Series www.thelancet.com Vol 404 September 21, 2024 1143 Respiratory Syncytial Virus 2024 1 Severe respiratory syncytial virus infection in children: burden, management, and emerging therapies Natalie I Mazur, Mauricio T Caballero, Marta C Nunes The global burden of respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in young children is high. The RSV prevention strategies approved in 2023 will be essential to lowering the global disease burden. In this Series paper, we describe clinical presentation, burden of disease, hospital management, emerging therapies, and targeted prevention focusing on developments and groundbreaking publications for RSV. We conducted a systematic search for literature published in the past 15 years and used a non-systematic approach to analyse the results, prioritising important papers and the most recent reviews per subtopic. Annually, 33 million episodes of RSV LRTI occur in children younger than 5 years, resulting in 3·6 million hospitalisations and 118 200 deaths. RSV LRTI is a clinical diagnosis but a clinical case definition and universal clinical tool to predict severe disease are non-existent. The advent of molecular point-of-care testing allows rapid and accurate confirmation of RSV infection and could reduce antibiotic use. There is no evidence-based treatment of RSV, only supportive care. Despite widespread use, evidence for high-flow nasal cannula (HFNC) therapy is insufficient and increased paediatric intensive care admissions and intubation indicate the need to remove HFNC therapy from standard care. RSV is now a vaccine- preventable disease in young children with a market-approved long-acting monoclonal antibody and a maternal vaccine targeting the RSV prefusion protein. To have a high impact on life-threatening RSV infection, infants at high risk, especially in low-income and middle-income countries, should be prioritised as an interim strategy towards universal immunisation. The implementation of RSV preventive strategies will clarify the full burden of RSV infection. Vaccine probe studies can address existing knowledge gaps including the effect of RSV prevention on transmission dynamics, antibiotic misuse, the respiratory microbiome composition, and long-term sequalae. Introduction Worldwide, respiratory syncytial virus (RSV) is associated with substantial morbidity and mortality in infants and young children.1,2,3 RSV is one of the most common pathogens associated with pneumonia hospitalisations in children.4,5 The clinical diagnosis of RSV disease in infants is challenging because of non-specific symptoms resembling other respiratory illnesses.6 Recognising the clinical features of RSV infection in infants and young children is crucial for clinical management, epidemiological surveillance, and in the development of clinically relevant endpoints for randomised clinical trials (RCTs).7 Although there is no specific treatment for RSV, we have reached a turning point for RSV prevention with two immunisations approved in 2023 to prevent RSV in infants8,9 as well as three vaccines for adults.10 As such, RSV can now be considered a vaccine-preventable disease. Although most children with severe RSV disease are previously healthy, understanding groups at high risk for severe disease could allow early prioritisation for targeted prevention of RSV as an interim strategy towards universal immunisation. Disease burden estimates and recognition of the associated risk factors by policy makers worldwide are also crucial to evaluate the implementation strategies available. In the past 15 years, major knowledge has been gained regarding protective immune responses against RSV and quantification of the real RSV burden, including data from low-income and middle-income countries (LMICs). Nonetheless there are still many knowledge gaps (panel). The implementation of RSV prevention by means of vaccine probe studies will contribute to addressing some of these knowledge gaps. In the first paper in this Series on RSV, we describe the clinical presentation, burden of disease, hospital management, emerging therapies, and targeted prevention of RSV, focusing on developments and groundbreaking publications in the last 15 years. The second paper presents the association between early RSV infection and long-term sequelae including recurrent LRTI and all-cause pneumonia, recurrent wheezing, and asthma.11 The authors also discuss possible causal Lancet 2024; 404: 1143–56 Published Online September 9, 2024 https://doi.org/10.1016/ S0140-6736(24)01716-1 This is the first in a Series of four papers about respiratory syncytial virus (papers 2 and 3 appear in The Lancet Respiratory Medicine). All papers in the Series are available at thelancet.com/ series/https://www.thelancet. com/series/respiratory-syncytial- virus Department of Pediatrics, Wilhelmina Children’s Hospital, Utrecht, Netherlands (N I Mazur MD PhD); Centro INFANT de Medicina Traslacional (CIMeT), Escuela de Bio y Nanotecnología, Universidad Nacional de San Martín (UNSAM), Buenos Aires, Argentina (M T Caballero MD MSc); Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina (M T Caballero); Center of Excellence in Respiratory Pathogens, Hospices Civils de Lyon and Centre International de Recherche en Infectiologie, Équipe Santé Publique, Épidémiologie et Écologie Évolutive des Maladies Infectieuses, Inserm U1111, CNRS UMR5308, ENS de Lyon, Lyon, France (M C Nunes PhD); South African Medical Research Council, Vaccines & Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (M C Nunes) Correspondence to: Natalie I Mazur, Department of Pediatrics, Wilhelmina Children’s Hospital, Utrecht 3584EA, Netherlands n.i.mazur@umcutrecht.nl Search strategy and selection criteria References for this Series paper were identified through a search of PubMed and the Cochrane Library for original research and reviews with no language restrictions from Jan 1, 2009, to May 1, 2024. We did not intend to do a systematic review of the literature with evidence grading. No inclusion or exclusion criteria were used. Instead, we selected articles that were most relevant to the subheadings used in this Series paper. We searched using the terms ‘’respiratory syncytial virus’’ or ‘’bronchiolitis’’ and ‘’infant’’ or ‘’child’’ or ‘’pediatric’’ and ‘’management’’ or ‘’treatment’’ or ‘’interventions’’ or ‘’severity’’ or types of therapies or supportive care (appendix p 4). See Online for appendix http://crossmark.crossref.org/dialog/?doi=10.1016/S0140-6736(24)01716-1&domain=pdf Series 1144 www.thelancet.com Vol 404 September 21, 2024 mechanisms to explain the association between RSV infection and asthma and full public health value of RSV prevention. The third paper focuses on RSV infections in adults and discusses diagnosis and disease burden, infection in vulnerable adult populations, prevention, and cost of care.10 The fourth paper reviews the efficacy and safety of RSV vaccination