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Summary Background The degree to which infection with SARS-CoV-2 confers protection towards subsequent reinfection is not well described. In 2020, as part of Denmark's extensive, free-of-charge PCR-testing strategy, approximately 4 million individuals (69% of the population) underwent 10·6 million tests. Using these national PCR-test data from 2020, we estimated protection towards repeat infection with SARS-CoV-2. Methods In this population-level observational study, we collected individual-level data on patients who had been tested in Denmark in 2020 from the Danish Microbiology Database and analysed infection rates during the second surge of the COVID-19 epidemic, from Sept 1 to Dec 31, 2020, by comparison of infection rates between individuals with positive and negative PCR tests during the first surge (March to May, 2020). For the main analysis, we excluded people who tested positive for the first time between the two surges and those who died before the second surge. We did an alternative cohort analysis, in which we compared infection rates throughout the year between those with and without a previous confirmed infection at least 3 months earlier, irrespective of date. We also investigated whether differences were found by age group, sex, and time since infection in the alternative cohort analysis. We calculated rate ratios (RRs) adjusted for potential confounders and estimated protection against repeat infection as 1 – RR. Findings During the first surge (ie, before June, 2020), 533 381 people were tested, of whom 11 727 (2·20%) were PCR positive, and 525 339 were eligible for follow-up in the second surge, of whom 11 068 (2·11%) had tested positive during the first surge. Among eligible PCR-positive individuals from the first surge of the epidemic, 72 (0·65% [95% CI 0·51–0·82]) tested positive again during the second surge compared with 16 819 (3·27% [3·22–3·32]) of 514 271 who tested negative during the first surge (adjusted RR 0·195 [95% CI 0·155–0·246]). Protection against repeat infection was 80·5% (95% CI 75·4–84·5). The alternative cohort analysis gave similar estimates (adjusted RR 0·212 [0·179–0·251], estimated protection 78·8% [74·9–82·1]). In the alternative cohort analysis, among those aged 65 years and older, observed protection against repeat infection was 47·1% (95% CI 24·7–62·8). We found no difference in estimated protection against repeat infection by sex (male 78·4% [72·1–83·2] vs female 79·1% [73·9–83·3]) or evidence of waning protection over time (3–6 months of follow-up 79·3% [74·4–83·3] vs ≥7 months of follow-up 77·7% [70·9–82·9]). Interpretation Our findings could inform decisions on which groups should be vaccinated and advocate for vaccination of previously infected individuals because natural protection, especially among older people, cannot be relied on. Funding None.

Background Proton-pump inhibitors (PPIs) have been reported to increase the risk of community-associated Clostridium difficile infection (CDI), but the association remains disputed. Methods A nationwide cohort study among adults in Denmark, 2010–2013, linking register data on C. difficile testing, filled prescriptions, and patient characteristics. All incident episodes of community-associated CDI (ie, positive culture, molecular assay, or toxin test in individuals without previous hospitalization in the prior 12 weeks and without a positive test for C. difficile in the prior 8 weeks) were identified in the Danish National Microbiological Database. Self-controlled case-series analyses were used to estimate incidence rate ratios (IRRs) for community-associated CDI, comparing periods with and without exposure to PPIs. By design, models took fixed confounders such as chronic disease, genetics, and socioeconomic status into account; further, time-varying confounders, including hospital stay and antibiotic and corticosteroid use were adjusted for. Results 3583 episodes of community-associated CDI were identified, of which 964 occurred during current use of PPIs, 324 occurred 0–6 months after treatment cessation, 123 occurred 6–12 months after treatment cessation, and 2172 occurred during time periods without use of PPIs. The adjusted IRR was 2.03 (95% confidence interval, 1.74–2.36), comparing use of PPI with nonuse. The increased risk remained elevated in later time periods: 1.54 (1.31–1.80) for 0–6 months, 1.24 (1.00–1.53) for 6–12 months after current use. Conclusions Use of PPIs was associated with moderately increased risk of community-associated CDI. The risk remained elevated up to 1 year after PPI treatment had ended.

Background A growing body of evidence supports the safety of the human papillomavirus (HPV) vaccines. However, concerns about autonomic dysfunction syndromes and non-specific symptoms continue to linger. These conditions are not easily captured by traditional diagnostic classification schemes and call for innovative approaches to the study of vaccine safety which take more general measures of all-cause morbidity into account. Methods Taking advantage of the unique Danish registers, including regional registration of absence from school, we conducted a cohort study of 14 068 adolescent Danish girls attending 5th through 9th grade in public schools in the municipality of Copenhagen during 1 August 2013–23 January 2018. We obtained time-varying HPV vaccination status and demographic information from nationwide registers. Using Poisson regression with random effects, we estimated rate ratios (RRs) of absence due to illness, comparing HPV-vaccinated girls with unvaccinated girls with adjustment for grade, season, calendar period, demographic factors and random effects at the individual, class and school levels. Results Our study included 6 206 188 school days with 213 221 days of absence from school due to illness (absence rate, 3.4%). Comparing absence rates due to illness in HPV-vaccinated and unvaccinated girls yielded an adjusted RR of 1.00 (95% confidence interval [CI], 0.98–1.03). Conclusions Our study provides an important and novel contribution to HPV vaccine safety. Using absence from school records, we were able to address important safety concerns without relying on medical diagnoses. We conclude that HPV vaccination does not increase the risk of morbidity in any manner that manifests as absence from school due to illness.

BACKGROUND: In Denmark, the acceptance of the HPV vaccination program has been threatened by reports of suspected adverse events. Epstein Barr Virus (EBV) infection is associated with symptoms of long-lasting tiredness and may be misinterpreted as HPV vaccine adverse events. The main aim of this study was to examine if EBV infection around time of HPV vaccination was a risk factor for later suspected vaccine adverse events.METHODS: The study was a nationwide register-based matched case-control study. Cases were females vaccinated against HPV in the period 2011 throughout 2017 with suspected adverse events. For each case, five HPV vaccinated females without suspected adverse events were selected. Information about EBV infection was obtained from the Danish Microbiology Database and assessed for three time periods: (1) before first HPV vaccination, (2) around time of HPV vaccination, and (3) any time during the study period 2010-2017. Multiple logistic regression was used to estimate the association between EBV and suspected adverse events.RESULTS: We identified 1217 cases, matched to 6085 controls. A higher proportion of cases (38; 3.1%) than controls (31; 0.5%) were tested for EBV around time of HPV vaccination and cases had elevated odds for testing both EBV positive (OR 4.52, 95% CI 2.68-7.63) and EBV negative (OR 20.99, 95% CI 5.81-75.79). Only five females were classified with acute/recent EVB infection in this period.CONCLUSION: Misinterpretation of EBV infection late symptoms is not a leading explanation for Danish females experiencing suspected adverse events after HPV vaccination. Although EBV cannot be excluded as an explanatory factor for a very small proportion of suspected adverse events, the findings are more likely explained by protopathic bias, i.e. the fact that a larger proportion of females suspecting adverse events are tested for EBV.

Summary Background Surveillance systems for surgical site infections (SSIs), as a measure of patient safety, help health institutions devise strategies to reduce or prevent them. No surveillance systems exist to monitor SSIs in Ghana. Aim To establish a system for monitoring trends and detecting outbreaks in order to create awareness of and control SSIs. Methods An active 30-day surveillance was undertaken at the general surgical unit of the Korle Bu Teaching Hospital, from July 1st, 2017 to December 31st, 2018 to identify SSI. It involved a daily inpatient surveillance of patients who had had a surgical procedure, followed by post-discharge surveillance by means of a healthcare personnel-based survey and a patient-based telephone survey. We supplied quarterly feedback of results to surgeons. Findings Among the 3267 patients included, 331 were identified with an SSI, a 10% incidence risk. Patients who acquired an SSI experienced increased morbidity including nine extra days in hospital and an adjusted relative mortality risk of 2.3 (95% confidence interval: 1.3 - 4.1; P=0.006) compared to patients without SSI. Forty-nine per cent (161/331) of SSIs were diagnosed post discharge using the healthcare personnel-based survey. The patient-based telephone survey contributed 12 additional cases. SSI incidence risk decreased from 12.8% to 7.5% during the study period. Conclusion Post-discharge surveillance is feasible using existing healthcare personnel, and the results highlight the high risk and burden of SSIs in Ghana. A surveillance system with feedback for monitoring SSIs may contribute to reducing SSIs; however, firm conclusions regarding the impact need longer observation time.

