Pertussis epidemic in Denmark, August 2023 to February 2024.

We report a record high pertussis epidemic in Denmark since August 2023. Highest incidence was in adolescents, while peak incidence in infants was lower vs previous epidemics in 2019 and 2016. Among infants aged 0-2 months, over half (29/48) were hospitalised and one infant died, underlining the disease severity in the youngest. To protect infants, pertussis vaccination in pregnant women was introduced in January 2024 in the national vaccination programme. Improved vaccination surveillance in pregnant women is being implemented.

Excess mortality in Europe coincides with peaks of COVID-19, influenza and respiratory syncytial virus (RSV), November 2023 to February 2024.

Since the end of November 2023, the European Mortality Monitoring Network (EuroMOMO) has observed excess mortality in Europe. During weeks 48 2023-6 2024, preliminary results show a substantially increased rate of 95.3 (95% CI:  91.7-98.9) excess all-cause deaths per 100,000 person-years for all ages. This excess mortality is seen in adults aged 45 years and older, and coincides with widespread presence of COVID-19, influenza and respiratory syncytial virus (RSV) observed in many European countries during the 2023/24 winter season.

Resurgence of Respiratory Syncytial Virus in the Summer of 2021 in Denmark-a Large out-of-season Epidemic Affecting Older Children.

Background: When coronavirus disease 2019 (COVID-19) restrictions were lifted in Denmark in the spring of 2021, a surge in respiratory syncytial virus (RSV) cases followed, causing a large out-of-season epidemic. This study aims to investigate the summer epidemic compared with 3 typical pre-COVID-19 RSV winter seasons using Danish registers to identify RSV cases, RSV-related admissions, and use of intensive care treatment. Methods: Incidence rates (IR) per 1000 person-years for RSV cases, RSV-related admissions, and intensive care treatment were calculated with 95% confidence interval (CI) for each season, stratified by age groups and incidence rate ratios (IRR) with 95% CI were calculated to compare the summer epidemic with the winter season for 2019-2020. Results: In the summer epidemic, the IR of RSV cases and admissions exceeded previous winter seasons for all age groups. The highest increases in IRs were seen among children aged 2 to 3 years and 4 to 5 years. The IRR of cases were 4.6 (95% CI, 4.1-5.2) and 3.3 (2.6-4.2) and the IRR of admissions were 3.3 (2.7-4.2) and 3.8 (2.3-6.5) in the 2 age groups, respectively, when compared with the winter season 2019-2020. Conclusions: Likely because of immunity debt following COVID-19 restrictions, the summer epidemic was significantly larger than previous winter seasons, most markedly among children aged 2 to 3 and 4 to 5 years but had a similar disease severity spectrum.

Identification of subgroups in the Danish population for targeted human papillomavirus vaccination efforts.

BACKGROUND: In the Danish childhood vaccination program, the human papillomavirus (HPV) vaccination coverage is lower than for other vaccines. To tailor a targeted HPV vaccination effort, we aimed to identify girls in Denmark with lower first dose HPV vaccination coverage than girls in general. METHODS: A population-based retrospective cohort study was performed of girls born in 2001-2004, residing in Denmark in September 2019 (N = 128,351). Data from the Danish Vaccination Register was linked to sociodemographic data from the Danish Civil Registration System and Statistics Denmark. Cox's proportional hazard regression models were used to compare vaccination uptake rates between subgroups of girls. RESULTS: HPV vaccination coverage at 14 years of age varied widely by municipality (53.4-80.6%). Girls living with neither of their parents had a lower chance of being vaccinated compared to girls living with both their parents (HR 0.43; 95% CI 0.41-0.46), likewise for girls attending special need education compared with girls attending public schools (HR 0.50; 95% CI 0.42-0.59). The vaccination uptake among immigrants was lower compared to Danish-born girls (HR 0.51; 95% CI 0.49-0.54), especially among immigrant girls whose parents had not passed any Danish exams. Finally, girls who were DTaP-IPV revaccinated had a 50% greater chance of being HPV vaccinated compared to girls who were not (HR 1.61; 95% CI 1.58-1.64). CONCLUSION: To increase the HPV vaccination uptake, we recommend vaccination efforts targeting girls living without any of their parents, girls attending special need education, immigrants, and girls who are not DTaP-IPV revaccinated. When targeting immigrants, the effort should focus on disseminating sufficient and understandable information about the Danish childhood vaccination program to the parents.

