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.

Validity and reliability of the Rosacea Area and Severity Index: A novel scoring system for clinical assessment of rosacea severity.

BACKGROUND: Rosacea is a common chronic inflammatory facial skin disorder. Standardized evaluation of the severity and extent of rosacea is important for baseline assessment and treatment effect. The currently used Investigator's Global Assessment (IGA) is unspecific and fails to consider subtypes/phenotypes of rosacea and area involvement. The Rosacea Area and Severity Index (RASI) was developed to give a more nuanced evaluation of rosacea features in four facial skin areas adjusted to the relative importance of each area of the face to obtain an overall severity score. OBJECTIVES: To validate RASI against the IGA and to assess the inter- and intraobserver reliability for RASI. METHODS: Sixteen dermatologists evaluated photographs of 60 adult patients with rosacea (3 photographs per patient, one from the front and one from each side). IGA and RASI scores were performed for interobserver reliability assessment. To determine intraobserver reliability, 14 dermatologists evaluated 10 other patients twice with at least 1 week interval. RESULTS: The IGA and RASI correlated well (Spearman correlation coefficient (SCC) = 0.75, 95% confidence interval (CI) = 0.72-0.78). Interobserver reliability was moderate for RASI and poor to moderate for IGA. Reliability was strongest for rhinophyma, followed by papules/pustules and erythema, and rather weak for telangiectasia. For area scores, interobserver reliability was strongest for cheeks, followed by nose, chin and forehead. We found a moderate-to-strong intraobserver agreement both for IGA and RASI. CONCLUSIONS: We have designed a new practical tool to examine clinical severity of rosacea. RASI proved simple and reliable in scoring clinical severity of rosacea with an agreement comparable to the currently used IGA although RASI will provide a more nuanced view of the current rosacea extent and severity. We suggest that RASI is used in the daily clinical setting as well as in clinical studies assessing the efficacy of rosacea therapies.

Underreporting of patients diagnosed with tuberculosis in the Region of Southern Denmark.

Background: Tuberculosis (TB) is a notifiable disease in Denmark. Underreporting leads to underestimation of the disease burden and may impede disease control. To date, no other published studies have examined underreporting of TB in the Danish setting. Method: Records of patients in the Region of Southern Denmark diagnosed with TB from 2009 to 2014 in the Danish National Patient Registry (DNPR) were linked to the national notification database. Medical records of non-notified patients were reviewed, followed by statistical comparison of demographic and medical parameters with notified TB patients in the region. Results: In the study period, 28.9% (n=30) of clinically diagnosed, culture-negative TB cases were not notified, corresponding to an overall TB underreporting rate of 7.5%. Non-notified patients had fewer co-morbidities and were less likely to have had previous TB episodes. Incidentally, we found a high number (71.1%) of erroneous TB diagnoses in the DNPR. Conclusions: Accurate data based on notification is essential to understand possible needs for preventive actions in the population. Our study demonstrates the existence of underreporting of culture-negative TB cases in the Region of Southern Denmark.

Review of tuberculosis treatment outcome reporting system in Denmark, a retrospective study cohort study from 2009 through 2014.

BACKGROUND: In Denmark, reporting of tuberculosis (TB) treatment outcome is voluntary and data incomplete. In the European Centre for Disease Prevention and Control most recent report presenting data from 2017, only 53.9% of Danish pulmonary TB cases had a reported outcome. Monitoring of TB treatment outcome is not feasible based on such limited results. In this retrospective study from 2009 to 2014, we present complete treatment outcome data and describe characteristics of cases lost to follow up. METHODS: All cases notified from 2009 through 2014 were reviewed. Hospital records were examined, and TB treatment outcome was categorized according to the World Health Organization's (WHO) definitions. RESULTS: A total of 2131 TB cases were included. Treatment outcome was reported to the Surveillance Unit in 1803 (84.6%) cases, of which 468 (26.0%) were reclassified. For pulmonary TB, 339 (28.9%) cases were reclassified between cured and treatment completed. Overall, the proportion of cases who achieved successful treatment outcome increased from 1488 (70.4%) to 1748 (81.8%). CONCLUSION: A high number of cases were reclassified during the review process. Increased focus on correct treatment outcome reporting is necessary in Denmark. A more comprehensive and exhaustive categorization of TB treatment outcome could be beneficial, especially for cases where collection of sputum or tissue towards the end of treatment is challenging.

