Point-of-Care Urine Lipoarabinomannan Testing to Guide Tuberculosis Treatment Among Severely Ill Inpatients With Human Immunodeficiency Virus in Real-World Practice: A Multicenter Stepped Wedge Cluster-Randomized Trial From Ghana.

BACKGROUND: The lateral flow urine lipoarabinomannan assay, Determine TB LAM (Determine LAM), offers the potential for timely tuberculosis (TB) treatment among people with human immunodeficiency virus (PWH). METHODS: In this cluster-randomized trial, Determine LAM was made available with staff training with performance feedback at 3 hospitals in Ghana. Newly admitted PWH with a positive World Health Organization four-symptom screening for TB, severe illness, or advanced HIV were enrolled. The primary outcome was days from enrollment to TB treatment initiation. We also reported the proportion of patients with a TB diagnosis, initiating TB treatment, all-cause mortality, and Determine LAM uptake at 8 weeks. RESULTS: We enrolled 422 patients including 174 (41.2%) in the intervention group. The median CD4 count was 87 (interquartile range [IQR], 25-205) cells/µL, and 32.7% were on antiretroviral therapy. More patients were diagnosed with TB in the intervention compared with the control group: 59 (34.1%) versus 46 (18.7%) (P < .001). Time to TB treatment remained constant, but patients were more likely to initiate TB treatment (adjusted hazard ratio, 2.19 [95% CI, 1.60-3.00]) during the intervention. Of patients with a Determine LAM test available, 41 (25.3%) tested positive. Of those, 19 (46.3%) initiated TB treatment. Overall, 118 patients had died (28.2%) at 8 weeks of follow-up. CONCLUSIONS: The Determine LAM intervention in real-world practice increased TB diagnosis and the probability of TB treatment but did not reduce time to treatment initiation. Despite high uptake, only half of the LAM-positive patients initiated TB treatment.

Experience with sotrovimab treatment of SARS-CoV-2-infected patients in Denmark.

AIMS: To evaluate the experience with use of sotrovimab following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in high-risk groups. METHODS: In a nationwide, population-based cohort study, we identified all individuals treated with sotrovimab (N = 2933) and stratified them by 4 high-risk groups: (A) malignant haematological disease, (B) solid organ transplantation, (C) anti-CD20 therapy ≤1 year and (D) other risks. Cox regression analysis was used to calculate hazard ratios for hospitalization, death and associated prognostic factors. RESULTS: Of 2933 sotrovimab-treated individuals, 83% belonged to high-risk groups (37.6% haematological malignancy, 27.4% solid organ transplantation and 17.5% treatment with anti-CD20 ≤1 year). Only 17.8% had other risks (11.8% were pregnant, 10.7% primary immunodeficiency, 21.2% other malignancy, 4.3% received anti-CD20 >1 year and 52.0% other/unknown causes). Within 90 days of infusion, 30.2% were hospitalized and 5.3% died. The main prognostic factors were the predefined high-risk groups, mainly malignant haematological disease and age ≥65 years. Number of COVID-19 vaccines (≥3) was associated with a decreased risk of hospitalization. The Delta but not the Omicron BA.2 variant was associated with a higher risk of death compared to the BA.1 variant. CONCLUSION: More than 90% of the patients treated with sotrovimab belonged to the very high-risk groups as described in the Danish guidelines. Sotrovimab-treated individuals remained at a high risk of hospitalization and death which was strongly associated with the underlying immunocompromised state and age. Having received >3 COVID-19 vaccines was association with decreased risk of death and hospitalization.

Genomic Epidemiology of a Major Mycobacterium tuberculosis Outbreak: Retrospective Cohort Study in a Low-Incidence Setting Using Sparse Time-Series Sampling.

Since 1992, Denmark has documented the largest outbreak of tuberculosis in Scandinavia ascribed to a single genotype, termed C2/1112-15. As of spring 2017, the International Reference Laboratory of Mycobacteriology in Copenhagen has collected and identified isolates from more than a thousand cases belonging to this outbreak via routine mycobacterial interspersed repetitive units-variable number of tandem repeats typing. Here, we present a retrospective analysis of the C2/1112-15 dataset, based on whole-genome data from a sparse time series consisting of 5 randomly selected isolates from 23 years of sampling. Even if these data are derived from only 12% of the collected isolates, we have been able to extract important key information, such as mutation rate and conserved single-nucleotide polymorphisms to identify discrete transmission chains, as well as the possible historical origins of the outbreak.

