Changing rates but persisting seasons: patterns of enterovirus infections in hospitalizations and outpatient visits in Denmark 2015-2022

BackgroundEnteroviruses (EV) constitute a diverse group of viruses manifesting a broad spectrum of clinical presentations in humans ranging from mild skin manifestations to more severe central nervous system (CNS) infection. Severe infections are reported with increased frequency globally, albeit the burden of diseases and the evolution of circulating viruses is largely unknown. We aimed to systematically explore contemporary trends in hospitalizations attributed to EV infections using national hospitalization discharge data.MethodsWe utilized the Danish National Patient Register which holds information on all contacts to Danish hospitals. We covered eight full years (2015-2022). Length-of-stay and administrative procedure codes were used to distinguish hospital admissions from outpatient visits. We utilized burden of disease estimates and distribution statistics.ResultsWe identified 1029 hospitalizations and 1970 outpatient visits due to EV infections. The hospital admissions were primarily associated with CNS-infections (n=570, 55.4%) and skin (n=252, 24.5%), with variation over the studied period. The admitted patients were predominately children (43.8%) though patients were identified in all ages. The clinical manifestation was associated with age, with CNS infections dominating in the neonates and adults, and skin infections dominating in children 1-2 years (17.2%). Outpatient visits were predominantly observed among children 1-2 years (55.0%), presenting with skin symptoms (77.9%). We show a seasonal pattern of EV infections with summer/fall peaks and markedly impact on the EV hospitalization burden related to COVID-19 mitigation measures including national lockdown periods. 25% of hospital admissions occurred during 2020-2022.ConclusionEV infections caused both hospital admissions and outpatient visits in the period studied, predominately among children aged 1-2 years. Overall, skin infections dominated the outpatient visits, while the majority of hospital admissions were due to CNS infections. The pandemic period did not change the seasonal pattern of EV infections but notably lowered the number of admissions to hospital with CNS infection and raised the number of outpatient admissions with skin infection

Community cohort study of rotavirus and other enteropathogens: are routine vaccinations associated with sex-differential incidence rates?

OBJECTIVE: Community studies in West Africa have demonstrated that routine vaccinations may have non-targeted effects, the female-male mortality ratio being reduced after administration of BCG and increased after diphtheria-tetanus-pertussis (DTP). We examined whether immunisation status was associated with infection with rotavirus and other enteropathogens. METHODS: We recruited 200 children shortly after birth and followed them until 2 years of age with weekly morbidity interviews and stool sampling. Vaccination status for each child was classified according to the most recent vaccination as documented by vaccination card. MAIN OUTCOME MEASURES: The female-male incidence rate ratios (IRR) of infection with an enteropathogen and of enteropathogen-associated diarrhoea were estimated for children according to whether they had received BCG or DTP as their last vaccination. RESULTS: For children who received BCG as their last vaccine, the adjusted female-male IRRs for primary rotavirus-infection and diarrhoea were 1.05 (95% CI: 0.21-5.28) and 0.0 (95% CI: 0-3.02), respectively. For children who received DTP as their last vaccine, the adjusted female-male IRRs were 1.93 (0.89-4.21) and 1.92 (0.70-5.32), respectively, for rotavirus-associated infection and diarrhoea. Restricted to the rotavirus season, the female-male IRRs for rotavirus infection and diarrhoea were 2.56 (1.17-5.63) and 2.63 (0.94-7.34), respectively. The female-male IRR for rotavirus-associated diarrhoea differed significantly among BCG and DTP recipients (p=0.02). Infections with enteropathogens not associated with diarrhoea were associated with lower female-male IRRs after BCG of 0.82 (0.55-1.23) and higher female-male IRRs after DTP vaccination of 1.32 (1.03-1.70) for primary infection (p=0.05). Though there were few infections with other diarrhoea-causing enteropathogens, these were also associated with a lower female-male IRR after BCG of 0.62 (0.26-1.52) and a higher female-male IRR after DTP vaccination of 1.51 (1.04-2.20) for all infection. CONCLUSION: Routine immunisations may affect morbidity for non-targeted infections. As in studies of infant mortality, BCG is associated with lower risk for girls, whereas, DTP is associated with higher risk for girls relative to boys

