Article Text

Effectiveness of nirsevimab immunoprophylaxis against respiratory syncytial virus-related outcomes in hospital and primary care settings: a retrospective cohort study in infants in Catalonia (Spain)
  1. Ermengol Coma1,
  2. Montserrat Martinez-Marcos2,
  3. Eduardo Hermosilla1,3,
  4. Jacobo Mendioroz2,
  5. Anna Reñé1,
  6. Francesc Fina1,
  7. Aida Perramon-Malavez4,
  8. Clara Prats4,
  9. Gloria Cereza5,6,
  10. Pilar Ciruela2,7,
  11. Valentí Pineda8,
  12. Andrés Antón9,
  13. Gemma Ricós-Furió10,11,
  14. Antoni Soriano-Arandes12,
  15. Carmen Cabezas2
  1. 1Primary Care Services Information System (SISAP), Institut Catala de la Salut, Barcelona, Spain
  2. 2Public Health Secretariat, Department of Health, Generalitat de Catalunya, Barcelona, Spain
  3. 3Idiap Jordi Gol, Universitat Autonoma de Barcelona, Barcelona, Spain
  4. 4Computational Biology and Complex Systems (BIOCOM-SC) Group, Departament de Fisica, Universitat Politecnica de Catalunya, Barcelona, Spain
  5. 5Catalan Centre of Pharmacovigilance. Directorate-General for Healthcare Planning and Regulation, Departament de Salut, Generalitat de Catalunya, Barcelona, Spain
  6. 6Department of Pharmacology, Therapeutics and Toxicology, Universitat de Barcelona, Barcelona, Spain
  7. 7CIBER Epidemiologia y Salud Pública (CIBERESP), Carlos III Health Institute, Madrid, Spain
  8. 8Pediatric Infectious Diseases Unit, Department of Pediatrics, Hospital Universitari Parc Taulí, Hospital de Sabadell, Sabadell, Spain
  9. 9Respiratory Virus Unit, Microbiology Department, Hospital Vall d'Hebron, Barcelona, Spain
  10. 10Pediatric’s Coordinator of Primary and Community Care, Departament de Salut, Generalitat de Catalunya, Barcelona, Spain
  11. 11Pediatric’s Coordinator of Primary and Community Care, Institut Català de la Salut, Barcelona, Spain
  12. 12Paediatric Infectious Diseases and Immunodeficiencies Unit, Children’s Hospital, Hospital Vall d'Hebron, Barcelona, Spain
  1. Correspondence to Montserrat Martinez-Marcos, Public Health Secretariat, Department of Health, Generalitat de Catalunya, Barcelona 08028, Spain; montserrat.martinezm{at}gencat.cat

Abstract

Background In Catalonia, infants under 6 months old were eligible to receive nirsevimab, a novel monoclonal antibody against respiratory syncytial virus (RSV). We aimed to analyse nirsevimab’s effectiveness across primary and hospital care outcomes.

Methods Retrospective cohort study from 1 October 2023 to 31 January 2024, including all infants born between April and September 2023. We established two cohorts based on nirsevimab administration (immunised and non-immunised). We followed individuals until the earliest moment of an outcome—RSV infection, primary care attended bronchiolitis and pneumonia, hospital emergency visits due to bronchiolitis, hospital admission or intensive care unit (ICU) admission due to RSV bronchiolitis—death or the end of the study. We used the Kaplan-Meier estimator and fitted Cox regression models using a calendar time scale to estimate HRs and their 95% CIs.

Results Among 26 525 infants, a dose of nirsevimab led to an adjusted HR for hospital admission due to RSV bronchiolitis of 0.124 (95% CI: 0.086 to 0.179) and an adjusted HR for ICU admission of 0.099 (95% CI: 0.041 to 0.237). Additionally, the adjusted HRs observed for emergency visits were 0.446 (95% CI: 0.385 to 0.516) and 0.393 (95% CI: 0.203 to 0.758) for viral pneumonia, 0.519 (95% CI: 0.467 to 0.576) for bronchiolitis attended in primary care and 0.311 (95% CI: 0.200 to 0.483) for RSV infection.

Conclusion We demonstrated nirsevimab’s effectiveness with reductions of 87.6% and 90.1% in hospital and ICU admissions, respectively. These findings offer crucial guidance for public health authorities in implementing RSV immunisation campaigns.

