Pediatrics: respiratory syncytial virus.

INDEX

1- INTRODUCTION
2- BRONCHIOLITIS DEFINITION
3- EPIDEMIOLOGY
4- RISK FACTORS FOR RESPIRATORY INFECTIONS
5- PHYSIOPATHOLOGY
6- CLINICAL PICTURE
7- SEVERITY CLASSIFICATION
8- COMPLEMENTARY EXAMINATIONS
9- CRITERIA FOR HOSPITALIZATION
10- TREATMENT
11- AVAILABLE THERAPEUTICS
12- RECOMMENDATIONS
13- REFERENCES

Introduction

Acute respiratory infections (ARI) persist as a major cause of morbidity and mortality in developing countries, constituting a significant public health challenge.
Respiratory syncytial virus (RSV) is the primary cause of ARIB in infants and children under 5 years of age worldwide. Throughout life, reinfections can occur, being mild or asymptomatic in adults, but presenting a substantial risk of severe disease in the older population.
Historically, neither antiviral therapy nor an effective approved vaccine was available for the prevention of RSV disease. The only method of prevention was passive prophylaxis with Palivizumab, a humanized monoclonal antibody against F-glycoprotein, which, although effective, is limited by its high cost and the need for multiple administrations.
Subsequent sections will address recently approved new therapies.

Bronchiolitis definition:

Bronchiolitis is defined as the first episode of acute lower respiratory infection in children under 2 years of age, of viral origin, manifesting clinically through obstruction of the lower airways, evidenced by cough, rales and/or wheezing. Although it generally presents a mild and self-limited clinical picture, in children under 5 years of age, in those over 60 years of age and in individuals with risk factors, it can trigger severe infections.

Epidemiology:

Worldwide, between 120 and 156 million cases of Acute Respiratory Infections (ARI) are reported annually, causing 1.4 million deaths in children under 5 years of age. More than 95% of these fatalities are concentrated in low and middle income countries. In Argentina, there is a constant increase in ARI cases during the winter season, associated with an increase in the demand for medical care, hospitalizations and mortality due to respiratory causes.

Local studies confirm that most ARIB, especially bronchiolitis and pneumonia, occur during the first years of life, with respiratory viruses being the main etiologic agents in children under 2 years of age. Although small variations in the prevalence and distribution of etiologic agents are observed, these have been changing over time due to new diagnostic techniques and characterization of respiratory viruses.

Among the clinical entities included in ARIB, bronchiolitis and pneumonia (with or without complications) stand out as the most relevant in terms of morbidity and mortality in this age group. Bronchiolitis is more frequent in infants, with a high incidence between 3 and 5 months of age. Approximately 3% of infants without risk factors require hospitalization, with a mortality of less than 1%. However, in the presence of risk factors, the situation changes significantly.

In infants under 30 days of life hospitalized for bronchiolitis, up to 35% may require intensive care with mechanical ventilation. In premature infants with bronchopulmonary dysplasia, the incidence of hospitalization can exceed 10%, and in patients with congenital heart disease, the need for intensive care is up to 4 times higher, with mortality reaching 37%. Infants with risk factors experience longer hospitalizations, with longer duration of oxygen requirement and an increased need for mechanical ventilation (MRA) as part of treatment.

Studies carried out in Argentina reflect results similar to those reported in other regions, highlighting that RSV represents 81.3% of the viruses identified as etiological agents in patients hospitalized for severe acute respiratory infection (SARI), with a case-fatality rate of 1.7%.
RSV circulation used to be concentrated in the autumn and winter months in temperate areas, but this dynamic has changed with the emergence of COVID-19. In tropical areas, circulation increases during the rainy season.

Risk factors for respiratory infections:

• Host: lack of breastfeeding, incomplete vaccination, premature infants, low birth weight, malnutrition, children under 3 months of age, congenital heart disease, immunodeficiencies, bronchopulmonary dysplasia, neurodevelopmental disorders (chronic encephalopathy, neuromuscular diseases).
• Environment: overcrowding, winter season, day care and/or school attendance, illiterate mother, adolescent mother, environmental contamination, household contamination (tobacco, biomass consumption for heating or cooking). RSV is transmitted by contaminated secretions from close contact, directly or through fomites. The most frequent route of transmission is contact with a sick person (ambulatory patients); in hospitalized patients, transmission may also be due to contaminated hands of staff. The incubation period is 2 to 8 days; the virus is shed in respiratory secretions for 3 to 8 days and may be prolonged in young and immunocompromised children.

Pathophysiology:

Infection begins in the epithelium of the upper respiratory tract and spreads to the lower airways in 1 to 3 days. Viral injury triggers an intense inflammatory response in the small airways (mononuclear leukocytes and neutrophils), leading to edema and necrosis of the respiratory epithelium with desquamation within the bronchial/bronchiolar lumen, resulting in obstruction. Part of the airway is partially obstructed with alteration of normal airflow and distal air trapping; others are completely obstructed causing atelectasis. Mechanical compromise of ventilation interferes with gas exchange. The most frequent alteration is hypoxemia secondary to hypoventilated areas.