Cerebrospinal fluid pleocytosis level as a diagnostic predictor? A cross-sectional study.

BACKGROUND: Lumbar puncture with quantification of leukocytes and differential count of cellular subsets in the cerebrospinal fluid is a standard procedure in cases of suspected neuroinfectious conditions. However, a number of non-infectious causes may result in a low leukocyte number (0-1000 cells/ml). We wanted to assess the diagnostic diversity of unselected adult patients with pleocytosis in the cerebrospinal fluid. METHODS: The study is based on data from cerebrospinal fluid (CSF) analyses of all adult patients (15 years or older) admitted to a large university hospital in Denmark during a two-year period (2008-2009). Data from the local patient administrative system supplied with data from patient charts were combined with laboratory data. RESULTS: A total of 5390 cerebrospinal fluid samples from 3290 patients were included. Pleocytosis >5 leucocytes/µl was found in samples from 262 patients of which 106 (40.5%) were caused by infection of the central nervous system (CNS), 20 (7.6%) by infection outside CNS, 79 (30.2%) due to non-infectious neurological diseases, 23 (8.8%) by malignancy, and 34 (13.0%) caused by other conditions. Significantly higher mean CSF leukocytes was found in patients suffering from CNS infection (mean 1135 cells/µl, p-value <0.0001). CONCLUSIONS: CNS infection, non-infectious neurological disease, malignancy, and infection outside CNS can cause pleocytosis of the cerebrospinal fluid. Leukocyte counts above 100/µl is mainly caused by CNS infection, whereas the number of differential diagnoses is higher if the CSF leukocyte counts is below 50/µl. These conditions are most commonly caused by non-infectious neurological diseases including seizures.

Substantial molecular evolution and mutation rates in prolonged latent Mycobacterium tuberculosis infection in humans.

The genome of Mycobacterium tuberculosis (Mtb) of latently infected individuals may hold the key to understanding the processes that lead to reactivation and progression to clinical disease. We report here analysis of pairs of Mtb isolates from putative prolonged latent TB cases. We identified two confirmed cases, and used whole genome sequencing to investigate the mutational processes that occur over decades in latent Mtb. We found an estimated mutation rate between 0.2 and 0.3 over 33 years, suggesting that latent Mtb accumulates mutations at rates similar to observations from cases of active disease.

Diabetes is associated with lower tuberculosis antigen-specific interferon gamma release in Tanzanian tuberculosis patients and non-tuberculosis controls.

BACKGROUND: Diabetes is increasingly common in TB endemic regions and plays a role as a possible risk factor for increased progression from latent TB infection (LTBI) to active TB disease. Although the pathophysiological mechanisms are not fully understood, the immune system is weakened in diabetes patients and therefore the validity of interferon gamma release assays (IGRA) may be compromised. The aim of the present study was to assess the association between diabetes and Mycobacterium tuberculosis (Mtb) antigen-specific interferon gamma (IFN-γ) release in a TB endemic area among culture-confirmed TB patients and non-TB controls. METHODS: Culture-confirmed pulmonary TB patients (n = 187) and healthy non-TB neighbourhood controls (n = 190) from Mwanza, Tanzania were tested for the presence of circulating T cells recognizing Mtb antigens using an IGRA. The diabetes status of all participants was assessed using a standard oral glucose tolerance test. The impact of diabetes on the performance of the IGRA was estimated using robust linear and logistic regression. RESULTS: Compared to normal glucose tolerance, diabetes was associated with reduced levels of Mtb-specific IFN-γ. Increasing levels of fasting blood glucose (B - 0.3, 95% confidence interval - 0.6 to - 0.03, p = 0.033) was negatively associated with IFN-γ. Although TB patients had higher specific and lower unspecific mitogen IFN-γ responses compared to non-TB controls, the association between diabetes and IFN-γ did not depend on TB status. CONCLUSION: Diabetes is associated with lower levels of Mtb antigen-specific IFN-γ, and the validity of IFN- γ tests for LTBI may be questionable in individuals with diabetes.