and immunoprophylaxis in young children, explores potential regulatory, policy, and implementation pathways for the RSVpreF maternal vaccine and nirsevimab, and discusses and the health economic evidence to inform product introduction decisions.12 Clinical presentation Severe paediatric RSV disease can be roughly classified by clinical syndrome in three age groups: neonates present with sepsis-like illness13–15 or apnoea,16 children younger than 2 years with bronchiolitis,6 and older children with pneumonia.17 Infants can develop respiratory failure, which can be life threatening. Bronchiolitis and pneumonia are primarily diagnosed based on clinical evaluation, and laboratory tests might not substantially change the management of these conditions. However, confirming a viral cause through molecular testing can be important to avoid the unnecessary use of antibiotics during severe lower respiratory tract infections (LRTIs). Advances in RSV testing in the past 10 years include RSV molecular point-of-care testing, allowing for rapid and affordable testing at the bedside, with a sensitivity and specificity that is non-inferior to PCR testing.18 A clinical dilemma for RSV LRTI is that the site of infection cannot be sampled (the lungs), except when a child is intubated; however, there is high concordance (0·89) for RSV PCR positivity between the upper and lower respiratory tract.19 One of the major challenges for clinicians is to predict who will progress towards severe disease. Research efforts have validated clinical tools to predict progression to severe disease to aid clinicians in early disease stages, yet these tools are not widely implemented.20 The majority of RSV infections in infants are asymptomatic or manifest with mild, self-limiting symptoms; however, RSV is also a leading cause of severe LRTI among young children.21 Among those who have at least one clinical sign of acute respiratory infections, only six of 100 children per year will fulfil the classic influenza- like illness definition.22 Therefore, the absence of consistent clinical presentations could lead to an underestimation of RSV incidence by 50–80% if influenza-like illness or severe acute respiratory infection (SARI) criteria alone are used.23 Moreover, severe RSV disease usually presents with hypoxaemia, wheezing, and chest in-drawing, which are not included in SARI or influenza-like illness case definitions.24 The WHO extended SARI case definition25 is more sensitive in detecting severe RSV cases, with only 3% of cases missed in paediatric intensive care units (PICUs) in LMICs.26 Although there are no pathognomonic clinical signs for severe RSV disease, it manifests primarily with upper respiratory symptoms such as rhinorrhoea and cough, before progressing to pulmonary symptoms (figure 2).6 Fever is not usually associated with RSV infection, occurring in about 15% of symptomatic cases,22,29 although the presence of fever increases with age.30 However, in the context of life-threatening RSV in LMICs, the presence of fever upon admission was high, with 58% of children presenting with a fever.26 After 4–6 days of upper respiratory tract clinical signs, children can develop increased breathing effort accompanied by retractions, wheezing, tachypnoea, and feeding difficulties.6 Even- tually, children with severe clinical progression can have hypoxaemia, anorexia, apnoea, lethargy, or irritability, indicating the need for hospitalisation.31 One of the major challenges facing clinicians is to predict who will progess towards severe disease. Standardised methods to assess RSV severity in infants are not available, making it difficult to reach a consensus on the endpoints needed to measure vaccine efficacy. Additionally, there are no standardised criteria for hospital or PICU admissions or for initiating respiratory support.32–34 Multiple scoring systems and cutoffs in key respiratory variables have been suggested to define outcomes for RSV intervention Key messages • Severe respiratory syncytial virus (RSV) disease presents as three age-related clinical syndromes (sepsis in neonates, bronchiolitis in infants, and pneumonia in young children) but cannot be clinically distinguished from other respiratory illnesses without viral testing • The worldwide burden of RSV is inequitably distributed, with the majority of life-threatening disease occurring in low-income and middle-income countries (LMICs; figure 1). All children are infected with RSV; approximately 5% develop RSV lower respiratory tract infection, 0·4% are hospitalised, and 0·02% die (figure 2) • A substantial proportion (16%) of infants with life-threatening RSV infection have severe comorbidities, even if the majority of infants with severe RSV are term and previously healthy • There is no treatment for RSV and hospital management consists of supportive care; high-flow nasal cannula therapy has been widely implemented for respiratory support despite insufficient evidence of efficacy against life-threatening disease • Prevention is key for RSV as antivirals are not yet available; RSV should be considered a vaccine-preventable disease for all infants globally; high-risk groups, especially in LMICs, should be prioritised as an interim strategy on the road to universal immunisation • The effect of RSV prevention on RSV transmission dynamics, antibiotic misuse, the respiratory microbiome composition, and long-term respiratory sequalae are crucial knowledge gaps (panel) Series www.thelancet.com Vol 404 September 21, 2024 1145 trials.7,20,35,36 Nevertheless, although some of these RSV clinical severity scores show promise, none of them are universally implemented due to either incomplete external validation in LMICs or the need for adaptation to challenging environments.20,35 Moreover, various clinical variables (eg, retractions, wheezing, or crackles) pose challenges for parameterisation due to potential measurement biases, biological variations, inadequate sampling power, and population heterogeneity.20,31,37,38 We have included an overview of the most frequently used clinical severity scores for bronchiolitis, the parameters used, and the level of validation (table). Disease burden The global incidence of RSV LRTI is inequitably distributed, with the highest incidence in LMICs (figure 1). An update on the global RSV LRTI burden among children younger than 5 years estimated that in 2019 33 million (95% uncertainty range [UR] 25·4–44·6) episodes of RSV LRTI resulted in 3·6 million (2·9–4·6) hospitalisations, 26 300 (48 000–74 500) in- hospital deaths and 118 200 overall deaths, translating to 0·02% of children younger than 5 years (figure 2).1 RSV- attributable (ie, RSV identified in the causal chain) overall mortality could be as high as 101 400 (84 500–125 200) including out-of-hospital deaths. Infants younger than 6 months have the highest disease burden (incidence of RSV LRTI: 96·3 [95% UR 67·9–142·6] per 