Background Although the vast majority of individuals succumbing to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are elderly, infection fatality rate (IFR) estimates for the age group ≥70 years are still scarce. To this end, we assessed SARS-CoV-2 seroprevalence among retired blood donors and combined it with national coronavirus disease 2019 (COVID-19) survey data to provide reliable population-based IFR estimates for this age group. Methods We identified 60 926 retired blood donors aged ≥70 years in the rosters of 3 regionwide Danish blood banks and invited them to fill in a questionnaire on COVID-19–related symptoms and behaviors. Among 24 861 (40.8%) responders, we invited a random sample of 3200 individuals for blood testing. Overall, 1201 (37.5%) individuals were tested for SARS-CoV-2 antibodies (Wantai) and compared with 1110 active blood donors aged 17–69 years. Seroprevalence 95% confidence intervals (CIs) were adjusted for assay sensitivity and specificity. Results Among retired (aged ≥70 years) and active (aged 17–69 years) blood donors, adjusted seroprevalences were 1.4% (95% CI, .3–2.5%) and 2.5% (95% CI, 1.3–3.8%), respectively. Using available population data on COVID-19–related fatalities, IFRs for patients aged ≥70 years and for 17–69 years were estimated at 5.4% (95% CI, 2.7–6.4%) and .083% (95% CI, .054–.18%), respectively. Only 52.4% of SARS-CoV-2–seropositive retired blood donors reported having been sick since the start of the pandemic. Conclusions COVID-19 IFR in the age group >69 years is estimated to be 65 times the IFR for people aged 18–69 years.

Background: The more infectious SARS-CoV-2 lineage B.1.1.7 rapidly spread in Europe after December, 2020, and a concern that B.1.1.7 could cause more severe disease has been raised. Taking advantage of Denmark's high RT-PCR testing and whole genome sequencing capacities, we used national health register data to assess the risk of COVID-19 hospitalisation in individuals infected with B.1.1.7 compared with those with other SARS-CoV-2 lineages. Methods: We did an observational cohort study of all SARS-CoV-2-positive cases confirmed by RT-PCR in Denmark, sampled between Jan 1 and March 24, 2021, with 14 days of follow-up for COVID-19 hospitalisation. Cases were identified in the national COVID-19 surveillance system database, which includes data from the Danish Microbiology Database (RT-PCR test results), the Danish COVID-19 Genome Consortium, the National Patient Registry, the Civil Registration System, as well as other nationwide registers. Among all cases, COVID-19 hospitalisation was defined as first admission lasting longer than 12 h within 14 days of a sample with a positive RT-PCR result. The study population and main analysis were restricted to the proportion of cases with viral genome data. We calculated the risk ratio (RR) of admission according to infection with B.1.1.7 versus other co-existing lineages with a Poisson regression model with robust SEs, adjusted a priori for sex, age, calendar time, region, and comorbidities. The contribution of each covariate to confounding of the crude RR was evaluated afterwards by a stepwise forward inclusion. Findings: Between Jan 1 and March 24, 2021, 50 958 individuals with a positive SARS-CoV-2 test and at least 14 days of follow-up for hospitalisation were identified; 30 572 (60·0%) had genome data, of whom 10 544 (34·5%) were infected with B.1.1.7. 1944 (6·4%) individuals had a COVID-19 hospitalisation and of these, 571 (29·4%) had a B.1.1.7 infection and 1373 (70·6%) had an infection with other SARS-CoV-2 lineages. Although the overall number of hospitalisations decreased during the study period, the proportion of individuals infected with B.1.1.7 increased from 3·5% to 92·1% per week. B.1.1.7 was associated with a crude RR of hospital admission of 0·79 (95% CI 0·72–0·87; p

Background Improper use of antibiotics leads to the emergence of resistant microorganisms as well as drug toxicity, increased healthcare costs, morbidity and mortality. Globally, an estimated 25–68% of hospitalized patients receive suboptimal antibiotic regimes. Information on the extent of this problem in Ghana is currently limited, particularly in surgical units. To strategize for interventions, we estimated the antibiotic use prevalence in surgical departments in a country-wide point prevalence survey (PPS) in Ghana. Methods Between October 2016 and December 2016, we conducted a cross-sectional multi-center country-wide PPS. This involved an audit of in-patients’ records from all units/departments of ten systematically selected hospitals in Ghana. Data were collected with a standardized questionnaire, adopted from the European Centre for Disease Prevention and Control. In this report, we present data on antibiotic use from the surgical units. Results Of 2107 eligible patients included in the PPS, 540 patients were identified in surgical units, of which 70.7% (382/540) received antibiotic therapy. A total of 636 antibiotic prescriptions were issued to these surgical patients; 224 (58.6%) for treatment, including 50 for treatment of hospital-acquired infections, and 144 (37.7%) for prophylaxis (medical and surgical). Median duration of antibiotic therapy prior to the survey was 5 days (interquartile range (IQR): 3-8 days). Surgical prophylaxis was administered for longer than the recommended one day in 107 of 144 (88.4%) patients. The choice of antibiotics was largely similar for community- and hospital-acquired infections as well as for prophylaxis. Only 3.7% of patients had microbiological analysis done on clinical samples. Conclusion We found a high prevalence of antibiotic use, with the choice of antibiotics, in some cases, inconsistent with the country’s treatment guidelines. Antibiotics were administered for long duration including antibiotics for prophylactic purposes and the majority was started without supporting microbiological analysis. Prescription practices that encourage rational use of antibiotics guided by microbiology and enforcement of antibiotic policy guidelines should be the target for future interventions. Electronic supplementary material The online version of this article (10.1186/s12889-019-7162-x) contains supplementary material, which is available to authorized users.

The COVID-19 pandemic has led to an unprecedented demand for real-time surveillance data in order to inform critical decision makers regarding the management of the pandemic. The aim of this review was to describe how the Danish national microbiology database, MiBa, served as a cornerstone for providing data to the real-time surveillance system by linkage to other nationwide health registries. The surveillance system was established on an existing IT health infrastructure and a close network between clinical microbiologists, information technology experts, and public health officials. In 2020, testing capacity for SARS-CoV-2 was ramped up from none to over 10,000 weekly PCR tests per 100,000 population. The crude incidence data mirrored this increase in testing. Real-time access to denominator data and patient registries enabled adjustments for fluctuations testing activity, providing robust data on crude SARS-CoV-2 incidence during the changing diagnostic and management strategies. The use of the same data for different purposes, for example, final laboratory reports, information to the public, contact tracing, public health, and science, has been a critical asset for the pandemic response. It has also raised issues concerning data protection and critical capacity of the underlying technical systems and key resources. However, even with these limitations, the setup has enabled decision makers to adopt timely interventions. The experiences from COVID-19 may motivate a transformation from traditional indicator-based public health surveillance to an all-encompassing information system based on access to a comprehensive set of data sources, including diagnostic and reference microbiology.

BackgroundThe pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has tremendous consequences for our societies. Knowledge of the seroprevalence of SARS-CoV-2 is needed to accurately monitor the spread of the epidemic and also to calculate the infection fatality rate (IFR). These measures may help the authorities to make informed decisions and adjust the current societal interventions. Blood donors comprise approximately 4.7% of the similarly aged population of Denmark and blood is donated in all areas of the country. The objective of this study was to perform real-time seroprevalence surveying among blood donors as a tool to estimate previous SARS-CoV-2 infections and the population based IFR.MethodsAll Danish blood donors aged 17-69 years giving blood April 6 to 17 were tested for SARS-CoV-2 immunoglobulin M and G antibodies using a commercial lateral flow test. Antibody status was compared between areas and an estimate of the IFR was calculated. The seroprevalence was adjusted for assay sensitivity and specificity taking the uncertainties of the test validation into account when reporting the 95% confidence intervals (CI).ResultsThe first 9,496 blood donors were tested and a combined adjusted seroprevalence of 1.7% (CI: 0.9-2.3) was calculated. The seroprevalence differed across areas. Using available data on fatalities and population numbers a combined IFR in patients younger than 70 is estimated at 82 per 100,000 (CI: 59-154) infections.ConclusionsThe IFR was estimated to be slightly lower than previously reported from other countries not using seroprevalence data. The IFR, including only individuals with no comorbidity, is likely several fold lower than the current estimate. This may have implications for risk mitigation. We have initiated real-time nationwide anti-SARS-CoV-2 seroprevalence surveying of blood donations as a tool in monitoring the epidemic.

Background: The degree to which infection with SARS-CoV-2 confers immunity towards subsequent infection is not yet known. In 2020, as part of Denmark’s extensive, free-of-charge PCR-testing strategy, 4 million individuals (69% of the population) underwent 10.6 million tests. Using these national PCR-test data from 2020, we estimated the natural immunity towards SARS-CoV-2 after infection and investigated differences by age, sex and time since infection. Methods: Analysing the second surge of the epidemic (September–December, 2020) we compared infection rates between those with and without a previous positive test from the first surge (March–May). In an alternative time-to-event analysis, we compared infection rates throughout the year between those with and without a previous confirmed infection three or more months earlier. Rate ratios were adjusted for potential cofounders and natural immunity was estimated as one minus the rate ratio. Findings: Among PCR positive individuals from the first surge, 0·65% tested positive again during the second surge compared with 3·3% without a previous infection. The natural immunity was 80·5% (95% CI 75·4–84·5). The time-to-event analysis gave a similar estimate, as did the use of two and four months’ separation between repeat positive tests, and limiting the cohort to frequently tested health staff only. Among those aged 65+ years, observed immunity was 47% (95% CI 24·7–62·8). There was no difference in immunity by sex or evidence of waning immunity over time. Interpretation: Person-identifiable test results from large scale national PCR-testing in Denmark suggest that the within-season immunity following symptomatic or non-symptomatic infection is around 80%, although significantly lower in the elderly. These findings may inform decisions of which groups to vaccinate and advocate for vaccination of previously infected individuals as natural protection among elderly citizens cannot be relied upon. Funding: No designated funding was received for this study. DM was funded by the European Centers for Disease Control and Prevention programme EUPHEM. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: The present study was based on existing administrative data and did not require ethical approval.

