICS for controller therapy, increasing the dose at the onset of symptoms does not seem beneficial, although increasing the dose of ICS-formoterol in patients already using this combination for maintenance therapy, compared to patients that receive ICSs alone for controller therapy and use a SABA for rescue. A factor to consider would be the potential advantages of using a single device, which would facilitate adherence, relative to the disadvantages involved in the stepping up of treatment and its higher cost.After interviewing the child and the family and assessing inhaler use and technique, we did not find any reason to suspect problems with adherence to controller therapy. Therefore, we decided to reinforce the controller treatment by increasing the dose of ICS to a medium dose. We also recommended continuing to use SABA for rescue therapy, scheduling a follow-up visit to reassess (if additional exacerbations or other features suggestive of poor asthma control developed in the interim) the need to step up treatment by adding a leukotriene or switching to a combination of ICS and LABA. If the latter strategy were selected, rescue therapy could consist of the same combination if formoterol had been chosen as the LABA, and otherwise of a SABA.Conflicts of interestThe authors have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1449639" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1321899" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1449638" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1321898" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Clinical scenario" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Literature search and analysis of evidence" "secciones" => array:2 [ 0 => array:3 [ "identificador" => "sec0015" "titulo" => "Focused clinical question (PICO strategy)" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Patient" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Intervention" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Comparison" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Outcome" ] ] ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Literature search" ] ] ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Commentary" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Resolution of the clinical scenario" ] 9 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-05-15" "fechaAceptado" => "2020-06-16" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1321899" "palabras" => array:4 [ 0 => "Asthma" 1 => "Disease progression" 2 => "Inhalation administration" 3 => "Steroids" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1321898" "palabras" => array:4 [ 0 => "Asma" 1 => "Progresión de la enfermedad" 2 => "Administración inhalada" 3 => "Esteroides" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "A clinical scenario is presented, from which a structured clinical question arises: In asthmatic children or adolescents with exacerbation symptoms, does the use of inhaled corticosteroids (newly instituted or base dose increased) reduce the risk of exacerbations that require systemic steroids and/or hospitalization? To answer it, we carried out a bibliographic search, with selection, evaluation and graduation of the evidence, following GRADE criteria. We did not find sufficient evidence to consider intermittent inhaled steroids as an alternative to maintenance inhaled steroids to avoid exacerbations that require the use of systemic steroids. The use of a combination of inhaled steroids with formoterol, as a rescue treatment at the onset of symptoms, is only effective when used by patients with this maintenance treatment, compared to those who only have inhaled steroids and rescue with beta2-agonists of short action; when patients already take maintenance combined therapy, combined rescue does not reduce the risk. In patients with asthma attacks attended in the emergency department, inhaled steroids compared to placebo reduce the risk of admission, but not when compared to systemic corticosteroids." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Se presenta un escenario clínico, del que surge una pregunta clínica estructurada: ¿En niños o adolescentes asmáticos con síntomas de exacerbación, el uso de corticoides inhalados (de nueva instauración o aumento de dosis habitual) reduce el riesgo de exacerbaciones que requieran corticoides sistémicos y/o ingreso? Para contestarla realizamos una búsqueda bibliográfica, con selección, valoración y jerarquización de la evidencia, siguiendo criterios GRADE. No encontramos evidencia suficiente como para considerar los corticoides inhalados intermitentes una alternativa a los corticoides inhalados de mantenimiento para evitar exacerbaciones que requieran el uso de corticoides sistémicos. El uso de una combinación de corticoides inhalados con formoterol, como tratamiento de rescate al inicio de síntomas, sólo es eficaz cuando la usan los pacientes con dicho tratamiento de base, en comparación con los que sólo tienen corticoides inhalados y hacen rescate con beta2-agonistas de acción corta; cuando los pacientes ya toman tratamiento combinado de base, el rescate combinado no mejora el riesgo. En pacientes con crisis asmáticas atendidas en urgencias, los corticoides inhalados en comparación con placebo reducen el riesgo de ingreso, pero no si se compara con corticoides sistémicos." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Ochoa Sangrador C, Díaz de Atauri AG, Martínez Rubio MV. ¿Son eficaces los corticoides inhalados en las exacerbaciones asmáticas? Evidentia praxis. An Pediatr (Barc). 2021;94:54." ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "The following is Supplementary data to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0070" ] ] ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "CI, confidence interval; NNT, number needed to treat; OR, odds ratio; RCT, randomised controlled trial." "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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Number of studies \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Design \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Limitations</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Number of patients \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Summary of results</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Final quality \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Relevance \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Bias \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Inconsistency \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Indirect relationship \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Imprecision \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Other \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Effect</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Baseline risk \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Relative effect (95% CI) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Absolute effect (95% CI) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Comparison: Inhaled corticosteroids vs placebo at onset of symptoms in preschool-age children</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Primary outcome: exacerbation requiring systemic corticosteroid therapy</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4<a class="elsevierStyleCrossRef" href="#bib0025">5</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">490 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43.4% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OR 0.48 (0.31−0.73) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NNT 7 (5−14) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Relevant \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Comparison: Inhaled corticosteroids vs placebo at onset of symptoms in school-age children</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Primary outcome: exacerbation requiring systemic corticosteroid therapy</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1<a class="elsevierStyleCrossRefs" href="#bib0025">5,19</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">145 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">48.6% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OR 0.57 (0.29−1.12) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Relevant \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Comparison: inhaled corticosteroids, increasing the dose (double) for rescue therapy vs maintaining the current dose in children aged 3−18 years</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Primary outcome: need of systemic corticosteroid therapy</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4<a class="elsevierStyleCrossRefs" href="#bib0040">8,9</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">673 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29.3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OR 1.07 (0.77−1.49) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Moderate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Relevant \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Comparison: SMART (maintenance and rescue therapy with budesonide-formoterol) vs inhaled corticosteroids for maintenance therapy and SABA (terbutaline) for rescue therapy in children aged 12−17 years with persistent asthma</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Primary outcome: severe exacerbation (hospital admission, oral corticosteroids for 3 days, emergency care)</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3<a class="elsevierStyleCrossRef" href="#bib0050">10</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">443 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23.1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OR 0.25 (0.10−0.55) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NNT 7 (5−12) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Relevant \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Comparison: SMART (maintenance and rescue therapy with budesonide-formoterol) vs inhaled corticosteroids-LABA for maintenance therapy and SABA (terbutaline) for rescue therapy in children aged 12−17 years with persistent asthma</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Primary outcome: severe exacerbation (hospital admission, oral corticosteroids for 3 days, emergency care)</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4<a class="elsevierStyleCrossRef" href="#bib0050">10</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1393 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.7% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OR 0.60 (0.29−1.17) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Relevant \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Comparison: SMART (controller and rescue therapy with budesonide/formoterol) vs controller therapy with inhaled corticosteroids/LABA + rescue therapy with formoterol in children aged 12−17 years with persistent asthma</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Primary outcome: severe exacerbation (hospital admission, oral corticosteroids for 3 days, emergency care)</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1<a class="elsevierStyleCrossRef" href="#bib0050">10</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">229 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12.1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OR 0.60 (0.29−1.17) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Very low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Relevant \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Comparison: Inhaled corticosteroids vs placebo in children aged <18 years with asthma exacerbations managed in emergency department</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Primary outcome: hospital admission</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3<a class="elsevierStyleCrossRef" href="#bib0030">6</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ 1<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">240 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15.2% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OR 0.19 (0.06−0.61) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NNT 9 (8−19) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Moderate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Relevant \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Comparison: Inhaled vs systemic corticosteroids in children aged <18 years with asthma exacerbations managed in emergency department</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Primary outcome: hospital admission</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6<a class="elsevierStyleCrossRef" href="#bib0030">6</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">498 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25.5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OR 0.69 (0.42−1.12) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Relevant \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Comparison: Inhaled and systemic corticosteroids vs systemic corticosteroids alone in children aged <18 years with asthma exacerbations managed in emergency department</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Primary outcome: hospital admission</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4<a class="elsevierStyleCrossRef" href="#bib0030">6</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1229 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28.2% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OR 0.75 (0.57−0.99) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NNT 19 (11−493) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Very low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Relevant \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2493071.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Effect size." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Publication bias." ] ] ] "descripcion" => array:1 [ "en" => "Grading of Recommendations, Assessment, Development and Evaluation (GRADE); Evaluated intervention: inhaled corticosteroid at onset of exacerbation symptoms (rescue therapy) or in asthma exacerbations diagnosed in the emergency department/outpatient setting (detailed information provided in the Supplemental material)." ] ] 1 => array:5 [ "identificador" => "upi0005" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc1.pdf" "ficheroTamanyo" => 821391 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:30 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Global Strategy for Asthma Management and Prevention" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Global Initiative for Asthma" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "WWW" => array:2 [ "link" => "www.ginasthma.org" "fecha" => "2019" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "SIGN158: British guideline on the management of asthma. Scottish Intercollegiate Guidelines Network" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "SIGN Guideline Development Group" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "WWW" => array:2 [ "link" => "https://www.research.manchester.ac.uk/portal/files/118099257/sign158.pdf" "fecha" => "2019" ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "GEMA 5.0. Guía Española para el Manejo del Asma. Available from: <a target="_blank" href="https://drive.google.com/file/d/18xQTM3k4H-ioIBccstfPExY8gXuFXQtf/view">https://drive.google.com/file/d/18xQTM3k4H-ioIBccstfPExY8gXuFXQtf/view</a>." ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "La formulación de recomendaciones en salud: el sistema GRADE" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "P. Alonso-Coello" 1 => "D. Rigau" 2 => "I. Sola" 3 => "L. Martinez Garcia" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Med Clin (Barc)" "fecha" => "2013" "volumen" => "140" "paginaInicial" => "366" "paginaFinal" => "373" ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Intermittent inhaled corticosteroid therapy versus placebo for persistent asthma in children and adults" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "J. Chong" 1 => "C. Haran" 2 => "B.F. Chauhan" 3 => "I. Asher" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/14651858.CD011032.pub2" "Revista" => array:2 [ "tituloSerie" => "Cochrane Database Syst Rev" "fecha" => "2015" ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inhaled corticosteroids in acute asthma: a systemic review and meta-analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "N. Kearns" 1 => "I. Maijers" 2 => "J. Harper" 3 => "R. Beasley" 4 => "M. Weatherall" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Allergy Clin Immunol" "fecha" => "2020" "volumen" => "8" "paginaInicial" => "605" "paginaFinal" => "617" ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association of inhaled corticosteroids and long-acting $beta$-agonists as controller and quick relief therapy with exacerbations and symptom control in persistent asthma a systematic review and meta-analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.M. Sobieraj" 1 => "E.R. Weeda" 2 => "E. Nguyen" 3 => "C.I. Coleman" 4 => "C.M. White" 5 => "S.C. 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Are inhaled corticosteroids effective in asthma exacerbations? Evidentia praxis

