Respiratory syncytial virus infection in children: clinical guidelines

List of Abbreviations

ALT – alanine aminotransferase

AST – aspartate aminotransferase

BPD – bronchopulmonary dysplasia

BOF – bronchial obstruction syndrome

WHO – World Health Organization

CHD – congenital heart disease

GC – glucocorticoids

RF – respiratory failure

IMV – invasive mechanical ventilation

CVS – cardiovascular syncope

UVC – short-wave ultraviolet radiation

ABDS – acid-base balance status

CPS – cardiopulmonary syncope

ICD-10 – International Classification of Diseases, 10th Revision

MRI – magnetic resonance imaging

OAB – acute bronchial obstruction

ARF – acute renal failure

ARVI – Acute respiratory viral infection

ICU – intensive care unit

ACLT – acute stenosing laryngotracheitis

RT-PCR – reverse transcription polymerase chain reaction

PCR – polymerase chain reaction

RCTs – randomized controlled trials

RNA – ribonucleic acid

RSV – respiratory syncytial virus

RSVI – respiratory syncytial virus infection

ESR – erythrocyte sedimentation rate

CPAP – continuous positive airway pressure

COPD – chronic obstructive pulmonary disease

RR – respiratory rate

FSBI – Federal State Budgetary Institution

Terms and Definitions

Disease – a disorder of the body's activity, working capacity, and ability to adapt to changing conditions of the external and internal environment, arising from the action of pathogenic factors, with a simultaneous change in the body's protective-compensatory and protective-adaptive reactions and mechanisms.

Instrumental diagnostics – diagnostics using various devices, apparatuses, and instruments to examine a patient.

Disease outcomes – the medical and biological consequences of a disease.

Quality of medical care – a set of characteristics reflecting the timeliness of medical care, the correctness of the choice of prevention, diagnosis, treatment, and rehabilitation methods in providing medical care, and the degree of achievement of the planned result.

Clinical guidelines for the provision of medical care to children – a regulatory document of the healthcare standardization system that defines the requirements for providing medical care to a patient with a specific disease, syndrome, or clinical situation.

Clinical situation – a case requiring the regulation of medical care regardless of the disease or syndrome.

Laboratory diagnostics – a set of methods aimed at analyzing test material using various specialized equipment.

Medical intervention – types of medical examinations and/or medical manipulations, as well as artificial termination of pregnancy, performed by a medical worker in relation to a patient, affecting the physical or mental state of a person and having a preventive, exploratory, diagnostic, therapeutic, or rehabilitative orientation.

Medical service – a medical intervention or a complex of medical interventions aimed at the prevention, diagnosis, and treatment of diseases, and medical rehabilitation, having an independent completed significance.

Nosological form – a set of clinical, laboratory, and instrumental diagnostic signs that make it possible to identify a disease (poisoning, injury, physiological state) and assign it to a group of conditions with a common etiology and pathogenesis, clinical manifestations, and general approaches to treatment and condition correction.

Disease complication – the addition of a physiological process disturbance syndrome to the disease; – violation of the integrity of an organ or its wall; – bleeding; – developed acute or chronic failure of the function of an organ or organ system.

Primary disease – a disease that, by itself or due to complications, necessitates priority medical care due to the greatest threat to working capacity, life, and health, or leads to disability, or causes death.

Patient – an individual to whom medical care is provided or who has applied for medical care, regardless of the presence of a disease and their condition.

Consequences (results) – disease outcomes, social and economic results of the application of medical technologies.

Symptom – any sign of a disease that can be determined regardless of the method used for this purpose.

Syndrome – a condition developing as a consequence of a disease and determined by a combination of clinical, laboratory, and instrumental diagnostic signs that allow it to be identified and assigned to a group of conditions with various etiologies but a common pathogenesis, clinical manifestations, and general approaches to treatment, which, at the same time, also depend on the underlying diseases of the syndrome.

Condition – changes in the body arising in connection with the action of pathogenic and/or physiological factors and requiring medical care.

Concomitant disease – a disease that has no causal relationship with the primary disease, is inferior to it in the degree of necessity for medical care, influence on working capacity, danger to life and health, and is not the cause of death.

Severity of a disease or condition – a criterion determining the degree of damage to human organs and/or body systems or the impairment of their functions caused by a disease or condition or their complication.

Level of certainty of evidence – reflects the degree of confidence that the found effect of a medical intervention is true.

Function of an organ, tissue, cell, or cell group – a property constituting a physiological process that implements an action specific to the corresponding structural unit of the body.

Viremia – a condition in which a virus enters the bloodstream and spreads throughout the body.

Syncytium – a type of tissue in humans, animals, plants, and fungi with incomplete cell demarcation, in which isolated areas of cytoplasm with nuclei are connected by cytoplasmic bridges.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Respiratory syncytial virus infection (RSVI) – an acute respiratory viral disease characterized by catarrhal syndrome, with predominant involvement of the lower respiratory tract, moderately pronounced temperature reaction and intoxication, with frequent development of bronchitis, bronchiolitis, and pneumonia, often with acute bronchial obstruction (ABO) and respiratory failure (RF) [1, 2].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Etiology. The pathogen of the infection is an RNA-containing virus belonging to the family Paramyxoviridae, genus Pneumovirus. The virus has a stable antigenic composition, and all known variants pathogenic to humans belong to a single serotype, although there is evidence of the isolation of two pathogen subtypes: A and B, which differ in the surface protein G, but do not differ in severity [3, 4, 5].

