The impact of living conditions and health interventions on tuberculosis, Denmark, 1876 to 2022.

BackgroundDenmark possesses an exceptional historical data collection on tuberculosis (TB) from 1876 to the present, providing a unique opportunity to assess TB epidemiology over 147 years in Denmark.AimOur aim was to describe the TB disease burden in Denmark in relation to historical events, living conditions and health interventions during the past 147 years.MethodsWe performed a nationwide register-based ecological study including all persons with TB in Denmark from 1876 through 2022, correlating the TB incidence to social, economic and health indicators.ResultsIn Denmark, the overall TB incidence and mortality declined markedly over the past 147 years, only marginally influenced by specific TB interventions such as sanatoria, Bacillus Calmette-Guèrin (BCG) vaccination, mass screenings and antibiotics. Parallel to this decline, the country experienced improved living conditions, as illustrated by decreased infant mortality and increased life expectancy and wealth. In 1978, Denmark became a low-incidence country for TB with risk groups predominantly affected, and with a continuous change in demographics towards fewer Danish-born cases and relatively more migrant cases.ConclusionsThe decline over time in TB incidence and mortality in Denmark preceded specific TB interventions and can, first of all, be attributed to improved living conditions. TB has now become a rare disease in Denmark, predominantly occurring in particular risk groups. Future elimination of TB will require a combination of specific health interventions in these risk groups combined with a continued focus on improving socioeconomic status and living conditions.

Tick-borne encephalitis.

Tick-borne encephalitis (TBE) is a viral tick-borne infection occurring in many parts of Europe and Asia as described in this review. Increasing TBE case numbers have been reported over recent decades. In Denmark the infection is rare (1-14 annual cases). The rise in TBE in Denmark is mainly driven by microfoci outside of Bornholm, primarily North Zealand. Clinical illness has a bi-phasic presentation: "summer-flu" which may be followed by a neuroinfection. No specific treatment exists, and mortality is less-than 1%. A considerable percentage of patients may experience neurological sequelae. TBE is preventable through vaccination.

Increase in invasive group A streptococcal infections and emergence of novel, rapidly expanding sub-lineage of the virulent Streptococcus pyogenes M1 clone, Denmark, 2023.

A highly virulent sub-lineage of the Streptococcus pyogenes M1 clone has been rapidly expanding throughout Denmark since late 2022 and now accounts for 30% of the new invasive group A streptococcal infections. We aimed to investigate whether a shift in variant composition can account for the high incidence rates observed over winter 2022/23, or if these are better explained by the impact of COVID-19-related restrictions on population immunity and carriage of group A Streptococcus.

Mortality, risk factors, and causes of death among people with tuberculosis in Denmark, 1990-2018.

OBJECTIVES: This study aimed to analyze mortality, risk factors, and causes of death among people with tuberculosis (TB). METHODS: This is a population-based cohort study with patients with TB ≥18 years notified from 1990 to 2018 in Denmark, compared with sex- and age-matched controls. Mortality was assessed in Kaplan-Meier models and risk factors for death were estimated in Cox proportional hazards models. RESULTS: Overall mortality was twofold higher among people with TB compared with controls up to 15 years after TB diagnosis (hazard ratio [HR]: 2.18, 95% confidence interval [CI]: 2.06-2.29, P <0.0001). Danes with TB were three times more likely to die than migrants (adjusted HR: 3.13, 95% CI: 2.84-3.45, P <0.0001). Risk factors for death included living alone, being unemployed, having low income, and comorbidities such as mental illness with substance abuse, lung diseases, hepatitis, and HIV. TB was the most common cause of death (21%), followed by chronic obstructive pulmonary disease (7%), lung cancer (6%), alcoholic liver disease (5%), and mental illness with substance abuse (4%). CONCLUSION: People with TB had substantially inferior survival up to 15 years after TB diagnosis, in particular, socially disadvantaged Danes with TB with specific comorbidities. This may reflect unmet needs for enhanced treatment of other medical/social conditions during TB treatment.

Social determinants of tuberculosis: a nationwide case-control study, Denmark, 1990-2018.

