World Journal of Pediatrics (2024) 20:11–25

https://doi.org/10.1007/s12519-023-00777-9

REVIEW ARTICLE

Expert consensus on the diagnosis, treatment, and prevention

of respiratory syncytial virus infections in children
Xian‑Li Zhang1 · Xi Zhang2 · Wang Hua1 · Zheng‑De Xie3 · Han‑Min Liu4 · Hai‑Lin Zhang5 · Bi‑Quan Chen6 ·
Yuan Chen7 · Xin Sun8 · Yi Xu9 · Sai‑Nan Shu10 · Shun‑Ying Zhao11 · Yun‑Xiao Shang12 · Ling Cao13 · Yan‑Hui Jia1 ·
Luo‑Na Lin1 · Jiong Li14 · Chuang‑Li Hao15 · Xiao‑Yan Dong16 · Dao‑Jiong Lin17 · Hong‑Mei Xu18 · De‑Yu Zhao19 ·
Mei Zeng20 · Zhi‑Min Chen21 · Li‑Su Huang1

Received: 29 August 2023 / Accepted: 26 October 2023 / Published online: 8 December 2023
© The Author(s) 2023, corrected publication 2024

Abstract
Background 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 5 years, 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 Consensus prevention · Respiratory syncytial virus · Treatment

Introduction countries, and it causes a disproportionate number of deaths

in low- and middle-income countries [1]. There is, however,
In the past decade, the substantial burden of respiratory syn- a scarcity of consensus or guidelines for the management
cytial virus (RSV) has attracted global attention. RSV is and prevention of RSV infections in children globally. Pre-
associated with about 33 million cases of lower respiratory vious guidelines focused on bronchiolitis have helped clini-
tract infections (LRTIs), three million hospitalizations, and cians manage RSV infections to some extent. Nevertheless,
over 100,000 deaths in children younger than 5 years each there are emerging evidences of distinct mechanistic path-
year globally, and no decline in morbidity, hospitalization, or ways employed by various viruses causing bronchiolitis, and
mortality has been observed over time [1, 2]. Infants in the these differences can be responsible for some of the hetero-
first 6 months of life are particularly vulnerable, with a mor- geneities observed in therapeutic interventions. Therapeutic
tality rate of 3.6% attributable to RSV [1]. RSV is the most management tailored to a virological diagnosis is an area for
common reason for infant hospitalization in high-income further study. Furthermore, despite two decades of evidence
suggesting that less treatment is preferable and advising sup-
portive rather than interventional therapy, the elimination
Extended author information available on the last page of the article of interventional care has not been achieved globally and

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12 World Journal of Pediatrics (2024) 20:11–25

remains a major challenge. With advancements in virology, third reviewer. A draft version of the document underwent
significant progress has been made in the epidemiology, a thorough evaluation process by consensus development
diagnosis, treatment, and prevention of RSV infections. To group members. The resulting comments were reviewed by
date, dramatic alternations in the epidemiologic profile of consensus development group members and subsequently
RSV have been reported as a result of the severe acute res- integrated into the final draft as appropriate.
piratory syndrome coronavirus 2 (SARS-CoV-2) pandemic A Delphi method was adopted to develop a consensus
[3–7]. The introduction of nonpharmaceutical interventions of pertinent statements. The consensus development group
(NPIs) led first to a sharp decline in global mortality from members were requested to vote on each statement of the
RSV infections and second to a resurgence of RSV when Delphi questionnaire according to a five-point Likert scale
NPIs had been lifted, which ultimately disrupted the routine (strongly agree/agree/neither agree nor disagree/disagree/
and historical seasonality and subsequently caused peaks strongly disagree) and provide open text comments, as
in atypical periods of the year, thus leading to a consid- appropriate. Consensus agreement was defined as an agree-
erable impact on global healthcare systems. In addition to ment by a minimum of 75% of the participants (i.e., 75%
palivizumab and nirsevimab, several candidate monoclo- agree or strongly agree). The Delphi questionnaire was
nal antibodies targeting RSV are currently in the pipeline. completed by all 25 experts via an online survey in July
Moreover, breakthroughs have been made in RSV vaccines. 2023, and final drafted recommendations were formulated.
Therefore, experts in epidemiology, infectious diseases, Recommendations that achieved consensus were compiled
respiratory medicine, and methodology jointly developed and then presented.
the present consensus, synthesizing the available evidence
to better guide clinical practice. The consensus applies to
children younger than 5 years, focusing on the most recent Results
research advancements in the epidemiology, clinical mani-
festations, diagnosis, treatment, and prevention of RSV Disease burden
infections.
Recommendations: RSV substantially contributes to
the morbidity and mortality burden globally in chil-
Methods dren younger than 5 years, particularly during the first
6 months of life. Geographical area, climate, economic
In January 2023, a steering committee meticulously assem- status, and nonpharmaceutical interventions affect the
bled a consensus development group, including 25 special- seasonality and dynamics of RSV. Epidemiological sur-
ists with clinical and/or research expertise in epidemiology, veillance of RSV infections in the pediatric population
infectious diseases, respiratory medicine, and methodology. should be conducted proactively.
The composition of the 25 members was carefully designed Human RSV is the predominant pathogen identified in
to ensure representation from various geographic regions of children younger than 5 years with LRTIs [1, 8–13]. RSV
China, including Beijing, Shanghai, Guangdong, Chong- strains are classified into subtypes A or B based on the
qing, Hebei, Liaoning, Jiangsu, Zhejiang, Anhui, Hubei, genetic variability of the second hypervariable 2 region of
Hainan, Sichuan, and Shanxi. All members were free of the G gene, and these subtypes cocirculate with alternat-
financial or intellectual conflicts of interest and were granted ing dominance annually [14]. There were about 33.0 mil-
unrestricted involvement. lion RSV-LRTI episodes, 3.6 million RSV-LRTI hospital
The evidence searches and reviews were conducted in admissions, and 101,400 RSV-attributable overall deaths
January 2023 using electronic databases, including PubMed, globally in children younger than 5 years in 2019. The
Embase, Web of Science, and the Cochrane Library. On these estimated global incidence rate of RSV-LRTIs is 48.8 per
websites, we searched for articles without date restrictions, 1000 children annually, with variations between developed
using variations in terms for “respiratory syncytial virus”, and developing countries (24.3/1000 vs. 51.6/1000) [1].
“RSV”, “lower respiratory tract infection”, “bronchiolitis”, Infants aged 0–6 months are at the greatest risk for RSV-
“acute”, “viral pneumonia”, “neonatal”, “infant” “children”, LRTIs, with one in five RSV-LRTI episodes, 39% of RSV-
and “pediatric”. Furthermore, a comprehensive search was LRTI hospitalizations, and 45% of RSV-attributable deaths
conducted to uncover additional pertinent literature by exam- occurring within this specific age group of infants [1]. The
ining the references of the selected publications. References mortality rate also peaks during the first 6 months of life,
were regularly updated during the drafting of the consensus. with RSV being responsible for 3.6% of deaths in children
Reviewers collaborated in pairs, independently performed aged 0–6 months [1]. Low- and middle-income countries
reference screening and data extraction, and resolved any account for > 95% of RSV-LRTI episodes and > 97% of
disagreements through discussion or consultation with a RSV-attributable deaths and RSV-LRTI in-hospital deaths,
World Journal of Pediatrics (2024) 20:11–25 13

