Respiratory syncytial virus (RSV) is the most important viral pathogen that causes acute lower respiratory tract infections (ALRTI) in children under 5 years old worldwide [1]. RSV infection is the primary factor in hospitalization for viral respiratory infection in infants and young children, and it seriously endangers children's health, especially for premature babies, infants and young children with congenital heart disease or primary immune deficiency. At present, there are no RSV vaccines and effective antiviral drugs for the treatment of RSV. The only humanized specific antibody that can be used for RSV prevention has not been introduced into domestic clinical applications. There are still some shortcomings in the epidemic, pathogenic mechanism, diagnosis, treatment and prevention of RSV infection in children. In order to further standardize the diagnosis, treatment and prevention of RSV infection in children, this expert consensus is specially formulated based on the latest research progress of RSV at home and abroad.
1 Disease burden and epidemic profile of RSV infection in children
1.1 Disease burden of RSV infection in children RSV is the most common viral pathogen that causes ALRTI in infants and young children [1], and its population infection rate increases with age. Serum epidemiological surveys show that the positive rate of anti-RSV IgG antibodies in the population is 71% between 1 and 6 months old, and gradually increases with age. It is 84%, 89%, 96% and 98% between 6 and 12 months old, 1 to 3 years old, 3 to 6 years old, and 6 to 20 years old, respectively, and 100% between 20 years old and above [2]. Epidemiological data show that in 2005, there were about 33.8 million cases of ALRTI in children caused by RSV infection, accounting for 22% of all children's ALRTIs, of which 55,600 to 199,000 deaths in children, accounting for 3% to 9% of all deaths [3]. A study by the Global Epidemiological Surveillance Network of RSV in 2015 assessing the burden of disease by the World Bank's revenue region showed that there were about 33.1 million new cases of RSV infection in children under 5 years of age around the world, of which 3.2 million children needed hospitalization (28% of all ALRTIs), and 59,600 deaths in hospitalized children (13% to 22% of ALRTI deaths); among children under 6 months, 1.4 million were hospitalized, of which 27,300 died; of all deaths, 99% of the children were from developing countries [4]. The five countries with the highest incidence of RSV infection are Pakistan , India, Nigeria , China and Indonesia, contributing nearly half of the world's RSV-ALRTI disease burden [5]. It is estimated that the incidence rate of ALRTI caused by RSV infection in my country is about 31.0 (18.7~50.8)/1 000 [4], accounting for 18.7% of ALRTI in children [6]. Ning et al. [7] conducted a meta-analysis of the pathogens of community-acquired pneumonia in children under 5 years old in my country, and found that RSV accounted for 17.3%; among the lower respiratory tract infection pathogens in children under 18 years old from 2013 to 2015, RSV accounted for 13.9%, ranking first among viral pathogens; among hospitalized children under 2 years old in North China, such as Beijing and Shandong, the detection rate of RSV is as high as 33.3%, ranking first among viral pathogens [8-9]. The incidence of RSV infection in neonates is not low. Research based on three communities shows that RSV infection occurs 40 times per 1,000 neonates each year, and the hospitalization rate of RSV-ALRTI in neonatal period is 15.9 (95%CI: 8.8-28.9)/1,000 [4].
After RSV infection, the risk factors for developing ALRTI include premature birth, low birth quality, male, siblings, mother smoking, a history of atopic dermatitis, non-breastfeeding and living environment, etc. [10]. High-risk groups who develop into severe illness include age <12>
The mortality rate of RSV infection in different countries varies greatly. According to the in-hospital case fatality ratios (hCFR) of children with RSV-ALRTI, the hCFR of all ages in developing countries is higher than that of developed countries, and the hCFR of low and low- and middle-income countries is significantly higher than that of high-income countries. Taking infants aged 6 to 11 months as an example, the hCFRs of low-income, low-middle-income, upper-middle-income and high-income countries were 9.3 (3.0 to 28.7)/1 000, 2.8 (1.8 to 4.4)/1 000, 2.4 (1.1 to 5.4) 0.9/1 000 and (0.2 to 4.0)/1 000, respectively. The RSV Global Online Mortality Database (RSV GOLD) reviewed the individual data of children aged 0 to 59 months who died from community-acquired RSV infection from January 1, 1995 to October 31, 2015, and found that the age of RSV-related deaths also varies in different income countries. The median age of low-income or low-middle-income countries was 5.0 months (IQR: 2.3 to 11.0 months), 4.0 months (2.0 to 10.0 months), and 7.0 months (3.6 to 16.8 months) in upper-middle-income countries [5]. However, compared with the historical RSV mortality rate, RSV-related mortality rates in all age groups and regions have a downward trend [4].