¿Son eficaces los corticoides inhalados en las exacerbaciones asmáticas? Evidentia praxis

Carlos Ochoa Sangradora,b,

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cochoas2@gmail.com

Corresponding author.

, Álvaro Gimeno Díaz de Ataurib,c, María Victoria Martínez Rubiob,d

a Servicio de Pediatría, Hospital Virgen de la Concha, Zamora, Spain

b Comité de Pediatría Basada en la Evidencia de la Asociación Española de Pediatría y de la Asociación Española de Pediatría de Atención Primaria, Madrid, Spain

c Servicio de Pediatría, Hospital 12 de Octubre, Madrid, Spain

d Centro de Salud Los Fresnos, Torrejón de Ardoz, Madrid, Spain

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            "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Routine immunisation schedule of the Spanish Association of Pediatrics 2021&#46;</p> <p id="spar1080" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">&#40;1&#41; Hepatitis B vaccine &#40;HB&#41;</span>&#46; &#8211; Doses of hexavalent vaccine at ages 2&#44; 4 and 11 months&#46; Children of HBsAg-positive mothers or mothers of unknown serologic status will also be given one dose of monovalent HB vaccine at birth&#44; in addition to 0&#46;5<span class="elsevierStyleHsp" style=""></span>mL of hepatitis B immune globulin &#40;HBIG&#41; if maternal HBsAg-positive status is confirmed&#46; Infants vaccinated at birth will adhere to the routine schedule for year 1 of life&#44; and thus will receive 4 doses of HB vaccine&#46; Unvaccinated children and adolescents should be given 3 doses of monovalent vaccine on a 0&#44; 1 and 6-month schedule&#46;</p> <p id="spar2080" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">&#40;2&#41; Diphtheria&#44; tetanus and acellular pertussis vaccine &#40;DTaP&#47;Tdap&#41;</span>&#46; &#8211; 5 doses&#58; primary vaccination with 2 doses&#44; at 2 and 4 months&#44; of DTaP &#40;hexavalent&#41; vaccine&#59; booster at 11 months &#40;third dose&#41; with DTaP &#40;hexavalent&#41; vaccine&#59; at 6 years &#40;fourth dose&#41; with the standard load vaccine &#40;DTaP-IPV&#41;&#44; preferable to the low diphtheria and pertussis antigen load vaccine &#40;Tdap-IPV&#41;&#44; and at 12&#8211;14 years &#40;fifth dose&#41; with Tdap&#46;</p> <p id="spar3080" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">&#40;3&#41; Inactivated poliovirus vaccine &#40;IPV&#41;</span>&#46; &#8211; 4 doses&#58; primary vaccination with 2 doses&#44; at 2 and 4 months&#44; and booster doses at 11 months &#40;with hexavalent&#41; and 6 years &#40;with DTaP-IPV or Tdap-IPV&#41;&#46;</p> <p id="spar4080" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">&#40;4&#41; <span class="elsevierStyleItalic">Haemophilus influenzae</span> type b conjugate vaccine &#40;Hib&#41;</span>&#46; &#8211; 3 doses&#58; primary vaccination at 2 and 4 months and booster dose at 11 months &#40;with hexavalent&#41;&#46;</p> <p id="spar5080" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">&#40;5&#41; Pneumococcal conjugate vaccine &#40;PCV&#41;</span>&#46; &#8211; 3 doses&#58; the first two at 2 and 4 months&#44; with a booster dose starting at 11 months of age&#46; The vaccine recommended in Spain by the CAV-AEP continues to be the PCV13&#46;</p> <p id="spar6080" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">&#40;6&#41; Rotavirus vaccine &#40;RV&#41;</span>&#46; &#8211; 2 or 3 doses of rotavirus vaccine&#58; at 2 and 3&#8211;4 months with the monovalent vaccine or at 2&#44; 3 and 4 months or 2&#44; 4 and 5&#8211;6 months with the pentavalent vaccine&#46; It is very important to start vaccination between 6 and 12 weeks of life in order to minimise risks&#44; and to complete it before 24 weeks for the monovalent vaccine or 32 weeks for the pentavalent vaccine&#46; Doses must be given at least 4 weeks apart&#46; Both vaccines may be given at the same time as any other vaccine&#46;</p> <p id="spar7080" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">&#40;7&#41; Meningococcal B vaccine &#40;MenB&#41;</span>&#46; &#8211; 4CMenB&#46; 3 doses&#58; start at age 2 months&#44; with a primary series of 2 doses at least 2 months apart and a booster starting at age 12 months and at least 6 months after the last dose in the primary series&#46; It can be administered at the same time as other vaccines in the schedule&#44; although this could increase fever&#44; so another option is to administer it 1 or 2 weeks apart from other injectable inactivated vaccines&#44; up to age 12 months&#44; to minimise potential reactogenicity&#46; The separation by 1&#8211;2 weeks is not necessary for the MenACWY&#44; MMR&#44; varicella and rotavirus vaccines&#46; Vaccination is also recommended at any age in risk groups&#58; anatomic or functional asplenia&#44; complement component deficiency&#44; treatment with eculizumab or ravulizumab&#44; haematopoietic stem cell transplant recipients&#44; infection by HIV&#44; prior episode of IMD caused by any serogroup&#44; and contacts of an index case of IMD caused by serogroup B in the context of an outbreak&#46;</p> <p id="spar8080" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">&#40;8&#41; Meningococcal C conjugate vaccine &#40;MenC&#41; and meningococcal ACWY conjugate vaccine &#40;MenACWY&#41;</span>&#46; &#8211; 1 dose of conjugate MenC-TT at age 4 months&#46; The CAV-AEP recommends 1 dose of the MenACWY conjugate vaccine at age 12 months and 12&#8211;14 years&#44; and a progressive catch-up vaccination schedule to be completed by age 18 years&#46; In ACs where vaccination with MenACWY is not included in the routine schedule&#44; if parents choose not to administer the MenACWY vaccine at 12 months&#44; the MenC-TT vaccine funded by the regional government must be administered instead&#46; Administration of the MenACWY vaccine is still particularly recommended in children and adolescents that are to live in countries where the vaccine is administered at this age &#40;United States&#44; Canada&#44; Argentina&#44; United Kingdom&#44; Austria&#44; Greece&#44; Netherlands&#44; Italy and Switzerland&#41; and for children with risk factors for IMD&#58; anatomic or functional asplenia&#44; complement component deficiency&#44; treatment with eculizumab or ravulizumab&#44; hematopoietic stem cell transplant recipients&#44; HIV infection&#44; prior episode of IMD caused by any serogroup&#44; and contacts of an index case of IMD caused by serogroup A&#44; C&#44; W or Y in the context of an outbreak&#46; Individuals traveling to Mecca for religious reasons and to the African meningitis belt during the dry season should also receive the MenACWY vaccine&#46;</p> <p id="spar9080" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">&#40;9&#41; Measles&#44; mumps and rubella vaccine &#40;MMR&#41;</span>&#46; &#8211; 2 MMR vaccine&#46; The first at age 12 months and the second at age 3&#8211;4 years&#46; The tetravalent MMRV vaccine may be administered for the second dose&#46; Susceptible patients outside the specified ages will be vaccinated with 2 doses of MMR at least 1 month apart&#46;</p> <p