Exclusion of older adults and immunocompromised individuals in influenza, pneumococcal and COVID-19 vaccine trials before and after the COVID-19 pandemic.

BACKGROUND: Older adults and immunocompromised individulas are often excluded from vaccine trials. AIM: We hypothesised that during the coronavirus disease 2019 (COVID-19) pandemic, the proportion of trials excluding these patients decreased. METHODS: Using the US Food and Drug Administration and and European Medicines Agency search engines, we identified all vaccines approved against pneumococcal disease, influenza (quadrivalent vaccines), and COVID-19 from 2011 to 2021. Study protocols were screened for direct and indirect age exclusion criteria and exclusion of immunocompromised individuals. In addition, we reviewed the studies with no explicit exclusion criteria and investigated the actual inclusion of those individuals. RESULTS: We identified 2024 trial records; 1702 were excluded (e.g., use of other vaccine or risk group); and 322 studies were eligible for our review. Among the pneumococcal and influenza vaccine trials (n = 193), 81 (42%) had an explicit direct age exclusion, and 150 (78%) had an indirect age-related exclusion. In total, 163 trials (84%) trials were likely to exclude older adults. Among the COVID-19 vaccine trials (n = 129), 33 (26%) had direct age exclusion and 82 (64%) had indirect age exclusion; in total, 85 (66%) trials were likely to exclude older adults. Therefore was a 18% decrease in the proportion of trials with age-related exclusion between 2011 and 2021 (only influenza and pneumococcal vaccine trials) and 2020-2021 (only COVID-19 vaccine trials) (p = 0.014). In a sub-analysis assessing observational and randomised trials, the decrease was 25% and 9%, respectively. Immunocompromised individuals were included in 87 (45%) of the pneumococcal and influenza vaccine trials compared with 54 (42%) of the COVID-19 vaccine trials (p = 0.058). CONCLUSIONS: During the COVID-19 pandemic, we found a decrease in the exclusion of older adults from vaccine trials but no significant change in the inclusion of immunocompromised individulas.

Long-Term Survival, Health, Social Functioning, and Education in Patients With an Enterovirus Central Nervous System Infection, Denmark, 1997-2016.

BACKGROUND: The long-term clinical course of patients with an enterovirus central nervous system infection (ECI) is poorly understood. METHODS: We performed a nationwide population-based cohort study of all Danish patients with ECI diagnosed 1997-2016 (n = 1745) and a comparison cohort from the general population individually matched on date of birth and sex (n = 17 450). Outcomes were categorized into mortality and risk of cancer and likely measures of neurological sequelae: neuropsychiatric morbidities, educational landmarks, use of hospital services, employment, receipt of disability pension, income, number of sick leave days, and nursing home residency. RESULTS: Mortality in the first year was higher among patients with ECI (mortality rate ratio [MRR] = 10.0; 95% confidence interval [CI], 4.17-24.1), but thereafter mortality was not higher (MMR = 0.94; 95% CI, 0.47-1.86). Long-term outcomes for patients with ECI were not inferior to those of the comparison cohort for risk of cancer, epilepsy, mental and behavioral disorders, dementia, depression, school start, school marks, high school education, use of hospital services, employment, receipt of disability pension, income, days of sick leave, or nursing home residency. CONCLUSIONS: Diagnosis of an ECI had no substantial impact on long-term survival, health, or social/educational functioning.

Risk of Neurological Disorders in Patients With European Lyme Neuroborreliosis: A Nationwide, Population-Based Cohort Study.

