Short‐ and mid‐term morbidity and primary‐care burden due to infant respiratory syncytial virus infection: A Spanish 6‐year population‐based longitudinal study

Pediatr Allergy Immunol. 2024;35:e14131.   | 1 of 12 https://doi.org/10.1111/pai.14131 wileyonlinelibrary.com/journal/pai Received:13January2024 | Revised:5April2024 | Accepted:8April2024 DOI: 10.1111/pai.14131 ORIGINAL ARTICLE Shortand midterm morbidity and primarycare burden due to infant respiratory syncytial virus infection: A Spanish 6year populationbased longitudinal study Sonia AresGómez1,2,3 | Narmeen Mallah1,2,4,5 | Jacobo PardoSeco1,2,3,6 | Alberto MalvarPintos7 | Olaia PérezMartínez7 | MaríaTeresa OteroBarrós7 | Nuria SúarezGaiche7 | MariaIsolina SantiagoPérez7 | JuanManuel GonzálezPérez8 | LuisRicardo LópezPérez8 | Benigno Rosón8 | RosaMaría AlvárezGil9 | OlgaMaría CesOzores9 | Victoria NartalloPenas9 | Susana MirásCarballal9 | Carmen RodríguezTenreiro1,2,3 | Irene RiveroCalle1,2,3,10 | Antonio Salas1,3,6,11 | Carmen DuránParrondo12 | Federico MartinónTorres1,2,3,10 1Genetics, Vaccines and Pediatric Infectious Diseases Research Group (GENVIP), Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Galicia, Spain 2WHO Collaborating Centre for Vaccine Safety, Santiago de Compostela, Spain 3Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain 4Department of Preventive Medicine, University of Santiago de Compostela (USC), Santiago de Compostela, Spain 5Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain 6Genética de Poblaciones en Biomedicina (GenPoB) Research Group, Instituto de Investigación Sanitaria (IDIS), 15706 Hospital Clínico Universitario de Santiago(SERGAS),SantiagodeCompostela,Galicia,Spain 7Department of Epidemiology, Dirección Xeral de Saude Pública, Consellería de Sanidade, Xunta de Galicia, Santiago de Compostela, Galicia, Spain 8Subdirección de Sistemas y Tecnologías de la Información, Consellería de Sanidade, Xunta de Galicia, Santiago de Compostela, Galicia, Spain 9Deparment of Communicable Diseases, Dirección Xeral de Saude Pública, Consellería de Sanidade, Xunta de Galicia, Santiago de Compostela, Galicia, Spain 10Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario and University of Santiago de Compostela (USC), Santiago de Compostela, Spain 11Unidade de Xenética, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Galicia, Spain 12Dirección Xeral de Saude Pública, Consellería de Sanidade, Xunta de Galicia, Santiago de Compostela, Galicia, Spain This is an open access article under the terms of the CreativeCommonsAttribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. ©2024TheAuthors.Pediatric Allergy and ImmunologypublishedbyEuropeanAcademyofAllergyandClinicalImmunologyandJohnWiley&SonsLtd. SoniaAres-GómezandNarmeenMallahcontributedequallytothiswork. Correspondence Federico MartinónTorres, Hospital Clínico Universitario de Santiago de Compostela, AChoupanas.n.,15701Santiagode Compostela, Spain. Email: federico.martin[email protected] Funding information Instituto de Salud Carlos III; Sanofi; AxenciaGalegadeInnovación;European Abstract Background: Themorbidityburdenofrespiratorysyncytialvirus(RSV)ininfantsextendsbeyondhospitalization.DefiningtheRSVburdenbeforeimplementingprophylaxisprogramsisessentialforevaluatinganypotentialimpactonshort-tomid-term morbidityandtheutilizationofprimaryhealthcare(PHC)andemergencyservices (ES). We established this reference data using a populationbased cohort approach. 2 of 12 | ARES-GÓMEZ et al. 1 | INTRODUCTION Respiratory Syncytial Virus (RSV) infection stands as the primary pathogenassociatedwithglobalhospitalizationsforlowerrespiratory tract infections (LRTI) in children.1,2 The most significant RSV burden is observed in young infants, with a global estimate of 6.6 million episodes of acute LRTI associated with RSV in infants aged 0–6 months.3Furthermore,3.6%ofdeathsininfantsaged28 daysto sixmonthsareattributedtoRSV.3 In the European Union, from 2006 to2018,nearly250,000annualhospitalizationswerelinkedtoRSV infections in children under five, with 75% of these cases occurring in infants under one year.4 In Spain, two out of every 100 children undertwoyearsofagearehospitalizedforRSV,averagingsixdays stay, and resulting in an estimated annual cost of €49.6 million to the Regional Development Fund; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias Editor: Ömer Kalayci Methods: Infants hospitalized for RSV from January 2016 to March 2023 were matched with non-hospitalized ones based on birthdate and sex. We defined the exposureassevereRSVhospitalization.Themainstudyoutcomeswereasfollows: (1)PHCandESvisitsforRSV,categorizedusingtheInternationalClassificationof Primary Care codes, (2) prescriptions for respiratory airway obstructive disease, and (3)antibacterialprescriptions.Participantswerefollowedupfrom30 daysbeforehospitalizationforsevereRSVuntiltheoutcomeoccurrenceorendofthestudy.Adjusted incidence rate ratios (IRRs) of the outcomes along with their 95% confidence intervals (CI) were estimated using Poisson regression models. Stratified analyses by type of PHC visit (nurse, pediatrician, or pharmacy) and followup period were undertaken. Wedefinedmid-termoutcomesasthosetakingplaceupto24 