IntroductionProlonged or recurrent cough is a common reason for referral to pediatric pulmonologists, yet few studies have assessed its causes. We examined records of children visiting respiratory outpatient clinics in Switzerland and assessed how diagnoses vary by age.MethodsWe analyzed data from the multicenter Swiss Paediatric Airway Cohort study. We included 363 children (median age 6 years, range 0-16) referred for prolonged or recurrent cough. From outpatient records, we extracted information on diagnostic investigations, final diagnoses proposed by pediatric pulmonologists, and treatments prescribed.ResultsAsthma and asthma-like conditions (cough variant asthma, episodic viral wheeze, and recurrent obstructive bronchitis) were diagnosed in 132 (36%) of 363 children, respiratory tract infections (RTI) including protracted bacterial bronchitis (PBB) in 51 (14%), upper airway cough syndrome (UACS) in 48 (13%), and postinfectious cough in 36 (10%); other diagnoses including gastroesophageal reflux disease (GERD) and somatic cough syndrome or tic cough were found in 23 (6%). No etiology was found in 73 children (20%). Asthma was diagnosed 3.5 times more often in schoolchildren while RTI including PBB was diagnosed three times more often in preschoolers. Inhaled corticosteroids were prescribed for 84% of children diagnosed with asthma and asthma-like conditions, antibiotics for 43% of children with RTI, and nasal corticosteroids for 83% of those with UACS.ConclusionCoughing children received a wide spectrum of diagnoses that differed between preschool and schoolchildren. Asthma accounted for 36% of diagnoses, which emphasizes the importance of comprehensive investigation beyond asthma in children with prolonged or recurrent cough.

INTRODUCTION: Switzerland has an ongoing debate about the appropriateness of national growth reference curves. The Swiss Society of Pediatrics currently recommends the growth references of the World Health Organization (WHO), while the Center for Pediatric Endocrinology Zurich has proposed alternative growth references based on local data. Specialists and researchers also use International Obesity Task Force (IOTF) references to define overweight and obesity. We investigated the fit of these three growth references to anthropometric measurements from schoolchildren in the canton of Zurich and assessed the prevalence of overweight, obesity, and short stature across the three references. METHODS: We analyzed data from 3755 children aged 6-17 years of the cross sectional LuftiBus in the school (LUIS) study, collected between 2013-2016 in the canton of Zurich. We calculated z-scores of height, weight, and body mass index (BMI) based on WHO, local, and IOTF references. We compared the mean and distribution of z-scores to the expected standard normal distribution using the Anderson-Darling test. We classified BMI based on cutoff values given by the three references: overweight (WHO: >90.0th percentile; local: >82.9[girls], >78.9[boys]; IOTF: >89.3[girls], >90.5[boys]), and obesity (WHO: >97.0; local: >96.8[girls], >95.5[boys]; IOTF: >98.6[girls], >98.9[boys]). We defined short stature as <3rd percentile of height-for-age. RESULTS: The mean z-scores in LUIS were 0.56 for height, 0.28 for weight, and 0.06 for BMI based on WHO references; 0.15 for height, 0.06 for weight, and -0.01 for BMI based on local references; and 0.19 for BMI based on IOTF references. WHO references provided a worse fit to the LUIS children than local references. Anderson-Darling goodness of fit A2 was 578.1 (WHO) vs. 48.1 (local) for height and 124.0 vs. 10.0 for weight, with lower values indicating better fit. WHO (A2: 24.3) and local references (A2: 0.8) fit the BMI of LUIS children better than IOTF (A2: 64.1). The WHO classified fewer children as overweight than the local and IOTF references (WHO: 9% vs. local: 15% vs. IOTF: 13%) but more children as obese (6% vs. 4% vs. 3%). The WHO defined fewer children as being of short stature than the local references (1% vs. 3%). CONCLUSIONS: Our findings suggest that anthropometric data of schoolchildren in Zurich differ notably from WHO and IOTF references potentially leading to misclassification of overweight, obesity, and short stature. Nationally representative and longitudinally collected data are needed to develop new Swiss growth references. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Lunge Zurich, Switzerland, funded the study set-up, development, and data collection with a grant to Alexander Moeller. This data analysis was supported through the grant NDS-2021-911 (SwissPedHealth) from the Swiss Personalized Health Network (SPHN) and the Strategic Focal Area Personalized Health and Related Technologies (PHRT) of the ETH Domain (Swiss Federal Institutes of Technology). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the ethics committee of the canton of Zurich (Kantonale Ethik Komission Zurich, Number: 2014-0491) and informed consent was obtained prior to participation I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Researchers can obtain datasets for analysis if a detailed concept sheet is presented for the planned analyses and approved by the principal investigators (Alexander Moeller, Philipp Latzin and Claudia Kuehni).