BACKGROUND: Lyme neuroborreliosis (LNB), caused by the tick-borne spirochetes of the Borrelia burgdorferi sensu lato species complex, has been suggested to be associated with a range of neurological disorders. In a nationwide, population-based cohort study, we examined the associations between LNB and dementia, Alzheimer's disease, Parkinson's disease, motor neuron disease, epilepsy, and Guillain-Barré syndrome. METHODS: We used national registers to identify all Danish residents diagnosed during 1986-2016 with LNB (n = 2067), created a gender- and age-matched comparison cohort from the general population (n = 20 670), and calculated risk estimates and hazard ratios. RESULTS: We observed no long-term increased risks of dementia, Alzheimer's disease, Parkinson's disease, motor neuron diseases, or epilepsy. However, within the first year, 8 (0.4%) of the LNB patients developed epilepsy, compared with 20 (0.1%) of the comparison cohort (difference, 0.3%; 95% confidence interval, .02-.6%). In the LNB group, 11 (0.5%) patients were diagnosed with Guillain-Barré syndrome within the first year after LNB diagnosis, compared with 0 (0.0%) in the comparison cohort. After the first year, the risk of Guillain-Barré was not increased. CONCLUSIONS: LNB patients did not have increased long-term risks of dementia, Alzheimer's disease, Parkinson's disease, motor neuron diseases, epilepsy, or Guillain-Barré. Although the absolute risk is low, LNB patients might have an increased short-term risk of epilepsy and Guillain-Barré syndrome.

Employment and disability pension after central nervous system infections in adults.

In this nationwide population-based cohort study using national Danish registries, in the period 1980-2008, our aim was to study employment and receipt of disability pension after central nervous system infections. All patients diagnosed between 20 and 55 years of age with meningococcal (n = 451), pneumococcal (n = 553), or viral (n = 1,433) meningitis or with herpes simplex encephalitis (n = 115), who were alive 1 year after diagnosis, were identified. Comparison cohorts were drawn from the general population, and their members were individually matched on age and sex to patients. Five years after diagnosis, the differences in probability of being employed as a former patient with pneumococcal meningitis or herpes simplex encephalitis versus being a member of the comparison cohorts were -19.9% (95% confidence interval (CI): -24.7, -15.1) and -21.1% (95% CI: -33.0, -9.3), respectively, and the corresponding differences in probability of receiving disability pension were 20.2% (95% CI: 13.7, 26.7) and 16.2% (95% CI: 6.2, 26.3). The differences in probability of being employed or receiving disability pension in former meningococcal or viral meningitis patients versus members of the comparison cohorts were small. In conclusion, pneumococcal meningitis and herpes simplex encephalitis were associated with substantially decreased employment and increased need for disability pension. These associations did not seem to apply to meningococcal meningitis or viral meningitis.

Microbiological and therapeutic challenges in infectious spondylodiscitis: a cohort study of 100 cases, 2006-2011.

BACKGROUND: The microbiological diagnosis of infectious spondylodiscitis is often difficult to establish and the disease requires prolonged antibiotic treatment. We analyzed the medical records of 100 patients admitted for infectious spondylodiscitis from 2006 to 2011 with an emphasis on (1) the diagnostic utility of blood cultures and invasive biopsies in the microbiological diagnosis, (2) clinical features differentiating Staphylococcus aureus infections from those with other aetiologies, and (3) evaluation of the outcome of the antimicrobial therapy. METHODS: A retrospective chart review was performed. RESULTS: Patients were diagnosed a median of 32 days after symptom onset and treated for a median of 91 days; 68% had abscesses, 65% experienced sequelae, and the 1-y crude mortality was 11%. Blood cultures yielded a diagnosis in 67%. Among blood culture-positive cases, no other culture or polymerase chain reaction results yielded further diagnoses. S. aureus infections comprised 58%. These cases compared to those with other aetiologies were younger, more frequently female, had a higher C-reactive protein, and more often had neutrocytosis, bacteraemia, and abscess formation. Presumed side effects mediated a change in treatment 33 times in 23 patients. Four patients experienced relapse. CONCLUSIONS: This contemporary case-series on infectious spondylodiscitis mostly concurs with previous studies. We emphasize the importance of thorough blood culture sampling before more invasive tests are considered. S. aureus infections exhibit, in particular, prominent pyogenic characteristics. Prospective studies evaluating the choice and duration of antimicrobial treatment are needed.

Educational achievement and economic self-sufficiency in adults after childhood bacterial meningitis.