Completeness of tuberculosis (TB) notification: inventory studies and capture-recapture analyses, six European Union countries, 2014 to 2016.

BackgroundProgress towards the World Health Organization's End TB Strategy is monitored by assessing tuberculosis (TB) incidence, often derived from TB notification, assuming complete case detection and reporting. This assumption is unlikely to hold in many settings, including European Union (EU) countries.AimWe aimed to assess observed and estimated completeness of TB notification through inventory studies and capture-recapture (CRC) methodology in six EU countries: Croatia, Denmark, Finland, the Netherlands, Portugal Slovenia.MethodsWe performed record linkage, case ascertainment and CRC analyses of data collected retrospectively from at least three national TB-related registers in each country between 2014 and 2016.ResultsObserved completeness of TB notification by inventory studies was 73.9% in Croatia, 98.7% in Denmark, 83.6% in Finland, 81.6% in the Netherlands, 85.8% in Portugal and 100% in Slovenia. Subsequent CRC analysis estimated completeness of TB notification to be 98.4% in Denmark, 76.5% in Finland and 77.0% in Portugal. In Croatia, CRC analyses produced implausible results while in the Netherlands and Slovenia, it was methodologically considered not meaningful.ConclusionInventory studies and CRC methodology suggest a TB notification completeness between 73.9% and 100% in the six EU countries. Mandatory reporting by clinicians and laboratories, and cross-checking of registers, strongly contributes to accurate notification rates, but hospital episode registers likely contain a considerable proportion of false-positive TB records and are thus less useful. Further strengthening routine surveillance to count TB cases, i.e. incidence, accurately by employing record-linkage of high-quality TB registers should make CRC studies obsolete in EU countries.

New tick-borne encephalitis virus hot spot in Northern Zealand, Denmark, October 2019.

During summer 2019, three patients residing by Tisvilde Hegn, Denmark were hospitalised with tick-borne encephalitis (TBE) after tick bites. A new TBE virus (TBEV) micro-focus was identified in tick nymphs collected around a playground in Tisvilde Hegn forest. Estimated TBEV prevalence was 8%, higher than in endemic areas around Europe. Whole genome sequencing showed clustering to a TBEV strain from Norway. This is the second time TBEV is found in Ixodes ricinus outside Bornholm, Denmark.

Co-circulation of multiple subtypes of enterovirus A71 (EV- A71) genotype C, including novel recombinants characterised by use of whole genome sequencing (WGS), Denmark 2016.

In Europe, enterovirus A71 (EV-A71) has primarily been associated with sporadic cases of neurological disease. The recent emergence of new genotypes and larger outbreaks with severely ill patients demonstrates a potential for the spread of new, highly pathogenic EV-A71 strains. Detection and characterisation of these new emerging EV variants is challenging as standard EV assays may not be adequate, necessitating the use of whole genome analysis.

Prognostic value of interferon-γ release assays, a population-based study from a TB low-incidence country.

BACKGROUND: The ability of interferon-γ release assays to predict the development of TB has been investigated in many studies, but few cases develop TB during follow-up limiting the generalisation of results. METHODS: We assessed QuantiFERON-TB Gold In-Tube test (QFT) results from 15 980 Danish individuals and data on all TB cases in Denmark from 2005 to 2012 and determined the predictive value of the QFT for coprevalent TB (0-90 days after testing) and incident TB (>90 days). RESULTS: Coprevalent TB was diagnosed in 10.7% (183/1703) and 0.3% (38/13 463) cases with a positive and negative QFT, respectively. For the QFT-positive cases, coprevalent TB was more frequent among persons <35 years compared with those >35  years (19.3% vs 7.2%, p<0.001). The cohort was followed-up for 52 807 person-years, median follow-up time was 3.36 years. For incident TB, the positive and negative predictive values (PPV and NPV) were 1.32% and 99.85%, respectively. Incidence rates (IR) for incident TB among QFT-positives and QFT-negatives were 383 per 10(5) and 45 per 10(5) person-years, respectively. Among cases with a positive QFT, IR for incident TB was associated with time interval since QFT (<2 years, p<0.001), but not with age (<35 years, p=0.087). CONCLUSIONS: We confirmed a high NPV of the QFT and found positive QFT associated with a higher risk of subsequent incident TB. Overall, the PPV for incident cases was 1.32%, and development of incident TB was associated with time interval after the QFT, but not with age.