Objectives: The aim of this study was to make a comprehensive economic assessment of the costs of hospital-acquired C. difficile infections (CDI).Methods: We carried out a retrospective matched cohort study utilizing Danish registry data with national coverage to identify CDI cases and matched reference patients without CDI (controls) for economic burden assessment in Denmark covering 2011–2014. Health care costs and public transfer costs were obtained from national registries, and calculated for 1 year prior to, and 2 years after index admission using descriptive statistics and regression analysis.Results: The study included 12,768 CDI patients and 23,272 matched controls. The total health care cost was significantly larger for CDI cases than controls throughout all periods. During the index admission period, cost was €12,867 per CDI case compared to €4,522 (p < 0.001) for controls, which increased to an average of €31,388 and €19,512 (p < 0.001) in Year 1 for the two groups, respectively. Excess costs were found both among infections with onset in hospitals and in the community. Diagnosis compatible with complications increased costs to on average >€91,000 per case. The regression analysis showed that CDI adds a substantial economic burden, but only explains about 1/3 of the crude difference observed in the matched analysis.Discussion: The major economic impact of hospital-acquired CDI with complications underlines the importance of preventing complications in these patients. Our study provides an informed estimate of the potential economic gain per patient by successful intervention, which is likely to be relatively comparable across countries.

Background There is limited data to guide the prevention and management of surgical site infections (SSI) in low- and middle-income countries. We prospectively studied aetiological agents associated with SSI and their corresponding antibiotic susceptibility patterns in a tertiary hospital in Ghana. Methods As part of a cohort study carried out at the surgical department of the Korle Bu Teaching Hospital (KBTH) from July 2017 to April 2019, wound swabs were collected from patients diagnosed with SSI. Isolates cultured from the wound swabs were identified by MALDI TOF and susceptibility testing was conducted according to EUCAST 2020 guidelines. Clinical data were monitored prospectively. Results Of 4577 patients, 438 developed an SSI and 352 microbial isolates were cultured. Isolates were predominantly Gram negative (286, 81%), a pattern seen for all kinds of surgery and all wound classes. The most common species included Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus and Acinetobacter baumannii. The majority of organisms were multi-drug resistant including 86% of E. coli, 52% of A. baumannii and 86% of K. pneumoniae; and 65% (17/26) of the cefotaxime-resistant K. pneumoniae were extended spectrum β-lactamase producing. One of 139 E. coli, 15 of 49 P. aeruginosa, and 6 of 23 A. baumannii were meropenem resistant, but no clonal pattern was found. There was a 1% (5/428) prevalence of methicillin-resistant S. aureus. Conclusions The predominance of Gram-negative organisms and the high level of multi-drug resistance indicate a need to re-evaluate antibiotic prophylaxis and treatment protocols in surgical practice in low- and middle-income countries.

Background The course of coronavirus disease 2019 (COVID-19) seems to be aggravated by air pollution, and some industrial chemicals, such as the perfluorinated alkylate substances (PFASs), are immunotoxic and may contribute to an association with disease severity. Methods From Danish biobanks, we obtained plasma samples from 323 subjects aged 30–70 years with known SARS-CoV-2 infection. The PFAS concentrations measured at the background exposures included five PFASs known to be immunotoxic. Register data was obtained to classify disease status, other health information, and demographic variables. We used ordered logistic regression analyses to determine associations between PFAS concentrations and disease outcome. Results Plasma-PFAS concentrations were higher in males, in subjects with Western European background, and tended to increase with age, but were not associated with the presence of chronic disease. Of the study population, 108 (33%) had not been hospitalized, and of those hospitalized, 53 (16%) had been in intensive care or were deceased. Among the five PFASs considered, perfluorobutanoic acid (PFBA) showed an unadjusted odds ratio (OR) of 2.19 (95% confidence interval, CI, 1.39–3.46) for increasing severities of the disease. Among those hospitalized, the fully adjusted OR for getting into intensive care or expiring was 5.18 (1.29, 20.72) when based on plasma samples obtained at the time of diagnosis or up to one week before. Conclusions Measures of individual exposures to immunotoxic PFASs included short-chain PFBA known to accumulate in the lungs. Elevated plasma-PFBA concentrations were associated with an increased risk of a more severe course of COVID-19. Given the low background exposure levels in this study, the role of exposure to PFASs in COVID-19 needs to be ascertained in populations with elevated exposures.

BackgroundThe Covid-19 pandemic is one of the most serious global public health threats in recent times. Understanding transmission of SARS-CoV-2 is of utmost importance to be able to respond to outbreaks and take action against spread of the disease. Transmission within the household is a concern, especially because infection control is difficult to apply within the household domain.MethodsWe used comprehensive administrative register data from Denmark, comprising the full population and all COVID-19 tests, to estimate household transmission risk and attack rate.ResultsWe studied the testing dynamics for COVID-19 and found that the day after receiving a positive test result within the household, 35% of potential secondary cases were tested and 13% of these were positive. After a primary case in 6,782 households, 82% of potential secondary cases were tested within 14 days, of which 17% tested positive as secondary cases, implying an attack rate of 17%. Among primary cases, those aged 0-24 were underrepresented when compared with the total population. We found an approximately linearly increasing relationship between attack rate and age. We investigated the transmission risk from primary cases by age, and found an increasing risk with age of primary cases for adults, while the risk seems to decrease with age for children.ConclusionsAlthough there is an increasing attack rate and transmission risk of SARS-CoV-2 with age, children are also able to transmit SARS-CoV-2 within the household.

Significant increases in excess all-cause mortality, particularly in the elderly, were observed during the winter of 2014/15 in England. With influenza A(H3N2) the dominant circulating influenza A subtype, this paper determines the contribution of influenza to this excess controlling for weather. A standardised multivariable Poisson regression model was employed with weekly all-cause deaths the dependent variable for the period 2008–2015. Adjusting for extreme temperature, a total of 26 542 (95% CI 25 301–27 804) deaths in 65+ and 1942 (95% CI 1834–2052) in 15–64-year-olds were associated with influenza from week 40, 2014 to week 20, 2015. This is compatible with the circulation of influenza A(H3N2). It is the largest estimated number of influenza-related deaths in England since prior to 2008/09. The findings highlight the potential health impact of influenza and the important role of the annual influenza vaccination programme that is required to protect the population including the elderly, who are vulnerable to a severe outcome.

Eurosurveillance.org is the online home of Eurosurveillance, Europe's journal on infectious disease surveillance, epidemiology, prevention and control.

ObjectiveTo provide population-level knowledge on individuals at high risk of severe and fatal coronavirus disease 2019 (COVID-19) in order to inform targeted protection strategies in the general population and appropriate triage of hospital contacts.Design, Setting, and ParticipantsNationwide population-based cohort of all 228.677 consecutive Danish individuals tested (positive or negative) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA from the identification of the first COVID-19 case on February 27th, 2020 until April 30th, 2020.Main Outcomes and MeasuresWe examined characteristics and predictors of inpatient hospitalization versus community-management, and death versus survival, adjusted for age-, sex- and number of comorbidities.ResultsWe identified 9,519 SARS-CoV-2 PCR-positive cases of whom 78% were community-managed, 22% were hospitalized (3.2% at an intensive care unit) and 5.5% had died within 30 days. Median age varied from 45 years (interquartile range (IQR) 31-57) among community-managed cases to 82 years (IQR 7589) among those who died. Age was a strong predictor of fatal disease (odds ratio (OR) 14 for 70-79-year old, OR 26 for 80-89-year old, and OR 82 for cases older than 90 years, when compared to 50-59-year old and adjusted for sex and number of comorbidities). Similarly, the number of comorbidities was strongly associated with fatal disease (OR 5.2, for cases with ≥4 comorbidities versus no comorbidities), and 82% of fatal cases had at least 2 comorbidities. A wide range of major chronic diseases were associated with hospitalization with ORs ranging from 1.3-1.4 (e.g. stroke, ischemic heart disease) to 2.2-2.7 (e.g. heart failure, hospital-diagnosed kidney disease, chronic liver disease). Similarly, chronic diseases were associated with mortality with ORs ranging from 1.2-1.3 (e.g. ischemic heart disease, hypertension) to 2.4-2.7 (e.g. major psychiatric disorder, organ transplantation). In the absence of comorbidities, mortality was relatively low (5% or less) in persons aged up to 80 years.Conclusions and RelevanceIn this first nationwide population-based study, increasing age and number of comorbidities were strongly associated with hospitalization requirement and death in COVID-19. In the absence of comorbidities, the mortality was, however, lowest until the age of 80 years. These results may help in accurate identification, triage and protection of high-risk groups in general populations, i.e. when reopening societies.