IMPORTANCE: To our knowledge, no previous study has examined functioning in adult life among persons who had bacterial meningitis in childhood. OBJECTIVE: To study educational achievement and economic self-sufficiency in adults diagnosed as having bacterial meningitis in childhood. DESIGN, SETTING, AND PARTICIPANTS: Nationwide population-based cohort study using national registries of Danish-born children diagnosed as having meningococcal, pneumococcal, or Haemophilus influenzae meningitis in the period 1977-2007 (n=2784 patients). Comparison cohorts from the same population individually matched on age and sex were identified, as were siblings of all study participants. End of study period was 2010. MAIN OUTCOMES AND MEASURES: Cumulative incidences of completed vocational education, high school education, higher education, time to first full year of economic self-sufficiency, and receipt of disability pension and differences in these outcomes at age 35 years among meningitis patients, comparison cohorts, and siblings. RESULTS: By age 35 years, among persons who had a history of childhood meningococcal (n=1338), pneumococcal (n=455), and H. influenzae (n=991) meningitis, an estimated 11.0% (41.5% vs 52.5%; 95% CI, 7.3%-14.7%), 10.2% (42.6% vs 52.8%; 95% CI, 3.8%-16.6%), and 5.5% (47.7% vs 53.2%; 95% CI, 1.9%-9.1%) fewer persons, respectively, had completed high school and 7.9% (29.3% vs 37.2%; 95% CI, 1.6%-14.2%), 8.9% (28.1% vs 37.0%; 95% CI, 0.6%-17.2%), and 6.5% (33.5% vs 40.0%; 95% CI, 1.4%-11.6%) fewer had attained a higher education compared with individuals from the comparison cohort. Siblings of meningococcal meningitis patients also had lower educational achievements, while educational achievements of siblings of pneumococcal and H. influenzae meningitis patients did not differ substantially from those in the general population. At end of follow-up, 3.8% (90.3% vs 94.1%; 95% CI, 1.1%-6.5%), 10.6% (84.0% vs 94.6%; 95% CI, 5.1%-16.1%), and 4.3% (90.6% vs 94.9%; 95% CI, 2.0%-6.6%) fewer meningococcal, pneumococcal, and H. influenzae meningitis patients were economically self-sufficient and 1.5% (3.7% vs 2.3%; 95% CI, -0.2% to 3.2%), 8.7% (10.0% vs 1.3%; 95% CI, 5.0%-12.4%), and 3.7% (6.2% vs 2.5%; 95% CI, 1.6%-5.8%) more received disability pension compared with individuals from the comparison cohort. CONCLUSIONS AND RELEVANCE: In a Danish population, bacterial meningitis in childhood was associated with lower educational achievement and economic self-sufficiency in adult life. This association may apply particularly to pneumococcal and H. influenzae meningitis, whereas for meningococcal meningitis the lower educational achievement may be family-related.

Pentraxin 3 in the cerebrospinal fluid during central nervous system infections: A retrospective cohort study.

The present study describes diagnostic and prognostic abilities of Cerebrospinal fluid (CSF) Pentraxin 3 (PTX3) in central nervous system (CNS) infections. CSF PTX3 was measured retrospectively from 174 patients admitted under suspicion of CNS infection. Medians, ROC curves and Youdens index was calculated. CSF PTX3 was significantly higher among all CNS infections and undetectable in most of the patients in the control group, and significantly higher in bacterial infections compared to viral and Lyme infections. No association was found between CSF PTX3 and Glasgow Outcome Score. PTX3 in the CSF can distinguish bacterial infection from viral and Lyme infections and non-CNS infections. Highest levels were found in bacterial meningitis. No prognostic abilities were found.

Fever of unknown origin: a retrospective study of 52 cases with evaluation of the diagnostic utility of FDG-PET/CT.