BACKGROUND:It is unclear if predictors of asthma attacks are the same as those of asthma symptom control in children.OBJECTIVE:We evaluated predictors for these two outcomes in a clinical cohort study.METHODS:The Swiss Paediatric Airway Cohort (SPAC) is a multicentre prospective clinical cohort of children referred to paediatric pulmonologists. This analysis included 516 children (5-16 years old) diagnosed with asthma. At baseline, we collected sociodemographic information, symptoms, personal and family history and environmental exposures from a parental baseline questionnaire, and treatment and test results from hospital records. Outcomes were assessed 1 year later by parental questionnaire: asthma control in the last 4 weeks as defined by GINA guidelines, and asthma attacks defined as any unscheduled visit for asthma in the past year. We used logistic regression to identify and compare predictors for suboptimal asthma control and asthma attacks.RESULTS:At follow-up, 114/516 children (22%), reported suboptimal asthma control, and 114 (22%) an incident asthma attack. Only 37 (7%) reported both. Suboptimal asthma control was associated with poor symptom control at baseline (e.g. ≥1 night wheeze/week OR: 3.2; 95% CI: 1.7-6), wheeze triggered by allergens (2.2; 1.4-3.3), colds (2.3; 1.4-3.6) and exercise (3.2; 2-5), a more intense treatment at baseline (2.4; 1.3-4.4 for Step 3 vs. 1), history of preschool (2.6; 1.5-4.4) and persistent wheeze (2; 1.4-3.2), and exposure to tobacco smoke (1.7; 1-2.6). Incident asthma attacks were associated with previous episodes of severe wheeze (2; 1.2-3.3) and asthma attacks (2.8; 1.6-5 for emergency care visits), younger age (0.8; 0.8-0.9 per 1 year) and non-Swiss origin (0.3; 0.2-0.5 for Swiss origin). Lung function, exhaled nitric oxide (FeNO) and allergic sensitization at baseline were not associated with control or attacks.CONCLUSION:Children at risk of long-term suboptimal asthma control differ from those at risk of attacks. Prediction tools and preventive efforts should differentiate these two asthma outcomes.

BACKGROUND:Epidemiological studies use different questions to assess recurrent cough in children. In two independent population-based studies, we assessed how prevalence estimates of cough vary depending on the questions parents are asked about their child's cough and how answers to the different questions overlap.METHODS:We analysed cross-sectional data from two population-based studies on respiratory health: LuftiBus in the School (LUIS), conducted in 2013-2016 among 6- to 17-year-school children in the Canton of Zurich, Switzerland, and the 1998 Leicester Respiratory Cohort (LRC) study, UK where we used data from 6- to 8-year-old children from the 2003 follow-up survey. Both studies used parental questionnaires that included the same three questions on the child's cough, namely cough without a cold, dry cough at night and coughing more than others. We assessed how the prevalence of cough varied depending on the question and how answers to the different questions on cough overlapped. We also assessed how results were influenced by age, sex, presence of wheeze and parental education.RESULTS:We included 3457 children aged 6-17 years from LUIS and 2100 children aged 6-8 years from LRC. All respiratory outcomes - cough, wheeze and physician-diagnosed asthma - were reported twice as often in the LRC as in LUIS. We found large differences in the prevalence of parent-reported cough between the three cough questions. In LUIS, 880 (25%) parents reported cough without a cold, 394 (11%) dry night cough, and 159 (5%) reported that their child coughed more than other children. In the LRC, these numbers were 1003 (48%), 527 (25%) and 227 (11%). There was only partial overlap of answers, with 89 (3%) answering yes to all questions in LUIS and 168 (8%) in LRC. Prevalence of all types of cough and overlap between the cough questions was higher in children with current wheeze.CONCLUSION:In both population-based studies prevalence estimates of cough depended strongly on the question used to assess cough with only partial overlap of responses to different questions. Epidemiological studies on cough can only be compared if they used exactly the same questions for cough.