id="spar9980" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">&#40;10&#41; Varicella vaccine &#40;Var&#41;</span>&#46; &#8211; 2 doses&#58; the first at age 15 months &#40;age 12 months is also acceptable&#41; and the second at age 3&#8211;4 years&#46; The tetravalent vaccine &#40;MMRV&#41; may be used for the second dose&#46; Susceptible patients outside the specified ages will be vaccinated with 2 doses of monovalent Var vaccine at least 1 month apart&#46;</p> <p id="spar1180" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">&#40;11&#41; Human papillomavirus vaccine &#40;HPV&#41;</span>&#46; &#8211; Universal routine vaccination of all girls and boys&#44; at age 12 years&#44; to prevent HPV-related oncological diseases&#46; All 3 HPV vaccines are authorised for use in male individuals&#44; although there is little evidence on the use of the HPV2 vaccine in this sex&#46; Administration of 2 doses at age 12 years&#46; The vaccination schedule depends on the vaccine used&#58; for the tetravalent vaccine&#44; a 2-dose series &#40;at 0 and 6 months&#41; between ages 9 and 13 years and a 3-dose series &#40;at 0&#44; 2 and 6 months&#41; in those aged &#8805;14 years&#59; for the 2-valent and 9-valent vaccines&#44; a 2-dose series &#40;at 0 and 6 months&#41; between ages 9 and 14 years and a 3-dose series &#40;at 0&#44; 1&#8211;2 &#91;depending on the vaccine used&#93; and 6 months&#41; in those aged &#8805;15 years&#46; The HPV vaccine may be administered at the same time as the MenC&#44; MenACWY&#44; hepatitis A and B and Tdap vaccines&#46; There are no data on its coadministration with the varicella vaccine&#44; 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in the presence of symptoms indicative of worsening asthma&#44; increasing the ICS dose to 4 times the usual is effective&#44; but that in children with good adherence to treatment&#44; increasing the dose to 5 times the usual is not&#46; You have also read that in patients in maintenance treatment with ICS-formoterol&#44; the GINA recommends increasing the dose as needed to up to a maximum of 72&#8239;&#956;g&#47;day of formoterol &#40;single maintenance and reliever therapy &#91;SMART&#93;&#41;&#46; It also recommends as-needed combination ICS-formoterol therapy in patients with very sporadic symptoms of asthma without maintenance therapy with ICSs and&#47;or before physical activity in patients with exercise-induced bronchoconstriction&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The GINA advises including these recommendations in the asthma action plan provided to the patients&#47;family&#46; You also see that for the management of asthmatic exacerbations in children aged more than 5 years at the primary care or emergency care levels&#44; the GINA recommends use of short-acting beta<span class="elsevierStyleInf">2</span> agonists &#40;SABAs&#41; and systemic corticosteroids &#40;SCSs&#41;&#44; although in patients that do not receive SCSs&#44; high-dose ICSs could be effective&#46; However&#44; neither the updated GINA strategy of 2019<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> nor the 2020 Spanish guideline &#40;Gu&#237;a Espa&#241;ola para el Manejo del Asma &#91;GEMA&#93;&#41;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> contemplate replacing SCSs by high-dose ICSs during an exacerbation&#44; although they do contemplate maintenance of ongoing high-dose ICS therapy or its initial prescription&#44; especially in exacerbations of moderate severity&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">You decide to revise the action plan for potential future exacerbations&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Literature search and analysis of evidence</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Focused clinical question &#40;PICO strategy&#41;</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Patient</span><p id="par0025" class="elsevierStylePara elsevierViewall">Children&#47;adolescents with asthma &#40;age 3&#8722;18 years&#59; excluding studies exclusively on subjects aged &#62;16 years or that do not present separate data for individuals under 18 years&#41;&#44; not receiving controller therapy or in treatment with low&#47;medium-dose ICS&#44; alone or in combination with a long-acting beta<span class="elsevierStyleInf">2</span> agonist &#40;LABA&#41;&#46;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">a&#41;</span><p id="par0030" class="elsevierStylePara elsevierViewall">With symptoms of acute exacerbation at home&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">b&#41;</span><p id="par0035" class="elsevierStylePara elsevierViewall">With exacerbation managed in unscheduled visit or emergency department&#46;</p></li></ul></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Intervention</span><p id="par0040" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">a&#41;</span><p id="par0045" class="elsevierStylePara elsevierViewall">High-dose ICS&#8239;&#43;&#8239;SABA or formoterol as needed&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">b&#41;</span><p id="par0050" class="elsevierStylePara elsevierViewall">Increased dose of ICS&#8239;&#43;&#8239;SABA or formoterol&#46;</p></li></ul></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Comparison</span><p id="par0055" class="elsevierStylePara elsevierViewall">Placebo&#8239;&#43;&#8239;SABA or formoterol as needed&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Outcome</span><p id="par0060" class="elsevierStylePara elsevierViewall">Asthma exacerbation requiring SCS therapy and&#47;or hospital admission&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Question&#58; in children or adolescents with asthma that exhibit features of exacerbation&#44; does the use of inhaled corticosteroids &#40;newly prescribed&#44; or with an increased dose&#41; reduce the risk of exacerbations requiring systemic corticosteroid therapy and&#47;or hospital admission&#63;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Literature search</span><p id="par0070" class="elsevierStylePara elsevierViewall">We did a literature search for randomised controlled trials &#40;RCTs&#41; and systematic reviews &#40;SRs&#41; in MEDLINE &#40;PubMed&#41;&#44; EMBASE&#44; Web of Science &#40;WoS&#41;&#44; CENTRAL and CINAHL on February 25&#44; 2020&#44; without any date or language restrictions&#46; The initial selection of articles was made by reading the abstracts&#44; with 2 reviewers each reading all abstracts and a third reviewer resolving any disagreement between them regarding the articles to be selected&#46; After this initial selection&#44; 2 reviewers read the full text of each of these articles to decide whether they would be included in the systematic review&#46; We completed the search by reviewing the bibliography of the articles in the final selection&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">The search strategy used in PubMed was&#58; &#40;&#171;Asthma&#187; &#91;MeSH&#93; OR &#171;Respiratory Sounds&#187; &#91;MeSH&#93; OR &#171;Bronchial Spasm&#187; &#91;MeSH&#93; OR &#171;Bronchoconstriction&#187; &#91;MeSH&#93;&#41; AND &#40;&#171;Disease Progression&#187; &#91;MeSH&#93; OR &#171;Exacerbation&#187; OR &#171;acute&#187; OR &#171;attack&#187; OR &#171;Reliever therapy&#187;&#41; AND &#40;&#171;Administration&#44; Inhalation&#187; &#91;Mesh&#93; OR &#171;Inhalation&#187; OR &#171;Inhaled&#187; OR &#171;nebulized&#187; OR &#171;SMART&#187; OR &#171;Single inhaler&#187; OR &#171;reliever therapy&#187;&#41; AND &#40;&#171;Steroids&#187;&#91; MeSH&#93; OR &#171;Steroids&#187; OR &#171;Corticosteroids&#187; OR &#171;formoterol&#187;&#41; AND &#40;&#171;child&#187; &#91;MeSH Terms&#93; OR &#171;child&#187; OR &#171;children&#187; OR &#171;adolescent&#187; &#91;MeSH Terms&#93; OR &#171;adolescent&#187;&#41; AND &#40;systematic&#91;sb&#93; OR Clinical Trial &#91;ptyp&#93;&#41;&#46; For the other databases&#44; we used an adaptation of this strategy &#40;Appendix B of Supplemental material&#41;&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">We assessed the quality of the evidence using the Grading of Recommendations&#44; Assessment&#44; Development and Evaluations &#40;GRADE&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> the risk of bias in RCTs with the Risk of Bias &#40;RoB&#41; tool of the Cochrane Collaboration&#44; the consistency of the results&#44; the direct relationship with the clinical scenario&#44; the precision&#44; the effect size&#44; the dose-response relationship&#44; publication bias&#44; the control of confounding factors&#44; the importance of the endpoint and the cost-benefit ratio&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">We made tables summarizing the evidence obtained from the data retrieved from the reviewed studies&#46; In the case of SRs that did not include separate analyses for the paediatric population&#44; we estimated composite effect sizes&#44; comparing 2 interventions by means of the systematic review software of the Cochrane Collaboration &#40;Review Manager 5&#46;3&#41; and more than 2 interventions with the Excel-based Bayesian network meta-analysis macro NetMetaXL and WinBUGS 1&#46;4&#46;3&#46; We used random effects models for paired meta-analysis and Bayesian inference with weakly informative priors&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Results</span><p id="par0090" class="elsevierStylePara elsevierViewall">The searches yielded 627 references&#44; excluding duplicates&#44; out of which we selected 50 for reading of the full text&#44; to which we added another 5 identified through the review of the references of those 50&#46; The final qualitative review included 22 articles &#40;Appendix B of Supplemental material&#41;&#46; Table S1 &#40;Appendix B of Supplemental material&#41; summarises the characteristics and results of 5 systematic reviews<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#8211;9</span></a> and one meta-analysis of the paediatric studies included in one of those reviews&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> We did not summarise the findings of one narrative review<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> and one systematic review<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> because they included RCTs that we had already evaluated separately or that were included in other reviews&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Table S2 &#40;Appendix B of Supplemental material&#41; summarises the characteristics and results of the 16 RCTs<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#8211;28</span></a> with information that supplemented the information obtained from SRs&#44; either because the trial was not included in the reviews or because it provided data for specific paediatric age subgroups that was not included in the review&#46; For 2 RCTs&#44; we analysed the data but did not take them into account because the controls were assigned to controller therapy with ICSs as an alternative to rescue therapy with ICSs<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;28</span></a>&#59; 2 RCTs included in the SRs made the same comparison&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#44;29</span></a> Another 5 RCTs could not be included in the composite analysis of SRs because they did not analyse the primary outcomes analysed in the reviews&#44;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;18&#44;26</span></a> because the sample consisted of hospitalised preschool-age children<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> or because they had a cross-sectional design<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a>&#59; the direction of effect in these studies&#44; however&#44; was consistent with the findings of the SR&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> presents evaluation of the quality of analysed evidence using the GRADE classification&#46; Figs&#46; S1&#8211;S5 and Tables S3 and S4 in Appendix B &#40;Supplemental material&#41; present the meta-analyses performed by our group to complete the overall analysis&#44; which included 13 RCTs&#44; the results of which are summarised in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Commentary</span><p id="par0105" class="elsevierStylePara elsevierViewall">Most reviews analyse the efficacy of ICSs&#44; as newly prescribed treatment or in increased doses relative to the onset of exacerbation features&#44; compared to placebo or to maintenance of the baseline dose of ICS&#46; Two analysed the SMART approach compared to controller ICS therapy&#44; alone or combined with a LABA&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;10</span></a> One review analysed the efficacy of ICS as reliever medication in asthma exacerbations diagnosed at the emergency department<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> compared to placebo or systemic steroid therapy&#46; In studies in which bronchodilators were not part of the intervention&#44; all patients could receive SABA as needed&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">The primary endpoints were usually exacerbation&#44; defined as the need of treatment with SCSs and&#44; in some studies&#44; the need for emergency care or hospital admission&#46; In analyses of the management of asthma exacerbations in the emergency setting&#44; the primary endpoint was the need for hospital admission&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> presents evaluation of the quality of analysed evidence using the GRADE classification&#46; It details the comparisons made in the studies and the outcome measures&#46; All these measures were considered &#8220;relevant&#8221; from a clinical perspective&#44; but not of critical importance&#46; We found that the quality of the evidence was low or very low&#44; save for the evidence on the comparison of ICSs versus placebo for management of asthma exacerbations in the emergency care setting and the comparison of increased-dose ICS therapy compared to maintaining the current dose of controller ICS therapy at the onset of symptoms&#44; which was considered of moderate quality&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">We could establish a