OBJECTIVES: Fever of unknown origin (FUO) is dynamic in its origin and will be an ongoing challenge to the clinician because of shifting disease epidemiology. Here we present a series of patients with classical FUO admitted to an infectious diseases department during a 5-y period, with an emphasis on the diagnostic utility of ¹8F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) in present-day cases of FUO. METHODS: Patient records were reviewed retrospectively. RESULTS: A final diagnosis was achieved for 31 of the 52 cases (60%). The final diagnoses of these 31 cases and their distribution in the respective diagnostic categories were: infections 32% (10/31), non-infectious inflammatory disease 55% (17/31), and malignancy 13% (4/31). In our study PET/CT successfully identified an infectious, inflammatory, or neoplastic cause of fever in 10 of the 22 patients (45%) who underwent this scan. CONCLUSIONS: During the past decade the proportion of non-infectious inflammatory diseases in FUO series has increased. Based on our findings we recommend: (1) a PET/CT scan be performed early in the diagnostic work-up of patients with FUO, and (2) restraint in performing invasive procedures in patients with FUO in whom no cause of fever has been determined during diagnostic work-up.

Incidence and impact on mortality of severe neurocognitive disorders in persons with and without HIV infection: a Danish nationwide cohort study.

OBJECTIVE: The risk of neurocognitive disorders in human immunodeficiency virus (HIV)-infected patients in the era of highly active antiretroviral therapy (HAART) is controversial. We aimed to compare the incidence and impact on mortality of severe neurocognitive disorders (SNCDs) in HIV-infected patients with that of the background population. METHODS: The method used was a nationwide, population-based cohort study using Danish registries. We calculated incidence rates, incidence rate ratios, mortality rate ratios, and Kaplan-Meier tables to estimate the incidence of and survival after SNCD in HIV-infected patients, compared with a general population control cohort matched by age and sex. RESULTS: We observed 32 cases of SNCDs among 4452 HIV-infected patients and 120 cases of SNCDs among 62 328 population control subjects. The overall risk of SNCD among HIV-infected patients was 1.0 case per 1000 person-years (PYR), compared with 0.23 cases per 1000 PYR for population control subjects but became 0.35 cases/1000 PYR after 2004, compared with 0.27 cases/1000 PYR in population control subjects. The absence of HAART and a low CD4 lymphocyte count increased the risk of SNCD. The mortality among HIV-infected patients with SNCD was higher than that among population controls with SNCD (median survival, 4.3 years vs 9.7 years [P = .02]). CONCLUSION: HIV-infected patients have an increased risk of SNCD, but the risk is low and has, in recent years, become comparable to that seen in the background population. In contrast, the mortality remains high among HIV-infected patients diagnosed with SNCD.

[Symptomatic SARS-CoV-2 reinfection in an otherwise healthy person].

This is a case report of a young healthcare worker with a mild case of COVID-19 during the first wave in 2020 with no initial triggering of antibody response. The second episode of symptomatic infection of the patient with symptoms of moderate COVID-19, occurred eight months later in the beginning of the second surge in Denmark. It is the first reported case of symptomatic SARS-CoV-2 reinfection in Denmark, and it illustrates the possibility of reinfection with a more severe course of COVID-19 after an initial natural infection also among young immunocompetent individuals.

Host Genetics and Antiviral Immune Responses in Adult Patients With Multisystem Inflammatory Syndrome.

COVID-19 associated multisystem inflammatory syndrome (MIS) is a rare condition mostly affecting children but also adults (MIS-A). Although severe systemic inflammation and multiorgan dysfunction are hallmarks of the syndrome, the underlying pathogenesis is unclear. We aimed to provide novel immunological and genetic descriptions of MIS-A patients. Cytokine responses (IL-6, IL-1ß, TNFα, CXCL10, type I, II and III interferons) following SARS-CoV-2 infection of peripheral blood mononuclear cells in vitro were analyzed as well as antibodies against IFNα and IFNω (by ELISA) in patients and healthy controls. We also performed whole exome sequencing (WES) of patient DNA. A total of five patients (ages 19, 23, 33, 38, 50 years) were included. The patients shared characteristic features, although organ involvement and the time course of disease varied slightly. SARS-CoV-2 in vitro infection of patient PBMCs revealed impaired type I and III interferon responses and reduced CXCL10 expression, whereas production of proinflammatory cytokines were less affected, compared to healthy controls. Presence of interferon autoantibodies was not detected. Whole exome sequencing analysis of patient DNA revealed 12 rare potentially disease-causing variants in genes related to autophagy, classical Kawasaki disease, restriction factors and immune responses. In conclusion, we observed an impaired production of type I and III interferons in response to SARS-CoV-2 infection and detected several rare potentially disease-causing gene variants potentially contributing to MIS-A.

