Acute viral bronchiolitis before and after implementation of nirsevimab prophylaxis in Italy: a multicentre retrospective cohort study

Summary

Background

Acute viral bronchiolitis is the leading cause of hospitalisation in the first year of life, with Respiratory Syncytial Virus (RSV) accounting for more than 60% of cases. A long-acting monoclonal antibody (nirsevimab) has been introduced for infants entering their first epidemic season. 2024–2025 season was the first with nirsevimab availability in Italy. We assessed its impact on bronchiolitis-related utilisation and clinical and virological characteristics of hospitalised infants.

Methods

We conducted a multicentre retrospective cohort study including infants <12 months with all-cause bronchiolitis during two seasons: pre-implementation (October 2023–April 2024) and post-implementation (October 2024–April 2025). Data were collected from 30 university hospitals across 15 regions using ICD-10 codes. Outcomes were compared using propensity score matching and multivariate regression analyses.

Findings

Following implementation, emergency department visits decreased by 48% (5076 vs 2633), pediatric ward admissions by 48% (2734 vs 1473) and pediatric intensive care unit admissions by 61% (334 vs 131). Analyses adjusted for local rollout showed reductions of 82% (RR 0.18), 84% (RR 0.16) and 79% (RR 0.20), respectively. Post-implementation, infants were older (aOR 1.07, 95% CI 1.04–1.10) with lower odds for low- (aOR 0.67, 95% CI 0.55–0.82) and high-flow (aOR 0.8; 95% CI 0.65–0.99) oxygen-therapy. RSV remained predominant (934/1473, 63%), while non-RSV infections increased (334/2734, 12% vs 305/1473, 21%). Most infants had not received prophylaxis; 372 (25%) hospitalised despite nirsevimab were younger (5.2 ± 3.5 vs 2.8 ± 1.9, p < 0.001) and had more comorbidities (11%, 82/745 vs 22%, 37/168, p < 0.001).

Interpretation

In Italy, nirsevimab was associated with reduced all-cause bronchiolitis-related utilisation and milder disease. Underlying conditions remained a determinant for severe outcomes despite prophylaxis.

Funding

No funding was received for this study.

Research in context.

Evidence before this study

We searched PubMed and Scopus for studies published between Jan 1, 2006, and Feb 1, 2026, using combinations of the terms “Respiratory Syncytial Virus”, “RSV”, “nirsevimab”, “bronchiolitis”, “hospitalisation”, “prophylaxis”, “real-world”, and “population impact”. We also screened reference lists of relevant articles to identify additional studies. We included randomised clinical trials and observational studies reporting the effectiveness or population-level impact of nirsevimab or other RSV preventive strategies in infants.

Respiratory syncytial virus (RSV) is the leading cause of acute viral bronchiolitis and hospitalisation in the first year of life worldwide.¹ For decades, palivizumab was the only available RSV preventive option, but its use was restricted to a small subgroup of high-risk infants.² The introduction of the long-acting monoclonal antibody nirsevimab and the maternal RSV pre-fusion F protein vaccine has markedly changed prevention strategies. Randomised trials, including the MELODY³ and HARMONIE⁴ studies, demonstrated high efficacy of nirsevimab in preventing RSV-related hospitalisation. Following regulatory approvals, several countries implemented large-scale immunisation programmes. Early real-world reports from France,⁵ Spain,⁶ Luxembourg,⁷ Belgium,⁸ and Chile,⁹ during the 2023–2024 season, and worldwide in the 2024–25 season¹⁰ reported marked reductions in RSV-related admissions after implementation.

Despite the rapidly expanding literature, most studies have focused on RSV-specific outcomes and were conducted in countries with relatively uniform national rollout strategies. However, nationwide analyses evaluating the impact of nirsevimab implementation on all-cause bronchiolitis burden, healthcare utilisation, clinical severity, and viral epidemiology remain scarce. In Italy, local and regional reports have confirmed findings from real-world experience, but nationwide data on the impact of these measures are still limited.

Added value of this study

This study provides one of the first large nationwide real-world evaluations of nirsevimab implementation in Italy, a country with heterogeneous regional rollout strategies, covering 30 of 38 pediatric university hospitals in 15 of 20 regions. Beyond confirming reductions in emergency visits and hospital admissions, it compares demographic and clinical characteristics of infants hospitalised for all-cause bronchiolitis before and after implementation and evaluates changes in clinical severity and viral patterns. Comorbidities emerged as key determinants of hospitalisation despite prophylaxis.

Implications of all the available evidence

Widespread use of long-acting RSV monoclonal antibodies can substantially reduce bronchiolitis burden. However, effectiveness depends on timely and coordinated implementation strategies and targeted protection to high-risk subgroups.

Introduction

Respiratory Syncytial Virus (RSV) is a leading global cause of lower respiratory tract infection in early childhood. Approximately 60% of infants experience a primary infection within their first year of life, and nearly all children are infected by the age of two.¹¹ Globally, RSV accounts for an estimated 34 million episodes of lower respiratory tract infection (LRTI) annually in children younger than five years, resulting in approximately 3.3 million hospitalisations and more than 120,000 deaths, predominantly in low-resource settings and among children with underlying conditions.¹²

RSV is responsible for nearly two-thirds of cases of acute viral bronchiolitis, the leading cause of hospitalisation in the first year of life.¹³ This condition represents a major burden for healthcare systems worldwide, with seasonal surges overwhelming hospital capacities, increasing healthcare costs, and generating indirect socioeconomic consequences related to parental work absences and long-term follow-up of respiratory sequelae.¹⁴

Currently, there is no specific medical treatment for bronchiolitis.¹⁵ For more than 30 years, the only available RSV preventive measure was palivizumab, a short-acting monoclonal antibody (mAb) that is costly, requires monthly administration throughout the RSV epidemic season, and is reserved for a small subset of high-risk infants, representing less than 5% of the pediatric population.¹⁶ Although palivizumab targets infants at high-risk, including those born preterm or with underlying conditions, these groups accounts for only about 25% of RSV-related severe cases. The majority of hospitalised cases occur in previously healthy term infants, highlighting the need for broader preventive strategies.^1,17

In recent years, new RSV preventive strategies have become available, including a long-acting monoclonal antibody (nirsevimab) and a maternal bivalent RSV pre-fusion F protein vaccine. Additional long-acting mAb for RSV prevention are also in advanced stages of development, reflecting a rapidly evolving landscape of immunoprophylactic strategies.