  • Immunisation
  • Child Health
  • Infectious Disease Medicine
  • Respiratory Medicine

Data availability statement

Data are available upon reasonable request.

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This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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WHAT IS ALREADY KNOWN ON THIS TOPIC

  • Respiratory syncytial virus (RSV) is a main cause of lower respiratory tract infections, such as pneumonia and bronchiolitis, in infants.

  • Nirsevimab, a new monoclonal antibody, has demonstrated high efficacy in preventing RSV-associated disease, particularly in reducing hospitalisation, as shown in previous clinical trials.

WHAT THIS STUDY ADDS

  • Catalonia initiated an RSV immunisation campaign, presenting a unique opportunity to assess the effectiveness of nirsevimab against various outcomes.

  • Our study reveals substantial effectiveness, with an 87.6% reduction in hospital admissions and a 90.1% reduction in intensive care unit admissions due to RSV bronchiolitis.

  • Additionally, we observed notable reductions in less severe outcomes, including primary care-diagnosed bronchiolitis (48.1%), RSV infections (68.9%), viral pneumonia (60.7%) and hospital emergency visits for bronchiolitis (55.4%).

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

  • These findings offer timely and crucial insights for healthcare authorities, informing strategies for RSV prevention and the planning of immunisation campaigns.

Introduction

Respiratory syncytial virus (RSV) infection is a worldwide public health concern due to its high contagiousness and potential to cause severe illness in the paediatric population.1 It is estimated that RSV is responsible for 70% of all bronchiolitis and 25% of pneumonia in infants under 1 year of age.2 RSV infection typically exhibits a seasonal pattern, with peak incidence in Spain usually observed between October and March.3

In March 2023, nirsevimab was commercialised in Spain. This recombinant human IgG1 kappa monoclonal antibody has demonstrated its efficacy and safety in preventing RSV infections in infants during their first epidemic season.4–9

Catalonia, an 8-million-inhabitant autonomous community in the northeast of Spain, introduced the recommendation and financing of nirsevimab in October 2023 as part of the infant immunisation programme.10 All infants born between April and September 2023 were offered a dose of nirsevimab in primary care practices (PCPs) during October, in addition to all newborns born between October 2023 and March 2024, preferably in public and private hospitals, or in PCPs during the first days of life. At the time of writing, the RSV epidemic wave has already ended (online supplemental figure 1), but the nirsevimab campaign is still underway for children born after October. Since the number of children is large and the observation period is adequate, it is a good time to analyse the data, focusing on the first group of children and providing useful and timely information to plan next season.

The objective of the study is to assess nirsevimab’s effectiveness in infants born between April and September 2023 during their first epidemic season.

Methods

Study design and settings

We conducted a retrospective cohort study using routinely collected data from five Catalan health databases. Nirsevimab exposure was obtained from the Catalan Shared Clinical Records, a comprehensive clinical database of electronic medical records that integrates data from the entire Catalan health system. We further linked data to the primary care electronic health records (EHRs) to analyse primary care-related outcomes. Data on hospital and intensive care unit (ICU) admissions were obtained from the Minimum Basic Data Set (CMBD in Catalan) and hospital emergency department visits from the CMBD-UR. Covariables and the eligible population were sourced from the central population register of the Catalan health service.11

All public PCPs in Catalonia use the same EHR system, known as ECAP, which has been previously validated and used for epidemiological research.12 The CMBD furnishes information on hospital discharges from all hospitals in Catalonia, encompassing both public and private hospitals.13

Participants and follow-up

We included all infants born between April and September 2023 in Catalonia and deemed eligible for immunisation with nirsevimab. We excluded those without a valid health identifier number and those who died or moved outside Catalonia before the start of the immunisation campaign. For the analysis of the primary care-related outcomes, we also excluded those infants who were not assigned to one of the public PCPs in Catalonia contributing to our database.

The study was conducted from 1 October 2023 to 31 January 2024. By the end of this period, the RSV epidemic in Catalonia had already concluded (online supplemental figure 1A,B). Two cohorts were established based on the nirsevimab administration date:

  • Exposed cohort (immunised with nirsevimab): infants who received a dose of nirsevimab during the study period.

  • Control cohort (non-immunised): infants who did not receive any dose of nirsevimab during the study period.

Exposure was dynamically defined. This means that infants who received one dose of nirsevimab may have previously contributed to the control cohort until the date of administration, at which point they became part of the exposed cohort.

