Evidentia praxis: nirsevimab y prevención de bronquiolitis en lactantes nacidos a término / Evidentia praxis: Nirsevimab and bronchiolitis prevention in term-born infants

Analizamos la evidencia publicada sobre la eficacia y seguridad de nirsevimab, un anticuerpo monoclonal, empleado para prevenir las infecciones de vías respiratorias bajas (IVRB) por virus respiratorio sincitial (VRS) en el lactante a término. Encontramos un ensayo clínico aleatorizado controlado con placebo doble ciego que incluyó 3012 lactantes, nacidos a término o pretérmino tardío, menores de un año con un seguimiento de al menos 150 días. La calidad de la evidencia se clasificó como baja para IVRB muy grave y moderada para IVRB que precisara asistencia o ingreso. La evidencia se sustenta sobre un escaso número de eventos (para ingresos hospitalarios sólo 29 casos, para IVRB con atención médica 78), por lo que cualquier estimación debe considerarse imprecisa. La eficacia, estimada como reducción relativa del riesgo (RRR) fue del 76,4% (intervalo de confianza del 95% [IC 95]: 62,3 a 85,2) para IVRB por VRS y del 76,8% (IC 95: 49,4 a 89,4%) para ingreso. No se encontraron diferencias en cuanto a seguridad. Existen dudas sobre la importancia clínica, por los criterios de gravedad empleados, y sobre su impacto, con un número necesario a tratar para evitar una IVRB con ingreso de 63 y que requiera asistencia médica de 24. Por la información disponible parece una intervención segura, de la que no esperamos efectos adversos comunes, pero no podemos descartar efectos de baja frecuencia. Asimismo, esperamos contar pronto con estimaciones más precisas de eficacia y seguridad (AU)

We reviewed the published evidence on the efficacy and safety of nirsevimab, a monoclonal antibody, used to prevent respiratory syncytial virus (RSV) associated lower respiratory tract infections (LRTI) in term infants. We have found a randomized double-blind placebo-controlled clinical trial that included 3012 infants, born at term or late preterm, less than one year of age with a follow-up of at least 150 days. The quality of the evidence was classified as low for very severe LRTI and moderate for LRTI requiring medical care or admission. The evidence is based on a small number of events (only 29 cases for hospital admissions, 78 for IVRB with medical care), so any estimate must be considered imprecise. Efficacy, estimated as relative risk reduction (RRR) was 76.4% (95% confidence interval [95 CI]: 62.3 to 85.2) for RSV associated LRTI that required medical care and 76.8% (CI 95: 49.4 to 89.4%) for hospital admission. No differences were found in terms of safety. There are doubts about the clinical importance, due to the severity criteria used, and about its impact, with a number needed to treat of 63 to avoid a LRTI with hospital admission and of 24 to avoid LRTI requiring medical care. Based on the available information, it seems a safe intervention, from which we do not expect common adverse effects, but we cannot rule out low-frequency effects. We also expect to have more precise estimates of efficacy and safety soon. (AU)

Comentario del Comité Asesor de Vacunas de la Asociación Española de Pediatría a Evidencias en Pediatría sobre nirsevimab / Comment by the Advisory Committee on Vaccines of the Spanish Association of Paediatrics on Evidences in Paediatrics about nirsevimab