Drug-resistant tuberculosis is a global cause of concern.

The number of patients with drug-resistant tuberculosis (DR-TB) is increasing worldwide. This review summarises the global epidemiology of DR-TB and current treatment challenges. Luckily, novel regimens comprising bedaquiline, pretomanid, linezolid, and moxifloxacin have seemingly mitigated the global threat posed by DR-TB. However, emerging resistance against bedaquiline and pretomanid, among other factors, persists as ongoing concerns in the global fight against DR-TB. While the new regimens are groundbreaking, the sustained development of novel drugs targeting the most resistant forms of tuberculosis is of utmost importance for future efforts against DR-TB.

Increased intracranial pressure in acute bacterial meningitis.

Acute bacterial meningitis (ABM) is associated with increased intracranial pressure (ICP) caused by bacterial invasion and the host response to infection. Antibiotic therapy is a sine qua non, and adjunct dexamethasone decreases mortality. The ICP increase may have a rapid course and death due to herniation is most often seen within the first week. Evidence regarding treatment of increased ICP in ABM is limited; this review summarises observational studies which point towards reduced mortality by applying a structured approach towards normalization of ICP in ABM.

The in-hospital tuberculosis diagnostic cascade and early clinical outcomes among people living with HIV before and during the COVID-19 pandemic - a prospective multisite cohort study from Ghana.

OBJECTIVES: The COVID-19 pandemic had a disruptive impact on tuberculosis (TB) and HIV services. We assessed the in-hospital TB diagnostic care among people with HIV (PWH) overall and before and during the pandemic. METHODS: In this prospective study, adult PWH admitted at three hospitals in Ghana were recruited if they had a positive World Health Organization four-symptom screen or one or more World Health Organization danger signs or advanced HIV. We collected data on patient characteristics, TB assessment, and clinical outcomes after 8 weeks and used descriptive statistics and survival analysis. RESULTS: We enrolled 248 PWH with a median clusters of differentiation 4 count of 80.5 cells/mm3 (interquartile range 24-193). Of those, 246 (99.2%) patients had a positive World Health Organization four-symptom screen. Overall, 112 (45.2%) patients obtained a sputum Xpert result, 66 (46.5%) in the prepandemic and 46 (43.4%) in the pandemic period; P-value = 0.629. The TB prevalence of 46/246 (18.7%) was similar in the prepandemic 28/140 (20.0%) and pandemic 18/106 (17.0%) population; P-value = 0.548. The 8-week all-cause mortality was 62/246 (25.2%), with no difference in cumulative survival when stratifying for the pandemic period; log-rank P-value = 0.412. CONCLUSION: The study highlighted a large gap in the access to TB investigation and high early mortality among hospitalized PWH, irrespective of the COVID-19 pandemic.

Use of the urine Determine LAM test in the context of tuberculosis diagnosis among inpatients with HIV in Ghana: a mixed methods study.

Background: The urine Determine LAM test has the potential to identify tuberculosis (TB) and reduce early mortality among people living with HIV. However, implementation of the test in practice has been slow. We aimed to understand how a Determine LAM intervention was received and worked in a Ghanaian in-hospital context. Design/Methods: Nested in a Determine LAM intervention study, we conducted a two-phase explanatory sequential mixed methods study at three hospitals in Ghana between January 2021 and January 2022. We performed a quantitative survey with 81 healthcare workers (HCWs), four qualitative focus-group discussions with 18 HCWs, and 15 in-depth HCW interviews. Integration was performed at the methods and analysis level. Descriptive analysis, qualitative directed content analysis, and mixed methods joint display were used. Results: The gap in access to TB testing when relying on sputum GeneXpert MTB/Rif alone was explained by difficulties in obtaining sputum samples and an in-hospital system that relies on relatives. The Determine LAM test procedure was experienced as easy, and most eligible patients received a test. HCWs expressed that immediate access to Determine LAM tests empowered them in rapid diagnosis. The HCW survey confirmed that bedside was the most common place for Determine LAM testing, but qualitative interviews with nurses revealed concerns about patient confidentiality when performing and disclosing the test results at the bedside. Less than half of Determine LAM-positive patients were initiated on TB treatment, and qualitative data identified a weak link in the communication of the Determine LAM results. Moreover, HCWs were reluctant to initiate Determine LAM-positive patients on TB treatment due to test specificity concerns. The Determine LAM intervention did not have an impact on the time to TB treatment as expected, but patients were, in general, initiated on TB treatment rapidly. We further identified a barrier to accessing TB treatment during weekends and that treatment by tradition is administrated early in the morning. Conclusion: The Determine LAM testing was feasible and empowered HCWs in the management of HIV-associated TB. Important gaps in routine care and Determine LAM-enhanced TB care were often explained by the context. These findings may inform in-hospital quality improvement work and scale-up of Determine LAM in similar settings.

