Assessment of effectiveness and impact of universal prophylaxis with nirsevimab for prevention of hospitalizations due to respiratory syncytial virus in infants. The NIRSE-GAL study protocol.

Nirsevimab has been recently licensed for universal RSV prophylaxis in infants. NIRSE-GAL is a three-year population-based study initiated in Galicia in September 2023. It aims to evaluate nirsevimab effectiveness against RSV-related hospitalizations lower respiratory tract infections (LRTI), severe RSV, all-cause LRTI, and all-cause hospitalization. NIRSE-GAL also aims to estimate nirsevimab impact on primary healthcare use in the short and mid-term, children's wheezing and asthma, and medical prescriptions for RSV. The immunization campaigns will be scheduled based on the expected start week for the RSV season and will last the whole season. Immunization will be offered to: i) infants born during the campaign (seasonal), ii) infants < 6 months at the start of the campaign (catch-up), and iii) infants with high-risk factors, aged 6-24 months at the start of the campaign (high-risk). The follow-up period will start: i) the immunization date for all immunized infants, ii) the start of the campaign, for the non-immunized catch-up or high-risk groups, or iii) the birthdate for the non-immunized seasonal group. Infants will be followed up until outcome occurrence, death, or end of study. Nirsevimab effectiveness will be estimated using Poisson and Cox regression models. Sensitivity and stratified analyses will be undertaken. The number of averted cases and the number needed to immunize will be estimated. Immunization failure and nirsevimab safety will be monitored. NIRSE-GAL was approved by the ethics committee of Galicia (CEIC 2023-377) and registered in ClinicalTrials.gov (ID: NCT06180993). Findings will be mainly shared via peer-reviewed publications and scientific conferences.

Palivizumab en niños nacidos de 35 semanas o menos de gestación y menores de 6 meses de edad al inicio de la estación de riesgo de infección por virus sincitial respiratorio / Palivizumab in children born at 35 weeks or less of gestation and children under 6 months of age at the beginning of the season at risk for respiratory syncytial virus infection

INTRODUCCIÓN: Este informe de ETS-R se realizó a solicitud de la Dirección General de Intervenciones Estratégicas en Salud Pública del Ministerio de Salud (DGIESP / MINSA); la cual motivó la formulación de una pregunta PICO conjuntamente con representantes tanto de la Dirección de Intervenciones por Curso de Vida y Cuidado Integral de la DGIESP como del Centro de Evaluación de Tecnologías en Salud (CETS) del Instituto Nacional de Salud. La pregunta PICO formulada fue la siguiente: P: pacientes pediátricos con alto riesgo de enfermedad por virus sincitial respiratorio (VSR); I: palivizumab; C: placebo o no administración; O: mortalidad, hospitalización por VSR, eventos adversos y calidad de vida. Para la presente evaluación, se consideró la primera categoría de alto riesgo de la ficha técnica DIGEMID, que corresponde a la población de recién nacidos de 35 semanas o menos de gestación y menores de 6 meses de edad al inicio de la estación de riesgo de infección por VSR. No se consideró población pediátrica con comorbilidades asociadas, como enfermedad pulmonar crónica, displasia broncopulmonar o cardiopatía congénita. OBJETIVOS: Describir la evidencia científica disponible sobre la eficacia y seguridad de la Inmunoglobulina Intravenosa (IgIV) para el tratamiento de encefalitis autoinmune en pacientes pediátricos que no mejoran con respuesta a pulsos de metilprednisolona y/o plasmaféresis. METODOLOGÍA: Se realizó una búsqueda sistemática en Medline/PubMed, The Cochrane Library y LILACS utilizando la estrategia de búsqueda descrita en el Anexo 01. Ésta se complementó con la búsqueda de evidencia en páginas institucionales de agencias gubernamentales y buscadores genéricos. Se priorizó la identificación y selección de ensayos clínicos aleatorizados controlados (ECA), revisiones sistemáticas (RS) de ECA, estudios observacionales comparativos, guías de práctica clínica (GPC), evaluaciones de tecnología sanitaria (ETS) y evaluaciones económicas (EE) de América Latina. La calidad de la evidencia se valoró usando: AMSTAR 2 para revisiones sistemáticas, la herramienta de la colaboración Cochrane para ensayos clínicos, la escala Newcastle-Ottawa para estudios no aleatorizados incluyendo cohortes y estudios de casos y controles, y AGREE II para valorar el rigor metodológico de las GPC. RESULTADOS: Tras la búsqueda sistemática se identificaron 207 artículos de los cuales 11 pararon a revisión a texto completo. De estos 11 documentos solo uno (GPC) correspondió con la pregunta PICO de interés. No se identificaron ECA o estudios observacionales comparativos, evaluaciones económicas, ni ETS que respondieran a la pregunta PICO de interés. CONCLUSIONES: Se revisó la mejor evidencia disponible sobre la eficacia y seguridad de la IgIV más metilprednisolona en pacientes pediátricos con encefalopatía autoinmune no mejoran con respuesta a pulsos de metilprednisolona y/o plasmaféresis (población objetivo). Se identificó solo una GPC que brinda recomendaciones para la población objetivo basada únicamente en consenso de expertos. Esta guía recomienda tanto la intervención como el comparador (prolongar el uso de metilprednisolona). No se cuenta con evidencia procedente de estudios tipo ECA u observacionales comparativos que evalúen la eficacia y seguridad de IgIV más metilprednisolona en la población objetivo, incluso ni en el contexto de primera línea. No se disponen de ETS ni evaluaciones económicas que respondan a la pregunta PICO de la presente revisión. Se espera que los resultados de ensayos clínicos en curso puedan brindar nueva información que permita responder a la pregunta de la presente revisión.