Respiratory syncytial virus (RSV) was first isolated in the USA in 1956 from monkeys by G. Morris; in 1957 R. Chanock et al. isolated 2 strains of the virus from sick children with pneumonia and bronchiolitis. The strains were isolated in cell cultures, where they formed syncytia, which is how the virus got its name.

Pathogenesis of RSVI is caused by a complex of processes developing at all stages of pathogen reproduction and their subsequent penetration into the host organism, including during the interaction of the virus with its defense systems [4,5,6].

In the process of disease development, a number of stages (phases) are distinguished that follow one another or develop simultaneously:

- Adsorption and introduction of RSV into the epithelial cells of the respiratory tract: the entry gates of the infection are the epithelial cells of the respiratory tract mucosa, including the bronchi and alveoli. The introduction of the virus is possible provided that specific cell receptors, represented for RSV by heparan sulfate, are present on them. RSV attachment occurs via the G protein, fusion with the cell is mediated by the F protein [5]. Then the viral envelope embeds into the cell membrane, and the nucleocapsid is released into the host cell cytoplasm. The reproduction of new virions is accompanied by a cytopathic effect (relative to the epithelial cells of the respiratory tract), their destruction, and rejection along with newly formed viruses.

- Penetration of pathogens into other parts of the body: RSV can penetrate from cell to cell by fusing cell membranes to form a syncytium. In such cases, it does not leave the cells, hiding from antibodies. Reproduction of the virus in macrophages is possible, but much slower than in epithelial cells. It is believed that macrophages participate in invasive infection, contributing to the development of interstitial pneumonia. Hematogenous and/or bronchogenic spread of RSV to the lower respiratory tract is possible.

The greatest changes are observed in the epithelium of medium and small bronchi, bronchioles, and alveoli [7]. Characteristically, there is a peculiar diffuse proliferation of their epithelium in the form of papillae or protrusions. Small round-cell and lymphoid infiltrates are identified around large bronchi and in the trachea. It is also characteristic to find syncytia, as well as multinucleated pseudogiant cells. In the enlarged lungs, small atelectases, emphysema, and plethora are noted. The bronchial lumens are filled with desquamated epithelium and inflammatory exudate, leading to impaired bronchial patency. Bronchitis and bronchiolitis with airway obstruction, typical of RSV infection, develop. A thick exudate appears in the alveoli, consisting predominantly of macrophages admixed with neutrophils and fine-grained protein masses. The valve mechanism of bronchial obstruction leads to air trapping in the lungs. In those lung segments where the obstruction of bronchioles or bronchi is complete, atelectases form.

The small caliber of the bronchi and bronchioles makes children particularly vulnerable to the development of acute bronchial obstruction (ABO). Mucosal edema of the small airways of only 1 mm in a child causes an increase in airflow resistance by more than 50%. The resulting uneven lung ventilation leads to alveolar hypoventilation, intra-alveolar pressure increases, lung elasticity is impaired, their distensibility worsens, and gas exchange becomes difficult, resulting in hypoxemia and hypercapnia. A shift in the acid-base balance towards respiratory acidosis occurs.

- Formation of an inflammatory focus, including in the lower respiratory tract: RSV infection causes rhinitis, pharyngitis, tracheitis, laryngitis, bronchitis, as well as combinations thereof. Among the most severe clinical variants are the development of bronchiolitis and pneumonia with ABO and pulmonary edema, which frequently requires transfer to the ICU [8].

Generalization of the process is possible (especially in infants in the first months of life), which is accompanied by the development of structural changes in other organs in the form of specific proliferations of epithelial and reticular cells, forming papillary outgrowths in blood and lymphatic vessels, the liver and biliary tract, pancreatic ducts, renal tubules, etc. Intestinal lesions are possible in the form of localized areas of epithelial vacuolization and its papillary proliferations.

- The outcome of RSV infection is most often recovery, however, in infants in the first months of life and in older children with risk factors, a fatal outcome is possible [10].

1.3 Epidemiology of the Disease or Condition

The virus is registered everywhere; according to the World Health Organization (WHO), the annual incidence worldwide amounts to up to 33 million cases of confirmed RSV infection (RSVI) with lower respiratory tract (LRT) involvement in children in the first 5 years of life [12]. An analysis of RSV incidence and mortality conducted in the pre-pandemic period showed that among children under five years of age in 2017, 3 million children were hospitalized, and 59,600 patients died [12]. The disease is most severe in infants in the first six months of life, among whom, according to the study, 1.4 million children were hospitalized and 27,300 died [12]. RSV accounts for up to 63% of all viral respiratory infections in infants in the first year of life [3].

The infection is highly contagious. The incubation period is 3–5 (up to 8) days. Infants in the first year of life are involved in the process in almost 100% of cases, and older children in 70–80% of cases. Immunity after a previous infection is unstable; a child can contract RSV repeatedly not only throughout life, but even within a single epidemic season. In case of reinfection, the disease is less severe. The route of transmission is airborne droplet and contact [3].

The source of infection in RSV is patients in the acute period of the disease, regardless of severity. Adults (staff and family members) are usually involved secondarily, carrying the infection in a mild, sometimes asymptomatic form, and therefore often serve as the source of nosocomial outbreaks of this infection [13]. The duration of virus shedding averages 10-14 days [3, 5].