Clinical picture:

• Symptoms of upper respiratory infection 1 to 3 days before (rhinorrhea, cough and possibly a low-grade fever).
• Symptoms of peripheral airway obstruction (cough, tachypnea, prolonged expiration, rales, wheezing) with or without intercostal retraction (pulling), nasal flaring or whining, progressing between the 3rd and 5th day, usually decreasing in intensity within 7 days.
• Complete clinical recovery (cough) may take two to three weeks (regeneration time of the ciliated epithelium).
• Insufficient fluid intake can lead to dehydration.
• Occasionally, apnea may occur; it tends to occur more frequently in younger patients.
• The appearance of late fever should raise suspicion of a bacterial complication (otitis media, pneumonia, among others).

Severity classification:

According to the degree of ventilatory incapacity, from clinical signs derived from compensatory mechanisms, different degrees of severity can be determined. The modified Tal scale (with four variables; respiratory frequency, wheezing, cyanosis, intercostal retractions) has proven to be very useful in practice, especially in cases of bronchial obstruction in children under 5 years of age. It has been used to standardize and norm the severity of bronchial obstruction.
The evaluation through such a modified score allows establishing severity categories that show a certain correlation with O2 saturation measured by pulse oximetry (Sat O2 ).

• 4 points or less: mild (≥ 98 %).
• From 5 to 8 points: moderate (93 %-97 %).
• 9 points or more: severe (≤ 92 %).

Complementary examinations:

The diagnosis of bronchiolitis is clinical, so routine complementary tests are not necessary in patients with typical bronchiolitis. It is not recommended to request routine chest X-rays in all patients with typical forms of bronchiolitis. It is useful if there is diagnostic doubt (suspicion of pneumonia or complication); also in severe or poorly progressive cases. Although it may be normal, the typical radiological pattern is that of airway involvement (air trapping, peribronchial thickening, discrete bilateral perihilar infiltrates, segmental or subsegmental atelectasis), hemogram and acute phase reactants are usually normal. Blood gases should be ordered when progressive respiratory failure is suspected.
Saturarometry is useful to monitor oxygenation, although it is not essential for the follow-up of patients with conditions that allow ambulatory management.

Etiological screening is not routinely performed in ambulatory patients. It is useful for epidemiological surveillance and to decide what measures to take in hospitalized patients; in them it can be useful to guide a more rational use of antibiotics if considered necessary.

The diagnosis can be made through the investigation of viral antigens by indirect immunofluorescence (IFA) in the aspirate of nasopharyngeal secretions. This method is fast and inexpensive, with high sensitivity and specificity in relation to viral culture. It should be requested when the patient is admitted, or as soon as possible (the possibility of identifying the virus decreases 72 hours after the onset of the disease). The use of molecular diagnosis (polymerase chain reaction; PCR) is recommended but not always available in our environment.

Criteria for hospitalization:

• Presence of severe respiratory distress (Tal ≥ 9 points) or hypoxemia (Sat O2 less than 92 %).
• History of apneas (evident or referred).
• Cyanosis.
• Inability to feed (or reduction of intake to 50% in the last 8 to 12 hours) with or without dehydration.
• Presence of a risk factor for severe ARIB (biological or socio-environmental).
• Presence of moderate respiratory distress that does not improve after an observation period of up to 2 hours (lower fever, check nasal passages for patency).

Admission to the Intensive Care Unit/Intensive Therapy Unit (ICU/ICU) is indicated if there is inability to maintain oxygen saturation greater than 92% despite increasing oxygen therapy, if there is deterioration of respiratory status with signs of exhaustion (signs compatible with acute impending respiratory claudication [ARC]), and if the patient presents with apneas. Evaluate the modality of ventilatory support (high-flow nasal cannula/noninvasive ventilation/invasive ventilation) according to the degree of patient compromise and the availability and ability to administer them.

Treatment:

Oxygen therapy: infants with bronchiolitis are at risk of developing hypoxemia. Oxygen is the only therapeutic measure with proven efficacy in bronchiolitis. Hospitalized patients should receive oxygen therapy to maintain oxygen saturation over 94%. With compatible clinical symptoms, even without saturation measurement, oxygen should be administered. For its discontinuation, stable values of SatO2 over 94% will be taken as reference values. In patients without risk factors and with favorable clinical evolution, oxygen therapy suspension could be considered with saturations between 92% and 94%.
Nasal cannulae are the recommended devices, although they should be used with caution in the acute stage, since nasal congestion may prevent adequate oxygen flow. Oxygen should be administered humidified and warmed with flows greater than 2 L/min. The use of oxygen with other forms of administration (high-flow nasal cannula / CAFO) as well as noninvasive ventilation (NIV) may be considered in those patients who do not respond to treatment.