1.2 Overview of the epidemic of RSV infection RSV infection is widely prevalent worldwide, and its popularity is affected by factors such as geographical location, temperature and humidity. In countries and regions in the northern hemisphere, there is a clear epidemic season for the epidemic of RSV, mainly concentrated in the winter and early spring seasons from November to February of the following year [17-18]; in the tropical and subtropical regions, the infection rate of RSV in the wet rainy season increased significantly [18]. Based on the method of molecular detection of RSV, with the positive detection rate of 10% or above as the threshold, the RSV epidemic season in northern my country began in the 41st week (mid-October) and ended in the 20th week of the following year (mid-May), and lasted for 33 weeks [16]; in the south, Wenzhou region, RSV infection is easy to occur in winter and spring, which is closely related to temperature [19].
2 Introduction to RSV and pathogenic mechanism of infection
2.1 Introduction to RSV RSV was isolated from the respiratory tract of chimpanzees in 1956. It is called respiratory syncytial virus because it causes adjacent cells to fusion during cell culture and cell lesions to form a syncytial structure similar to syncytials. According to the virus species, it is divided into human respiratory syncytial virus (HRSV) (isolated from infant respiratory specimens in 1957), bovine respiratory syncytial virus (BRSV) and murine respiratory syncytial virus (MRSV). RSV was originally belonged to the genus Pneumovirus of Paramyxoviridae. In 2015, the International Committee on Taxonomy of Viruses (ICTV) changed the RSV to the Orthopneumovirus of Pneumoviridae, and renamed HRSV to the human orthopneumovirus in 2016 [20]. The genome structure of the RSV is a non-segmental single-strand negative strand RNA, with a total length of about 15.2 kb, encoding 11 proteins, namely the non-structural proteins NS1, NS2, nucleocapsid protein N, phosphoprotein P, matrix protein M, small hydrophobicin SH, adhesion protein G, fusion protein F, M2-1, M2-2 and polymerase subunit protein L (Figure 1, 2) [21].
G and F proteins are two important glycoproteins on the surface of the RSV membrane. They are important antigen proteins for viruses and are the main viral antigens that stimulate the body to produce neutralizing antibodies. G protein is mainly responsible for adhesion to host cells, and F protein mediates the fusion of viruses with host cell membrane [21]. Among the protein sequences of the entire genome of RSV, the G protein encoding gene has a large variation and is divided into the first high variable region and the second high variable region. Currently, genotype identification of RSV is carried out internationally based on the nucleotide sequence at the 3' end of the second high variable region. Compared with G protein, F protein has high conservatism in both subtypes and subtypes, and is a hot topic protein in the development of antibodies, vaccines and other therapeutic drugs.
RSV has only one serotype, which is divided into two subtypes: A and B.Studies have shown that the two subtypes A and B of RSV have characteristics of single subtypes that are mainly or co-popular in one country or region, and one subtype of A and B will be replaced by another subtype after a period of popularity and continue to be popular [22-23]. RSV subtypes A and B are alternately prevalent in northern my country. Compared with subtype B, when subtype A is highly prevalent, the RSV season starts 3 to 5 weeks ahead of schedule and the duration is extended by about 6 weeks [16].
According to the genetic characteristics of the second highly variable region of RSV G protein, RSV A isoform is divided into 15 genotypes and RSV B isoform is divided into 30 genotypes [24]. In recent years, the viruses RSV A-ON1 and RSV B-BA9 inserted into repeat sequences have become widely popular genotypes worldwide. In 2012, it was reported in the Ontario region of Canada that the RSV A isoform had 72 base insertions in the second hypervariable region of G protein, named the new genotype ON1 [25]. Since then, the ON1 genotype has become popular around the world [26]. Research on the molecular epidemic characteristics of RSV in my country shows that before 2008, the RSV A subtype in my country was mainly dominated by GA genotype, and from 2010 to 2013, the number of new genotype ON1 increased, gradually replacing the NA1 genotype became the prevalent genotype in my country [22]. In 2003, 60 nucleotide repeat sequences of RSV B genotype BA genotype strain appeared in the HVR2 region. Since then, BA genotype has evolved and new genotypes have been produced. By 2018, BA has been divided into 15 genotypes, but BA9 genotype is still the dominant genotype that is popular internationally [6-8, 22]. The BA9 genotype was first discovered in my country in 2006. It has been popular in 15 provinces and cities in my country since 2008, becoming the dominant prevalent genotype of RSV B subtype [27].