BACKGROUND: The global vision is a world free of tuberculosis (TB). Even in resource-rich TB low-incidence settings, we need more focus on the role of social risk factors to end the TB epidemic. METHODS: Nationwide, retrospective register-based, case-control study from 1990 to 2018, including all TB patients in Denmark ≥18 years old (n = 9581) matched 1:3 on sex and age with population controls. TB risk factors were assessed in logistic regression models and estimated by odds ratio (OR). RESULTS: All TB patients had considerably lower socio-economic status compared with controls (P < 0.0001). Among ethnic Danes, TB was mostly found among males, persons between 35 and 65 years, those living alone, those with low educational level, persons on social welfare benefits and those with low income. Conversely, for migrants, being younger, sex and living alone were less important, whereas having children was protective. In an adjusted multivariable regression model among Danes, key risk factors for TB were being on disability pension (OR = 2.7) and cash benefits (OR = 4.7). For migrants, fewer social risk factors increased TB risk, although low income and cash benefits did (OR = 3.1). CONCLUSION: Even today in a resourceful setting, socio-economic status drives disparities in health. In our study, multifactorial social deprivation was highly associated with TB. Especially household structure, education, employment and income were important risk factors that should be addressed in the future to accelerate TB control and end the TB epidemic.

The prevalence of diabetes among tuberculosis patients in Denmark.

SETTING: It is estimated that 25% of the world's population are infected with Mycobacterium tuberculosis and that 463 million people are living with diabetes mellitus (DM), a number that is increasing. Patients with DM have three times the risk of developing tuberculosis (TB) and there is significant interaction between DM and TB, suggesting that DM affects not only risk of TB but also TB presentation, treatment response and outcome. OBJECTIVE: The aim was determining the prevalence of DM among TB patients in Denmark and to assess risk factors. DESIGN: Patient files from all notified TB cases in Denmark from 2009 to 2014 were retrospectively assessed. RESULTS: In total, 1912 patients were included and 5.0% had DM. Patients with DM were older, had more comorbidities, came from outside Denmark, and had a higher mortality compared to non-DM-patients. None of the patients from Greenland had DM. Patients with low socio-economic status had a low prevalence of DM. We found a higher prevalence of DM among Danish-born < 54 year and migrant ≥ 75 year compared to a Danish background population. CONCLUSION: We found a higher prevalence of DM among TB patients with known risk factors, and a surprisingly low prevalence among patients with low socioeconomic status and patients from Greenland.

Immunisation of healthcare workers in the Nordic countries: Variation in recommendations and practices and a lack of assessment.

Healthcare workers (HCWs) are at increased risk of both exposure and transmission of infectious disease. Two European Union (EU) directives state that health services are responsible for assessing their employees' potential exposure to infectious diseases and offering immunisation free of charge. We assessed current policy for immunisation of HCWs and the availability of vaccine coverage data in the Nordic countries by surveying national vaccination experts in Denmark, Finland, Iceland, Norway and Sweden, as well as Swedish county medical officers (CMOs). All national experts and 17 of 21 Swedish CMOs responded. All EU countries had transposed the European directives into national law, while Norway and Iceland had similar national legislation. Recommendations or guidelines were issued in Denmark, Finland, Iceland, Norway and 15 of 17 responding Swedish counties. The range of diseases covered differed by countries and Swedish counties. HCW vaccine coverage data were not systematically collected; incomplete estimates were only available for Finland and two Swedish counties. In conclusion, recommendations or guidelines exist in the Nordic countries, but their impact cannot be assessed, as vaccine uptake among HCWs is not currently measured. Systematic collection of data is a necessary step towards improving HCW immunisation policy and practice in the Nordic countries.

Clinical features of tuberculous lymphadenitis in a low-incidence country.

BACKGROUND: Tuberculous lymphadenitis (TBLA) is the most common extrapulmonary manifestation of tuberculosis (TB) in Denmark. However, the clinical features of patients with TBLA have never been systematically studied in this setting. METHODS: Patients treated for TBLA in Central Region Denmark from 2007 to 2016 were identified using the national TB surveillance register and The Danish Hospital Patient Registry. Data of clinical characteristics and treatment were extracted from hospital records. RESULTS: Eighty-three TBLA patients were identified. The median age was 32 years (IQR 23-42); 71 (85.5%) were migrants; 58 (69.9%) presented with cervical lymphadenopathy; and 45 (54.2%) had one or more systemic TB symptom such as fever, chills, night sweats, fatigue, and weight loss. Sixty-five patients had no comorbidities (78.3%). HIV co-infection was seen in five (7.2%) of the 69 who were tested for HIV. Abscesses and/or draining sinuses were noted in 13 (15.7%) patients and 15 (18.1%) had concurrent pulmonary infection. The median time from first hospital contact to treatment initiation was 42 days (IQR 16-82) and admitted patients were hospitalised for a median of 7 days (IQR 3-13.5). For 24 patients (28.9%), lymph node material was not sent for mycobacterial culture and 52 (62.7%) had microbiologically confirmed TB. Treatment outcome was successful for 70 patients (84.3%). CONCLUSION: In Denmark, TBLA is mainly seen among young and previously healthy migrants presenting with cervical lymphadenopathy and sparse systemic symptoms. The diagnosis is often considerably delayed and not microbiologically verified, implying diagnostic difficulties. Treatment outcome needs to be improved.