Novel Connections of Common Childhood Illnesses Based on More Than 5 Million Diary Registrations From Birth Until Age 3 Years.

BACKGROUND: All children experience numerous episodes of illness during the first 3 years of life. Most episodes are mild and handled without medical attention but nevertheless burden the families and society. There is a large, and still unexplained, variation in the burden of illness between children. OBJECTIVE: To describe and provide a better understanding of the disease burden of common childhood diseases through a data-driven approach investigating the communalities between symptom patterns and predefined variables on predispositions, pregnancy, birth, environment, and child development. METHODS: The study is based on the prospectively followed clinical mother-child cohort COpenhagen Prospective Studies on Asthma in Childhood, which includes 700 children with daily symptom registration in the first 3 years of life, including symptoms of cough, breathlessness, wheeze, cold, pneumonia, sore throat, ear infections, gastrointestinal infections, fever, and eczema. First, we described the number of episodes of symptoms. Next, factor analysis models were used to describe the variation in symptom load in the second year of life (both based on n = 556, with >90% complete diary). Then we characterized patterns of similarity between symptoms using a graphical network model (based on n = 403, with a 3-year monthly compliance of >50%). Finally, predispositions and pregnancy, birth, environmental, and developmental factors were added to the network model. RESULTS: The children experienced a median of 17 (interquartile range, 12-23) episodes of symptoms during the first 3 years of life, of which most were respiratory tract infections (median, 13; interquartile range, 9-18). The frequency of symptoms was the highest during the second year of life. Eczema symptoms were unrelated to the other symptoms. The strongest association to respiratory symptoms was found for maternal asthma, maternal smoking during the third trimester, prematurity, and CDHR3 genotype. This was in contrast to the lack of associations for the well-established asthma locus at 17q21. CONCLUSIONS: Healthy young children are burdened by multiple episodes of symptoms during the first 3 years of life. Prematurity, maternal asthma, and CDHR3 genotype were among the strongest drivers of symptom burden.

Excess all-cause mortality in the USA and Europe during the COVID-19 pandemic, 2020 and 2021.

Both the USA and Europe experienced substantial excess mortality in 2020 and 2021 related to the COVID-19 pandemic. Methods used to estimate excess mortality vary, making comparisons difficult. This retrospective observational study included data on deaths from all causes occurring in the USA and 25 European countries or subnational areas participating in the network for European monitoring of excess mortality for public health action (EuroMOMO). We applied the EuroMOMO algorithm to estimate excess all-cause mortality in the USA and Europe during the first two years of the COVID-19 pandemic, 2020-2021, and compared excess mortality by age group and time periods reflecting three primary waves. During 2020-2021, the USA experienced 154.5 (95% Uncertainty Interval [UI]: 154.2-154.9) cumulative age-standardized excess all-cause deaths per 100,000 person years, compared with 110.4 (95% UI: 109.9-111.0) for the European countries. Excess all-cause mortality in the USA was higher than in Europe for nearly all age groups, with an additional 44.1 excess deaths per 100,000 person years overall from 2020-2021. If the USA had experienced an excess mortality rate similar to Europe, there would have been approximately 391 thousand (36%) fewer excess deaths in the USA.

Effectiveness of the 23-valent pneumococcal polysaccharide vaccine against invasive pneumococcal disease among 948,263 individuals ≥ 65 years of age: a Danish cohort study.

This study aimed to estimate the effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPV23) against invasive pneumococcal disease (IPD) among individuals ≥ 65 years of age. We used Danish nationwide databases to obtain information on PPV23 vaccination, covariates, and IPD and linked data on an individual level using a unique personal identifier. A total of 948,263 individuals were included and followed between June 15, 2020, and September 18, 2021 (58.6% were vaccinated during follow-up). The adjusted vaccine effectiveness was 42% (95% confidence interval (CI): 9-63%) for all-serotype IPD and 58% (95% CI: 21-78%) for PPV23-serotype IPD, using no vaccination as the reference.