La bronquiolitis sigue siendo un problema de salud de primer orden en nuestro país, pues genera anualmente miles de consultas en Atención Primaria, colapso en las plantas de hospitalización y cuidados intensivos pediátricas y costes millonarios al Sistema Nacional de Salud. Su interés es máximo, además, porque la mayoría de los que requerirán ingreso hospitalario serán lactantes sanos, sin ningún tipo de factor de riesgo conocido. La altísima incidencia de la enfermedad y la ausencia de un tratamiento específico hace que los pediatras asistamos impasibles a esta epidemia anual, sin poder ofrecer una opción ni preventiva ni terapéutica a nuestros pacientes. En noviembre de 2022, la Agencia Europea de Medicamentos autorizó la comercialización de un anticuerpo monoclonal específico contra la proteína F del virus respiratorio sincitial (VRS), tras los resultados de los ensayos iniciales realizados en más de 3000 lactantes en los que se demostró una eficacia en la prevención de hospitalizaciones por VRS superior al 75%. En mayo de 2023 se comunicaron los resultados preliminares del estudio HARMONIE, llevado a cabo en más de 8000 individuos, representando la primera experiencia en vida real con el uso de nirsevimab y obteniéndose una eficacia superior al 80% en la prevención de hospitalización por bronquiolitis. En este texto se exponen los argumentos del Comité Asesor de Vacunas de la Asociación Española de Pediatría que sustentan la recomendación que hizo este organismo para su uso sistemático en recién nacidos y lactantes menores de 6 meses en España (AU)

Bronchiolitis continues to be a major health problem in Spain, as it generates thousands of consultations in primary care every year, a backlog in paediatric hospitalisation and intensive care wards, and millions in costs to the National Health System. Most of those who require hospital admission are healthy infants, without any known risk factor. The very high incidence of the disease and the absence of a specific treatment means that paediatricians are impassive in the face of this annual epidemic, unable to offer our patients either a preventive or therapeutic option. In November 2022, the European Medicines Agency granted marketing authorisation for a monoclonal antibody specific against respiratory syncytial virus (RSV) F protein, following results from initial trials in more than 3,000 infants that demonstrated greater than 75% efficacy in preventing RSV hospitalisations. Preliminary results from the HARMONIE study, conducted in over 8000 individuals, were reported in May 2023, representing the first real-life experience with the use of nirsevimab and showing greater than 80% efficacy in preventing hospitalisations for bronchiolitis. This text presents the arguments of the Vaccine Advisory Committee of the Spanish Association of Paediatrics to support the recommendation made by this group for its routine use in newborns and infants under 6 months of age in Spain(AU)

Temporal-spatial analysis of hospitalizations for bronchiolitis in Brazil: prediction of epidemic regions and periods for immunization against the Respiratory Syncytial Virus.

OBJECTIVE: Due to the high cost and short term of passive immunization against the respiratory syncytial virus, the main virus causing acute viral bronchiolitis, predicting epidemic regions and epidemic months is extremely important. The objective of this study is to identify both the month when the seasonal peak begins and Brazilian regions and states with the highest incidence of monthly hospitalizations due acute viral bronchiolitis. METHODS: Based on data obtained from DATASUS, monthly hospitalization rates due acute viral bronchiolitis were calculated for every 10,000 live births to children under 12 months of age in all Brazilian states and the Federal District between 2000 and 2019. Seasonal autoregressive integrated moving average models were estimated to forecast monthly hospitalization rates in 2020. RESULTS: A higher incidence of hospitalizations was found for male children, especially under six months of age. As for Brazilian regions, between 2000 and 2019, the South region registered the highest incidence of hospitalizations, followed by the Southeast, Midwest, North and Northeast regions, in this order. Considering the seasonal peak, the period between March and July 2020 comprised the highest expected hospitalization rates. CONCLUSIONS: Palivizumab is suggested to be started between February/March and June/July for most Brazilian states, with the exception of Rio Grande do Sul, which, in addition to presenting the highest rates of hospitalizations for acute viral bronchiolitis per 10,000 live births, has the longest seasonal peak between May and September.

Epidemiology and prevention of respiratory syncytial virus infections in children in Italy.

