A register and questionnaire study of long-term general health symptoms following SARS-CoV-2 vaccination in Denmark.

Many individuals who refuse COVID-19 vaccination have concerns about long-term side effects. Here, we report findings on self-reported symptoms from a Danish survey- and register study. The study included 34,868 vaccinated primary course recipients, 95.8% of whom received mRNA vaccines, and 1,568 unvaccinated individuals. Participants had no known history of SARS-CoV-2 infection. Using g-computation on logistic regression, risk differences (RDs) for symptoms between vaccinated and unvaccinated persons were estimated with adjustments for possible confounders. Within six weeks after vaccination, higher risks were observed for physical exhaustion (RD 4.9%, 95% CI 1.1% to 8.4%), fever or chills (RD 4.4%, 95% CI 2.1% to 6.7%), and muscle/joint pain (RD 7.0%, 95% CI 3.1% to 10.7%), compared to unvaccinated individuals. Beyond twenty-six weeks, risks were higher among the vaccinated for sleeping problems (RD 3.0, 95% 0.2 to 5.8), fever or chills (RD 2.0, 95% CI 0.4 to 3.6), reduced/altered taste (RD 1.2, 95% CI 0.2 to 2.3) and shortness of breath (RD 2.6, 95% CI 0.9 to 4.0). However, when examining pre-omicron responses only, the difference for reduced/altered taste was significant. As expected, the risk of experiencing physical exhaustion, fever or chills, and muscle/joint pain was higher among persons who responded within six weeks of completing the primary course. No significant differences were observed for the 7-25-week period after vaccination. Associations for the period beyond 26 weeks must be interpreted with caution and in the context of undetected SARS-CoV-2 infection, wide confidence intervals, and multiple testing. Overall, we observe no concerning signs of long-term self-reported physical, cognitive, or fatigue symptoms after vaccination.

Comparison of morbidity and mortality after bloodstream infection with vancomycin-resistant versus -susceptible Enterococcus faecium: a nationwide cohort study in Denmark, 2010-2019.

The emergence of bloodstream infections (BSI) caused by vancomycin-resistant Enterococci (VRE) has caused concern. Nonetheless, it remains unclear whether these types are associated with an excess risk of severe outcomes when compared with infections caused by vancomycin-susceptible Enterococci (VSE). This cohort study included hospitalized patients in Denmark with Enterococcus faecium-positive blood cultures collected between 2010 and 2019 identified in the Danish Microbiology Database. We estimated 30-day hazard ratio (HR) of death or discharge among VRE compared to VSE patients adjusted for age, sex, and comorbidity. The cohort included 6071 patients with E. faecium BSI (335 VRE, 5736 VSE) among whom VRE increased (2010-13, 2.6%; 2014-16, 6.3%; 2017-19; 9.4%). Mortality (HR 1.08, 95%CI 0.90-1.29; 126 VRE, 37.6%; 2223 VSE, 37.0%) or discharge (HR 0.89, 95%CI 0.75-1.06; 126 VRE, 37.6%; 2386 VSE, 41.6%) was not different between VRE and VSE except in 2014 (HR 1.87, 95% CI 1.18-2.96). There was no interaction between time from admission to BSI (1-2, 3-14, and >14 days) and HR of death (P = 0.14) or discharge (P = 0.45) after VRE compared to VSE, despite longer time for VRE patients (17 vs. 10 days for VSE, P < 0.0001). In conclusion, VRE BSI was not associated with excess morbidity and mortality. The excess mortality in 2014 only may be attributed to improved diagnostic- and patient-management practices after 2014, reducing time to appropriate antibiotic therapy. The high level of mortality after E. faecium BSI warrants further study.

The effectiveness of pollen allergen immunotherapy on allergic rhinitis over 18 years: A national cohort study in Denmark.