theoretical hierarchy of clinical scenarios based on the baseline risk&#46; The lowest risk would correspond to patients not taking controller treatment that start to develop symptoms&#44; in which case we would want to know whether ICS therapy would be effective in an exacerbation&#46; The next level would correspond to patients receiving ICSs for maintenance therapy&#44; in who we would consider whether or not to increase the dose at the beginning of an exacerbation&#46; The highest level would correspond to patients receiving an ICS-LABA combination for maintenance therapy&#44; in who we would consider whether to keep using this combination or use a SABA for rescue therapy&#46; We investigated the recommendations that would apply to these 3 scenarios to include them in the asthma action plan provided to parents&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Another scenario that we could not include in this theoretical hierarchy was the treatment of asthma exacerbations in the emergency department&#46; Simply put&#44; these patients have already reached the outcome that interventions in the previous scenarios attempt to prevent&#44; regardless of the fact that their baseline risk was not the same&#46; In this subset of patients&#44; we could establish a particular risk hierarchy based on the compared treatments&#44; from lower to higher steps of treatment&#44; in increasing order&#44; ICSs versus placebo&#44; ICSs versus SCSs and&#44; lastly&#44; ICSs and SCSs versus SCSs alone&#46; On the other hand&#44; the interventions and outcome measures analysed in this scenario&#44; unlike the previous scenarios&#44; take place in the short-term&#46; Information from these studies provides direct evidence to guide the development of protocols for management in the emergency care setting&#44; although it could serve as indirect evidence for other scenarios&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">There is evidence of low-quality that in patients with persistent asthma that are not under maintenance therapy&#44; the use of ICSs for a week at the onset of exacerbation symptoms reduces the risk of requiring SCSs&#59; this evidence is imprecise and indirect &#40;preschool-age children&#41;&#44; so estimates of the effect size based on it would be undependable&#46; There is also evidence of moderate quality that in patients undergoing maintenance therapy with ICSs&#44; increasing the dose to double or even 5-fold when symptoms develop does not reduce the risk of exacerbation requiring SCSs &#40;weak recommendation against treatment&#41;&#46; The observed effect may reflect differences in outcomes between patients that receive corticosteroids versus those that do not&#44; without a dose-dependent effect associated to dose increases&#44; but we do not know whether this is a short-term effect or a cumulative effect of repeated doses&#46; On the other hand&#44; we did not find sufficient evidence in support of intermittent ICS therapy as an alternative to maintenance ICS therapy in patients that experience exacerbations&#46; It is worth noting that the 4 RCTs that compared these 2 regimens &#40;2 in school-age children<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;19</span></a> and 2 in preschool-age children<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;29</span></a>&#41; did not find significant differences&#44; although the direction of effect supported controller ICS therapy&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">There is low-quality evidence that in paediatric patients aged 12&#8722;17 years with persistent asthma&#44; SMART &#40;budesonide&#47;formoterol for maintenance and rescue&#41; compared to ICSs for controller therapy and SABA &#40;terbutaline&#41; for rescue reduces the risk of severe exacerbation&#44; with 7 patients needing treatment to prevent 1 severe exacerbation&#46; There is no evidence of SMART being better compared to ICS-LABA combination for maintenance and a SABA &#40;terbutaline&#41; or formoterol for rescue in this subset of patients&#46; Although the outcomes of SMART in adults support its efficacy&#44; the evidence available for the paediatric age group suggests that in patients receiving combination therapy&#44; the benefits would be much smaller compared to patients receiving ICSs alone for maintenance&#46; It should be taken into account that SMART is contemplated in patients that are already receiving combination therapy for maintenance&#44; and thus the evidence on its efficacy would not apply to patients managed with ICS therapy alone&#44; unless the decision is made to step up the treatment&#46; It is also important to take into account the high cost of combination therapy compared to the use of a SABA for rescue therapy &#40;combination therapy costs between 8 and 40 times the usual cost of SABAs&#41;&#46; Therefore&#44; SMART is an option to consider in patients under maintenance therapy with ICS-formoterol &#40;weak recommendation in favour&#41;&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Last of all&#44; there is evidence of moderate quality that in patients under 18 years that present to the emergency department with asthma exacerbations&#44; the use of ICSs compared to placebo reduce the risk of hospital admission&#44; with 9 patients requiring treatment to prevent 1 hospitalization&#46; In the same scenario&#44; ICSs have not been proven to perform better than SCSs &#40;low-quality evidence&#41;&#44; while there is evidence of very low quality suggesting that ICSs combined with SCSs very lightly reduce the risk of admission compared to use of SCSs alone&#44; with 19 patients needing to be treated to avoid 1 hospitalization&#46; It is unclear whether this evidence applies to patients that start to develop features of an exacerbation managed at the primary care level&#44; although this could be an option in patients currently not treated with ICSs and in who SCSs have never been prescribed before&#44; especially if the possibility of continuing treatment with ICSs as controller therapy is being considered &#40;weak recommendation in favour&#41;&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Interestingly&#44; although we presented the results according to the theoretical risk hierarchy&#44; if we consider the baseline risk of control groups we do not find the expected trend&#44; which may be explained by the fact that the greater the risk&#44; the higher the step of treatment that control groups are receiving&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Resolution of the clinical scenario</span><p id="par0150" class="elsevierStylePara elsevierViewall">Taking into account all the available information&#44; we had to revise the action plan for our patient&#44; including a personalised rescue therapy plan that would depend on the controller therapy we decided to recommend&#46; We needed to decide whether the patient required step-up treatment with addition of an antileukotriene&#44; increase of the ICS to a medium dose or a combination of ICS-LABA&#46; While the patient had a recent exacerbation&#44; resorting