Nirsevimab is an IgG1 mAb targeting the highly neutralisation-sensitive site Ø on the pre-fusion RSV protein, allowing single-dose administration to all infants during their first epidemic season.¹⁸ Furthermore, the maternal vaccine contains stabilised pre-fusion glycoproteins from RSV A and RSV B and is administered between the 24th and 36th week of gestation.¹⁹

Following regulatory approvals, several countries introduced large scale RSV immunisation programmes. However, the real-world impact of these strategies depends on the timing and organisation of their implementation within national health systems.⁸ The European Medicines Agency (EMA) approved nirsevimab in October 2022, with early implementation in the 2023–2024 RSV season in countries including France,⁵ Spain,⁶ Luxembourg,⁷ and Belgium.⁸ In these countries, marked reduction in RSV-related bronchiolitis healthcare utilisation have been reported in early national real-world studies. In August 2023, the agency also approved the bivalent RSV pre-fusion F vaccine for maternal immunisation during pregnancy. Randomised clinical trials and emerging real-world studies demonstrated that maternal RSV vaccine significantly reduces RSV-related hospitalisations and healthcare utilisation among infants.20, 21, 22 Furthermore, recent evidence suggests that combining maternal vaccination with long-acting mAb prophylaxis provides broader protection than antibody administration alone, with potential additional reductions in all-cause hospitalisations and substantial cost savings.^23,24

Italy represents a particularly complex context for the implementation of national preventive strategies. The country is geographically and politically divided into 20 regions with substantial administrative autonomy in healthcare organisation. Although the Italian National Health Service is publicly funded and nationally regulated, regional authorities are responsible for healthcare delivery and may implement region-specific prevention programmes, leading to substantial interregional differences in access to services.

The Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA) approved nirsevimab in January 2023 and the RSV pre-fusion F vaccine in November 2023. However, nationwide free and voluntary administration was formally authorised only for nirsevimab from October 2024, with implementation beginning on November 1st, 2024.²⁵ The measure also included infants born before the epidemic season (up to 100 days of age) and children younger than two years with underlying conditions. From 2024 to 2025 epidemic season onward, nirsevimab became available across all Italian regions, although regional implementation led to heterogeneous access and supply. In contrast, free maternal vaccine was implemented in only two regions (Sicily and Molise), with very low uptake (Appendix 1). Therefore, in Italy, during the first season of implementation of the new preventive strategies, RSV prevention relied exclusively on nirsevimab prophylaxis.

Regional disparities resulted in staggered rollouts of prophylaxis, with nirsevimab administration beginning between late October 2024 and January 2025, generating heterogeneous immunisation coverage across the country.^26,27 Furthermore, while infants born during the epidemic season typically received the mAb at birth before hospital discharge, older infants required active recall by primary care services. The timing of prophylaxis initiation and regional recall strategies are detailed in Appendices 1 and 2.

To evaluate the real-world impact of the first national season of new RSV prevention strategies, we conducted a multicentre study involving Italian university hospitals affiliated with pediatric residency programmes, coordinated through the National Observatory of Pediatric Residents (ONSP), a nationwide network encompassing all pediatric trainees across Italy.

Methods

Study design and population

This multicentre retrospective cohort study was conducted in 30 of the 38 university hospitals affiliated with pediatric residency programmes in Italy, representing 15 of the 20 Italian regions and ensuring balanced geographical coverage across northern, central, and southern Italy (Appendix 3).

Participating centres are major paediatric university hospitals that serve as tertiary referral centres within their regional healthcare networks. Although the study was not designed as a population-based surveillance analysis, these centres represent the principal public referral institutions for moderate-to-severe bronchiolitis requiring hospital admission in their regions.

Four regions (Valle d’Aosta, Trentino-Alto Adige, Basilicata, and Molise) were not represented due to the absence of affiliated hospitals. In the Veneto region, the two eligible hospitals with pediatric residency programmes declined participation; consequently, this region was not included in the study. A detailed list of the participating centres is provided in Appendix 4.

Study periods and exposure definition

Data were collected for two epidemic seasons: pre-implementation (1st October 2023–30th April 2024) and post-implementation (1st October 2024–30th April 2025) corresponding to the first national season of nirsevimab prophylaxis. To minimise misclassification of exposure to nirsevimab, the post-implementation season was aligned with the regional start date of nirsevimab implementation and stratified according to the month in which nirsevimab administration began in each region and analysed through April 2025. Specifically, the post-implementation season was interpreted in relation to the regional start date of prophylaxis administration, which ranged from November 2024 to January 2025. This approach reduced temporal misclassification and avoided attributing bronchiolitis-related healthcare utilisation to the intervention before local implementation of prophylaxis.

In the only centre that had implemented maternal vaccination during the study period (Sicily), none of the mothers of hospitalised infants had received this intervention; therefore, vaccine exposure was not included in the analysis.

Data collection

Emergency department (ED) visits and hospital admissions for all-cause acute bronchiolitis were identified using predefined ICD-10 diagnostic codes (J21.0, J21.1, J21.8, and J21.9), applied consistently across participating hospitals. Only infants younger than 12 months presenting with a first episode of all-cause bronchiolitis were included.

For hospitalised infants, detailed demographic and clinical data were retrospectively extracted from medical records, including comorbidities, viral aetiology, respiratory support, and RSV prophylaxis. Comorbidities were defined as pre-existing medical conditions documented before hospitalisation. Preterm birth was defined as gestational age ≤36 + 6 weeks. Length of hospital stay, need for low- or high-flow oxygen therapy, and duration of respiratory support were recorded as indicators of clinical severity.