monthsoffollow-up period. Results: The study included 6626 children (3313 RSV-hospitalized; 3313 non- hospitalized) with a median follow-up of 53.7 months (IQR = 27.9, 69.4). After a 3- month followup, severe RSV was associated with a considerable increase in PHC visitsforwheezing/asthma(IRR = 4.31,95%CI:3.84–4.84),lowerrespiratoryinfections(IRR = 4.91,95%CI:4.34–5.58),andbronchiolitis(IRR = 4.68,95%CI:2.93–7.65). SevereRSVwasalsoassociatedwithmorePHCvisitsforthepediatrician(IRR = 2.00, 95% CI: 1.96–2.05), nurse (IRR = 1.89, 95% CI: 1.75–1.92), hospital emergency (IRR = 2.39, 95%CI: 2.17–2.63), primaryhealthcare emergency(IRR:1.54,95%CI: 1.31–1.82),aswellaswithimportantincreaseinprescriptionsforobstructiveairway diseases(IRR = 5.98,95%CI:5.43–6.60)andantibacterials(IRR = 4.02,95%CI:3.38– 4.81).Allfindingsremainedsubstantialuntil2 yearsofpost-infection. Conclusions: Severe RSV infection in infants significantly increases shortto midtermrespiratorymorbidityleadingtoanescalationinhealthcareutilization(PHC/ES attendance)andmedicationprescriptionsforupto2 yearsafterward.Ourapproach could be useful in assessing the impact and costeffectiveness of RSV prevention programs. KEYWORDS asthma,hospitalizations,infants,primaryhealthcare,respiratorysyncytialvirus,Spain,viral bronchiolitis Key message We provided an approach for a comprehensive assessment ofrespiratorysyncytialvirus(RSV)ininfantsthatextends beyond hospitalization. Through a six-year population- based longitudinal study, we showed that severe RSV infection in infants significantly increases shortand midterm morbidity leading to an escalation in primary healthcareutilizationandmedicationprescriptionsforuptotwo yearsafterhospitalizationforsevereRSV.Ourstudycould be useful in assessing the impact and costeffectiveness of RSV prevention programs. 13993038, 2024, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pai.14131 by Consorcio Interuniversitario Do Sistema Universitario De Galicia (Cisug), Wiley Online Library on [09/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | 3 of 12 ARES-GÓMEZ et al. National Health System.5,6 Most RSVrelated episodes (93.1%) occur inchildrenwithoutanycomorbidity,andapproximately27%ofthe totaldirecthealthcareexpensesareunrelatedtohospitalizations.7 TheeconomicandhealthimpactofRSVextendsbeyondtheacute episode. Children with a history of RSV infections are up to three timesmorelikelytodeveloprecurrentwheezingepisodesthanthose without such a history.8AnassociationbetweenRSVinfectioninearly years and the onset of childhood asthma has also been reported.9,10 Adouble-blindclinicaltrialinvestigatingtheimpactofamonoclonal antibodyagainstRSVontheoccurrenceofwheezingdaysduringthe firstyearofliferevealeda61%reductioninwheezingdays,thereby providing compelling evidence for a causal relationship.11 Recently, both a longacting monoclonal antibody and a maternalvaccinehavebeenapprovedinEuropeforRSVprophylaxisin infants.12–14 Galicia, an autonomous community with a 2.7 million population in Northwest Spain, became the world's first region to introducenirsevimabaspartofthe2023regionalimmunizationprogram (IP).15,16 Recommended actions toward effective RSV immunizationpoliciesencompassestimatingtheRSVburdeninspecific populations.17 From 2017 to 2023 (excluding COVID-19 seasons, 2019–2021), the infant RSV hospitalization rate per season in Galicia, Spain, ranged between 3.34 and 5.03 hospital admissions per 100,000 inhabitants.18 As part of the burden assessment and effort to establish the background burden of RSV in primary care/emergency care utilizationandmedicationuse,thisretrospectivepopulation-basedfollowup study was initiated in collaboration with the Galician General Directorate of Public Health. Hereby, we provide a detailed analysis oftheassociationofsevereRSVinfectionsacquiredduringthefirst year of life with the need for physician consultation, nurse visits, emergency department visits, and medical prescriptions for respiratory symptoms. We also report on the association of severe RSV infections with the subsequent development of clinical episodes ofmid-termrespiratorymorbidity,definedasupto2 yearsoffollowup. This approach could prove useful in settings like ours to assesstheneedforandevaluatetheeffectivenessofimmunization strategies against RSV. 2 | METHODS 2.1 | Study design and population Aretrospectivepopulation-basedcohortstudywasundertakenin Galicia, Northwest Spain, using registry data of children born between January 1st, 2016, and March 3rd, 2023, inclusive. Galicia, withapproximately2.7millioninhabitants,recorded14,479birthsin 2022, with 5.5 and 5.4 births per 1000 persons in 2021 and 2022, respectively.19 The population was divided into two groups based on their exposure to RSV infection that required hospitalization within 30 days(hospitalized vs.non-hospitalized).Data on hospitalized children for RSV during infancy were obtained from the Minimum Basic Data Set (MBDS) hospital registries. Hospitalizations for RSV were considered if any of the following international classification of diseases (ICD10) codes were present at any position inthedischargediagnosis:J21.0(Acutebronchiolitisduetorespiratorysyncytialvirus),J20.5(Acutebronchitisduetorespiratory