BACKGROUND: Because long-term effectiveness of pollen allergen immune therapy (AIT) for allergic rhinitis (AR) is not well-described, we studied effectiveness over 18 years in Denmark. METHODS: A register-based cohort study using data on filled prescriptions, 1995-2016, Denmark. In a cohort of 1.1 million intranasal corticosteroid inhaler users (proxy for AR), we matched users treated with grass, birch or mugwort AIT 1:2 with non-treated users on baseline year and 24 characteristics in the 3 years prior to baseline. The primary outcome was the odds ratio (OR) of using anti-allergic nasal inhaler during the pollen season in the treated versus non-treated group by years since baseline. RESULTS: Among 7760 AR patients treated with pollen AIT, the OR of using nasal inhaler 0-5 years after baseline was reduced when compared with 15,520 non-treated AR individuals (0-2 years, OR 0.84 (0.81-0.88); 3-5 years, OR 0.88 (0.84-0.92)), but was close to unity or higher thereafter (6-9 years, OR 1.03 (0.97-1.08); 10-18 years, OR 1.18 (1.11-1.26)). In post hoc analyses, results were more consistent for those who already had 3 of 3 baseline years of use, and in patients using nasal inhaler in the latest pollen season (0-2 years, OR 0.76 (0.72-0.79); 3-5 years OR 0.86 (0.81-0.93); 6-9 years, OR 0.94 (0.87-1.02); 10-18 years, OR 0.94 (0.86-1.04)) as opposed to no such use. CONCLUSIONS: Patients treated with pollen AIT in routine care to a higher degree stopped using anti-allergic nasal inhaler 0-5 years after starting the standard 3 years of therapy, and not beyond 5 years. Post hoc analyses suggested effectiveness was more consistent among patients with persistent AR.

Post-acute symptoms 4 months after SARS-CoV-2 infection during the Omicron period: a nationwide Danish questionnaire study.

Post-acute symptoms are not uncommon after SARS-CoV-2 infection with pre-Omicron variants. How Omicron and COVID-19 booster vaccination influence the risk of post-acute symptoms is less clear. We analyzed data from the nationwide Danish questionnaire study EFTER-COVID comprising 44,553 individuals ≥15 years old, tested between July 2021 and January 2022, in order to evaluate the association of the Omicron variant and COVID-19 booster vaccination with post-acute symptoms and new-onset general health problems, four months after infection with SARS-CoV-2. Risk differences (RDs) were estimated by comparing Omicron -cases to controls, Omicron to Delta -cases, and Omicron vaccinated cases with three to -two doses, adjusted for age, sex, BMI, self-reported chronic diseases, Charlson comorbidity index, healthcare occupation, and vaccination status. Four months after testing for SARS-CoV-2 during the Omicron period, cases experienced substantial post-acute symptoms and new-onset health problems compared to controls; the largest RD was observed for memory issues (RD=7.2%, 95%CI: 6.4 to 8.1). However, risks were generally lower than in the Delta period, particularly for dysosmia (RD=-15.0%, 95%CI: -17.0 to -13.2) and dysgeusia (RD=-11.2%, 95%CI: -13.2 to -9.5). Booster vaccination was associated with fewer post-acute symptoms and new-onset health problems, four months after Omicron infection, compared to two COVID-19 vaccine doses.

A Danish questionnaire study of acute symptoms of SARS-CoV-2 infection by variant, vaccination status, sex and age.

It is not well-described how the acute symptoms of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) differ by variant, vaccination, sex and age. A cross-sectional questionnaire study linked to national testing- and registry data was conducted among 148,874 SARS-CoV-2 first time reverse transcription polymerase chain reaction (RT-PCR) test-positive individuals and corresponding date-matched symptomatic test-negative controls. Major SARS-CoV-2 variants (Index/wild type, Alpha, Delta and Omicron) were defined using periods of predominance. Risk differences (RDs) were estimated for each of 21 predefined acute symptoms comparing: (1) test-positive and -negative individuals, by variant period, (2) vaccinated and unvaccinated test-positives, by variant period, (3) individuals tested positive during the Omicron and Delta periods, by vaccination status, and (4) vaccinated Omicron test-positive and -negative individuals, by age and sex. Compared to pre-Omicron, RDs between test-positive and test-negative individuals during the Omicron period were lower for most symptoms. RDs for altered sense of smell (dysosmia) and taste (dysgeusia) were highest for Delta (RD = 50.8 (49.4-52.0) and RD = 54.7 (53.4-56.0), respectively) and lowest for Omicron (RD = 12.8 (12.1-13.5) and RD = 11.8 (11.1-12.4), respectively). Across variants, vaccinated individuals reported fewer symptoms. During Omicron, females and 30-59 year-old participants reported more symptoms.

