2023+中国专家共识：儿童呼吸道合胞病毒感染的诊断、治疗和预防（英文版）.pdf

Vol.:(0123456789)1 3World Journal of Pediatrics https:/doi.org/10.1007/s12519-023-00777-9REVIEW ARTICLEExpert consensus onthediagnosis,treatment,andprevention ofrespiratory syncytial virus infections inchildrenXianLiZhang1 XiZhang2 WangHua1 ZhengDeXie3 HanMinLiu4 HaiLinZhang5 BiQuanChen6 YuanChen7 XinSun8 YiXu9 SaiNanShu10 ShunYingZhao11 YunXiaoShang12 LingCao13 YanHuiJia1 LuoNaLin1 JiongLi14 ChuangLiHao15 XiaoYanDong16 DaoJiongLin17 HongMeiXu18 DeYuZhao19 MeiZeng20 ZhiMinChen21 LiSuHuang1Received:29 August 2023/Accepted:26 October 2023 The Author(s)2023AbstractBackground Respiratory syncytial virus(RSV)is the leading global cause of respiratory infections and is responsible for about 3 million hospitalizations and more than 100,000 deaths annually in children younger than 5years,representing a major global healthcare burden.There is a great unmet need for new agents and universal strategies to prevent RSV infections in early life.A multidisciplinary consensus development group comprising experts in epidemiology,infectious diseases,respiratory medicine,and methodology aims to develop the current consensus to address clinical issues of RSV infections in children.Data sources The evidence searches and reviews were conducted using electronic databases,including PubMed,Embase,Web of Science,and the Cochrane Library,using variations in terms for“respiratory syncytial virus”,“RSV”,“lower respira-tory tract infection”,“bronchiolitis”,“acute”,“viral pneumonia”,“neonatal”,“infant”“children”,and“pediatric”.Results Evidence-based recommendations regarding diagnosis,treatment,and prevention were proposed with a high degree of consensus.Although supportive care remains the cornerstone for the management of RSV infections,new monoclonal antibodies,vaccines,drug therapies,and viral surveillance techniques are being rolled out.Conclusions This consensus,based on international and national scientific evidence,reinforces the current recommenda-tions and integrates the recent advances for optimal care and prevention of RSV infections.Further improvements in the management of RSV infections will require generating the highest quality of evidence through rigorously designed studies that possess little bias and sufficient capacity to identify clinically meaningful end points.Keywords Consensusprevention Respiratory syncytial virus TreatmentIntroductionIn the past decade,the substantial burden of respiratory syn-cytial virus(RSV)has attracted global attention.RSV is associated with about 33 million cases of lower respiratory tract infections(LRTIs),three million hospitalizations,and over 100,000 deaths in children younger than 5years each year globally,and no decline in morbidity,hospitalization,or mortality has been observed over time 1,2.Infants in the first 6months of life are particularly vulnerable,with a mor-tality rate of 3.6%attributable to RSV 1.RSV is the most common reason for infant hospitalization in high-income countries,and it causes a disproportionate number of deaths in low-and middle-income countries 1.There is,however,a scarcity of consensus or guidelines for the management and prevention of RSV infections in children globally.Pre-vious guidelines focused on bronchiolitis have helped clini-cians manage RSV infections to some extent.Nevertheless,there are emerging evidences of distinct mechanistic path-ways employed by various viruses causing bronchiolitis,and these differences can be responsible for some of the hetero-geneities observed in therapeutic interventions.Therapeutic management tailored to a virological diagnosis is an area for further study.Furthermore,despite two decades of evidence suggesting that less treatment is preferable and advising sup-portive rather than interventional therapy,the elimination of interventional care has not been achieved globally and Extended author information available on the last page of the article World Journal of Pediatrics1 3remains a major challenge.With advancements in virology,significant progress has been made in the epidemiology,diagnosis,treatment,and prevention of RSV infections.To date,dramatic alternations in the epidemiologic profile of RSV have been reported as a result of the severe acute res-piratory syndrome coronavirus 2(SARS-CoV-2)pandemic 37.The introduction of nonpharmaceutical interventions(NPIs)led first to a sharp decline in global mortality from RSV infections and second to a resurgence of RSV when NPIs had been lifted,which ultimately disrupted the routine and historical seasonality and subsequently caused peaks in atypical periods of the year,thus leading to a consid-erable impact on global healthcare systems.In addition to palivizumab and nirsevimab,several candidate monoclo-nal antibodies targeting RSV are currently in the pipeline.Moreover,breakthroughs have been made in RSV vaccines.Therefore,experts in epidemiology,infectious diseases,respiratory medicine,and methodology jointly developed the present