Ethnicity was recorded as a categorical variable (Caucasian vs non-Caucasian) based on information available in medical records at each participating centre and assigned according to local clinical documentation practices. This classification reflects routinely collected clinical data.

Virological assessment

As part of routine clinical care, hospitalised infants underwent nasopharyngeal swab testing analysed using a multiplex PCR assay (FilmArray, BioFire Diagnostics), capable of detecting common respiratory viruses, including RSV, influenza A/B virus, rhinovirus, human metapneumovirus, bocavirus, parainfluenza virus, coronavirus, and adenovirus. The assay was consistently used across participating hospitals and remained unchanged over the study period.

Outcomes

The primary outcome of the study was to evaluate the national and regional change in all-cause bronchiolitis-related emergency department (ED) visits, pediatric wards (PW) admissions and pediatric intensive care (PICU) admissions across the pre- and post-implementation seasons.

Secondary outcomes included comparisons of demographic and clinical characteristics, and viral aetiology between seasons.

Statistical analysis

Continuous variables are reported as means with 95% confidence intervals (CIs), and categorical variables as count and percentage. Cases with missing key demographic (age at admission, sex, ethnicity, gestational age at birth, birth weight), clinical (date of hospital admission, length of hospital stay, need and duration of oxygen treatment) or virological data were removed from the analyses. To evaluate the robustness of the findings to potential bias from missing data, a multiple imputation analysis using chained equations was performed as a sensitivity analysis (Appendix 6), incorporating all variables included in the primary models and accounting for the multicentre structure of the data.

Comparisons between pre- and post-implementation seasons were preliminary assessed using standardised mean difference (SMDs).

We performed two distinctive analyses: (1) a centre-level analysis on healthcare utilisation, including ED visits, PW and PICU admissions; and (2) a patient-level detailed analyses. In both analyses, the 2023–2024 season (pre-implementation) was compared with the 2024–2025 season (post-implementation).

Analysis of healthcare utilisation

As introduction of universal prophylaxis with nirsevimab in Italy followed a staggered regional rollout, Poisson regression models were used to estimate adjusted rate ratios (RRs) with 95% CIs, accounting for regional variation in timing of nirsevimab implementation. Rollout timing and regional population of infants aged younger than 12 months were included as covariates to account for differences in exposure and population at risk.

As data on the immunisation coverage in targeted population were not uniformly available at regional or national level, proxy variables were included as covariates in the Poisson regression models. These included the regional start date of immunisation campaign, used to estimate the proportion of epidemic season potentially covered by RSV prophylaxis, and the regional population of infants younger than 12 months in each season, based on national demographic statistics. According to official data from the Italian National Institute of Statistic (ISTAT), the population of infants younger than 12 months was 777,823 in 2023–2024 and 754,750 in 2024–2025 (http://demo.istat.it, accessed on March 12, 2026).

Analysis at patient level

To minimise baseline differences between groups, propensity score matching (1:1 ratio) was performed between pre- and post-implementation seasons, based on age at admission, sex and ethnicity, with a target standardised mean difference (SMD) of less than 0.100. After matching, differences between seasons were assessed by means of a binary logistic regression (BLR), modelled through an a priori approach including the following explanatory covariates: age at admission (continuous variable, days), length of hospital stay (continuous variable, days), sex (female vs male), ethnicity (Caucasian vs not Caucasian), birth weight (continuous variable, kg), comorbidities (yes vs no), need for low- and high-flow oxygen therapy (ever vs never), duration of respiratory support (continuous variable, days), and virological status (i.e. negative, positive as sole pathogen, positive as coinfection). Models were adjusted for region, grouped by start of universal prophylaxis campaigns (proportion of epidemic season potentially benefiting from RSV immunisation), and receipt of nirsevimab prophylaxis. Associations were reported as adjusted odds ratios (aOR) with 95% CI. All tests were two-sided, and confidence intervals were calculated at the 95% level.

Analyses were performed using SPSS version 27.0 (IBM Corp., Armonk, NY, USA), R (version 4.4.1), GraphPad Prism 10.5 (GraphPad Software LLC, Boston, MA, USA) and Rstudio (version 2025.05.0 Build 496; Posit Software, PBC; Boston, MA, USA) software, by means of the packages fmsb (version 0.7.5), cobalt (version 4.6.2), matchit (version 4.7.2).

Ethics

The study was approved by the National Pediatric Ethics Committee as a retrospective pharmacological investigation (protocol code 0012258-21/01/2026-AIFA). The study was conducted in accordance with the Declaration of Helsinki.

Given the retrospective nature of the study and the use of anonymised routinely collected clinical data, the requirement for informed consent was waived in accordance with national regulations and ethics committee approval.

Results

Impact of nirsevimab on all-cause bronchiolitis-related healthcare utilisation

Across the pre- (2023–2024) and post-implementation (2024–2025) seasons, a substantial reduction in all-cause bronchiolitis-related healthcare utilisation was observed consistently across all participating centres (Table 1) (Fig. 1).

Table 1.

Comparison of all-cause bronchiolitis-related emergency department visits, pediatric ward admissions, and pediatric intensive care unit (PICU) admissions across participating hospitals during the pre- and post-implementation seasons.