with disadvantaged economic status as a substantial risk Clinical features

factor [1]. It is noteworthy that mere 26% of RSV-attrib-
utable deaths in children younger than 5 years occurred Recommendations: clinicians should pay close attention to
within hospital settings, which is even more pronounced in infants and young children with RSV infections, especially
low-income countries, as only 19% of the RSV-attributable those at high risk, who are often severely affected by LRTIs
deaths occurred in hospitals [1]. The striking disparity that manifest as bronchiolitis and peak 2–4 days after onset.
between in-hospital and community deaths in low-income RSV can lead to extrapulmonary manifestations, such as
settings can mostly be explained by inadequate health- central nervous system infections.
care accessibility, high healthcare expenses, and restricted The clinical manifestations of RSV infections in chil-
hospital bed capacity during an RSV epidemic. Another dren widely vary in severity according to age. Infants and
explanation posits that deaths might occur in children with young children are usually severely affected by potentially
rapidly progressive illnesses despite their initial presenta- life-threatening LRTIs manifesting as bronchiolitis and/or
tion lacking signs of serious illness. The annual global pneumonia, whereas older children typically exhibit mild
expenditures for managing inpatient and outpatient cases upper respiratory tract infections [25–27]. When diagnos-
of RSV-LRTIs in children younger than 5 years amount to ing bronchiolitis, it should be taken into account that symp-
approximately €5 billion, 65% of which originates from toms usually peak 2 to 4 days after onset, during which time
developing countries [15]. The substantial disease burden symptoms of upper respiratory infections (e.g., fever, nasal
of RSV highlights the necessity for immunization pro- congestion, runny nose) subside but manifestations such as
grams targeting early life. shortness of breath, nasal swelling, intercostal or supracla-
RSV typically causes seasonal outbreaks globally, vicular contractures, use of accessory respiratory muscles,
with epidemics occurring from November to April or and grunts are incredibly exacerbated [28]. A hallmark char-
May in the Northern Hemisphere and from May to Sep- acteristic is a minute-to-minute variation in clinical find-
tember in the Southern Hemisphere, while seasonal ings [29]. On auscultation, crackles with recurrent wheez-
waves are typically associated with rainy seasons in the ing may be the predominant feature of bronchiolitis. Most
tropics [11, 16–18]. This variation can be attributed to children with bronchiolitis have either normal radiographs
the preference of RSV for cooler temperatures and higher or radiographic findings consistent with simple bronchioli-
humidity. In tropical regions, large aerosol droplets are tis, such as peribronchial thickening, hyperinflation, and
formed due to higher humidity and stable tempera- atelectasis [29]. The severity of clinical manifestations also
tures, resulting in less variability across the year. The varies considerably depending on whether the infection is
introduction and relaxation of NPIs during the SARS- primary or secondary. Almost all children have been infected
CoV-2 pandemic and their subsequent effects on RSV with RSV by the age of 2 years and repeated infections are
circulation have demonstrated the potential of specific common throughout life. LRTIs usually occur with initial
measures to prevent RSV infections [3–7]. NPIs have infections and may be present in more than 50% of second-
substantially affected RSV transmission by augment- ary infections [30–33]. Although the severity of the disease
ing the number of RSV-naive children and diminishing decreases after the third infection, approximately a quarter
population immunity against RSV [19, 20]. Growing of patients exhibit symptoms of LRTIs [33]. Infants aged
evidence suggests the potential for medium-term nega- 2–6 months are at the highest risk of developing RSV-LRTIs
tive effects through an immunity debt, in which a greater [30–32]. RSV infections cause inflammation that leads to
proportion of the population is susceptible to diseases airway obstruction and bronchial smooth muscle spasms.
after a long period of reduced exposure [4, 5, 21, 22]. Apnea occurs in up to 20% of infants and young children,
This immunity debt is a particular concern for RSV, for predominantly preterm infants, and may be the predominant
which temporary immunity is obtained through exposure symptom in infants admitted to the hospital. The relative
to the virus and maternal antibodies wane quickly; with- immaturity of ventilation control may contribute to its patho-
out seasonal exposure, immunity decreases and suscep- genesis [26, 34, 35]. Children with severe RSV infections
tibility to future, and potentially more severe, infections may develop respiratory failure, necessitating admission to
increase. In addition to NPIs, virus‒virus interactions intensive care units (ICUs) or the need for ventilatory sup-
can interfere with RSV dynamics and seasonality [23, port [36]. The risk factors associated with severe disease
24]. Profound and unprecedented changes in RSV sea- include preterm birth (delivery at < 12 weeks of gestation),
sonality pose new challenges in tackling RSV. Ongoing chronic lung disease of prematurity, and hemodynamically
monitoring of respiratory disease indicators is required significant congenital heart disease [37]. A multicenter
to inform future healthcare system planning, and the retrospective study examining risk factors associated with
development and use of RSV immunoprophylactic inter- severe RSV infections showed that 53% of children admit-
ventions should be considered. ted to the pediatric ICU (PICU) were classified as having a
14 World Journal of Pediatrics (2024) 20:11–25