2.2 The pathogenic mechanism of RSV infection The pathogenic mechanism of RSV infection is relatively complex, involving the combined effects of pathogenic factors, airway epithelial cell-related factors, immune system response, nervous system response, host factors and environmental factors [28]. RSV infection is most likely to affect the respiratory system, and its main mechanisms are airway obstruction, bronchial smooth muscle spasm and subsequent airway hyperresponsiveness.
2.2.1 Airway obstruction caused by inflammation Airway obstruction caused by inflammation is the main pathogenic mechanism of lower respiratory tract infection of RSV. Epithelial cells of the trachea, bronchiolus, and alveolar are the main target cells for RSV infection. RSV infection can cause the fall of airway cilia and airway epithelial cells. The accumulation of fallen airway epithelial cells and neutrophils , cellulose, and lymphocytes in the airway cause airway obstruction. At the same time, the excessive secretion of mucus and airway edema aggravate airway obstruction [29]. Neutrophils not only damage airway epithelial cells by releasing oxygen free radicals, neutrophil elastase, and proteolytic enzymes, but also neutrophils can promote mucus secretion by upregulating the expression of tumor necrosis factor (TNF)-α and interleukin (IL)-13 [30]. During airway inflammation, TNF-α can in turn promote neutrophil recruitment and is associated with the expression of mucin 5AC (MUC5AC). After the body showed a Th17 dominant immune response after RSV infection, the expression of IL-17 as the main effector increased, and the secretion of IL-17 can lead to the production of a large amount of mucus.
2.2.2 Bronchial smooth muscle spasm RSV infection can cause bronchial smooth muscle spasm. The trachea and bronchial epithelium may fall off due to damage and inflammatory reactions, resulting in exposure of sensory nerve endings and release of active substances to cause bronchial smooth muscle spasm; these transmitters can react to peripheral target cells and cause elevated neurogenic factors. In addition to increasing the reactivity of sensory fibers, neurogenic factors can also promote the release of acetylcholine, sensory neuropeptide P substances, etc., thereby increasing the contraction amplitude of airway smooth muscle cells (ASMCs). For example, nerve growth factor (NGF) causes continuous tension in the airway smooth muscle and affects the distribution of parasympathetic nerves, etc. [28]. The neuropeptide P substance increases the calcium ion concentration in ASMC, thereby increasing the contraction force of ASMC. At the same time, it can activate mast cells to release histamine, leukotriene, IL-6, interferon-γ and prostaglandin D2, etc., and has a strong bronchial contraction effect.
2.2.3 Airway hyperresponsiveness after infection Infants and young children are prone to hyperresponsiveness after RSV infection, which is closely related to the later recurrent wheezing and the occurrence of asthma. The occurrence of airway hyperresponsiveness is related to the body's immune response, neuromodulation mechanism and persistence of the virus.After RSV infecting the airway epithelium, differentiation of Th2 and Th17 lymphocytes is promoted, showing Th2 dominant immune response. Studies have shown that RSV infection can promote the differentiation of Th2 lymphocytes through the Jagged-1/Notch-1 signaling pathway [32]. Interferon-γ is significantly inhibited as the most typical Th1 cytokine, and IL-13 and IL-10 of Th2 cytokine are key factors that lead to high airway reactivity. After RSV infection, a large amount of expression of IL-13 can be detected in lung tissues, and infants with higher levels of IL-10 in nasopharyngeal secretions are more likely to develop repeated breathing [33]. After the body showed a Th17 dominant immune response after RSV infection, the expression of IL-17 as the main effector factor increases, which can synergistically increase the risk of high airway reactivity in Th2-type cytokine response. In addition, the expression of NGF and neurotrophic factor receptors increased significantly after RSV infection [34], suggesting that the hyperresponsiveness of the airway after RSV infection may or at least partly be related to abnormal nerve control of airway smooth muscle tone. During the acute infection period, it may promote the overgrowth of neurites with high content of neuropeptide P, and in turn promote long-term reconstruction of the airway non-adrenal non-cholinergic nerves, leading to sustained airway hyperresponsiveness [28]. In addition, overexpression of neural factors reduces the production of catecholamines and aggravates the dysregulation of airway smooth muscle tone [35]. Animal experiments have confirmed that the virus can exist for a long time in the airway epithelium after RSV infection [29]. The persistent existence of RSV infection may continue to stimulate the host's defense mechanism. In addition, the long-term existence of the virus can destroy the airway microecological balance. The virus can lead to adaptive remodeling of the airway ultrastructure through interaction with the host protein, causing the airway hyperresponsiveness [36].