Characteristics and Clinical Outcome of Bone and Joint Tuberculosis From 1994 to 2011: A Retrospective Register-based Study in Denmark.

BACKGROUND: Most information on bone-joint (BJ)-tuberculosis is based on data from high-incidence areas. We conducted a nationwide register-based analysis of BJ-tuberculosis in Denmark from 1994 to 2011. METHODS: We linked data from the national tuberculosis surveillance system on BJ-tuberculosis, hospital records, the Danish Hospital and Civil Registration System. RESULTS: We identified 282 patients with BJ-tuberculosis, 3.6% of all tuberculosis cases (n = 7936). Spinal tuberculosis was found in 153 of 282 patients (54.3%); 83.3% of all cases were immigrants. Danes were older and had higher Charlson comorbidity index scores than immigrants (P < .01). C-reactive protein and erythrocyte sedimentation rates were elevated in most cases. Median time to diagnosis after first hospital contact was 19.5 days for spinal tuberculosis and 28 days for other forms of BJ-tuberculosis (P = .01). Of patients with spinal tuberculosis, 54/133 (40.6%) had neurologic deficits at admission and 17.3% presented with cauda equina. Diagnosis was culture verified in 87%. (Resistance to any drug was found in 10.2%). Median time on antituberculous treatment for patients with spinal and other forms of BJ-tuberculosis was 9 months and 7 months, respectively (P < .01). Surgery was required in 44.4% patients with spinal tuberculosis and in 32.6% patients with other forms of BJ-tuberculosis (P = .04). Sequelae were reported in 57.5% of patients with spinal tuberculosis and 29.1% of patient with other forms of BJ-tuberculosis (P < .01). One-year mortality was 25.5% among Danes compared with 1.3% among immigrants (P < .01). CONCLUSIONS: BJ-tuberculosis was rare and seen mainly in younger immigrants in Denmark. More than half of cases were spinal tuberculosis, presenting with more severe symptoms and worse outcome, compared with other forms of BJ-tuberculosis.

Tuberculous meningitis in Denmark: a review of 50 cases.

BACKGROUND: Tuberculous meningitis is the most severe manifestation of extrapulmonary tuberculosis with a high mortality rate and a high rate of sequelae among survivors. The aim of this study is to assess the current epidemiology, clinical features, diagnostic procedures, treatment and outcome in patients with tuberculous meningitis in Denmark, a country with a low tuberculosis incidence. METHODS: A nationwide retrospective study was conducted, comprising all patients notified with tuberculous meningitis (TBM) in Denmark from 2000-2008. Medical records were reviewed using a standardised protocol. RESULTS: Fifty patients, including 12 paediatric patients, were identified. 78% of the patients were immigrants from countries of high tuberculosis endemicity. 64% of all patients had a pre-existing immunosuppressive condition; 10% were HIV positive, 48% were HIV seronegative and 42% had an unknown HIV status. Median symptom duration before admission was 14 days in the Danish patient population and 20 days in the immigrant group. Biochemical analysis of cerebrospinal fluid (CSF) samples revealed pleocytosis in 90% with lymphocyte predominance in 66%. Protein levels were elevated in 86%. The most common findings on neuro-radiological imaging were basal meningeal enhancement, tuberculomas and hydrocephalus. Lumbar puncture was performed on 42 patients; 31 of these specimens (74%) had a positive CSF culture for mycobacteria and 9.5% were smear positive for acid-fast bacilli. The overall mortality rate was 19% and 48% of the remaining patients had neurological sequelae of varying degree. CONCLUSION: TBM is a rare but severe manifestation of extrapulmonary TB in Denmark. The clinician must be prepared to treat empirically if the suspicion of TBM has arisen to improve treatment outcome.