high risk for severe RSV infections [37]. This study revealed of virus culture. While virus culture as a diagnostic test has
that hemodynamically significant congenital heart disease largely been superseded by molecular and antigenic testing,
emerged as the predominant risk factor, with chronic lung cultivation is still required to obtain viruses for phenotypic
disease, neuromuscular disease, congenital airway defects, analysis and as controls for other assay types. Serological
and preterm birth following suit in terms of prevalence. RSV assays are mostly employed in seroepidemiological studies
infections can affect other organs beyond the respiratory and research, but their utility in diagnosing acute RSV infec-
system. The central nervous system may also be involved, tions in clinical settings is limited [42]. Children’s endog-
leading to diseases including central apnea, epilepsy, RSV enous serological responses are less detectable or distinguish-
encephalopathy, RSV encephalitis, and RSV meningitis. A able in the presence of maternally derived or preexisting
systematic review and aggregated case series of 155 indi- antibodies [43–46]. RSV antigen detection by RADTs via
vidual cases from 26 countries in 2021 revealed that a range antigen capture and by DFAs via monoclonal antibodies for
of 1.2%–6.5% of children with RSV infections exhibit symp- antigen detection in infected cells are both less sensitive than
toms of acute encephalitis or encephalopathy [38]. Seizures quantitative reverse transcription polymerase chain reactions
were the most frequently reported neurological feature in (qRT‒PCRs) [47–54]. They are prone to higher false-posi-
this study (127/150, 85%), and RSV was detected in the tive results owing to cross-reactivity with similar proteins of
central nervous system in 12 cases [38]. Moreover, RSV related viruses, such as human metapneumovirus, and higher
infections have the potential to cause myocardial injury, false-negative results, mainly owing to antigenic variation
arrhythmias, myocarditis, and possibly fulminant myocardi- among viruses [55]. RADTs are still employed because they
tis [39–41]. Additional extrapulmonary manifestations, such are less costly and require less time, expertise, and mainte-
as rash, hyponatremia resulting from increased secretion of nance than qRT‒PCRs. Nevertheless, the key advantage of
antidiuretic hormone, and hepatitis, have also been reported RADTs, namely, their faster turnaround time, has been chal-
in children with RSV infections [40]. lenged by molecular point-of-care tests (mPOCTs), which
are gaining popularity in clinical laboratories and offer a
Laboratory diagnosis turnaround time comparable to that of RADTs but with the
performance of qRT-PCRs [56]. Currently, qRT-PCR-based
Recommendations: polymerase chain reaction-based assays assays have emerged as the mainstream diagnostic techniques
have emerged as the mainstream diagnostic technique for for RSV infections in children owing to their remarkable sen-
RSV infections in children owing to their excellent sensitiv- sitivity (86.4%–100%) and specificity (97.7%–100%) and
ity, specificity, and rapid turnaround time. are widely used instead of virus culture [48, 56–60]. Certain
There are four main ways to diagnose RSV (Table 1): nucleic acid amplification assays allow for discrimination
molecular detection using nucleic acid amplification tech- between RSV-A and RSV-B. However, they are more expen-
niques, rapid antigen detection tests (RADTs), direct immu- sive and not always available compared to antigen detection.
nofluorescence assays (DFAs), and virus culture. Viral cul- Elevated temperatures, freeze‒thaw cycles, and changes in
ture has previously been considered the gold standard for pH adversely affect viral infectivity [61]. Specimens should
RSV diagnosis given its excellent specificity. Nonetheless, be maintained at 4 °C for testing within 1–2 days, and those
its limited sensitivity, labor-intensive requirements, and long that cannot be tested within this timeframe should be stored
assay duration impose constraints on the practical application at − 70 °C or below for subsequent testing [57].

Table 1  Detection methods for RSV infections

Methods Test type Sensitivity Specificity Test time Notes

Nucleic acid Rapid molecular tests 90.6%–100% 99.4%–100%

13 min–1 h The mainstream diagnostic techniques; concerns about
amplification oversensitivity in detecting clinically insignificant
techniques low-level viral titers; require evaluation of assay
Molecular tests 86.4%–100% 97.7%–100% 1–8 h performance by external quality assessment
Antigen detection RADTs 72.4%–90% 89.5%–100% < 0.5 h Limited sensitivity in older models; automated tests
offer better performance; negative specimens should
be verified with another method
DFAs 93.5%–94.1% 96.8%–99.8% 1–4 h Requires a swab that allows for an appropriate number
of epithelial cells to be collected
Virus culture Shell vial culture – – 1–2 d Traditionally considered the gold standard; many fac-
Virus culture – – 3–7 d tors affect the success of virus isolation

RSV respiratory syncytial virus, RADTs rapid antigen detection tests, DFAs direct immunofluorescence assays
World Journal of Pediatrics (2024) 20:11–25 15