syncytial virus), J12.1 (Respiratory syncytial virus pneumonia), or B97.4 (Respiratory syncytial virus as the cause of diseases classified elsewhere). Data on non-hospitalized children were obtained from the Galician registry of children with public health assistance (Health Card). Matchingofhospitalizedandnon-hospitalizedinfantsona1:1 ratio was done by the day of birth to control for changes in RSV seasonality, virus epidemiology, and diagnosis. Participants were alsomatchedbysexforbiologicalplausibility.Inthecaseofthe multiple matching option, the one with the lowest number on the health card was chosen. To ensure comparability, all participants had approximately 100% compliance in the first year of life in the pediatric control, as per prescheduled visits outlined in the Healthy Child regional program in Galicia (named “Programa do Neno San”).20 2.2 | Data AlldatarequiredfortheanalysiswereextractedfromtheGalician Health Care Services (SERGAS) electronic registries, including (MBDS) hospital registries, Galician registry HC card, Primary Health Care (PHC), Emergency services (ES), and Medication Prescriptions (MP).Anonymizeddatafromtheseregistrieswereobtainedforeach participant from the day of birth until June 16th, 2023. 2.3 | Outcomes The main study outcomes encompassed PHC and ES visits, along with medication prescriptions from the initiation of the followup period. These outcomes are detailed below: 2.3.1 | Primaryhealthcare(PHC) Visits at demand to the pediatrician, nurse, pharmacy, and social worker Datafromvisitstothepediatrician,nurse,andpharmacywereextractedfromthePHCrecordsatSERGAS.Examinationofvisitsto the social worker aimed to identify potential disparities in social status between the two groups. PHC episodes Episodes related to respiratory sequelae associated with severe RSV infections were categorized using the International Classification of Primary Care (ICPC2) codes, following the 13993038, 2024, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pai.14131 by Consorcio Interuniversitario Do Sistema Universitario De Galicia (Cisug), Wiley Online Library on [09/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 4 of 12 | ARES-GÓMEZ et al. adaptedSpanishversion(CIAP-2).21 Individual outcomes encompassed various respiratory conditions, including Otitis media/acute myringitis (H71), Respiratory fatigue/dyspnea (R02), Gasping/ wheezing (R03), Other breathing problems (R04), Cough (R05), Sneezing/stuffy nose (R07), Other nasal signs/symptoms (R08), Upper acute respiratory infection (R74), Acute tonsillitis (R76), Acute laryngitis/tracheitis (R77), Acute Bronchitis/bronchiolitis (R78,subdividedintoR78.00forbronchitisandR78.01foracute bronchiolitis),andInfluenza/flu(R80). Composite outcomes were created to capture broader patternsof RSVmorbidity,including Wheezing/Asthma(R02, R03, R04,R05,R78.00,R78.01,R79,R95,R96),LRTI(R02,R03,R04, R78,R78.00,R78.01,R79,R81.00,R81.01,R81.02,R81.03,R82), Acute LRTI (H71, R71, R72, R74, R75, R76, R77, R78, R78.00, R78.01,R80,R81.00,R81.01,R81.02,R81.03,R82,R83),Upper Respiratory Infections (H01, H02, H04, H29, H70, H71, H72, H74, R05,R07,R08,R09,R21,R25,R72,R74,R75,R76,R77),Allotitis (H01, H02, H04, H29, H70, H71, H72, and H74), and Otitis media (H71, H72, and H74). 2.3.2 | EmergencyService(ES)visits ESvisitswereanalyzedbyconsideringeachofthetotalnumberof ES visits to primary care ES (PCE) and hospital ES (HE), separately. 2.3.3 | Prescriptionofmedications Prescriptions of medications were extracted from digitalized and centralizedmedicalprescriptionsanddispensations.Eachprescriptionislinkedtoapatient'suniqueidentificationnumberatSERGAS. Prescriptionswereanalyzedasthenumberofepisodiceventswith prescriptionofantibacterials(ATCcodeJ01comprisesantibacterials forsystemicuse,exceptantimycobacterials,whichareclassifiedin J04)ordrugsforobstructiveairwaydiseases(ATCcodeR03include: R03AAdrenergics,inhalants,R03BOtherdrugsforobstructiveairwaydiseases,inhalants,R03CAdrenergicsforsystemicuse,R03D Other systemic drugs for obstructive airway diseases). 2.4 | Followup period Alloutcomes wereexaminedacrossfivetimesintervals,withthe startingpointsetupto30 daysbeforehospitalizationforRSV.Given thatallthehospitalizedparticipantswerematchedbybirthdaytoa non-hospitalizedchild,thetime0fortheinitiationoftheobservation wasestablishedasthehospitalizationdayalsofortheircorrespondingmatch,ensuringanequivalentobservationperiod.Becauseeach hospitalizedparticipantwasmatched1:1toanon-hospitalizedchild bytheexactdayofbirth,weobtainedthesamefollow-upinboth groups. In addition, with this approach, we were able to follow each pairofchildrenthesamedaysbeforeandafterthehospitalization date.Thefivefollow-upintervalswereasfollows:30 daysbefore hospitalization until the day before hospital admission (−30 to −1 days),fromhospitaladmissionto89 daysafterhospitalization(0 to89 days),from90 daysto364 days yearafterhospitalization(90 to 364 days), from 365 to 729 days after hospitalizations (365 to 729 days),andfrom730 daysafterhospitalizationtilltheendofthe study,June 16th, 2023(≥730 days).Cumulative follow-up periods were also considered (30 days before hospitalization until 89 days [−30 to 89 days], from 30 days before hospitalization until 1 year afterhospitalization[−30to364 days],from30 daysbeforehospitalization until 2 years after hospitalization [−30 to 729 days], and 30 daysbeforehospitalizationtilltheendofstudy[−30 daystillthe endofstudy]). 