1000 children per year), accounting for a fifth of all infections and nearly 40% of all RSV hospitalisations (appendix p 2). Of these hospitalisations, the majority (61%) were during the first 3 months of life. Infants younger than 6 months also accounted for more Figure 1: Heat map of incidence rate estimates of RSV acute lower respiratory infection per 1000 children for children younger than 5 years in 2019 Data from the latest global burden estimates for RSV was used to make a heat map of global incidence of RSV acute lower respiratory tract infection (data for 137 LMICs were available).1 A scale of colours was used to show higher (purple) and lower (yellow) incidence. Country-specific incidence rates estimates were used if available. If country-specific data were not available, incidence for countries classified by World Bank income regions was used (ie, low income, lower-middle income, upper-middle income, and high income) and the aggregate value for the region was used. Ploty.js software was used to make the world map. RSV=respiratory syncytial virus. 30 40 50 60 70 80 Incidence rate per 1000 children of RSV acute lower respiratory tract infection Figure 2: Global epidemiology of severe RSV infection among children younger than 5 years Global epidemiology of severe RSV according to global burden estimates in 2019: all children are infected with RSV,21 33 million (5%) of 690 million children younger than 5 years have RSV LRTI,27 3 million (0·4%) are hospitalised, and 118 200 (0·02%) children die from RSV LRTI.1 RSV infects primarily through the nose, but also through the eyes.28 There are well defined risk factors for severe RSV disease. Figure was created using Piktochart. LTRI=lower respiratory tract infection. RSV=respiratory syncytial virus. Risk factors Younger than 6 months in the RSV season Prematurity Chronic heart disease Chronic lung disease Down syndrome Neuromuscular disease Epidemiology 100% RSV infections 4–6 days Clinical presentation Routes of infection Eyes Nose 0·02% deaths 0·4% hospitalisation 5% LRTI Upper respiratory tract infection • Rhinorrhoea • Cough LRTI • Retractions • Wheezing • Tachypnoea • Feeding difficulty • Hypoxaemia • Apnoea • Lethargy Series 1146 www.thelancet.com Vol 404 September 21, 2024 than half of all in-hospital RSV-associated deaths and 45% of RSV-attributable deaths.1 Although RSV is not a common cause of death in neonates, neonates account for approximately 1 of 5 RSV-attributable deaths in the first 6 months of life. However, data on neonatal RSV are scarce and potentially underestimated due to non-specific neonatal clinical presentation. The RSV LRTI incidence in the community among infants younger than 6 months was three times higher in LMICs compared with high-income countries (HICs); whereas the incidence of RSV LRTI hospitalisation was lower in LMICs than HICs, suggesting inadequate access to health care in LMICs (appendix p 2). Moreover, LMICs have the highest burden of mortality with more than 97% of the overall RSV-attributable deaths occurring in LMICs and more than 70% of these occurring outside the hospital. Potentially the high rates of community deaths are due to insufficient awareness: in vulnerable contexts, inadequate parental awareness of severity could contribute to as many as 20% of out-of-hospital deaths attributed to RSV.52–54 In addition, severe apnoea related to RSV can be a finding that is easily missed even for well trained physicians. Overall, RSV awareness is still insufficient, with only 3% of parents of children who were admitted to the PICU with life-threatening disease in LMICs having heard of RSV before hospital admission.26 Accurately quantifying RSV-associated deaths is challenging. Many RSV-associated deaths in LMICs occur in the community, making ascertainment difficult. Moreover, the role of RSV in mortality could be underestimated if the virus goes undetected at the time of death. By contrast, deaths among infants with RSV (classified as RSV-associated deaths) might be due to other pathogens, with RSV not being in the causal chain of death (ie, not RSV-attributable deaths).55 An analysis from the Child Health and Mortality Prevention Surveillance (CHAMPS) Network on the causal pathways and pathogen-specific causes of fatal pneumonia in children aged 1–59 months (median age 9 months) revealed that RSV was causally associated with 29 (6%) of 455 fatal pneumonia episodes in six countries in sub-Saharan Africa and Bangladesh.56 Therefore, estimates of RSV mortality should be considered as the minimum estimate of the true burden, particularly for out-of-hospital deaths, which account for 21·8% of the deaths included in the CHAMPS study. Further quantification of true burden of RSV community deaths is needed. Studies from two African countries, one lower- middle-income (Kenya) and one upper-middle-income (South Africa), used different methodologies to estimate the annual incidence of severe RSV LRTI based on health- care use surveys and hospitalisation data among chil d ren younger than 5 years.2,3 Non-hospitalisation rates (ie, children reporting symptoms of severe illness, yet who did not seek care at a hospital) were three times higher than hospitalisation rates in Kenya (1077 vs 349 per 100 000 children), whereas they were similar in South Africa (927 and 802 per 100 000 children), reflecting the inadequate hospital access in LMICs and therefore increased outpatient visits.2,3 In Europe, a large prospective birth cohort study of healthy term-born infants, revealed that during the first year of life 1 in 56 of all symptomatic RSV episodes required hospitalisation.57,58 Furthermore, among children hospitalised in HICs, approximately 4–6% necessitate intensive care support.57,59,60 Data on the burden of RSV-associated intensive care unit admissions from LMICs are scarce; however, a 2024 large multicentre study identified RSV in 30% of children admitted to the PICU with SARI in ten LMICs eligible for Gavi, the Global Vaccine Alliance.26 Likewise, there is a high burden of disease in children born prematurely. The estimated global number of RSV LRTI in the first year of life among preterm Panel: Respiratory syncytial virus major new insights and remaining knowledge gaps Major new insights in the past 15 years • The majority of life-threatening respiratory syncytial virus (RSV) infection occurs in low-income and middle-income countries (LMICs) and more than 70% of RSV deaths occur out of the hospital • Infants younger than 6 months at the start of the RSV season are at the highest risk of death • Insights into the structure of the surface RSV fusion protein have allowed an understanding of neutralising antibodies and have been the key to successful RSV vaccine development • RSV is now a vaccine-preventable disease as new preventive interventions have been approved and implemented in several countries • Initial real-world effectiveness data of RSV