Background Several studies have investigated a possible association between respiratory infection and acute myocardial infarction (MI). As both influenza and pneumococcal infections are vaccine preventable, understanding the populations affected by virus-induced cardiovascular complications is important to guide public health and clinical practice. Aim This observational study aimed to quantify the association between laboratory-confirmed respiratory bacteria or virus infections and risk of first MI or stroke, by using self-controlled case series (SCCS) analysis of anonymised linked electronic Danish health records. Methods The SCCS method was used to determine the relative incidence of the first event of MI and stroke occurring within 28 days after laboratory-confirmed respiratory infections compared with the baseline time period. Results In the age and season adjusted analyses for first acute MI, the incidence ratios (IR) of a MI event occurring during the risk period were significantly elevated following a Streptococcus pneumoniae infection with values of 20.1, 11.0 and 4.9 during 1–3, 4–7 and 8–14 days, respectively and following respiratory virus infection with values of 15.2, 4.5 and 4.4 during 1–3, 8–14 and 15–28 days, respectively. The significantly elevated IRs for stroke following an S. pneumoniae infection were 25.5 and 6.3 during 1–3 and 8–14 days, respectively and following respiratory virus infection 8.3, 7.8 and 6.2 during 1–3, 4–7 and 8–14 days, respectively. Conclusion This study suggested a significant cardiovascular event triggering effect following infection with S. pneumoniae and respiratory viruses (mainly influenza), indicating the importance of protection against vaccine-preventable respiratory infections.

Background: In 2014, Denmark experienced a rapid decline in vaccination uptake for the human papillomavirus (HPV) vaccine after a successful introduction of the vaccine in 2009. Before the decline, the uptake of the first HPV vaccine was around 90% for girls born in the period 1998 to 2000, while it dropped to 54% for girls born in 2003. The decline followed negative public attention from 2013 coinciding with increasing suspected adverse-event reporting to the Danish Medicines Agency. The aim of this study is to describe the HPV-vaccination uptake, to quantify relevant HPV-related media coverage, and analyse the relation between media coverage and HPV-vaccination acceptance in Denmark in year 2009-2016. Methods: Three types of data were used for the analysis: Immunisation data from 243,415 girls, media coverage (8524 news items) and Google search activity. We used changes in the correlation between media coverage and vaccination uptake to identify a changing point in their relationship. The relationship before and after the changing point was analysed determined on the interactions between vaccination uptake, media and search activity, with search activity as a proxy for public attention. Results: We identified July 2013 as a changing point in the relationship between media coverage and vaccination uptake. We found no significant relationship between media coverage and vaccination uptake in the first part of the time series (June 2009 to June 2013), whereas from July 2013 and onwards there was a negative Pearson's correlation of - 0.52. The changing point coincides with both an increase in Google searches for "HPV side effects" and media coverage with negative content. Conclusions: Following a successful launch of the HPV-vaccination programme, concerns about vaccine safety shifted the public opinion and the coverage by the media. The noticeable shift in correlation between vaccination uptake and media coverage before and after July 2013 could indicate that increased media coverage influenced the decline in vaccination uptake. Media monitoring may represent an important tool in future monitoring and assessment of confidence in vaccination programmes.

Background Each year more than 4,000 cases of campylobacteriosis are reported in Denmark, making it the most common bacterial gastrointestinal infection. Here we describe a case-control study to identify sources of infection with a focus on environmental factors. Methods From January to December 2016, we conducted a prospective case-control study among Danish persons aged 1-30 years. Participants were invited by letter to complete an online questionnaire. Crude and adjusted ORs were calculated and final parsimonious multivariate models developed using logistic regression. Results The study recruited 1366 cases and 4,418 controls, of whom 65% and 66%, respectively, completed the questionnaire. A multivariate model for domestically acquired cases showed, among others, increased risk of infection with bathing in fresh water (OR=5.1), contact to beach sand (OR=1.8), owning a pet dog with diarrhea (OR=4.6), and eating minced beef (OR=2.6) or chicken (OR=2.5). The model for children highlighted similar risk factors but also included bathing in a paddling pool (OR=13.6) and eating fresh strawberries (OR=5.3). A separate analysis for persons reporting foreign travel showed increased infection risk when traveling to Asia, Africa, or Turkey and that eating from street kitchens and having contact to water during traveling were also risk factors. Conclusion Environmental factors and animal contact account for a sizeable proportion of domestic Campylobacter infections in the age group studied. The study also re-confirmed handling/consumption of chicken as an important risk factor while highlighting minced beef as a potential new risk factor. Overall, these results contribute to a better understanding of the transmission dynamics of Campylobacter and will be used to improve national guidelines for prevention of infection.

Background In temperate zones, all-cause mortality exhibits a marked seasonality, and influenza represents a major cause of winter excess mortality. We present a statistical model, FluMOMO, which estimate influenza-associated mortality from all-cause mortality data and apply it to Danish data from 2010/11 to 2016/17. Methods We applied a multivariable time series model with all-cause mortality as outcome, influenza activity and extreme temperatures as explanatory variables while adjusting for time trend and seasonality. Three indicators of weekly influenza activity (IA) were explored: percentage of consultations for influenza-like illness (ILI) at primary health care, national percentage of influenza-positive samples, and the product of ILI percentage and percentage of influenza-positive specimens in a given week, that is, the Goldstein index. Results Independent of the choice of parameter to represent influenza activity, the estimated influenza-associated mortality showed similar patterns with the Goldstein index being the most conservative. Over the 7 winter seasons, the median influenza-associated mortality per 100 000 population was 17.6 (range: 0.0-36.8), 14.1 (0.3-31.6) and 8.3 (0.0-25.0) for the 3 indicators, respectively, for all ages. Conclusion The FluMOMO model fitted the Danish data well and has the potential to estimate all-cause influenza-associated mortality in near real time and could be used as a standardised method in other countries. We recommend using the Goldstein index as the influenza activity indicator in the FluMOMO model. Further work is needed to improve the interpretation of the estimated effects.

Background Varicella, most often a benign disease of childhood, is associated with an increased risk of arterial ischemic stroke in children. The aim of the present study was to estimate the incidence of post-varicella arterial ischemic stroke in the Danish child population and describe clinical characteristics of children admitted with post-varicella arterial ischemic stroke. Methods In the Danish National Patient Register, we identified inpatients 28 days to 16 years of age with a discharge diagnosis of stroke or cerebrovascular disease from 2010 to 2016. Medical files were reviewed, and children with arterial ischemic stroke and varicella infection less than 12 months before onset of symptoms were included. Results We identified 15 children with arterial ischemic stroke and varicella less than 12 months before. In nine children, the diagnosis was confirmed by detection of varicella zoster virus DNA or varicella zoster virus immunoglobulin G in the cerebrospinal fluid. All children were previously healthy, the mean age was four years, and 67% were male. The median time from varicella rash to arterial ischemic stroke was 4.6 months. The most common location of arterial ischemic stroke was the basal ganglia, and affected vessels were most often in the anterior circulation. Fifty-three percent experienced neurological sequelae of varying degree. Conclusions In Denmark, where varicella vaccination is not part of the childhood vaccination program, the estimated risk of post-varicella arterial ischemic stroke was one case (including possible cases) per 26,000 children with varicella.

Background: In recent years, human papillomavirus (HPV) vaccination of boys has been added to childhood vaccination programmes in several countries but, so far, no systematic population-based assessment with long-term follow-up has been undertaken of the relative incidence of adverse outcomes following HPV vaccination in this group. We investigated if quadrivalent HPV (qHPV) vaccination of 10-17-year-old boys is associated with any unusual risk of autoimmune diseases, neurological diseases or venous thromboembolism.Methods: We conducted a national cohort study of 568 410 boys born in Denmark 1988-2006 and followed for 4 million person-years during 2006-16, using nationwide registers to obtain individual-level information about received doses of the qHPV vaccine and hospital records for 39 autoimmune diseases, 12 neurological diseases and venous thromboembolism. For each outcome, we estimated incidence rate ratios (RRs) with 95% confidence intervals (CIs) according to qHPV vaccination status.Results: Altogether 7384 boys received at least one dose of the qHPV vaccine at age 10-17 years. Overall, RRs were close to unity for the combined groups of autoimmune diseases (RR = 0.96; 95% CI: 0.71-1.28, n = 46 cases in qHPV-vaccinated boys) and neurological diseases (RR = 0.67; 0.41-1.10, n = 16), as well as for venous thromboembolism (RR = 0.88; 0.33-2.35, n = 4). After taking multiple testing into account, none of the 52 individual outcomes studied appeared to occur in excess among qHPV-vaccinated boys.Conclusions: Although additional large-scale epidemiological studies are warranted, our findings provide population-based reassurance that qHPV vaccination of 10-17-year-old boys is unlikely to be associated with an elevated risk of autoimmune diseases, neurological diseases or venous thromboembolism.