to a use LABA seemed unwarranted given the concerns that have been raised about the safety of these drugs in children aged less than 12 years&#46; We also decided against adding a leukotriene due to the reports of neuropsychiatric adverse events&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> Therefore&#44; we tried to identify barriers to adherence and develop strategies to overcome them&#44; or&#44; if we concluded that adherence was not the problem&#44; to increase ICS therapy to a medium dose&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">As for the action plan in case the patient starts to develop symptoms of an exacerbation&#44; there were two possible options&#58; to recommend a SABA as rescue therapy or to use a combination of ICS-SABA or ICS-formoterol&#46; From what we gathered&#44; in patients already receiving ICS for controller therapy&#44; increasing the dose at the onset of symptoms does not seem beneficial&#44; although increasing the dose of ICS-formoterol in patients already using this combination for maintenance therapy&#44; compared to patients that receive ICSs alone for controller therapy and use a SABA for rescue&#46; A factor to consider would be the potential advantages of using a single device&#44; which would facilitate adherence&#44; relative to the disadvantages involved in the stepping up of treatment and its higher cost&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">After interviewing the child and the family and assessing inhaler use and technique&#44; we did not find any reason to suspect problems with adherence to controller therapy&#46; Therefore&#44; we decided to reinforce the controller treatment by increasing the dose of ICS to a medium dose&#46; We also recommended continuing to use SABA for rescue therapy&#44; scheduling a follow-up visit to reassess &#40;if additional exacerbations or other features suggestive of poor asthma control developed in the interim&#41; the need to step up treatment by adding a leukotriene or switching to a combination of ICS and LABA&#46; If the latter strategy were selected&#44; rescue therapy could consist of the same combination if formoterol had been chosen as the LABA&#44; and otherwise of a SABA&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conflicts of interest</span><p id="par0165" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A clinical scenario is presented&#44; from which a structured clinical question arises&#58; In asthmatic children or adolescents with exacerbation symptoms&#44; does the use of inhaled corticosteroids &#40;newly instituted or base dose increased&#41; reduce the risk of exacerbations that require systemic steroids and&#47;or hospitalization&#63; To answer it&#44; we carried out a bibliographic search&#44; with selection&#44; evaluation and graduation of the evidence&#44; following GRADE criteria&#46; We did not find sufficient evidence to consider intermittent inhaled steroids as an alternative to maintenance inhaled steroids to avoid exacerbations that require the use of systemic steroids&#46; The use of a combination of inhaled steroids with formoterol&#44; as a rescue treatment at the onset of symptoms&#44; is only effective when used by patients with this maintenance treatment&#44; compared to those who only have inhaled steroids and rescue with beta2-agonists of short action&#59; when patients already take maintenance combined therapy&#44; combined rescue does not reduce the risk&#46; In patients with asthma attacks attended in the emergency department&#44; inhaled steroids compared to placebo reduce the risk of admission&#44; but not when compared to systemic corticosteroids&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Se presenta un escenario cl&#237;nico&#44; del que surge una pregunta cl&#237;nica estructurada&#58; &#191;En ni&#241;os o adolescentes asm&#225;ticos con s&#237;ntomas de exacerbaci&#243;n&#44; el uso de corticoides inhalados &#40;de nueva instauraci&#243;n o aumento de dosis habitual&#41; reduce el riesgo de exacerbaciones que requieran corticoides sist&#233;micos y&#47;o ingreso&#63; Para contestarla realizamos una b&#250;squeda bibliogr&#225;fica&#44; con selecci&#243;n&#44; valoraci&#243;n y jerarquizaci&#243;n de la evidencia&#44; siguiendo criterios GRADE&#46; No encontramos evidencia suficiente como para considerar los corticoides inhalados intermitentes una alternativa a los corticoides inhalados de mantenimiento para evitar exacerbaciones que requieran el uso de corticoides sist&#233;micos&#46; El uso de una combinaci&#243;n de corticoides inhalados con formoterol&#44; como tratamiento de rescate al inicio de s&#237;ntomas&#44; s&#243;lo es eficaz cuando la usan los pacientes con dicho tratamiento de base&#44; en comparaci&#243;n con los que s&#243;lo tienen corticoides inhalados y hacen rescate con beta2-agonistas de acci&#243;n corta&#59; cuando los pacientes ya toman tratamiento combinado de base&#44; el rescate combinado no mejora el riesgo&#46; En pacientes con crisis asm&#225;ticas atendidas en urgencias&#44; los corticoides inhalados en comparaci&#243;n con placebo reducen el riesgo de ingreso&#44; pero no si se compara con corticoides sist&#233;micos&#46;</p></span>"
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as&#58; Ochoa Sangrador C&#44; D&#237;az de Atauri AG&#44; Mart&#237;nez Rubio MV&#46; &#191;Son eficaces los corticoides inhalados en las exacerbaciones asm&#225;ticas&#63; Evidentia praxis&#46; An Pediatr &#40;Barc&#41;&#46; 2021&#59;94&#58;54&#46;</p>"
      ]
    ]
    "apendice" => array:1 [
      0 => array:1 [
        "seccion" => array:1 [
          0 => array:4 [
            "apendice" => "<p id="par0175" class="elsevierStylePara elsevierViewall">The following is Supplementary data to this article&#58;<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
            "identificador" => "sec0070"
          ]
        ]
      ]
    ]
    "multimedia" => array:2 [
      0 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0005"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">CI&#44; confidence interval&#59; NNT&#44; number needed to treat&#59; OR&#44; odds ratio&#59; RCT&#44; randomised controlled trial&#46;</p>"