ObjectivesPopulation-based studies of children with dry night cough alone compared with those who also wheeze are few and inconclusive. We compared how children with dry night cough differ from those who wheeze. MethodsLuftiBus in the school is a population-based study of schoolchildren conducted between 2013 and 2016 in Zurich, Switzerland. We divided children into four mutually exclusive groups based on reported dry night cough (henceforth referred as "cough") and wheeze and compared parent-reported symptoms, comorbidities, exposures, FeNO, spirometry, and healthcare use and treatment. ResultsAmong 3457 schoolchildren aged 6-17 years, 294 (9%) reported "cough," 181 (5%) reported "wheeze," 100 (3%) reported "wheeze and cough," and 2882 (83%) were "asymptomatic." Adjusting for confounders in a multinomial regression, children with "cough" reported more frequent colds, rhinitis, and snoring than "asymptomatic" children; children with "wheeze" or "wheeze and cough" more often reported hay fever, eczema, and parental histories of asthma. FeNO and spirometry were similar among "asymptomatic" and children with "cough," while children with "wheeze" or "wheeze and cough" had higher FeNO and evidence of bronchial obstruction. Children with "cough" used healthcare less often than those with "wheeze," and they attended mainly primary care. Twenty-two children (7% of those with "cough") reported a physician diagnosis of asthma and used inhalers. These had similar characteristics as children with wheeze. ConclusionOur representative population-based study confirms that children with dry night cough without wheeze clearly differed from those with wheeze. This suggests asthma is unlikely, and they should be investigated for alternative aetiologies, particularly upper airway disease.

Introduction: Prolonged or recurrent cough in children has different underlying causes, which vary across settings and age. We assessed diagnostic testing and final diagnosis given to children visiting respiratory outpatient clinics in Switzerland. Methods: We analysed data from the multicentre Swiss Paediatric Airway cohort study. We included 363 children (median age 6 years, range 0-16, 60% male) referred for prolonged or recurrent cough. We extracted information on diagnostic investigations, final diagnoses proposed by paediatric pulmonologists, and treatment prescribed from outpatient records. Results: Final diagnosis was asthma and asthma-like conditions in 133 (37%), respiratory tract infections (RTI) including protracted bacterial bronchitis in 50 (14%), upper airway cough syndrome (UACS) in 45 (12%), post-infectious cough in 36 (10%), and unknown or other diagnoses in 99 (27%). Among children aged < 5 years, 27% had asthma, 24% RTI, and 14% UACS while among those aged ≥ 5 years, 42% had asthma, 12% UACS and 8% RTI. Fractional exhaled nitric oxide was measured in 73%, lung function in 71%, and chest X-rays were done in 25%. Most children (83%) diagnosed with asthma were prescribed inhaled corticosteroids, alone or in combination with long-acting beta agonists, 42% of the children with RTI were prescribed antibiotics and 82% of those diagnosed with UACS were prescribed nasal corticosteroids. Conclusion: Asthma was the most common diagnosis, in a third of the children. Final diagnoses differed strongly by age. The cause of cough was unknown in 20% of the children, highlighting the diagnostic challenge and the need for further research to improve diagnosis of prolonged and recurrent cough. Funding: SNSF 320030_212519

ABSTRACT Background Distinguishing phenotypes among children with cough helps understand underlying causes. Using a statistical data-driven approach, we identified cough phenotypes and we aimed to validate them based on measurable traits, physician diagnoses, and prognosis. Methods We used data from 531 children aged 5–16 years from the Swiss Paediatric Airway Cohort—a multicentre clinical cohort of children seen in outpatient clinics since 2017. We included children with any parent-reported cough (i.e. cough without a cold, cough at night, cough more than others, or cough longer than 4 weeks) without current wheeze. We applied latent class analysis to identify phenotypes using 9 symptoms and characteristics and selected the best model using the Akaike Information Criterion. We assigned children to the most likely phenotype and compared the resulting groups with regards to parental history, comorbidities, measurable traits, physician diagnoses, and prognosis after 1 year. Results Our analysis distinguished 4 cough phenotypes: 1. unspecific dry cough (25%); 2. non-allergic infectious and night cough with snoring and otitis (4%); 3. allergic dry night cough with snoring (9%); and 4. allergic cough (61%). Children with the allergic phenotype often had family or personal history of atopy and were diagnosed with asthma. Fractional exhaled nitric oxide was highest for the allergic phenotype [median 17.9 parts per billion (ppb)] and lowest for the non-allergic infectious phenotype (median 7.0 ppb). Positive allergy test results differed across phenotypes (p<0.001) and were most common among the allergic (70%) and least common among the unspecific dry cough (31%) phenotypes. Subsequent wheeze was thrice as high among the allergic than the unspecific dry cough phenotype. Conclusion We distinguished 4 clinically-relevant cough phenotypes; they differed by measurable traits, physician diagnoses, and prognosis. Although we excluded children with current wheeze, most children belonged to allergy-related phenotypes and possibly need allergy and asthma work-ups. Three key messages Latent class analysis identified 4 cough phenotypes distinguished by measurable traits, diagnoses, and prognosis. Most children belonged to allergy-related phenotypes and possibly need allergy and asthma work-ups. Symptom-based cough phenotypes correlate with measurable traits and potentially apply to all healthcare settings.