3 Clinical manifestations and prognosis of RSV infection in children
RSV is an important pathogen that causes severe respiratory infection in infants. RSV infection cannot produce permanent immunity and cannot protect children from reinfection. The clinical manifestations of RSV infection vary greatly, which can be manifested as mild upper respiratory tract infection or otitis media, or severe lower respiratory tract infection, which is related to the child's age, underlying diseases, environmental exposure factors and previous respiratory tract infection history. RSV can cause severe infection in high-risk children and can involve organs outside the respiratory system [37].
3.1 Upper respiratory tract infection caused by RSV Most of the early childhood RSV infection is limited to the upper respiratory tract, and is clinically manifested as upper respiratory tract irritation symptoms, such as nasal congestion, runny nose, cough and hoarseness. Congestion and edema can be seen in the nasal mucosa, pharynx, bulbous conjunctiva, tympanic membrane, etc. At the same time, it is often accompanied by fever [38].
3.2 Lower respiratory tract infection caused by RSV Children with RSV infection can develop lower respiratory tract infection, mainly manifested as bronchiolitis or pneumonia [38], which is more common in infants and children <2>
Physical examination can reveal signs of increased breathing work (nose fan, three depression signs, etc.), cyanosis occurs in severe cases, auscultation and obvious delay in exhalation phase, and widespread wheezing and wet rales can be heard in both lungs. In severe cases, it is accompanied by tachycardia and dehydration.
RSV bronchiolitis is sometimes difficult to distinguish from RSV pneumonia in clinical practice. Therefore, the World Health Organization (WHO) recommends that all lower respiratory tract infections caused by RSV be managed as pneumonia in developing countries [43].
RSV bronchiolitis is divided into three types according to the condition (Table 1), which is also of great help to clinical work [44].
Children with persistent severe wheezing need to be distinguished from congenital airway/pulmonary abnormalities, congenital cardiovascular development (extraairway compression), bronchial foreign bodies, severe pneumonia, bronchial asthma, etc.
3.3 Other system diseases caused by RSV In addition to respiratory diseases, RSV infection can lead to other system diseases. Cardiovascular system involvement can cause myocardial injury, right heart insufficiency, etc. A few studies have reported fatal interstitial myocarditis, severe arrhythmias and even heart failure after RSV infection [9]. Central nervous system involvement may cause central apnea, epilepsy, RSV encephalopathy, RSV encephalitis, RSV meningitis, etc. [45-46]. In addition, very few cases may experience hypothermia, rash, thrombocytopenia and conjunctivitis [47].
3.4 Prognosis of RSV infection Most children with RSV infection can fully recover without leaving any sequelae. However, children with RSV infection in infancy have about 4 times the probability of developing asthma than healthy babies [48]. Children with premature babies, congenital heart disease or diseases such as Down syndrome and immune function deficiency tend to have worse clinical manifestations after RSV infection, and the proportion of respiratory sequelae is higher. Common manifestations are continuous wheezing or asthma, decreased activity endurance, etc., and this impairment of lung function can last for more than 10 years [49].
Infants may experience bronchiolites obliterans (BO) after severe RSV infection, and these children are often insensitive to traditional treatment measures (including respiratory management) [50]. There are also reports that severe RSV infection in infancy is related to chronic obstructive pulmonary disease (COPD) in adults, but it is not yet confirmed whether this airway obstruction is caused by RSV infection or the specific constitution of the child [38].
4 Laboratory examination for RSV infection
4.1 General laboratory examination Routine peripheral blood tests often indicate normal leukocyte count and neutrophil ratio, while the lymphocyte ratio is significantly increased. C-reactive protein is in the normal range.