Effectiveness of palivizumab immunoprophylaxis in infants with respiratory syncytial virus disease in Colombia.

INTRODUCTION: Respiratory syncytial virus (RSV) is one of the most important childhood infections. OBJECTIVE: To evaluate the effectiveness and safety of palivizumab immunoprophylaxis in preterm infants at a high risk of severe respiratory syncytial virus infection during the RSV season in Colombia. METHODOLOGY: A prospective observational non-comparative multicenter study in six Colombian cities. At the beginning of the RSV infection season, palivizumab prophylaxis, up to five doses, was administered to infants born at ≤32 weeks of gestation, infants younger than six months, infants under one year of age with bronchopulmonary dysplasia (BPD), infants one year or less of age with hemodynamically significant acyanotic and non-acyanotic congenital heart disease (CHD), and with follow-up during the immunoprophylaxis until one month after the last dose. RESULTS: The study enrolled 600 patients, 91.8% of which were born at ≤ 32 weeks of gestation. BPD was observed in 54.9% of infants. 49% were born at < 32 weeks gestation and presented BPD. 6.9% had hemodynamically significant acyanotic and non-acyanotic CHD 53.3% received three or more doses of palivizumab. The mean interval between doses was 39.6 days. 1.8% of patients were hospitalized due to a confirmed RSV infection. Overall mortality was 1.2%, whereas the mortality by RSV in infants undergoing prophylaxis was 0.2%. CONCLUSIONS: Palivizumab was a clinically effective, well-tolerated treatment in the Colombian population. The safety profile of palivizumab reflects the findings from previous studies in developed countries.

Effect of delayed palivizumab administration on respiratory syncytial virus infection-related hospitalisation: A retrospective, observational study.

ABSTRACT: Respiratory syncytial virus (RSV) infection is an important cause of hospitalization in infants and young children. Monthly administration of palivizumab during the RSV season is effective in preventing severe infections in children with comorbidities. However, determining the onset of the RSV season for starting palivizumab is often challenging. The present study aimed to evaluate the ideal timing to start palivizumab and its effect on hospitalization in the real world.We performed a retrospective, observational study to identify the relationship between the timing of the first dose of palivizumab administration and RSV-related hospitalization. Medical records from 2015 to 2019 were reviewed. We included patients who had indications for palivizumab as of July 1 in each year. We counted the proportion of children receiving palivizumab and the number of RSV infection-related hospitalizations each month. We also evaluated the differences in background and underlying disease between children with and without hospitalization.A total of 498 patients were included, and 105 (21.0%) completed the first dose in July when the RSV season usually begins in Japan. Twenty-three (4.6%) patients were hospitalized for RSV infection during the observation period, with 13 (56.5%) hospitalizations before their first dose of palivizumab. The remaining 10 patients were hospitalized after receiving 1 or more doses of palivizumab. Children living with siblings and children with cyanosis originating from congenital heart disease had a higher risk of RSV with odds ratios of 5.1 (95% confidence interval 1.48-17.6, P < .01) and 3.3 (95% confidence interval 1.33-7.94, P < .01), respectively.Delays in administering palivizumab at the beginning of the season increases the rate of RSV infection-related hospitalization. To maximize prophylactic effectiveness, administering the first dose as early as possible in the RSV season is crucial, with priority for cyanotic children or those with siblings.

Coadministration of Anti-Viral Monoclonal Antibodies With Routine Pediatric Vaccines and Implications for Nirsevimab Use: A White Paper.

