Respiratory Syncytial Virus in Children: A Comprehensive Review on Publication Trends, Epidemiology, Pathogenesis, Vaccines, and Prevention Strategies

Abstract

Respiratory syncytial virus (RSV) is a prevalent viral respiratory infection that affects a significant number of children under five globally. RSV tends to have a more severe impact on premature newborns, young children, elderly folks, and those with weakened immune systems, as opposed to healthy adults. RSV is transferred through respiratory droplets by either coming into close contact with an infected person or touching objects that have been contaminated. The genetic material of RSV is composed of 11 proteins. Among these 11, two proteins facilitate the binding of the virus to the respiratory epithelial cells and the merging with host cells. After fusion, the viral material is transferred to the host cell, where viral reproduction occurs. Ongoing strategies encompass the creation of maternal vaccinations to safeguard newborns in their first months, monoclonal antibodies to offer rapid protection for up to 5 months, and pediatric vaccines for more enduring safeguarding. However, there is a need for enhancements in infection surveillance and reporting to enhance the detection of cases and gain a more comprehensive understanding of seasonal infection patterns. For the differential diagnosis of respiratory infections in children, it is recommended to utilize both rapid diagnostic assays and confirmatory laboratory testing.

1. Introduction

Respiratory syncytial virus (RSV), a highly contagious virus, was identified over 60 years ago and is a significant contributor to lower respiratory infections (LRIs). RSV infection exhibits a seasonal pattern, with a yearly surge in infection rates during the rainy season in tropical regions and the cold season in temperate regions [1, 2, 3, 4, 5]. Approximately, 15–50% of initial respiratory syncytial virus (RSV) infections in newborns and young children affect the lower respiratory tract. The predominant lower respiratory tract infection (LRI) is bronchiolitis, which can also manifest as croup or pneumonia. Infants and young children face a significant risk of contracting RSV infection and experiencing associated mortality. In older children and adults, symptoms of RSV infection are typically absent or mild. RSV is a significant cause of illness and death among immunocompromised adults, individuals with chronic cardiopulmonary disease, and the elderly.

RSV infection had a global impact in 2016, affecting around 24.8 million individuals and leading to 76,000 fatalities. RSV was responsible for roughly 3.3 million instances of lower respiratory infections (LRIs) and resulted in 26,300 fatalities among children under the age of 5 in 2019 [6]. The annual prevalence of lower respiratory infections (LRIs) caused by respiratory syncytial virus (RSV) is 7.03% among high-risk people and 4.66% among older persons in industrialized countries [7, 8]. Hospitalization is a frequent occurrence during the initial 5 years of life, with the highest rates observed among newborns who are 3 months old [9]. By age three, most children become infected with RSV [10] and subsequently experience frequent reinfections throughout their lifespan as their immune response to this virus weakens with time [11]. RSV infection presents symptoms such as airway obstruction, rhinorrhea, dyspnea, wheezing, hypoxia, and, in severe instances, pneumonia and bronchiolitis. In addition, the occurrence of asthma has been strongly linked to respiratory syncytial virus (RSV) infection throughout the early stages of infancy.

2. Publication scenario on respiratory syncytial virus

A literature search was primarily conducted by coining respiratory virus as a keyword in the “PubMed” database, which yielded 108,815 articles from 2000 to 2023 (Figure 1). To concentrate on the syncytial viruses, the search was refined by the following keywords: Respiratory syncytial viruses under the search results of respiratory virus, which generated 13,045 articles. The search was again refined by the keywords ‘“respiratory syncytial virus in India,” which generated 146 articles. The search was refined further with the term “respiratory syncytial virus in infants in India,” which generated only 90 articles (Figure 2).

Figure 1.

Represents the publication scenario on respiratory viruses.

Figure 2.

Represents the publication scenario on respiratory syncytial viruses.

3. Epidemiology

RSV is a highly prevalent human virus, primarily because individuals do not develop long-lasting immunity after infection, resulting in frequent reinfection. The virus has a high prevalence rate of 90% among children during the initial 24 months of their lives, and it commonly reinfects older children and adults. Most people infected with RSV will experience an upper respiratory sickness, but a notable percentage may suffer a lower respiratory tract illness, primarily bronchiolitis. Infants under 1 year are more susceptible to developing lower respiratory complications, with approximately 40% of initial infections leading to bronchiolitis. Globally, it is estimated that respiratory syncytial virus (RSV) is accountable for around 33 million cases of lower respiratory tract diseases, resulting in three million hospitalizations and up to 199,000 deaths among children. The majority of these fatalities occur in countries with minimal resources. RSV incidence exhibits seasonal fluctuations; however, the specific seasonal patterns differ across different regions. In temperate climates, there is a notable increase in cases throughout the winter and spring seasons. On the other hand, tropical and equatorial climates may have fewer prominent spikes in RSV cases, with a more evenly distributed occurrence throughout the year. A particular group of patients, such as preterm infants, individuals with preexisting cardiac, pulmonary, neurologic, and immunological problems, and the elderly, experience notably increased rates of illness and death [12, 13].