MRSA CC398 is an emerging MRSA strain found in livestock, mainly in pigs. Direct occupational livestock contact is the principal risk factor for human MRSA CC398 infection. Nonetheless, in recent years, an increasing number of MRSA CC398 cases has been observed in persons without known pig contact. Such cases, referred to as MRSA CC398 of unknown origin (MUO CC398), have, like livestock-onset (LO) MRSA CC398 cases, been found concentrated in rural, livestock-producing areas. The presence of MUO CC398 cases indicates alternative and unknown MRSA CC398 transmission pathways into the community. We performed a nationwide study in Denmark of the geographic distributions of MRSA cases in general and persons with MUO CC398 or LO MRSA CC398 infections (1 January 2006-11 February 2015), with the Danish population as background population. Place of living of study persons was mapped using the ArcGIS software, and information on pig farms was retrieved from the Central Husbandry Register. The incidence of MUO CC398 infections was clearly higher in rural than in urban areas, and such cases lived on average closer to pig farms than the general population. However, within three pig-farming-dense municipalities, patients with MUO CC398 infections did not live closer to pig farms than population controls. This shows that direct environmental spread from neighbouring pig farms of MRSA CC398 is unlikely. Instead, community spread through other means of transmission than direct spread from farms may more likely explain the clustering of MUO CC398 in livestock-dense areas.

SUMMARYVaricella, usually a mild disease of childhood, can also cause complications and hospitalization. Universal varicella immunization is implemented in several countries worldwide, but not in Denmark. Taking advantage of unique national registers, we aimed to estimate the incidence of paediatric varicella hospitalizations and assess determinants for hospitalization. For this purpose, we designed a nationwide, retrospective register study of paediatric varicella hospitalizations and applied a case–cohort design and logistic regression analysis comparing hospitalized varicella patients to a sample of the entire paediatric population in Denmark. Varicella patients were identified in The Danish National Patient Register and referents were randomly selected from the Danish Civil Registration System. The incidence of paediatric varicella admissions was 11/100 000 children 0–18 years of age/year. Of admitted children 67·1% had complications and 30·0% had underlying disease. All categories of underlying disease significantly increased the odds of hospitalization as well as male gender and not having been born in Denmark. In conclusion, we found a considerable burden of paediatric varicella disease in Danish hospitals, of similar magnitude as in other European countries comparable to Denmark. With this study we have provided epidemiological data needed for considering implementation of varicella vaccine in Denmark.

Major surgery carried out in low- and middle-income countries is associated with a high risk of surgical site infections (SSI), but knowledge is limited regarding contributory factors to such infections. This study explores factors related to patients developing an SSI in a teaching hospital in Ghana. A prospective cohort study of patients undergoing abdominal surgical procedures was conducted at Korle Bu Teaching Hospital. Patient characteristics, procedures and environmental characteristics were recorded. A 30-day daily surveillance was used to diagnose SSI, and Poisson regression analysis was used to test for association of SSI and risk factors; survival was determined by proportional hazard regression methods. We included 358 patients of which 58 (16.2%; 95% CI 12.7–20.4%) developed an SSI. The median number of door openings during an operation was 79, with 81% being unnecessary. Door openings greater than 100 during an operation (P = 0.028) significantly increased a patient's risk of developing an SSI. Such patients tended to have an elevated mortality risk (hazard ratio 2.67; 95% CI 0.75–9.45, P = 0.128). We conclude that changing behaviour and practices in operating rooms is a key strategy to reduce SSI risk.

The global challenges and threats from infectious diseases including antimicrobial drug resistance and emerging infections due to the rapidly changing climate require that we continuously revisit the fitness of our infrastructure. The databases used for surveillance represent an important infrastructure. Historically, many databases have evolved from different needs and from different organizations. Despite growing data storage and computing capacities, data are, however, rarely used to their full potential. The objective of this review was to outline different data sources available in Denmark. We applied a one-health perspective and included data sources on animal demographics and movements, medicine prescription, diagnostic test results as well as relevant data on human health. Another objective was to suggest approaches for fit-for-purpose integration of data as a resource for risk assessment and generation of evidence for policies to protect animal and human health. Danish databases were reviewed according to a systematic procedure including ownership, intended purposes of the database, target and study populations, metrics and information used, measuring methods (observers, diagnostic tests), recording procedures, data flow, database structure, and control procedures to ensure data quality. Thereby, structural metadata were gathered across available Danish databases including animal health, zoonotic infections, antimicrobial use, and relevant administrative data that can support the overall aim of supporting risk assessment and development of evidence. Then illustrative cases were used to assess how combinations and integration of databases could improve existing evidence to support decisions in animal health policies (e.g., combination of information on diseases in different herds or regions with information on isolation of pathogens from humans). Due to the complexity of databases, full integration at the individual level is often not possible. Still, integration of data at a higher level (e.g., municipality or region) can provide important information on risks and hence risk management. We conclude by discussing how databases by linkage can be improved in the future, and emphasize that legal issues are important to address in order to optimize the use of the available data.

Background Suspected adverse events (AE) after human papillomavirus (HPV) vaccines include postural orthostatic tachycardia syndrome (POTS), chronic fatigue syndrome (CFS), complex regional pain syndrome (CRPS) and symptoms including headache and orthostatic intolerance. Aim We aimed to identify phenotypes of AEs after HPV vaccination, defined as patterns of AE terms (signs, symptoms, diagnoses), and to evaluate if identified phenotypes reflected previously suspected symptomatology or heightened public concerns over HPV vaccine safety since 1 January 2015. Methods We conducted a retrospective observational study using latent class cluster analysis of all serious AE reports (n = 963) reported by females residing in Denmark between September 2009 and August 2017. Resulting clusters were characterised according to AE terms associated with POTS, CFS and CRPS before (September 2009–December 2014) and during (January 2015–August 2017) a time of heightened media activity regarding HPV vaccines. Results Four clusters of AE reports were distinguished. The most common symptoms were fatigue, dizziness and headache but their frequency varied among clusters. The majority of reports in one cluster were submitted during a period of heightened media activity, including an anomalous spike in submissions in December 2015; a high proportion of these reports included the symptoms cognitive disorder (78%), abdominal pain (77%), dysuria (60%) and sleep disorder (60%). Conclusions Non-specific symptoms including headache, fatigue and dizziness feature prominently in serious AE reports from females in Denmark. Our analysis identified a cluster of reports, likely media stimulated, with a focus on symptoms of CFS and POTS.

Objectives: Weekly monitoring of European all-cause excess mortality, the EuroMOMO network, observed high excess mortality during the influenza B/Yamagata dominated 2017/18 winter season, especially among elderly. We describe all-cause excess and influenza-attributable mortality during the season 2017/18 in Europe. Methods: Based on weekly reporting of mortality from 24 European countries or sub-national regions, representing 60% of the European population excluding the Russian and Turkish parts of Europe, we estimated age stratified all-cause excess morality using the EuroMOMO model. In addition, age stratified all-cause influenza-attributable mortality was estimated using the FluMOMO algorithm, incorporating influenza activity based on clinical and virological surveillance data, and adjusting for extreme temperatures. Results: Excess mortality was mainly attributable to influenza activity from December 2017 to April 2018, but also due to exceptionally low temperatures in February-March 2018. The pattern and extent of mortality excess was similar to the previous A(H3N2) dominated seasons, 2014/15 and 2016/17. The 2017/18 overall all-cause influenza-attributable mortality was estimated to be 25.4 (95%CI 25.0-25.8) per 100,000 population; 118.2 (116.4-119.9) for persons aged 65. Extending to the European population this translates into over-all 152,000 deaths. Conclusions: The high mortality among elderly was unexpected in an influenza B dominated season, which commonly are considered to cause mild illness, mainly among children. Even though A(H3N2) also circulated in the 2017/18 season and may have contributed to the excess mortality among the elderly, the common perception of influenza B only having a modest impact on excess mortality in the older population may need to be reconsidered. info:eu-repo/semantics/publishedVersion