Assessment of the Risk of Psychiatric Disorders, Use of Psychiatric Hospitals, and Receipt of Psychiatric Medication Among Patients With Lyme Neuroborreliosis in Denmark.

Importance: The association of Lyme neuroborreliosis with the development of psychiatric disease is unknown and remains a subject of debate. Objective: To investigate the risk of psychiatric disease, the percentage of psychiatric hospital inpatient and outpatient contacts, and the receipt of prescribed psychiatric medications among patients with Lyme neuroborreliosis compared with individuals in a matched comparison cohort. Design, Setting, and Participants: This nationwide population-based matched cohort study included all residents of Denmark who received a positive result on an intrathecal antibody index test for Borrelia burgdorferi (patient cohort) between January 1, 1995, and December 31, 2015. Patients were matched by age and sex to a comparison cohort of individuals without Lyme neuroborreliosis from the general population of Denmark. Data were analyzed from February 2019 to March 2020. Exposures: Diagnosis of Lyme neuroborreliosis, defined as a positive result on an intrathecal antibody index test for B burgdorferi. Main Outcomes and Measures: The 0- to 15-year hazard ratios for the assignment of psychiatric diagnostic codes, the difference in the percentage of psychiatric inpatient and outpatient hospital contacts, and the difference in the percentage of prescribed psychiatric medications received among the patient cohort vs the comparison cohort. Results: Among 2897 patients with Lyme neuroborreliosis (1646 men [56.8%]) and 28 970 individuals in the matched comparison cohort (16 460 men [56.8%]), the median age was 45.7 years (interquartile range [IQR], 11.5-62.0 years) for both groups. The risk of a psychiatric disease diagnosis and the percentage of hospital contacts for psychiatric disease were not higher among patients with Lyme neuroborreliosis compared with individuals in the comparison cohort. A higher percentage of patients with Lyme neuroborreliosis compared with individuals in the comparison cohort received anxiolytic (7.2% vs 4.7%; difference, 2.6%; 95% CI, 1.6%-3.5%), hypnotic and sedative (11.0% vs 5.3%; difference, 5.7%; 95% CI, 4.5%-6.8%), and antidepressant (11.4% vs 6.0%; difference, 5.4%; 95% CI, 4.3%-6.6%) medications within the first year after diagnosis, after which the receipt of psychiatric medication returned to the same level as the comparison cohort. Conclusions and Relevance: In this population-based matched cohort study, patients with Lyme neuroborreliosis did not have an increased risk of developing psychiatric diseases that required hospital care or treatment with prescription medication. The increased receipt of psychiatric medication among patients with Lyme neuroborreliosis within the first year after diagnosis, but not thereafter, suggests that most symptoms associated with the diagnosis subside within a short period.

Central and peripheral nervous system complications of COVID-19: a prospective tertiary center cohort with 3-month follow-up.