The incidence in the Russian Federation was characterized by autumn-winter-spring seasonality with a peak in February-March [3, 8, 9]. The highest number of RSV cases in the structure of respiratory infections among all age groups of the Russian population is registered in the winter period – 30-35% [3, 8, 9]. According to generalized WHO data, 90% of all recorded RSV cases are registered among young children [11]. During the COVID-19 pandemic (2020–2022), RSV lost its typical seasonal pattern and occurred year-round with a peak incidence in the autumn-winter period [14, 15–19]. According to several authors and observations in the Russian Federation, there was a shift in seasonal incidence peaks by 6–8 weeks, as well as the detection of RSV cases in atypical summer months [20]. A special risk group includes premature infants with a body weight ≤ 2.5 kg, children suffering from bronchopulmonary dysplasia (BPD), congenital heart defects (CHD), organ transplant recipients, and patients with systemic and chronic diseases, who in most cases require hospitalization in the ICU with mechanical ventilation [21]. RSV accounts for an average of 30–33% of hospitalizations of infants in the first year of life with ARVI, 22–30% of cases of severe lower respiratory tract disease, and 60–62% of community-acquired viral pneumonias among hospitalized children with lower respiratory tract lesions [8]. Immunity after a previous infection is unstable; a child can contract RSV repeatedly not only throughout life, but also within a single epidemic season, and in case of reinfection, the disease is less severe [13].

1.4 Features of Coding the Disease or Condition

B97.4 – Respiratory syncytial virus as the cause of diseases classified in other chapters

J00 – Acute nasopharyngitis

J02.8 – Acute pharyngitis

J04.1 – Acute tracheitis

J04.2 – Acute laryngotracheitis

J06.0 – Acute laryngopharyngitis

J20.5 – Acute bronchitis,

J21.0 – Acute bronchiolitis

1.5 Classification of the disease or condition

Classification: [1]

I. By form (severity) of the disease:

• Mild

• Moderate

• Severe

II. By clinical course:

• smooth (uncomplicated)

• nonsmooth (complicated)

III. By presence of symptoms:

• Typical

• Atypical (asymptomatic)

IV. By lesion localization (topical signs):

• Acute rhinitis

• Acute pharyngitis

• Acute tracheitis

• Acute laryngitis

• Acute bronchitis

• Acute bronchiolitis

• Acute pneumonia

• Combinations of anatomical locations (e.g., laryngotracheobronchitis)

Comments: RSV manifestations vary widely from asymptomatic and mild forms with rapidly resolving catarrhal symptoms in the nasopharynx to the development of severe lower respiratory tract lesions with a fatal outcome [1, 2, 3]

1.6 Clinical presentation of the disease or condition

The incubation period is 3–5 (up to 8) days. The disease can begin both acutely and gradually. The clinical form of the disease depends on the patient's age and immune status. The risk of developing severe bronchitis and respiratory failure is high in young children, patients with chronic heart and lung diseases, immunodeficiency states, HIV infection, and internal organ transplantation. RSV is typically characterized by an acute onset with a gradual increase in disease severity, subfebrile or absent body temperature, and moderate intoxication (lethargy, weakness, malaise, decreased appetite), which may be absent. The disease manifests with moderately expressed catarrhal symptoms in the nasopharynx (sparse serous rhinitis and pharyngitis, laryngotracheitis is possible) with involvement of the lower respiratory tract in the form of obstructive bronchitis and bronchiolitis. In children older than 6 years and adults, the disease generally runs a milder course and is limited to upper respiratory tract symptoms (rhinopharyngitis, laryngotracheitis) [22].

In young children, lower respiratory tract involvement is more frequently observed: bronchitis, bronchiolitis [23, 21]. The disease begins with rhinopharyngitis; on days 2–3, signs of lower respiratory tract involvement appear with the development of bronchitis and bronchiolitis. Acute bronchial obstruction syndrome occurs. The severity of the patient's condition during this period is determined by the severity of respiratory failure. Dyspnea appears with a predominance of expiration and intercostal retractions. Cough is paroxysmal and distressing. In the lungs, against the background of harsh breathing, dry wheezing rales are auscultated; in some patients, there are multiple disseminated small- and medium-bubble moist rales. Bronchiolitis is characterized by abundant disseminated fine-bubble moist and crepitant rales, and percussion reveals a boxy sound due to developing emphysema [21, 22, 23].

Assessment of RSV severity.

In mild severity, body temperature does not exceed 38.5°C and may remain normal; intoxication (malaise, weakness, decreased appetite) and catarrhal (scant serous rhinitis and pharyngitis) syndromes are mild to moderate. Symptoms of lower respiratory tract involvement are typically absent. This form is observed predominantly in children over 3 years of age.

Moderate severity with typical clinical symptoms predominates in 86–90% of cases, primarily in infants and toddlers. The disease manifests with moderately severe catarrhal symptoms (rhinitis, pharyngitis, laryngitis, and tracheitis) against the background of a normal or low-grade fever, which may rise in some cases on the 2nd–3rd day of illness. Acute stenosing laryngotracheitis may develop [22]. Intoxication symptoms are moderate (restlessness, lethargy, decreased appetite). Manifestations of acute bronchitis are present, frequently with acute bronchial obstruction syndrome, or bronchiolitis, complicated by grade I–II respiratory failure (RF). Complete recovery generally occurs within 5–7 days; this is observed in individuals of all age groups, but predominantly in children over 3 years of age.