The role of diabetes co-morbidity for tuberculosis treatment outcomes: a prospective cohort study from Mwanza, Tanzania.

BACKGROUND: Due to the association between diabetes and pulmonary tuberculosis (TB), diabetes may threaten the control of TB. In a prospective cohort study nested in a nutrition trial, we investigated the role of diabetes on changes in anthropometry, grip strength, and clinical parameters over a five months follow-up period. METHODS: Among pulmonary TB patients with known diabetes status, we assessed anthropometry and clinical parameters (e.g. haemoglobin) at baseline and after two and five months of TB treatment. A linear mixed-effects model (repeated measurements) was used to investigate the role of diabetes during recovery. RESULTS: Of 1205 TB patients, the mean (standard deviation) age was 36.6 (13.0) years, 40.9% were females, 48.9% were HIV co-infected, and 16.3% had diabetes. TB patients with diabetes co-morbidity experienced a lower weight gain at two (1.3 kg, CI95% 0.5; 2.0, p = 0.001) and five months (1.0 kg, CI95% 0.3; 1.7, p = 0.007). Similarly, the increase in the level of haemoglobin was lower among TB patients with diabetes co-morbidity after two (Δ 0.6 g/dL, CI95% 0.3; 0.9 p < 0.001) and five months (Δ 0.5 g/dL, CI95% 0.2; 0.9 p = 0.004) of TB treatment, respectively. CONCLUSION: TB patients initiating TB treatment with diabetes co-morbidity experience delayed recovery of body mass and haemoglobin, which are important for the functional recovery from disease.

[New and rediscovered treatments for tuberculosis].

Tuberculosis (TB) is still a major challenge for global health, but in recent years there have been several important developments in treatment options. Shorter treatment regimens for latent TB, based on conventional drugs, offer better adherence and fewer side effects, while new and repurposed antibiotics have opened the door to more effective, shorter and less side effect-heavy treatments for drug susceptible TB and multidrug-resistant/extensively drug resistant TB as well as atypical mycobacterioses. This review investigates how these shorter and predominantly oral treatments, in the future, are expected to be used in combination with individualized precision medicine.

The Induced Immune Response in Patients With Infectious Spondylodiscitis: A Prospective Observational Cohort Study.

Introduction: Infectious spondylodiscitis is a rare infection of the intervertebral disc and the adjacent vertebral bodies that often disseminates and requires long-term antibiotic therapy. Immunologic profiling of patients with infectious spondylodiscitis could allow for a personalized medicine strategy. We aimed to examine the induced immune response in patients with infectious spondylodiscitis during and after antibiotic therapy. Furthermore, we explored potential differences in the induced immune response depending on the causative pathogen and the dissemination of the disease. Methods: This was a prospective observational cohort study that enrolled patients with infectious spondylodiscitis between February 2018 and August 2020. A blood sample was collected at baseline, after four to six weeks of antibiotic therapy (during antibiotic therapy), and three to seven months after end of antibiotic therapy (post-infection). The induced immune response was assessed using the standardized functional immune assay TruCulture®. We used a panel of three immune cell stimuli (lipopolysaccharide, Resiquimod and polyinosinic:polycytodylic acid) and an unstimulated control. For each stimulus, the induced immune response was assessed by measuring the released concentration of Interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-12p40, IL-17A, Interferon-γ (IFN-γ) and Tumor necrosis factor-α (TNF-α) in pg/mL. Results: In total, 49 patients with infectious spondylodiscitis were included. The induced immune responses were generally lower than references at baseline, but the cytokine release increased in patients after treatment with antibiotic therapy. Post-infection, most of the released cytokine concentrations were within the reference range. No significant differences in the induced immune responses based on stratification according to the causative pathogen or dissemination of disease were found. Conclusion: We found lower induced immune responses in patients with infectious spondylodiscitis at baseline. However, post-infection, the immune function normalized, indicating that an underlying immune deficiency is not a prominent factor for spondylodiscitis. We did not find evidence to support the use of induced immune responses as a tool for prediction of the causative pathogen or disease dissemination, and other methods should be explored to guide optimal treatment of patients with infectious spondylodiscitis.