OBJECTIVE: To systematically describe central (CNS) and peripheral (PNS) nervous system complications in hospitalized COVID-19 patients. METHODS: We conducted a prospective, consecutive, observational study of adult patients from a tertiary referral center with confirmed COVID-19. All patients were screened daily for neurological and neuropsychiatric symptoms during admission and discharge. Three-month follow-up data were collected using electronic health records. We classified complications as caused by SARS-CoV-2 neurotropism, immune-mediated or critical illness-related. RESULTS: From April to September 2020, we enrolled 61 consecutively admitted COVID-19 patients, 35 (57%) of whom required intensive care (ICU) management for respiratory failure. Forty-one CNS/PNS complications were identified in 28 of 61 (45.9%) patients and were more frequent in ICU compared to non-ICU patients. The most common CNS complication was encephalopathy (n = 19, 31.1%), which was severe in 13 patients (GCS ≤ 12), including 8 with akinetic mutism. Length of ICU admission was independently associated with encephalopathy (OR = 1.22). Other CNS complications included ischemic stroke, a biopsy-proven acute necrotizing encephalitis, and transverse myelitis. The most common PNS complication was critical illness polyneuromyopathy (13.1%), with prolonged ICU stay as independent predictor (OR = 1.14). Treatment-related PNS complications included meralgia paresthetica. Of 41 complications in total, 3 were para/post-infectious, 34 were secondary to critical illness or other causes, and 4 remained unresolved. Cerebrospinal fluid was negative for SARS-CoV-2 RNA in all 5 patients investigated. CONCLUSION: CNS and PNS complications were common in hospitalized COVID-19 patients, particularly in the ICU, and often attributable to critical illness. When COVID-19 was the primary cause for neurological disease, no signs of viral neurotropism were detected, but laboratory changes suggested autoimmune-mediated mechanisms.

A case of thrombocytopenia and multiple thromboses after vaccination with ChAdOx1 nCoV-19 against SARS-CoV-2.

Recently, reports of severe thromboses, thrombocytopenia, and hemorrhage in persons vaccinated with the chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19, AZD1222, Vaxzevria; Oxford/AstraZeneca) against severe acute respiratory syndrome coronavirus 2 have emerged. We describe an otherwise healthy 30-year-old woman who developed thrombocytopenia, ecchymosis, portal vein thrombosis, and cerebral venous sinus thrombosis the second week after she received the ChAdOx1 nCoV-19 vaccine. Extensive diagnostic workup for thrombosis predispositions showed heterozygosity for the prothrombin mutation, but no evidence of myeloproliferative neoplasia or infectious or autoimmune diseases. Her only temporary risk factor was long-term use of oral contraceptive pills (OCPs). Although both the prothrombin mutation and use of OCPs predispose to portal and cerebral vein thrombosis, the occurrence of multiple thromboses within a short time and the associated pattern of thrombocytopenia and consumption coagulopathy are highly unusual. A maximum 4T heparin-induced thrombocytopenia (HIT) score and a positive immunoassay for anti-platelet factor 4/heparin antibodies identified autoimmune HIT as a potential pathogenic mechanism. Although causality has not been established, our case emphasizes the importance of clinical awareness. Further studies of this potentially new clinical entity have suggested that it should be regarded as a vaccine-induced immune thrombotic thrombocytopenia.

Long-term mortality in patients diagnosed with pneumococcal meningitis: a Danish nationwide cohort study.

The objective of the study was to determine the long-term mortality and the causes of death in patients diagnosed with pneumococcal meningitis. The authors performed a nationwide, population-based cohort study including all Danish patients diagnosed with pneumococcal meningitis from 1977 through 2006 and alive 1 year after diagnosis. Data were retrieved from medical databases in Denmark. The absolute and relative risks of all-cause and cause-specific death were analyzed by using Kaplan-Meier survival curves, Poisson regression analysis, Cox regression analysis, and cumulative incidence functions. The authors identified 2,131 pneumococcal meningitis patients and an age- and gender-matched, population-based cohort of 8,524 individuals. Compared with the background population, the pneumococcal meningitis patients had an increased long-term mortality varying from an 8-fold increased mortality in the age category 0-<20 years to a 1.5-fold increased mortality in those aged 60-<80 years. The increased risk of death stemmed from neoplasms, liver diseases, and nervous system diseases. The excess mortality due to neoplasms stemmed mainly from a 5-fold increased risk of death due to hematologic neoplasms. To improve survival in patients surviving the acute phase of pneumococcal meningitis, physicians should meticulously screen this patient population for neurologic sequelae and comorbidity predisposing to the disease.

Imported melioidosis in Danish travellers: a diagnostic challenge.