Recruitment centre (Start of universal prophylaxis with nirsevimab)	Emergency department visits			Pediatric ward admissions			PICU admissions
	2023–24	2024–25	Crude % of reduction	2023–24	2024–25	Crude % of reduction	2023–24	2024–25	Crude % of reduction
Piedmont (November 2024)	611	262	57.1%	284	125	56.0%	28	12	57.1%
Regina Margherita Hospital (Turin)	462	203	56.1%	248	107	56.9%	20	10	50.0%
Maggiore della Carità Hospital (Novara)	149	59	60.4%	36	18	50.0%	8	2	75.0%
Lombardia(November 2024)	811	303	62.6%	257	102	60.3%	48	17	64.6%
IRCCS San Raffaele (Milan)	119	43	63.9%	47	21	55.3%	11	2	81.8%
Spedali Civili (Brescia)	74	56	24.3%	65	32	50.8%	18	7	61.1%
F. Del Ponte Hospital (Varese)	392	91	76.8%	102	27	73.5%	5	3	40.0%
IRCSS San Gerardo (Monza)	226	113	50.0%	43	22	48.8%	14	5	64.3%
Friuli-Venezia Giulia (November 2024)
S. Maria Misericordia Hospital (Udine)	195	90	53.8%	69	23	66.7%	27	6	77.8%
Liguria (December 2024)
G. Gaslini Institute (Genova)	470	352	25.1%	247	153	38.1%	13	12	7.7%
Emilia-Romagna (November 2024)	381	244	35.9%	312	185	40.7%	24	13	45.8%
S. Orsola-Malpighi Hospital (Bologna)	208	107	48.6%	208	108	48.1%	14	6	57.1%
University Hospital (Modena)	173	137	20.8%	104	77	26.0%	10	7	30.0%
Tuscany (November 2024)	405	129	68.1%	312	73	76.6%	52	10	80.8%
Meyer IRCCS (Florence)	182	66	63.7%	148	25	83.1%	48	10	79.2%
Le Scotte University Hospital (Siena)	111	32	71.2%	111	34	69.4%	3	0	100.0%
University Hospital (Pisa)	112	31	72.3%	53	14	73.6%	1	0	100.0%
Umbria (January 2025)
Hospital Trust (Perugia)	147	117	20.4%	75	58	22.7%	8	5	37.5%
Marche (December 2024)
Salesi Hospital (Ancona)	93	65	30.1%	52	21	59.6%	11	4	63.6%
Abruzzo (January 2025)	76	102	−34.2%	55	79	−43.6%	7	7	0%
S. Salvatore Hospital (L'Aquila)	35	42	−20.0%	23	30	−30.4%	5	4	20.0%
S.S. Annunziata Hospital (Chieti)	41	60	−46.3%	32	49	−53.1%	2	3	−50.0%
Lazio(December 2024)	488	285	41.6%	245	167	31.8%	38	17	55.3%
Umberto I Hospital (Rome)	273	130	52.4%	168	109	35.1%	24	7	70.8%
Policlinico Gemelli (Rome)	215	155	27.9%	64	49	23.4%	13	9	30.8%
S. Andrea Hospital (Rome)	N/A	N/A	N/A	13	9	30.8%	1	1	0.0%
Campania (November 2024)	268	134	50.0%	578	364	37.0%	20	10	50.0%
Santobono Pausillipon (Naples)	N/A	N/A	N/A	416	293	29.6%	18	10	44.4%
S. Giovanni di Dio and Ruggi d'Aragona Hospital (Salerno)	123	59	52.0%	107	36	66.4%	2	0	100.0%
Sant'Anna and Sebastiano Hospital (Caserta)	145	75	48.3%	55	35	36.4%	0	0	0.0%
Apulia (November 2024)	316	156	50.6%	36	10	72.2%	4	1	75.0%
Giovanni XXIII Hospital (Bari)	316	156	50.6%	41	11	73.2%	N/A	N/A	N/A
Casa Sollievo della Sofferenza (Foggia)	N/A	N/A	N/A	50	24	52.0%	1	1	0.0%
Calabria (December 2024)
Annunziata Hospital (Catanzaro/Cosenza)	40	12	70.0%	36	10	72.2%	4	1	75.0%
Sicily (November 2024)	541	292	46.0%	287	153	46.7%	44	15	65.9%
ARNAS Civico Children Hospital (Palermo)	458	254	44.5%	191	124	35.1%	9	4	55.6%
S. Antonio Abate Hospital (Trapani)	N/A	N/A	N/A	43	11	74.4%	2	3	−50.0%
S. Marco Hospital (Catania)	N/A	N/A	N/A	16	5	68.8%	0	0	0.0%
Policlinico G. Martino (Messina)	83	38	54.2%	37	13	64.9%	33	8	75.8%
Sardinia (December 2024)
Arnas G. Brotzu e A. Cao (Cagliari)	234	90	61.5%	82	14	82.9%	9	1	88.9%
Total	5076	2633	48.1%	2734	1473	48.0%	334	131	61.2%

Inter-seasonal difference	Rate Ratio	95% CI	Rate Ratio	95% CI	Rate Ratio	95% CI
Baseline	2.528	1.210; 5.437	2.636	1.063; 6.844	1.738	0.463; 6.136
Effect of universal prophylaxis	0.178	0.077; 0.403	0.159	0.057; 0.432	0.204	0.050; 0.873
Estimated inter-seasonal effectiveness of universal prophylaxis in reduction in healthcare utilisation (%)	82.2%	59.7; 92.3	84.1%	56.8; 94.3	79.6%	12.7; 9.0

N/A = not available. Outcomes refer to all-cause bronchiolitis.

Cases were identified using ICD-10 diagnostic codes J21.0, J21.1, J21.8, and J21.9. Rate ratios (RRs) and 95% confidence intervals (CIs) were estimated using binomial regression models to analyse the number of hospitalisations, with the logarithm of hospitalizations in the previous season included as an offset. The proportion of the epidemic season (November to March) covered by nirsevimab was included as the main explanatory variable.

Fig. 1.

Impact of nirsevimab implementation on bronchiolitis-related healthcare utilisation. a) Percentage reduction in Emergency Department (ED) visits, Pediatric Ward (PW) admissions, and Pediatric Intensive Care Unit (PICU) admissions between the pre-implementation and post-implementation seasons, across participating regions; b) Association between seasonal nirsevimab coverage (range 0.0–1.0) and adjusted hospitalisation rate ratios across centres. Footnotes: Points represent observed rate ratios (2025 vs 2024) for each centre; the solid line indicates model-predicted rate ratios (RRs) from a negative binomial model, and the shaded area represents the 95% confidence interval (95% CI).