Routine childhood vaccinations are key for the protection of children from a variety of serious and potentially fatal diseases. Current pediatric vaccine schedules mainly cover active vaccines. Active vaccination in infants is a highly effective approach against several infectious diseases; however, thus far, for some important viral pathogens, including respiratory syncytial virus (RSV), vaccine development and license by healthcare authorities have not been accomplished. Nirsevimab is a human-derived, highly potent monoclonal antibody (mAb) with an extended half-life for RSV prophylaxis in all infants. In this manuscript, we consider the potential implications for the introduction of an anti-viral mAb, such as nirsevimab, into the routine pediatric vaccine schedule, as well as considerations for coadministration. Specifically, we present evidence on the general mechanism of action of anti-viral mAbs and experience with palivizumab, the only approved mAb for the prevention of RSV infection in preterm infants, infants with chronic lung disease of prematurity and certain infants with hemodynamically significant heart disease. Palivizumab has been used for over two decades in infants who also receive routine vaccinations without any alerts concerning the safety and efficacy of coadministration. Immunization guidelines (Advisory Committee on Immunization Practices, Joint Committee on Vaccination and Immunization, National Advisory Committee on Immunization, Centers for Disease Control and Prevention, American Academy of Pediatrics, The Association of the Scientific Medical Societies in Germany) support coadministration of palivizumab with routine pediatric vaccines, noting that immunobiologics, such as palivizumab, do not interfere with the immune response to licensed live or inactivated active vaccines. Based on the mechanism of action of the new generation of anti-viral mAbs, such as nirsevimab, which is highly specific targeting viral antigenic sites, it is unlikely that it could interfere with the immune response to other vaccines. Taken together, we anticipate that nirsevimab could be concomitantly administered to infants with routine pediatric vaccines during the same clinic visit.

A Comparison of Respiratory Syncytial Viral Prophylaxis in Multiple Births versus Singletons in the Canadian Registry of Palivizumab.

OBJECTIVE: The aim of this study is to compare respiratory illness-related hospitalization (RIH) and respiratory syncytial virus (RSV)-related hospitalization (RSVH) in multiple births versus singletons, who received palivizumab during the RSV season and participated in the Canadian registry of palivizumab (CARESS). STUDY DESIGN: Prospective, observational study of infants aged <2 years recruited across 32 centers over 12 RSV seasons from 2005 to 2017. Demographic data were collected at enrolment and RIH events were recorded monthly. RESULTS: A total of 25,003 infants were enrolled of whom 6,949 (27.8%) were of multiple birth, and 18,054 (72.2%) were singletons. A significantly larger proportion of the multiple births were premature (80.2%) compared with the singleton group (56.8%). Multiples had a lower gestational age (mean ± standard deviation): 31.2 ± 3.2 versus 33.2 ± 5.5 weeks and birth weight (mean: 1,590 ± 606.8 vs. 2,069.4 ± 1068.5 g; both p < 0.0005). They were younger at enrolment (4.5 ± 5.0 vs. 6.1 ± 6.8 months), and fewer attended daycare (1.9 vs. 4.6%), and experienced exposure to smoking (24.5 vs. 29.9%), but more lived in a crowded household (36.7 vs. 19.4%); all p < 0.0005. Multiples had a longer length of neonatal stay (51.1 ± 65.9 vs. 47.9 ± 67.8 days), and more required respiratory support (65.7 vs. 57.7%), but for shorter duration (22.6 ± 32.9 vs. 24.7 ± 40.6 days); all p < 0.001. RIH and RSVH rates (%) in multiples versus singletons were 4.7; 7.7 and 1.4; and 1.6, respectively. Cox regression showed that multiples had a lower risk of RIH compared with singletons (hazard ratio [HR] = 0.616, 95% confidence interval [CI]: 0.543-0.698, p < 0.0005), but not RSVH (HR: 0.77, 95% CI: 0.57-1.02, p = 0.071). CONCLUSION: Multiple birth infants, who are known to be at greater risk for severe RSVH compared with singletons, are well protected by palivizumab, provided adherence to the monthly injection scheme is guaranteed.

Palivizumab's real-world effectiveness: a population-based study in Ontario, Canada, 1993-2017.

OBJECTIVE: To evaluate the effectiveness of two palivizumab programmes targeting high-risk infants, defined by prematurity, diagnosis of comorbidities and geography, and assess potential disparities by neighbourhood income. DESIGN: Controlled, interrupted time series. SETTING: Ontario, Canada. PATIENTS: We used linked health and demographic administrative databases to identify all children born in hospitals 1 January 1993 through 31 December 2016. Follow-up ended at the earliest of second birthday or 30 June 2017. INTERVENTION: Palivizumab-eligibility: child was born very preterm and ≤6 months old during respiratory syncytial virus (RSV) season; <24 months old with significant chronic lung or congenital heart disease; or ≤6 months, born preterm or residents of remote regions. MAIN OUTCOME: Severe RSV-related illness, defined as hospitalisation or death with a diagnosis of bronchiolitis, RSV pneumonia or RSV. RESULTS: 3 million births and 87 000 RSV-related events were identified. Over the study period, rates of severe RSV-related illness declined 65.4% among the highest risk group, eligible infants <6 months (230.6 to 79.8 admissions per 1000 child-years). Relative to changes among ineligible infants <6 months, rates dropped 10.4% (95% CI -18.6% to 39.4%) among eligible infants immediately following introduction of a national palivizumab programme in 1998. Initially, rates were considerably higher among infants from low-income neighbourhoods, but income-specific rates converged over time among eligible infants <6 months; such convergence was not seen among other children. CONCLUSIONS: Incidence of severe RSV-related illness declined over the study period. While we cannot attribute causality, the timing and magnitude of these declines suggest impact of palivizumab in reducing RSV burden and diminishing social inequities among palivizumab-eligible infants.