Hydration: in the ambulatory patient, the caregiver should be advised to offer abundant fluids by mouth. Lack of intake is interpreted as a sign of poor evolution and determines the need for immediate consultation (risk of hypoxemia and/or dehydration). In patients requiring hospitalization, the same criteria will be maintained if they are able to ingest liquids. When parenteral hydration is indicated, fluid and electrolyte intake should be started according to standardized maintenance needs and then corrected according to the patient's real requirements (according to diuresis and urine density). In case of previous deficit (dehydration), it will be corrected initially.

Feeding: whenever possible, breastfeeding shall be maintained. Efforts should be made to maintain adequate nutritional intake. It is important to observe the child during feeding to assess coordination between sucking, swallowing and breathing mechanisms, and to detect/prevent aspiration of food. It is recommended to keep the nostrils clear, administer small volumes of food frequently, and establish periodic breaks to allow the child to rest. The extent of ventilatory impairment may require fractionated feeding or even discontinuation of oral intake when the respiratory rate exceeds 60 breaths per minute. The use of a nasogastric or orogastric tube may be used if necessary.

Kinesiotherapy: its application is not necessary in ambulatory patients. Parents will be recommended to keep the nostrils permeable by suctioning secretions and to keep the patient in a semi-sitting position. For those requiring hospitalization, the same recommendations apply. Kinesiotherapy may be used when there are abundant secretions that may increase the risk of causing atelectasis. The appropriate technique should be chosen, bearing in mind the risk of triggering therapy-induced bronchoobstruction. In all cases, risks and benefits should be assessed; it is advisable to initially test tolerance to this treatment with pulse oximetry monitoring. In cases where kinesiotherapy is required, it should be carried out by a qualified professional.

Antipyretics: when appropriate, antipyretics, such as paracetamol or ibuprofen, may be used in usual doses.
The routine use of bronchodilators in the management of typical bronchiolitis is not indicated. Given the heterogeneity that could encompass the term bronchiolitis, salbutamol may be used as a therapeutic test in the initial management, particularly in older infants, or with a history of respiratory or atopy. Without clinical response (expressed by decreased respiratory frequency and/or effort), bronchodilators should be discontinued. There is no evidence that the use of corticosteroids has a beneficial effect in typical bronchiolitis.

Therapeutics available:

The use of monoclonal antibodies against RSV (Palivizumab) in children with risk factors (mainly premature infants and those with bronchopulmonary dysplasia) has been shown to be useful in reducing the risk of hospitalization due to this infection (passive immunity). Its recommendations are clearly defined by the National Ministry of Health and agreed upon by the Argentine Pediatrics Society.

In November 2023, following approval by the European Commission and the U.S. Food and Drug Administration (FDA), the National Administration of Drugs, Food and Medical Technology (ANMAT) approved Nirsevimab, a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody produced using recombinant DNA technology, for the prevention of lower respiratory tract illness caused by respiratory syncytial virus (RSV) that applies directly to infants born during or entering their first season of virus circulation, and for children up to 24 months of age who remain vulnerable to severe RSV illness until their second season.

A bivalent RSV vaccine was recently approved for use in pregnant women between 32 to 36 weeks with the aim of generating antibodies against the virus that will pass through the placenta to the fetus and provide immunity to the infant in the first 6 months of life. The vaccine contains 60 μg of stabilized respiratory syncytial virus subgroup A prefusion F antigen and 60 μg of stabilized respiratory syncytial virus subgroup B prefusion F antigen. It has approvals from the U.S. Food and Drug Administration (FDA) and the National Administration of Drugs, Food and Medical Technology (ANMAT) and as of 2024 is part of the National Vaccination Calendar.

Recommendations:

To the community: teach to recognize warning signs, encourage early consultation, minimize self-medication and reduce risk factors for ARIB.

To professionals: raise awareness of the magnitude of the problem and the impact of preventive action, achieve adequate management of patients with ARI, recognize severity criteria and make timely referrals. The message should be consistent with the one given to the community, focusing on prevention and the application of standardized behaviors.
Recommendations to professionals to prevent morbimortality due to acute respiratory infections low preventive actions:

• Recommend pregnancy monitoring from the first trimester.
• Encourage breastfeeding.
• Stimulate the control of household contamination.
• Make sure your patients receive all vaccinations.
• Instruct mothers on the warning signs of ARIB.
• Insist on the value of early consultation.
• Identify patients at risk for severe ARI.
• Strengthening of the situation room/epidemiological surveillance. Patient behavior
• Make a correct diagnosis.
• Evaluate the severity of the condition.
• Monitor response to treatment.
• Rational use of antibiotics and oxygen.
• Make sure the mother understands the directions.
• Do not delay referral when necessary.
• Prioritize care for patients at risk of severe ARI.
• Biosafety standards in health centers and hospitals.

Authors: Scientific Advisory. Medical area. Science Team.

References:

• Recommendations for the management of acute lower respiratory infections in children under 2 years of age. Update 2021. Archivos Argentinos de Pediatría 2021.