No episodes of oxygen desaturation or carbon dioxide retention were observed in this cross-sectional study assessing children with exercise-induced symptoms wearing a surgical facemask during a submaximal treadmill exercise test https://bit.ly/3GuxhvO.

Background: Few studies compare predictors of asthma symptom control and asthma attacks in the same population of children. We evaluated predictors for these two outcomes in a clinical cohort study. Methods: SPAC is a multicentre prospective clinical cohort of children from paediatric respiratory outpatient clinics. This analysis included children aged 5 years or more diagnosed with asthma. At baseline, we collected sociodemographic information, symptoms, personal and family history and exposures from a parental questionnaire, and treatments and test results from hospital records. Outcomes were assessed 1 year later by parental questionnaire. We used logistic regression to identify and compare predictors for suboptimal asthma control and asthma attacks. Results: At follow-up, 114 (22%) of the 516 children, reported suboptimal asthma control in the last 4 weeks, and 114 (22%) an incident asthma attack in the past year. Only 37 (7%) reported both. Suboptimal asthma control was predicted by exposure to tobacco smoke, poor symptom control at baseline, wheeze triggered by allergens, colds and exercise, and a more intense baseline treatment. Incident asthma attacks were associated with younger age, non-Swiss origin, no paternal asthma history, previous episodes of severe wheeze and previous asthma attacks at baseline. Lung function, FeNO and allergy tests at baseline were not associated with asthma control or asthma attacks. Conclusion: Predictors of suboptimal asthma control differ from those of asthma attacks. Future prediction scores and preventive efforts should differentiate these two asthma outcomes. Funding: SNSF:320030_182628 and SLA:2019-03_641670

Introduction: Distinction of phenotypes among children with cough can help understand underlying causes. We used a data-driven approach to identify cough phenotypes in children and assess their clinical validity. Methods: We included 531 children aged 5-16 years with cough (i.e. without cold, at night, more than others or more than 4 weeks) but no wheeze from the Swiss Paediatric Airway Cohort. We applied latent class analysis to identify phenotypes using cough characteristics and symptoms from parental questionnaires and selected the best fitting model and optimum number of classes using Akaike Information Criteria. We tested the validity of the phenotypes by comparing characteristics, objective tests, doctors’ diagnosis, and one-year prognosis. Results: We identified four cough phenotypes: allergic (61%), infectious (4%), mixed (9%) and nonspecific (25%). Children of the allergic phenotype were older and had more frequently a history of atopy. FeNO differed across groups (p<0.001) being highest in the allergic (17.9 ppb, 95% CI 15.6-19.5) and lowest in the infectious phenotype (7.0 ppb, 95% CI 5.0-17.7). Similarly, positive allergy tests were common in the allergic (70%) and rare in the nonspecific phenotype (31%). 80% of children in the allergic phenotype were diagnosed with asthma compared to 44-55% in other phenotypes. A diagnosis of chronic cough was more frequent in the mixed (44%) and infectious phenotypes (39%). At one-year follow up, children of the allergic phenotype more often developed wheeze and cough persisted less often. Conclusion: The four identified phenotypes of cough without wheeze are valuable to understand underlying causes and predict short-term prognosis which is essential for clinical management. Funding: SNSF 320030_182628