Point-of-Use Water Treatment and Use among Mothers in Malawi

A national household survey was conducted in Malawi to determine awareness and use of a socially marketed water treatment product. In all, 64% of mothers were aware of the product, and 7% were using it. Both poor and rural mothers had lower awareness and use rates. Targeting promotion to rural populations could enhance program effectiveness

Respiratory syncytial virus-associated hospitalisation in adults with 2 comorbidities in two European countries:a modelling study

Background: Individuals with comorbidities are at increased risk of severe respiratory syncytial virus (RSV) infection. We estimated RSV-associated respiratory hospitalization among adults aged ≥45 years with comorbidities in Denmark and Scotland. Methods: By analyzing national hospital and virologic data, we estimated annual RSV-associated hospitalizations by 7 selected comorbidities and ages between 2010 and 2018. We estimated rate ratios of RSV-associated hospitalization for adults with comorbidity than the overall population. Results: In Denmark, annual RSV–associated hospitalization rates per 1000 adults ranged from 3.1 for asthma to 19.4 for chronic kidney disease (CKD). In Scotland, rates ranged from 2.4 for chronic liver disease to 9.0 for chronic obstructive pulmonary disease (COPD). In both countries, we found a 2- to 4-fold increased risk of RSV hospitalization for adults with COPD, ischemic heart disease, stroke, and diabetes; a 1.5- to 3-fold increased risk for asthma; and a 3- to 7-fold increased risk for CKD. RSV hospitalization rates among adults aged 45 to 64 years with COPD, asthma, ischemic heart disease, or CKD were higher than the overall population. Conclusions: This study provides important evidence for identifying risk groups and assisting health authorities in RSV vaccination policy making

Current practices for respiratory syncytial virus surveillance across the EU/EEA Member States, 2017

Background: Respiratory syncytial virus (RSV) is a major contributor to lower respiratory tract infections worldwide and several vaccine candidates are currently in development. Following vaccine introduction, reliable RSV surveillance should enable monitoring of vaccination impact. Data on the RSV disease burden in the European Union and European Economic Area (EU/EEA) are sparse. Aim: The aim of this study was to gather knowledge on current practices of national RSV surveillance in the EU/EEA. Methods: National Coordinators and National Focal Points for Influenza (epidemiologists and virologists) from the EU/EEA countries (n = 31) were invited to participate in an online survey in August and September 2017. The questionnaire covered questions on epidemiological and laboratory aspects of RSV surveillance. Results: All EU/EEA countries except Liechtenstein replied to the survey. Eighteen countries reported to have a sentinel surveillance system, 26 countries a non-sentinel surveillance system and three countries to have neither. RSV data collection was mostly done within the context of influenza surveillance. A wide range of diagnostic and characterisation assays was used for the detection of RSV. Discussion: The majority of EU/EEA countries have some surveillance for RSV in place. The prevailing integration of RSV surveillance into the existing influenza sentinel surveillance system may lead to under-reporting of RSV. The documented variations in existing RSV surveillance systems and their outputs indicate that there is scope for developing guidelines on establishing comparable methods and outcomes for RSV surveillance across the EU/EEA, to ensure the availability of a consistent evidence base for assessing future vaccination programmes.S

Estimation of the number of RSV-associated hospitalisations in adults in the European Union

Respiratory syncytial virus causes a high annual number of hospital admissions in adults across the European Union (roughly 160 000 per year). About 92% of these admissions occur in adults aged & GE;65 years.Background Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in adults that can result in hospitalizations. Estimating RSV-associated hospitalization is critical for planning RSV-related healthcare across Europe. Methods We gathered RSV-associated hospitalization estimates from the RSV Consortium in Europe (RESCEU) for adults in Denmark, England, Finland, Norway, Netherlands, and Scotland from 2006 to 2017. We extrapolated these estimates to 28 European Union (EU) countries using nearest-neighbor matching, multiple imputations, and 2 sets of 10 indicators. Results On average, 158 229 (95% confidence interval [CI], 140 865-175 592) RSV-associated hospitalizations occur annually among adults in the EU (& GE;18 years); 92% of these hospitalizations occur in adults & GE;65 years. Among 75-84 years, the annual average is estimated at 74 519 (95% CI, 69 923-79 115) at a rate of 2.24 (95% CI, 2.10-2.38) per 1000. Among & GE;85 years, the annual average is estimated at 37 904 (95% CI, 32 444-43 363) at a rate of 2.99 (95% CI, 2.56-3.42). Conclusions Our estimates of RSV-associated hospitalizations in adults are the first analysis integrating available data to provide the disease burden across the EU. Importantly, for a condition considered in the past to be primarily a disease of young children, the average annual hospitalization estimate in adults was lower but of a similar magnitude to the estimate in young children (0-4 years): 158 229 (95% CI, 140 865-175 592) versus 245 244 (95% CI, 224 688-265 799)