In our population, all-cause ED visits decreased from 5076 to 2633 (48% reduction); in adjusted analyses accounting for the local timing of universal prophylaxis, nirsevimab was associated with a relative risk (RR) of 0.178 corresponding to an estimated 82.2% reduction in healthcare utilisation between seasons.

All-cause pediatric wards (PW) admissions declined from 2734 to 1473 (48% reduction); when analysing the peak month of decline at each centre, occurring approximately two months after local initiation of nirsevimab prophylaxis, the mean reduction reached 71% (Appendix 5). In adjusted analyses, nirsevimab was associated with an RR of 0.159 (84.1% reduction).

Finally, PICU admissions decreased from 334 to 131 (61% reduction); in adjusted analyses, nirsevimab was associated with an RR of 0.204, corresponding to an estimated 79.6 in reduction in healthcare utilisation.

Regional prophylaxis strategies

Marked differences were observed according to the timing and recall strategies adopted by individual regions (Appendix 1).

The greatest reduction in all-cause hospitalisations (mean 84.5%) was observed in regions initiating prophylaxis from November with recall of infants born from April (Tuscany, Friuli-Venezia Giulia). Regions initiating prophylaxis in December or January with recall of infants born during the epidemic season reported substantial reductions in hospitalisations (up to 78%), including Marche, Umbria, Abruzzo, and Sardinia, although regional variability was observed.

Regions starting in November with recall from July or August showed a 73% reduction (Molise, Apulia, Campania), whereas those initiating in November with recall of infants born from January achieved a 68% reduction (Piedmont, Lombardia, Sicily). Regions beginning in December with recall of infants born from January showed a mean reduction of 63% (Lazio, Calabria, Liguria).

Demographic and clinical characteristics of hospitalised infants

A total of 2734 infants were hospitalised in the pre-implementation season compared with 1473 in the post-implementation season. In the pre-implementation season, most infants had not received prophylaxis (2649/2734, 97.4%), while 71 (2.6%) had received palivizumab. During the 2024–2025 season, 1062 of 1473 infants (72.0%) had not received prophylaxis, 39 (2.6%) had received palivizumab, and 372 (25.2%) had received nirsevimab.

The demographic characteristics of hospitalised infants with all-cause bronchiolitis were similar between seasons, with most patients being male, of Caucasian ethnicity, and born at term (Table 2). However, infants hospitalised in the post-implementation season were significantly older (aOR 1.066, 95% CI 1.036–1.096) (Table 3) (Appendix 6).

Table 2.

Demographic and clinical characteristics of the study population before and after propensity score matching.

	Before matching			After matching
	2023–2024	2024–2025	SMD	2023–2024	2024–2025	SMD
Total cases (TOT)	2734	1473	–
Complete cases (N/TOT, %)	1663 (60.8%)	1236 (84.0%)	–	1236 (100%)	1236 (100%)	–
Age (months; average, 95% CI)	3.8 (3.7; 4.0)	4.6 (4.5; 4.9)	0.259	4.7 (4.5; 4.9)	4.6 (4.5; 4.9)	0.013
Birth weight (kg; average, 95% CI)	3.2 (3.1; 3.2)	3.2 (3.1; 3.2)	0.051	3.2 (3.1; 3.2)	3.2 (3.1; 3.2)	0.010
Female sex (n/N, %)	791 (47.6%)	510 (41.6%)	0.060	503 (40.9%)	510 (41.6%)	0.023
Preterm (n/N, %)	218 (13.1%)	157 (12.0%)	0.005	165 (14.0%)	157 (12.0%)	0.030
Caucasian ethnicity (n/N, %)	1428 (85.9%)	1013 (82.7%)	0.001	1030 (83.7%)	1013 (82.7%)	0.034
Breastfeeding (n/N, %)	931 (56.0%)	677 (55.3%)	0.022	588 (47.8%)	677 (55.3%)	0.044
Maternal smoking (n/N, %)	45 (2.7%)	11 (0.9%)	0.015	24 (1.9%)	11 (0.9%)	0.001
Comorbidities (n/N, %)	219 (13.2%)	223 (18.0%)	0.026	211 (17.1%)	223 (18.0%)	0.026
Length of hospital stay (days; average, 95% CI)	5.9 (5.8; 6.1)	5.6 (5.3; 5.8)	0.027	5.4 (5.1; 5.6)	5.6 (5.3; 5.8)	0.040
Duration of oxygen therapy (days; average, 95% CI)	3.8 (3.6; 4.0)	3.0 (2.8; 3.2)	0.181	3.3 (3.1; 3.5)	3.0 (2.8; 3.2)	0.144
Need for low-flow oxygen therapy (n/N, %)	906 (54.5%)	561 (45.8%)	0.060	670 (54.4%)	561 (45.8%)	0.171
Need for high-flow oxygen therapy (n/N, %)	800 (48.1%)	480 (39.3%)	0.071	537 (43.7%)	480 (39.3%)	0.110
Prophylaxis with nirsevimab (n/N, %)	0 (−)	351 (28.7%)	0.863	0 (−)	351 (28.7%)	0.897

n = number of observations, N = number of complete cases, SMD = standardised mean difference.

Outcomes refer to all-cause bronchiolitis and are not restricted to RSV-confirmed infections. Bronchiolitis cases were identified using ICD-10 diagnostic codes J21.0, J21.1, J21.8, and J21.9.

Table 3.

Demographic and clinical characteristics of hospitalised infants with all-cause bronchiolitis in the pre- and post-implementation seasons, expressed as adjusted odds ratios with 95% confidence intervals.