4.2 Imaging examination The imaging manifestations after RSV infection are not specific, and can be manifested as increased texture of both lungs, small patchy shadows, and emphysema [51].
4.3 RSV etiology examination RSV infection diagnosis must be based on etiology results. The collection and delivery of clinical samples is crucial for laboratory diagnosis of RSV. Samples used for RSV detection are best collected during the acute phase of the disease [52]. RSV is an enveloped RNA virus and is very prone to inactivation in the external environment. It is almost impossible to isolate the virus after freeze-thawing clinical samples. Samples used for RSV isolation should be bedside inoculated [53]. Samples used for nucleic acid detection of in viral . In order to avoid nucleic acid degradation, they should be temporarily present at 4 ℃ after collection and sent for testing as soon as possible. If they are not sent for testing for 72 hours, they should be stored at -80 ℃ at low temperature [54-56].
The appropriate types of samples used for RSV detection mainly include nasopharyngeal swabs, nasopharyngeal aspirates, bronchial alveolar lavage fluid and other respiratory samples. It is best to collect endotracheal wash or bronchial alveolar lavage fluid for children undergoing mechanical ventilation. It is not recommended to collect oropharyngeal swab specimens [57-61].
The methods that can be used for RSV detection include antigen detection, nucleic acid detection, virus isolation, and antibody detection. The advantages and disadvantages of various detection methods are shown in Table 2. Currently, the methods that can be used in the diagnosis of clinical RSV infection are mainly antigen detection and nucleic acid detection. Positive antigen detection means that the virus is in an active replication and proliferation state, which is related to clinical manifestations and turns negative quickly after the acute phase, but the sensitivity of this method is lower than that of nucleic acid detection, so it should be noted in clinical applications.
4.3.1 Antigen detection
4.3.1.1 Rapid antigen detection The first generation of commercialized RSV rapid antigen detection methods include chromatographic immunochromatography (CIA) and colloidal gold immunochromatography (GICA), etc. [62]. The test results can generally be obtained within 30 minutes. The operator does not need special training and is suitable for bedside testing. However, this type of detection method has the defect of low sensitivity [63-64]. The second-generation rapid antigen detection method uses fluorescent labels to interpret the results using an automatic reading device, reducing the probability of misjudgment and improving the sensitivity of RSV detection [65]. However, all RSV rapid antigen detection methods currently cannot distinguish subtypes A and B.
4.3.1.2 Immunofluorescence method to detect antigen includes direct immunofluorescence (DFA) and indirect immunofluorescence (IFA), where DFA is used shorter, so it is more commonly used. DFA detection method is to detect RSV-specific antigens in the shedding respiratory epithelial cells in clinical samples with fluorescently labeled monoclonal antibodies. Compared with virus isolation or nucleic acid amplification detection, the sensitivity and specificity of DFA detection of RSV are 84%~100% and 86%~100% respectively [66-67]. Commercialized multiple DFA detection reagents can simultaneously detect a group of 7 common respiratory viruses including RSV [68]. Immunofluorescence requires sufficient respiratory columnar epithelial cells in the sample, and requires nasopharyngeal aspirate, bronchial alveolar lavage or nasopharyngeal swab samples to be tested. Insufficient cell count or samples from other parts of the respiratory tract are not suitable for this detection [53].
4.3.2 Nucleic acid detection The use of nucleic acid detection methods for RSV detection has high sensitivity and specificity [69]. The multiviral nucleic acid detection kit developed based on acute respiratory infection syndrome can quickly identify multiple respiratory pathogen nucleic acids from respiratory samples at the same time, better promoting the clinical application of nucleic acid detection technology [69]. The molecular diagnostic kit for RSV bedside detection integrates nucleic acid extraction, amplification and detection systems, and has excellent sensitivity and specificity. The overall time of experiments can be reduced to 30 min ~ 1 h [69-70].
Since RSV genome replication is accomplished by RNA-dependent polymerase, the viral genome is prone to mutated in replication [3], resulting in false negative results [71]. Therefore, when applying nucleic acid detection kits, the laboratory must have a corresponding evaluation mechanism [71].