consensus,synthesizing the available evidence to better guide clinical practice.The consensus applies to children younger than 5years,focusing on the most recent research advancements in the epidemiology,clinical mani-festations,diagnosis,treatment,and prevention of RSV infections.MethodsIn January 2023,a steering committee meticulously assem-bled a consensus development group,including 25 special-ists with clinical and/or research expertise in epidemiology,infectious diseases,respiratory medicine,and methodology.The composition of the 25 members was carefully designed to ensure representation from various geographic regionsof China,including Beijing,Shanghai,Guangdong,Chong-qing,Hebei,Liaoning,Jiangsu,Zhejiang,Anhui,Hubei,Hainan,Sichuan,and Shanxi.All members were free of financial or intellectual conflicts of interest and were granted unrestricted involvement.The evidence searches and reviews were conducted in January 2023 using electronic databases,including PubMed,Embase,Web of Science,and the Cochrane Library.On these websites,we searched for articles without date restrictions,using variations in terms for“respiratory syncytial virus”,“RSV”,“lower respiratory tract infection”,“bronchiolitis”,“acute”,“viral pneumonia”,“neonatal”,“infant”“children”,and“pediatric”.Furthermore,a comprehensive search was conducted to uncover additional pertinent literature by exam-ining the references of the selected publications.References were regularly updated during the drafting of the consensus.Reviewers collaborated in pairs,independently performed reference screening and data extraction,and resolved any disagreements through discussion or consultation with a third reviewer.A draft version of the document underwent a thorough evaluation process by consensus development group members.The resulting comments were reviewed by consensus development group members and subsequently integrated into the final draft as appropriate.A Delphi method was adopted to develop a consensus of pertinent statements.The consensus development group members were requested to vote on each statement of the Delphi questionnaire according to a five-point Likert scale(strongly agree/agree/neither agree nor disagree/disagree/strongly disagree)and provide open text comments,as appropriate.Consensus agreement was defined as an agree-ment by a minimum of 75%of the participants(i.e.,75%agree or strongly agree).The Delphi questionnaire was completed by all 25 experts via an online survey in July 2023,and final drafted recommendations were formulated.Recommendations that achieved consensus were compiled and then presented.ResultsDisease burdenRecommendations:RSV substantially contributes to the morbidity and mortality burden globally in chil-dren younger than 5years,particularly during the first 6months of life.Geographical area,climate,economic status,and nonpharmaceutical interventions affect the seasonality and dynamics of RSV.Epidemiological sur-veillance of RSV infections in the pediatric population should be conducted proactively.Human RSV is the predominant pathogen identified in children younger than 5years with LRTIs 1,813.RSV strains are classified into subtypes A or B based on the genetic variability of the second hypervariable 2 region of the G gene,and these subtypes cocirculate with alternat-ing dominance annually 14.There were about 33.0 mil-lion RSV-LRTI episodes,3.6 million RSV-LRTI hospital admissions,and 101,400 RSV-attributable overall deaths globally in children younger than 5years in 2019.The estimated global incidence rate of RSV-LRTIs is 48.8 per 1000 children annually,with variations between developed and developing countries(24.3/1000 vs.51.6/1000)1.Infants aged 06months are at the greatest risk for RSV-LRTIs,with one in five RSV-LRTI episodes,39%of RSV-LRTI hospitalizations,and 45%of RSV-attributable deaths occurring within this specific age group of infants 1.The mortality rate also peaks during the first 6months of life,with RSV being responsible for 3.6%of deaths in children aged 06months 1.Low-and middle-income countries account for 95%of RSV-LRTI episodes and 97%of RSV-attributable deaths and RSV-LRTI in-hospital deaths,World Journal of Pediatrics 1 3with disadvantaged economic status as a substantial risk factor 1.It is noteworthy that mere 26%of RSV-attrib-utable deaths in children younger than 5years occurred within hospital settings,which is even more pronounced in low-income countries,as only 19%of the RSV-attributable deaths occurred in hospitals 1.The striking disparity between in-hospital and community deaths in low-income settings can mostly be explained by inadequate health-care accessibility,high healthcare expenses,and restricted hospital bed capacity during an RSV epidemic.Another explanation posits that deaths might occur in children with rapidly progressive illnesses despite their initial presenta-tion lacking signs of serious illness.The annual global expenditures for managing inpatient and outpatient cases of RSV-LRTIs in children