In severe RSV infection, , recorded predominantly in infants under one year of age, the degree of temperature elevation may vary and lacks significant diagnostic value. In some cases, a high (>38.5°C) and short-lived febrile reaction is possible, while in newborns, especially premature ones, hypothermia may occur. Catarrhal syndrome and intoxication are moderate. Altered mental status («lethargy», «obtundation») correlates with the degree of RF. The infant is lethargic and adynamic; breathing is noisy and wheezing on expiration; auscultation reveals numerous scattered wheezes or diffuse crepitations. There is marked pallor, persistent perioral cyanosis, acrocyanosis, and pronounced dyspnea (over 80 breaths per minute) at rest involving accessory muscles, tension of the sternocleidomastoid muscle, and marked retraction of the intercostal spaces and epigastric region. Signs of lower respiratory tract involvement are characteristic (obstructive bronchitis, bronchiolitis, or bronchopneumonia with grade II–III RF). In children of the first two years of life, acute bronchiolitis is the main form of bronchitis, which is associated with a smaller bronchial diameter and rich vascularization of the bronchial mucosa. The main etiological factors of acute bronchiolitis are respiratory viruses; respiratory syncytial virus (RSV) accounts for 60–80% of cases during the peak season [24, 25].

Oxygen saturation is reduced to <90%. Bradypnea and apnea may develop, as well as cardiopulmonary syncope, which is the sudden cessation of effective respiration/circulation accompanied by weakened inspiratory breath sounds and generalized cyanosis.

In RSV infection, there is a discrepancy between the severity of lower respiratory tract involvement and the intensity of fever/general intoxication syndrome [21, 24–27]. When assessing the severity of the disease with the development of lower respiratory tract involvement syndromes, one should focus on symptoms characterizing the degree of respiratory failure (RF) [21, 24–27].

Grades of RF:

I. Dyspnea, tachycardia, nasal flaring upon significant physical exertion;

II. Dyspnea, tachycardia upon minor physical exertion; mild cyanosis of the lips and perioral region; nasal flaring, intercostal and/or subcostal retractions.

III. Severe dyspnea, tachypnea at rest; shallow breathing; generalized cyanosis of the skin and mucous membranes, acrocyanosis; involvement of accessory muscles in the act of breathing. The child is lethargic, adynamic or, conversely, extremely agitated. Characterized by a decrease in blood O₂ saturation (SaO₂ <90%) and O₂ partial pressure (PaO₂ <60 mmHg). Hypoxic encephalopathy (altered consciousness, seizures) may develop, as well as cardiopulmonary syncope (CPS) – sudden cessation of effective respiration / circulation.

IV. Hypoxemic coma. Consciousness is absent; breathing is arrhythmic, periodic, and shallow; apnea.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of RSV infection is established following etiological diagnostics (molecular biological tests—detection of viral RNA in nasopharyngeal swabs or aspirates, enzyme-linked immunosorbent assay, or determination of a rising titer of specific antibodies in blood serum). In the absence of etiological diagnostics, a syndromic diagnosis is made.

2.1 Complaints and Anamnesis

Complaints and anamnesis are described in the clinical presentation section.

2.2 Physical Examination

Data obtained during physical examination are described in the clinical presentation section.

Comments: It is necessary to assess the involvement of accessory muscles in the act of breathing and to count the respiratory rate.

2.3 Laboratory Diagnostics

The main methods of laboratory diagnostics for RSV infection are: the RT-PCR method, which detects RSV RNA; the immunofluorescence assay and immunochromatographic method for detecting RSV viral particles in patient secretions; and the ELISA method, which determines class M (IgM) and G (IgG) immunoglobulins against RSV in blood serum or plasma. Diagnostics are typically performed if the patient is hospitalized in a healthcare facility or based on epidemiological indications.

Comments: The RT-PCR method allows the detection of pathogen RNA in the early stages of the disease; the incubation period is 2–4 days, while the average duration of virus shedding by an infected person is 5–7 days from the onset of the disease. Virus shedding is prolonged when the lower respiratory tract is involved in the inflammatory process. Detection of viral RNA is a more reliable method for confirming cases in the early stages compared to testing for IgM. The specificity of the method – is 100%, and the sensitivity – is 100%.

Comments: Considering the possibility of co-infection with multiple viruses and the similarity of the clinical presentation, simultaneous screening for other infections that may present with a similar clinical picture is necessary. There is also literature data indicating a reduction in the unjustified use of systemic antibacterial drugs when rapid tests for respiratory viruses are employed.

Comments: The ELISA method determines serum IgM antibodies (in the early stages of the disease) and IgG antibodies. IgM antibodies appear on the 4th–5th day from the onset of the disease. Seroconversion with a 2-4-fold or greater increase in IgG antibodies in paired sera in the absence of blood IgM antibodies is also grounds for establishing the diagnosis. However, in 10–30% of cases, patients with a past infection may remain seronegative [42]. This may occur in the early stages of infection before the immune response develops, when antibodies have not yet been produced by the immune system, or in the late stages of infection, years after exposure, when antibodies in the blood may not be detected. A single detection of IgG antibodies, regardless of their concentration, does not allow the result to be interpreted as evidence of an acute infection. The specificity of the method is 97%, and the sensitivity is 100%. The efficacy of detecting specific IgM via ELISA in children aged two to five years and older is high (Se 88.9; Sp 97.6).

