Passive Immunoprophylaxis against Respiratory Syncytial Virus in Children: Where Are We Now?

Respiratory syncytial virus (RSV) represents the main cause of acute respiratory tract infections in children worldwide and is the leading cause of hospitalization in infants. RSV infection is a self-limiting condition and does not require antibiotics. However hospitalized infants with clinical bronchiolitis often receive antibiotics for fear of bacteria coinfection, especially when chest radiography is performed due to similar radiographic appearance of infiltrate and atelectasis. This may lead to unnecessary antibiotic prescription, additional cost, and increased risk of development of resistance. Despite the considerable burden of RSV bronchiolitis, to date, only symptomatic treatment is available, and there are no commercially available vaccines. The only licensed passive immunoprophylaxis is palivizumab. The high cost of this monoclonal antibody (mAb) has led to limiting its prescription only for high-risk children: infants with chronic lung disease, congenital heart disease, neuromuscular disorders, immunodeficiencies, and extreme preterm birth. Nevertheless, it has been shown that the majority of hospitalized RSV-infected children do not fully meet the criteria for immune prophylaxis. While waiting for an effective vaccine, passive immune prophylaxis in children is mandatory. There are a growing number of RSV passive immunization candidates under development intended for RSV prevention in all infants. In this review, we describe the state-of-the-art of palivizumab's usage and summarize the clinical and preclinical trials regarding the development of mAbs with a better cost-effectiveness ratio.

Current State and Challenges in Developing Respiratory Syncytial Virus Vaccines.

Respiratory syncytial virus (RSV) is the main cause of acute respiratory tract infections in infants and it also induces significant disease in the elderly. The clinical course may be severe, especially in high-risk populations (infants and elderly), with a large number of deaths in developing countries and of intensive care hospitalizations worldwide. To date, prevention strategies against RSV infection is based on hygienic measures and passive immunization with humanized monoclonal antibodies, limited to selected high-risk children due to their high costs. The development of a safe and effective vaccine is a global health need and an important objective of research in this field. A growing number of RSV vaccine candidates in different formats (particle-based vaccines, vector-based vaccines, subunit vaccines and live-attenuated vaccines) are being developed and are now at different stages, many of them already being in the clinical stage. While waiting for commercially available safe and effective vaccines, immune prophylaxis in selected groups of high-risk populations is still mandatory. This review summarizes the state-of-the-art of the RSV vaccine research and its implications for clinical practice, focusing on the characteristics of the vaccines that reached the clinical stage of development.

Impact of Rhinovirus Infections in Children.

Rhinovirus (RV) is an RNA virus that causes more than 50% of upper respiratory tract infections in humans worldwide. Together with Respiratory Syncytial Virus, RV is one of the leading causes of viral bronchiolitis in infants and the most common virus associated with wheezing in children aged between one and two years. Because of its tremendous genetic diversity (>150 serotypes), the recurrence of RV infections each year is quite typical. Furthermore, because of its broad clinical spectrum, the clinical variability as well as the pathogenesis of RV infection are nowadays the subjects of an in-depth examination and have been the subject of several studies in the literature. In fact, the virus is responsible for direct cell cytotoxicity in only a small way, and it is now clearer than ever that it may act indirectly by triggering the release of active mediators by structural and inflammatory airway cells, causing the onset and/or the acute exacerbation of asthmatic events in predisposed children. In the present review, we aim to summarize the RV infection's epidemiology, pathogenetic hypotheses, and available treatment options as well as its correlation with respiratory morbidity and mortality in the pediatric population.

Respiratory Syncytial Virus: The Influence of Serotype and Genotype Variability on Clinical Course of Infection.

Respiratory syncytial virus (RSV) belongs to the recently defined Pneumoviridae family, Orthopneumovirus genus. It is the leading cause of acute bronchiolitis and one of the most common causes of infant viral death worldwide, with infection typically occurring as recurrent seasonal epidemics. There are two major RSV subtypes, A and B, and multiple genotypes, which can coexist during RSV epidemic season every year and result in different disease severity. Recently, new RSV genomic sequences and analysis of RSV genotypes have provided important data for understanding RSV pathogenesis. Novel RSV strains do spread rapidly and widely, and a knowledge of viral strain-specific phenotypes may be important in order to include the more virulent strains in future therapeutical options and vaccine development. Here we summarize recent literature exploring genetic and molecular aspects related to RSV infection, their impact on the clinical course of the disease and their potential utility in the development of safe and effective preventive and therapeutic strategies.