Effect of digestion on stability of palivizumab IgG1 in the infant gastrointestinal tract.

BACKGROUND: Potentially, orally administered antibodies specific to enteric pathogens could be administered to infants to prevent diarrheal infections, particularly in developing countries where diarrhea is a major problem. However, to prevent infection, such antibodies would need to resist degradation within the gastrointestinal tract. METHODS: Palivizumab, a recombinant antibody specific to respiratory syncytial virus (RSV), was used in this study as a model for examining the digestion of neutralizing antibodies to enteric pathogens in infants. The survival of this recombinant IgG1 across digestion in 11 infants was assayed via an anti-idiotype ELISA and RSV F protein-specific ELISA. Concentrations were controlled for any dilution or concentration that occurred in the digestive system using mass spectrometry-based quantification of co-administered, orally supplemented, indigestible polyethylene glycol (PEG-28). RESULTS: Binding activity of Palivizumab IgG1 decreased (26-99%) across each phase of in vivo digestion as measured by both anti-idiotype and RSV F protein-specific ELISAs. CONCLUSION: Antibodies generated for passive protection of the infant gastrointestinal tract from pathogens will need to be more resistant to digestion than the model antibody fed to infants in this study, or provided in higher doses to be most effective. IMPACT: Binding activity of palivizumab IgG1 decreased (26-99%) across each phase of in vivo infant digestion as measured by both anti-idiotype and RSV F protein-specific ELISAs. Palivizumab was likely degraded by proteases and changes in pH introduced in the gut. Antibodies generated for passive protection of the infant gastrointestinal tract from pathogens will need to be more resistant to digestion than the model antibody fed to infants in this study, or provided in higher doses to be most effective. The monoclonal antibody IgG1 tested was not stable across the infant gastrointestinal tract. The observation of palivizumab reduction was unlikely due to dilution in the gastrointestinal tract. The results of this work hint that provision of antibody could be effective in preventing enteric pathogen infection in infants. Orally delivered recombinant antibodies will need to either be dosed at high levels to compensate for digestive losses or be engineered to better resist digestion. Provision of enteric pathogen-specific recombinant antibodies to at-risk infants could provide a new and previously unexplored pathway to reducing the infection in infants. The strategy of enteric recombinant antibodies deserves more investigation throughout medicine as a novel means for treatment of enteric disease targets.

Pharmacological management of human respiratory syncytial virus infection.

INTRODUCTION: Human respiratory syncytial virus (hRSV) is the primary viral cause of respiratory diseases, leading to bronchiolitis and pneumonia in vulnerable populations. The only current treatment against this virus is palliative, and no efficient and specific vaccine against this pathogen is available. AREAS COVERED: The authors describe the disease symptoms caused by hRSV, the economic and social impact of this infection worldwide, and how this infection can be modulated using pharmacological treatments, preventing and limiting its dissemination. The authors discuss the use of antibodies as prophylactic tools -such as palivizumab- and the use of nonspecific drugs to decrease the symptoms associated with the infection -such as bronchodilators, corticoids, and antivirals. They also discuss current vaccine candidates, new prophylactic treatments, and new antivirals options, which are currently being tested. EXPERT OPINION: Today, many researchers are focused on developing different strategies to modulate the symptoms induced by hRSV. However, to achieve this, understanding how current treatments are working and their shortcomings needs to be further elucidated.

Seasonality and coinfection of bronchiolitis: epidemiological specificity and consequences in terms of prophylaxis in tropical climate.

OBJECTIVE: To describe the viruses involved, seasonality and coinfection in hospitalised children with suspected bronchiolitis. METHODS: Over the period 1/07/2007 to 31/12/2008, all children hospitalised for bronchiolitis in the paediatric ward were prospectively included, and had respiratory syncytial virus (RSV) screenings. We retrospectively tested all samples for RSVA, RSVB, rhinovirus (RV), human metapneumovirus, parainfluenza 1, 2, 3, 4, influenza A and influenza B. RESULTS: 198 children were tested, and 23% were negative for all viruses. RSVA was predominant in 2008 (64% of all viruses) and RSVB in 2007 (66% of all viruses). RV was frequent during both seasons (24% of all viruses). Flu was not found during the study period. Virus distribution was similar regardless of season or age, and identical to typical patterns in temperate countries. Coinfections were less frequent than in temperate regions because respiratory virus seasons seem to be better separated. The bronchiolitis season started in August and finished in December with a peak in October. CONCLUSION: The specific seasonality of bronchiolitis infection requires palivizumab prophylaxis starting in early July for high-risk infants.