2.5 | Statistical analysis To determine the association of severe RSV with each of the study outcomes, an independent Poisson regression model was employedforeachoutcomeofinterest.Countdatawereanalyzed, and to address overdispersion, robust variance through the sandwichmethodwasutilized.22 Incidence rate ratios (IRR) and their 95% confidence intervals (CI) were estimated, adjusting for the number of visits to the Healthy Child regional program to account forpossibleconfounding.AllanalyseswereperformedinRversion 4.3.1. 3 | RESULTS 3.1 | General study population characteristics Atotalof3313childrenhospitalizedforRSVduringinfancywere registeredoversevenRSVseasons(2016–2017,2017–2018,2018– 2019, 2019–2020, 2020–2021, 2021–2022, 2022–2023). The medianfollow-upwas53.7 months(InterquartilerangeIQR = 27.9,69.4) withamedianageof75 days(IQR = 40,106.4)athospitalization.The annualdistributionofhospitalizationswasasfollows:2016(n = 551), 2017 (n = 451),2018(n = 366),2019(n = 642),2020(n = 247),2021 (n = 395),2022(n = 606),and2023(n = 55).Throughoutthestudyperiod, the median and range of pediatrician visits, as per the Healthy Childregionalprogram'sprescheduledvisits,were20(IQR:14–25) forhospitalizedinfantsand15(IQR:2–22)fornon-hospitalizedones. 3.2 | RSV severe infection during infancy and primary healthcare (PHC) utilization 3.2.1 | Visitsatdemandtothepediatrician,nurse, pharmacy, and social worker Theriskofrequiringavisittothepediatricianininfantswhohad beenhospitalizedforRSVdoublesthatofnon-hospitalizedinfants 13993038, 2024, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pai.14131 by Consorcio Interuniversitario Do Sistema Universitario De Galicia (Cisug), Wiley Online Library on [09/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | 5 of 12 ARES-GÓMEZ et al. duringthemonthbeforehospitalization(−30to−1 days,IRR = 2.15 [95%CI:2.07–2.23])aswellasinthefirst3 monthsafterhospitalization(0to89 days,IRR = 2.00[95%CI:1.96–2.05]).Theneedfor pediatrician visits on demand gradually declines with time after RSV hospitalization, but it remains higher in RSV-hospitalized infants thaninnon-hospitalizedonesuntiltheendofthestudy(≥730 days IRR = 1.10[95%CI:1.09–1.12])(Table 1). Similarly, severe RSV infection during infancy is associated with almosttwicetheriskofdemandinganursevisituntil3 monthsafter hospitalization (−30 to −1 days, IRR = 1.94 [95% CI: 1.81–2.08]; 0 to89 days,IRR = 1.83[95%CI:1.75–1.92]).ThenursevisitsondemandremainhigherinRSV-hospitalizedinfantsthaninthosewho werenothospitalizedforRSVuntiltheendofthestudy(≥730 days, IRR = 1.17[95%CI:1.14–1.21]),yetthemagnitudeofthedemanded visits decreased with time (Table 1). Inthe30 daysbeforehospitalizationforsevereRSV,theriskof visitingthepharmacyissubstantiallyhigherinRSV-hospitalized infantsthaninnon-hospitalizedones(−30to−1 days,IRR = 2.67 [95% CI: 1.74–4.21]), yet the association weakens right after hospitalization,reachingborderlineuntilthefirstyearafterhospitalization (0 to 89 days, IRR = 1.28 [95% CI: 1.01–1.64], 90 to 364 days,IRR = 1.29[95%CI:1.06–1.58]),thenlosingitsstatistical significance after that period (Table 1). RSVhospitalizationwasnotassociatedwithincreasedvisitsto the social worker at any moment after infection (Table 1). Table S1summarizestheassociationofsevereRSVwithvisitsat demand to the pediatrician, nurse, pharmacy, and social worker for cumulative followup timeframes. 3.2.2 | Primaryhealthcare(PHC)episodes Figure 1 and Table S2 represent the association of severe RSV infections during infancy with individual and composite respiratoryepisodes,characterizedbasedonCIAP-2codes.Until2023, bronchiolitisepisodeswereclassifiedundertheCIAP-2code(R78) which included both bronchitis and bronchiolitis episodes. In 2023,CIAP-2codificationincorporatedtheR78.01codewhichallows for a more precise classification of bronchiolitis. The associationofsevereRSVwiththeoccurrenceofsubsequentrespiratory episodeswasmostprominentintheinitial3 monthsfollowinghospitalizationforR78(0to89 days,IRR = 5.01[95%CI:4.38–5.75]) TABLE 1 Incidencerateratio(IRR)and95%confidenceinterval(CI)ofon-demandprimarycarevisitsininfantscomparedtonon-RSV- hospitalizedchildren. Followup time (days) Outcome Hospitalized (N = 3313) Not hospitalized (N = 3313) IRR (95% CI)% (N)Mean (SD) % (N)Mean (SD) −30to−1 Pediatrician 71.1% (2356) 3.1 (3.2) 34.0% (1126) 1.2 (2.2) 2.15 (2.07–2.23) Nurse 30.5% (1012) 0.9 (1.6) 14.4% (477) 0.4 (1.1) 1.94(1.81–2.08) Pharmacy 0.9% (30) 0.0 (0.3) 0.4% (12) 0.0 (0.2) 2.67 (1.74–4.21) Social worker 0.4% (14) 0.0 (0.1) 0.5% (16) 0.0 (0.2) 0.67 (0.41–1.10) 0to89 Pediatrician 91.8%(3040) 9.1 (7.2) 57.3%(1899) 3.8(5.1) 2.00 (1.96–2.05) Nurse 49.5% (1640) 1.8(2.6) 27.5% (911) 0.9(1.8) 1.83(1.75–1.92) Pharmacy 1.9% (63) 0.1 (0.4) 1.0% (33) 0.0 (0.4) 1.28(1.01–1.64) Social worker 1.0% (32) 0.0 (0.3) 0.7% (23) 0.0 (0.2) 1.29(0.92–1.83) 90 to 364 Pediatrician 92.4% (3062) 16.0 (13.6) 67.0% (2220) 9.0 (11.3) 1.42 (1.40–1.44) Nurse 62.8%(2081) 3.3 (4.1) 41.7%(1380) 1.9 (3.2) 1.42 (1.37–1.46) Pharmacy 2.1% (71) 0.1 (0.7) 1.5% (49) 0.0 (0.5) 1.29(1.06–1.58) Social worker 1.2% (41) 0.0 (0.6) 0.9% (31) 0.0 (0.6) 1.01(0.80–1.28) 365 to 729 Pediatrician 74.2% (2459) 13.9 (14.9) 53.3% (1767) 8.7(13.1) 1.20(1.18–1.22) Nurse 46.8%(1550) 2.2 (3.4) 30.2% (1000) 1.3 (2.7) 1.28(1.23–1.33) Pharmacy 0.6% (21) 0.0 (0.3) 0.6% (20) 0.0 (0.3) 0.75 (0.53–1.07) Social worker 0.9% (29) 0.0 (0.5) 1.0% (32) 0.0 (0.5) 0.91(0.70–1.18) ≥730 Pediatrician 65.0% (2153) 24.8(30.5) 50.8%(1684) 16.8(27.1) 1.10 (1.09–1.12) Nurse 49.2% (1629) 3.2 (5.1) 34.7%(1148) 2.0 (4.2) 1.17 (1.14–1.21) Pharmacy 0.6% (19) 0.0 (0.3) 0.4% (14) 0.0 (0.2) 1.41 (0.92–2.20) Social worker 2.2% (72) 0.1 (1.0) 2.7% (90) 0.2 (1.3) 0.70(0.62–0.80) Note: Data are presented by type of primary care specialist visit and stratified by followup period since severe RSV infection. N: total number of infants with at least one visit for pediatrician, nurse, pharmacist, or social worker. The same infant could visit the pediatrician, nurse, pharmacist, and/ orsocialworker,hence,thetotalofthesevisitsmaynotbeequaltothatofinfants(3133perexposurestrata);%:percentageofchildrenwithatleast one visit for pediatrician, nurse, pharmacist, or social worker. Abbreviation:SD,standarddeviation. 13993038, 2024, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pai.14131 by Consorcio Interuniversitario Do Sistema Universitario De Galicia (Cisug), Wiley Online Library on [09/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 6 of 12 | ARES-GÓMEZ et al. andR78.01(0to89 days,IRR = 4.68[95%CI:2.93–7.65])coded diagnosis.Theriskofbronchiolitis,asaspecificdiagnosis(R78.01), ininfantswhohadbeenhospitalizedforsevereRSVremainedsignificantlyhigherthanthatinthenon-hospitalizedinfantsupto oneyearafterhospitalization[90to364 days,IRR = 2.45(95%CI: 1.55–3.94)](Table S2). Beyond 90 days of hospitalization for severe RSV, the risk of needing PHC for bronchitis (R78) was 26% lower in hospitalized thaninnon-hospitalizedinfants(90to364 days,IRR = 0.74[95%CI: 0.62–0.88]).OfthebronchitisepisodesobservedinthesevereRSV infectioncases,70%occurredwithinthefirst4 monthsoffollow-up coinciding with the period around hospitalization; meanwhile, amongnon-hospitalizedinfants,only30%ofthebronchitisepisodes took place during this followup period. PHCvisitsforrespiratoryfatigue/dyspneawereinfrequent,with onlythreeepisodesreportedduringthe0to89 daysoffollow-upperiodinnon-hospitalizedinfantscomparedwith17episodesinhospitalizedones(IRR = 5.53[95%CI:1.79–24.29])(Figure 1, Table S2). No significant association was observed between severe RSV infectionsandPHCvisitsforinfluenzaatanyfollow-upperiod.The cumulativenumberofinfluenza-relatedPHCvisitsattheendofthe study (June 16th, 2023) was 200 in participants who had severe RSV duringinfancyand124inthosewhowerenothospitalizedforRSV (IRR = 1.20[95%CI:0.93–1.54])(Table S3). FIGURE 1 Incidencerateratiosfor primarycarediagnosticcodes(CIAP-2 codes) in children attending primary care afterRSVhospitalizationcomparedto not-hospitalizedchildren,reportedby different length followup periods since hospitalizationday.Eachfoloowupperiod isrepresentedbyaspecificcolor.CIAP2 codes included in the composite enpoints: Acuterespiratoryinfection:H71,R71, R72,R74,R75,R76,R77,R78,R78.00, R78.01,R80,R81.00,R81.01,R81.02, R81.03,R82,R83;2Allotitis:H01,H02, H04, H29, H70, H71, H72, H74; Lower respiratory infections: R02, R03, R04, R78,R78.00,R78.01,R79,R81.00, R81.01,R81.02,R81.03,R82;Upper respiratory infections: H01, H02, H04, H29,H70,H71,H72,H74,R05,R07,R08, R09, R21, R25, R72, R74, R75, R76, R77; Otitismedia:H71,H72,H74;Wheezing/ Asthma;R02,R03,R04,R05,R78.00, R78.01,R79,R95,R96. Follow-up time periods (days) −30to−1 0to89 90 to 364 365 to 729 More than 729 0.10.5 1.05.0 50.0 IRR ( 95%CI ) Otherbreathing problems(R04) Re spiratoryfatigue/dyspnea(R02) Influenza/flu(R80) Bronchiolitis(R78.01) Bronchitis/ bronchiolitis(R78) Acutelaryngitis(R77) Acutetonsilitis(R76) UpperARI (R74) Othernasal signs(R08) Sneezing/stuffynose(R07) Cough(R05) Gasping/wheezing (R03) Otitis media/acute miringitis (H71) *Wheezingorasthma *Otitismedia *Upperrespiratory infection *Lower respiratoryinfection *All Otitis *Acute respiratoryinfection 13993038, 2024, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pai.14131 by Consorcio Interuniversitario Do Sistema Universitario De Galicia (Cisug), Wiley Online Library on [09/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | 7 of 12 ARES-GÓMEZ et al. 3.2.3 | Compositeoutcomes:wheezing/ asthma and others Theexaminationofthecompositeoutcomesofrespiratorymorbidity following severe RSV infections revealed that during the first3 monthsoffollow-up,severeRSVinfectionduringinfancy is associated with a more than fourfold higher risk of PHC visits forwheezing/asthma(IRR = 4.31[95%CI:3.84–4.84])andLRTI (IRR = 4.91[95%CI:4.34–5.58])(Figure 1, Table S2).Additionally, during that same follow-up period (0–89 days), infants who had been hospitalized for severe RSV have more than twofold higher risk of acute respiratory infections (IRR = 2.23 [95% CI: 2.06–2.41]), a 54% higher risk of all otitis (IRR = 1.54 [95% CI: 1.18–2.02])and57%higherriskofotitismedia/acutemiringitis (IRR = 1.57[95%CI:1.18–2.11])comparedwithnon-hospitalized infants (Figure 1, Table S2). 