The Epidemiology and Clinical Characteristics of Pediatric Tuberculosis in Denmark 2009-2014 Highlights Targets for Prevention.

BACKGROUND: In Western Europe, most pediatric tuberculosis (TB) cases occur among immigrants; however, data are rarely stratified by first/second-generation immigrants and many cases may be preventable. METHODS: This was a nationwide study of children <18 years with TB from 2009 to 2014 in Denmark. Demographic, clinical, microbiologic and treatment outcome data were obtained from registers and medical records. RESULTS: We identified 145 cases; 99 were immigrants (68%) of which 54 (55%) were second-generation immigrants. Most first-generation immigrants (73%) were diagnosed by passive case finding as was half the second-generation immigrants (52%), in contrast to Danish children who were mostly diagnosed by active case finding (70%). Symptoms were often nonspecific, and one-third of the children had normal blood tests at time of diagnosis. First-generation immigrants were most often infected abroad (84%) as opposed to Danish children (9%) and second-generation immigrants (30%). Approximately one-third of the children represented cases of TB disease that could possibly have been prevented by screening or rigorous contact tracing. The overall treatment success rate was 97%, and cases of unsuccessful treatment were restricted to immigrant adolescents. CONCLUSIONS: The majority of pediatric TB in Denmark occurred among immigrant children with symptomatic TB, whereas more Danish children were diagnosed at earlier disease stages. Almost one-third of TB cases may represent missed opportunities to prevent TB disease. Improvements include enhanced adult case detection with comprehensive contact investigation among children, tailored screening and vaccination of immigrant children, and raised awareness of diagnosing and treating latent TB infection in children.

Long-term risk of tuberculosis among migrants according to migrant status: a cohort study.

BACKGROUND: The majority of tuberculosis (TB) cases in low-incidence countries occur in migrants. Only few studies have assessed the long-term TB risk in migrants after immigration, and datasets have not considered this across a range of diverse migrant groups. This nationwide study aimed to investigate long-term TB risk among migrants according to migrant status and region of origin. METHODS: This cohort study included all migrants aged ≥ 18 years who obtained residence in Denmark from 1993 to 2015, with a mean follow-up of 10.8 years [standard deviation (SD) 7.3]. Migrants were categorized based on legal status of residence and region of origin. Incidence rates (IR) and rate ratios (IRR) were estimated by Poisson regression. RESULTS: A total of 142 314 migrants were included. Across all migrants, the TB risk was highest during year 1 of residence (IR 275/100 000 person-years; 95% CI 249-305) followed by a gradual decline, though TB risk remained high for over a decade. Compared with the Danish-born population, the IRRs after 7-8 years were particularly higher among former asylum seekers (IRR 31; 95% CI 20-46), quota refugees (IRR 31; 95% CI 16-71), and family-reunified with refugees (IRR 22; 95% CI 12-44). Sub-Saharan African migrants also experienced elevated risk (IRR 75; 95% CI 51-109). The proportion of migrants with pulmonary TB was 52.4%. CONCLUSION: All migrant groups experienced an initial high TB risk, but long-term risk remained high in key migrant groups. Most European countries focus TB screening on or soon after arrival. Our study suggests that approaches to TB screening should be adapted, with migrant populations benefiting from long-term access to preventive health services.

[Tuberculosis among children and adolescents].

Diagnosing tuberculosis (TB) in children and adolescents pose a diagnostic challenge due to sparse symptoms and clinical signs. Children are at a much higher risk than adults of progression to severe disease. In this review, the presentation and management of childhood TB is described. TB in children indicates ongoing transmission and is an indicator of failing disease control in the community. Tests suited to predict progression are warranted, and targeting latent infection is essential to achieve TB elimination. We recommend a low threshold for referral of children suspected of active or latent TB.

Tuberculosis incidence among migrants according to migrant status: a cohort study, Denmark, 1993 to 2015.