	B (SE)	aOR	95%CI
Age (months)	0.06 (0.014)	1.066	1.036; 1.096
Sex (female)	0.104 (0.093)	1.110	0.924; 1.333
Ethnicity (Caucasian)	0.013 (0.127)	1.013	0.790; 1.298
Birth weight	−0.034 (0.036)	0.967	0.901; 1.038
Comorbidities (any)	−0.037 (0.138)	0.964	0.735; 1.263
Breastfeeding (ever)	0.138 (0.101)	1.147	0.942; 1.398
Length of hospital stay (days)	0.045 (0.017)	1.046	1.011; 1.082
Duration of O2 therapy (days)	−0.014 (0.026)	0.986	0.938; 1.037
Need for low-flow oxygen therapy	−0.398 (0.102)	0.672	0.550; 0.820
Need for high-flow oxygen therapy	−0.230 (0.129)	0.795	0.647; 0.994
RSV infection (as a single agent)	−0.778 (0.153)	0.745	0.569; 0.975
Coinfections	1.072 (0.189)	2.922	2.018; 4.231

B = regression coefficient, SE = standard error, aOR = adjusted odds ratio, CI = confidence intervals.

Outcomes refer to all-cause bronchiolitis. Cases were identified using ICD-10 diagnostic codes J21.0, J21.1, J21.8, and J21.9. Estimates were obtained from multivariable logistic regression models.

Among infants hospitalised with all-cause bronchiolitis, several markers of clinical severity improved between the two seasons (Table 3) (Appendix 7). The proportion of infants requiring low-flow oxygen decreased from 51.2% to 39.3% (aOR 0.672, 95% CI 0.550–0.820) and the proportion requiring high-flow oxygen decreased from 49.3% to 39.0% (aOR 0.795; 95% CI 0.647–0.994), indicating an overall reduction in clinical severity.

In our cohort, length of hospital stays (mean 5.9 days, CI 95% 5.8–8.1 vs 5.6 days, CI 95% 5.3–5.8; SMD 0.03) and duration of oxygen therapy (3.8 days, CI 95% 3.6–4.0 vs 3.0 days, CI 95% 2.8–3.2; SMD 0.181) decreased between seasons. After matching, no significant differences were observed in the duration of oxygen therapy, whereas length of hospital stays increased in post-implementation cohort.

Viral detection

Despite the introduction of nirsevimab, RSV remained the leading etiological agent in both seasons, although its relative frequency declined significantly after prophylaxis implementation, from 75% (2031/2734 cases) to 63.4% (934/1473 cases) after implementation (p < 0.001) (Table 4).

Table 4.

Respiratory viruses detected among infants hospitalised with all-cause bronchiolitis.

	2023–24	2024–25	p-value
Respiratory Syncytial Virus (n, %)
Detected alone	1650 (61%)	727 (49.3%)
In coinfection	381 (14.0%)	207 (14.0%)
Total	2031 (75.0%)	934 (63.4%)	<0.001
Influenza A/B (n, %)
Detected alone	20 (0.7%)	32 (2.2%)
In coinfection	6 (0.2%)	7 (0.5%)
Total	26 (1.0%)	39 (2.6%)	<0.001
Rhinovirus (n, %)
Detected alone	123 (4.5%)	103 (7.0%)
In coinfection	44 (1.6%)	52 (3.5%)
Total	167 (6.1%)	155 (10.5%)	<0.001
Metapneumovirus (n, %)
Detected alone	47 (1.7%)	36 (2.4%)
In coinfection	17 (0.6%)	18 (1.2%)
Total	64 (2.3%)	54 (3.7%)	0.003
Bocavirus (n, %)
Detected alone	2 (0.1%)	2 (0.1%)
In coinfection	4 (0.1%)	0 (0.0%)
Total	6 (0.2%)	2 (0.1%)	0.33
Parainfluenza (n, %)
Detected alone	14 (0.5%)	11 (0.7%)
In coinfection	6 (0.2%)	3 (0.2%)
Total	20 (0.7%)	14 (1.0%)	0.18
Sars-CoV-2 (n, %)
Detected alone	19 (0.7%)	4 (0.3%)
In coinfection	3 (0.1%)	1 (0.1%)
Total	27 (0.9%)	21 (1.4%)	0.07
Others (n, %)
Total	24 (0.9%)	20 (1.4%)	0.06
Negative or not performed test (n, %)
Total	347 (12.7%)	229 (15.5%)	0.03
Total (n)	2734	1473

n = number of observations.

Virological testing was performed as part of routine clinical care using multiplex PCR assays for respiratory viruses. Outcomes refer to all-cause bronchiolitis. Cases were identified using ICD-10 diagnostic codes J21.0, J21.1, J21.8, and J21.9.

In our population, all regions showed a reduction in RSV prevalence except Abruzzo, where a 16% increase was observed. In parallel, the proportion of non-RSV respiratory viruses among hospitalised cases increased, including influenza (1.0%, 26/2734 vs 2.6%, 39/1473; +1.6%), rhinovirus (6.1%, 167/2734 vs 10.5%, 155/1473; +4.4%), metapneumovirus (2.3%, 64/2734 vs 3.7%, 54/1473; +1.4%). Viral co-infections also increased in the post-implementation season (OR 2.999, 95% IC 2.018; 4.231).

Among the 372 infants hospitalised despite receiving nirsevimab prophylaxis, 168 (44%) tested positive for RSV, 134 (36%) for non-RSV respiratory viruses, and 70 (18%) had no identifiable pathogen. Among the 168 RSV-positive infants hospitalised despite prophylaxis, the majority were male and younger, compared with the RSV-positive group that had not received prophylaxis. However, they exhibited a significantly higher rate of comorbidities (+11.0%, 82/745 vs 37/168, p < 0.001), particularly prematurity (+4.1%, 22/745 vs 12/168, p < 0.001) and congenital heart diseases (+2.5%, 13/745 vs 7/168, p < 0.05) (Appendix 8).