A hybrid register and questionnaire study of Covid-19 and post-acute sick leave in Denmark.

Post-acute sick leave is an underexplored indicator of the societal burden of SARS-CoV-2. Here,  we report findings about self-reported sick leave and risk factors thereof from a hybrid survey and register study, which include 37,482 RT-PCR confirmed SARS-CoV-2 cases and 51,336 test-negative controls who were tested during the index- and alpha-dominant waves. We observe that an additional 33 individuals per 1000 took substantial sick leave following acute infection compared to persons with no known history of infection, where substantial sick leave is defined as >1 month of sick leave within the period 1-9 months after the RT-PCR test date. Being female, 50-65 years, or having certain pre-existing health conditions such as obesity, chronic lung diseases, and fibromyalgia each increase risk for taking substantial sick leave. Altogether, these results may help motivate improved diagnostic and treatment options for persons living with post-Covid conditions.

A standardised protocol for relative SARS-CoV-2 variant severity assessment, applied to Omicron BA.1 and Delta in six European countries, October 2021 to February 2022.

Several SARS-CoV-2 variants that evolved during the COVID-19 pandemic have appeared to differ in severity, based on analyses of single-country datasets. With decreased testing and sequencing, international collaborative studies will become increasingly important for timely assessment of the severity of new variants. Therefore, a joint WHO Regional Office for Europe and ECDC working group was formed to produce and pilot a standardised study protocol to estimate relative case-severity of SARS-CoV-2 variants during periods when two variants were co-circulating. The study protocol and its associated statistical analysis code was applied by investigators in Denmark, England, Luxembourg, Norway, Portugal and Scotland to assess the severity of cases with the Omicron BA.1 virus variant relative to Delta. After pooling estimates using meta-analysis methods (random effects estimates), the risk of hospital admission (adjusted hazard ratio (aHR) = 0.41; 95% confidence interval (CI): 0.31-0.54), admission to intensive care unit (aHR = 0.12; 95% CI: 0.05-0.27) and death (aHR = 0.31; 95% CI: 0.28-0.35) was lower for Omicron BA.1 compared with Delta cases. The aHRs varied by age group and vaccination status. In conclusion, this study demonstrates the feasibility of conducting variant severity analyses in a multinational collaborative framework and adds evidence for the reduced severity of the Omicron BA.1 variant.

Risk of reinfection, vaccine protection, and severity of infection with the BA.5 omicron subvariant: a nation-wide population-based study in Denmark.

