Whole-blood culture-derived cytokine combinations for the diagnosis of tuberculosis.

Introduction: The diagnosis of tuberculosis (TB) disease and TB infection (TBI) remains a challenge, and there is a need for non-invasive and blood-based methods to differentiate TB from conditions mimicking TB (CMTB), TBI, and healthy controls (HC). We aimed to determine whether combination of cytokines and established biomarkers could discriminate between 1) TB and CMTB 2) TB and TBI 3) TBI and HC. Methods: We used hemoglobin, total white blood cell count, neutrophils, monocytes, C-reactive protein, and ten Meso Scale Discovery analyzed cytokines (interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon (IFN)-É£, and tumor necrosis factor (TNF)-α) in TruCulture whole blood tubes stimulated by lipopolysaccharides (LPS), zymosan (ZYM), anti-CD3/28 (CD3), and unstimulated (Null) to develop three index tests able to differentiate TB from CMTB and TBI, and TBI from HC. Results: In 52 persons with CMTB (n=9), TB (n=23), TBI (n=10), and HC (n=10), a combination of cytokines (LPS-IFN-É£, ZYM-IFN-É£, ZYM-TNF-α, ZYM-IL-1ß, LPS-IL-4, and ZYM-IL-6) and neutrophil count could differentiate TB from CMTB with a sensitivity of 52.2% (95% CI: 30.9%-73.4%) and a specificity of 100 % (66.4%-100%). Null- IFN-É£, Null-IL-8, CD3-IL-6, CD3-IL-8, CD3-IL-13, and ZYM IL-1b discriminated TB from TBI with a sensitivity of 73.9% (56.5% - 91.3%) and a specificity of 100% (69.2-100). Cytokines and established biomarkers failed to differentiate TBI from HC with ≥ 98% specificity. Discussion: Selected cytokines may serve as blood-based add-on tests to detect TB in a low-endemic setting, although these results need to be validated.

Prevalence estimates of tuberculosis infection in adults in Denmark: a retrospective nationwide register-based cross-sectional study, 2010 to 2018.

BackgroundTuberculosis (TB) elimination requires identifying and treating persons with TB infection (TBI).AimWe estimate the prevalence of positive interferon gamma release assay (IGRA) tests (including TB) and TBI (excluding TB) in Denmark based on TBI screening data from patients with inflammatory bowel disease (IBD) or inflammatory rheumatic disease (IRD).MethodsUsing nationwide Danish registries, we included all patients with IBD or IRD with an IGRA test performed between 2010 and 2018. We estimated the prevalence of TBI and positive IGRA with 95% confidence intervals (CI) in adolescents and adults aged 15-64 years after sample weighting adjusting for distortions in the sample from the background population of Denmark for sex, age group and TB incidence rates (IR) in country of birth.ResultsIn 13,574 patients with IBD or IRD, 12,892 IGRA tests (95.0%) were negative, 461 (3.4%) were positive and 221 (1.6%) were indeterminate, resulting in a weighted TBI prevalence of 3.2% (95% CI: 2.9-3.5) and weighted positive IGRA prevalence of 3.8% (95% CI: 3.5-4.2) among adults aged 15-64 years in the background population of Denmark. Unweighted TBI prevalence increased with age and birthplace in countries with a TB IR higher than 10/100,000 population.ConclusionEstimated TBI prevalence is low in Denmark. We estimate that 200,000 persons have TBI and thus are at risk of developing TB. Screening for TBI and preventive treatment, especially in persons born in high TB incidence countries or immunosuppressed, are crucial to reduce the risk of and eliminate TB.

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.