Recommendations: appropriate collection timing and supplementation when S ­ pO2 remains continuously below
specimen quality greatly influence the sensitivity of virus 90%–92% [73, 74]. A randomized controlled trial (RCT)
detection. We advise nasopharyngeal swab specimen col- found that using an oxygen saturation threshold of 90%
lection preferably in the first 4 days following disease onset, (compared with a threshold of 94%) for determining oxygen
if conditions permit, for molecular or antigenic detection of administration and hospital discharge significantly reduced
RSV infections. the need for supplemental oxygen, length of stay, and read-
The timing of sampling directly affects the accuracy of a mission rates [75].
laboratory diagnosis. For the highest sensitivity, we advise Respiratory support for infants and young children with
collecting specimens preferably in the first 4 days following bronchiolitis is generally provided in a stepwise fashion.
disease onset. The duration of RSV shedding in outpatients Traditionally, hypoxemia has been treated by administering
averages 9.8 ± 4.8 days in adults and can be even longer in low-flow or standard subnasal oxygen via nasal prongs at
children (up to 30 days), particularly in very young age and maximum ceiling rates of 2–3 L/minute or via face masks
immunocompromised patients (median, 16 days) [62–64]. at maximum ceiling rates of 15 L/minute [76]. Infants who
The number of positive samples drops more rapidly with are at risk of progressing to respiratory failure typically
time after disease onset when using antigen detection com- undergo advanced management with humidified high-flow
pared with qRT‒PCR, indicating that the sensitivity of anti- nasal cannula oxygen (HFNC) and/or nasal continuous posi-
gen detection is primarily high only within the initial days tive airway pressure ventilation (nCPAP) before resorting
after disease onset [65]. Notably, diagnostic sensitivity fell to tracheal intubation. HFNC enables the administration
by varying degrees when nucleic acid or antigen testing was of high flows (up to 2–3 L/kg/minute with a maximum of
available earlier [66]. Hence, it is imperative to take into 60 L/minute) with humidification to improve patient toler-
account factors such as the time of sampling from disease ance [77]. Evidence for the efficacy of HFNC therapy is
onset, age, immunological status, and the specific technolo- predominantly observational, with studies documenting
gies employed for detection when interpreting diagnostic improved respiratory parameters and reduced intubation
results. rates following the adoption of HFNC therapy [78]. One
Airway epithelial cells are the primary targets of RSV multicenter randomized trial suggested that nCPAP may be
infection in vivo. The anatomical site of specimen collection more effective than HFNC as the initial respiratory support
is an important factor influencing the sensitivity of diagnos- for young infants admitted to a PICU for moderate-to-severe
tic laboratory testing. Samples from nasopharyngeal swabs acute viral bronchiolitis (relative risk, 1.63) [79]. Nonethe-
are more sensitive than those from oropharyngeal swabs less, there were no significant differences between HFNC
because of the higher viral load in the nasopharynx than and nCPAP for time to liberation from respiratory support
in the oropharynx [67, 68]. Furthermore, nasopharyngeal (52.9 h for HFNC vs. 47.9 h for nCPAP) [80]. As the HFNC
specimens are more sensitive to RSV than mid-turbinate system is easily set up and well tolerated by patients, it has
specimens [69–71]. been widely adopted in the PICU and for the interhospi-
tal transport of critically ill children and is considered an
Treatment effective means of providing postextubation support, par-
ticularly in underserved settings [81]. However, in children
Recommendations: supportive care to improve airway with hemodynamic instability, intractable apnea, or loss of
patency, ensure oxygen demand, and guarantee adequate protective airway reflexes, clinicians should prioritize initial
feeding and hydration is the mainstay of treatment for chil- endotracheal intubation over the use of HFNC or nCPAP
dren with RSV infections. [82].
Airway obstruction and atelectasis in bronchiolitis can Superficial nasal aspiration to improve airway patency,
result in hypoxemia, which can be relieved by oxygen sup- oxygen saturation, and feeding is appealing given that infants
plementation. Currently, there is a paucity of evidence sup- are obligatory nasal breathers. Nevertheless, there is a lack
porting the pulse oxygen saturation ­(SpO2) cutoff value for of RCTs that have investigated the effects of nasal aspiration
initiating oxygen supplementation. The American Academy on bronchiolitis. The available evidence of limited quality
of Pediatrics (AAP) practice guideline suggests S ­ pO2 90% indicates a potential association between deep nasal aspira-
as the threshold for initiating oxygen supplementation [72]. tion and adverse outcomes as well as an extended duration
The British National Institute of Health and Care Excel- of hospitalization [83]. Further evaluation of the benefits of
lence advises the same ­SpO2 threshold for initiating oxy- nasal aspiration is needed.
gen supplementation for children aged > 6 weeks as the Infants hospitalized with RSV bronchiolitis often expe-
AAP, whereas a 92% S ­ pO2 threshold is advised for infants rience difficulty maintaining adequate hydration to ensure
aged < 6 weeks or children of any age with underlying health the stability of internal water and electrolyte levels owing
conditions [73]. In China, it is advised to initiate oxygen to nasal congestion or hypoxemia related to lower airway
16 World Journal of Pediatrics (2024) 20:11–25