4.3.3 Virus isolation Virus isolation is the gold standard for diagnosis of RSV infection [71]. However, virus isolation is time-consuming and labor-intensive and is not suitable for clinical diagnosis of RSV infection. The shell vial assay combines centrifugation-enhanced vaccination and immunofluorescence detection, which greatly shortens the culture time and takes only 16 hours to report the results.
4.3.4 Serological test The specific IgG detection of RSV is mainly used for seroepidemic surveillance or clinical retrospective diagnosis [72]. RSV IgM antibody positive cannot be used as a laboratory indicator for clinical diagnosis of RSV infection alone.
5 Treatment of RSV infection in children
5.1 General treatment For acute patients, the changes in the condition should be observed and evaluated. When the blood oxygen saturation continues to be lower than 90% to 92% [11,73], oxygen therapy should be given. For severe children, respiratory supportive treatments such as non-invasive persistent positive pressure ventilation (CPAP) or mechanical ventilation can also be selected. When upper airway obstruction and causes dyspnea or feeding difficulties, oral and nasal suction or 9 g/L saline drops can be given to relieve nasal congestion and keep the respiratory tract unobstructed [74].
If the child can eat normally, it is recommended to continue oral feeding. If there is shortness of breath, difficulty breathing, and choking after eating can easily cause aspiration, the nasogastric tube can be given nutritional intake, and if necessary, intravenous nutrition can be given to ensure the stability of the environment of the water and electrolytes in the body [75].
5.2 Drug treatment
5.2.1 Antiviral drug
5.2.1.1 Interferon For lower respiratory tract infection caused by RSV infection, in conventional basic treatments such as anti-infection, anti-asthma, oxygen respiration and fluid, recombinant human α interferon can be tried for antiviral treatment [76-77]. Interferon α1b 2-4 μg/(kg·time), 2 times/d, the course of treatment is 5-7 days [78]; Interferon α2b 100,000 to 200,000 IU/(kg·time), 2 times/d, the course of treatment is 5-7 days [79].
5.2.1.2 Ribavirin There is currently no sufficient evidence to prove the effectiveness of ribavirin in the treatment of RSV infection [80], so routine use is not recommended.
5.2.2 Bronchodilator The efficacy of bronchodilator (such as β2 receptor agonist) alone or in combination with anticholinergic drugs in children with wheezing after RSV infection is unclear [81]. For children with RSV infection and wheezing symptoms, bronchodilator can be tried [44], and then the clinical effect is observed. If the clinical symptoms are relieved after the medication, you can continue to use it; if there is no improvement after the medication, consider discontinuing the medication.For severe children with respiratory failure that require ventilator-assisted ventilation, bronchodilator may also increase the risk of adverse reactions such as tachycardia, and should be used with caution [81]. Recommended dosage: atomized and inhaled by aerated aeration, <6>
5.2.3 Glucocorticoid It is not recommended to routinely use systemic glucocorticoids [83-84]; for children with a family history of allergic constitution or allergic diseases, atomized inhaled glucocorticoids combined with bronchodilator can be tried to treat it, which can inhibit airway inflammation, improve ventilation and relieve the symptoms of asthma. Recommended dosage: budesonide 0.5~1.0 mg/time, 1~2 times a day depending on the severity of the disease.
5.2.4 Hypertonic saline atomization inhalation The efficacy of 3% hypertonic saline atomization inhalation in the lower respiratory tract infection caused by RSV is still controversial and is not recommended as a conventional drug [85]. For children who cause severe asthma after RSV infection, when other treatments are not effective and hospitalized for more than 3 days, 3% hypertonic saline atomization treatment can be considered [86]. The atomization time is required to be less than 20 minutes. Close monitoring is required during the medication. If the clinical symptoms of children who take 48 to 72 hours of medication do not relieve, aggravate, or have irritating cough, they should be stopped immediately, and pay attention to suction to keep the airway unobstructed.
5.2.5 Leukotriene receptor antagonist is not recommended as a conventional drug [87]. For children with repeated wheezing after RSV infection, leukotriene receptor antagonists can be tried orally to prevent wheezing attacks [88], and its therapeutic effectiveness needs to be further confirmed.
5.2.6 Antibacterial drugs are not recommended as conventional drugs, and preventive drugs are not recommended [89]; when secondary bacterial infection is considered, or when there are high-risk factors for bacterial infection in severe cases, antibacterial drugs can be used for anti-infection treatment.