4. Etiology

RSV is an RNA virus that belongs to the Paramyxoviridae family and is classified in the genus pneumovirus. It has a single-stranded and negative-strand RNA structure. The discovery of RSV in chimpanzees occurred in 1955, and its identification as a human infection followed shortly after that. Other animal respiratory syncytial viruses belong to the same genus as human RSV. These viruses do not infect people and will not be mentioned further on this page. The RSV has a bilipid-layer envelope that encloses a ribonucleoprotein core. It also contains many membrane proteins, one responsible for attaching to host cells, while another for fusing with host cells (Figure 3). RSV isolates are categorized into two primary antigenic groups, A and B, subdivided into 13 genotypes for RSV-A and 20 for RSV B. The G protein is the primary source of genetic variation between A and B, which exhibits around 50% genetic dissimilarity. Subsequently, the MH-2 and SH proteins also contribute to genetic diversity. During outbreaks, strains from both groups can be present simultaneously. However, the specific proportions of groups A and B and their subtypes might fluctuate from year to year [14, 15, 16].

Figure 3.

Represents the structure of human ortho pneumovirus (respiratory syncytial virus).

5. Pathogenesis

RSV invades the cells lining the airways, and after multiplying for a few days, the infected cells detach and block the smaller bronchioles in the lower airway. RSV is less damaging to cells in a laboratory setting than viruses, such as influenza. However, it is believed that the shedding of ciliated columnar cells from the upper respiratory tract enables the virus to enter the lower respiratory tract [17]. The obstructing material in the bronchioles is not solely composed of mucus, cell debris, and DNA but also exhibits a significant presence of neutrophils infiltrating the area. This is accompanied by swelling (edema) of the tissue beneath the lining (submucosa) and outer layer (adventitial tissue), which causes additional blockage of the narrow air passages (small airways) [18]. Bronchiolitis, the most common manifestation of RSV infection in infants, occurs when the bronchioles become blocked. It typically starts with symptoms similar to a common cold but gradually progresses to a persistent cough, increased breathing rate, and effort and can be detected through the presence of crackles and wheezing when listening with a stethoscope. The clinical examination findings can exhibit significant variations during brief intervals due to the accumulation or clearance of airway material by coughing or movement of the infants [19, 20, 21, 22].

6. Risk factors for disease

Infants below the age of 3 months are at the highest risk for childhood RSV disease, with the risk steadily reducing as they become older. Additional factors that increase the likelihood of experiencing severe sickness include being male, being born prematurely, and having preexisting lung disease or congenital heart disease [23]. Having older siblings at home also heightens the likelihood of hospitalization due to RSV. Significantly, the majority of the burden of RSV disease is experienced by children who do not have any preexisting comorbidities [24]. This has significant implications for the overall healthcare expenses and the disease burden on the population. Although there is a significant amount of literature discussing the influence of comorbidities, especially prematurity, on the severity of RSV infection, most hospitalizations include infants who have no prior health issues. The estimates differ across different locations, with South Africa reporting that 50% of infants were previously healthy, whereas Switzerland reported up to 70%, Israel reported 90%, and Northern Spain reported 95% [25, 26, 27, 28, 29].

7. Diagnosis

The American Academy of Pediatrics (AAP) suggests that clinical judgment is a rational approach for diagnosing respiratory syncytial virus (RSV). Diagnostic tests are occasionally helpful but seldom have an impact on therapy decisions. Nasopharyngeal washes or tracheal secretions are more reliable samples for confirming RSV than nasal swabs; they are more typically used because of their convenience. Real-time PCR is the most accurate tool for diagnosing RSV. The enzyme immunoassay (EIA) is widely used as a quick detection test because it provides results in approximately 30 minutes, is cost-effective, and has an objective endpoint. The enzyme immunoassay (EIA) exhibits a specificity of 90–95% in the presence of RSV in the population, while its sensitivity ranges from 50–90%. Hence, clinical symptoms should not be disregarded even if the result is negative for RSV. Direct and indirect immunofluorescent assays are accessible, but they necessitate proficient staff and a significant amount of time to obtain results. RSV cultures are another diagnostic test option; however, their application is limited due to factors such as high cost, time requirements, and variability in laboratory techniques. Washes and aspirates are more likely to grow in culture, but it takes 4 days to 2 weeks to obtain a response. At this point, the youngster should show signs of improvement or fully recover from the infection. Chest radiographs are not conclusive for diagnosis; however, they can reveal hyperinflation, peribronchial thickening, or atelectasis [30, 31].