BACKGROUND: Estimates of immunity and severity for the SARS-CoV-2 omicron subvariant BA.5 are important to assess the public health impact associated with its rapid global spread despite vaccination. We estimated natural and vaccine immunity and severity of BA.5 relative to BA.2 in Denmark, a country with high mRNA-vaccination coverage and free-of-charge RT-PCR testing. METHODS: This nation-wide population-based study in Denmark included residents aged 18 years or older who had taken an RT-PCR test between 10 April and 30 June, 2022 (ie, the outcome period), and who the national COVID-19 surveillance system identified as having information since February 2020 on RT-PCR tests, whole-genome sequencing, vaccinations, and hospitalisation with a positive RT-PCR test and COVID-19 as the main diagnosis. First, we used a case-control design, in which cases were people infected with BA.5 or BA.2 during the outcome period and controls were people who tested negative for SARS-CoV-2 infection during the outcome period. We calculated the protection provided by a previous PCR-confirmed omicron infection against BA.5 and BA.2 infection and hospitalisation among triple-vaccinated individuals. Second, we compared vaccination status in people infected with BA.5 versus BA.2 and estimated relative vaccine protection against each subvariant. Third, we compared rates of hospitalisation for COVID-19 among people infected with BA.5 versus BA.2. We estimated effects using logistic regression with adjustment for sex, age, region, PCR-test date, comorbidity and, as appropriate, vaccination and previous infection status. FINDINGS: A total of 210 (2·4%) of 8678 of BA.5 cases, 192 (0·7%) of 29 292 of BA.2 cases, and 33 972 (19·0%) of 178 669 PCR-negative controls previously had an omicron infection, which was estimated in the adjusted analyses to offer 92·7% (95% CI 91·6-93·7) protection against BA.5 infection and 97·1% (96·6-97·5) protection against BA.2 infection. We found similarly high amounts of protection against hospitalisation owing to infection with BA.5 (96·4% [95% CI 74·2-99·5]) and BA.2 (91·2% [76·3-96·7]). Vaccine coverage (three mRNA doses vs none) was 9307 (94·2%) of 9878 among BA.5 cases and 30 581 (94·8%) of 32 272 among BA.2 cases, although in the adjusted analysis, there was a trend towards slightly higher vaccination coverage among BA.5 cases than BA.2 cases (OR 1·18 [95% CI 0·99-1·42]; p=0·064), possibly suggesting marginally poorer vaccine protection against BA.5. The rate of hospitalisation due to COVID-19 was higher among the BA.5 cases (210 [1·9%] of 11 314) than among the BA.2 cases (514 [1·4%] of 36 805), with an OR of 1·34 (95% CI 1·14-1·57) and an adjusted OR of 1·69 (95% CI 1·22-2·33), despite low and stable COVID-19 hospitalisation numbers during the study period. INTERPRETATION: The study provides evidence that a previous omicron infection in triple-vaccinated individuals provides high amounts of protection against BA.5 and BA.2 infections. However, protection estimates greater than 90% might be too high if individuals with a previous infection were more likely than those without one to come forward for a test for reasons other than suspicion of COVID-19. Our analysis also showed that vaccine protection against BA.5 infection was similar to, or slightly weaker than, protection against BA.2 infection. Finally, there was evidence that BA.5 infections were associated with an increased risk of hospitalisation compared with BA.2 infections. FUNDING: There was no funding source for this study.

Observed protection against SARS-CoV-2 reinfection following a primary infection: A Danish cohort study among unvaccinated using two years of nationwide PCR-test data.

Background: The level of protection after a SARS-CoV-2 infection against reinfection and COVID-19 disease remains important with much of the world still unvaccinated. Methods: Analysing nationwide, individually referable, Danish register data including RT-PCR-test results, we conducted a cohort study using Cox regression to compare SARS-CoV-2 infection rates before and after a primary infection among still unvaccinated individuals, adjusting for sex, age, comorbidity and residency region. Estimates of protection against infection were calculated as 1 minus the hazard ratio. Estimates of protection against symptomatic infections and infections leading to hospitalisation were also calculated. The prevalence of infections classified as symptomatic or asymptomatic was compared for primary infections and reinfections. The study also assessed protection against each of the main viral variants after a primary infection with an earlier variant by restricting follow-up time to distinct, mutually exclusive periods during which each variant dominated. Findings: Until 1 July 2021 the estimated protection against reinfection was 83.4% (95%CI: 82.2-84.6%); but lower for the 65+ year-olds (72.2%; 95%CI: 53.2-81.0%). Moderately higher estimates were found for protection against symptomatic disease, 88.3% overall (95%CI: 85.9-90.3%). First-time cases who reported no symptoms were more likely to experience a reinfection (odds ratio: 1.48; 95%CI: 1.35-1.62). By autumn 2021, when infections were almost exclusively caused by the Delta variant, the estimated protection following a recent first infection was 91.3% (95%CI: 89.7-92.7%) compared to 71.4% (95%CI: 66.9-75.3%) after a first infection over a year earlier. With Omicron, a first infection with an earlier variant in the past 3-6 months gave an estimated 51.0% (95%CI: 50.1-52.0%) protection, whereas a first infection longer than 12 months earlier provided only 19.0% (95%CI: 17.2-20.5%) protection. Protection by an earlier variant-infection against hospitalisation due to a new infection was estimated at: 86.6% (95%CI: 46.3-96.7%) for Alpha, 97.2% (95%CI: 89.0-99.3%) for Delta, and 69.8% (95%CI: 51.5-81.2%) for the Omicron variant. Interpretation: SARS-CoV-2 infection offered a high level of sustained protection against reinfection, comparable with that offered by vaccines, but decreased with the introduction of new main virus variants; dramatically so when Omicron appeared. Protection was lower among the elderly but appeared more pronounced following symptomatic compared to asymptomatic infections. The level of estimated protection against serious disease was somewhat higher than that against infection and possibly longer lasting. Decreases in protection against reinfection, seemed primarily to be driven by viral evolution. Funding: None.