Characteristics and predictors for tuberculosis related mortality in Denmark from 2009 through 2014: A retrospective cohort study.

OBJECTIVES: Mortality from tuberculosis (TB) has been declining since 2000, nevertheless there is still a significant number of patients who die before or during TB treatment. The aims were to examine and describe predictors associated with TB related mortality. METHODS: Patients notified with TB from 2009 though 2014 in Denmark were included. Data were extracted from national registers and patient records were examined for clinical information and treatment outcome. Cox proportional hazards regression was used to examine TB related mortality. RESULTS: A total of 2131 cases were identified, 141 (6.6%) patients died before or during TB treatment. TB related mortality accounted for 104 cases (73.8%) and decreased significantly from 6.7% to 3.2% (p = .04) during the study period. Within 1 months of diagnosis, 49% of TB related deaths had occurred. The strongest risk factors present at time of diagnosis, associated with TB related mortality, were: age > 70 years, Charlson comorbidity index > 1, alcohol abuse, weight loss, anemia, and C-reactive protein > 100 mg/L (p < .05). CONCLUSION: The majority of TB related deaths occurred soon after diagnosis, emphasizing that TB patients identified to have a high risk of mortality should be closely monitored before and during the intensive treatment period to improve their outcomes.

Two measles clusters in connection with short inner-European air travels indicating impediments to effective measles control: A cluster analysis.

Importation and transmission of measles via air travel is a public health concern to countries, which are close to or have achieved elimination, i.e., to the majority of countries in Europe. In 2018, two measles cases occurred in Berlin residents, who flew within Europe while being infectious. In addition to contact tracing through passenger manifests, we contacted national authorities in flight destination countries or embarking countries and inquired about epidemiologically linked measles cases to the two Berlin index cases. We identified eight epidemiologically linked cases (six males, median age: 32 years) from three countries associated with three air-travels. Consequently measles was imported to Germany (Bavaria), Denmark and possibly Sweden. Our investigations revealed impediments to an effective public health response indicating the need to revisit current guidelines and methods to better control transmission of measles related to air travel.

Tuberculosis among Patients Undergoing Solid Organ Transplantation or Dialysis in a Low-Endemic Country, 2004-2017.

BACKGROUND: The risk of active TB among solid organ transplant (SOT) recipients and patients initiating chronic dialysis in a country with low incidence of TB is not well elucidated. METHODS: Patients aged >18 years who were transplanted with a solid organ or initiated chronic dialysis at Copenhagen University Hospital in the period 2004-2017 were followed from date of transplantation or initiation of dialysis. Data on demographics and outcomes were obtained from nationwide registries. RESULTS: We included 1,989 SOT recipients and 1,305 patients initiating chronic dialysis, who were followed for a total of 9,785 and 4,196 person-years (PY), respectively. Only a minority of patients had been screened for latent TB prior to SOT or initiation of dialysis. The incidence rates (IRs)/100,000 PY of TB among patients from medium/high TB endemic areas were 358 (95% CI 115-1,110) and 1,266 (95% CI 681-2354) for SOT and dialysis patients, respectively, whereas IRs among patients of Danish origin were 11 (95% CI 2-81) and 31 (95% CI 4-218). CONCLUSION: The incidence of TB among immunosuppressed immigrants from medium/high TB endemic countries was very high, while the risk of TB among patients from low-endemic countries was minimal.

Tuberculosis Transmission in Danish Children: A Nationwide Register-based Study.