Background Although the timely isolation of patients is an essential intervention to limit spread of drug-resistant bacteria, information about the colonization status is often unavailable or lost when patients are readmitted or transferred between hospitals. Therefore, carriers of drug resistant bacteria are not recognized sufficiently early, and proper and timely isolation precautions are not taken. Consequently, resistant bacteria of public health concerns including vancomycin resistant enterococci (VRE) and methicillin resistant Staphylococcus aureus (MRSA) can spread epidemically. To ensure timely identification and proper isolation of such patients we developed an automatic real-time alert of carriers of drug resistant bacteria. Objectives The aim of this paper is to describe the system, called MiBAlert, and share the initial experiences in connection with an outbreak of VRE in the greater Copenhagen area (the Capital region), Denmark. Methods We obtained data on cases of VRE from hospitals in Copenhagen during the period when the first version of MiBAlert was implemented and log-data on the use of MiBAlert. Furthermore, a survey was conducted among 88 staff members to investigate their experiences of MiBAlert. Results The alert is a tool directed toward healthcare personnel accessing the electronic health record (EHR) and those further involved in the care and treatment of the patient. It is based on a web service using data from the national microbiological database, MiBa. MiBAlert is a real-time electronic non-intrusive alert generated automatically in the header of the EHR each time record is accessed. On February 15, 2015 a pilot version of MiBAlert was launched. All positive tests for VRE throughout 1year were shown with alert status by MiBAlert visible to all medical staff with access to EHR. The alert system was automatically updated directly in the EHR across the five hospitals in the Capital region. We found that the system performed satisfactorily, being operational 24/7 all 135 trial days, apart from 72min, for all the hospitals. Of the staff who responded to the survey, 82% considered that MiBAlert overall improved compliance with isolation precautions regarding VRE-positive patients. We found a marked decline of new patients infected or colonized with VRE concomitant with the implementation of MiBAlert and the survey results. Conclusion We found that MiBAlert was a valuable tool in a bundle approach to counter a multiple hospital outbreak of VRE, and that it has a great potential to improve the control of other drug-resistant bacteria.

Listeria monocytogenes may contaminate and persist in food production facilities and cause repeated, seemingly sporadic, illnesses over extended periods of time. We report on the investigation of two such concurrent outbreaks. We compared patient isolates and available isolates from foods and food production facilities by use of whole-genome sequencing and subsequent multilocus sequence type and single nucleotide polymorphism analysis. Outbreak cases shared outbreak strains, defined as Listeria monocytogenes isolates belonging to the same sequence type with fewer than five single nucleotide polymorphism differences. We performed routine food consumption interviews of L. monocytogenes patients and compared outbreak cases with sporadic cases. Two outbreaks were defined, each consisting of ten outbreak cases in the period 2013-15. Seven outbreak cases and a fetus in gestational week 38 died. Listeria monocytogenes isolates from cold smoked or gravad fish products or their two respective production environments were repeatedly found to belong to the outbreak strains. Outbreak cases more often than sporadic cases stated that they consumed the relevant fish products, odds ratio 10.7. Routine collection and typing of food isolates was key to solving the outbreaks. Furthermore, these outbreaks illustrate the value of whole-genome sequencing for outbreak definition and investigation. Whole-genome sequencing combined with epidemiological investigations provided the discriminatory power to recognize low-intensity, extended time-period outbreaks and link them to food products from two different contaminated production facilities with sufficient strength for food authorities to intervene on. Cold smoked and gravad fish constitute risk products and may be responsible for more listeriosis cases than previously recognized.

BACKGROUND Listeriosis is a serious foodborne infection. Outbreaks of listeriosis occur rarely, but have often proved difficult to solve. In June 2014, we detected and investigated a listeriosis outbreak in Denmark using patient interviews and whole-genome sequencing (WGS). METHODS We performed WGS on Listeria monocytogenes isolates from patients and available isolates from ready-to-eat foods and compared them using single-nucleotide polymorphism (SNP) analysis. Case patients had L. monocytogenes with ≤3 SNPs (the outbreak strain) isolated in September 2013-December 2014. Through interviews, we established case patients' food and clinical histories. Food production facilities were inspected and sampled, and we performed trace-back/trace-forward of food delivery chains. RESULTS In total, 41 cases were identified; 17 deaths occurred (41%). An isolate from a delicatessen meat (spiced meat roll) from company A was identical to the outbreak strain. Half of the patients were infected while hospitalized/institutionalized; institutions were supplied food by company A. The outbreak strain was repeatedly isolated from further samples taken within this company and within companies in its distribution chain. Products from company A were traced and recalled from >6000 food establishments, after which the outbreak ended. CONCLUSIONS Ready-to-eat spiced meat roll from a single production facility caused this outbreak. The product, served sliced and cold, is popular among the elderly; serving it at hospitals probably contributed to the high case-fatality rate. WGS used for patient isolates and isolates from food control inspections, coupled with routine epidemiological follow-up, was instrumental in swiftly locating the source of infections, preventing further illnesses and deaths.

Objective To evaluate the association between quadrivalent human papillomavirus vaccination and syndromes with autonomic dysfunction, such as chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome. Design Population-based self-controlled case series. Setting Information on human papillomavirus vaccinations and selected syndromes with autonomic dysfunction (chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome) identified using ICD-10 (international classification of diseases, revision 10) diagnostic codes from Danish nationwide registers. Participants 869 patients with autonomic dysfunction syndromes from a cohort of 1 375 737 Danish born female participants aged 10 to 44 years during 2007-16. Main outcome measures Self-controlled case series rate ratios (95% confidence intervals) of the composite outcome of chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome, adjusted for age and season, comparing female participants vaccinated and unvaccinated with the quadrivalent human papillomavirus vaccine. Chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome were also considered separately in secondary analyses. Results During 10 581 902 person years of follow-up, 869 female participants with syndromes of autonomic dysfunction (136 with chronic fatigue syndrome, 535 with complex regional pain syndrome, and 198 with postural orthostatic tachycardia syndrome) were identified. Quadrivalent human papillomavirus vaccination did not statistically significantly increase the rate of a composite outcome of all syndromes with autonomic dysfunction in a 365 day risk period following vaccination (rate ratio 0.99, 95% confidence interval 0.74 to 1.32) or the rate of any individual syndrome in the risk period (chronic fatigue syndrome (0.38, 0.13 to 1.09), complex regional pain syndrome (1.31, 0.91 to 1.90), or postural orthostatic tachycardia syndrome (0.86, 0.48 to 1.54)). Conclusions When vaccination is introduced, adverse events could occur in close temporal relation to the vaccine purely by chance. These results do not support a causal association between quadrivalent human papillomavirus vaccination and chronic fatigue syndrome, complex regional pain syndrome, or postural orthostatic tachycardia syndrome, either individually or as a composite outcome. An increased risk of up to 32% cannot be formally excluded, but the statistical power of the study suggests that a larger increase in the rate of any syndrome associated with vaccination is unlikely.

Background: In 2013–15, Denmark experienced an increase in reported suspected adverse events following vaccination (AEFI) against human papilloma virus (HPV). Dedicated centres (“One Access”) were established in order to standardize management of patients who experienced medically unexplained physical symptoms after HPV vaccination. Since One Access was targeted patients with suspected AEFI after HPV vaccination, we used this opportunity to estimate completeness in AEFI reporting to the Danish Medicines Agency (DMA), and explore the topic of AEFI reporting from the perspective of physicians working at the centres to better understand health professionals’ reporting behaviour. Methods: The study consisted of a quantitative and a qualitative part. In the quantitative analysis, we used the Danish civil registry number to merge a line-list of all One Access patients referred in 2015 with total number of patients who had reported suspected serious AEFI following HPV vaccination to the DMA in the years 2009–2015. We conducted four semi-structured interviews with doctors representing three out of five regions. The Theoretical Domains Framework together with empirical data from two clinical fieldtrips guided the formation of the qualitative study. Results: Among 1577 One Access patients, only 404 (26%) were reported to the DMA. We found significant regional differences in reporting completeness (p < 0.001) and differences between regions when looking at reporters’ backgrounds (healthcare professionals vs non-professionals; p = 0.004). We identified several factors of importance for reporting behaviour amongst physicians, mainly under the domains of Knowledge, Motivation & Goals, and Environmental Context. Conclusions: Despite an official aim of homogenous case management, reporting of suspected AEFI was incomplete with large regional differences. The qualitative study corroborated that reporting behaviour was contextual. This observation represents an important caveat in interpreting data from AEFI reporting, in particular when these data are used for research or policymaking.