Comments: viral infections in a complete blood count (CBC) typically present with leukopenia or normocytosis, and an increased percentage of lymphocytes and monocytes. However, changes similar to bacterial infections (leukocytosis, left shift of the leukocyte formula, accelerated ESR) may be present.

Comments: in uncomplicated RSV infection, there are no specific changes; with febrile fever associated with bronchiolitis, or secondary bacterial infection, signs of a "toxic kidney" may appear – proteinuria, cylindruria, leukocyturia, and hematuria, caused by the development of tubulointerstitial nephritis associated with RSV infection; additionally, urinary tract infection may develop or exacerbate.

Comments: Screening for bacterial infection and sepsis (blood culture – microbiological culture for sterility, urine culture – microbiological (culture) examination of urine for aerobic and facultatively anaerobic opportunistic microorganisms, blood serum C-reactive protein (CRP) testing, and/or blood procalcitonin testing) is performed when high fever is combined with SpO₂ dropping below 92% and apnea. In other situations, the probability of bacteremia in children with bronchiolitis is extremely low. Exceptions include cases of nosocomial RSV infection, development of bronchiolitis in children with cyanotic congenital heart disease (CHD), or other congenital and perinatal conditions requiring intensive care unit (ICU) admission [7].

2.4 Instrumental Diagnostics

Comments: The use of this method is recommended in patients with lower respiratory tract involvement (acute bronchitis, bronchiolitis, pneumonia) and symptoms of respiratory failure (dyspnea, tachypnea, tachycardia, cyanosis) to assess the degree of hypoxemia and determine the need for oxygen support. Pulse oximetry is a simple and reliable screening method that helps identify patients with hypoxemia who require respiratory support and assesses the effectiveness of oxygen therapy.

Comments: The use of this method is recommended in patients with underlying cardiac pathology for the early detection of decompensation and/or when rhythm and conduction disorders or myocarditis are suspected in children with lower respiratory tract involvement (acute bronchitis, bronchiolitis, pneumonia) and symptoms of respiratory failure (dyspnea, tachypnea, tachycardia, cyanosis, SaO₂ < 95%) during the course of RSV infection.

Comments: This diagnostic method is justified when pneumonia—either RSV-induced or viral-bacterial due to bacterial flora activation—is suspected. Pneumonia must be ruled out if body temperature exceeds 38⁰C for more than 3 days, with symptoms of toxicity, dullness on percussion, or asymmetric rales.

Radiological signs of bronchiolitis: hyperinflation of lung tissue, enhanced bronchovascular markings, areas of pulmonary hypoventilation, and atelectasis, which are sometimes mistaken for pneumonia, leading only to unjustified antibiotic prescription; flattening and low standing of the diaphragmatic domes, and blunting of the costophrenic angles.

Comments: This diagnostic method is justified when inflammatory changes in the lower respiratory tract are suspected, including viral pneumonia, bronchiolitis obliterans, or underlying lung pathology (bronchopulmonary dysplasia, malformations, etc.).

2.5 Other Procedures

If PCR and ELISA methods are unavailable, other rapid detection methods for RSV infection can be used:

Comments: The immunochromatographic method is based on the binding of RSV to a monoclonal antibody; the resulting complexes migrate to the test strip area containing immobilized anti-RSV antibodies. Particles accumulating in the test area produce color development. Results can be obtained in 15–30 minutes. The sensitivity of the method is – 75–95%; specificity is – 90–98%. If negative results are obtained, confirmation of RSV infection using other, more sensitive methods is recommended.

Comments: The principle of IFA is based on binding virus-infected cells (nasopharyngeal swab) to specific antibodies labeled with a fluorescent dye. Fluorescence is detected using a fluorescence microscope.

Comments: The principle of ICC is based on binding actively functioning viral antigens in mucosal cells or blood lymphocytes using specific murine monoclonal antibodies. The method examines the localization and evaluates the amount of detected antigen in cells. In children in their first and second years of life, the sensitivity of the method is – 87.4–93.4; specificity is 93.6–85.1 [9, 36].

Comments: Given the high frequency of acute otitis media in children with rhinitis, otoscopy is recommended for patients with rhinitis, especially in the presence of fever. ENT complications develop predominantly in the first days of the disease, but may also occur later.

Comments: to address the issue of the necessity of transferring the child to the ICU in order to prevent the development of complications: cardiopulmonary syncope, cerebral edema, etc.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Treatment of patients with RSV infection is carried out both on an outpatient basis and in a hospital setting. Outpatient treatment is provided to children with mild and moderate disease severity without complications. For mild and moderate RSV infection, therapy follows the general principles of ARVI management. Patients with bronchiolitis, viral pneumonia, respiratory failure, cardiac complications, and severe underlying comorbidities are subject to hospitalization in an infectious diseases hospital (department/beds) with an ICU in its structure.

Feeding of children is organized depending on the child's age and somatic status characteristics.

Specific etiotropic therapy for RSV infection currently does not exist. Treatment is carried out for the following purposes:

• prevention of the progression of the infectious process, for which broad-spectrum immunomodulatory drugs with antiviral activity are used;

• relief of respiratory failure;

• relief of fever;

• relief of catarrhal syndrome;

• prevention and/or relief of complications;

• nutritional support.