preventive monoclonal antibodies show high coverage and efficacy Remaining knowledge gaps • Burden: the global burden of RSV-associated paediatric intensive care unit admissions, community deaths, and severe disease in LMICs need to be further quantified to facilitate implementation of RSV vaccines; little is known about the burden of RSV during the neonatal period • Management: further validation of a clinical severity score is needed to guide global uniformity in assessment of the severity of RSV infection; efficacy of widely implemented high-flow nasal cannula against clinical outcomes of RSV infection needs to be studied • Vaccine impact: vaccine probe studies can allow assessment of the effect of new RSV prevention on secondary outcomes such as community mortality, all-cause lower respiratory tract infection, RSV transmission, antibiotic misuse, long-term respiratory sequelae, and the respiratory microbiome Series www.thelancet.com Vol 404 September 21, 2024 1147 Pa ra m et er s De si gn ed fo r R SV Ta rg et p op ul at io n O ut co m e us ed to te st th e sc or e St ud y do ne to te st o r c re at e th e sc or e M od el b ui ld in g m et ho d re po rt ed M od el p er fo rm an ce an d va lid at io n U se r Se tt in g Te st ed in LM IC s Co m m en ts W an g Br on ch io lit is Se ve rit y Sc or e39 –4 1 RR , r et ra ct io ns , w he ez in g, g en er al co nd iti on N o Yo un ge r t ha n 24 m on th s Pu lse o xi m et ry Cr os s- se ct io na l st ud y N o O bs er ve r a gr ee m en t Ph ys ici an s O ut pa tie nt Ye s, Tü rk iy e Lo w pe rfo rm an ce an d re lia bi lit y M od ifi ed Ta l S co re 42 ,4 3 Sp O 2, R R, w he ez e, ac ce ss or y re sp ira to ry m us cle u se N o Yo un ge r t ha n 12 m on th s Su pp le m en ta ry ox yg en Ra nd om ise d cli ni ca l t ria l N o Re lia bi lit y, R O C Ph ys ici an s O ut pa tie nt N o N o pr ed ict io n ox yg en th er ap y Re SV in et S co re 38 Fe ed in g to le ra nc e, m ed ica l in te rv en tio n, re sp ira to ry d iffi cu lty , RR , a pn oe a, g en er al co nd iti on , f ev er N o H ea lth y, yo un ge r th an 2 4 m on th s W oo d- Do w ne s Sc or e, le ng th o f st ay , P IC U, tr ea tm en ts Re tr os pe ct iv e an d pr os pe ct iv e st ud y N o Cr on ba ch ’s co effi cie nt , r el ia bi lit y, RO C, e xt er na l va lid at io n Ph ys ici an s an d pa re nt s O ut pa tie nt an d in pa tie nt Ye s, da ta se ts fro m C ol om bi a an d Rw an da Ex te rn al ly va lid at ed fo r RS V M od ifi ed re sp ira to ry in de x sc or e44 ,4 5 RR , r et ra ct io ns , w he ez in g, m en ta l st at us N o Yo un ge r t ha n 24 m on th s, le ss th an fo ur w he ez in g ep iso de s >2 d ay s h os pi ta l st ay s, ox yg en th er ap y, in tr av en ou s hy dr at io n Pr os pe ct iv e ob se rv at io na l st ud y N o RO C, se ns iti vi ty an al ys is, p os iti ve a nd ne ga tiv e pr ed ict iv e va lu es , e xt er na l va lid at io n Ph ys ici an s In pa tie nt N o Lo w pe rfo rm an ce an d re lia bi lit y Br on ch io lit is Sc or e o f Sa nt Jo an d e De u42 ,4 6 Sp O 2, h ea rt ra te , R R, w he ez e, in dr aw in g, ai r e nt ry N o H ea lth y, yo un ge r th an 2 4 m on th s PI CU , l en gt h of st ay , m or ta lit y Pr os pe ct iv e ob se rv at io na l st ud y N o Cr on ba ch ’s co effi cie nt , i nt ra cla ss co rre la tio n co effi cie nt re lia bi lit y, RO C Ph ys ici an s In pa tie nt s N o Ev al ua tio n of bo th v al id ity a nd re lia bi lit y Gl ob al R es pi ra to ry Se ve rit y Sc or e41 ,4 2, 47 Ap pe ar an ce , w he ez in g, ra le s, re tr ac tio ns , c ya no sis , le th ar gy , p oo r a ir m ov em en t, RR , Sp O 2 m ov em en t Ye s H ea lth y, te rm , yo un ge r t ha n 10 m on th s Le ng th o f s ta y Pr os pe ct iv e co ho rt st ud y M iss in g va lu es im pu ta tio n, fa ct or a na ly sis , lik el ih oo d ra tio , lo gi st ic re gr es sio n RO C, co rre la tio n w ith le ng th o f s ta y, ex te rn al v al id at io n Ph ys ici an s O ut pa tie nt an d in pa tie nt N o In te rn al co ns ist en cy Br on ch io lit is Se ve rit y Sc or e48 ,4 9 RR , r et ra ct io ns , dy sp no ea , au sc ul ta tio n N o Ch ild re n w ith as th m a, br on ch io lit is or w he ez in g N ot sp ec ifi ed Re tr os pe ct iv e an d pr os pe ct iv e st ud y N o Re lia bi lit y, R O C Ph ys ici an s O ut pa tie nt Ye s, In di a Lo w pe rfo rm an ce an d re lia bi lit y Es ca la d e Se ve rid ad d e la B ro nq ui ol iti s Ag ud a42 ,5 0, 51 W he ez in g, cr ac kl es , br ea th in g eff or t, in sp ira to ry to ex pi ra to ry ra tio , R R, he ar t r at e N o H ea lth y, te rm , yo un ge r t ha n 12 m on th s Br on ch io lit is se ve rit y (h om e, w ar d, P IC U) Cr os s- se ct io na l st ud y N o Cr on ba ch ’s co effi cie nt , f ac to r an al ys is, re lia bi lit y Ph ys ici an s O ut pa tie nt an d in pa tie nt N o In te rn al co ns ist en cy Sc or es u se d or d ev el op ed fo r a st hm a w er e ex clu de d. T he m os t f re qu en tly st ud ie d cli ni ca l s ev er ity sc or es a cc or di ng to a 2 02 4 re vi ew 20 w er e al l i nc lu de d in th e t ab le . L M IC s= lo w -in co m e an d m id dl e- in co m e co un tr ie s. PI CU =p ae di at ric in te ns iv e ca re u ni t. RO C= re ce iv er o pe ra tin g ch ar ac te ris tic cu rv e. R R= re sp ira to ry ra te . R SV =r es pi ra to ry sy nc yt ia l v iru s. Sp O 2= pu lse o xy ge n sa tu ra tio n. Ta bl e: O ve rv ie w a nd e vi de nc e su m m ar y fo r s ev er it y sc or in g in lo w er re sp ira to ry tr ac t i lln es se s Series 1148 www.thelancet.com Vol 404 September 21, 2024 infants in 2019 was 1·6 million (95% UR 1·4–2·0), with 533 000 (385 000–730 000) hospitalisations, and 26 760 (11 190–46 240) deaths attributable to RSV, with only 11% of these being in-hospital.61 Of note, these estimates were inversely proportional to gestational age, with higher rates of RSV hospitalisation in infants born at lower gestational ages (appendix p 3). Preterm infants accounted for a fourth of all RSV LRTI hospitalisations. Early preterm infants (<32 weeks gestational age) were twice as likely to be hospitalised compared with late preterm infants (32–37 weeks gestational age), with this increased risk continuing in their second year of life. The majority of RSV LRTI cases (93%), hospitalisations (92%), and in-hospital deaths (89%) among preterm infants occurred in LMICs (appendix p 2).61 The burden of endemic respiratory viruses was substantially reduced globally during the first year of the COVID-19 pandemic.62 A systematic literature review for studies published from Jan 1, 2020, to June 30, 2022, compared with data from 2019 found that the rates of RSV LRTI hospitalisation in 2020 decreased by nearly 80% in HICs, 13·8% in upper-middle-income countries, and 42·3% in Kenya (the only lower-middle-income country included) in children younger than 5 years.63 In 2021, these rates started to increase, and in HICs, annualised rates had returned to similar levels as in 2019 by March, 