A nationwide questionnaire study of post-acute symptoms and health problems after SARS-CoV-2 infection in Denmark.

A considerable number of individuals infected with SARS-CoV-2 continue to experience symptoms after the acute phase. Here, we report findings from a nationwide questionnaire study in Denmark including 61,002 RT-PCR confirmed SARS-CoV-2 cases and 91,878 test-negative controls aged 15-years or older. Six to twelve months after the test, the risks of 18 out of 21 symptoms were elevated among test-positives. The largest adjusted risk differences (RD) were observed for dysosmia (RD = 10.92%, 95% CI 10.68-11.21%), dysgeusia (RD = 8.68%, 95% CI 8.43-8.93%), fatigue/exhaustion (RD = 8.43%, 95%CI 8.14-8.74%), dyspnea (RD = 4.87%, 95% CI 4.65-5.09%) and reduced strength in arms/legs (RD = 4.68%, 95% CI 4.45-4.89%). During the period from the test and until completion of the questionnaire, new diagnoses of anxiety (RD = 1.15%, 95% CI 0.95-1.34%) or depression (RD = 1.00%, 95% CI 0.81-1.19%) were also more common among test-positives. Even in a population where the majority of test-positives were not hospitalized, a considerable proportion experiences symptoms up to 12 months after infection. Being female or middle-aged increases risks.

Risk of hospitalisation associated with infection with SARS-CoV-2 omicron variant versus delta variant in Denmark: an observational cohort study.

BACKGROUND: Estimates of the severity of the SARS-CoV-2 omicron variant (B.1.1.529) are crucial to assess the public health impact associated with its rapid global dissemination. We estimated the risk of SARS-CoV-2-related hospitalisations after infection with omicron compared with the delta variant (B.1.617.2) in Denmark, a country with high mRNA vaccination coverage and extensive free-of-charge PCR testing capacity. METHODS: In this observational cohort study, we included all RT-PCR-confirmed cases of SARS-CoV-2 infection in Denmark, with samples taken between Nov 21 (date of first omicron-positive sample) and Dec 19, 2021. Individuals were identified in the national COVID-19 surveillance system database, which included results of a variant-specific RT-PCR that detected omicron cases, and data on SARS-CoV-2-related hospitalisations (primary outcome of the study). We calculated the risk ratio (RR) of hospitalisation after infection with omicron compared with delta, overall and stratified by vaccination status, in a Poisson regression model with robust SEs, adjusted a priori for reinfection status, sex, age, region, comorbidities, and time period. FINDINGS: Between Nov 21 and Dec 19, 2021, among the 188 980 individuals with SARS-CoV-2 infection, 38 669 (20·5%) had the omicron variant. SARS-CoV-2-related hospitalisations and omicron cases increased during the study period. Overall, 124 313 (65·8%) of 188 980 individuals were vaccinated, and vaccination was associated with a lower risk of hospitalisation (adjusted RR 0·24, 95% CI 0·22-0·26) compared with cases with no doses or only one dose of vaccine. Compared with delta infection, omicron infection was associated with an adjusted RR of hospitalisation of 0·64 (95% CI 0·56-0·75; 222 [0·6%] of 38 669 omicron cases admitted to hospital vs 2213 [1·5%] of 150 311 delta cases). For a similar comparison by vaccination status, the RR of hospitalisation was 0·57 (0·44-0·75) among cases with no or only one dose of vaccine, 0·71 (0·60-0·86) among those who received two doses, and 0·50 (0·32-0·76) among those who received three doses. INTERPRETATION: We found a significantly lower risk of hospitalisation with omicron infection compared with delta infection among both vaccinated and unvaccinated individuals, suggesting an inherent reduced severity of omicron. Our results could guide modelling of the effect of the ongoing global omicron wave and thus health-care system preparedness. FUNDING: None.

Molecular epidemiology of the SARS-CoV-2 variant Omicron BA.2 sub-lineage in Denmark, 29 November 2021 to 2 January 2022.