Discussion

This multicentre study provides nationwide real-world evidence of the population-level impact of the first national season of nirsevimab prophylaxis on all-cause bronchiolitis-related healthcare utilisation in Italy. Across 30 university hospitals, representative of 15 of 20 Italian regions, we observed a marked reduction in all-cause ED visits, PW admissions, and PICU admissions during the post-implementation season compared with the previous epidemic period.

Although similar reductions have been reported in international real-world studies conducted after the introduction of nirsevimab, potential confounders must be considered, including seasonal variability in viral circulation, and possible modifications in hospital admission practices. Some reductions in bronchiolitis-related hospitalisations were also observed in individual hospitals before the local start of prophylaxis, likely reflecting natural inter-seasonal variability in bronchiolitis epidemics rather than an effect of the intervention. Nevertheless, recent multicentre studies have described similar seasonal patterns of bronchiolitis hospitalisations in the years immediately preceding nirsevimab implementation, supporting the use of the most recent pre-intervention season as a pragmatic baseline comparator.²⁸ The consistency of reductions across centres following programme implementation supports a substantial contribution of prophylaxis to the observed trends; however, the observational design of the study precludes causal inference, and residual confounding cannot be excluded.

The overall reduction rate in our study was lower than those reported in clinical trials and some national studies.⁹ This difference is likely attributable to the heterogeneous timing of prophylaxis implementation across Italian regions, where campaigns began between October and January. In analyses adjusted for the local timing of universal prophylaxis, nirsevimab was associated with reduction of 82.2% in ED visits (RR 0.18), 84.1% in PW admissions (RR 0.16) and 79.6% in PICU admissions (RR 0.20). Moreover, when analysing peak reductions in hospitalisations the mean reduction in all-cause hospital admissions reached 71%, an impact broadly comparable to the efficacy observed in randomised trials such as MELODY³ and HARMONIE⁴ and with findings from other international real-world experiences. For example, during the first season of implementation, nirsevimab prophylaxis was associated with reductions in RSV-related hospitalisations ranging between 70% and 80% in both France⁵ and Spain,²⁹ and with reductions of up to 90% in USA.³⁰

The reduction in all-cause hospitalisations differed across regions, suggesting that the population-level impact of nirsevimab programmes is strongly influenced by the timing and organisation of prophylaxis implementation (Appendix 1 and 5). Regions that implemented nirsevimab administration earlier experienced a more rapid decline in admissions, whereas those with delayed rollout showed smaller reductions or, in the case of Abruzzo, an increase in RSV-related admissions, highlighting the importance of timely and coordinated implementation strategies. However, the present analysis was not designed to formally evaluate this relationship, and these observations should therefore be interpreted cautiously. The increase observed in Abruzzo may reflect local differences in implementation strategies, including the relatively late initiation of nirsevimab administration for infants born during the epidemic season (January 2025), potentially lower immunisation coverage, or natural inter-seasonal variability in viral circulation.

Moreover, marked differences were observed in recall strategies across regions. These strategies were not uniform and depended on the organisational capacity of each regional programme to identify and actively contact infants born before programme initiation. In our cohort, regions initiating prophylaxis in November and recalling infants born from April (Tuscany, Friuli-Venezia Giulia) showed greater reductions in all-cause hospitalisations (mean 84.5%) compared with regions that recalled infants only back to January (mean 68%). These findings suggest that differences in the effectiveness of recall strategies may have influenced the proportion of infants effectively protected, despite similar implementation dates.

Immunisation coverage is likely to be an important determinant of the population-level impact of nirsevimab implementation. Regional differences in coverage may partly explain the heterogeneity in reductions observed across centres, consistent with multinational evidence showing greater reductions in respiratory disease–related healthcare use at higher coverage levels.³¹ However, in Italy, data on immunisation coverage were not uniformly available at the regional or national level. To account for this limitation, proxy variables reflecting timing of implementation and population at risk were included as covariates in a Poisson regression models in our analysis, allowing partial adjustment for regional differences in exposure to prophylaxis.

In our cohort, a total of 1473 infants were hospitalised for all-cause bronchiolitis during the post implementation season. Of these, 1062 (72%) had not received any prophylaxis, while 372 (25.2%) had previously received nirsevimab. The demographic characteristics of hospitalised patients with all-cause bronchiolitis were similar between the two seasons; however, in the post-implementation period, we observed a significant increase in age at admission. This finding has also been reported in other national studies worldwide and in regional reports from Italy.^32,33 In Italy, this trend may be explained by the immunisation strategies implemented during the 2024–25 season: in all regions, neonates born during the epidemic season were immunised at birth in maternity wards, whereas infants born out of RSV season and younger than 100 days were immunised by their primary care pediatricians. This latter approach was less systematic and resulted in gaps in immunisation coverage between these groups.

Consistently, several markers of clinical severity improved after nirsevimab implementation. During the 2023–24 season, infants hospitalised required low- and high-flow oxygen therapy significantly more frequently and for longer durations than those hospitalised in the post-implementation season. This observation supports the notion that widespread administration of nirsevimab not only reduces case numbers but may also modulates clinical severity contributing to a shift in the clinical profile of hospitalised infants.

Notably, our study is among the first to report that, among patients requiring hospitalisation despite receiving the long-acting mAb, the prevalence of comorbidities was significantly higher compared with those who had not received prophylaxis. Specifically, in our study, among the 168 infants hospitalised for RSV bronchiolitis despite having received nirsevimab, we observed a higher prevalence of underlying conditions, including prematurity and congenital heart diseases, although the small numbers observed for some conditions require cautious interpretation. Our findings are consistent with recent evidence suggesting that the effectiveness of nirsevimab may be lower in infants with underlying risk factors compared with healthy term infants and that these conditions may represent important individual risk factors for hospitalisation, possibly reflecting the fact that prophylaxis reduces the risk of severe RSV disease but does not necessarily prevent infection.^34,35 However, this observation should also be interpreted in the context of potential differences in hospitalisation practices across regions, as admission thresholds for bronchiolitis may vary according to patients’ underlying conditions and comorbidities. These findings highlight the need for continued surveillance and for potentially targeted preventive strategies in vulnerable groups, potentially including enhanced prevention measures and tailored pharmacological approaches for infants with significant comorbidities. In addition, the development of other long-acting monoclonal antibodies, such as clesrovimab, further highlights the rapidly evolving landscape of RSV prevention, which may influence future implementation strategies and policy decisions.