Immune and inflammatory response in bronchiolitis due to respiratory Syncytial Virus and Rhinovirus infections in infants.

Bronchiolitis is a common disease in infancy, mostly due to Respiratory Syncytial Virus and Rhinovirus. In addition to acute infection, viral bronchiolitis is responsible for sequelae including recurrent wheezing and asthma. The analysis of the viral characteristics and of the pathogenesis of the infection shows differences between the two viruses that may be helpful for the development of therapies and preventive strategies.

Latest options for treatment of bronchiolitis in infants.

Bronchiolitis is the most frequent pathology associated with lower respiratory tract infection in newborns and young infants. The treatment of bronchiolitis is essentially supportive therapy for respiratory distress, hypoxia and dehydration. To date, no specific antiviral drug is used on a routine basis for the treatment of RSV infections. Currently, the only antiviral drug approved for the infection is ribavirin; however, its use is limited due to adverse side effects and the risks it poses to healthcare providers. Moreover, several drugs have been routinely administered for years in infants with acute RSV bronchiolitis, even if their efficacy is often not confirmed by clinical evidence, and studies on emerging antiviral drugs are still ongoing. In the present paper we review the recent literature about the drugs used during acute bronchiolitis and we summarize the main recommendations of national and international guidelines and the latest options for the treatment of bronchiolitis.

Exposure to vehicular traffic is associated to a higher risk of hospitalization for bronchiolitis during the first year of life.

BACKGROUND: The most common cause of hospitalization for children younger than age one is bronchiolitis. Several prenatal and environmental risk factors may affect the incidence of hospitalization for bronchiolitis. The aim of this study was to investigate the relation between exposure to vehicular traffic and the incidence of hospitalization for bronchiolitis in children during their first year of life in Italy. METHODS: A multicenter prospective birth cohort study, where equal numbers of newborns of 33-34, 35-37 and ≥38 wGA were recruited at birth (1814 children) in 30 Italian neonatology units. Two interviewer-administered questionnaires were used to collect data. The first interview was carried out at the end of the Italian epidemic season. The second interview was carried out when the child was one year old. Data on possible prenatal, perinatal, and postnatal/environmental risk factors and on vehicular traffic density in the zone of residence were collected. On each interview, parents were also asked about any hospitalizations of the child. The outcome measure was the hospitalization for bronchiolitis (International Health Service ICD-9 code 466). RESULTS: Univariate analysis demonstrated that exposure to air pollution due to vehicular traffic, was significantly associated with an increased risk of hospitalization for bronchiolitis. The adjusted risk from logistic regression model confirmed that children exposed to air pollution due to vehicular traffic were at increased risk of hospitalization for bronchiolitis. CONCLUSIONS: Exposure to air pollution due to vehicular traffic may increase the risk of hospitalization for bronchiolitis in the first year of life.

Prenatal tobacco smoke exposure increases hospitalizations for bronchiolitis in infants.

BACKGROUND: Tobacco smoke exposure (TSE) is a worldwide health problem and it is considered a risk factor for pregnant women's and children's health, particularly for respiratory morbidity during the first year of life. Few significant birth cohort studies on the effect of prenatal TSE via passive and active maternal smoking on the development of severe bronchiolitis in early childhood have been carried out worldwide. METHODS: From November 2009 to December 2012, newborns born at ≥ 33 weeks of gestational age (wGA) were recruited in a longitudinal multi-center cohort study in Italy to investigate the effects of prenatal and postnatal TSE, among other risk factors, on bronchiolitis hospitalization and/or death during the first year of life. RESULTS: Two thousand two hundred ten newborns enrolled at birth were followed-up during their first year of life. Of these, 120 (5.4%) were hospitalized for bronchiolitis. No enrolled infants died during the study period. Prenatal passive TSE and maternal active smoking of more than 15 cigarettes/daily are associated to a significant increase of the risk of offspring children hospitalization for bronchiolitis, with an adjHR of 3.5 (CI 1.5-8.1) and of 1.7 (CI 1.1-2.6) respectively. CONCLUSIONS: These results confirm the detrimental effects of passive TSE and active heavy smoke during pregnancy for infants' respiratory health, since the exposure significantly increases the risk of hospitalization for bronchiolitis in the first year of life.