HPV vaccination has been offered to 12-year-old girls as part of the Danish Childhood Vaccination Programme since 2009. From 2013, an increasing number of suspected severe adverse events (AE) without a documented causal link to the vaccine was observed, resulting in public concerns about vaccine safety and a decline in uptake. This study aimed at describing the group of females reporting AE and comparing them to vaccinated peers not reporting AE. A questionnaire focusing on demographics, lifestyle, and health-related issues was distributed to 251 female cases who had reported severe AE and 1,003 female controls randomly selected from the population-based Danish Vaccination Registry. All had been HPV-vaccinated. There were no significant differences on measures of self-reported psychiatric or somatic conditions before vaccination. More cases reported being physically very active prior to first HPV vaccination (OR 4.2) whereas fewer cases than controls sometimes (OR 0.31) or often/always (OR 0.36) felt sad. This is unexpected because two recent Danish registry-based case-control studies concluded that females reporting severe AE were more likely to consult a psychologist/psychiatrist and to have pre-existing psychiatric conditions before first HPV vaccination. One of these studies also showed that cases had increased health-care seeking regarding a number of somatic conditions prior to first vaccination. Our study adds value when seeking to understand the lifeworld of the affected females and their interpretations of their everyday lives pre- and post-HPV vaccination.

BACKGROUND: The human papillomavirus vaccine (HPV vaccine) was introduced into the Danish Childhood Vaccination Programme in 2009. Following a national debate questioning the safety of the vaccine, the coverage decreased from an uptake of >90% for the first dose of the HPV vaccine to an uptake of 52% in girls born in 2003. The aim of this study was to identify changes in determinants for HPV vaccine hesitancy in the period when the debate spiraled and to identify determinants for specific hesitancy towards the HPV vaccine among girls who received the second dose of the measles, mumps and rubella vaccine.METHODS: We included girls born in the period 1999-2003 who were residing in Denmark between their 12th and 13th birthday (n = 161,528). Data from the Danish Vaccination Register were linked with demographic data from the Danish Civil Registration System. We used multiple logistic regression models to identify associations between determinants and the uptake of the first dose of the HPV vaccine (HPV1).RESULTS: For girls born in 1999-2000, low uptake was seen in children of increasing birth order, young or old age of mother, non-Danish origin, low uptake of other childhood vaccines, and in girls living with one parent. For girls born in 2001-2003, most of these determinants of low uptake became less significant. Birth order and origin showed different tendencies when comparing birth cohorts 1999-2000 with birth cohorts 2001-2003.CONCLUSIONS: We found demographic disparities in the uptake of HPV1 that were generally in line with existing literature. More importantly, the results indicate that determinants for hesitancy towards the HPV vaccines changed during a period of intense public debate regarding the safety of the HPV vaccine. This may indicate that the public concerns over safety disproportionally affect those who trusted vaccines prior to the debate.

Influenza-like illness (ILI) estimation from web search data is an important web analytics task. The basic idea is to use the frequencies of queries in web search logs that are correlated with past ILI activity as features when estimating current ILI activity. It has been noted that since influenza is seasonal, this approach can lead to spurious correlations with features/queries that also exhibit seasonality, but have no relationship with ILI. Spurious correlations can, in turn, degrade performance. To address this issue, we propose modeling the seasonal variation in ILI activity and selecting queries that are correlated with the residual of the seasonal model and the observed ILI signal. Experimental results show that re-ranking queries obtained by Google Correlate based on their correlation with the residual strongly favours ILI-related queries.

Background Widely recognized as a major public health threat globally, the rapid increase of antibiotic resistance in bacteria could soon render our most effective method to combat infections obsolete. Factors influencing the burden of resistance in human populations remain poorly described, though temperature is known to play an important role in mechanisms of bacterial growth and transmission. Methods Here, we present the first evidence that ambient temperatures may modulate the rate of increase of antibiotic resistance across Europe. Using a comprehensive dataset containing information across 28 countries, for 17 years (2000–2016), 3 common bacterial pathogens, and 4 antibiotic classes collectively representing over 4 million tested isolates, we show that antibiotic resistance has increased more rapidly in warmer regions over a period of nearly 2 decades. Results Specifically, we show that European countries with 10°C warmer ambient temperatures have experienced more rapid increases in antibiotic resistance to E. coli and K. pneumoniae over the 17-year period, ranging between 0.33%/year (95% CI 0.2, 0.5) and 1.2%/year (0.4, 1.9), even after accounting for recognized drivers of resistance including antibiotic consumption and population density. We found a decreasing relationship for S. aureus and methicillin of -0.4%/year (95% CI −0.7, 0.0), reflecting widespread declines in MRSA across Europe over the study period. Conclusion Our findings suggest that rising temperatures globally may hasten the spread of resistance and complicate efforts to mitigate it. Disclosures All authors: No reported disclosures.

SUMMARYRotavirus (RV) infections affect young children, but can also occur in adults. We sought to identify risk factors for RV infections in adults aged ⩾18 years in Denmark, and to describe illness and genotyping characteristics. From March 2005 to February 2009, we recruited consecutive cases of laboratory-confirmed RV infection and compared them with healthy controls matched by age, gender and municipality of residence. We collected information on illness characteristics and exposures using postal questionnaires. We calculated univariable and multivariable matched odds ratios (mOR) with conditional logistic regression. The study comprised 65 cases and 246 controls. Illness exceeded 10 days in 31% of cases; 22% were hospitalized. Cases were more likely than controls to suffer serious underlying health conditions [mOR 5·6, 95% confidence interval (CI) 1·7–18], and to report having had close contact with persons with gastrointestinal symptoms (mOR 9·4, 95% CI 3·6–24), in particular young children aged 18 years. Close contact with young children or adults with gastrointestinal symptoms is the main risk factor for RV infection in adults in Denmark. RV vaccination assessments should consider that RV vaccination in children may indirectly reduce the burden of disease in adults.

Background: Understanding the influence of media coverage upon vaccination activity is valuable when designing outreach campaigns to increase vaccination uptake.Objective: To study the relationship between media coverage and vaccination activity of the measles-mumps-rubella (MMR) vaccine in Denmark.Methods: We retrieved data on media coverage (1622 articles), vaccination activity (2 million individual registrations), and incidence of measles for the period 1997-2014. All 1622 news media articles were annotated as being provaccination, antivaccination, or neutral. Seasonal and serial dependencies were removed from the data, after which cross-correlations were analyzed to determine the relationship between the different signals.Results: Most (65%) of the anti-vaccination media coverage was observed in the period 1997-2004, immediately before and following the 1998 publication of the falsely claimed link between autism and the MMR vaccine. There was a statistically significant positive correlation between the first MMR vaccine (targeting children aged 15 months) and provaccination media coverage (r=.49, P=.004) in the period 1998-2004. In this period the first MMR vaccine and neutral media coverage also correlated (r=.45, P=.003). However, looking at the whole period, 1997-2014, we found no significant correlations between vaccination activity and media coverage.Conclusions: Following the falsely claimed link between autism and the MMR vaccine, provaccination and neutral media coverage correlated with vaccination activity. This correlation was only observed during a period of controversy which indicates that the population is more susceptible to media influence when presented with diverging opinions. Additionally, our findings suggest that the influence of media is stronger on parents when they are deciding on the first vaccine of their children, than on the subsequent vaccine because correlations were only found for the first MMR vaccine.

Background The Lives Saved Tool (LiST) is a widely used resource for evidence-based decision-making regarding health program scale-up in low- and middle-income countries. LiST estimates the impact of specified changes in intervention coverage on mortality and stunting among children under 5 years of age. We aimed to improve the estimates of the parameters in LiST that determine the rate at which the effects of interventions to prevent stunting attenuate as children get older. Methods We identified datasets with serial measurements of children’s lengths or heights and used random effects models and restricted cubic splines to model the growth trajectories of children with at least six serial length/height measurements. We applied WHO growth standards to both measured and modelled (smoothed) lengths/heights to determine children’s stunting status at multiple ages (1, 6, 12, 24 months). We then calculated the odds ratios for the association of stunting at one age point with stunting at the next (“stunting-to-stunting ORs”) using both measured and smoothed data points. We ran analyses in LiST to compare the impact on intervention effect attenuation of using smoothed rather than measured stunting-to-stunting ORs. Results A total of 21,786 children with 178,786 length/height measurements between them contributed to our analysis. The odds of stunting at a given age were strongly related to whether a child is stunted at an earlier age, using both measured and smoothed lengths/heights, although the relationship was stronger for smoothed than measured lengths/heights. Using smoothed lengths/heights, we estimated that children stunted at 1 month have 45 times the odds of being stunted at 6 months, with corresponding odds ratios of 362 for the period 6 to 12 months and 175 for the period 12 to 24 months. Using the odds ratios derived from the smoothed data in LiST resulted in a somewhat slower attenuation of intervention effects over time, but substantial attenuation was still observed in the LiST outputs. For example, in Mali the effect of effectively eliminating SGA births reduced prevalence of stunting at age 59 months from 44.4% to 43.7% when using odds ratios derived from measured lengths/heights and from 44.4% to 41.9% when using odds ratios derived from smoothed lengths/heights. Conclusions Smoothing of children’s measured lengths/heights increased the strength of the association between stunting at a given age and stunting at an earlier age. Using odds ratios based on smoothed lengths/heights in LiST resulted in a small reduction in the attenuation of intervention effects with age and thus some increase in the estimated benefits, and may better reflect the true benefits of early nutritional interventions. Electronic supplementary material The online version of this article (10.1186/s12889-017-4744-3) contains supplementary material, which is available to authorized users.