2022. However, in middle-income countries, rates were still lower in 2022 than 2019.63 Conversely, a South African study found that by 2021 the incidence of RSV LRTI hospitalisations in children younger than 5 years was similar to pre-pandemic years.64 A systematic review also found a transient but significantly higher proportion of children aged 12–24 months were hospitalised with RSV LRTI in high-income and upper- middle-income countries during the pandemic years than in 2019.63,65 Hospital management Supportive care by way of fluid hydration and respiratory support are the foundation of evidence-based in-hospital management of RSV-bronchiolitis and pneumonia.66 There is, however, no evidence-based therapy for RSV infection (figure 3).67–75 Low level of evidence for nebulised hypertonic saline suggested a reduced length of hospital stay of 0·40 days (95% CI –0·69 to –0·11), although this is not clinically relevant.71 The incidence of bacterial co-infections in patients with RSV infection is reported to be lower than 11%, but nearly a third of children with RSV LRTI are treated unnecessarily with antibiotics.76,77 To prevent antibiotic misuse in the age of threatening global antimicrobial resistance, there should be a high threshold for Figure 3: Evidence-based treatment of severe RSV infection The intervention and recommendation for use in hospital management (recommended or not recommended) are listed, and the quality of evidence for this recommendation is presented (ie, high, moderate, low, or very low). Quality of evidence was assessed based on GRADE-criteria and if possible, taken from Cochrane review of the literature.67–75 GRADE= Grading of Recommendations, Assessment, Development, and Evaluations. RSV=respiratory syncytial virus. Intervention Inhaled corticosteroid Systemic corticosteroids Leukotriene antagonist Monoclonal antibodies and immunoglobulins Antibiotics Ribavirin Conventional chest physiotherapy Chest physiotherapy based on slow expiratory techniques Steam inhalation Bronchodilators Nebulised hypertonic saline Quality of evidence Recommendation Not recommended Not recommended Not recommended Not recommended Not recommended Not recommended Not recommended Not recommended Not recommended Not recommended Not recommended High Moderate Low Very low Level of evidence according to GRADE criteria Series www.thelancet.com Vol 404 September 21, 2024 1149 antibiotics administration in the case of RSV infection. The decision to administer antibiotics should not only be based on elevated c-reactive protein but also include overall indicators of serious bacterial infection, such as neonatal age and deterioration while ventilated.76 Practical tools are needed to help physicians identify serious bacterial infections in the case of RSV LRTI, allowing for more targeted antibiotic use. With worsening respiratory distress, children might be unable to maintain oral hydration, necessitating in-hospital hydration through nasogastric or isotonic intravenous fluids.6 In two RCTs, there was no difference in length of hospital stay for both hydration modalities, and, as such, the nasogastric route might be preferred due to increased chance of success and less complications.78 In the case of increasing respiratory distress, minimal handling has been the well accepted practice to allow a child to save all energy expenditure for breathing. A 2023 RCT challenged the value of minimal handling by showing no difference in time to improvement for the group with frequent changes in body position and physical activity compared with the minimal handling group.79 Hospital admission is severely disruptive and can have an impact on patients and their families.80 Psychological problems for parents can extend for more than 6 months after infant PICU admission.81 Data on hospitalisation impact are often limited to data in premature infants although the majority of hospitalised infants were born at term.82 Future management strategies should incorporate support for post-traumatic stress experienced by caregivers. Oxygen therapy is a mainstay of RSV management, both in general hospital wards and PICUs. An evidence- based threshold of 90% oxygen saturation for oxygen supplementation has been established in a double-blind RCT in infants aged 6–52 weeks with bronchiolitis.83 Notably, children aged 0–6 weeks were excluded, which is the typical age at presentation of severe bronchiolitis. Furthermore, a cohort study found no difference in outcomes in children aged 1–24 months who were hospitalised with bronchiolitis if adhering to a 90% threshold when awake and an 88% threshold when asleep compared with 90% for both thresholds.84 Lack of long-term adverse outcomes for lower oxygen thresholds (as low as 88%) was supported by a 2023 systematic review.85 Implementation of a 90% threshold for hospital referral and supplemental oxygen can improve patient management by reducing length of hospital stay, duration of oxygen supplementation, and costs. However, there is still a widespread implementation gap in clinical practice and national guidelines despite endorsement by WHO and the American Academy of Pediatrics. Respiratory support is the foundation of life-saving treatment for severe RSV, but supplementation and length of hospital stay can be reduced by adhering to evidence-based thresholds. High-flow nasal cannula (HFNC) oxygen therapy has been increasingly used in the past decade for management Figure 4: Proportion of life-threatening RSV disease in children receiving HFNC compared with LF (A) Data on proportion of life-threatening RSV disease in children, defined as requiring mechanical ventilation, was extracted from all RCTs comparing HFNC and LF;87–100 if the data on life-threatening disease were available, the RCT was included. A dual axis (red and black) is shown for interpretability, as trial size varied too much to fit in one figure. All studies in blue circles use the standard black axis. The Franklin trial, indicated in a red circle (comparatively large and percentages low [<1·5%]), uses the x axis indicated in red. The circle sizes are proportional to the sample size in the trial, with the center of the circle at the point estimate. Country and site of trial setting are written in the circles. The dotted line represents equal percentage of the outcome in both trial groups. (B) Data on proportion of life-threatening RSV disease in children, defined as PICU admission, was extracted from all RCTs comparing HFNC and LF; if the data were available, the RCT was included in the figure. The circle sizes are proportional to the sample sizes in the trial, where the centre of the circle at the point estimate. Country where the RCT was conducted is written in the circle. The dotted line represents equal percentage of the outcome in both trial groups. HFNC=high-flow nasal canula. LF=low-flow nasal canula. PICU=paediatric intensive care unit. RCT=randomised clinical trial. In favour of LF In favour of HFNC PICU Netherlands PICU USA PICU South Africa General ward Australia and New Zealand In favour of LF In favour of HFNC Netherlands Australia and New Zealand Türkiye Türkiye Australia Italy France 0 755025 (0·5) 100 75 50 (1) 25 0 Pr op or tio n of ch ild re n in H FN C gr ou p re qu iri ng m ec ha ni ca l v en til at io n (% ) Proportion of children in LF group requiring mechanical ventilation (%) 100 A 0 2010 100 20 10 0 Pr op or tio n of ch ild re n in H FN C gr ou p re qu iri ng PI CU a dm iss io n (% ) Proportion of children in LF group requiring PICU admission (%) 100 B Series 1150 www.thelancet.com Vol 404 September 21, 2024 of hospitalised infants besides standard low-flow nasal cannula (LF) oxygen therapy. HFNC uses humidified heated air blended with oxygen and, unlike LF, administers a degree of positive pressure to the airways. Practical advantages include ease of use for hospital staff and increased comfort. 