We followed non-immunised participants from the beginning of the immunisation campaign in Catalonia (1 October 2023) until the earliest of receiving a dose of nirsevimab (at which point they switched to the exposed cohort), an outcome, death or the end of the study. Immunised participants were followed from the day they received nirsevimab immunoprophylaxis until the earliest of an outcome, death or the end of the study.

Study outcomes

Several outcomes were analysed:

  • Primary care attended bronchiolitis: defined as a clinical diagnosis of bronchiolitis based on International Classification of Diseases 10th version (ICD-10) codes recorded in the primary care EHR (online supplemental table 1).

  • RSV infection: measured as a positive rapid antigen test performed in primary care settings. Since 2021, rapid antigen tests for influenza (A and B), adenovirus, SARS-CoV-2 and RSV have been available in all paediatric PCPs for testing children with respiratory infection symptoms or fever without a focus.14

  • Viral pneumonia diagnosed in primary care: viral pneumonia diagnoses recorded in the primary care EHR were defined according to the ICD-10 classification, including all codes used in the Information System for Surveillance of Infections in Catalonia (online supplemental table 1).15

  • Hospital emergency department visits due to bronchiolitis: any hospital emergency visit for all-cause bronchiolitis.

  • Hospital admission for RSV-related disease: hospital admission with a discharge diagnosis of bronchiolitis due to RSV. In Catalonia, all paediatric patients with suspected acute low respiratory tract infections (LRTIs) who are admitted to hospital are tested for RSV as well as influenza A and B viruses and SARS-CoV-2.

  • Admission to ICU for RSV-related disease: any admission to the ICU during the hospital stay due to bronchiolitis caused by RSV.

In our analysis, hospital emergency department visits and primary care diagnoses outcomes encompassed all-cause bronchiolitis, as the majority of cases are reported as non-specific bronchiolitis (96.2% in primary care attended bronchiolitis and 87.4% in emergency visits).

Furthermore, we analysed the occurrence of a negative control outcome, (impetigo diagnoses registered in the primary care EHR), to identify potential unmeasured confounding. Negative control outcomes are events that are known not to be causally affected by the exposure of interest, here nirsevimab immunisation.16

Finally, we conducted a sensitivity analysis including hospital admissions for bronchiolitis caused by other pathogens as an outcome, for which no association with nirsevimab was expected.

Additional covariables

Covariables used for confounding assessment included sociodemographics: age (in days) at the beginning of the study, sex, area of residence, nationality (Spanish or immigrant), rurality and socioeconomic status. We assessed socioeconomic status using the validated socioeconomic index from the Catalan Agency for Healthcare Quality and Assessment, calculated at the health basic area level.17 Rurality of residence was measured, with rural areas defined by a population <10 000 inhabitants and a density <150 inhabitants per km2, as per regional guidance.

Statistical analysis

For descriptive analyses, we expressed continuous variables as median (IQR), and summarised categorical variables as a number (percentages). We assessed confounding by indication by using the standardised mean difference (SMD) of all covariables to compare both cohorts. We considered SMD >0.1 to be imbalanced and adjusted it in multivariable analysis.18

We computed the cumulative incidence (risk) curves of each outcome using the Kaplan-Meier estimator. Cox regression models using a calendar time scale19 were then fitted to calculate HRs and 95% CIs for each of the study outcomes according to immunisation status. All Cox models were also adjusted for any confounders with an SMD >0.1. Six models were conducted separately for each of the outcomes. Visual inspection of Schoenfeld residuals against the transformed time was used to evaluate the proportionality of hazards (online supplemental figure 2). We estimated effectiveness as the per cent reduction in risk (1 minus adjusted HR expressed as percentage). Finally, Cox regression models stratified by month of birth were performed as part of a post hoc analysis requested by one of the manuscript reviewers.

All analyses were conducted using R V.4.0.0 (libraries survival and survminer).20 21

Results

Before exclusions, 27 121 infants born between April and September 2023 were eligible for nirsevimab immunisation. We excluded 596 infants due to exclusion criteria (figure 1). We therefore analysed data from 26 525 infants (97.8%). For the analysis of the primary care outcomes, we excluded 1570 infants (5.9%) not assigned to a public PCP.

Figure 1

Population flow chart.

By the end of the study period, 23 127 infants (87.2%) had been immunised against RSV. Online supplemental figure 3 shows the rapid uptake of the nirsevimab coverage, with 76.3% of infants having received nirsevimab within the first month of the immunisation campaign.