Quantiferon test for tuberculosis screening in sarcoidosis patients.

BACKGROUND: Tumour necrosis factor-alpha (TNF-α) inhibitors have been introduced in the treatment of refractory sarcoidosis. These biologics may reactivate latent tuberculosis infection (LTBI). Despite its known limitations, the tuberculin skin test (TST) is currently used for the diagnosis of LTBI in Danish sarcoidosis patients. We report the results of a screening using the interferon-gamma release assay (IGRA) QuantiFERON TB Gold (QFN) for the diagnosis of LTBI. We aimed to assess whether the QFN is reliable for diagnosing LTBI among sarcoidosis patients and if results are influenced by disease activity or immunosuppressive treatment. METHODS: A prospective study was performed from 2005 to 2007 among sarcoidosis patients who were candidates for TNF-α inhibitor treatment. Information on immunosuppressive treatment was obtained from the medical records. Disease activity was assessed by biochemistry, chest roentgenograms and pulmonary function tests. The predictive value of QFN results was evaluated by follow-up in the Danish National Tuberculosis Registry. RESULTS: A total of 44 sarcoidosis patients (22 men) with a median age of 39 y (range 25-59 y) were enrolled; 93% had a negative QFN test result and 7% had an indeterminate result. Forty-three percent had disease activity and 57% (n = 25) received immunosuppressive treatment. There was no significant difference in QFN interferon-γ response between subjects with or without disease activity (p > 0.4) and between treated vs non-treated patients (p > 0.5). At follow-up using the Danish tuberculosis registry, there was no occurrence of tuberculosis among study participants. CONCLUSIONS: The predictive value of the QFN seems good among Danish sarcoidosis patients and the results appear to be unaffected by sarcoidosis disease activity and immunosuppressive treatment.

Polyacrylamide gel treatment of antiretroviral therapy-induced facial lipoatrophy in HIV patients.

BACKGROUND: Today, highly active antiretroviral therapy is lifesaving for most HIV-infected patients, but the treatment can result in facial lipoatrophy, which changes the face so radically that patients may develop severe psychological and social problems. Since 2001 polyacrylamide gel (PAAG) has been used successfully in HIV patients abroad. This article describes the results of a Danish study. METHODS: Forty HIV patients recruited from two major referral hospitals in the capitol area of Copenhagen, Denmark, each received a series of PAAG gel injections (small deposits in several sessions) with a 14-day interval. Patient satisfaction, injector's evaluation, evaluation by an external specialist in plastic surgery, and long-term aesthetic effect and complications were registered with follow-up until 2 years. RESULTS: All patients were very satisfied or satisfied with the result. The injector found the result very satisfying in 33 cases and a slight irregularity in 7. The external specialist found improvement in all cases with a one-grade reduction of the lipoatrophy in 11 cases, a two-grade reduction in 20, and a three-grade reduction in 3 cases. No filler-associated complications were recorded. CONCLUSION: This study has shown that PAAG can normalize contours in patients suffering from facial lipoatrophy within 3-6 sessions, with a mean amount of gel per session of 1.8 ml and a mean total amount of 8.8 ml. The results are in accordance with those of other large studies, confirming a high degree of biocompatibility and safety.

Classification of patients referred under suspicion of tick-borne diseases, Copenhagen, Denmark.