Following emergence of the SARS-CoV-2 variant Omicron in November 2021, the dominant BA.1 sub-lineage was replaced by the BA.2 sub-lineage in Denmark. We analysed the first 2,623 BA.2 cases from 29 November 2021 to 2 January 2022. No epidemiological or clinical differences were found between individuals infected with BA.1 versus BA.2. Phylogenetic analyses showed a geographic east-to-west transmission of BA.2 from the Capital Region with clusters expanding after the Christmas holidays. Mutational analysis shows distinct differences between BA.1 and BA.2.

Risk of hospitalisation associated with infection with SARS-CoV-2 lineage B.1.1.7 in Denmark: an observational cohort study.

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<0·0001) and an adjusted RR of 1·42 (95% CI 1·25-1·60; p<0·0001). The adjusted RR was increased in all strata of age and calendar period-the two covariates with the largest contribution to confounding of the crude RR. INTERPRETATION: Infection with SARS-CoV-2 lineage B.1.1.7 was associated with an increased risk of hospitalisation compared with that of other lineages in an analysis adjusted for covariates. The overall effect on hospitalisations in Denmark was lessened due to a strict lockdown, but our findings could support hospital preparedness and modelling of the projected impact of the epidemic in countries with uncontrolled spread of B.1.1.7. FUNDING: None.

Chronic hyperglycemia, hypercholesterolemia, and metabolic syndrome are associated with risk of tendon injury.

Tendon injury is a considerable problem affecting both physically active and sedentary people. The aim of this study was to examine the relationship between markers for metabolic disorders (hyperglycemia, hypercholesterolemia, and metabolic syndrome) and the risk of developing tendon injuries requiring referral to a hospital. The Copenhagen City Heart Study is a prospective study of diabetic and non-diabetic individuals from the Danish general population with different physical activity levels. The cohort was followed for 3 years via national registers with respect to tendon injuries. Data from 5856 individuals (median age 62 years) were included. The overall incidence of tendon injury in both upper and lower extremities that required an out-patient or in-house visit to a hospital was ~5.7/1000 person years. Individuals with elevated HbA1c (glycated hemoglobin) even in the prediabetic range (HbA1c>5.7%) had a ~3 times higher risk of tendon injury in the lower extremities only, as compared to individuals with normal HbA1C levels. Hypercholesterolemia (total cholesterol>5 mmol/L) increased risk of tendon injury in the upper extremities by ~1.5 times, and individuals with metabolic syndrome had ~2.5 times higher risk of tendon injury in both upper and lower extremities. In conclusion, these data demonstrate for the first time in a large cohort with different physical activity levels that the indicators for metabolic syndrome are a powerful systemic determinant of tendon injury, and two of its components, hyperglycemia and hypercholesterolemia, each independently make tendons susceptible for damage and injury.

Retrospective markers of paediatric atopic dermatitis persistence after hospital diagnosis: A nationwide cohort study.

BACKGROUND: Atopic dermatitis (AD) normally onsets in childhood and mostly resolves before adolescences. Disease persistence is known to be difficult to study properly, and current predictors are insufficient to identify more than a small fraction of patients at risk. OBJECTIVE: To study personal AD medicine history as a retrospective marker of persistent AD. METHODS: The study population included all Danish first hospital contacts with a diagnosis of AD (ICD-10, L20) between 1995 and 2012. National register data following the diagnosis were used to define persistent AD activity until 2017 according to personal AD medicine history before diagnosis. Activity was defined as filled prescriptions for topical corticosteroids (TCS) or calcineurin inhibitors (TCI), dermatologist contacts or hospital re-contacts for AD. Risk ratios (RR) for persistent activity (defined as activity >4 of the most recent 5 years) were estimated according to AD medicine history (prescriptions filled prior to diagnosis) adjusted for age at onset, parental AD and basic covariates. RESULTS: A total of 13 628 patients were diagnosed at ages 0-16 years and had up to 21 years of follow-up. 10 years after diagnosis, 67% showed activity (9.5% persistent). Among prior TCS users (69%), the RR10y of persistent activity increased 1- to 6-fold with increasing strength of strongest TCS/TCI ever, and with number of TCS courses. Prior use of antibiotics (RR10y 1.32, 95% CI 1.09-1.59) and antihistamines (RR10y 1.65, 95% CI 1.42-1.91) increased the RR10y in a dose-dependent manner. In >90% of patients, prior medication use occurred <4 years before diagnosis. CONCLUSIONS AND CLINICAL RELEVANCE: The strength and type of AD medication used in the previous 4 years may predict 10-year persistence of AD. Since children may be misjudged as having milder disease when seen between flares of skin lesions, this information may improve physicians' ability to determine the correct prognosis independently of current AD severity.