The control and nirsevimab groups were balanced without adjustment in terms of sex, rurality and socioeconomic status, but differed in age (106 vs 88 days) and nationality (82.2% vs 87.1% of Spanish nationality), all with SMD >0.1 (table 1 and online supplemental figure 4).

Table 1

Baseline characteristic stratified by immunisation status

Among infants immunised with nirsevimab, 1560 primary care attended bronchiolitis, 604 hospital emergency visits for bronchiolitis, and 52 hospital admissions and 8 ICU admissions due to RSV bronchiolitis occurred. Conversely, in the control group, we observed 617 primary care bronchiolitis, 354 hospital emergency visits, 76 hospital admissions and 17 ICU admissions. Figures 2 and 3 depict the cumulative incidence of each outcome in both groups. Notably, the control group showed higher incidence rates for all outcomes, particularly for severe cases. For instance, the incidence rates of hospital admission due to RSV bronchiolitis were 9.55 per 100 000 person-days for non-immunised infants, as compared with 2.16 for immunised infants. Similarly, incidence rates of ICU admissions were 2.13 and 0.33, and incidence rates of primary care bronchiolitis were 93.9 and 69.7, respectively (table 2).

Table 2

Number of different outcomes, incidence rates (per 100 000 person-days), unadjusted HRs, adjusted HRs and effectiveness according to nirsevimab immunisation status

Figure 2

Estimated risk of hospital and intensive care unit (ICU) admissions due to bronchiolitis caused by respiratory syncytial virus according to immunisation status.

Figure 3

Estimated risk of RSV infections, primary care attended bronchiolitis, viral pneumonia and hospital emergency visits according to immunisation status. RSV, respiratory syncytial virus.

A dose of nirsevimab led to an adjusted HR for hospital admission of 0.124 (95% CI: 0.086 to 0.179) and an adjusted HR for ICU admission of 0.099 (95% CI: 0.041 to 0.237). In addition, the adjusted HRs observed for emergency visits were 0.446 (95% CI: 0.385 to 0.516) and 0.393 (95% CI: 0.203 to 0.758) for viral pneumonia, 0.519 (95% CI: 0.467 to 0.576) for primary care bronchiolitis and 0.311 (95% CI: 0.200 to 0.483) for RSV infection (table 2). Table 2 also presents nirsevimab’s effectiveness for each outcome, showcasing an effectiveness of 90.1% (95% CI: 76.3% to 95.9%) against ICU admission and 87.6% (95% CI: 82.1% to 91.4%) against hospital admission.

Impetigo diagnoses were used as a negative control outcome. They were recorded at similar frequencies in the two groups leading to an adjusted HR of 1.09 (95% CI: 0.80 to 1.48) (online supplemental figure 5). In addition, in a sensitivity analysis, we estimated the effectiveness of nirsevimab in preventing hospital admissions due to bronchiolitis caused by other pathogens, with an adjusted HR of 0.936 (95% CI: 0.420 to 2.087), indicating no association. Furthermore, HRs for hospital admission stratified by month (post hoc analysis) were consistent with the main results (online supplemental table 2).

Finally, two deaths were observed in our study population (both not immunised). These deaths were not related to RSV infection but were infants who were admitted to the hospital immediately after birth and remained hospitalised until the date of their death.

Discussion

This study offers a valuable estimation of nirsevimab effectiveness against various outcomes in infants aged <6 months old prior to the onset of their first RSV epidemic season. Using a comprehensive linked database that integrates primary and hospital care data, we investigated the impact of the Catalan immunisation programme on reducing RSV-related outcomes.10 Our analysis found that nirsevimab effectiveness against hospital and ICU admissions was 87.6% and 90.1%, respectively. Furthermore, we observed significant and clinically relevant reductions in less severe outcomes, including all-cause bronchiolitis attended in primary care (48.1%), RSV infections (68.9%), viral pneumonia (60.7%) and hospital emergency visits due to non-specific bronchiolitis (55.4%). To our knowledge, this study represents the first report to include outcomes of different severity in a real-world setting, providing a comprehensive assessment of the impact of nirsevimab across all levels of care.