To provide better care for patients suspected of having a tick-transmitted infection, the Clinic for Tick-borne Diseases at Rigshospitalet, Copenhagen, Denmark was established. The aim of this prospective cohort study was to evaluate diagnostic outcome and to characterize demographics and clinical presentations of patients referred between the 1st of September 2017 to 31st of August 2019. A diagnosis of Lyme borreliosis was based on medical history, symptoms, serology and cerebrospinal fluid analysis. The patients were classified as definite Lyme borreliosis, possible Lyme borreliosis or post-treatment Lyme disease syndrome. Antibiotic treatment of Lyme borreliosis manifestations was initiated in accordance with the national guidelines. Patients not fulfilling the criteria of Lyme borreliosis were further investigated and discussed with an interdisciplinary team consisting of specialists from relevant specialties, according to individual clinical presentation and symptoms. Clinical information and demographics were registered and managed in a database. A total of 215 patients were included in the study period. Median age was 51 years (range 17-83 years), and 56 % were female. Definite Lyme borreliosis was diagnosed in 45 patients, of which 20 patients had erythema migrans, 14 patients had definite Lyme neuroborreliosis, six had acrodermatitis chronica atrophicans, four had multiple erythema migrans and one had Lyme carditis. Furthermore, 12 patients were classified as possible Lyme borreliosis and 12 patients as post-treatment Lyme disease syndrome. A total of 146 patients (68 %) did not fulfil the diagnostic criteria of Lyme borreliosis. Half of these patients (73 patients, 34 %) were diagnosed with an alternative diagnosis including inflammatory diseases, cancer diseases and two patients with a tick-associated disease other than Lyme borreliosis. A total of 73 patients (34 %) were discharged without sign of somatic disease. Lyme borreliosis patients had a shorter duration of symptoms prior to the first hospital encounter compared to patients discharged without a specific diagnosis (p<0.001). When comparing symptoms at presentation, patients discharged without a specific diagnosis suffered more often from general fatigue and cognitive dysfunction. In conclusion, 66 % of all referred patients were given a specific diagnosis after ended outpatient course. A total of 32 % was diagnosed with either definite Lyme borreliosis, possible Lyme borreliosis or post-treatment Lyme disease syndrome; 34 % was diagnosed with a non-tick-associated diagnosis. Our findings underscore the complexity in diagnosing Lyme borreliosis and the importance of ruling out other diseases through careful examination.

Multidrug-resistant tuberculosis: treatment outcome in Denmark, 1992-2007.

A retrospective nationwide study including all culture-verified multidrug-resistant (MDR) tuberculosis (TB) cases was performed in Denmark. The aim was to examine the long-term treatment outcome of MDR-TB, to assess if MDR-TB transmission occurs, and to evaluate a rapid mutation analysis detecting rifampin and isoniazid resistance in this cohort. Clinical data were obtained from patient records. A restriction fragment length polymorphism genotype database of all TB cases was compared for identical strains indicating active transmission. Twenty-nine cases of MDR-TB were identified and the incidence was low at 0.5%. Acquired MDR-TB and active transmission was rare. Mutations in rifampin (rpoB) and isoniazid (katG, inhA) genes correctly determined resistance in 100% and 82% of all isolates tested, respectively. Initial treatment success was 89% for 27 MDR-TB patients with available outcome data. Initially 3 patients defaulted; no deaths were reported. Including successfully re-treated default patients and censoring patients who spent <2 y in the cohort, long-term treatment success was achieved for all 26 patients (mean follow-up 8.9 y). MDR-TB has a good prognosis in the high-income, low TB burden country of Denmark. Continued surveillance and rapid detection of resistance mutations directly in smear-positive patients may improve the standard of MDR-TB care.

[First Danish case of Mycobacteriumchimaerainfection from cardiac surgery with contaminated heater-cooler unit].

Infection with Mycobacterium chimaera has globally been linked to cardiac surgery using cardiopulmonary bypass devices with contaminated heater-cooler units (HCU). This is a case report of M. chimaera infection linked to HCU in Denmark in which we show, how difficult the diagnosis can be. A 67-year-old man had an aortic graft and valvular replacement using HCU. Post-operatively he developed progressing symptoms of intermittent fever, malaise and endocarditis with septic embolic events, and despite extensive diagnostic work-up, he remained undiagnosed for 16 months following surgery.