3.3 | RSV severe infection during infancy and emergency services visits: Primary care emergency (PCE) and hospital emergency (HE) Atotalnumberof55,294ESvisitswererecordedduringthestudy period: 17,492 visits took place in primary care emergency (PCE) settings, 35,123 visits were in hospital emergency departments (HE), and 2679 visits were transferred from PCE to HE. Compared with non-hospitalizedchildren, patientswho hadbeen hospitalizedfor severeRSVhavemorethantwicetheriskofvisitingHE(0–89 days, IRR:2.39[95%CI:2.17–2.63]);and54%higherriskofrequiringPCE (0to89 days,IRR:1.54[95%CI:1.31–1.82])duringthefirstthree monthsafterhospitalization(Table 2).AhigherriskofrequiringHE or PCE was observed until the end of the study, yet with a lower magnitude of association. Beyond two years of followup, the risk of visitingHEandPCEaftersevereRSVinfectionwas24%(≥730 days, IRR = 1.24[95%CI:1.20–1.29]),and13%(≥730 days,IRR = 1.13[95% CI:1.08–1.17]),respectively(Table 2). Table S4 represents the association of severe RSV with the risk ofrequiringHEorPCEbycumulativefollow-uptimeframes. 3.4 | RSV severe infection during infancy and prescription of medications The number of episodic events with prescription of antibacterials, obstructive airway disease drugs, or any of both was substantially higherinRSV-relatedhospitalizedchildrenthaninnon-RSVhospitalized children.The most pronounced associationwas found for the prescription of obstructive airway disease drugs during themonthbeforehospitalizationforsevereRSVinfection(−30 to−1 days,IRR = 7.41[95%CI:6.04–9.18])and3 monthsafteradmission(0to89 days,IRR = 5.98[95%CI:5.43–6.60])(Table 3). In thefirst3 monthsafteradmission,theriskofrequiringaprescription of any of the two drugs was 5.50 times higher in hospitalizedinfantsthaninnon-hospitalizedones(0–89 days,IRR = 5.50 [95%CI:5.05–5.99])(Table 3).HospitalizedinfantsforsevereRSV were also at fourfold higher risk of receiving antibacterials prescriptionduringthefirst3 monthsafteradmissionthanthenon- hospitalizedones(0to89 days,IRR = 4.02[95%CI:3.38–4.81]) (Table 3). Significant associations between severe RSV infection during infancy and the prescription of antibacterials and/or obstructive airway disease drugs were sustained throughout all followup periods (Table 3). Findings on the prescription of those drugs during cumulative follow-up periods are summarized in Table S5. TABLE 2 Incidencerateratio(IRR)ofprimarycareemergency(PCE)visitsandhospitalemergencies(HE)alongwiththeir95%confidence intervals(CI)inRSVhospitalizedchildrencomparedtothosenothospitalizedchildren. Followup time (days) Outcome Hospitalized (N = 3313) Not Hospitalized (N = 3313) IRR (95% CI)Mean (SD) % (N)Mean (SD) % (N) −30to−1 PCE 0.2 (0.5) 14.9% (495) 0.0 (0.2) 3.2% (105) 4.89(4.03–5.99) HE 0.9 (1) 58.4%(1936) 0.1 (0.4) 9.9%(328) 6.52(5.88–7.25) 0to89 PCE 0.1 (0.5) 9.9% (327) 0.1 (0.3) 5.6%(185) 1.54(1.31–1.82) HE 0.5 (0.9) 30.4% (1006) 0.2 (0.5) 12.5% (413) 2.39 (2.17–2.63) 90 to 364 PCE 0.7 (1.5) 30.7% (1017) 0.4 (1.0) 22.8%(755) 1.29 (1.21–1.39) HE 1.6 (2.2) 58.4%(1934) 0.8(1.4) 35.9% (1190) 1.69 (1.61–1.77) 365 to 729 PCE 0.8(1.6) 31.8%(1055) 0.5 (1.2) 22.6% (749) 1.25 (1.17–1.33) HE 1.4 (2.3) 49.5% (1641) 0.7 (1.6) 30.9% (1023) 1.45(1.38–1.52) ≥730 PCE 1.7 (3.2) 41.1% (1362) 1.2 (2.6) 32.9% (1090) 1.13(1.08–1.17) HE 2.1 (3.4) 50.6% (1676) 1.3 (2.6) 36.1% (1197) 1.24 (1.20–1.29) Note: N: total number of children who attended at least once to primary care or hospital emergency. %, percentage of children who attended at least once to primary care or hospital emergency. Abbreviation:SD,standarddeviation. 13993038, 2024, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pai.14131 by Consorcio Interuniversitario Do Sistema Universitario De Galicia (Cisug), Wiley Online Library on [09/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 8 of 12 | ARES-GÓMEZ et al. 4 | DISCUSSION Our study delineates the considerable shortto midterm burden resultingfrominfantRSV.Wedemonstrateanelevatedutilizationof PHC services during childhood following severe RSV infections in infancy. This highlights a substantial increase in both PHC and ES visits, indicating a heightened risk of developing midterm respiratory morbidities. These findings significantly contribute to understanding the broader healthrelated and socioeconomic impact of severe RSV infections beyond their acute phase. These aspects should be considered in evaluating the costeffectiveness of prevention programs. We observed that severe RSV infection during infancy is associated with a twofold increased risk of needing a pediatric or nurse consultation and more than fivefold the risk of ES visits during the first3 monthsafterinfection. Thisunderscoresthe heavy burden that severe RSV infections may impose on PHC/ES. Research on RSV burden in PHC is limited, with most studies focusing on hospitalizations,leavingPHCunderstudied.Globalestimatesofacute lower respiratory infections due to RSV in 2019 did not specifically report the burden of RSVassociated acute lower respiratory tract infections in