Vlad Dima(1), Adrian Ioan Toma(2),(3), Roxana Elena Bohîl?ea(1),(4)
(1) Department of Obstetrics, Gynecology and Neonatology, Filantropia Clinical Hospital, Bucharest, Romania
(2) Department ofNeonatology,Life Memorial Hospital, Bucharest, Romania
(3)Department ofNeonatology,University ”Titu Maiorescu”, Bucharest, Romania
(4)Department ofObstetrics and Gynecology,“Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
Correspondence to: Adrian Ioan Toma, MD, PhD, adrian.toma@prof.utm.ro
Abstract
Respiratory syncytial virus (RSV) causes a spectrum of respiratory diseases in infants and young children that can lead to hospitalizations and many outpatient visits, resulting in a huge public health and economic burden. Most hospitalizations occur in otherwise healthy infants, highlighting the need to protect all infants against RSV. Moreover, there is evidence of an association between RSV respiratory disease in early life and recurrent asthma-like wheezing symptoms. Therefore, RSV is considered a global health priority. However, the only prevention strategy currently available is a monoclonal antibody (mAb) indicated in former preterm infants or those with severe comorbidities, thus leaving the majority of the infant population unprotected against this virus. Therefore, the development of RSV prevention strategies for all infants entering their first RSV season represents a large unmet medical need.Current prevention strategies include maternal immunization, infant immunization with vaccines, and infant immunization with licensed monoclonal antibodies.The use of mAb is limited to a small population of infants and does not provide a solution for the protection of all children, while vaccine development in infants has faced various challenges, including the immaturity of the infant immune system, highlighting that future pediatric vaccines will be the most probably used in older infants (>6 months) and children.Maternal immunization and infant immunization with long-acting monoclonal antibodies are two feasible strategies to protect all children against RSV. Based on current data, immunization of infants with long-acting monoclonal antibodies may represent the most effective approach to protect all children entering their first RSV season.
Keywords: respiratory syncytial virus, prevention, morbidities, prematurity, economic burden, survival
Introduction
Almost 100% of children are infected with RSV in the first 2 years of life (1). 10% will go to the doctor and of these, one in ten will require hospitalization(2). Today, an unacceptably high number of infants suffer from severe respiratory illness due to RSV. Importantly, most RSV hospitalizations occur in apparently healthy term infants (3).Globally, RSV is the most significant cause of death from acute lower respiratory tract infections (ALRIs) in the first year of life(4). Although disease surveillance and data collection for RSV infection have often not been prioritized, global estimates in 2015 reported that there were 33 million episodes of RSV-ALRI resulting in approximately three million hospital admissionsand 59,600 deaths in hospitals in children under 5 years old. In children younger than 6 months of age, 1,4 million hospital admissions and 27300 hospital deaths were due to RSV. There were 120 000 deaths in total, of which at least 50% occurred in infants younger than 5 months(5,6).
Why should we prevent RSV infections?
RSV is highly contagious and causes frequent reinfections in children – even several times in the same season – and is generally transmitted by direct or indirect contact with oral or nasopharyngeal secretions(7). Symptoms of an RSV infection generally begin after an incubation period of 4-6 days, with flu-like symptoms and manifestations affecting the upper airways, such as nasal congestion, rhinorrhea, and cough. In newborns and children under 2 years of age, the clinical picture may progress to bronchiolitis, the most common clinical syndrome associated with severe RSV infection (8,9). Bronchiolitis is an inflammation of the small airways of the lungs that occur after the onset of rhinitis and is associated with cough and dyspnea; younger children may also present with fever, feeding difficulties and irritability(10). In neonates, especially infants, RSV infection may be associated with other clinical manifestations such as pneumonia and wheezing (11).RSV morbidity is now known to extend beyond the acute episode; RSV infections occurring during the first year of life, including those not requiring hospitalization, are associated with an increased risk of recurrent wheezing and the development of asthma(10,11,12).A Scottish study of about 740 000 newborns followed up to age 18 showed that children hospitalized for RSV infections in the first 2 years of life had a threefold higher risk of hospitalization for asthma and used significantly more anti-asthma medications compared to controls(13).
How prone are premature newborns to RSV infection?