Recurrent tuberculosis in patients infected with the predominant Mycobacterium tuberculosis outbreak strain in Denmark. New insights gained through whole genome sequencing.

OBJECTIVES: Recurrent tuberculosis (TB) is defined by more than one TB episode per patient and is caused by reinfection with a new M. tuberculosis (Mtb) strain or relapse with the previous strain. In Denmark, a major TB outbreak caused by one specific Mtb genotype "DKC2" is ongoing. Of the 892 patients infected with DKC2 between 1992 and 2014, 32 had recurrent TB with 67 TB episodes in total. METHODS: The 32 cases were evaluated in terms of number of single-nucleotide polymorphism (SNP) differences and time between episodes derived from whole-genome sequencing data. RESULTS: For four TB cases, the subsequent episodes could be confirmed as relapse and for one case as reinfection. Eight cases with SNP differences <6, theoretically indicating relapse, could be classified as likely reinfections based on phylogenetic analysis in combination with geographical data. Subsequent TB episodes for the remaining 19 cases could not be classified as relapse or reinfection even though they all had a SNP difference of <6 SNPs. CONCLUSIONS: In newer studies, investigating recurrent TB with the use of WGS, the number of SNPs has been used to distinguish between relapse and reinfection. The algorithm proposed for this is not valid in the Danish TB outbreak setting as our findings challenge the interpretation of few SNP differences as representing relapse. However, when including phylogenetic analysis and geographical data in the analysis, classification of 13 of the 32 cases were possible.

Lyme neuroborreliosis in adults: A nationwide prospective cohort study.

The goal of this paper is to characterize the clinical presentation, serological results, current antibiotic treatment practice, including compliance with current European guidelines, and outcome in adults with Lyme neuroborreliosis (LNB) diagnosed at departments of infectious diseases in Denmark. Using a nationwide prospective cohort of patients with central nervous system infections, we identified all adults (≥ 18 years of age) treated for LNB at departments of infectious diseases in Denmark from 2015 through 2017. The database contains information on baseline demographics, history of tick bite, erythema migrans, clinical presentation, laboratory results of blood samples, and cerebrospinal (CSF) biochemistry (e.g. specific Borrelia burgdorferi sensu lato (s.l.) antibodies in serum, B. burgdorferi s.l. intrathecal antibody index) as well as antibiotic therapy. Outcome was assessed by the Glasgow Outcome Scale (GOS) and the presence of residual symptoms at follow-up one month after discharge. We included 194 LNB patients with a median age of 59 years (range 18-85 years, interquartile range [IQR] 47-69 years). The female-to-male ratio was 0.8. A total of 177 of 191 (93 %) of patients had early (second stage) LNB. A history of tick bite or erythema migrans was registered in 75 (39 %) and 49 (25 %) patients, respectively. The median duration of neurological symptoms before first hospital contact was 21 days (range 0-600 days, IQR 10-42 days). Predominant symptoms consisted of radicular pain in 135 of 194 (70 %), cranial nerve paresis in 88 of 194 (45 %), headache in 71 of 185 (38 %), and extremity paresis in 33 of 194 (17 %) patients. Serum-B. burgdorferi s.l. IgM and/or IgG antibodies were detectable in 166 of 181 (92 %) patients at the time of first CSF investigation. Median duration of antibiotic treatment was 14 days (range 10-35 days, IQR 14-21 days) and 59 (39 %) of the patients received intravenous ceftriaxone and/or benzylpenicillin G throughout treatment. At the 1-month follow-up, GOS was unfavorable (< 5) in 54 of 193 (28 %) patients. An unfavorable GOS score was more often registered in patients with ≥ 45 days of symptom duration (20 of 45 (44 %) vs. 34 of 145 (23 %); P = 0.006). In conclusion, a European cohort of adult patients with LNB diagnosed between 2015-2017 presented with classic symptoms and CSF findings. However, a substantial diagnostic delay was still observed. In disagreement with current guidelines, a substantial part of LNB patients were treated with antibiotics longer than 14 days and/or intravenously as route of administration.