disease. Therefore, maintaining proper hydration remains a development of antiviral medications aimed at directly
fundamental aspect of medical treatment. For children who impeding viral replication. Nonetheless, the number of
can tolerate enteral feeding, strategies to maintain hydration antiviral medicines approved for clinical usage is lim-
include frequent feedings in smaller portions or orogastric or ited due to either adverse effects or the development of
nasogastric feedings [84–86]. A multicenter randomized trial resistance [95]. Ribavirin, a well-established antiviral
in Australia and New Zealand comparing nasogastric hydra- agent with broad efficacy against RNA viruses, is not fre-
tion with intravenous hydration in infants aged 2–12 months quently employed in treatment because of concerns over
revealed no significant differences in terms of length of stay, its potential carcinogenic and teratogenic effects as well
adverse events, ICU admission, or the need for ventilation as detrimental outcomes in fetal development. However,
but a higher successful first-attempt insertion rate in the it is worth noting that these deleterious effects have only
former [86]. Plasma antidiuretic hormone levels may be been observed in rodent models instead of in primates or
elevated in certain instances, resulting in fluid retention and human beings [96]. Available data regarding the safety of
hyponatremia [87]. If intravenous fluids are administered, ribavirin in pediatric patients are limited [97]. There is a
isotonic fluids are preferred to prevent hyponatremia [73]. limited amount of research with suboptimal quality and
Recommendations: the role of nebulized 3% hypertonic small sample sizes that has examined the impact of riba-
saline in children with RSV-LRTIs is controversial. How- virin on RSV infections in children. In a systematic review
ever, according to the latest meta-analysis, it improves clini- conducted in 2022, the available data from 10 observa-
cal symptoms, reduces hospitalization rates, and shortens tional studies encompassing both adult and pediatric popu-
the length of stay. lations, as well as an RCT involving healthy infants, were
Nebulized hypertonic saline (HS) solution at a concen- synthesized. The findings of this review indicated that
tration of 3% or more has been found to hydrate the airway the administration of ribavirin did not yield significant
surface, reduce airway edema, improve mucus clearance, reductions in mortality rates, proportions of mechanically
and exhibit good tolerability with few adverse effects [88]. ventilated patients, viral load levels, or rates of bacterial
Numerous rigorous studies have been undertaken to investi- coinfections among previously healthy individuals with
gate the efficacy of treatment with HS in children with RSV- RSV infections. The available evidence exhibits substan-
LRTIs, but they have yielded conflicting findings in certain tial heterogeneity, covering variations in the routes of
instances. Multiple RCTs have demonstrated no differences administration, doses and durations of ribavirin therapy.
in admission rate and average length of stay between the Hence, it is not advisable to administer ribavirin to pedi-
nebulized 3% HS and control groups [89–92]. In contrast, atric patients without underlying health conditions. None-
the latest systematic meta-analyses from RCTs indicated theless, ribavirin may serve as an alternative treatment for
that HS nebulization improved clinical symptoms, reduced RSV infections in immunocompromised patients. A study
hospitalization rates, and shortened the length of stay [93, found that in patients with hematological malignancies and
94]. A systematic analysis enrolling 4186 children from 150 hematological stem cell transplants, mortality was signifi-
RCTs and 32 publications showed that 3% HS nebulization cantly reduced when ribavirin was administered, with a
was effective in reducing the length of stay and symptom relative risk of 0.32 [97].
severity in children with acute bronchiolitis [94]. A meta- Several novel antiviral drugs are under investigation.
analysis pooled 35 RCTs and found that HS nebulization Ziresovir (AK-0529), a potent, selective, and orally bio-
significantly reduced length of stay and hospitalization rates, available RSV F protein inhibitor that primarily blocks the
as well as improved 24-, 48-, and 72-hour clinical severity entry of the virus into the host cell, is currently the only
scores in children with bronchiolitis [93]. Moreover, there direct-acting antiviral agent against RSV that has completed
were no significant differences between the effects of HS at a phase 3 registration clinical study. The clinical study met
a concentration of 3% and those at concentrations exceeding the primary and key secondary endpoints, showing signifi-
3%. Therefore, it can be considered a treatment option for cant clinical improvement in RSV bronchiolitis accompanied
children with RSV-LTRIs. by a marked reduction in viral load and a favorable safety
Recommendations: antiviral medications are not typically profile. Along with other novel antivirals, such as RV521,
advised for previously healthy children with RSV-LRTIs, JNJ-53718678, and EDP-938, they showed good pharma-
considering their safety and effectiveness. Nonetheless, the cokinetics and potent antiviral effects in phase 2 and 3 clini-
administration of antiviral drugs, such as ribavirin, may cal trials [98–101]. The nebulized RSV antiviral drug ALX-
yield favorable outcomes in children with immunodefi- 0171 reduced the RSV load in mid-nasal turbinate samples
ciency. New, promising antiviral candidates are under clini- but did not provide significant relief from clinical symptoms
cal trials. [102].
In light of the significant global burden of RSV infec- Recommendations: administration of nebulized or sys-
tions, considerable resources have been dedicated to the temic glucocorticoids is not advised as a routine treatment
World Journal of Pediatrics (2024) 20:11–25 17

for children with RSV-LRTIs due to the absence of signifi- sulfate as a bronchodilator is also not associated with sig-
cant benefits in both short- and long-term outcomes. nificant improvements in the bronchiolitis severity score or
Considerable studies have been undertaken to investigate length of stay [113, 114].
the efficacy of glucocorticoids in the treatment of children Based on a rigorous evidence-based medical rationale,
with RSV infections. These studies have yielded findings international guidelines rarely advise the routine adminis-
pertaining to various outcomes, including the remission tration of bronchodilators in managing bronchiolitis [72].
of clinical symptoms, hospitalization rates, length of stay, Infected children exhibit a high degree of heterogeneity in
and long-term prognosis. Given that RSV is the predomi- their clinical presentation, immune response, and molecular
nant pathogen in the pathogenesis of bronchiolitis, a large immune profile and show different responses to treatment
portion of the studies on RSV have relied on investigations options, which raise the requirement for phenotype-specific
conducted on individuals diagnosed with bronchiolitis of treatment strategies. An RCT enrolled 200 children with
unidentified etiology. However, the administration of gluco- bronchiolitis and showed that for children with eczema
corticoids by different routes, doses, and formulations does or a family history of asthma in a first-degree relative, the
not yield the expected outcomes [103–108]. administration of oral dexamethasone combined with sal-
High-quality evidence from RCTs consistently suggests butamol nebulization reduced the time to discharge from
that both nebulized and systemic glucocorticoids with dif- 27.1 hours to 18.6 hours. Patients with clinical features, such
ferent dosages, durations, and types do not prevent hos- as eczema or a family history of asthma in a first-degree
pital admission and do not improve short- and long-term relative, may benefit from salbutamol combination therapy
outcomes in children with RSV-LRTIs. Therefore, it is [109]. A study conducted at Sapienza University, Rome,
generally not advisable to administer glucocorticoids, not- Italy, prospectively enrolled 312 healthy full-term infants
withstanding their potential efficacy in particular popula- hospitalized for bronchiolitis during 12 epidemic seasons,
tions. As mentioned in the section on bronchodilators, oral with diagnosis confirmed by positive RSV nucleic acid in
dexamethasone combined with salbutamol nebulization has nasopharyngeal washings and sequencing of RSV genotypes
been shown to reduce the length of stay in a select subset of [115]. Stratification data based on genotypes revealed that
children with bronchiolitis with eczema or a family history low-virulence RSV genotypes preferentially caused bron-
of asthma in a first-degree relative [109]. chiolitis in infants who might have a genetic susceptibility
Recommendations: administration of bronchodilators, to asthma and atopy. This specific population may be better
such as the beta-2 agonist salbutamol, is not advised as a treated with bronchodilators.
routine treatment for children with RSV-LRTIs. Recommendations: the prevalence of RSV with bacte-
There is no observed benefit in administering inhaled rial coinfections is low. The administration of antibiotics in
bronchodilators, such as beta-2 agonists alone or in combi- children with RSV-LRTIs is generally discouraged, unless
nation with other therapies, to children with wheezing after there is sufficient suspicion or definitive evidence of bacte-
RSV infections [110, 111]. A 2014 Cochrane systematic rial coinfections.
review assessed the effects of bronchodilators on infantile Determining the accurate prevalence of subsequent bacte-
bronchiolitis and concluded that the administration of sal- rial infections among infants and toddlers who are hospital-
butamol did not significantly reduce hospital admissions or ized for RSV infections poses a considerable challenge. A
shorten the length of stay [111]. Another 2020 systematic 9-year prospective study was conducted at the University of
review and meta-analysis of 13 RCTs with 977 participants Rochester School of Medicine in New York involving 565
showed that treatment of infantile bronchiolitis with salbuta- children with RSV infections, with the aim of investigating
mol resulted in increased respiratory and heart rates but did the prevalence of secondary bacterial infections in these chil-
not improve clinical severity scores, length of stay, or oxy- dren. The results showed that the rate of secondary bacterial
gen saturation in infants with bronchiolitis [110]. Hence, it is infections was only 1.2% in children with RSV infections
not advisable to propose the administration of salbutamol in overall. Among the 352 children who did not receive anti-
the treatment of pediatric patients with RSV-LRTIs due to its biotics, the rate of secondary bacterial infections was found
lack of efficacy in improving clinical outcomes and its poten- to be 0.6% [116]. However, the administration of antibiotics
tial for adverse effects. A recently published retrospective in the treatment of bronchiolitis continues to be substantial,
study analyzed children diagnosed with acute bronchiolitis estimated at about 25%, despite the well-established viral
in December during four epidemic periods, enrolling 1767 etiology of the disease and the low prevalence of subsequent
children [112]. The study showed that with the decreasing bacterial infections [117, 118]. Several factors contribute to
rate of salbutamol administration over time, hospitalization the elevated utilization of antibiotics, including the manifes-
rates could be reduced without changing readmission rates tation of a high fever, challenges in accurately interpreting
within 72 hours, further supporting the unnecessary admin- chest radiographs, the apparent ill appearance of infants,
istration of salbutamol. The administration of magnesium and the concern for missing an alternative diagnosis, such
18 World Journal of Pediatrics (2024) 20:11–25