Sex-differences in COVID-19 associated excess mortality is not exceptional for the COVID-19 pandemic.

Europe experienced excess mortality from February through June, 2020 due to the COVID-19 pandemic, with more COVID-19-associated deaths in males compared to females. However, a difference in excess mortality among females compared to among males may be a more general phenomenon, and should be investigated in none-COVID-19 situations as well. Based on death counts from Eurostat, separate excess mortalities were estimated for each of the sexes using the EuroMOMO model. Sex-differential excess mortality were expressed as differences in excess mortality incidence rates between the sexes. A general relation between sex-differential and overall excess mortality both during the COVID-19 pandemic and in preceding seasons were investigated. Data from 27 European countries were included, covering the seasons 2016/17 to 2019/20. In periods with increased excess mortality, excess was consistently highest among males. From February through May 2020 male excess mortality was 52.7 (95% PI: 56.29; 49.05) deaths per 100,000 person years higher than for females. Increased male excess mortality compared to female was also observed in the seasons 2016/17 to 2018/19. We found a linear relation between sex-differences in excess mortality and overall excess mortality, i.e., 40 additional deaths among males per 100 excess deaths per 100,000 population. This corresponds to an overall female/male mortality incidence ratio of 0.7. In situations with overall excess mortality, excess mortality increases more for males than females. We suggest that the sex-differences observed during the COVID-19 pandemic reflects a general sex-disparity in excess mortality.

Cost of Illness in Young Children: A Prospective Birth Cohort Study.

Childhood illness is extremely common and imposes a considerable economic burden on society. We aimed to quantify the overall economic burden of childhood illness in the first three years of life and the impact of environmental risk factors. The study is based on the prospective, clinical mother-child cohort Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010) of 700 children with embedded randomized trials of fish-oil and vitamin D supplementations during pregnancy. First, descriptive analyses were performed on the total costs of illness, defined as both the direct costs (hospitalizations, outpatient visits, visit to the practitioner) and the indirect costs (lost earnings) collected from the Danish National Health Registries. Thereafter, linear regression analyses on log-transformed costs were used to investigate environmental determinants of the costs of illness. The median standardized total cost of illness at age 0-3 years among the 559 children eligible for analyses was EUR 14,061 (IQR 9751-19,662). The exposures associated with reduced costs were fish-oil supplementation during pregnancy (adjusted geometric mean ratio (GMR) 0.89 (0.80; 0.98), p = 0.02), gestational age in weeks (aGMR = 0.93 (0.91; 0.96), p < 0.0001), and birth weight per 100 g (aGMR 0.98 (0.97; 0.99), p = 0.0003), while cesarean delivery was associated with higher costs (aGMR = 1.30 (1.15; 1.47), p < 0.0001). In conclusion, common childhood illnesses are associated with significant health-related costs, which can potentially be reduced by targeting perinatal risk factors, including maternal diet during pregnancy, cesarean delivery, preterm birth and low birth weight.

Preliminary report of an outbreak of SARS-CoV-2 in mink and mink farmers associated with community spread, Denmark, June to November 2020.

In June-November 2020, SARS-CoV-2-infected mink were detected in 290 of 1,147 Danish mink farms. In North Denmark Region, 30% (324/1,092) of people found connected to mink farms tested SARS-CoV-2-PCR-positive and approximately 27% (95% confidence interval (CI): 25-30) of SARS-CoV-2-strains from humans in the community were mink-associated. Measures proved insufficient to mitigate spread. On 4 November, the government ordered culling of all Danish mink. Farmed mink constitute a potential virus reservoir challenging pandemic control.

Real-time monitoring shows substantial excess all-cause mortality during second wave of COVID-19 in Europe, October to December 2020.

The European monitoring of excess mortality for public health action (EuroMOMO) network monitors weekly excess all-cause mortality in 27 European countries or subnational areas. During the first wave of the coronavirus disease (COVID-19) pandemic in Europe in spring 2020, several countries experienced extraordinarily high levels of excess mortality. Europe is currently seeing another upsurge in COVID-19 cases, and EuroMOMO is again witnessing a substantial excess all-cause mortality attributable to COVID-19.