BACKGROUND: Tuberculosis (TB) remains a major public health issue among children worldwide. Data on TB transmission in children living in low-incidence countries is limited. METHODS: We studied TB transmission in ethnic Danish children younger than 15 years of age between 2000 and 2013. Identification of children with TB disease and information on demographics and TB contacts were retrieved from the national TB surveillance register and the International Reference Laboratory of Mycobacteriology. RESULTS: In total, 88 children with TB disease were identified in the study period, corresponding to a mean annual incidence of 6.9 per 1,000,000 children younger than 15 years of age. The male to female ratio was 1.3. Median age was 5 years (interquartile range, 3-8.5). Seventy-three (83%) children had a known TB contact of which 60% was among household contacts with recent TB, predominantly parents. Sixty-six (75%) children were classified as part of epidemiologic clusters. Thirty-five (40%) children had culture verified TB of which information on genotypes was available for 34 (97%). Of these, 35% belonged to cluster C2/1112-15, the most prevalent cluster among adult Danes. CONCLUSIONS: We found on-going TB transmission in Danish children within the households of a low TB incidence population. These findings emphasize the need for early diagnosis of TB in children, thorough contact tracing and increased focus on risk groups.

Think central nervous system tuberculosis, also in low-risk children: a Danish nationwide survey.

BACKGROUND: Paediatric central nervous system (CNS) tuberculosis (TB) imposes a high risk of death and neurologic sequelae, particularly if the diagnosis is delayed. Children from non-TB endemic countries are particularly at risk of delayed or missed diagnosis. We aimed to investigate CNS TB in Denmark, a TB low-endemic country and where Bacillus Calmette-Guerin (BCG) vaccination is not a part of the vaccination schedule. METHODS: A nationwide retrospective case survey of all children with CNS TB in 2000-2015 identified through the National Danish TB Notification Register. We assessed epidemiology, clinical and paraclinical features, diagnostic criteria, treatment and outcome. RESULTS: Nine ethnic Danes and 12 children from TB-endemic countries with CNS TB were identified. Clinical features, C-reactive protein, chest X-ray and indirect TB screening assays all had low sensitivity (19-75%). All (18/18) patients had elevated cerebrospinal fluid (CSF) white blood cells and 15 of 17 (88%) had a combination of at least two characteristic CSF findings (lymphocyte predominance, elevated protein and/or hypoglycorrhachia). Cerebral computed tomography and magnetic resonance imaging were abnormal in 10 of 16 (63%) and 12 of 14 (86%), respectively. Treatment was initiated after a median of 3 days in children from TB-endemic countries, and after 10 days in ethnic Danish children. One patient died (5%): A native Danish girl who died before the diagnosis was established. CONCLUSIONS: Children from non-TB endemic countries may be at risk of delayed diagnosis and poorer prognosis compared to high-risk children. Cerebral magnetic resonance imaging and characteristic CSF findings had high diagnostic sensitivity.

Predictors for Pulmonary Tuberculosis Treatment Outcome in Denmark 2009-2014.

Monitoring of tuberculosis (TB) treatment outcome is essential to ensure an effective TB control program. In this nationwide retrospective cohort study from Denmark we present TB treatment outcome rates and risk factors associated with an unfavourable outcome. All patients notified with pulmonary TB from 2009 through 2014 were included. Logistic regression analyses were used to identify risk factors for unfavourable outcome. In total, 1681 pulmonary TB cases were included. TB treatment success rates increased during the study period. In 2014, the treatment success rate reached 85% for new culture positive cases whereas 7% cases interrupted treatment. The mortality decreased during the study period from 12.3% to 4.1%. Several risk factors associated with unfavourable outcome were identified in a multivariable model: male (OR: 2.56), Greenlandic origin (OR: 1.80), abuse of alcohol (OR: 2.90), history of mental disorder (OR: 2.46), and anaemia at time of treatment initiation (OR: 1.92). In a TB low incidence setting such as the Danish, it is important to maintain focus on preventing an unfavourable TB outcome. Patient management and treatment can be optimized by taking into consideration risk factors such as those identified in the present study.

Extrapulmonary Tuberculosis in Denmark From 2009 to 2014; Characteristics and Predictors for Treatment Outcome.