primary care, such as general practice and outpatient settings.3A study conductedintheUnitedStatesbetween2008 and 2014, reported that over twothirds of healthcare consultations for RSVattributable conditions in infants occurred in outpatient settings, constituting about 40% of total medical costs related to RSV. Only 13% occurred in emergencies, and 10% resulted in hospitalizations.23Ourresearchextendsthesefindingsbyofferingdetailed insights into morbidity patterns in primary care settings, as indicatedbyCIAP-2. The use of composite endpoints in our study, including related codes under broader categories, aimed for more robust end points that may be less dependent on codification practice differences across primary care professionals. Concretely, bronchitis/bronchiolitis, lower and upper respiratory episodes, and wheezing/ asthmaupto1 yearafterinfection,werethemostfrequentcauses of increased need of primary care attendance. Consistent with our findings, a systematic review of the economic and health impact of RSVaffirmedthatthemostfrequentcomplicationofsevereRSV infection is acute bronchiolitis.8 In Spain, nearly 90% of bronchiolitis cases are managed in primary care offices, revealing the burden imposed by this disease on PHC.24Asix-yearfollow-upstudy of American children who had RSV bronchiolitis during infancy reported that around half of these children develop asthma during thefirst6 yearsoflife.10Similarly,inAustralia,apopulation-based cohortstudyindicatedthathospitalizationforsevereRSVdisease inthefirst2 yearsoflifewasassociatedwithalmostfourtimesthe riskofsubsequenthospitalizationforthefirstepisodeofasthma.25 Furthermore, the same research group reported that, despite RSV TABLE 3 Incidencerateratio(IRR)and95%confidenceintervals(CI)ofantibacterials,obstructiveairwaydiseasedrugprescriptionin childrenwhowereRSVhospitalizedduringinfancycomparedtothosewhowerenotRSV-hospitalizedchildren. Followup time (days) Outcome Hospitalized (N = 3313) Not hospitalized (N = 3313) IRR (95% CI)Mean (SD) % (N)Mean (SD) % (N) −30to−1 Antibacterials 0 (0.2) 2.2% (73) 0 (0.1) 0.5% (15) 4.38(2.73–7.39) Obstructive airway disease drugs 0.3 (1.1) 14.2% (469) 0 (0.3) 1.8%(59) 7.41(6.04–9.18) Antibacterialsorobstructiveairway disease drugs 0.3 (1.1) 15%(498) 0 (0.4) 2.1%(68) 6.91(5.72–8.41) 0to89 Antibacterials 0.2(1.8) 10.3% (340) 0 (0.5) 3%(98) 4.02(3.38–4.81) Obstructive airway disease drugs 1 (2.5) 31%(1028) 0.1 (0.7) 7.9% (261) 5.98(5.43–6.6) Antibacterialsorobstructiveairway disease drugs 1.2 (3.3) 34.8%(1153) 0.2 (1) 9.4% (313) 5.50 (5.05–5.99) 90 to 364 Antibacterials 0.4 (1.7) 18.7%(621) 0.2(0.8) 10.2% (339) 1.94 (1.76–2.14) Obstructive airway disease drugs 1.7 (4.1) 40.2% (1332) 0.4 (2.1) 14.3% (473) 3.43 (3.23–3.65) Antibacterialsorobstructiveairway disease drugs 2.1 (4.7) 46.5% (1540) 0.6 (2.4) 19.9% (660) 2.97(2.82–3.13) 365 to 729 Antibacterials 0.7(2.8) 27.1%(898) 0.3 (0.9) 16.2% (537) 1.76 (1.63–1.9) Obstructive airway disease drugs 1.4(3.8) 36.1% (1196) 0.5 (1.7) 17.1% (566) 2.40 (2.27–2.55) Antibacterialsorobstructiveairway disease drugs 2.1 (5.1) 46.8%(1549) 0.8(2.2) 25.7%(850) 2.15 (2.05–2.26) ≥730 Antibacterials 1.1 (3.4) 36.6% (1211) 0.6 (1.6) 24.6%(815) 1.35(1.28–1.43) Obstructive airway disease drugs 2.2 (5.6) 38.1%(1262) 0.9 (3.5) 21.4% (710) 1.83(1.75–1.91) Antibacterialsorobstructiveairway disease drugs 3.3 (7.3) 49.9% (1653) 1.5 (4.4) 32.5% (1076) 1.64(1.58–1.70) Note: N, total number of children with at least one episodic event with a prescription of obstructive airway disease drug or antibacterials; %, percentage of children with at least one episodic event with a prescription of obstructive airway disease drug or antibacterials. Abbreviation:SD,standarddeviation. 13993038, 2024, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pai.14131 by Consorcio Interuniversitario Do Sistema Universitario De Galicia (Cisug), Wiley Online Library on [09/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | 9 of 12 ARES-GÓMEZ et al. burdenbeinghighestinchildrenyoungerthan6 months,therisk ofhospitalizationforsubsequentasthmawashigherinchildren whodevelopRSVdiseaseatanageolderthan6 months,withan IRRofsubsequentasthmaof2.0(95%CI,1.4–2.7)and1.7(95%CI, 1.0–2.5)forchildrenhospitalizedforRSVatanageof6to<12 and 12–24 months,respectively.26Inlinewiththesefindings,Szabo et al. estimated, through a metaanalysis, that after RSV hospitalization during infancy,the attributableriskof asthmadue to RSV ranges from 13% to 22% among children younger than five, from11%to27%amongthoseaged5to11 yearsandwas32% amongchildren12 yearsandolder.27Thebiologicalexplanationof the association between RSV and asthma is related to an immuneresponse cluster characterized by lower non-interferon-gamma and higher type2 and type17 cytokines.28 We also found that severe RSV is associated with a considerableincreaseintheriskofrequiringobstructiveairwaydisease and antibacterial treatments for more than 2 years after hospitalization. Theincreaseintheriskof antibacterial useand that of acute tonsillitis after severe RSV may suggest that the host is more vulnerable to secondary bacterial infections after a severe RSV infection. Several previous studies reported