Asthma-like symptoms in young children increase the risk of COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) may originate in early life and share disease mechanisms with asthma-like symptoms in early childhood. This possibility remains unexplored on account of the lack of long-term prospective studies from infancy to the onset of COPD. OBJECTIVE: We aimed to investigate the relationship between asthma-like symptoms in young children and development of COPD. METHODS: In a population-based cohort of women who gave birth at the central hospital in Copenhagen during period from 1959 to 1961, we investigated data from 3290 mother-child pairs who attended examinations during pregnancy and when the children were aged 1, 3, and 6 years. COPD was assessed from the Danish national registries on hospitalizations and prescription medication since 1994. A subgroup of 930 individuals underwent spirometry testing at age 50 years. RESULTS: Of the 3290 children, 1 in 4 had a history of asthma-like symptoms in early childhood. The adjusted hazard ratio for hospitalization for COPD was 1.88 (95% CI = 1.32-2.68), and the odds ratio for prescription of long-acting muscarinic antagonists was 2.27 (95% CI = 1.38-3.70). Asthma-like symptoms in early childhood were also associated with a reduced FEV1 percent predicted and an FEV1-to-forced vital capacity ratio at age 50 years (-3.36% [95% CI = -5.47 to -1.24] and -1.28 [95% CI = -2.17 to -0.38], respectively) and with COPD defined according to Global Initiative for Chronic Obstructive Lung Disease stage higher than 1 (odds ratio = 1.96 [95% CI = 1.13-3.34]). CONCLUSION: This 60-year prospective follow-up of a mother-child cohort demonstrated a doubled risk for COPD from childhood asthma-like symptoms.

Symptom burden of atopic dermatitis in early childhood assessed from daily monitoring of symptoms and topical steroid use.

BACKGROUND: To our knowledge, disease burden of atopic dermatitis (AD) as number of days with symptoms and medical treatment has never been studied as measure of severity. OBJECTIVES: To investigate risk factors for AD burden in the first 3 years of life. METHODS: The Copenhagen Prospective Studies on Asthma in Childhood2010 included 700 children. AD burden was assessed by daily diary entries with information on AD and steroid days measuring 18 possible heritable, prenatal, and postnatal environmental exposures. RESULTS: The children with AD had a median (interquartile range) of 136 symptom days (61-294 days) and 72 steroid days (27-145 days) during the first 3 years of life, with the highest disease burden in the second year of life. The multivariable risk factor analysis showed that maternal AD and childhood allergic sensitization were associated with a higher number of AD days and maternal AD, filaggrin mutation, and allergic sensitization were associated with a higher number of steroid days. LIMITATIONS: Participants with a personal interest in atopic diseases could be more likely to participate. CONCLUSION: Children's burden of AD, assessed quantitatively as AD and steroid days, demonstrated positive associations with maternal AD, filaggrin mutation, and early-life allergic sensitization, with the highest disease burden in the second year of life.

Choice of therapeutic interventions and outcomes for the treatment of infections caused by multidrug-resistant gram-negative pathogens: a systematic review.

Background: Antimicrobial resistance is an increasingly serious threat to public health, and the increased occurrence of multidrug-resistant (MDR) bacteria is a concern in both high-income and low- and middle-income countries. The purpose of this systematic review was to identify and critically appraise current antimicrobial treatment options for infections with MDR Gram-negative bacteria. Methods: A literature search for treatment of MDR extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, A. baumannii, and P. aeruginosa was conducted in MEDLINE in January 2019. Relevant studies published in English, German, and French that evaluated clinical success, microbiological success, and 30-day mortality outcomes were included. The population of interest was adult patients. Results: Of 672 studies, 43 met the inclusion criteria. Carbapenems are the most common antibiotics used for the treatment of ESBL-producing Enterobacteriaceae. The clinical and microbiological success was similar for group 1 carbapenems (imipenem, meropenem, or doripenem), group 2 carbapenems (ertapenem), and non-carbapenem antibiotics. Mortality data were contradictory for group 1 carbapenems compared to group 2 carbapenems. The most common treatment option for A. baumannii and P. aeruginosa infections was intravenous colistin, regardless of infection site. Clinical success and mortality were similar in A. baumannii infections treated with colistin combination therapy vs. colistin monotherapy, whereas heterogeneous results were found with respect to microbiological success. Monotherapy and colistin combination therapy were used against P. aeruginosa with clinical and microbiological success (70-100%) depending on the infection site and severity, and the antibiotic used. Ceftazidime-avibactam therapy for ESBL-producing Enterobacteriaceae and P. aeruginosa showed good clinical success in one study. Conclusion: We did not find robust evidence for antibiotic treatment of any infection with MDR Gram-negative bacteria, including ESBL-producing Enterobacteriaceae, A. baumannii, and P. aeruginosa, that would lead to a firm recommendation for one specific antibiotic over another or for monotherapy over combination therapy. The choice of antibiotic treatment should be based on susceptibility testing balancing the expected clinical success rate against the risk of development of antibiotic resistance and the risk of severe side effects.