Treatment of children with RSV infection should begin immediately after the appearance of the first symptoms of the disease, taking into account their severity.

3.1 Conservative Treatment

Carried out both on an outpatient basis and in a hospital setting. Outpatient treatment is provided to children with mild and moderate disease severity without complications. Children with lower respiratory tract involvement are subject to hospitalization. The choice of therapeutic tactics depends on the severity, level of respiratory tract involvement, child's age, and symptoms of the disease.

3.1.1 Etiopathogenetic therapy with immunomodulatory drugs with broad antiviral activity.

Comments: the use of interferons is most effective in the first 3 days from the onset of the disease. Preparations of interferon alfa-2b can be used as a nasal spray and drops, gel, and ointment for topical use. With intranasal application, the concentration of the active substance achieved in the blood has no clinical significance. In newborns and infants, interferon formulations in suppositories can be used to achieve a systemic effect. In the treatment of acute bronchiolitis, interferon therapy is adjunctive: currently, there is insufficient evidence of the effect of antiviral agents on the course of bronchiolitis.

Comments: The efficacy and safety of managing children with acute bronchiolitis without systemic antibacterial drugs has been proven both in Russia and abroad.

Comments: In the presence of shortness of breath, there is pathological fluid loss through perspiration, which requires rehydration. The main route of rehydration is oral. If oral rehydration is impossible, fluid should be administered via a nasogastric tube. If drinking is impossible, as well as in Grade II-III exicosis, parenteral rehydration is necessary. For this purpose, sodium chloride** (0.9% solution) (ATX code: B05CB01) or Sodium chloride complex solution [Potassium chloride+Calcium chloride+Sodium chloride]** (ATX code: B05BB01) should be used. However, considering the potential risk of pulmonary edema, the volume of intravenous infusions should be limited to no more than 20 ml/kg/day.

Symptomatic therapy

Comments: In patients with a history of seizure disorders or when seizures develop against the background of the current disease, it is indicated to reduce body temperature above 37.5-38.5ºС). Drugs are used in accordance with the instructions for use.

Comments: In infants of the first months of life, Viburcol suppositories can be used for antipyretic and anti-inflammatory purposes. Drugs are used in accordance with the instructions for use.

3.2 Surgical Treatment

• Surgical treatment is not indicated.

3.3 Other Treatment

Comments: Oxygen therapy is carried out with humidified oxygen intranasally or via a mask when blood SaO₂ values are below 92-94%. Most specialists recognize the need to supply oxygen until this value stably reaches 95%. In severe bronchiolitis, signs of pronounced hypoxia, and episodes of apnea, it is advisable to use CPAP (Continuous Positive Airway Pressure) – continuous positive airway pressure therapy.

On an outpatient basis, patients are prescribed syndromic therapy by a doctor (depending on the identified clinical symptoms) using local remedies in the form of gargles, warm drinks or insufflations, inhalations, lozenges and pastilles for resorption, and physiotherapeutic procedures to reduce local inflammation and pain severity, and prevent secondary infection of the upper respiratory tract mucosa.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Special methods of medical rehabilitation for patients with RSV infection have not been developed. Patients who have had RSV infection without involvement of small bronchi and bronchioles recover quickly and independently. The exception is patients who have developed complications. In this case, rehabilitation measures are carried out in accordance with the complications that have arisen.

5. Prevention and Dispensary Observation

Prevention of RSV infection is carried out according to the same rules as the prevention of ARVI: maintaining a healthy lifestyle, limiting contact with infected patients, observing mask mandates, hand washing, etc.

In hospitals, preventive measures should mainly aim to prevent nosocomial infection and the spread of the infection. The best ways to prevent nosocomial RSV infection are wearing masks and frequent hand washing, and hand disinfection should be performed before and after contact with the patient, objects in their immediate vicinity, and after removing gloves.

Maintaining breastfeeding for at least 6 months is considered optimal, as one of the protective factors against RSV infection is breast milk containing IgG, IgA, interferon-α, oligosaccharides, and a number of other protective factors.

To date, the approved specific immunoprophylaxis agent for RSV infection with a high efficacy and safety profile is the monoclonal antibody against the RSV F-protein, palivizumab**. The drug contains humanized IgG1 monoclonal antibodies that target the RSV fusion F protein. The palivizumab** molecule consists of human (95%) and murine (5%) amino acid sequences. Since it is not a human immunoglobulin, palivizumab** carries no risk of transmitting other infections.

In the Russian Federation, palivizumab** was registered in 2010. According to the instructions for use, palivizumab** can be used in children under 6 months of age born at 35 weeks of gestation or earlier; in children under 2 years of age who required treatment for BPD within the previous 6 months, or who have hemodynamically significant congenital heart disease — indications and doses correspond to the package leaflet. More than 12 years of experience in immunizing high-risk children in Moscow has demonstrated high efficacy of immunoprophylaxis, as confirmed by a decrease in the incidence of acute respiratory viral infections and the absence of severe forms of RSV infection in the immunized cohort [69].

Comments: Immunoprophylaxis is carried out in accordance with the manufacturer's instructions for use. Prevention of RSV infection is carried out in: children under 6 months of age born at 35 weeks of gestation or earlier; children under 2 years of age who required treatment for bronchopulmonary dysplasia within the past 6 months; children under 2 years of age with hemodynamically significant congenital heart defects.