Respiratory syncytial virus (RSV) is the leading global cause of respiratory infections in infants and the second most frequent cause of death during the first year of life. This highly contagious seasonal virus is responsible for approximately 3 million hospitalizations and 120,000 deaths annually among children under the age of 5 years. Bronchiolitis is the most common severe manifestation; however, RSV infections are associated with an increased long-term risk for recurring wheezing and the development of asthma. There is an unmet need for new agents and a universal strategy to prevent RSV infections starting at the time of birth. RSV is active between November and April in Italy, and prevention strategies must ensure that all neonates and infants under 1 year of age are protected during the endemic season, regardless of gestational age at birth and timing of birth relative to the epidemic season. Approaches under development include maternal vaccines to protect neonates during their first months, monoclonal antibodies to provide immediate protection lasting up to 5 months, and pediatric vaccines for longer-lasting protection. Meanwhile, improvements are needed in infection surveillance and reporting to improve case identification and better characterize seasonal trends in infections along the Italian peninsula. Rapid diagnostic tests and confirmatory laboratory testing should be used for the differential diagnosis of respiratory pathogens in children. Stakeholders and policymakers must develop access pathways once new agents are available to reduce the burden of infections and hospitalizations.

Saudi experts' recommendation for RSV prophylaxis in the era of COVID-19: Consensus from the Saudi Pediatric Pulmonology Association.

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and viral pneumonia in pediatrics worldwide. In the Kingdom of Saudi Arabia (KSA), the prevalence of RSV is 23.5% in pediatric patients with acute lower respiratory tract illness. Coronavirus disease (COVID-19) poses critical public health and socioeconomic challenges in KSA. The Saudi Pediatric Pulmonology Association (SPPA), a subsidiary of the Saudi Thoracic Society (STS), developed a task force to determine the potential challenges and barriers to the RSV immunoprophylaxis program during the era of COVID-19 and to compose a practical, nationwide, and multidisciplinary approach to address these challenges. Some of the recommendations to manage these challenges include increasing the number of RSV immunoprophylaxis clinics, drive-thru visits, home-care services, and swift referrals to the RSV immunoprophylaxis program specialists. Additional training is required for healthcare personnel to add RSV immunoprophylaxis to the regular immunization schedule.

RSV Lower Respiratory Tract Illness in Infants of Low- and Middle-income Countries.

This review addresses differences in respiratory syncytial virus (RSV) lower respiratory tract illness (LRTI) between industrialized and developing countries and provides observations associated with the dissimilar consequences of viral infection in both environments. RSV LRTI is an important cause of morbidity and mortality in infants worldwide. Its burden is highest in developing countries, where most hospitalizations and mortality occur. Palivizumab has been approved for disease prevention in premature infants in numerous countries but its cost and requirement for several doses hampers its routine use. The significant gap between low- and high-income countries in mortality rates stresses the need to identify specific risk factors for RSV LRTI prevention in different populations. CONCLUSION: RSV LTRI continues to be a serious problem for industrialised and developing countries, although mortality occurs preferentially in the latter. Several vaccines and monoclonal antibodies to prevent severe disease are advancing steadily in late phase trials. The next decade may witness a change in the landscape of RSV infections in young infants.

Prevention of Pediatric Respiratory Syncytial Virus Lower Respiratory Tract Illness: Perspectives for the Next Decade.

The landscape of infant bronchiolitis and viral pneumonia may be altered by preventive interventions against respiratory syncytial virus under evaluation today. Pediatric wards in 2018 in developing countries may differ from those attended by future generation pediatricians who may not witness the packed emergency rooms, lack of available beds, or emergency situations that all physicians caring for children with RSV experience every year. In this review, we describe and discuss different prevention strategies under evaluation to protect pediatric patients. Then, we outline a number of potential challenges, benefits, and concerns that may result from successful interventions after licensure.

Long term follow-up of Palivizumab administration in children born at 29-32 weeks of gestation.