Introduction: Population-based studies that compare children presenting with night cough alone to those who wheeze or report both symptoms are few and inconclusive. Methods: We analysed data from Luftibus in the school, a population-based study of schoolchildren in Zurich, Switzerland conducted in 2013-2016. We divided children into four mutually exclusive groups based on reported night cough and wheeze, and compared reported characteristics, spirometry, FeNO, healthcare use and management. Results: We included 3427 children, among whom 8% reported night cough alone, 5% reported wheeze alone, 3% reported both night cough and wheeze and 83% none (asymptomatic). Children with night cough alone differed in many aspects from children with wheeze. Night cough was more strongly associated with upper respiratory symptoms while wheeze was more closely associated with a family or personal history of atopy. Lung function was reduced and FeNO increased in children with wheeze, while there was no difference between children with night cough alone and asymptomatic children. Children with night cough alone used healthcare services less often than children with wheeze, and they attended mainly primary care. Of those reporting night cough alone, however, 8% (22) reported a doctor diagnosis of asthma and asthma treatment. This subgroup shared characteristics with children with wheeze. Conclusion: Most children who report night cough alone do not have features typical for asthma and may not benefit from asthma diagnosis workup and treatment. Only a small subgroup (8%) has asthma-like features and might warrant further investigations. Funding: SNSF: 320030_182628; Lunge Zürich

Introduction The Predicting Asthma Risk in Children (PARC) tool uses questionnaire-based respiratory symptoms collected from preschool children to predict asthma risk 5 years later. The tool was developed and validated in population cohorts but not validated using a clinical cohort. We aimed to externally validate the PARC tool in a pediatric pulmonology clinic setting. Methods The Swiss Paediatric Airway Cohort (SPAC) is a prospective cohort of children seen in pediatric pulmonology clinics across Switzerland. We included children aged 1-6 years with cough or wheeze at baseline who completed the 2-year follow-up questionnaire. The outcome was defined as current wheeze plus use of asthma medication. We assessed performance using: sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV), area under the curve (AUC), scaled Brier's score, and Nagelkerke's R-2 scores. We compared performance in SPAC to that in the original population, the Leicester Respiratory Cohort (LRC). Results Among 346 children included, 125 (36%) reported the outcome after 2 years. At a PARC score of 4: sensitivity was higher (95% vs. 79%), specificity lower (14% vs. 57%), and NPV and PPV comparable (0.84 vs. 0.87 and 0.37 vs. 0.42) in SPAC versus LRC. AUC (0.71 vs. 0.78), R-2 (0.18 vs. 0.28) and Brier's scores (0.13 vs. 0.22) were lower in SPAC. Conclusions The PARC tool shows some clinical utility, particularly for ruling out the development of asthma in young children, but performance limitations highlight the need for new prediction tools to be developed specifically for the clinical setting.

Introduction: Epidemiological studies use different questions to assess cough in children. We compared parents’ answers to different questions on cough in their children and how this affected prevalence estimates. Methods: We analysed data from Luftibus in the School, a study on respiratory health in schoolchildren, conducted in Switzerland, in 2013-16. Parents completed a questionnaire with three different questions on their child’s cough used in large epidemiological studies: does your child “cough apart from colds”, “has dry night cough” and “cough more than other children”. We assessed the proportion answering ‘’yes’’ to each question, how the answers overlapped and how this differed by age, sex and presence of wheeze. Results: We included 3427 children (age 6-17 years, 50% girls). The prevalence of cough differed substantially depending on the question asked. 872 (25%) parents reported cough apart from colds, 390 (11%) dry night cough, and 158 (5%) that their child coughs more than other children. We found only partial overlap between the cough questions (Figure 1). Only 3% of parents answered yes to all three questions. The overlap was broader for children who also reported wheeze, but did not vary by age or sex. Conclusion: The questions used to assess cough in children strongly affect prevalence of cough. We therefore need to be careful when interpreting and comparing studies. Funding: SNSF:320030_182628; Lunge Zürich

ABSTRACTWe assessed how prevalence estimates of cough in 6-17-year-olds vary depending on the question asked in the population-based Luftibus in the school (LUIS) study. 3427 parents answered three different questions on cough. The prevalence of parent-reported cough varied substantially depending on the question: 25% of parents reported cough without a cold, 11% dry night cough and 5% that their child coughs more than other children. There was only partial overlap with 3% answering yes to all questions. This suggests that the exact question used to assess cough strongly affects prevalence estimates and must be taken into account when comparing studies.