OBJECTIF: Décrire les virus impliqués, la saisonnalité et la coinfection chez les enfants hospitalisés avec une suspicion de bronchiolite. MÉTHODES: Au cours de la période du 01/07/2007 au 31/12/2008, tous les enfants hospitalisés pour bronchiolite dans le service de pédiatrie ont été prospectivement inclus et soumis à un dépistage du virus respiratoire syncytial (VRS). Nous avons testé rétrospectivement tous les échantillons pour RSVA, RSVB, rhinovirus (RV), métapneumovirus humain, Parainfluenza 1, 2, 3, 4, Influenza A, et Influenza B. RÉSULTATS: 198 enfants ont été testés et 23% étaient négatifs pour tous les virus. RSVA était prédominant en 2008 (64% de tous les virus) et RSVB en 2007 (66% de tous les virus). RV était fréquent pendant les deux saisons (24% de tous les virus). La grippe n'a pas été trouvée pendant la période d'étude. La distribution des virus était similaire quelle que soit la saison ou l'âge, et identique aux modèles typiques dans les pays tempérés. Les coinfections étaient moins fréquentes que dans les régions tempérées car les saisons virales respiratoires semblent mieux séparées. La saison des bronchiolites a commencé en août et s'est terminée en décembre avec un pic en octobre. CONCLUSION: La saisonnalité spécifique de l'infection bronchiolite nécessite une prophylaxie au palivizumab débutant en juillet pour les nourrissons à haut risque.

Palivizumab compliance in congenital heart disease patients: factors related to compliance and altered lower respiratory tract infection viruses after palivizumab prophylaxis.

BACKGROUND: Lower respiratory tract infections caused by respiratory syncytial virus can be severe during infancy, which requires admission to the hospital. These infections may be more severe especially in patients with congenital heart disease. Passive immunisation with palivizumab, a monoclonal antibody, is recommended in high-risk infants. We tried to determine the compliance rates, factors affecting compliance, and also other microorganisms responsible for lower respiratory tract infections after palivizumab prophylaxis in these patients. METHODS: We evaluated patients' compliance to prophylaxis with palivizumab in two consecutive respiratory syncytial virus seasons from pharmacy records. We also investigated factors affecting compliance and the frequency of hospitalisations for lower respiratory tract infections. We investigated the causative microorganisms detected in hospitalised patients. RESULTS: In this study, 86.7% of the desired number of injections was achieved in 176 patients in two seasons. Out of these, 117 patients (66.4%) received all the doses they were prescribed. Although not statistically significant, compliance to prophylaxis was higher in male patients, cyanotic patients, those who started under 1 year old, and who lived in the city centre. Human metapneumovirus, parainfluenza type 3, and bocavirus were detected in the hospitalised patients. CONCLUSION: Patients with congenital heart disease can survive the period of infancy with less problem by making palivizumab prophylaxis more effective, and awareness about non- respiratory syncytial virus factors may be a guide for the development of new treatments.

Cost-analysis of Withdrawing Immunoprophylaxis for Respiratory Syncytial Virus in Infants Born at 33-35 Weeks Gestational Age in Quebec: A Multicenter Retrospective Study.

BACKGROUND: In 2015, the Quebec Ministry of Health limited palivizumab prophylaxis for respiratory syncytial virus (RSV) in premature infants to those born at <33 weeks gestational age (wGA), unless other indications were present. We compared RSV-related costs for 2 seasons before the change (2013-2014, 2014-2015) and 2 seasons after (2015-2016, 2016-2017) in premature infants 33-35 wGA. METHODS: Using payer and societal perspectives, costs associated with hospitalizations for RSV and lower respiratory tract infection (LRTI) in infants born at 33-35 wGA were estimated. Inputs were from a 2013-2017 retrospective cohort study in 25 Quebec hospitals of RSV/LRTI hospitalizations among infants <6 months old at the start of, or born during, the RSV season. Resource utilization data (hospital stay, procedures, visits, transportation, out-of-pocket expenses and work productivity) were collected from charts and parent interviews allowing estimation of direct and indirect costs. Costs, including palivizumab administration, were derived from provincial sources and adjusted to 2018 Canadian dollars. Costs were modeled for preterm infants hospitalized for RSV/LRTI pre- and postrevision of guidelines and with matched term infants hospitalized for RSV/LRTI during 2015-2017 (comparator). RESULTS: Average total direct and indirect costs for 33-35 wGA infants were higher postrevision of guidelines ($29,208/patient, 2015-2017; n = 130) compared with prerevision ($16,976/patient, 2013-2015; n = 105). Total costs were higher in preterm infants compared with term infants (n = 234) postrevision of guidelines ($29,208/patient vs. $10,291/patient). CONCLUSIONS: Immunoprophylaxis for RSV in infants born at 33-35 wGA held a cost advantage for hospitalizations due to RSV/LRTI.