From an etiological perspective, despite the decline in absolute RSV-related cases following the introduction of nirsevimab prophylaxis, RSV remained the most frequently detected virus. This was accompanied by an increase in the detection of non-RSV respiratory viruses. However, this result should be interpreted cautiously, as the higher proportion of non-RSV viruses may partly reflect the proportional change in viral distribution rather than true viral replacement. When absolute numbers of hospitalised cases are considered, most respiratory viruses did not increase in frequency between seasons, except for Influenza A. Moreover, nirsevimab is not expected to provide sterilising immunity or substantially alter viral circulation at the population level. These findings are reassuring and suggest that no clear shift in viral circulation occurred during the study period.

Finally, our study also documented a significant increase in viral co-infections. Co-infections may suggest a potential decrease in RSV virulence, requiring the presence of other viruses to trigger bronchiolitis, or could reflect viral interference phenomena. Such findings align with emerging reports and warrant close surveillance in subsequent epidemic seasons.³⁶

This study has limitations. Its retrospective design and the inclusion of only hospitals affiliated with pediatric residency programmes limit national representativeness, particularly as four regions lacked eligible hospitals and one declined participation. Second, the study was not designed as a population-based national surveillance analysis; data were collected from major paediatric referral centres affiliated with residency programmes, and outcomes from non-participating hospitals may not have been captured. Third, the analysis compared the post-implementation season with a single pre-intervention baseline; although multiple historical seasons or time-series analyses would be preferable, consistent multi-year datasets were not uniformly available across centres because data were retrieved from local hospital databases rather than centralised surveillance systems. Moreover, diagnostic practices for RSV varied across centres in earlier seasons, which would have introduced additional heterogeneity and potential selection bias if a longer observation period had been considered.

Hospitalisation rates could not be reliably estimated, as participating centres do not have clearly defined catchment populations and denominator data were not uniformly available; therefore, absolute counts were used as a pragmatic measure of temporal change within centres. The comparison was conducted within the same network of centres, characterised by stable catchment areas, similar admission criteria, and consistent data collection procedures across the two seasons, supporting the use of raw counts as a proxy for temporal changes. The observed reductions were consistent across centres and of a magnitude unlikely to be explained by random inter-seasonal fluctuation.

Furthermore, data on individual or regional immunisation coverage were not available and proxy measures were used, so residual confounding related to differential uptake of prophylaxis cannot be excluded. Variability in clinical management and admission criteria across hospitals may also have influenced the results. Finally, maternal vaccination was not analysed because uptake during the study period was negligible in Italy.

Conclusions

In conclusion, the first national season of nirsevimab prophylaxis in Italy was associated with a substantial reduction in all-cause bronchiolitis-related healthcare utilisation and clinical severity. However, heterogeneous regional implementation limited the full potential impact of this strategy. These findings highlight the importance of systematic, timely, and equitable implementation of RSV immunisation programmes to maximise the population-level impact of prophylaxis strategies, as well as the need for targeted protection of infants with underlying comorbidities, and continued surveillance of evolving viral epidemiology.

Representativeness of the study population

The study population consisted of consecutively enrolled infants younger than 12 months admitted for bronchiolitis in participating centres, providing a pragmatic representation of hospitalised cases within tertiary care settings, although not fully representative at the population level.

In our study, ethnicity was recorded across centres as a categorical variable (Caucasian vs non-Caucasian), based on routinely collected clinical information. However, given the simplified nature of this classification, these data should be interpreted with caution. Ethnicity is a sociocultural construct rather than a biological trait, and residual confounding from unmeasured socioeconomic and structural determinants of health cannot be excluded. Within this framework, our findings are presented using a strengths-based perspective, highlighting opportunities to improve equitable access to preventive strategies and reduce disparities in respiratory health outcomes.

Contributors

MS and FM conceived and designed the study, performed the literature search, contributed to writing the manuscript, prepared the figures, and conducted data interpretation, and supervision.

MR and EB contributed to data analysis, methodology, and interpretation.

MS, GDF, LS, AA, GM, FC, MM, LR, SC, GL, FF, SA, MA, SP, MP, AF, FCa, AB, LA, MC, GC, MPa, FB, GB, MDF, AD, FDP, MT, LT, DLR, and AA collected the data.

MS, FM, AC, RN, LR, GT, MB, FR, SB, ACa, GF, GL, GC, LI, AM, FG, GV, DC, AA, EZ, FA, SB, LM, GS, MR, FCa, FB, AB, ML, LB, DB, FP, RC, AC, CF, FG, LP, MP, MF, and AA contributed to data interpretation, manuscript revision, and supervision.

MS, FM, MR, EB, AC, AP, AD, EF, MGC, EM, LP, and MM contributed to revising the manuscript in response to reviewers’ comments.

All authors had full access to data in the study, verified them, and take responsibility for the decision to submit the manuscript for publication.

Data sharing statement

Individual participant data collected for this study cannot be made publicly available due to ethical constraints, patient confidentiality, and compliance with national and institutional data protection regulations. The study is based on retrospective data extracted from medical records across multiple centres under ethics approvals that do not permit data sharing outside the participating institutions. No additional data are available.

Declaration of interests

The authors declare no conflicts of interest related to the present manuscript.

FM, MR, and FFg report having received, within the past 36 months: consulting fees; payments or honoraria for lectures/presentations/speakers’ bureaus/manuscript writing/or educational events; support for attending meetings/travel; and participation on data safety monitoring boards/advisory boards.