Primary ciliary dyskinesia (PCD) is a rare genetic disease that causes recurrent respiratory infections. People with PCD may be at higher risk of severe coronavirus disease 2019 (COVID-19), and therefore vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is important. We studied vaccination willingness, speed of vaccination uptake, side effects, and changes in social contact behaviour after vaccination in people with PCD. We used data from COVID-PCD, an international participatory cohort study. A COVID-19 vaccination questionnaire was emailed to participants in May 2021 and 423 participants from 31 countries replied (median age: 30 years, range 1–85 years; 261 (62%) female). Vaccination uptake and willingness were high, with 273 of 287 adults (96%) being vaccinated or willing to be in June 2021; only 4% were hesitant. The most common reason for hesitancy was fear of side effects, reported by 88%. Mild side effects were common, but no participant reported severe side effects. Half of the participants changed their social behaviour after vaccination by seeing friends and family more often. The high vaccination willingness in the study population might reflect the extraordinary effort taken by PCD support groups to inform people about COVID-19 vaccination. Clear and specific information and involvement of representatives is important for high vaccine uptake.

Background: Little is known on the effect of COVID19 preventive measures on respiratory symptoms in children. We studied the effect of these measures on respiratory symptoms in children previously followed by paediatric pulmonologists. Methods: The Swiss Paediatric Airway Cohort is a prospective cohort of children aged 0-16 years seen by paediatric pulmonologists in Switzerland. Parents completed a monthly questionnaire on respiratory symptoms and treatment for 1 year. We compared the questionnaires completed in October 2019-February 2020 (preCOVID-winter), March-April 2020 (lockdown with school closures) and October 2020-February 2021 (COVID-winter). We used logistic regression to study the association between the period and respiratory infections, symptoms and treatment use. Results were adjusted for sex, age and previous severity of respiratory symptoms. Results: Among the 392 questionnaires (204 children, mean age 9 years, 48% female), 83 were completed during preCOVID-winter, 91 in lockdown and 218 in COVID-winter. Compared to preCOVID-winter, questionnaires completed in lockdown and COVID-winter were less likely to report on respiratory infections (aOR 0.12, 95%CI 0.05-0.31; aOR 0.22, 0.10-0.46), cough (aOR 0.31, 0.14-0.67; aOR 0.17, 0.08-0.36), dyspnoea (aOR 0.30, 0.10-0.96; aOR 0.34, 0.11-1.1), wheeze (aOR 0.15, 0.05-0.47; aOR 0.30, 0.12-0.71), treatment for respiratory problems (aOR 0.22, 0.06-0.85; aOR 0.06, 0.01-0.30), and asthma control-drugs use (aOR 0.65, 0.23-1.8; aOR 0.14, 0.04-0.49). Conclusion: Children in this clinical cohort had less respiratory infections and symptoms during the COVID19 pandemic compared to a previous similar period, probably due to preventive measures.

Background: Rotavirus (RV) infection is the leading cause of diarrhoea-associated morbidity and mortality globally among children under 5 years of age. RV vaccination is available, but has not been implemented in many national immunisation plans, especially in highly developed countries. This systematic review aimed to estimate the prevalence and incidence of health care use for RV gastroenteri-tis (RVGE) among children aged under 5 years in highly developed countries without routine RV vaccination. Methods: We searched MEDLINE and Embase databases from January 1st 2000 to December 17th 2018 for publications reporting on incidence or prevalence of RVGE-related health care use in children below 5 years of age: primary care and emergency department (ED) visits, hospitalisations, nosocomial infections and deaths. We included only studies with laboratory-confirmed RV infection, undertaken in highly developed countries with no RV routine vaccination plans. We used random effects meta-analysis to generate summary estimates with 95% confidence intervals (CI) and prediction intervals. Results: We screened 4033 abstracts and included 74 studies from 21 countries. Average incidence rates of RVGE per 100 000 person-years were: 2484 (95% CI 697-5366) primary care visits, 1890 (1597-2207) ED visits, 500 (422-584) hospitalisations, 34 (20-51) nosocomial infections and 0.04 (0.02-0.07) deaths. Average proportions of cases of acute gastroenteritis caused by RV were: 21% (95% CI 16-26%) for primary care visits; 32% (25-38%) for ED visits; 41% (36-47%) for hospitalisations, 29% (25-34%) for nosocomial infections and 12% (8-18%) for deaths. Results varied widely between and within countries, and heterogeneity was high (I-2 > 90%) in most models. Conclusion: RV in children under 5 years causes many healthcare visits and hospitalisations, with low mortality, in highly developed countries without routine RV vaccination. The health care use estimates for RVGE obtained by this study can be used to model RV vaccine cost-effectiveness in highly developed countries. (C) 2021 The Author(s). Published by Elsevier Ltd.