11 RCTs comparing standard oxygen with HFNC showed an overall minor reduction in length of hospital stay and duration of oxygen therapy (<1 day).86 Two RCTs showed lower rates of escalation of care for HFNC versus LF therapy, with no effect on duration of therapy, PICU admission rate, or length of hospital stay.87,88 Higher rates of PICU admission were, however, observed in the HFNC group, underlying the importance of relevant trial endpoints (ie, PICU admission or mechanical ventilation) to properly assess efficacy of HFNC. Moreover, high rates of crossover to HFNC in the LF group showed that early initiation of HFNC can avoid late initiation of HFNC without any effect on clinical course of disease. In fact, use of HFNC can delay mechanical ventilation and put a child in an at- risk situation.89 In figure 4, we extracted relevant clinical endpoints if available from all conducted RCTs comparing HFNC and LF.87,88,90–100 There was no trend towards efficacy against life- threatening RSV disease defined as mechanical ventilation (figure 4A) and PICU admission (figure 4B) for HFNC compared with LF. In fact, there was a trend towards increased PICU admissions and mechanical ventilation in the HFNC group. The global increase in PICU admission rates for viral bronchiolitis in the past decade can probably be explained by the concomitant adoption of HFNC,101,102 or alternatively, by a low threshold of admission to critical care in viral bronchiolitis.103 Beyond HFNC, mechanical ventilation through endotracheal intubation was introduced in the management of viral bronchiolitis in the 1960s, and since the 1980s several options for non-invasive respiratory support are being increasingly used in the PICU due to the potential to avoid complications associated with invasive mechanical ventilation. Non-invasive ventilation includes options that provide volume or pressure support or provide pressure support upon spontaneous breathing, including nasal continuous positive airway pressure (CPAP) delivered via a face mask and HFNC. The effect of non-invasive respiratory support remains to be determined in PICU. A Cochrane review of CPAP for viral bronchiolitis found no reduction in the need for mechanical ventilation with a low level of evidence.104 In summary, large adequately powered trials are needed to find out the efficacy of non-invasive ventilation compared with conventional oxygen supplementation against relevant clinical outcomes.104 Until then, clinicians should be hesitant to use CPAP for bronchiolitis management due to potential adverse outcomes (eg, local nasal mucosal damage, aspiration secondary to gastric insufflation, and pneumothorax) and the delay of definitive care. Similarly, the insufficient evidence for efficacy, high costs, and increased PICU admissions support the removal of HFNC from standard care in general paediatric wards. Emerging therapies Treatment Antiviral therapy has not shown much promise in the treatment of RSV infection, with the dilemma that the delay in treatment is too long for antivirals to effectively interrupt viral replication and therefore prevent an associated immune response. A phase 2b trial published in 2021 of ALX-0171, a trivalent RSV antiviral nebulised nanobody, showed no clinical response, measured as improved oxygen saturation levels or decrease in severity scores, despite a faster drop in viral load compared with placebo.105 For most RSV therapeutic candidates development has halted. At least four antiviral compounds have been terminated or the development status is unclear in late-phase trials (NCT04225897, NCT04583280, NCT05559905, and NCT06170242):106,107 EDP-938 failed phase 2b trials, although development is being continued for children and high-risk adults106 and EDP-323 is being evaluated in a phase 2 controlled human infection model with expected completion in May, 2024 (NCT06170242). Overall, prevention of infection is a more promising approach than treatment as administering treatment within 24–48 h of symptom onset is rarely feasible. The therapeutic window has often passed once health care is sought (median symptom duration before hospitalisation is 4 days and before first health-care contact is 3 days).108 Prevention: non-pharmaceutical interventions and transmission Although precise studies on the airborne transmissibility of RSV are scarce, RSV is known to be transmitted through direct and indirect contact with virus-conta- minated droplets on hands or fomites.109 Transmission in households generally occurs through school-aged children and adolescents, and viral shedding is more prolonged in young infants and symptomatic patients.22 The COVID-19 pandemic led governments to implement a series of non-pharmacological measures to reduce the circulation of SARS-CoV-2.63,110 These measures, which included physical distancing, quarantines, use of face masks, and handwashing, notably reduced the circulation of RSV and other respiratory viruses.111 These measures resulted in a dramatic drop in outpatient consultations and hospitalisations due to RSV, especially in the southern hemisphere.112 The implemen tation of simple non-pharmacological preventive measures, such as handwashing, could be useful in reducing infections by RSV and other viruses in young or at-risk infants. Disinfecting toys, surfaces, and fomites every 2 weeks significantly decreased the presence of viral genetic material for RSV and other respiratory viruses in the environment.112,113 Series www.thelancet.com Vol 404 September 21, 2024 1151 Prevention: monoclonal antibodies Advances in RSV vaccine research have been driven by insights into the immune responses to RSV and innovative applications of structural immunology in antigen design. The primary focus of these efforts has been the RSV surface prefusion (preF) glycoprotein.114,115 Information regarding safety, regulatory, policy, and implementation pathways for RSV prevention is discussed separately in the