6. Organization of Medical Care

Treatment of patients with RSV infection is carried out both on an outpatient basis and in a hospital setting. Outpatient treatment is provided to children with mild to moderate disease severity without complications. For mild and moderate RSV infection, therapy is administered according to the general principles of management for acute respiratory viral infections.

Patients with bronchiolitis, respiratory failure, pneumonia, or generalized forms of RSV infection are subject to hospitalization in an infectious diseases hospital equipped with an ICU.

Indications for hospitalization:

• moderate and severe RSV infection, especially with a complicated course or exacerbation of comorbid conditions in children of the first 2 years of life, as well as older children with an exacerbation or threat of exacerbation of concomitant cardiovascular and bronchopulmonary diseases;

• appearance of signs of acute bronchiolitis or pneumonia with acute obstructive bronchitis in newborns, especially premature infants with low birth weight (≤2.5 kg at birth);

• hemodynamic instability with the development of centralization of peripheral circulation (cold extremities, cyanosis, skin marbling against the background of general pallor and hyperthermia, development of collapse and coma);

• burdened premorbid background: congenital malformations of the lungs and bronchi, including bronchopulmonary dysplasia (BPD), cardiac and vascular defects (CHD and VCD), orphan, systemic (cystic fibrosis, alveolitis, etc.) autoimmune and chronic conditions, including chronic obstructive pulmonary disease (COPD), bronchial asthma, history of organ transplantation;

Indications for hospitalization expand as the patient's age decreases, since deterioration often occurs catastrophically with rapid progression and generalization of the process, and proper medical tactics frequently determine the child's survival.

Indications for patient discharge from a medical organization

Patients are discharged from the hospital upon stabilization of their condition and relief of signs of respiratory failure and intoxication.

7. Additional Information

Risk factors for the development of acute bronchiolitis and its severe course requiring hospitalization and treatment in an intensive care unit (ICU) include the following:

- male sex;

- prematurity and low birth weight (less than 2500 grams);

- age under 3–6 months and body weight under 5 kg;

- fetal alcohol syndrome;

- congenital pneumonia, meconium aspiration syndrome, and mechanical ventilation in the neonatal period;

- low socio-economic status and insufficient education of the child's caregivers;

- crowding (overcrowded living conditions);

- presence of older siblings in the family, especially those attending childcare facilities;

- passive smoking, including electronic cigarettes, and environmental pollution;

- bronchopulmonary dysplasia (BPD), cystic fibrosis, airway malformations;

- severe congenital and perinatal central nervous system lesions, Down syndrome, neuromuscular diseases;

- food aspiration, including that associated with GER;

- congenital heart disease (CHD) with congestive heart failure and/or pulmonary hypertension;

- congenital or acquired immunodeficiencies; [25, 27].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Lobzin, Yuri Vladimirovich – MD, Full Member of the RAS, President of the Pediatric Research and Clinical Center of Infectious Diseases under the Federal Medical-Biological Agency, Chief Freelance Specialist in Pediatric Infectious Diseases of the Russian Ministry of Health and the Federal Medical-Biological Agency, President of the NGO "Euro-Asian Society for Infectious Diseases"

2. Volodin, Nikolai Nikolaevich – MD, Full Member of the RAS, Head of the Scientific and Advisory Department at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, President of the Russian Association of Perinatal Medicine Specialists

3. Zhdanov, Konstantin Valerievich – MD, Corresponding Member of the RAS, Professor, Director of the Pediatric Research and Clinical Center of Infectious Diseases under the Federal Medical-Biological Agency, Chief Freelance Specialist in Infectious Diseases of the Saint Petersburg Health Committee, Deputy President of the NGO "Euro-Asian Society for Infectious Diseases"

4. Gorelov, Alexander Vasilievich – MD, Full Member of the RAS, Deputy Director for Science at the Central Research Institute of Epidemiology of Rospotrebnadzor, Chairman of the Board of the National Association of Infectious Diseases Specialists named after Academician V.I. Pokrovsky

5. Usenko, Denis Valerievich – MD, Associate Professor, Leading Researcher at the Clinical Department of Infectious Pathology, Central Research Institute of Epidemiology of Rospotrebnadzor, Executive Director of the National Association of Infectious Diseases Specialists named after Academician V.I. Pokrovsky

6. Babachenko, Irina Vladimirovna – MD, Professor, Head of the Research Department of Droplet Infections, Pediatric Research and Clinical Center of Infectious Diseases under the Federal Medical-Biological Agency, Member of the NGO "Euro-Asian Society for Infectious Diseases"

7. Rychkova, Svetlana Vladislavovna – MD, Associate Professor, Head of the Medical Care Organization Department, Pediatric Research and Clinical Center of Infectious Diseases under the Federal Medical-Biological Agency, Pediatrician

8. Ovsyannikov, Dmitry Yurievich – MD, Head of the Department of Pediatrics at the Peoples' Friendship University of Russia named after Patrice Lumumba, Member of the Russian Association of Perinatal Medicine Specialists

9. Krsheminskaya, Irina Vladimirovna – PhD, Associate Professor of the Department of Pediatrics at the Peoples' Friendship University of Russia named after Patrice Lumumba, Member of the Russian Association of Perinatal Medicine Specialists

10. Goleva, Olga Vladimirovna – PhD, Senior Researcher at the Research Department of Virology and Molecular Biological Research Methods, Pediatric Research and Clinical Center of Infectious Diseases under the Federal Medical-Biological Agency

Conflict of interest: none

Appendix A2. Methodology for Developing Clinical Guidelines

The evidence base for the recommendations includes publications included in the Cochrane Library, EMBASE, MEDLINE, Clinicalkey ELSEVIER databases, and the electronic library (www.elibrary.ru). The search depth was 20 years

Methods used to assess the quality and strength of evidence: - expert consensus; - assessment of significance in accordance with the levels of evidence and grades of recommendation.