Immunological, Viral, Environmental, and Individual Factors Modulating Lung Immune Response to Respiratory Syncytial Virus.

Respiratory syncytial virus is a worldwide pathogen agent responsible for frequent respiratory tract infections that may become severe and potentially lethal in high risk infants and adults. Several studies have been performed to investigate the immune response that determines the clinical course of the infection. In the present paper, we review the literature on viral, environmental, and host factors influencing virus response; the mechanisms of the immune response; and the action of nonimmunological factors. These mechanisms have often been studied in animal models and in the present review we also summarize the main findings obtained from animal models as well as the limits of each of these models. Understanding the lung response involved in the pathogenesis of these respiratory infections could be useful in improving the preventive strategies against respiratory syncytial virus.

Risk factors for bronchiolitis hospitalization during the first year of life in a multicenter Italian birth cohort.

BACKGROUND: Respiratory Syncytial Virus (RSV) is one of the main causes of respiratory infections during the first year of life. Very premature infants may contract more severe diseases and 'late preterm infants' may also be more susceptible to the infection. The aim of this study is to evaluate the risk factors for hospitalization during the first year of life in children born at different gestational ages in Italy. METHODS: A cohort of 33-34 weeks gestational age (wGA) newborns matched by sex and age with two cohort of newborns born at 35-37 wGA and > 37 wGA were enrolled in this study for a three-year period (2009-2012). Hospitalization for bronchiolitis (ICD-9 code 466.1) during the first year of life was assessed through phone interview at the end of the RSV season (November-March) and at the completion of the first year of life. RESULTS: The study enrolled 2314 newborns, of which 2210 (95.5 %) had a one year follow-up and were included in the analysis; 120 (5.4 %) were hospitalized during the first year of life for bronchiolitis. Children born at 33-34 wGA had a higher hospitalization rate compared to the two other groups. The multivariate analysis carried out on the entire population associated the following factors with higher rates for bronchiolitis hospitalization: male gender; prenatal treatment with corticosteroids; prenatal exposure to maternal smoking; singleton delivery; respiratory diseases in neonatal period; surfactant therapy; lack of breastfeeding; siblings <10 years old; living in crowded conditions and/or in unhealthy households and early exposure to the epidemic RSV season. When analysis was restricted to preterms born at 33-34 wGA the following variables were associated to higher rates of bronchiolitis hospitalization: male gender, prenatal exposure to maternal smoking, neonatal surfactant therapy, having siblings <10 years old, living in crowded conditions and being exposed to epidemic season during the first three months of life. CONCLUSION: Our study identified some prenatal, perinatal and postnatal conditions proving to be relevant and independent risk factors for hospitalization for bronchiolitis during the first year of life. The combination of these factors may lead to consider palivizumab prophylaxis in Italy.

Continuity of care in children with special healthcare needs: a qualitative study of family's perspectives.

BACKGROUND: To explore parents' experiences and perceptions on informational, management and relational continuity of care for children with special health care needs from hospitalization to the first months after discharge to the home. METHODS: Semi-structured interviews and a focus group were carried out to capture parents' experiences and perceptions. Transcripts were analyzed using a directed approach to the qualitative content analysis. RESULTS: 16 families participated to this study: 13 were involved in interviews (10 face-to-face and 3 by phone) and 3 in a focus group, within 1-6 months after discharge from the University Hospital of Bologna (S.Orsola/Malpighi) and from hospitals of Bologna Province. To parents of children with special health care needs, the three domains of continuity of care were relevant in a whole but with different key elements during hospitalization, at discharge and after discharge. Moreover, empowerment emerged from parents' narratives as essential to help parents cope with the transition from the hospital setting to the new responsibilities connected with the home care of their child. Parent's perceptions about the family pediatrician concerned his/her centrality in the activation and coordination of the healthcare network. Moreover, parents exhibited different attitudes towards involvement in decision making: some wished and expected to be involved, others preferred not to be involved. CONCLUSIONS: Care coordination for children with special care needs is a complex process that need to be attended to during the hospitalization phase and after discharge to the community. The findings of this study may contribute to elucidating the perceptions and experiences of parents with children with special health care needs about the continuity of care from hospital to community care.

Positive effect of human milk feeding during NICU hospitalization on 24 month neurodevelopment of very low birth weight infants: an Italian cohort study.