5.3 Symptomatic treatment of other systems outside the respiratory system On this basis, when other systems are abnormal, such as circulatory system, pulmonary hypertension, arrhythmia, myocardial damage and even heart failure, and the nervous system experiences changes in consciousness state such as drowsiness, coma, and even convulsions, corresponding symptomatic treatment should be actively given.
6New progress in drug prevention and treatment of RSV infection
In recent years, several new drugs for RSV infection prevention and treatment have initially shown good clinical application prospects. According to the mechanism of action of drugs, it mainly includes two categories: antibodies and fusion inhibitors [90].
6.1 Antibody Antibody drugs that have entered or completed the phase II clinical trial stage mainly include MEDI8897 (MedImmune LLC) [91], ALX-0171 (Ablynx) [92] and intravenous immunoglobulin RI-001 (ADMA Biologics) [93]. MEDI8897 is a recombinant IgG1κ monoclonal antibody that extends the half-life by modifying the Fc region, targeting the F protein of RSV. It has good safety in the results of phase one and second clinical trials, with a half-life increasing to 85-117 days, and has a good protective effect as a preventive antibody [91]; the antibody has entered the phase III clinical trial stage. ALX-0171 is the first nano-antibody trimer that can be directly atomized and inhaled. It is used for the treatment of RSV. It is the same as the site of action of parisizumab. It is better than parisizumab in blocking RSV replication. It has good physical stability and can tolerate extreme conditions during drug atomization [92]. Immunoglobulin RI-001 has completed 4 phase I clinical trials and 2 phase II clinical trials, and the results show that it has good antiviral and anti-infective effects [93].
6.2 Fusion inhibitor mainly acts on the stage of binding and invasion of viruses to host cells. By affecting the allostericity of RSV fusion protein F, it blocks the virus from entering host cells and is used for the treatment of RSV. At present, the main ones that have completed or entered the second phase clinical trial stage include Ziresovir (AK-0529, RO-0529, Ark Biosciences) [94], GS-5806 (Gilead Sciences) [95] and JNJ-53718678 (Johnson Johnson) [96].AK0529 is an RSV fusion protein inhibitor. In non-clinical pharmacological studies, AK0529 has a dose-dependent strong antiviral activity for RSV A and B subtypes and is less cytotoxic. In vivo experiments, oral administration of AK0529 showed strong antiviral efficacy using BALB/c mouse RSV infection model [94].
7 Prevention of RSV infection
RSV is mainly transmitted through contact with the secretions or contaminants containing viruses. Direct contact is the most common transmission pathway, but droplets and aerosols can also cause transmission [97-98]. RSV can survive on hands and dirt for several hours [99]. Hand washing and contact protection are important measures to prevent transmission. The incubation period after HRSV infection is 2 to 8 days, usually 4 to 6 days.
7.1 General prevention
7.1.1 Family prevention Strengthen education on RSV infection and prevention and treatment; advocate breastfeeding for at least 6 months [11]; avoid exposure to tobacco and other smoke; during the RSV epidemic season, restrict high-risk infants from going to child care institutions [11]; wash hands in any place (wash hands with soap or alcohol-containing solution), especially high-risk infants when exposed to older children at risk of respiratory infection [100-101]; develop good cough hygiene habits.
7.1.2 Hospital Prevention Personnel who are in direct contact with children should disinfect their hands before and after contact with the children. If they cannot use ethanol disinfectants, wash their hands frequently with soap and water, and use personal protective equipment (surgical masks, goggles and isolation gowns) [102-105]; it is recommended to isolate the children in a single ward or in the same ward with other RSV-infected children (centralized isolation treatment of children), and restrict the transfer of the children from the ward [104, 106]. During the outbreak, medical staff should try to avoid taking care of children with RSV-infected children and taking care of non-infected children; medical staff should continue to receive relevant education, including the symptoms, epidemiology, diagnosis and transmission of RSV infection [104, 106].
7.2 Specific prevention
7.2.1 Drug prevention Palizumab is a specific antibody against RSV and has not been introduced to domestic clinical applications. Premature infants with significant hemodynamic abnormalities in heart disease and chronic lung disease (gestation age <32>
7.2.2 Vaccine There is currently no vaccine available. A variety of genetically engineered vaccines, nucleic acid vaccines, granular vaccines and new RSV vaccine candidate adjuvants are currently in the preclinical and early clinical development stages