The development of the hypothalamus-pituitary-adrenal axis during infancy may be affected by antenatal glucocorticoid therapy.

BACKGROUND: Developmental changes in the hypothalamus-pituitary-adrenal (HPA) axis during infancy have been reported in term infants, but those in preterm infants have yet to be elucidated. If developmental changes in the HPA axis of preterm infants are modulated by any factors, it may affect their future health. Few studies have examined the lasting consequences of antenatal glucocorticoids on the development of the HPA axis. METHODS: We measured pre- and post-palivizumab vaccination salivary cortisol values in two conforming periods of three-months intervals during infancy, and compared cortisol values and the response of cortisol secretion between groups with and without antenatal glucocorticoid (AG) therapy. RESULTS: Although the strength of the response of cortisol secretion to palivizumab fell age-dependently (until late infancy) in the Non-AG group, the opposite pattern was exhibited in the AG group. The changes of the delta cortisol values between the 2 groups were significant. CONCLUSIONS: This study suggests that the HPA axis of preterm infants whose mothers receive AG therapy may be upregulated during infancy, possibly leading to long lasting health problems.

Estimating the impact of multiple immunization products on medically-attended respiratory syncytial virus (RSV) infections in infants.

BACKGROUND: Palivizumab, a monoclonal antibody and the only licensed immunization product for preventing respiratory syncytial virus (RSV) infection, is recommended for children with certain high-risk conditions. Other antibody products and maternal vaccines targeting young infants are in clinical development. Few studies have compared products closest to potential licensure and have primarily focused on the effects on hospitalizations only. Estimates of the impact of these products on medically-attended (MA) infections in a variety of healthcare settings are needed to assist with developing RSV immunization recommendations. METHODS: We developed a tool for practicing public health officials to estimate the impact of immunization strategies on RSV-associated MA lower respiratory tract infections (LRTIs) in various healthcare settings among infants <12 months. Users input RSV burden and seasonality and examine the influence of altering product efficacy and uptake assumptions. We used the tool to evaluate candidate products' impacts among a US birth cohort. RESULTS: We estimated without immunization, 407,360 (range: 339,650-475,980) LRTIs are attended annually in outpatient clinics, 147,240 (126,070-168,510) in emergency departments (EDs), and 33,180 (24,760-42,900) in hospitals. A passive antibody candidate targeting all infants prevented the most LRTIs: 196,470 (48% of visits without immunization) outpatient clinic visits (range: 163,810-229,650), 75,250 (51%) EDs visits (64,430-86,090), and 18,140 (55%) hospitalizations (13,770-23,160). A strategy combining maternal vaccine candidate and palivizumab prevented 58,210 (14% of visits without immunization) LRTIs in outpatient clinics (range: 48,520-67,970), 19,580 (13%) in EDs (16,760-22,400), and 8,190 (25%) hospitalizations (6,390-10,150). CONCLUSIONS: Results underscore the potential for anticipated products to reduce serious RSV illness. Our tool (provided to readers) can be used by different jurisdictions and accept updated data. Results can aid economic evaluations and public health decision-making regarding RSV immunization products.

Expansion of the 1st WHO international standard for antiserum to respiratory syncytial virus to include neutralisation titres against RSV subtype B: An international collaborative study.

An International Standard to harmonise results from RSV subtype A neutralisation assays was generated and established by the World Health Organization in 2018. Here we report on a study to expand the use of that standard to include neutralisation assays using human sera against RSV subtype B and to test its ability to harmonise neutralisation titres from neutralisation assays including complement. The study included 11 laboratories from 6 countries. All participants used their own in-house virus neutralisation assay and their own virus stocks. The study samples comprised the current International Standard (16/284) and its potential replacement (16/322), individual sera from naturally infected humans, a monoclonal antibody to RSV (palivizumab) and samples from the BEI Resources panel of human antiserum and immune globulin to RSV. Of the 11 laboratories that took part in the study, 5 returned data from neutralisation assays with and without the inclusion of serum complement. The study showed that inter-laboratory variability in neutralisation titres was significantly reduced when values were expressed relative to 16/284 or 16/322. Complement did not affect the ability of the International Standard to decrease inter-laboratory variability as the standard was able to reduce the differences between titres from assays with and without complement. Based on these results, we will recommend to the WHO Expert Committee on Biological Standardisation (ECBS) that 16/284 and 16/322 be expanded in their use to include neutralisation assays against RSV/B.