An observational study from Italy retrospectively evaluated all children aged 0–6 years with a diagnosis of RSV infection from September 2014 to August 2019.Data were available from 624 children with RSV infection (346 males, 55.4%, and 278 females, 44.6%). All patients had respiratory distress requiring hospitalization and recovered after medical attention. The distribution of registered hospitalized cases according to age showed that 509/624 patients (81.6%) were under 1 year of age, 390/624 (62.5%) were under 3 months of age and 256/624 (41%) were less than 30 days old. Of the 509 patients under 1 year of age, 390 (76.6%) were between 0 and 3 months of age and 256 (50.3%) were under 1 month of age.Prematurity (<37 weeks of gestational age) was detected in 153/624 patients (24.5%) and 6/624 (0.96%) had a diagnosis of bronchodysplasia. Of these 153 preterm infants, 111/153 (72.5%) were late preterm (34–37 weeks), 20/153 (13.1%) were moderate preterm (32–33 + 6 weeks), 13/ 153 (8.5%) were very preterm (28–31 + 6 weeks) and 9/153 (5.9%) were extremely preterm (<28 weeks).Additional underlying risk factors for RSV infection included 31 cases (4.97%) with congenital heart disease, 28 (4.49%) with neurologic involvement, 5 (0.8%) with an immunologic disease, 6 (0.96%) with oncological disorders and 4 (0.64%) with cystic fibrosis. The study showed that morbidities play an important role in the risk of RSV infection. At least one underlying condition and, in most cases, prematurity were detected in more than 30% of patients. This rate was higher than that reported in other studies (14).
A study conducted in Austria in a tertiary care center included 745 infants, children, and adolescents hospitalized for respiratory disease with a positive RSV test between January 1, 2009 and December 31, 2015.Associated comorbidities were prematurity in 15% of cases, followed by neurological impairment (3.5%) and hemodynamically significant congenital heart disease (2.95%). Age ≤ 2 months and associated conditions/comorbidities were associated with more severe disease. Most cases (96%) were under 24 months and 91% were under 12 months. Viral co-infection (most common influenza virus, adenovirus, and rhinovirus) was diagnosed in 5% ofcases, leading to a more severe course of the disease. The main risk factors for coinfection were siblings and crowding. Mortality was 0.27% (2/745). Prematurity and underlying morbidities play a marked role in the occurrence and severe evolution of RSV(15).
What is the economic impact of RSV infection?
RSV is a leading cause of hospitalization in infants and RSV-related morbidity results in the increased emergency department and outpatient visits. This translates into significant economic costs that could be reduced and even avoided if effective strategies to prevent RSV infection were implemented.
A recent publication from Italy confirms the high hospitalization costs associated with bronchiolitis(16). Where the etiology was related to RSV, costs were, on average,about 6% higher compared to bronchiolitis of other etiologies. This is due to the longer hospital stay and more frequent intensive care unit admissions of RSV patients. Age at the admission of less than 3 months has been shown to be a risk factor for severe bronchiolitis (17).
The economic impact of RSV infection in neonates and children needs to be evaluated in terms of both direct and indirect costs on health resources and services, including emergency department and hospital visits, as well as resource use in subsequent years, such as additional hospital admissions and medication use due to wheezing or asthma (13).
The BARI study published in September 2022 revealed the clinical and economic burden of RSV-infected Spanish children. The average direct healthcare cost per RSV-specific case and medically assisted ALRI was €1753 in the first year of life, €896 in the second, and €683 between 2 and 5 years. Hospitalization was the main driver of these costs, accounting for 55.6%, 38.0%, and 33.4%, in each respective age group. In RSV-specific cases, the average direct healthcare cost per medically attended case was higher, mainly due to hospitalization (18).
A retrospective analysis of data on RSV-associated hospitalizations from the French Hospital Database of all children aged < 5 years admitted with RSV from 2010 to 2018 showed that the cost of associated hospitalization increased between 2010 - 2011 and 2017 -2018, from EUR 93,2 million, to EUR 124, 1 million, respectively, and infants < 1 year accounted for 80% of the economic burden.(19)
Conclusion
Severe RSV infection is one of the major causes of global mortality in young children, with 99% of deaths occurring in developing countries in 2015(20).
Given the high cost, mAb is recommended only in high-risk infants, including those born preterm and those with hemodynamically significant BPD and CHD, and in selected cases of rare clinical pathologic conditions (eg, neuromuscular disease, congenital anatomic lung abnormalities). However, many RSV-related pediatric hospitalizations do not fully meet the criteria for mAb, and in developing countries,the mAb are not available(21).
RSV prevention policy should be adapted to the seasonal patterns of RSV, to protect the most vulnerable patients from severe disease; in tropical regions with longer and more variable RSV seasons, a year-round immunization schedule for maternal and infant immunization may be appropriate.
It is therefore essential that, pending the availability of effective maternal or pediatric RSV vaccines, each country obtains accurate RSV epidemiological surveillance data to inform future decisions about the most appropriate immunization schedule for local circumstances.
The enormous health and economic burden of RSV has made the development and implementation of RSV protection strategies a high global priority with the goal of protecting all infants. The most effective option for protecting all children against RSV may be the long-acting use of monoclonal antibodies, underscoring the need to adopt this new technology. National guidelines should be updated to support these strategies, and all stakeholders (parents, healthcare providers, and health strategy makers) should be informed of the benefits of these technologies to ensure successful implementation in future immunization programs.
References