BACKGROUND: Severe respiratory syncytial virus (RSV) bronchiolitis requiring hospitalization induces long term immunological and respiratory abnormalities. The long-term immunomodulation effect of Palivizumab (RSV monoclonal antibody) prophylaxis and its impact on the development of asthma remain controversial. Our aim was to evaluate airway hyper-reactivity, systemic inflammatory markers, allergic parameters and respiratory morbidity, 5-7 years following Palivizumab administration to children born at 29-32 weeks of gestation (WGA). METHODS: Children born at 29-32 WGA were evaluated at age 5-7 years. Methacholine challenge test (MCT), serum inflammatory cytokines, fractional exhaled nitric oxide (FeNO), blood tests for eosinophil count, IgE and assessment of respiratory morbidity by questionnaire were compared between those born before Palivizumab prophylaxis was extended to 29-32 WGA and those who received Palivizumab prophylaxis. RESULTS: Of 42 children recruited, 27 received Palivizumab and 15 did not. The mean gestational age and weight were lower in the Palivizumab group. Similar values of spirometry, MCT, FeNO and allergic parameters were observed in the two groups. The Palivizumab group had higher IL4, IL5 and IL13 (Th2 cytokines), IL6, IL17α, and G-CSF (Th17 activation), and lower IL12 and higher INF-γ (Th1 cytokines). CONCLUSION: Compared to children who did not receive immunoprophylaxis, among children who received Palivizumab, no beneficial effects on long-term respiratory morbidity, airway reactivity or allergic parameters were observed, and levels of Th2 and Th17 cytokines implicated in the pathogenesis of asthma were higher. These findings cast doubt on the potential long-term beneficial effect of Palivizumab on asthma inception.

Practice variation among Dutch paediatricians in palivizumab prescription rates: the importance of parental counselling approach.

AIM: To investigate differences in palivizumab prescription rates between Dutch paediatricians, and the role of parent counselling in this practice variation. METHODS: A retrospective chart review of premature infants <32 weeks of gestation, aged less than six months at the start of the winter season, born between January 2012 and July 2014, in three secondary hospital-based paediatric practices in the Netherlands. RESULTS: We included 208 patients, 133 (64%) of whom received palivizumab. Prescription rates varied considerably between the three hospitals: 8% (6/64), 89% (32/36) and 99% (97/98). A noticeable difference in the way parents were counselled about palivizumab was the use of the number needed to treat (NNT). In the hospital with the lowest prescription rate (8%), an NNT of 20 to prevent one hospitalisation was explicitly discussed with parents. Bronchiolitis-related hospital admissions occurred in 11.3% of patients receiving palivizumab compared to 20.0% in nonimmunised infants (p = 0.086). CONCLUSION: Considerable practice variation exists among Dutch paediatricians regarding palivizumab prescription rates. The counselling method seems to play an important role. Presenting palivizumab prophylaxis as a preference-sensitive decision, combined with the explicit use and explanation of an NNT, leads many parents to refrain from respiratory syncytial virus immunisation.

Effectiveness of Respiratory Syncytial Virus Immunoprophylaxis in Reducing Bronchiolitis Hospitalizations Among High-Risk Infants.

We sought to determine the real-world effectiveness of respiratory syncytial virus (RSV) immunoprophylaxis in a population-based cohort to inform policy. The study population included infants born during 1996-2008 and enrolled in the Kaiser Permanente Northern California integrated health-care delivery system. During the RSV season (November-March), the date of RSV immunoprophylaxis administration and the following 30 days were defined as RSV immunoprophylaxis protected period(s), and all other days were defined as unprotected period(s). Numbers of bronchiolitis hospitalizations were determined using International Classification of Diseases, Ninth Revision, codes during RSV season. We used a proportional hazards model to estimate risk of bronchiolitis hospitalization when comparing infants' protected period(s) with unprotected period(s). Infants who had ever received RSV immunoprophylaxis had a 32% decreased risk of bronchiolitis hospitalization (adjusted hazard ratio = 0.68, 95% confidence interval: 0.46, 1.00) when protected periods were compared with unprotected periods. Infants with chronic lung disease (CLD) had a 52% decreased risk of bronchiolitis hospitalization (adjusted hazard ratio = 0.48, 95% confidence interval: 0.25, 0.94) when protected periods were compared with unprotected periods. Under the new 2014 American Academy of Pediatrics (AAP) guidelines, 48% of infants eligible for RSV immunoprophylaxis on the basis of AAP guidelines in place at birth would no longer be eligible, but nearly all infants with CLD would remain eligible. RSV immunoprophylaxis is effective in decreasing hospitalization. This association is greatest for infants with CLD, a group still recommended for receipt of RSV immunoprophylaxis under the new AAP guidelines.

Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a-mediated T reg expansion.

Respiratory syncytial virus-bronchiolitis is a major independent risk factor for subsequent asthma, but the causal mechanisms remain obscure. We identified that transient plasmacytoid dendritic cell (pDC) depletion during primary Pneumovirus infection alone predisposed to severe bronchiolitis in early life and subsequent asthma in later life after reinfection. pDC depletion ablated interferon production and increased viral load; however, the heightened immunopathology and susceptibility to subsequent asthma stemmed from a failure to expand functional neuropilin-1+ regulatory T (T reg) cells in the absence of pDC-derived semaphorin 4a (Sema4a). In adult mice, pDC depletion predisposed to severe bronchiolitis only after antibiotic treatment. Consistent with a protective role for the microbiome, treatment of pDC-depleted neonates with the microbial-derived metabolite propionate promoted Sema4a-dependent T reg cell expansion, ameliorating both diseases. In children with viral bronchiolitis, nasal propionate levels were decreased and correlated with an IL-6high/IL-10low microenvironment. We highlight a common but age-related Sema4a-mediated pathway by which pDCs and microbial colonization induce T reg cell expansion to protect against severe bronchiolitis and subsequent asthma.

Bronchiolitis in Infants and Children.

Bronchiolitis is among the most common illnesses in infants and children, and is the most common cause for hospitalization in infants in the U.S. This illness can be caused by many viruses, most commonly respiratory syncytial virus. It is diagnosed clinically by history and physical exam findings, with a narrow role for ancillary testing. Management is supportive, with medications demonstrating limited utility in multiple studies. Preventive measures include hand hygiene, breastfeeding, avoiding tobacco smoke exposure, and isolation precautions for hospitalized patients. Palivizumab prophylaxis is recommended for infants with qualifying high risk conditions. Recent evidence-based clinical practice guidelines have been published by the American Academy of Pediatrics to guide diagnosis, treatment, and prevention of bronchiolitis.

Respiratory Syncytial Virus Bronchiolitis in Children.

Bronchiolitis is a common lower respiratory tract infection in infants and young children, and respiratory syncytial virus (RSV) is the most common cause of this infection. RSV is transmitted through contact with respiratory droplets either directly from an infected person or self-inoculation by contaminated secretions on surfaces. Patients with RSV bronchiolitis usually present with two to four days of upper respiratory tract symptoms such as fever, rhinorrhea, and congestion, followed by lower respiratory tract symptoms such as increasing cough, wheezing, and increased respiratory effort. In 2014, the American Academy of Pediatrics updated its clinical practice guideline for diagnosis and management of RSV bronchiolitis to minimize unnecessary diagnostic testing and interventions. Bronchiolitis remains a clinical diagnosis, and diagnostic testing is not routinely recommended. Treatment of RSV infection is mainly supportive, and modalities such as bronchodilators, epinephrine, corticosteroids, hypertonic saline, and antibiotics are generally not useful. Evidence supports using supplemental oxygen to maintain adequate oxygen saturation; however, continuous pulse oximetry is no longer required. The other mainstay of therapy is intravenous or nasogastric administration of fluids for infants who cannot maintain their hydration status with oral fluid intake. Educating parents on reducing the risk of infection is one of the most important things a physician can do to help prevent RSV infection, especially early in life. Children at risk of severe lower respiratory tract infection should receive immunoprophylaxis with palivizumab, a humanized monoclonal antibody, in up to five monthly doses. Prophylaxis guidelines are restricted to infants born before 29 weeks' gestation, infants with chronic lung disease of prematurity, and infants and children with hemodynamically significant heart disease.