fourth paper in this series.12 In this Series paper, we discuss the two RSV preventive products approved in 2023, and refer to the fourth paper in this Series for a brief discussion of other vaccines in development for children. Prophylaxis with monoclonal antibodies (mAbs) has been a time-tested approach to protect infants from RSV. Since 1998, palivizumab was the only market-approved prophylactic to protect infants against RSV-associated hospitalisation. Palivizumab use is largely limited to high- risk infants in HICs due to high costs and administration via monthly injections during the RSV season. In early 2023, nirsevimab, an extended half-life mAb against site Ø of preF, received market approval in Europe and the USA for all infants. The phase 3 MELODY trial showed 74·5% (95% CI 49·6–87·1) efficacy up to 150 days against medically attended RSV LRTI in healthy preterm and term infants.116 The extended-half-life of this intervention was 68·7 (SD 10·9 days), which allows for improved protection over an entire RSV season with a single injection. First-year implementation experiences reported more than 92% coverage and real-life effectiveness against RSV hospitalisation as high as 96% in Spain.117,118 High global demand could not keep up with supply due to production shortages.119 Other mAbs against RSV are on the horizon. Phase 3 trial results are expected at the end of 2024 for clesrovimab, an extended half-life mAb against site IV of preF. With a half-life of 43–48 days, the phase 2 results showed preliminary efficacy in infants of 80·6% (–141·2 to 99·6) against medically attended RSV LRTI up to 150 days.120 Registration of this mAb is anticipated as early as 2026. Given the production costs and pricing, mAbs will probably not become widely available in LMICs.121 The clinical development programme of RSM01, an extended-half-life mAb against site Ø, is aimed at LMIC access with the aim of affordable pricing at less than US$4 per dose. A phase 1 trial in adults was completed in 2022.122 Implementation for mAbs includes administration at birth, which confers immediate protection and can be year-round or seasonal. Prevention: maternal vaccination Vaccinating pregnant people is an alternative strategy for protecting infants against RSV. RSVpreF (Pfizer, Puurs, Belgium), a bivalent prefusion protein vaccine to be used during pregnancy, was approved in several countries from mid-2023.8 A large global phase 3 trial that enrolled 31% of people who were pregnant in LMICs reported an efficacy in infants of 82·4% (95% CI 57·5–93·9) in preventing severe medically attended RSV LRTI within the first 90 days of life, and 70·0% (50·6–82·5) within 180 days.8,123 To date, two other RSV maternal vaccine candidates with RSV F protein as the antigenic target were evaluated in phase 3 clinical trials, after which development was discontinued due to not achieving the study primary objective or safety concerns.124,125 Additionally, one mRNA- based vaccine (mRNA-1345) is in phase 2 development. Although results among people who are pregnant are pending for mRNA-1345 (NCT06143046), it has an acceptable safety profile and good immunogenic responses in adults and people older than 60 years.126–128 In older adults, mRNA-1345 showed more than 80% efficacy in preventing RSV LRTI for a median 112 days post- vaccination and more than 60% during an extended median follow-up of 8·6 months.126,129 Advantages of maternal vaccination include a lower price than mAb therapy; however, factors such as timing in relation to birth, placental integrity, and maternal health might influence the effect of maternal vaccination. Targeted prevention Ideally, RSV prevention will target all infants but at a minimum, will target children at high risk of life- threatening disease as an interim strategy until RSV prevention is widely available. The research field of RSV prevention is rapidly changing with the implementation of preventive immunisations with nirsevimab or RSVpreF in multiple countries across the world.117,130 Nonetheless, accessibility to these preventive measures poses challenges for many LMICs.55 Risk factors associated with severe RSV disease are important to identify priority target populations for RSV prevention and designing cost-effective RSV prophylaxis strategies. Patient-related risk factors There are key clinical and epidemiological aspects of severe RSV disease in young children worldwide (eg, the higher burden of hospitalisations, intensive care unit admissions, and mortality among infants younger than 6 months)1,25,131,132 to support the immunisation strategy to protect this vulnerable population.1,133 Underlying medical conditions for severe RSV disease include prematurity, neurological disease, Down syndrome, chronic lung disease, immunodeficiency, and congenital heart disease (figure 1).134–137 However, the majority of children hospitalised with RSV are born at term and have no underlying medical conditions, and among these children, younger age is the most important risk factor.57 There is no clear underlying genetic risk profile; in large genome-wide association studies no single nucleotide polymorphisms were significantly associated with severity.138,139 Single-cell sequencing, transcriptomics, lipidomics, and immune responses have helped to identify potential biomarkers for infants requiring RSV hospitalisation,140–143 although there is no consensus on biomarkers, which makes the clinical application not yet clear.144 Series 1152 www.thelancet.com Vol 404 September 21, 2024 Exposure-related risk-factors Associated viral factors, such as RSV strain and co- detection with other pathogens (except Haemophilus spp), were not associated with increased disease severity.145 Another important aspect is the relationship between RSV seasonality and young age during the RSV season in countries with a clear seasonal pattern of viral circulation, with infants younger than 6 months during the period of viral circulation being at higher risk and with worse clinical outcomes than children aged between 6 months and 5 years.57,146,147 Exposures to other children potentially carrying RSV, such as having siblings or attending daycare or nursery, are known risk factors for RSV infection.148 Socioeconomic risk factors Although sociodemographic aspects are often over- shadowed by biological factors, more than 70% of RSV- attributable deaths occur out of the hospital, where medical care is inadequate, particularly in conditions of structural poverty.52,148–150 Therefore, gaining a detailed understanding of the pathways of community deaths from RSV could facilitate the implementation of RSV prevention in LMICs. 