BackgroundMigrants account for the majority of tuberculosis (TB) cases in low-incidence countries in western Europe. TB incidence among migrants might be influenced by patterns of migration, but this is not well understood.AimTo investigate differences in TB risk across migrant groups according to migrant status and region of origin.MethodsThis prospective cohort study included migrants ≥ 18 years of age who obtained residency in Denmark between 1 January 1993 and 31 December 2015, matched 1:6 to Danish-born individuals. Migrants were grouped according to legal status of residency and region of origin. Incidence rates (IR) and incidence rate ratios (IRR) were estimated by Poisson regression.ResultsThe cohort included 142,314 migrants. Migrants had significantly higher TB incidence (IR: 120/100,000 person-years (PY); 95% confidence interval (CI): 115-126) than Danish-born individuals (IR: 4/100,000 PY; 95% CI: 3-4). The IRR was significantly higher in all migrant groups compared with Danish-born (p < 0.01). A particularly higher risk was seen among family-reunified to refugees (IRR: 61.8; 95% CI: 52.7-72.4), quota refugees (IRR: 46.0; 95% CI: 36.6-57.6) and former asylum seekers (IRR: 45.3; 95% CI: 40.2-51.1), whereas lower risk was seen among family-reunified to Danish/Nordic citizens (IRR 15.8; 95% CI: 13.6-18.4) and family-reunified to immigrants (IRR: 16.9; 95% CI: 13.5-21.3).DiscussionAll migrants had higher TB risk compared with the Danish-born population. While screening programmes focus mostly on asylum seekers, other migrant groups with high risk of TB are missed. Awareness of TB risk in all high-risk groups should be strengthened and screening programmes should be optimised.

Epidemiology of tuberculous lymphadenitis in Denmark: A nationwide register-based study.

BACKGROUND: Tuberculous lymphadenitis (TBLA) is the most common extrapulmonary manifestation of tuberculosis (TB), often claimed to be reactivation. We aimed to describe the epidemiology of TBLA in Denmark, as it has not previously been investigated specifically although extrapulmonary TB has been associated with an increased long-term mortality and delays in the diagnosis. METHODS: Register-based study of all patients notified with TBLA in Denmark from 2007 through 2016 utilizing six different nationwide registers. Patients were identified through the national TB surveillance register, and the diagnosis evaluated based on microbiology, pathology and/or clinical assessment. RESULTS: In total, 13.5% (n = 489) of all TB patients in Denmark had TBLA with annual proportions from 9.4 to 15.7%. Most patients were immigrants between 25-44 years. Incidence rates ranged from as high as 1,014/100,000 for Nepalese citizens to as a low as 0.06/100,000 for Danes. Danes had a significant higher median age and significant more risk factors and comorbidities, as well as an increased overall mortality, compared with immigrants (p<0.05). A significant and much higher proportion of unique MIRU-VNTR genotypes were seen among TBLA patients compared to other TB manifestations. CONCLUSION: In Denmark, TBLA is a common manifestation of TB, especially in young immigrants from high-incidence countries. In Danes, it is a rare disease manifestation and associated with higher morbidity and mortality. To our knowledge, this is the first study suggesting that TBLA is predominantly associated with reactivation of latent TB infection based on genotyping although this remains to be clarified.

[Measles are eliminated in Denmark].

Measles vaccination has led to a significant fall in the number of measles cases and measles-related deaths worldwide. However, many countries still struggle to eliminate the disease. To obtain elimination, a minimum of 95% vaccination coverage for both of the measles, mumps, and rubella (MMR) vaccines is necessary as well as an efficient surveillance system and timely public health response. Presenting data on reported cases and vaccination coverage in the latest 20 years, this article describes how measles are eliminated in Denmark and recommends, how the Danish measles surveillance system can be further improved to maintain the status.

Epidemiology of pertussis in Denmark, 1995 to 2013.

We describe incidence and age distribution of laboratory-confirmed pertussis in Denmark from 1995 to 2013. Notification has been mandatory since 2007. Since 1997, an acellular monocomponent vaccine has been used. The latest epidemic occurred in 2002 with an incidence of 36 per 100,000; since 1995, only six infant deaths have been recorded. The inter-epidemic incidence lies below 10 per 100,000. In 1995, the mean age of confirmed cases was 9.2 years (95% confidence interval (CI): 7.9-10.5; median: 5.1), this gradually increased to 23.9 years in 2013 (95% CI: 22.0-25.8; median: 15.7). In 1995, 14% of laboratory-confirmed cases were 20 years and older, 43% in 2013. In the study period, the highest incidence among children was among those younger than one year with incidences between 84 and 331 per 100,000 in inter-epidemic periods (mean: 161/100,000) and 435 for the epidemic in 2002. After introduction of a preschool booster in 2003, the highest incidence among children one year and older changed gradually from three to five-year-olds in 2003 to 12 to 14-year-olds in 2013. In 2013, PCR was the primary method used for laboratory-diagnosis of pertussis in Denmark, while serology was the method with the highest percentage of positive results.