TEMPORAL TREND OF HOSPITALIZATIONS FOR ACUTE BRONCHIOLITIS IN INFANTS UNDER ONE YEAR OF AGE IN BRAZIL BETWEEN 2008 AND 2015.

OBJECTIVE: To evaluate the trend of hospitalization for acute bronchiolitis in infants under one year of age, in the past eight years and after the implementation of the palivizumab immunization program in Brazil. METHODS: The study is a retrospective analysis of data on infants younger than one year of age, who were hospitalized with acute bronchiolitis between 2008 and 2015 in Brazil. The Brazilian National Health System database was used. The rates of hospitalization in the pre-implementation (2008-2012) and post-implementation (2014-2015) periods of the palivizumab immunization program were evaluated. The total number of admissions in the same period was used as a comparison. RESULTS: Between January 2008 and December 2015, 263,679 hospitalizations for bronchiolitis were recorded in infants younger than one year of age, 60% represented by boys. The incidence of hospitalization for bronchiolitis increased by 49% over this period (8.5 to 12.7 per 1,000 inhabitants per year). Between 2013 and 2014, the incidence rate of hospitalization for acute bronchiolitis decreased by 8% (12.5 to 11.5 per 1,000 inhabitants per year). However, in the second year of the program, hospitalization rate increased again by 10% (12.7 per 1,000 inhabitants per years). CONCLUSIONS: Acute bronchiolitis presented increasing rates of hospitalization over the study period. Hospitalization incidence for acute bronchiolitis declined one year after the implementation of palivizumab but increased again in the second year of the program.

Temporal trend of hospitalizations for acute bronchiolitis in infants under one year of age in brazil between 2008 and 2015 / Tendência temporal das hospitalizações por bronquiolite aguda em lactentes menores de um ano no brasil entre 2008 e 2015

ABSTRACT Objective: To evaluate the trend of hospitalization for acute bronchiolitis in infants under one year of age, in the past eight years and after the implementation of the palivizumab immunization program in Brazil. Methods: The study is a retrospective analysis of data on infants younger than one year of age, who were hospitalized with acute bronchiolitis between 2008 and 2015 in Brazil. The Brazilian National Health System database was used. The rates of hospitalization in the pre-implementation (2008-2012) and post-implementation (2014-2015) periods of the palivizumab immunization program were evaluated. The total number of admissions in the same period was used as a comparison. Results: Between January 2008 and December 2015, 263,679 hospitalizations for bronchiolitis were recorded in infants younger than one year of age, 60% represented by boys. The incidence of hospitalization for bronchiolitis increased by 49% over this period (8.5 to 12.7 per 1,000 inhabitants per year). Between 2013 and 2014, the incidence rate of hospitalization for acute bronchiolitis decreased by 8% (12.5 to 11.5 per 1,000 inhabitants per year). However, in the second year of the program, hospitalization rate increased again by 10% (12.7 per 1,000 inhabitants per years). Conclusions: Acute bronchiolitis presented increasing rates of hospitalization over the study period. Hospitalization incidence for acute bronchiolitis declined one year after the implementation of palivizumab but increased again in the second year of the program.

RESUMO Objetivo: Avaliar a tendência de hospitalização por bronquiolite aguda (BA) em lactentes menores de um ano de idade nos últimos oito anos no Brasil e, secundariamente, após a implementação do programa de imunização por palivizumabe. Métodos: Análise retrospectiva dos dados de lactentes menores de um ano de idade, hospitalizados com diagnóstico de BA entre 2008 e 2015 no Brasil, utilizando o banco de dados do Sistema Único de Saúde (SUS). Foram avaliadas as taxas de hospitalização nos períodos pré-implementação (2008-2012) e pós-implementação (2014-2015) do programa de imunização por palivizumabe. O número total de internações no mesmo período foi utilizado como comparação. Resultados: Entre janeiro de 2008 e dezembro 2015 foram registradas 263.679 internações por bronquiolite em lactentes menores de um ano de idade, 60% representado por meninos. A incidência de hospitalização por bronquiolite aumentou em 49% ao longo desse período (8,5 para 12,7 por mil ­habitantes/­ano). Entre 2013 e 2014, a taxa de incidência de hospitalização por BA diminuiu 8% (12,5 para 11,5 por mil habitantes/ano). Porém, no segundo ano do programa, a taxa de internação aumentou novamente em 10% (12,7 por mil habitantes/ano). Conclusões: A BA apresentou taxas de hospitalização crescente ao longo do período estudado. A incidência de hospitalizações de BA apresentou declínio um ano após a implementação de palivizumabe e retornou à tendência crescente no segundo ano do programa.