2021 reports showed that infants who die from RSV in the community are younger than 6 months, typically without severe underlying conditions, and often present mild clinical signs and symptoms compared with hospitalised children.52,149,151 Moreover, these children usually live in socioeconomically vulnerable backgrounds, such as overcrowded houses in slums or impoverished, densely populated neighbour- hoods with little access to public transportation and primary health-care facilities.52,53,150,152 Other character- istics of infant RSV-associated community deaths compared with hospital deaths are shorter durations of disease and lower histopathological severity.53 In order for RSV prevention to have the highest impact against life-threatening RSV, urgent access to preventive interventions is needed in vulnerable populations where access to new therapeutics will probably be delayed or not become available at all. Long-term respiratory sequelae Although several observational studies show an association between early-life RSV infection and recurrent wheezing and asthma in childhood,153 there are few clinical trials that can establish a causal relationship. A population-based birth cohort study in the USA published in 2023 estimated that 15% of asthma diagnoses by age 5 years could be prevented by avoiding RSV infection during infancy.154 Similarly, a birth-cohort study from South Africa found that a first episode of severe RSV LRTI in infancy was associated with an increased risk of recurrent wheezing in early childhood.155 Infants with more severe RSV LRTI showed an increased risk of developing recurrent wheezing in the first year of life.156 However, few randomised clinical trials have explored the efficacy of preventive immunisation with palivizumab in preterm infants to prevent recurrent wheezing and asthma in childhood.157,158 These clinical trials did not show effective prevention of asthma onset at the age of 5 years compared with placebo. Large sample sizes and long-term follow-up are required to show efficacy of RSV prevention on the development of asthma. Therefore, understanding the long-term real-life impact of new preventive measures can not only address the longstanding question of the causal relationship between RSV infection and the development of wheezing phenotypes, but also allow the establishment of expanded objectives for implementation strategies and cost-effectiveness estimations. The link between RSV infection in early life and long-term respiratory health are further explored in the second paper in this Series.11 Conclusions and future directions We have entered a new era of paediatrics in which RSV has become a vaccine-preventable disease in all children. Although universal immunisation should be the target, high-risk groups could be prioritised in the process of vaccine implementation, including LMIC populations carrying the highest burden of life-threatening RSV. Treatment of RSV shows little promise and supportive care is the foundation of management. The advent and widespread implementation of HFNC does not have an evidence base and this therapy should be removed from standard practice. Implementation of RSV preventive strategies as a vaccine probe study will help to address existing knowledge gaps (panel). Vaccine implementation will have real-world impact including effectiveness against all-cause LRTI and impact on the respiratory microbiome. Gaps in knowledge remain, including the effect of RSV prevention on long-term RSV sequalae (eg, wheezing and asthma), and vaccine implementation could elucidate the (causal) relationship between RSV infection and asthma. This knowledge can be discovered by investigating vaccine probe type approaches using real-world data in which the difference in the outcome of interest between immunised and non-immunised individuals or populations can be ascribed to the vaccine-specific pathogen, and as such outcomes that were not assessed in the licensure trials can be evaluated.159 A vaccine probe study approach allows examination of associations between RSV infection (prevented by immunisation) and outcomes that might require large numbers of participants. Other gaps in knowledge include the potential of future paediatric vaccination to interrupt transmission of RSV to vulnerable populations and patterns of transmission between different populations (young children, older children, adults, and older adults). Furthermore, the effect of RSV vaccination against antibiotic misuse remains to be found out. Contributors All authors contributed to the conceptualisation, draft writing, data curation, and visualisation of the Series paper. Declaration of interests NIM report grants from the Gates Medical Research Institute, the Dutch Lung Foundation, and the Bill & Melinda Gates Foundation; consulting Series www.thelancet.com Vol 404 September 21, 2024 1153 and speaker fees have been paid to the University Medical Center Utrecht for Abbvie, Medimmune, Sanofi, and Merck; and ReSVinet and the Bill & Melinda Gates Foundation have provided support for NIM for attending meetings. MCN reports grants from the Bill & Melinda Gates Foundation, European & Developing Countries Clinical Trials Partnership, Pfizer, AstraZeneca, and Sanofi and personal fees from Pfizer and Sanofi. MTC reports grants from the Bill & Melinda Gates Foundation, and personal fees from Sanofi, outside the submitted work. Acknowledgments We would like to thank Milan Verrijn Stuart (Department of Paediatric Infectious Diseases and Immunology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, Netherlands) and Eddy Rigaud (Center of Excellence in Respiratory, Université Claude Bernard Lyon 1, Lyon, France) for their excellent assistance in designing the figures for this Series paper. We would like to acknowledge Manon van de Werff for assistance in manuscript formatting. Partial funding from the Dutch Lung Foundation Grant 5.2.20.020. Figures 2, 3, and 4 were created with BioRender.com. Editorial note: The Lancet Group takes a neutral position with respect to territorial claims in published maps and institutional affiliations. References 1 Li Y, Wang X, Blau DM, et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis. 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N Engl J Med 2013; 368: 1791–99. 158 Scheltema NM, Nibbelke EE, Pouw J, et al. Respiratory syncytial virus prevention and asthma in healthy preterm infants: a randomised controlled trial. Lancet Respir Med 2018; 6: 257–64. 159 Feikin DR, Scott JAG, Gessner BD. Use of vaccines as probes to define disease burden. Lancet 2014; 383: 1762–70. Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies. Severe respiratory syncytial virus infection in children: burden, management, and emerging therapies Introduction Clinical presentation Disease burden Hospital management Emerging therapies Treatment Prevention: non-pharmaceutical interventions and transmission Prevention: monoclonal antibodies Prevention: maternal vaccination Targeted prevention Patient-related risk factors Exposure-related risk-factors Socioeconomic risk factors Long-term respiratory sequelae Conclusions and future directions Acknowledgments References