Infections with Burkholderia pseudomallei (melioidosis) are rare events in Scandinavian countries, but the bacterium may be contracted during travel to endemic areas, i.e. Southeast Asia (especially Thailand) and northern Australia. Here, 5 travel-related cases occurring within the last 3 y in Denmark are reported, with particular emphasis on diagnostic and therapeutic challenges posed to health staff with little experience in the management of melioidosis. A newly developed B. pseudomallei-specific polymerase chain reaction test was applied and was able to correctly identify all isolates.

Changes in Lyme neuroborreliosis incidence in Denmark, 1996 to 2015.

Lyme neuroborreliosis (LNB) has recently been added to the list of diseases under the European Union epidemiological surveillance in order to obtain updated information on incidence. The goal of this study was to identify temporal (yearly) variation, high risk geographical regions and risk groups, and seasonal variation for LNB in Denmark. This cohort-study investigated Danish patients (n = 2791) diagnosed with LNB (defined as a positive Borrelia burgdorferi sensu lato (s.l.) intrathecal antibody test) between 1996-2015. We calculated incidence and incidence ratios of LNB by comparing 4-yr groups of calendar-years, area of residency, sex and age, income and education groups, and the number of new LNB cases per month. The incidence of LNB was 2.2 per 100,000 individuals and year in 1996-1999, 2.7 in 2004-2007 and 1.1 per 100,000 individuals in 2012-2015. Yearly variations in LNB incidence were similar for most calendar-year groups. LNB incidence was highest in Eastern Denmark and among males and individuals who were 0-14 yrs old, who had a yearly income of >449,000 DKK, and who had a Master's degree or higher education. The number of LNB cases was highest from July to November (p < 0.001). In conclusion, based on Danish nationwide data of patients with positive B. burgdorferi s.l. intrathecal antibody index (1996-2015) the incidence of LNB was found to increase until 2004-2007 but thereafter to decline. European surveillance studies of Lyme borreliosis should be encouraged to monitor the incidence trend.

Long term survival, health, social functioning, and education in patients with European Lyme neuroborreliosis: nationwide population based cohort study.

OBJECTIVE: To estimate long term survival, health, and educational/social functioning in patients with Lyme neuroborreliosis compared with the general population. DESIGN: Nationwide population based cohort study using national registers. SETTING: Denmark. PARTICIPANTS: All Danish residents diagnosed during 1986-2016 as having Lyme neuroborreliosis (n=2067), defined as a positive Borrelia burgdorferi intrathecal antibody test and a clinical diagnosis of Lyme borreliosis, and a comparison cohort from the general population matched on sex and date of birth (n=20 670). MAIN OUTCOME MEASURES: Mortality rate ratios, incidence rate ratios of comorbidities, and differences in educational and social outcomes. RESULTS: Mortality among patients with Lyme neuroborreliosis was not higher than in the general population (mortality rate ratio 0.90, 95% confidence interval 0.79 to 1.03). Lyme neuroborreliosis patients had increased risk of haematological (incidence rate ratio 3.07, 2.03 to 4.66) and non-melanoma skin cancers (1.49, 1.18 to 1.88). At diagnosis, Lyme neuroborreliosis patients had slightly higher employment and lower disability pension rates. After five years, patients and comparison cohort members had similar numbers of hospital contacts (difference -0.22, 95% confidence interval -0.45 to 0.02, in-hospital days/year; 0.37, -0.10 to 0.83, outpatient visits/year), employment rates (difference 1.5%, -2.1% to 5.1%), income (difference -1000, -20 000 to 18 000, Danish kroner), days of sick leave (difference -0.3, -3.5 to 3.0, per year), rates of receipt of a disability pension (difference -0.9%, -3.2% to 1.3%), and number of children (difference -0.10, -0.27 to 0.08). More patients were married (difference 4.8%, 2.2% to 7.4%) and had completed high school education (difference 7%, 1% to 12%). CONCLUSION: A verified diagnosis of Lyme neuroborreliosis had no substantial effect on long term survival, health, or educational/social functioning. Nevertheless, the diagnosis decreased labour market involvement marginally and was associated with increased risk of haematological and non-melanoma skin cancers.