Environmental and Genetic Determinants of Serum 25(OH)-Vitamin D Levels during Pregnancy and Early Childhood.

Vitamin D insufficiency has become a common health problem worldwide, particularly among pregnant women and young children. Therefore, we sought to identify environmental, dietary, and genetic determinants of serum 25(OH)-vitamin D (25(OH)D) levels during pregnancy and early childhood. 25(OH)D was measured in women at 24-weeks of gestation (n = 738) and one-week postpartum (n = 284) in the population-based Danish COPSAC2010 mother-child cohort; and in cord blood (n = 257) and age 4 years (n = 298) in children from the at-risk COPSAC2000 mother-child cohort. Environmental, dietary, and genetic variables were tested for association with 25(OH)D using linear regression analyses. After adjusting for season of blood sampling, determinants of lower 25(OH)D levels during pregnancy in the women were higher pre-pregnancy BMI, lower age at birth, lower genetic vitamin D score, lower dietary vitamin D intake, and lower social circumstances. In children, the determinants were lower maternal age at birth, higher pre-pregnancy BMI, lower genetic vitamin D score, older siblings, exposure to tobacco smoking, and female sex. Genetics was an important determinant at all time points, alone explaining 2%-11% of the variance in 25(OH)D. Important determinants of circulating 25(OH)D levels during pregnancy and early childhood include environmental factors, diet, and to a large extent genetics.

Genetic, Clinical, and Environmental Factors Associated With Persistent Atopic Dermatitis in Childhood.

Importance: Knowledge about factors associated with persistence of atopic dermatitis (AD) during childhood is sparse. Objective: To explore heritable, environmental, and clinical factors associated with persistent AD based on 13 years' follow-up of an at-risk birth cohort. Design, Setting, and Participants: In the Copenhagen Prospective Study on Asthma in Childhood 2000 (COPSAC2000) clinical birth cohort study, 411 children born to mothers with asthma were followed up until the age of 13 years at a clinical research unit in Copenhagen, Denmark, from August 1998 to June 2015. Atopic dermatitis was diagnosed prospectively during close clinical follow-up according to the criteria of Hanifin and Rajka. Data were gathered on parental history, social circumstances, and environmental factors through parent interviews. The cohort was followed up with biannual visits to the clinic until the age of 7 years and were seen again at age 13 years. Data were analyzed from August 2015 to January 2018. Main Outcomes and Measures: Atopic dermatitis was diagnosed using Hanifin and Rajka major and minor criteria, and severity was determined by Scoring Atopic Dermatitis (SCORAD) index, with possible scores from 0 to 83, with higher scores indicating more severe AD. Results: Of the 411 children in the cohort, 203 (49.4%) were male and 186 (45.3%) were diagnosed with AD before the age of 13 years; 40 of 166 children (24.1%) had persistent AD at the age of 13 years, and 126 (76.0%) experienced remission. Factors associated with persistent AD to age 13 years included heritability, environmental exposures, asthma and allergic sensitization, clinical presentation at the time of diagnosis, the composition of Hanifin and Rajka diagnostic minor criteria, and AD severity according to SCORAD. A higher AD genetic risk score was associated with an increased the risk for persistent AD (multivariable odds ratio [OR], 1.8; 95% CI, 1.1-2.9; P = .02), together with paternal asthma (multivariable OR, 3.7; 95% CI, 1.2-11.5; P = .02); paternal AD (multivariable OR, 6.2; 95% CI, 1.17-23.2; P = .007), and higher social circumstances (multivariable OR, 1.6; 95% CI, 1.0-2.5; P = .05). Particular clinical presentations at time of diagnosis were also associated with specific minor criteria of Hanifin and Rajka (Dennie-Morgan and anterior neck folds, white dermographism, intolerance to wool, itching when sweating, tendency to skin infection, food intolerance, and food allergy) (OR, 2.6; 95% CI, 1.1-6.2; P = .03) as well as increased severity at diagnosis (OR, 1.1; 95% CI, 1.0-1.1; P = .007). Conclusions and Relevance: In a birth cohort of children at risk for asthma who received close clinical follow-up to age 13 years, known genetic AD risk variants, paternal asthma and AD, high social circumstances, diagnostic minor criteria, and disease severity at onset were associated with persistent AD at age 13 years. These findings may be applied in clinical practice to evaluate the likely disease course for individual patients.