as pneumonia. A systematic review conducted in 2014 by Although preterm infants and those with underlying
Cochrane encompassed seven RCTs that were either single- lung or heart disease are at the highest risk for severe ill-
blind or double-blind to compare the effectiveness of antibi- ness, the majority of RSV-related hospitalizations occur in
otics against a placebo or control in the treatment of bronchi- healthy full-term infants [127]. Next-generation RSV pre-
olitis, involving a total of 824 children aged < 2 years with vention antibodies have been engineered with Fc mutations
bronchiolitis, and the findings did not support the admin- to extend their half-life and enable single-dose protection for
istration of antibiotics for the treatment of bronchiolitis in all infants in an entire RSV season. The leading candidate
terms of oxygen saturation, bronchodilator application, tube is nirsevimab, a monoclonal antibody approved by multiple
feeding, wheezing, shortness of breath, feeding difficulties, countries for the prevention of RSV-LRTIs in infants aged
fever, cough, symptom duration, readmission, and PICU 0–12 months before or during their first RSV season, and
admission [117]. A systematic analysis conducted in 2017 in children up to 24 months of age who remain vulnerable
included only two RCTs and found that the administration to severe RSV disease through their second RSV season
of antibiotics did not reduce the proportion of children with [128]. Nirsevimab demonstrated an overall efficacy of 75%
persistent symptoms at follow-up, rehospitalized for respira- in preventing the need for medical care in term and pre-
tory disease within 6 months, or with wheezing at 6 months term infants, was effective in reducing hospitalization, and
compared with the control group [119]. Based on the avail- provided more prolonged protection than a placebo [129,
able evidence, it is not advisable to prescribe antibiotics for 130]. Clesrovimab, another anti-F monoclonal antibody,
RSV-LRTIs. Clinicians are more concerned about scenarios is currently undergoing assessment in a phase 2b/3 trial
necessitating the utilization of antibiotics. Limited evidence (NCT04767373), which determines the efficacy of reduc-
suggests that serum C-reactive protein > 60 mg/L and pro- ing RSV disease in healthy pre- and full-term infants [131].
calcitonin ≥ 2 µg/L can be used as diagnostic markers to Another potential long-acting antibody, trinomab, is also
identify bacterial infections in children with LRTIs and may in the early stages of clinical trials for RSV prevention in
provide guidance for the administration of antibiotics [120, infants [132].
121]. Further research is necessary to establish conclusive The administration of intravenous immunoglobulin
evidence on the exact indications of bacterial coinfections (IVIG) for the management of RSV infections is pre-
and to address inquiries pertaining to the immediate and dominantly grounded in empirical management or case
lasting advantages of antibiotics [116, 122]. reports [133]. Limited and inconclusive evidence sup-
ports a potential beneficial effect of intravenous adminis-
Prevention tration of nonspecific human immunoglobulin in patients
with severe bronchiolitis and animals infected with RSV
Recommendations: a new strategy for preventing RSV infec- [134, 135]. However, an RCT investigating the effects of
tions: a single injection of a long-acting monoclonal anti- immunoglobulin therapy on RSV-LRTIs in children did
body is advised for infants before or during the first RSV not yield any significant differences between the treat-
season to prevent RSV-LRTIs. Administration of intravenous ment and placebo groups in terms of outcomes such as
nonspecific immunoglobulin is not advised as routine man- mortality, length of stay, ventilation time, oxygen depend-
agement for children with RSV infections. ence, or adverse events [136, 137]. There may be a small,
Maternal antibodies are generally protective against neo- nonenveloped, and transmissible virus in the blood donor
natal RSV infections in the first weeks of life. However, population, although IVIG is manufactured under strin-
these antibodies rapidly wane and vary in effectiveness gent safety guidelines. Therefore, safety concerns remain
[123]. The administration of monoclonal antibodies is con- with the administration of immunoglobulin in viral infec-
sidered a favorable approach for the prophylaxis of RSV tions [138]. RSV infections are primarily treated with
infections due to their high pathogen specificity [124]. Pal- supportive care; therefore, IVIG therapy is not advised
ivizumab, the first licensed monoclonal antibody for RSV for children with RSV infections.
prophylaxis, has been granted approval by multiple countries Recommendations: nonpharmaceutical interventions
[125]. It functions as a humanized monoclonal antibody tar- remain the predominant approach for RSV prevention. High-
geting the RSV F-glycoprotein. Palivizumab is administered risk populations should take nonpharmaceutical interven-
as five monthly intramuscular injections during the peak tions to prevent RSV infections. Efficient pediatric RSV
season to infants born before 29 weeks gestation, infants vaccines are not currently available except for monoclonal
born before 32 weeks gestation with chronic lung disease antibodies, but several vaccines are currently in clinical
of prematurity, and infants with hemodynamically signifi- trials.
cant heart disease [126]. However, the cost-effectiveness of As RSV is spread by horizontal transmission, via saliva
palivizumab prevents its universal use, even among infants droplets, and through contact with contaminated objects and
at high risk. surfaces, NPIs (such as frequent and accurate hand hygiene,
World Journal of Pediatrics (2024) 20:11–25 19