The aim of this study was to determine the effect of human milk feeding during NICU hospitalization on neurodevelopment at 24 months of corrected age in very low birth weight infants. A cohort of 316 very low birth weight newborns (weight ≤ 1500 g) was prospectively enrolled in a follow-up program on admission to the Neonatal Intensive Care Unit of S. Orsola Hospital, Bologna, Italy, from January 2005 to June 2011. Neurodevelopment was evaluated at 24 months corrected age using the Griffiths Mental Development Scale. The effect of human milk nutrition on neurodevelopment was first investigated using a multiple linear regression model, to adjust for the effects of gestational age, small for gestational age, complications at birth and during hospitalization, growth restriction at discharge and socio-economic status. Path analysis was then used to refine the multiple regression model, taking into account the relationships among predictors and their temporal sequence. Human milk feeding during NICU hospitalization and higher socio-economic status were associated with better neurodevelopment at 24 months in both models. In the path analysis model intraventricular hemorrhage-periventricular leukomalacia and growth restriction at discharge proved to be directly and independently associated with poorer neurodevelopment. Gestational age and growth restriction at birth had indirect significant effects on neurodevelopment, which were mediated by complications that occurred at birth and during hospitalization, growth restriction at discharge and type of feeding. In conclusion, our findings suggest that mother's human milk feeding during hospitalization can be encouraged because it may improve neurodevelopment at 24 months corrected age.

Measuring parents' perspective on continuity of care in children with special health care needs.

INTRODUCTION: Children with special health care needs are an exponentially growing population needing integrated health care programmes that involve primary, community, hospital and tertiary care services. The aims of the study are (1) to develop and validate the Special Needs Kids Questionnaire (SpeNK-Q) designed to measure parents' perspective on continuity of care for children with special health care needs and (2) to evaluate the continuity of care based on parental experiences in this population. METHODS: SpeNK-Q was derived from a previous qualitative study and was based on Haggerty's constructs of informational, management and relational continuity. Parents of preterm birth children completed the 20-item SpeNK-Q at the second or subsequent planned follow-up visit after the child's hospital discharge. Principal component analysis was used to examine the structure of the instrument. RESULTS: Principal component analysis of 101 questionnaires administered allowed us to identify five factors explaining 60.2% of item variance: informational continuity; coordination of care; continuity of family-paediatrician relationship; family support; information on care plan. CONCLUSIONS AND DISCUSSION: SpeNK-Q proved to be a psychometrically promising instrument. Its utilisation could improve the identification of areas for service development, the delivery of coordinated care and support policy makers in redesigning integrated services.

Inter-society consensus document on treatment and prevention of bronchiolitis in newborns and infants.

Acute bronchiolitis is the leading cause of lower respiratory tract infection and hospitalization in children less than 1 year of age worldwide. It is usually a mild disease, but some children may develop severe symptoms, requiring hospital admission and ventilatory support in the ICU. Infants with pre-existing risk factors (prematurity, bronchopulmonary dysplasia, congenital heart diseases and immunodeficiency) may be predisposed to a severe form of the disease. Clinical diagnosis of bronchiolitis is manly based on medical history and physical examination (rhinorrhea, cough, crackles, wheezing and signs of respiratory distress). Etiological diagnosis, with antigen or genome detection to identify viruses involved, may have a role in reducing hospital transmission of the infection. Criteria for hospitalization include low oxygen saturation (<90-92%), moderate-to-severe respiratory distress, dehydration and presence of apnea. Children with pre-existing risk factors should be carefully assessed.To date, there is no specific treatment for viral bronchiolitis, and the mainstay of therapy is supportive care. This consists of nasal suctioning and nebulized 3% hypertonic saline, assisted feeding and hydration, humidified O2 delivery. The possible role of any pharmacological approach is still debated, and till now there is no evidence to support the use of bronchodilators, corticosteroids, chest physiotherapy, antibiotics or antivirals. Nebulized adrenaline may be sometimes useful in the emergency room. Nebulized adrenaline can be useful in the hospital setting for treatment as needed. Lacking a specific etiological treatment, prophylaxis and prevention, especially in children at high risk of severe infection, have a fundamental role. Environmental preventive measures minimize viral transmission in hospital, in the outpatient setting and at home. Pharmacological prophylaxis with palivizumab for RSV bronchiolitis is indicated in specific categories of children at risk during the epidemic period. Viral bronchiolitis, especially in the case of severe form, may correlate with an increased incidence of recurrent wheezing in pre-schooled children and with asthma at school age.The aim of this document is to provide a multidisciplinary update on the current recommendations for the management and prevention of bronchiolitis, in order to share useful indications, identify gaps in knowledge and drive future research.