          "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="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Number of studies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Design&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Limitations</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Number of patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Summary of results</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Final quality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Relevance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Bias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Inconsistency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Indirect relationship&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Imprecision&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Other&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Effect</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Baseline risk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Relative effect &#40;95&#37; CI&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Absolute effect &#40;95&#37; CI&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Comparison&#58; Inhaled corticosteroids vs placebo at onset of symptoms in preschool-age children</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Primary outcome&#58; exacerbation requiring systemic corticosteroid therapy</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">490&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43&#46;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">OR 0&#46;48 &#40;0&#46;31&#8722;0&#46;73&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NNT 7 &#40;5&#8722;14&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Relevant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Comparison&#58; Inhaled corticosteroids vs placebo at onset of symptoms in school-age children</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Primary outcome&#58; exacerbation requiring systemic corticosteroid therapy</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;19</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">145&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&#46;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">OR 0&#46;57 &#40;0&#46;29&#8722;1&#46;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Relevant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Comparison&#58; inhaled corticosteroids&#44; increasing the dose &#40;double&#41; for rescue therapy vs maintaining the current dose in children aged 3&#8722;18 years</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Primary outcome&#58; need of systemic corticosteroid therapy</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">673&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29&#46;3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">OR 1&#46;07 &#40;0&#46;77&#8722;1&#46;49&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Moderate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Relevant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Comparison&#58; SMART &#40;maintenance and rescue therapy with budesonide-formoterol&#41; vs inhaled corticosteroids for maintenance therapy and SABA &#40;terbutaline&#41; for rescue therapy in children aged 12&#8722;17 years with persistent asthma</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Primary outcome&#58; severe exacerbation &#40;hospital admission&#44; oral corticosteroids for 3 days&#44; emergency care&#41;</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">443&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23&#46;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">OR 0&#46;25 &#40;0&#46;10&#8722;0&#46;55&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NNT 7 &#40;5&#8722;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Relevant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Comparison&#58; SMART &#40;maintenance and rescue therapy with budesonide-formoterol&#41; vs inhaled corticosteroids-LABA for maintenance therapy and SABA &#40;terbutaline&#41; for rescue therapy in children aged 12&#8722;17 years with persistent asthma</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Primary outcome&#58; severe exacerbation &#40;hospital admission&#44; oral corticosteroids for 3 days&#44; emergency care&#41;</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1393&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">OR 0&#46;60 &#40;0&#46;29&#8722;1&#46;17&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Relevant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Comparison&#58; SMART &#40;controller and rescue therapy with budesonide&#47;formoterol&#41; vs controller therapy with inhaled corticosteroids&#47;LABA&#8239;&#43;&#8239;rescue therapy with formoterol in children aged 12&#8722;17 years with persistent asthma</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Primary outcome&#58; severe exacerbation &#40;hospital admission&#44; oral corticosteroids for 3 days&#44; emergency care&#41;</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">229&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&#46;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">OR 0&#46;60 &#40;0&#46;29&#8722;1&#46;17&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Very low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Relevant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Comparison&#58; Inhaled corticosteroids vs placebo in children aged &#60;18 years with asthma exacerbations managed in emergency department</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="13" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Primary outcome&#58; hospital admission</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43; 1<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">240&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#46;2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">OR 0&#46;19 &#40;0&#46;06&#8722;0&#46;61&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NNT 9 &#40;8&#8722;19&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Moderate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Relevant&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Comparison&#58; Inhaled vs systemic corticosteroids in children aged &#60;18 years with asthma exacerbations managed in emergency department</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">6<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Comparison&#58; Inhaled and systemic corticosteroids vs systemic corticosteroids alone in children aged &#60;18 years with asthma exacerbations managed in emergency department</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                            0 => "B&#46; Benard"
                            1 => "V&#46; Bastien"
                            2 => "B&#46; Vinet"
                            3 => "R&#46; Yang"
                            4 => "M&#46; Krajinovic"
                            5 => "F&#46;M&#46; Ducharme"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1183/13993003.00711-2017"
                      "Revista" => array:4 [
                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "2017"
                        "volumen" => "50"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29025888"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/23412879/0000009400000001/v1_202101160808/S2341287920302167/v1_202101160808/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "44360"
    "tipo" => "SECCION"
    "en" => array:2 [
      "titulo" => "Special Article"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "en"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/23412879/0000009400000001/v1_202101160808/S2341287920302167/v1_202101160808/en/main.pdf?idApp=UINPBA00005H&text.app=https://analesdepediatria.org/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2341287920302167?idApp=UINPBA00005H"
]