staying at home, physical distancing, and wearing masks) which is strongly associated with the development of recur-
are the most effective and safe methods to reduce the risk of rent wheezing and asthma later in life [155–158]. A recent
respiratory virus infections. Moreover, NPIs have a preven- review of 906 patients with asthma found that viral LRTIs in
tive effect against environmental factors that promote the infants aged ≤ 2 years were associated with an increased risk
spread of the virus, such as tobacco smoke, air pollution, of asthma for up to 20 years thereafter (odds ratio = 5.0; 95%
temperature drops, and indoor crowding [139]. NPIs are confidence interval, 3.3–7.5), with RSV as the predominant
cost-effective for controlling respiratory diseases. During pathogen (83.3%) [159]. Another prospective population-
the SARS-CoV-2 pandemic, the global deployment of NPIs based cohort study showed that the prevalence of asthma at
has been associated with a significant decrease in the inci- age 5 years was higher in children with RSV infections in
dence of RSV compared with the past [140–142]. Wearing a infancy than in children without evidence of RSV infections
mask is an important measure of NPIs and has a significant in infancy (21% vs. 16%) [150]. Nevertheless, it is unclear
preventive effect not only on respiratory infections in healthy whether RSV infections are causal factors, markers of sus-
children but also in immunocompromised children, includ- ceptibility to respiratory illness, or both [160, 161]. A sys-
ing those undergoing hematopoietic stem cell transplanta- tematic review and meta-analysis of 35 studies appraised the
tion, as well as newborns in high-risk enclosed settings [143, strength of evidence for a causal effect between laboratory-
144]. Nevertheless, due to the special vulnerability of chil- confirmed RSV-LRTIs before the age of 2 years and recur-
dren, wearing masks also causes discomfort and side effects ring wheezing illnesses [162]. The results were consistent
such as increased heart rate, headache, fatigue, attention with the hypothesis that a substantial proportion of the asso-
disorders, and claustrophobia [145]. This assertion holds ciation between RSV infections and subsequent wheezing
special validity in the case of young infants who encounter comes from shared genetic predisposition, with insufficient
challenges when attempting to don masks. Therefore, other evidence to advise immunoprophylaxis for the prevention of
preventive interventions, such as staying at home or away wheezing illness. Long-term follow-up studies are needed
from crowds, are advised during RSV outbreaks for young before assuming that prevention of RSV-LRTIs can reduce
infants. During the RSV season, medical staff should strictly recurrent wheezing or asthma.
implement NPIs when caring for hospitalized children. In conclusion, RSV substantially contributes to morbid-
Despite the considerable disease burden of RSV infec- ity and mortality globally in children younger than 5 years,
tions, there are few vaccine options for preventing pediat- especially during the first 6 months of life and in low- and
ric RSV infections [146]. Efforts to develop an RSV vac- middle-income countries. Profound and unprecedented
cine continue to be vigorous. Currently, there are various changes in RSV epidemiology after the SARS-CoV-2 pan-
approaches for developing RSV vaccines, including particle- demic pose new challenges in tackling RSV. Healthcare
based, vector-based, live attenuated or chimeric, subunit, professionals must address the increasing challenge of RSV
and mRNA vaccines [147]. However, there are no licensed in clinical practice. Here, we produced evidence-based rec-
pediatric RSV vaccines available for implementation in ommendations that pertain to the diagnosis, treatment, and
clinical settings. The development of vaccines remains prevention of RSV infections. Transparency in production
uninterrupted, and failures and updates continue to occur. and reporting promotes scientific discourse and improves
Encouragingly, several candidate vaccines are undergoing the usability of the consensus for clinicians. The consensus
phase 3 trials. Maternal vaccines for infant protection are development group acknowledges that the lack of high-qual-
also under development [148]. ity evidence for certain recommendations is a limitation of
this consensus but tries to take this into consideration when
formulating recommendations. Further studies orientated
Long‑term consequences by clinical problems will be required to address knowledge
gaps and help inform the management and prevention of
Recommendations: RSV-LRTIs in early childhood are asso- RSV infections.
ciated with long-term complications, including impaired
lung function, recurrent wheezing, and asthma. Acknowledgements The authors thank Yu-Hang Wu, Lin-Juan Xiang,
Increasing evidence suggests an unequivocal associa- Qun Wang, Xin-Xin Zeng and Jia-Li Bao for providing feedback on
written language and providing organizational support.
tion between early-life RSV-LRTIs in children and the sub-
sequent development of asthma, recurrent wheezing, and Author contribution ZXL: conceptualization, investigation, methodol-
impaired lung function [149–154]. The immune response of ogy, visualization, writing—original draft, and writing—review and
the body after RSV infections in infants and children, along editing. HW, JYH, and LLN: conceptualization, investigation, meth-
odology, writing—original draft, and writing—review and editing.
with the influence of neuromodulatory mechanisms and the ZX, XZD, LHM, ZHL, CBQ, CY, SX, XY, SSN, ZSY, SYX, CL, LJ,
persistence of RSV leading to adaptive remodeling of air- HCL, DXY, LDJ, XHM, and ZDY: conceptualization, investigation,
way ultrastructure, may cause airway hyperresponsiveness, methodology, writing—review and editing. ZM: conceptualization,
20 World Journal of Pediatrics (2024) 20:11–25