Increased Risk of Inflammatory Bowel Disease in Families with Tonsillectomy: A Danish National Cohort Study.

BACKGROUND: The possible etiologic link between tonsillectomy and inflammatory bowel diseases remains unclear. To investigate the hereditary component, we assessed the risk of inflammatory bowel disease after own tonsillectomy as well as after tonsillectomy among family members. METHODS: A nationwide Danish cohort of 7,045,288 individuals was established and linked to comprehensive national registers with data on kinship, tonsillectomy surgery, and diagnosis of inflammatory bowel disease from all health sectors. We used Poisson regression models to estimate hospital contact rate ratios (RR) for Crohn's disease and ulcerative colitis, with 95% confidence intervals (CI), between individuals with or without tonsillectomy, as well as between individuals with or without tonsillectomized relatives. RESULTS: During 189 million person-years of follow-up between 1977 and 2014, 276,673 individuals were tonsillectomized, 22,015 developed Crohn's disease, and 49,550 developed ulcerative colitis. Rates of inflammatory bowel disease were elevated up to 20 years after own tonsillectomy (Crohn's disease: RR 1.52 [95% CI = 1.43, 1.61]; ulcerative colitis: RR 1.24 [95% CI = 1.18, 1.29]). RRs for Crohn's disease was 1.22 (95% CI = 1.17, 1.27) after first-degree relatives' tonsillectomy, 1.14 (95% CI = 1.08, 1.19) after second-degree relatives' tonsillectomy, and 1.08 (95% CI = 1.01, 1.15) after third-degree relatives' tonsillectomy. Corresponding RRs for ulcerative colitis were 1.10 (95% CI = 1.07, 1.13), 1.05 (95% CI = 1.01, 1.08), and 1.03 (95% CI = 0.98, 1.09). CONCLUSIONS: Even individuals with tonsillectomized family members were at increased risk of inflammatory bowel disease. These findings call into question a direct influence of tonsillectomy on gastrointestinal inflammation and point instead toward shared hereditary or environmental factors. See video abstract at, http://links.lww.com/EDE/B464.

Familial aggregation of tonsillectomy in early childhood and adolescence.

BACKGROUND: The tonsils are immunological gatekeepers against pathogens. Immunological response to tonsillitis may vary clinically from no enlargement of the tonsils to nearly obstructive conditions. In this investigation, we studied the familial aggregation of tonsillectomy, as an indicator of the extent to which tonsillar immune responses to infections might be genetically controlled. METHODS: Data on kinship relations and vital status from the Danish Civil Registration System were used to establish a cohort of Danes with relatives born since 1977. Tonsillectomies in all hospitals and clinics from 1977 to 2013 were identified in national registers together with the indication for tonsillectomy. Rate ratios (RRs) for tonsillectomy >1 year after tonsillectomy in specific types of relatives (first to fourth degree) were estimated in Poisson regression models with adjustment for calendar period, sex, age, and total number of specified relatives. RESULTS: A cohort of 2.4 million persons was followed for 44,100,697 million person-years (mean 18.4 years/person), and included 148,190 tonsillectomies. RRs of tonsillectomy were consistently higher when the relatedness and the number of tonsillectomized relatives were higher. RRs were similar in boys and girls, but were larger in early childhood. Additional analyses suggested that this relatively higher RR at younger ages was due to a larger influence of shared environment at younger ages, whereas the genetic influence was similar at all ages. Results were similar for tonsillectomies performed strictly due to tonsillitis. CONCLUSIONS: Genetic factors appear to predispose to severe tonsillitis underlying tonsillectomies, regardless of age and sex. Further studies are needed to understand how genes regulate the tonsils' immune response against infections.