Respiratory syncytial virus infections in infants affected by primary immunodeficiency.

Primary immunodeficiencies are rare inherited disorders that may lead to frequent and often severe acute respiratory infections. Respiratory syncytial virus (RSV) is one of the most frequent pathogens during early infancy and the infection is more severe in immunocompromised infants than in healthy infants, as a result of impaired T- and B-cell immune response unable to efficaciously neutralize viral replication, with subsequent increased viral shedding and potentially lethal lower respiratory tract infection. Several authors have reported a severe clinical course after RSV infections in infants and children with primary and acquired immunodeficiencies. Environmental prophylaxis is essential in order to reduce the infection during the epidemic season in hospitalized immunocompromised infants. Prophylaxis with palivizumab, a humanized monoclonal antibody against the RSV F protein, is currently recommended in high-risk infants born prematurely, with chronic lung disease or congenital heart disease. Currently however the prophylaxis is not routinely recommended in infants with primary immunodeficiency, although some authors propose the extension of prophylaxis to this high risk population.

The use of humanized monoclonal antibodies for the prevention of respiratory syncytial virus infection.

Monoclonal antibodies are widely used both in infants and in adults for several indications. Humanized monoclonal antibodies (palivizumab) have been used for many years for the prevention of respiratory syncytial virus infection in pediatric populations (preterm infants, infants with chronic lung disease or congenital heart disease) at high risk of severe and potentially lethal course of the infection. This drug was reported to be safe, well tolerated and effective to decrease the hospitalization rate and mortality in these groups of infants by several clinical trials. In the present paper we report the development and the current use of monoclonal antibodies for prophylaxis against respiratory syncytial virus.

Respiratory syncytial virus infection in infants and correlation with meteorological factors and air pollutants.

BACKGROUND: Respiratory Syncytial Virus (RSV) is the most important cause of severe respiratory infections in infants with seasonal epidemics. Environmental factors (temperature, humidity, air pollution) could influence RSV epidemics through their effects on virus activity and diffusion. METHODS: We conducted a retrospective study on a paediatric population who referred to our Paediatric Emergency Unit in order to analyze the correlation between weekly incidence of RSV positive cases during winter season in Bologna and meteorological factors and air pollutants concentration. RESULTS: We observed a significant correlation between the incidence of RSV infections and the mean minimum temperature registered during the same week and the previous weeks.The weekly number of RSV positive cases was also correlated to the mean PM10 concentration of the week before. CONCLUSIONS: RSV epidemic trend in Bologna (Italy) is related to the mean minimum temperature, and the mean PM10 concentration.

Urinary neutrophil gelatinase-associated lipocalin at birth predicts early renal function in very low birth weight infants.

Preterm infants are exposed to conditions that can impair renal function. We evaluated the ability of serum and urinary neutrophil gelatinase-associated lipocalin (sNGAL and uNGAL) to predict renal function in the first weeks of life. From September 2008 to July 2009, infants weighing ≤1500 g at birth with no major congenital anomalies or sepsis were eligible. We measured sNGAL and uNGAL levels at birth. To evaluate renal function, we determined changes in serum creatinine (sCreat) and estimated GFR (eGFR) from birth to d 21. Forty neonates (mean GA, 27 ± 2 wk) completed the study. Renal function improved in 32 of 40 (80%) infants (normal renal function, NRF group) (sCreat, from 0.97 ± 0.2 to 0.53 ± 0.13 mg/dL; eGFR, from 15.3 ± 4.1 to 28.6 ± 7.9 mL/min), whereas renal function worsened in 8 of 40 (20%) infants (impaired renal function, IRF group) (sCreat, from 0.71 ± 0.27 to 0.98 ± 0.43 mg/dL; eGFR from 23 ± 14.7 to 16.4 ± 9.1 mL/min). The uNGAL/urinary creatinine (uCreat) ratio at birth was higher in the IRF group (31.05 ng/mg) than the NRF group (6.0 ng/mg), and uNGAL was significantly higher in IRF group, detecting IRF with a cutoff of 100 ng/mL. uNGAL levels at birth may have a predictive role in very LBW (VLBW) infants.