Evaluation of the enterovirus laboratory surveillance system in Denmark, 2010 to 2013.

The primary aim of the Danish enterovirus (EV) surveillance system is to document absence of poliovirus infection. The conflict in Syria has left many children unvaccinated and movement from areas with polio cases to Europe calls for increased awareness to detect and respond to virus-transmission in a timely manner. We evaluate the national EV laboratory surveillance, to generate recommendations for system strengthening. The system was analysed for completeness of viral typing analysis and clinical information and timeliness of specimen collection, laboratory results and reporting of clinical information. Of 23,720 specimens screened, 2,202 (9.3%) were EV-positive. Submission of cerebrospinal fluid and faecal specimens from primary diagnostic laboratories was 79.5% complete (845/1,063), and varied by laboratory and patient age. EV genotypes were determined in 68.5% (979/1,430) of laboratory-confirmed cases, clinical information was available for 63.1% (903/1,430). Primary diagnostic results were available after a median of 1.4 days, typing results after 17 days, detailed clinical information after 33 days. The large number of samples typed demonstrated continued monitoring of EV-circulation in Denmark. The system could be strengthened by increasing the collection of supplementary faecal specimens, improving communication with primary diagnostic laboratories, adapting the laboratory typing methodology and collecting clinical information with electronic forms.

Occupational Tuberculosis in Denmark through 21 Years Analysed by Nationwide Genotyping.

Tuberculosis (TB) is a well-known occupational hazard. Based on more than two decades (1992-2012) of centralized nationwide genotyping of all Mycobacterium tuberculosis culture-positive TB patients in Denmark, we compared M. tuberculosis genotypes from all cases notified as presumed occupational (N = 130) with M. tuberculosis genotypes from all TB cases present in the country (N = 7,127). From 1992 through 2006, the IS6110 Restriction Fragment Length Polymorphism (RFLP) method was used for genotyping, whereas from 2005 to present, the 24-locus-based Mycobacterial Interspersed Repetitive Unit-Variable Number of Tandem Repeat (MIRU-VNTR) was used. An occupational TB case was classified as clustered if the genotype was 100% identical to at least one other genotype. Subsequently, based on genotype, time period, smear positivity, geography, susceptibility pattern, and any reported epidemiological links between the occupational cases and any potential source cases, the occupational case was categorized as confirmed, likely, possible or unlikely occupationally infected. Among the 130 notified presumed occupational cases, 12 (9.2%) could be classified as confirmed and 46 (35.4%) as unlikely, accounting for nearly half of all cases (44.6%). The remaining 72 cases (55.4%) were categorized as possible. Within this group, 15 cases (11.5%) were assessed to be likely occupational. Our study shows that genotyping can serve as an important tool for disentangle occupational TB in high-income low incidence settings, but still needs to be combined with good epidemiological linkage information.

[Post-exposure prophylaxis against measles]. / Posteksponeringsprofylakse mod mæslinger.

This review article deals with the newest guidelines in post-exposure prophylaxis against measles and puts forward recommendations on how this prophylaxis should be handled with regards to children in all ages, both immunosuppressed and competent.

Phylogenetic and epidemiological analysis of measles outbreaks in Denmark, 2013 to 2014.

Despite the introduction of safe, effective vaccines decades ago and joint global public health efforts to eliminate measles, this vaccine-preventable disease continues to pose threats to children's health worldwide. During 2013 and 2014, measles virus was introduced into Denmark through several independent importations. This resulted in a number of secondary cases (n=7), with two clusters in 2013 and one in 2014. In total, there were 44 cases of measles. Most cases (n=41) were laboratory confirmed by detection of measles virus genome by real-time reverse transcription (RT)-PCR and IgM antibodies. The viruses from confirmed cases were genotyped by sequencing. Only one genotype circulated each year, i.e. D8 and B3, respectively. Sequencing of measles virus from different clinical specimens from the same patients revealed that sequence variants of measles viruses might co-exist and co-transmit during an outbreak. The majority of the cases were unvaccinated (n=27) or recipients of one dose of measles-mumps-rubella (MMR) vaccine (n=7). In addition, two fully vaccinated adult cases were reported in 2014. We demonstrate the transmission of measles virus in a population in which the two-dose MMR vaccination coverage rate was 80% and how even vaccinated individuals may be at risk of contracting measles once transmission has been established.