that respiratory viral infections like RSV often increase the host predisposition to secondary respiratory bacterial infections caused by pathobionts, such as Streptococcus pneumonia and Staphylococcus aureus, which may lead to life-threatening sequelae.11,29,30 In the case of copathogenesis, RSV and secondary bacterial infections, RSV infections were suggested to facilitate bacterial adhesion in epithelialcellsandincrementthebacterialcapacitytocolonize the airway. Clinical studies also observed that the upper airway microbiota of RSVinfected children is significantly enriched with Haemophilus influenza and Streptococcus pneumonia.31,32 The hostresponsetoRSVinfectionischaracterizedbytherecruitment of innate immune cells and the release of inflammatory cytokines, suchasIL-17Aandothersolublemediators.33,34 Proteomics and metagenomics analysis showed an association between RSV infectionandtheneutrophilinfluxintotheairwayanddegranulationwhichismarkedbyoverexpressionofproteinswithknown antibacterial activity.35 In this sense, the airway secretions of RSVinfected children have significantly greater antibacterial activity compared to RSVnegative children.35 In addition, the RSVassociated, neutrophilmediated antibacterial response in the airway was suggested to act as a regulatory mechanism that modulates bacterial growth in the airways of RSVinfected children.35 In their randomized control trial, Lewnard and colleagues, also found that RSV infections significantly contribute to substantial antimicrobial use among young infants.36 Our findings underscore the heavy burden of RSV on PHC, justifying the need for estimatingPHCutilizationwhenassessingRSVburdenonpublichealth and evaluating the costeffectiveness of prevention programs.37 The main strength of our study lies in its populationbased nature,minimizingtheriskofpopulation-selectionbias.Matchingthe exposed(severeRSV-infectedinfants)andunexposedparticipants by birthday helped control for changes in RSV seasonality, virus epidemiology, and diagnosis. The inclusion of healthcare needs relatedtoRSVandtheuseofproxiesfordiseaseepisodespotentially relatedtoRSVallowedforacomprehensiveevaluationofPHCexpenses.TheprolongedstudyperiodcoveringsixRSVseasonsand theextendedfollow-updurationproviderobustestimatesofPHC associated with severe RSV. However, due to the observational nature of this study, our findings establish associations rather than causality. The use of PHC indicators, encompassing visits to pediatrician, nurses, pharmacies, social workers, and emergency department, along with individual and composite outcomes of respiratorydiseaserelated episodes and treatment, makes a valuable contribution to comprehensively understanding the economic and health impact of RSV infections in infants. Consequently, it could prove useful for conducting costeffectiveness analyses on preventive measures against RSV infections. Furthermore, this approach may assist in establishing reference background data to objectively evaluate the effectiveness and impact of the newly available preventive toolsonthisexpandedburdenofRSVinfection. While our study is registrybased, potential limitations related to data registry errors were addressed by conducting independent replication for data cleaning and analysis. Data from private care were not included, but this limitation is mitigated by universal public health coverage in Galicia. We focused on severe RSV leading to hospitalization,andoutpatientRSV-LRTIcaseswerenotincludedin our study due to a lack of specific RSV codification in emergency registries. The study's observational nature necessitates acknowledging these associations, emphasizing the need for further research to establish causality. The impact of severe RSV infection on PHC events may commence before patient admission, justifying the inclusion of the 30 days preceding hospitalization in the follow-up period. A sensitivity analysis, starting from hospital discharge to 90 days later, confirmed our findings, reinforcing that the impact of severe RSV infection on PHC/ES use begins even before hospital admission. Additionally,wehaveperformed3moresensitivityanalyseswith chunks of the follow-up period (90–365 days, >365–730 days, >730 daystilltheendofthestudy).Thesensitivityanalysisresults arepresentedindetailassupplementarymaterialannexedtothis report (Tables S2–S5). These findings reinforce the notion that the impact of severe RSV infection on PHC/ES use starts even before hospital admission, and this should be considered in the disease burdenquantification. 5 | CONCLUSIONS Severe RSV infections in infants have notable short and midterm consequencesforhealthcareutilization,manifestinginanincreased number of visits to pediatricians for respiratoryrelated consultations, mainly bronchitis/bronchiolitis, lower and upper respiratory episodes,andasthma/wheezingdiagnosis.Prescriptionsofantibacterials or obstructive airway disease drugs, and visits to primary care 13993038, 2024, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pai.14131 by Consorcio Interuniversitario Do Sistema Universitario De Galicia (Cisug), Wiley Online Library on [09/07/2024]. 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