Acute viral bronchiolitis in South Africa: Strategies for management and prevention.

Management of acute viral bronchiolitis is largely supportive. There is currently no proven effective therapy other than oxygen for hypoxic children. The evidence indicates that there is no routine benefit from inhaled, rapid short-acting bronchodilators, adrenaline or ipratropium bromide for children with acute viral bronchiolitis. Likewise, there is no demonstrated benefit from routine use of inhaled or oral corticosteroids, inhaled hypertonic saline nebulisation, montelukast or antibiotics. The last should be reserved for children with severe disease, when bacterial co-infection is suspected. Prevention of respiratory syncytial virus (RSV) disease remains a challenge. A specific RSV monoclonal antibody, palivizumab, administered as an intramuscular injection, is available for children at risk of severe bronchiolitis, including premature infants, young children with chronic lung disease, immunodeficiency, or haemodynamically significant congenital heart disease. Prophylaxis should be commenced at the start of the RSV season and given monthly during the season. The development of an RSV vaccine may offer a more effective alternative to prevent disease, for which the results of clinical trials are awaited. Education of parents or caregivers and healthcare workers about diagnostic and management strategies should include the following: bronchiolitis is caused by a virus; it is seasonal; it may start as an upper respiratory tract infection with low-grade fever; symptoms are cough and wheeze, often with fast breathing; antibiotics are generally not needed; and the condition is usually self limiting, although symptoms may occur for up to four weeks in some children.

Respiratory syncytial virus seasonality in Brazil: implications for the immunisation policy for at-risk populations

Respiratory syncytial virus (RSV) infection is the leading cause of hospitalisation for respiratory diseases among children under 5 years old. The aim of this study was to analyse RSV seasonality in the five distinct regions of Brazil using time series analysis (wavelet and Fourier series) of the following indicators: monthly positivity of the immunofluorescence reaction for RSV identified by virologic surveillance system, and rate of hospitalisations per bronchiolitis and pneumonia due to RSV in children under 5 years old (codes CID-10 J12.1, J20.5, J21.0 and J21.9). A total of 12,501 samples with 11.6% positivity for RSV (95% confidence interval 11 - 12.2), varying between 7.1 and 21.4% in the five Brazilian regions, was analysed. A strong trend for annual cycles with a stable stationary pattern in the five regions was identified through wavelet analysis of the indicators. The timing of RSV activity by Fourier analysis was similar between the two indicators analysed and showed regional differences. This study reinforces the importance of adjusting the immunisation period for high risk population with the monoclonal antibody palivizumab taking into account regional differences in seasonality of RSV.

Respiratory syncytial virus seasonality in Brazil: implications for the immunisation policy for at-risk populations.

Respiratory syncytial virus (RSV) infection is the leading cause of hospitalisation for respiratory diseases among children under 5 years old. The aim of this study was to analyse RSV seasonality in the five distinct regions of Brazil using time series analysis (wavelet and Fourier series) of the following indicators: monthly positivity of the immunofluorescence reaction for RSV identified by virologic surveillance system, and rate of hospitalisations per bronchiolitis and pneumonia due to RSV in children under 5 years old (codes CID-10 J12.1, J20.5, J21.0 and J21.9). A total of 12,501 samples with 11.6% positivity for RSV (95% confidence interval 11 - 12.2), varying between 7.1 and 21.4% in the five Brazilian regions, was analysed. A strong trend for annual cycles with a stable stationary pattern in the five regions was identified through wavelet analysis of the indicators. The timing of RSV activity by Fourier analysis was similar between the two indicators analysed and showed regional differences. This study reinforces the importance of adjusting the immunisation period for high risk population with the monoclonal antibody palivizumab taking into account regional differences in seasonality of RSV.