BACKGROUND: Extrapulmonary tuberculosis (EPTB) represents an increasing percentage of tuberculosis (TB) cases in Europe. However, strategies on TB prevention and successful treatment outcomes primarily target pulmonary TB. In this nationwide study, we present characteristics of EPTB, treatment outcomes, and predictors for unfavorable treatment outcomes. METHODS: All patients diagnosed with EPTB from 2009 to 2014 were included. Logistic regression analyses were used to identify risk factors for unfavorable outcome. The following definitions were used: unfavorable outcome: the sum of treatment failed, lost to follow-up, and not evaluated; patient delay: time from TB-related symptom onset until first hospital contact related to TB; doctor delay: time from first TB-related contact in the health care system to start of TB treatment. RESULTS: A total of 450 EPTB cases were notified, which represented 21.1% of all TB cases in Denmark. Immigrants accounted for 82.9%. Lymph nodes were the most common site of EPTB (55.4%) followed by pleural TB (13.4%). Patient delay was significantly longer among immigrants than Danes (60 vs 30 days; P < .01), whereas doctor delay was significantly longer among Danes (38.5 vs 28 days; P < .01). Treatment completion rates were high and reached 90.9% in 2014. Male gender (odds ratio [OR], 5.18; 95% confidence interval [CI], 1.79-15.04) and age 0-24 years (OR, 16.39; 95% CI, 2.02-132.64) were significantly associated with unfavorable outcome. CONCLUSIONS: EPTB represented a significant number of all TB cases and was predominantly seen among younger immigrants in Denmark. To maintain high treatment completion rates, increased focus on male gender and young age is needed.

Neurotransmitter transporters: molecular function of important drug targets.

The concentration of neurotransmitters in the extracellular space is tightly controlled by distinct classes of membrane transport proteins. This review focuses on the molecular function of two major classes of neurotransmitter transporter that are present in the cell membrane of neurons and/or glial cells: the solute carrier (SLC)1 transporter family, which includes the transporters that mediate the Na(+)-dependent uptake of glutamate, and the SLC6 transporter family, which includes the transporters that mediate the Na(+)-dependent uptake of dopamine, 5-HT, norepinephrine, glycine and GABA. Recent research has provided substantial insight into the structure and function of these transporters. In particular, the recent crystallizations of bacterial homologs are of the utmost importance, enabling the first reliable structural models of the mammalian neurotransmitter transporters to be generated. These models should be an important tool for developing specific drugs that, through selective interaction with transporters, could improve the treatment of serious neurological and psychiatric disorders.

QuantiFERON­TB Gold In-Tube test performance in Denmark.

BACKGROUND: Little is known about the QuantiFERON-TB Gold In-Tube Test (QFT) in extreme age groups. The test performance has been reported to be impaired in children and elderly, but reports are diverging. The aim of this study was to evaluate QFT performance in patients with and without Tuberculosis (TB). METHODS: A retrospective study analysing the results of 18,850 QFT performed in Denmark 2005-2010. The effect of age, sex, localisation of TB, and result of culture on QFT performance (positive, negative and indeterminate results) was determined. RESULTS: Among 383 patients with TB, indeterminate rate was low (3.9%, 15/383). Sensitivity was high (86.1%, 317/368) and not affected by sex or localization of TB disease, but declined with increasing age (p < 0.0001). In children 1-4 years old, sensitivity was high (100%, 9/9). Among 15,709 persons without TB, the indeterminate rate was 5.1% (804/15,709) and significantly higher in infants <1 year (15.6%, 5/32) and elderly >65 years (8.1%, 219/2715) compared to the adult population 15-64 years (4.5%, 552/12,317). Indeterminate results were due to a low positive control in 99.6% (801/804). CONCLUSION: In Denmark, a TB low incidence country, the overall QFT performance was good. The sensitivity in children (≥ 1) was high although few children were included, whereas sensitivity declined with increasing age. Indeterminate rates were higher in infants and elderly. In contrast to current guidelines, our data suggest that the QFT performs well in children ≥ 1 years in low endemic regions but that the test should be used with care among the elderly.