Article information

ISSN: 23412879
Original language: English

DOI:10.1016/j.anpede.2020.06.004

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	15	12	27
2024 October	108	61	169
2024 September	77	52	129
2024 August	74	74	148
2024 July	123	30	153
2024 June	112	48	160
2024 May	92	32	124
2024 April	75	48	123
2024 March	72	26	98
2024 February	52	26	78
2024 January	64	24	88
2023 December	89	26	115
2023 November	99	60	159
2023 October	135	34	169
2023 September	97	32	129
2023 August	83	25	108
2023 July	87	36	123
2023 June	88	36	124
2023 May	85	35	120
2023 April	72	21	93
2023 March	140	37	177
2023 February	74	21	95
2023 January	80	21	101
2022 December	141	30	171
2022 November	87	34	121
2022 October	102	61	163
2022 September	73	26	99
2022 August	86	41	127
2022 July	117	54	171
2022 June	60	46	106
2022 May	82	44	126
2022 April	84	43	127
2022 March	100	61	161
2022 February	85	37	122
2022 January	96	53	149
2021 December	93	40	133
2021 November	91	47	138
2021 October	165	72	237
2021 September	90	38	128
2021 August	81	52	133
2021 July	70	38	108
2021 June	95	45	140
2021 May	97	51	148
2021 April	207	103	310
2021 March	119	48	167
2021 February	60	39	99
2021 January	102	31	133
2020 December	52	22	74

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