younger than 5years amount to approximately 5 billion,65%of which originates from developing countries 15.The substantial disease burden of RSV highlights the necessity for immunization pro-grams targeting early life.RSV typically causes seasonal outbreaks globally,with epidemics occurring from November to April or May in the Northern Hemisphere and from May to Sep-tember in the Southern Hemisphere,while seasonal waves are typically associated with rainy seasons in the tropics 11,1618.This variation can be attributed to the preference of RSV for cooler temperatures and higher humidity.In tropical regions,large aerosol droplets are formed due to higher humidity and stable tempera-tures,resulting in less variability across the year.The introduction and relaxation of NPIs during the SARS-CoV-2 pandemic and their subsequent effects on RSV circulation have demonstrated the potential of specific measures to prevent RSV infections 37.NPIs have substantially affected RSV transmission by augment-ing the number of RSV-naive children and diminishing population immunity against RSV 19,20.Growing evidence suggests the potential for medium-term nega-tive effects through an immunity debt,in which a greater proportion of the population is susceptible to diseases after a long period of reduced exposure 4,5,21,22.This immunity debt is a particular concern for RSV,for which temporary immunity is obtained through exposure to the virus and maternal antibodies wane quickly;with-out seasonal exposure,immunity decreases and suscep-tibility to future,and potentially more severe,infections increase.In addition to NPIs,virusvirus interactions can interfere with RSV dynamics and seasonality 23,24.Profound and unprecedented changes in RSV sea-sonality pose new challenges in tackling RSV.Ongoing monitoring of respiratory disease indicators is required to inform future healthcare system planning,and the development and use of RSV immunoprophylactic inter-ventions should be considered.Clinical featuresRecommendations:clinicians should pay close attention to infants and young children with RSV infections,especially those at high risk,who are often severely affected by LRTIs that manifest as bronchiolitis and peak 24days after onset.RSV can lead to extrapulmonary manifestations,such as central nervous system infections.The clinical manifestations of RSV infections in chil-dren widely vary in severity according to age.Infants and young children are usually severely affected by potentially life-threatening LRTIs manifesting as bronchiolitis and/or pneumonia,whereas older children typically exhibit mild upper respiratory tract infections 2527.When diagnos-ing bronchiolitis,it should be taken into account that symp-toms usually peak 2 to 4days after onset,during which time symptoms of upper respiratory infections(e.g.,fever,nasal congestion,runny nose)subside but manifestations such as shortness of breath,nasal swelling,intercostal or supracla-vicular contractures,use of accessory respiratory muscles,and grunts are incredibly exacerbated 28.A hallmark char-acteristic is a minute-to-minute variation in clinical find-ings 29.On auscultation,crackles with recurrent wheez-ing may be the predominant feature of bronchiolitis.Most children with bronchiolitis have either normal radiographs or radiographic findings consistent with simple bronchioli-tis,such as peribronchial thickening,hyperinflation,and atelectasis 29.The severity of clinical manifestations also varies considerably depending on whether the infection is primary or secondary.Almost all children have been infected with RSV by the age of 2 years and repeated infections are common throughout life.LRTIs usually occur with initial infections and may be present in more than 50%of second-ary infections 3033.Although the severity of the disease decreases after the third infection,approximately a quarter of patients exhibit symptoms of LRTIs 33.Infants aged 26months are at the highest risk of developing RSV-LRTIs 3032.RSV infections cause inflammation that leads to airway obstruction and bronchial smooth muscle spasms.Apnea occurs in up to 20%of infants and young children,predominantly preterm infants,and may be the predominant symptom in infants admitted to the hospital.The relative immaturity of ventilation control may contribute to its patho-genesis 26,34,35.Children with severe RSV infections may develop respiratory failure,necessitating admission to intensive care units(ICUs)or the need for ventilatory sup-port 36.The risk factors associated with severe disease include preterm birth(delivery at 12weeks of gestation),chronic lung disease of prematurity,and hemodynamically significant congenital heart disease 37.A multicenter retrospective study examining risk factors associated with severe RSV infections showed that 53%of children admit-ted to the pediatric ICU(PICU)were classified as having a World Journal of Pediatrics1 3high risk for severe RSV infections 37.This study revealed that hemodynamically sign