Data representations and -analyses of binary diary data in pursuit of stratifying children based on common childhood illnesses.

In this article we analyse diary reports concerning childhood symptoms of illness, these data are part of a larger study with other types of measurements on childhood asthma. The children are followed for three years and the diaries are updated, by the parents, on a daily basis. Here we focus on the methodological implications of analysing such data. We investigate two ways of representing the data and explore which tools are applicable given both representations. The first representation relies on proper alignment and point by point comparison of the signals. The second approach takes into account combinations of symptoms on a day by day basis and boils down to the analysis of counts. In the present case both methods are well applicable. However, more generally, when symptom episodes are occurring more at random locations in time, a point by point comparison becomes less applicable and shape based approaches will fail to come up with satisfactory results. In such cases, pattern based methods will be of much greater use. The pattern based representation focuses on reoccurring patterns and ignores ordering in time. With this representation we stratify the data on the level of years, so that possibly yearly differences can still be detected.

Knemometry is more sensitive to systemic effects of inhaled corticosteroids in children with asthma than 24-hour urine cortisol excretion.

BACKGROUND: Pharmacodynamic assessment of the systemic effect of inhaled corticosteroids (ICSs) is often done by measuring 24-hour urine free cortisol (UFC) excretion. Knemometry assessing short-term lower-leg growth rate (LLGR) is a more rarely used alternative. OBJECTIVE: The primary aim of this study was to compare the sensitivity of LLGR and 24-hour UFC excretion for evaluating systemic exposure to ICSs in prepubertal children with asthma. The secondary aim was to evaluate factors influencing the precision of LLGR calculated by the traditional 1 leg nonparametric method versus a new 2 leg parametric method. METHODS: The study evaluated 60 children with mild asthma aged 5 to 12 years participating in a randomized controlled trial of ICSs with longitudinal concomitant assessments of LLGR and 24-hour UFC excretion. The sensitivity of the safety assessments was analyzed by comparing LLGR and 24-hour UFC in the placebo run-in period with values in the ICS treatment period by using paired t tests. Factors with a potential influence on LLGR were analyzed by means of ANOVA and the Levene test of homogeneity. RESULTS: The mean LLGR was significantly reduced during the ICS versus placebo run-in periods: 0.18 mm/wk (SD, 0.55 mm/wk) versus 0.45 mm/wk (SD, 0.39 mm/wk), with a mean difference of 0.27 mm/wk (95% CI, 0.05-0.48 mm/wk; P = .02). In contrast, there was no difference in 24-hour UFC excretion: 6.91 nmol/mmol (SD, 4.67 nmol/mmol) versus 7.58 nmol/mmol (SD, 6.17 nmol/mmol), with a mean difference of 0.67 nmol/mmol (95% CI, -1.13 to 2.48 nmol/mmol; P = .46). We observed no significant difference in parametric determined LLGR caused by the child's age or sex, investigator, or season of measurement, whereas some differences were observed for the nonparametric LLGR. CONCLUSION: These findings suggest that knemometry is a more sensitive pharmacodynamic measure of systemic effects of ICSs than 24-hour UFC excretion and that a parametric determination of LLGR increases the sensitivity of the method. These findings should be considered by legislative authorities in the future.