8. Vaccines

Over the past 10 years, there has been a notable surge in the quantity of trials evaluating various techniques for RSV vaccination. Currently, 34 distinct RSV vaccines are being developed, with 21 progressing from Phase 1 to Phase 3 clinical trials. RSV possesses several surface proteins, but the primary focus for immunization lies on two essential glycoproteins: the fusion (F) and attachment (G) proteins. Both factors are essential for the ability of the virus to infect and cause disease while also having a significant capacity to stimulate the production of defensive neutralizing antibodies [32, 33, 34, 35, 36]. RSV is classified into two subtypes, RSV-A and RSV-B, primarily based on changes in the G protein. However, the F protein is more conserved between the subtypes, making it a more favorable target for creating vaccines and monoclonal antibodies (MAbs). Following the identification of two distinct structural forms of the F protein, namely “pre-fusion F” (preF) and “post-fusion F” (postF), and the recognition that the preF conformation elicits more potent neutralizing antibodies, it has emerged as the preferred focus for interventions targeting respiratory syncytial virus (RSV) [37, 38, 39, 40, 41]. The existing RSV vaccine candidates can be categorized into live-attenuated (LAV) or chimeric vaccines, protein-based, recombinant vector-based, and nucleic acid-based vaccines [42].

9. RSV prevention

Supportive treatment is the primary therapeutic approach for acute RSV infection, focusing on preventing severe disease and the need for hospitalization. Furthermore, since sterilizing immunity against RSV cannot be attained through infection, reinfection persists throughout the lifespan of both children and adults. Therefore, it is crucial to have effective and long-lasting immunization [43, 44, 45, 46, 47, 48]. The initial evaluation of the RSV vaccine occurred shortly after the initial identification of RSV in critically ill infants. Regrettably, the initial formalin-inactivated RSV vaccine demonstrated that when children who received the vaccine were naturally exposed to RSV, they developed vaccine-enhanced RSV illness (ERD), resulting in an 80% hospitalization rate and the mortality of two infants. The ERD phenomenon has been extensively investigated and is thought to be partly caused by an excessive memory Th2 response, insufficient antibody affinity maturation, inadequate toll receptor signaling, and a diminished CD8 T-cell response [49, 50, 51]. ERD hindered the development of RSV vaccines for a significant period, which raised safety concerns. However, with the ongoing progress in our comprehension of RSV structural biology and the mechanism of action, there have been notable breakthroughs in tactics for preventing RSV. The numerous preventive strategies can be categorized into two groups: firstly, passive immunization using monoclonal antibodies (mAB) or maternal vaccination during pregnancy, and secondly, active immunization using different types of vaccines developed explicitly for newborns and adults [34, 52].

10. Summary

Despite developments in medicine, RSV still challenges society and healthcare systems. Despite being a global priority, the creation of a safe and effective vaccination for RSV has been ineffective for over 50 years. Although this field has been encouraging advancements, a reliable and efficient RSV vaccine is not expected shortly. Consequently, palivizumab continues to be the sole existing immunotherapy for preventing severe RSV in high-risk newborns, a status it has maintained for the last 20 years. The limited recommendations by the AAP for the use of RSV IP in high-risk pediatric groups have unfortunately resulted in a significant rise in RSV hospitalizations and illness severity. Considering this evidence, the NPA recommends the use of RSV IP for vulnerable newborns aged 29–35 weeks gestational age, which is in line with the FDA’s recommendation for palivizumab. With the increasing burden of RSV, the AAP should reevaluate its guidelines regarding RSV immunoprophylaxis in high-risk populations, particularly infants born at 29 weeks of gestational age or earlier. Risk stratification methods can assist in identifying vulnerable infants and children who would benefit most from RSV IP utilization.

11. Future prospects

There is great hope that RSV infection prevention and therapy will reach a clinical level within the next 5–10 years. Surface glycoproteins, however, are mutable, as is the case with other RNA viruses. Because of the potential impact on clinical trial outcomes and future product efficacy, it is crucial to identify and track the worldwide mutations and distribution of RSV to create antibodies and small-molecule inhibitors. This therapy should also be studied because of the potential for a synergistic approach involving a mixture of two or more antibodies or small-molecule inhibitors to decrease host immunity’s viral evasion. It has yet to be seen whether combination therapy, which is an effective method for creating synergy and preventing drug resistance in other viruses, would treat RSV.

Furthermore, it is possible that the timing of treatment initiation is crucial. For instance, anti-RSV medication has a better chance of producing positive therapeutic effects when used early in the infection’s progression. Vaccines necessitate additional clinical trials of the RSV mRNA vaccine. We anticipate the approval and marketing of multiple effective programs to enhance our capacity to control RSV infection shortly since current research and clinical progress statistics on RSV infection prevention are hopeful.

Conflict of interest

The author declares there is no conflict of interest.