Potential Barriers to Healthcare in Malawi for Under-five Children with Cough and Fever: A National Household Survey

Failure to access healthcare is an important contributor to child mortality in many developing countries. In a national household survey in Malawi, we explored demographic and socioeconomic barriers to healthcare for childhood illnesses and assessed the direct and indirect costs of seeking care. Using a cluster-sample design, we selected 2,697 households and interviewed 1,669 caretakers. The main reason for households not being surveyed was the absence of a primary caretaker in the household. Among 2,077 children aged less than five years, 504 episodes of cough and fever during the previous two weeks were reported. A trained healthcare provider was visited for 48.0% of illness episodes. A multivariate regression model showed that children from the poorest households (p=0.02) and children aged >12 months (p=0.02) were less likely to seek care when ill compared to those living in wealthier households and children of higher age-group respectively. Families from rural households spent more time travelling compared to urban households (68.9 vs 14.1 minutes; p<0.001). In addition, visiting a trained healthcare provider was associated with longer travel time (p<0.001) and higher direct costs (p<0.001) compared to visiting an untrained provider. Thus, several barriers to accessing healthcare in Malawi for childhood illnesses exist. Continued efforts to reduce these barriers are needed to narrow the gap in the health and healthcare equity in Malawi

Molecular epidemiology and the evolution of human coxsackievirus A6

Coxsackievirus A6 (CV-A6) infection is a major etiologic agent for hand, foot and mouth disease (HFMD) in recent years. HFMD outbreaks associated with CV-A6 results from the evolutionary dynamics of CV-A6 and the appearance of novel recombinant forms (RFs). To examine this, 151 variants collected between 2013 and 2014 from Germany, Spain, Sweden, Denmark, and Thailand were genotyped for the VP1 capsid and 3Dpol genes. Analysis of the VP1 gene showed an increasing likelihood between CV-A6 genome recombination and sequence divergence (estimated substitution rate of 8.1 × 10-3 substitutions/site/year and RFs half-life of 3.1 years). Bayesian phylogenetic analysis showed that recent recombination groups (RF-E, -F, -H, -J and -K) shared a common ancestor (RF-A). Thirty-nine full-length genomes of different RFs revealed recombination breakpoints between the 2A-2C and the 5' untranslated regions. The emergence of new CV-A6 recombination groups has become widespread in Europe and Asia within the last 8 years

Recommendations for respiratory syncytial virus surveillance at national level

Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infections and hospitalisations among young children and is globally responsible for many deaths in young children, especially in infants aged <6 months. Furthermore, RSV is a common cause of severe respiratory disease and hospitalisation among older adults. The development of new candidate vaccines and monoclonal antibodies highlights the need for reliable surveillance of RSV. In the European Union (EU), no up-to-date general recommendations on RSV surveillance are currently available. Based on outcomes of a workshop with 29 European experts in the field of RSV virology, epidemiology and public health, we provide recommendations for developing a feasible and sustainable national surveillance strategy for RSV that will enable harmonisation and data comparison at the European level. We discuss three surveillance components: active sentinel community surveillance, active sentinel hospital surveillance and passive laboratory surveillance, using the EU acute respiratory infection and World Health Organization (WHO) extended severe acute respiratory infection case definitions. Furthermore, we recommend the use of quantitative reverse transcriptase PCR-based assays as the standard detection method for RSV and virus genetic characterisation, if possible, to monitor genetic evolution. These guidelines provide a basis for good quality, feasible and affordable surveillance of RSV. Harmonisation of surveillance standards at the European and global level will contribute to the wider availability of national level RSV surveillance data for regional and global analysis, and for estimation of RSV burden and the impact of future immunisation programmes