Sensitivity analysis showing lack of protection in hospital admissions due to bronchiolitis caused by other pathogens, along with the absence of association between nirsevimab immunisation and our negative control outcome, underscore the robustness of our findings. These results rule out residual confounding in our cohorts.16

The observed differences in effectiveness between RSV infections and bronchiolitis diagnosed in primary care may be attributed to the fact that within these diagnoses of bronchiolitis, some are non-specific and not caused by RSV. However, RSV is the most common pathogen identified in infants with LRTI,1 so it is expected that the overall burden of LRTI disease is reduced by nirsevimab, even when medical attention is not required.22

Our results are in line with the 77.3% (95% CI: 50.3% to 89.7%) efficacy against hospitalisation for RSV shown in randomised clinical trials.8 Considering that only a few countries have introduced immunisation with nirsevimab this season, studies on its effectiveness are scarce. Our finding on nirsevimab effectiveness in preventing hospital admissions due to RSV is consistent with other works. A study conducted in some hospitals in other regions of Spain demonstrates effectiveness against RSV hospital admissions similar to ours, ranging between 70% and 84%.23 Similarly, a report from the Centers for Disease Control and Prevention found a 90% reduction in RSV-associated hospitalisation,24 and reports from Galicia show great reductions in 2023–2024 season compared with previous seasons in RSV hospital admissions in infants born between April and September.25 Additionally, in Luxembourg, researchers observed reductions in hospitalisation of approximately 69%.26 Nevertheless, our study adds value by complementing previous research with a primary care perspective.

Our study has some limitations. The observational nature of our data may have led to some type of confounding. Nevertheless, our analysis of a negative control outcome suggested comparability of the cohorts. Due to administrative and data registration delays, we were unable to include infants born after 30 September 2023 in our analysis. These infants would be the youngest during the RSV epidemic and therefore the ones most likely to benefit from immunisation with nirsevimab. We anticipate that data on these children will become available in the future, allowing us to complement our work in further research. Despite this limitation, our study provides valuable and timely insights into the effectiveness of nirsevimab across multiple outcomes for infants who were less than 6 months old before the onset of the RSV epidemic. Our study did not undertake an analysis of potential adverse effects; hence, it is imperative that future studies with appropriate designs be conducted to explore this aspect further. Additionally, the fact that in some settings, the majority of bronchiolitis cases are recorded as non-specific may lead to an underestimation of the effectiveness of less specific outcomes. Finally, changes in the community transmission of RSV during the study period could have a differential effect on the number of outcomes recorded in each cohort. However, our Cox regression model using a calendar time scale approach has been identified as an unbiased method for analysing outcomes with time-varying incidence and rapid uptake of immunisations.19

This study also boasts several strengths. The comprehensive linkage and coverage within our database, incorporating outcomes from both primary and hospital care, is unprecedented. Additionally, Catalonia’s universal healthcare system, supported by centralised health databases, previously used in vaccine research studies,27 28 maximises the completeness of outcome ascertainment. Finally, our study period encompasses the entirety of the 2023–2024 RSV epidemic wave (online supplemental figure 1A).

In conclusion, nirsevimab has demonstrated significant effectiveness in protecting infants against a wide range of outcomes associated with RSV infection. These early real-world data provide valuable insights into the effects of nirsevimab in mitigating the burden of RSV-associated disease in infants. Moreover, they offer essential evidence to inform public health authorities and guide decision-making processes regarding the implementation and prioritisation of RSV immunisation campaigns.

Data availability statement

Data are available upon reasonable request.

Ethics statements

Patient consent for publication

Ethics approval

The study was approved by the Clinical Research Ethics Committee of the IDIAP Jordi Gol with reference number 24/015-EOm.

Acknowledgments

The authors would like to thank all healthcare professionals in primary care practices, hospitals, laboratory centres and governmental health departments in Catalonia for their dedication and hard work in making possible the nirsevimab immunisation programme. Their efforts have been instrumental in the success of this campaign.

References

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Footnotes

  • X @ErmengolComa, @prats_clara, @tonisoriano66

  • Contributors EC, MM-M, CC and JM conceived and designed the study. EC and FFA conducted data extraction, collection, curation and verified the underlying data reported in the manuscript. EH performed the statistical analysis. EC and MM-M wrote the first draft of the manuscript and act as guarantors for the overall content.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests AS-A has received an honorarium for attending scientific meetings from Sanofi, MSD and Pfizer. VP has received an honorarium for attending scientific meetings from Sanofi and Pfizer. AA has received sponsorship from Sanofi to attend scientific meetings.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.