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      The effects of macrolides in children with reactive airway disease: a systematic review and meta-analysis of randomized controlled trials

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          Childhood reactive airway diseases (RADs) are concerning problems in children’s airways and may be preceded by bronchiolitis and may progress to childhood asthma. The severity of the disease is indicated by deterioration in pulmonary functions, increased usage of rescue medications, and recurrent wheezing episodes. Macrolides have both antimicrobial and anti-inflammatory functions and have been used as adjunctive therapy in childhood RADs.

          Patients and methods

          We conducted a meta-analysis to evaluate the effect of macrolides in children with RAD. Literature searches were systematically conducted using an electronic database from inception to August 2018. The Cochrane review risk of bias assessment tool was used to assess the quality of each randomized controlled trial.


          Sixteen randomized controlled trials comprising 1,415 participants were investigated in this meta-analysis. Children treated with macrolide therapy showed significantly better pulmonary functions in both forced expiratory volume in one second (% predicted) (difference in means=−9.77, 95% CI=−14.18 to −5.35, P<0.001; I 2=0%) and forced expiratory flow 25–75 (% predicted) (difference in means=−14.14, 95% CI=−26.11 to −2.18, P=0.02; I 2=29.56%). In addition, the short-acting β-agonist usage days and recurrent wheezing risk were significantly lowered in children with macrolide treatment (standardized difference in means=−0.34, 95% CI=−0.59 to −0.09, P=0.007, I 2=27.05% and standardized difference in means=−0.53, 95% CI=−0.81 to −0.26, P<0.001, I 2=0%, respectively). Furthermore, the growth of Moraxella catarrhalis from nasal swabs was less in children treated with macrolides (odds ratio=0.19, 95% CI=0.11–0.35, P<0.001). Children who took macrolides had a lower risk of adverse events (risk ratio=0.83, 95% CI=0.70–0.98, P=0.024, I 2=0%).


          This current meta-analysis suggested that adjunctive therapy with macrolides is safe and effective for achieving better outcomes in childhood RAD.

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          Most cited references 64

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          Rhinovirus illnesses during infancy predict subsequent childhood wheezing.

          The contribution of viral respiratory infections during infancy to the development of subsequent wheezing and/or allergic diseases in early childhood is not established. To evaluate these relationships prospectively from birth to 3 years of age in 285 children genetically at high risk for developing allergic respiratory diseases. By using nasal lavage, the relationship of timing, severity, and etiology of viral respiratory infections during infancy to wheezing in the 3rd year of life was evaluated. In addition, genetic and environmental factors that could modify risk of infections and wheezing prevalence were analyzed. Risk factors for 3rd year wheezing were passive smoke exposure (odds ratio [OR]=2.1), older siblings (OR=2.5), allergic sensitization to foods at age 1 year (OR=2.0), any moderate to severe respiratory illness without wheezing during infancy (OR=3.6), and at least 1 wheezing illness with respiratory syncytial virus (RSV; OR=3.0), rhinovirus (OR=10) and/or non-rhinovirus/RSV pathogens (OR=3.9) during infancy. When viral etiology was considered, 1st-year wheezing illnesses caused by rhinovirus infection were the strongest predictor of subsequent 3rd year wheezing (OR=6.6; P < .0001). Moreover, 63% of infants who wheezed during rhinovirus seasons continued to wheeze in the 3rd year of life, compared with only 20% of all other infants (OR=6.6; P < .0001). In this population of children at increased risk of developing allergies and asthma, the most significant risk factor for the development of preschool childhood wheezing is the occurrence of symptomatic rhinovirus illnesses during infancy that are clinically and prognostically informative based on their seasonal nature.
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            Viruses and bacteria in acute asthma exacerbations – A GA 2 LEN‐DARE * systematic review

            To cite this article: Papadopoulos NG, Christodoulou I, Rohde G, Agache I, Almqvist C, Bruno A, Bonini S, Bont L, Bossios A, Bousquet J, Braido F, Brusselle G, Canonica GW, Carlsen KH, Chanez P, Fokkens WJ, Garcia‐Garcia M, Gjomarkaj M, Haahtela T, Holgate ST, Johnston SL, Konstantinou G, Kowalski M, Lewandowska‐Polak A, Lødrup‐Carlsen K, Mäkelä M, Malkusova I, Mullol J, Nieto A, Eller E, Ozdemir C, Panzner P, Popov T, Psarras S, Roumpedaki E, Rukhadze M, Stipic‐Markovic A, Todo Bom A, Toskala E, van Cauwenberge P, van Drunen C, Watelet JB, Xatzipsalti M, Xepapadaki P, Zuberbier T. Viruses and bacteria in acute asthma exacerbations – A GA2LEN‐DARE systematic review. Allergy 2011; 66: 458–468. Abstract A major part of the burden of asthma is caused by acute exacerbations. Exacerbations have been strongly and consistently associated with respiratory infections. Respiratory viruses and bacteria are therefore possible treatment targets. To have a reasonable estimate of the burden of disease induced by such infectious agents on asthmatic patients, it is necessary to understand their nature and be able to identify them in clinical samples by employing accurate and sensitive methodologies. This systematic review summarizes current knowledge and developments in infection epidemiology of acute asthma in children and adults, describing the known impact for each individual agent and highlighting knowledge gaps. Among infectious agents, human rhinoviruses are the most prevalent in regard to asthma exacerbations. The newly identified type‐C rhinoviruses may prove to be particularly relevant. Respiratory syncytial virus and metapneumovirus are important in infants, while influenza viruses seem to induce severe exacerbations mostly in adults. Other agents are relatively less or not clearly associated. Mycoplasma and Chlamydophila pneumoniae seem to be involved more with asthma persistence rather than with disease exacerbations. Recent data suggest that common bacteria may also be involved, but this should be confirmed. Although current information is considerable, improvements in detection methodologies, as well as the wide variation in respect to location, time and populations, underline the need for additional studies that should also take into account interacting factors.
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              Detection of pathogenic bacteria during rhinovirus infection is associated with increased respiratory symptoms and asthma exacerbations.

              Detection of either viral or bacterial pathogens is associated with wheezing in children; however, the influence of both bacteria and viruses on illness symptoms has not been described.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                08 November 2018
                : 12
                : 3825-3845
                [1 ]Department of Pediatrics, Hsinchu MacKay Memorial Hospital, Hsinchu, Taiwan
                [2 ]Department of Family Medicine, Taipei Mackay Memorial Hospital, Taipei, Taiwan
                [3 ]Department of Medical Library, MacKay Memorial Hospital, Tamsui Branch, New Taipei City, Taiwan
                [4 ]Department of Family Medicine, Hsinchu MacKay Memorial Hospital, Hsinchu, Taiwan, 5767@ 123456mmh.org.tw
                Author notes
                Correspondence: Tzu-Lin Yeh, Department of Family Medicine, Hsinchu MacKay Memorial Hospital, Number 690, Section 2, Guangfu Road, Hsinchu 300, Taiwan, Tel +886 3 611 9595, Fax +886 3 611 0900, Email 5767@ 123456mmh.org.tw
                © 2018 Lei et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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