Target audience for these clinical guidelines:

- anesthesiologist-resuscitologist;

- bacteriologist;

- virologist;

- disinfectantologist;

- health station physician;

- infectious disease physician;

- clinical laboratory diagnostics physician;

- clinical pharmacologist;

- laboratory physician;

- neurologist;

- general practitioner (family physician);

- pediatrician;

- municipal (district) pediatrician;

- precinct pediatrician;

- preventive medicine physician;

- medical rehabilitation physician;

- emergency admission physician;

- internist;

- adolescent physician;

- precinct internist;

- epidemiologist.

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for grading levels of evidence certainty (LEC) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Federal Law No. 52-FZ of March 30, 1999 (as amended on July 24, 2023) "On the Sanitary and Epidemiological Welfare of the Population"

2. Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021 (as amended on May 25, 2022) "On approval of sanitary rules and norms SanPiN 3.3686-21 'Sanitary and epidemiological requirements for the prevention of infectious diseases'" (Registered with the Ministry of Justice of Russia on February 15, 2021, No. 62500)

3. Order of the Ministry of Health of Russia No. 1122n dated December 6, 2021 "On approval of the national schedule of preventive vaccinations, the schedule of preventive vaccinations by epidemiological indications, and the procedure for conducting preventive vaccinations" (Registered with the Ministry of Justice of Russia on December 20, 2021, No. 66435)

4. Order of the Ministry of Health and Social Development of Russia No. 521n dated May 5, 2012 (as amended on February 21, 2020) "On approval of the Procedure for providing medical care to children with infectious diseases" (Registered with হওয়ার the Ministry of Justice of Russia on July 10, 2012, No. 24867)

5. Order of the Russian Ministry of Health No. 804n dated October 13, 2017 (as amended on September 24, 2020, with rev. as of October 26, 2022) "On Approval of the Nomenclature of Medical Services" (Registered with the Ministry of Justice of Russia on November 7, 2017, No. 48808)

6. Order of the Russian Ministry of Health No. 302n dated May 16, 2019 (as amended on November 19, 2020) "On Approval of the Procedure for Dispensary Observation of Minors, Including During the Period of Education and Upbringing in Educational Organizations" (Registered with the Ministry of Justice of Russia on June 7, 2019, No. 54887)

7. Clinical Guidelines – Pneumonia (Community-Acquired) – 2022-2023-2024 (January 18, 2022) – Approved by the Ministry of Health of the Russian Federation

8. Clinical Guidelines – Bronchitis. 2021. Approved by the Ministry of Health of the Russian Federation

9. Immunoprophylaxis of Respiratory Syncytial Infection in Children. Methodological guidelines for pediatricians. Moscow. Pediatr. 51 p.

10. Clinical guidelines. Acute bronchiolitis. 2016. Approved by the Ministry of Health of the Russian Federation

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Respiratory syncytial virus (RSV) infection is an acute viral respiratory disease characterized by a moderate fever and intoxication, frequent development of bronchitis, bronchiolitis, and pneumonia, often accompanied by obstructive syndrome (OS) and respiratory failure (RF), especially in young children. In older age, patients with RSV infection present with symptoms typical of acute respiratory viral infections (ARVI).

The causative agent is an RNA-containing virus belonging to the family Paramyxoviridae, genus Pneumovirus. The source of infection in RSV infection is primarily patients in the acute period of the disease, regardless of severity. RSV can account for up to 30% of ARVI cases. The transmission route of the infection: airborne droplet and contact-household via fomites; regular hand washing reduces the likelihood of infection. The virus is most frequently isolated during the 1st–2nd weeks of illness.

The incubation period averages 3–5 days, up to 8 days. Immunity following the infection is unstable, and the infection is highly contagious; a child may contract it multiple times not only throughout life, but even within a single epidemic season. RSV infection runs a less severe course upon reinfection. It occurs year-round.

There is no vaccination against RSV infection.

Specific immunoprophylaxis of RSV infection involves administering an immunoglobulin antibody preparation to children at risk for a life-threatening course of RSV infection. It is a recombinant immunoglobulin directed against the RSV fusion protein. It is prescribed to children with bronchopulmonary dysplasia and patients with hemodynamically significant congenital heart defects under 24 months of age, as well as premature infants born before 35 weeks of gestation whose age at the time of initiating immunoprophylaxis is no more than 6 months. Based on individual indications, passive immunoprophylaxis of RSV infection may be administered to children with immunodeficiencies, severe neuromuscular diseases, congenital malformations, and orphan diseases with a genetic pathology affecting respiratory function.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Differential diagnosis of bronchial obstruction [70]

1.