Effectiveness of Palivizumab against Respiratory Syncytial Virus: Cohort and Case Series Analysis.

OBJECTIVE: To measure the real-world effectiveness of palivizumab immunoprophylaxis against respiratory syncytial virus (RSV)-confirmed infection before age 2 years in a population-cohort of high-risk infants. STUDY DESIGN: Palivizumab is funded for high-risk infants in Western Australia. We used probabilistically linked administrative data encompassing RSV laboratory-confirmed infections, hospital admissions, and palivizumab dispensing records for a cohort of 24 329 high-risk infants admitted to neonatal intensive care units, born 2002-2013 with follow-up to 2015. We used a traditional cohort method with Cox proportional hazards regression and a self-controlled case series analysis to assess effectiveness of palivizumab in reducing RSV-confirmed infection by number of doses. RESULTS: From the cohort of 24 329 infants, 271 (1.1%) received at least 1 dose of palivizumab and 1506 (6.2%) had at least 1 RSV-confirmed infection before age 2 years. Using the traditional cohort approach, we found no protective association of palivizumab receipt with RSV detection (adjusted hazard ratio = 0.99 [95% CI 0.5, 1.9] for 1 dose). However, using a self-controlled case series to eliminate confounding by indication, a protective association was seen with a 74% lower RSV incidence (relative incidence = 0.26; 95% CI 0.11, 0.67) following any dose of palivizumab compared with control (nonexposed) periods. CONCLUSIONS: After accounting for confounding by indication through a self-controlled analysis, palivizumab appeared effective for reducing virologically confirmed RSV in this high-risk cohort.

Bronchiolitis: an update on management and prophylaxis.

Bronchiolitis is an acute respiratory illness that is the leading cause of hospitalization in young children less than 2 years of age in the UK. Respiratory syncytial virus is the most common virus associated with bronchiolitis and has the highest disease severity, mortality and cost. Bronchiolitis is generally a self-limiting condition, but can have serious consequences in infants who are very young, premature, or have underlying comorbidities. Management of bronchiolitis in the UK is guided by the National Institute for Health and Care Excellence (2015) guidance. The mainstays of management are largely supportive, consisting of fluid management and respiratory support. Pharmacological interventions including nebulized bronchodilators, steroids and antibiotics generally have limited or no evidence of efficacy and are not advised by National Institute of Health and Care Excellence. Antiviral therapeutics remain in development. As treatments are limited, there have been extensive efforts to develop vaccines, mainly targeting respiratory syncytial virus. At present, the only licensed product is a monoclonal antibody for passive immunisation. Its cost restricts its use to those at highest risk. Vaccines for active immunisation of pregnant women and young infants are also being developed.

Respiratory illness and respiratory syncytial virus hospitalization in infants with a tracheostomy following prophylaxis with palivizumab.

Data on respiratory-related illness and respiratory syncytial virus (RSV) infection in children with a tracheostomy are sparse. We determined respiratory illness hospitalization (RIH) and RSV-related hospitalization (RSVH) hazard ratios in children with a tracheostomy following prophylaxis compared with infants' prophylaxed for standard indications (prematurity ≤ 35 weeks' gestational age, bronchopulmonary dysplasia, and significant congenital heart disease) and children with complex medical disorders. Children who received ≥ 1 injection of palivizumab were prospectively enrolled across 32 Canadian sites during the RSV season. Respiratory illness event data were collected monthly. Data were analyzed using t tests, chi-square tests, and Cox proportional hazards adjusted for confounders. A total of 23,597 infants were enrolled; 220 tracheostomy, 19,402 standard indications, 3975 complex medical disorders. Of the 220 tracheostomy infants, 30 had bronchopulmonary dysplasia, 18 were premature, 12 had congenital heart disease, and 160 had other medical complexities. RIH and RSVH incidences (tracheostomy, standard indications, complex medical disorders) were 24.5%, 6.2%, and 9.8% and 2.0%, 1.5%, and 1.8% respectively. RIH hazard was significantly higher in tracheostomy infants compared with standard indications (HR = 1.8, 95% CI 1.1-3.0, p = 0.02) but was similar between the tracheostomy and complex medical disorders groups (HR = 1.3, 95% CI 0.7-2.2, p = 0.37). RSVH hazard was also similar in tracheostomy infants relative to standard indications and complex medical disorders (both p > 0.75). Children with tracheostomies who received palivizumab had an increased RIH hazard compared with the standard indications group. Similar RSVH hazard between tracheostomy, standard indications, and complex medical disorders groups suggests that children with tracheostomies may benefit from palivizumab by reducing RSVH during the RSV season.