SUMMARYThe surveillance of Clostridium difficile (CD) in Denmark consists of laboratory based data from Departments of Clinical Microbiology (DCMs) sent to the National Registry of Enteric Pathogens (NREP). We validated a new surveillance system for CD based on the Danish Microbiology Database (MiBa). MiBa automatically collects microbiological test results from all Danish DCMs. We built an algorithm to identify positive test results for CD recorded in MiBa. A CD case was defined as a person with a positive culture for CD or PCR detection of toxin A and/or B and/or binary toxin. We compared CD cases identified through the MiBa-based surveillance with those reported to NREP and locally in five DCMs representing different Danish regions. During 2010–2014, NREP reported 13 896 CD cases, and the MiBa-based surveillance 21 252 CD cases. There was a 99·9% concordance between the local datasets and the MiBa-based surveillance. Surveillance based on MiBa was superior to the current surveillance system, and the findings show that the number of CD cases in Denmark hitherto has been under-reported. There were only minor differences between local data and the MiBa-based surveillance, showing the completeness and validity of CD data in MiBa. This nationwide electronic system can greatly strengthen surveillance and research in various applications.

We developed a model that enabled a back-calculation of the annual salmonellosis seroincidence from measurements of Salmonella antibodies and applied this model to 9677 serum samples collected from populations in 13 European countries. We found a 10-fold difference in the seroincidence, which was lowest in Sweden (0.06 infections per person-year), Finland (0.07), and Denmark (0.08) and highest in Spain (0.61), followed by Poland (0.55). These numbers were not correlated with the reported national incidence of Salmonella infections in humans but were correlated with prevalence data of Salmonella in laying hens (P < .001), broilers (P < .001), and slaughter pigs (P = .03). Seroincidence also correlated with Swedish data on the country-specific risk of travel-associated Salmonella infections (P = .001). Estimates based on seroepidemiological methods are well suited to measure the force of transmission of Salmonella to human populations, in particular relevant for assessments where data include notifications from areas, states or countries with diverse characteristics of the Salmonella surveillance.

BACKGROUND The impact of the 13-valent pneumococcal conjugate vaccine (PCV13) at the population level is unclear. We explored PCV13's effect in reducing invasive pneumococcal disease (IPD)-related morbidity and mortality, and whether serotype-specific changes were attributable to vaccination or expected as a part of natural, cyclical variations. METHODS This was a Danish nationwide population-based cohort study based on the linkage of laboratory surveillance data and the Danish Civil Registration System. Changes in IPD incidence and mortality during baseline (2000-2007), 7-valent pneumococcal conjugate vaccine (PCV7) (2008-2010), and PCV13 (2011-2013) periods were estimated. Predicted incidences of serotypes were estimated controlling for cyclical trends from historical patterns observed during the past 20 years. RESULTS We observed a 21% reduction (95% confidence interval [CI], 17%-25%) in IPD incidence in the total population after PCV13's introduction, and a 71% reduction (95% CI, 62%-79%) in children aged

Diarrhea and linear growth faltering continue to burden low-income countries and are among the most important contributors to poor health during early childhood. Diarrhea is thought to adversely affect linear growth, but catch-up growth can occur if no additional insults are experienced. We sought to characterize catch-up growth in relation to diarrhea burden in a multisite dataset of 1007 children. Using longitudinal anthropometry and diarrheal surveillance data from 7 cohort studies in 4 countries, we examined the relation between diarrhea prevalence and growth in 3- to 6-mo periods using linear mixed-effect models. Growth during each period was calculated as a function of age using linear splines. We incorporated the longitudinal prevalence of diarrhea in both current and previous periods into the model. Diarrhea during the current period was associated with slower linear and ponderal growth. Faster (catch-up) growth in length was observed in children with no diarrhea in age groups immediately after an age group in which diarrhea was experienced [age group >6-12 mo: 0.03 mm/mo for each percentage diarrhea prevalence in the previous period (95% CI: 0.007, 0.06) relative to 11.3 mm/mo mean growth rate; age group >12-18 mo: 0.04 mm/mo (95% CI: 0.02, 0.06) relative to 8.9 mm/mo mean growth rate; age group >18-24 mo: 0.04 mm/mo (95% CI: 0.003, 0.09) relative to 7.9 mm/mo mean growth rate]. The associations were stronger in boys than in girls when separate models were run. Similar results were observed when weight was the outcome variable. When diarrheal episodes are followed by diarrhea-free periods in the first 2 y of life, catch-up growth is observed that may allow children to regain their original trajectories. The finding of a greater effect of diarrhea on linear growth in boys than in girls was unexpected and requires additional study. Diarrhea burdens are high throughout the first 2 y of life in these study sites, therefore reducing the likelihood of catch-up growth. Extending diarrhea-free periods may increase the likelihood of catch-up growth and decrease the prevalence of stunting.

We tested whether the effect of influenza activity on invasive pneumococcal disease incidence and severity varies between age and comorbidity groups. Weekly rates of invasive pneumococcal disease were obtained from the Danish National Laboratory Surveillance System (1977-2007). Influenza-like illness data were collected from a sentinel surveillance system at the Statens Serum Institut (Copenhagen, Denmark). We fitted Poisson regression models for invasive pneumococcal disease, with predictors of seasonality, trends and influenza activity, and allowed the influenza activity variable to vary by comorbidity level and clinical presentation. Influenza activity accounted for 8.4% (95% CI 4.8-11.9%) and 6.9% (95% CI 5.4-10.2%) of all invasive pneumococcal disease cases among those aged 15-39 and ≥40 years, respectively, but had no measurable impact among children aged

Summary Campylobacter is the most frequently occurring cause of bacterial gastroenteritis in Europe. Unlike other zoonotic diseases, European-wide incidences of Campylobacter infections have increased during the past decade, resulting in a significant disease burden. In Denmark, campylobacteriosis is notifiable by laboratory and a unique registration system of electronic transfer and storage of notified Campylobacter cases linked to the national person register of age, gender and geographical location allows collection of comprehensive case data. Using national surveillance data, we describe Campylobacter infections in Denmark from 2000 to 2015, focusing on age-specific incidences, geography, seasonality and outbreaks. During the observed period, a total of 60,725 Campylobacter infections were registered with a mean annual incidence of 69.3 cases/100,000 population. From 2000 to 2014, the incidence of campylobacteriosis decreased by 20%, followed by an apparent increase of 20% from 2014 to 2015. Approximately one-third of cases were travel-related. Incidences were highest in males, young adults aged 20–29 years and children under 5 years of age. Generally, children under 10 years of age living in rural areas were at higher risk of infection. Infection patterns were seasonal with an increase from May to October, peaking in August. Outbreaks were identified each year, including four large waterborne outbreaks which all occurred following heavy rainfall events. For the most part, patterns of Campylobacter infection in Denmark during 2000 to 2015 remained remarkably constant and followed what is known about the disease with respect to demographic, temporal and spatial characteristics. To establish better targeted prevention and control measures, the current knowledge gaps regarding both Campylobacter microbiology (degree of clonal diversity and clustering) and the importance of different risk factors (food versus environment/climate) need to be filled.

BACKGROUNDIn 2015, Denmark launched an automated surveillance system for hospital-acquired infections, the Hospital-Acquired Infections Database (HAIBA).OBJECTIVETo describe the algorithm used in HAIBA, to determine its concordance with point prevalence surveys (PPSs), and to present trends for hospital-acquired bacteremiaSETTINGPrivate and public hospitals in DenmarkMETHODSA hospital-acquired bacteremia case was defined as at least 1 positive blood culture with at least 1 pathogen (bacterium or fungus) taken between 48 hours after admission and 48 hours after discharge, using the Danish Microbiology Database and the Danish National Patient Registry. PPSs performed in 2012 and 2013 were used for comparison.RESULTSNational trends showed an increase in HA bacteremia cases between 2010 and 2014. Incidence was higher for men than women (9.6 vs 5.4 per 10,000 risk days) and was highest for those aged 61–80 years (9.5 per 10,000 risk days). The median daily prevalence was 3.1% (range, 2.1%–4.7%). Regional incidence varied from 6.1 to 8.1 per 10,000 risk days. The microorganisms identified were typical for HA bacteremia. Comparison of HAIBA with PPS showed a sensitivity of 36% and a specificity of 99%. HAIBA was less sensitive for patients in hematology departments and intensive care units. Excluding these departments improved the sensitivity of HAIBA to 44%.CONCLUSIONSAlthough the estimated sensitivity of HAIBA compared with PPS is low, a PPS is not a gold standard. Given the many advantages of automated surveillance, HAIBA allows monitoring of HA bacteremia across the healthcare system, supports prioritizing preventive measures, and holds promise for evaluating interventions.Infect Control Hosp Epidemiol 2017;38:559–566