investigation, methodology, supervision, visualization, and writing— 5. Agha R, Avner JR. Delayed seasonal RSV surge observed during
review and editing. CZM: conceptualization, investigation, methodol- the COVID-19 pandemic. Pediatrics. 2021;148:e2021052089.
ogy, resources, supervision, visualization, and writing—review and 6. Eden JS, Sikazwe C, Xie R, Deng YM, Sullivan SG, Michie
editing. HLS: conceptualization, investigation, methodology, project A, et al. Off-season RSV epidemics in Australia after easing of
administration, resources, supervision, visualization, writing—original COVID-19 restrictions. Nat Commun. 2022;13:2884.
draft, and writing—review and editing. ZXL, HW, JYH, LLN, ZX, 7. Castagno E, Raffaldi I, Del Monte F, Garazzino S, Bondone
XZD, LHM, ZHL, CBQ, CY, SX, XY, SSN, ZSY, SYX, CL, LJ, HCL, C. New epidemiological trends of respiratory syncytial virus
DXY, LDJ, XHM, and ZDY contributed equally to this work. bronchiolitis during COVID-19 pandemic. World J Pediatr.
2023;19:502–4.
Funding None. 8. O’Brien KL, Baggett HC, Brooks WA, Feikin DR, Hammitt LL,
Higdon MM, et al. Causes of severe pneumonia requiring hospi-
Data availability Data sharing is not applicable to this article as no tal admission in children without HIV infection from Africa and
datasets were generated or analyzed during the current study. Asia: the PERCH multi-country case-control study. The Lancet.
2019;394:757–79.
Declarations 9. Bénet T, Sánchez Picot V, Messaoudi M, Chou M, Eap T, Wang
J, et al. Microorganisms associated with pneumonia in chil-
Conflict of interest Author Zhi-Min Chen is a member of the Editorial dren <5 years of age in developing and emerging countries:
Board for World Journal of Pediatrics. The paper was handled by the the GABRIEL pneumonia multicenter, prospective, case–
other Editor and has undergone a rigorous peer review process. Author control study. Clin Infect Dis Off Publ Infect Dis Soc Am.
Zhi-Min Chen was not involved in the journal's review of, or decisions 2017;65:604–12.
related to, this manuscript. Other authors have no conflict of interest 10. Global Burden of Disease Pediatrics Collaboration, Kyu HH,
to disclose. No financial or nonfinancial benefits have been received Pinho C, Wagner JA, Brown JC, Bertozzi-Villa A, et al. Global
or will be received from any party related directly or indirectly to the and National Burden of Diseases and Injuries Among Chil-
subject of this article. dren and Adolescents Between 1990 and 2013: findings from
the Global Burden of Disease 2013 Study. JAMA Pediatr.
Ethical approval Not needed. 2016;170:267.
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of respiratory syncytial virus infection in hospitalized children
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as you give appropriate credit to the original author(s) and the source, Epidemiological study of respiratory syncytial virus-associated
provide a link to the Creative Commons licence, and indicate if changes acute lower respiratory tract infection in hospitalized children
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World Journal of Pediatrics (2024) 20:11–25 25

Authors and Affiliations

Xian‑Li Zhang1 · Xi Zhang2 · Wang Hua1 · Zheng‑De Xie3 · Han‑Min Liu4 · Hai‑Lin Zhang5 · Bi‑Quan Chen6 ·
Yuan Chen7 · Xin Sun8 · Yi Xu9 · Sai‑Nan Shu10 · Shun‑Ying Zhao11 · Yun‑Xiao Shang12 · Ling Cao13 · Yan‑Hui Jia1 ·
Luo‑Na Lin1 · Jiong Li14 · Chuang‑Li Hao15 · Xiao‑Yan Dong16 · Dao‑Jiong Lin17 · Hong‑Mei Xu18 · De‑Yu Zhao19 ·
Mei Zeng20 · Zhi‑Min Chen21 · Li‑Su Huang1

10
* Mei Zeng Department of Pediatrics, Tongji Hospital, Tongji Medical
[email protected] College, Huazhong University of Science and Technology,
Wuhan, China
* Zhi‑Min Chen
11
[email protected] Department of Respiratory Disease, Beijing Children’s
Hospital, Capital Medical University, Beijing, China
* Li‑Su Huang
12
[email protected] Department of Pediatric Respiratory, Shengjing Hospital
of China Medical University, Shenyang, China
1
Department of Infectious Disease, Children’s Hospital, 13
Respiratory Department, Children’s Hospital Affiliated
Zhejiang University School of Medicine, 3333 Binsheng
to Capital Institute of Pediatrics, Beijing, China
Road, Binjiang District, Hangzhou 310052, China
14
2 Department of Clinical Epidemiology, Aarhus University,
Clinical Research Unit, Xin Hua Hospital Affiliated
Aarhus, Denmark
to Shanghai Jiao Tong University School of Medicine,
15
Shanghai, China Department of Respirology, Children’s Hospital of Soochow
3 University, Suzhou, China
Beijing Pediatric Research Institute, Beijing Children’s
16
Hospital, Capital Medical University, Beijing, China Department of Respiratory, Children’s Hospital of Shanghai,
4 Children’s Hospital Affiliated to Shanghai Jiao Tong
Department of Pediatric Pulmonology, West China Second
University School of Medicine, Shanghai, China
University Hospital, Sichuan University, Chengdu, China
17
5 Department of Infectious Disease, Hainan Women
Department of Pediatric Pulmonology, the Second Affiliated
and Children’s Medical Center, Haikou, China
Hospital & Yuying Children’s Hospital, Wenzhou Medical
18
University, Wenzhou, China Department of Infectious Disease, Children’s Hospital
6 of Chongqing Medical University, Chongqing, China
Department of Infectious Disease, Anhui Provincial
19
Children’s Hospital, Hefei, China Department of Respiratory, Children’s Hospital of Nanjing
7 Medical University, Nanjing, China
Department of Pediatrics, the Second Hospital of Hebei
20
Medical University, Shijiazhuang, China Department of Infectious Diseases, Children’s Hospital
8 of Fudan University, 399 Wanyuan Road, Minhang District,
Department of Pediatrics, Xijing Hospital, the Fourth
Shanghai 201102, China
Military Medical University, Xi’an, China
21
9 Department of Respiratory Diseases, Children’s Hospital,
Department of Infectious Disease, Guangzhou Women
Zhejiang University School of Medicine, 3333 Binsheng
and Children’s Medicine Center, Guangzhou Medicine
Road, Binjiang District, Hangzhou 310052, China
University, Guangzhou, China