Whole blood mycobacterial growth assays (WBMGA) quantify mycobacterial growth in fresh blood samples and may have potential for assessing tuberculosis vaccines and identifying individuals at risk of ...tuberculosis. We evaluated the evidence for the underlying assumption that
WBMGA results can predict
tuberculosis susceptibility.
A systematic search was done for studies assessing associations between WBMGA results and tuberculosis susceptibility. Meta-analyses were performed for eligible studies by calculating population-weighted averages.
No studies directly assessed whether WBMGA results predicted tuberculosis susceptibility. 15 studies assessed associations between WBMGA results and proven correlates of tuberculosis susceptibility, which we divided in two categories. Firstly, WBMGA associations with factors believed to reduce tuberculosis susceptibility were statistically significant in all eight studies of: BCG vaccination; vitamin D supplementation; altitude; and HIV-negativity/therapy. Secondly, WBMGA associations with probable correlates of tuberculosis susceptibility were statistically significant in three studies of tuberculosis disease, in a parasitism study and in two of the five studies of latent tuberculosis infection. Meta-analyses for associations between WBMGA results and BCG vaccination, tuberculosis infection, tuberculosis disease and HIV infection revealed consistent effects. There was considerable methodological heterogeneity.
The study results generally showed significant associations between WBMGA results and correlates of tuberculosis susceptibility. However, no study directly assessed whether WBMGA results predicted actual susceptibility to tuberculosis infection or disease. We recommend optimization and standardization of WBMGA methodology and prospective studies to determine whether WBMGA predict susceptibility to tuberculosis disease.
Tuberculosis (TB) is a prevalent disease causing an estimated 1.6 million deaths and 10.6 million new cases annually. Discriminating TB disease from differential diagnoses can be complex, ...particularly in the field. Increased levels of complement component C1q in serum have been identified as a specific and accessible biomarker for TB disease but the source of C1q in circulation has not been identified. Here, data and samples previously collected from human cohorts, a clinical trial and a non-human primate study were used to identify cells producing C1q in circulation. Cell subset frequencies were correlated with serum C1q levels and combined with single cell RNA sequencing and flow cytometry analyses. This identified monocytes as C1q producers in circulation, with a pronounced expression of C1q in classical and intermediate monocytes and variable expression in non-classical monocytes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
There is an urgent medical need to differentiate active tuberculosis (ATB) from latent tuberculosis infection (LTBI) and prevent undertreatment and overtreatment. The aim of this study was to ...identify biomarker profiles that may support the differentiation between ATB and LTBI and to validate these signatures.
The discovery cohort included adult individuals classified in four groups: ATB (n = 20), LTBI without prophylaxis (untreated LTBI; n = 20), LTBI after completion of prophylaxis (treated LTBI; n = 20), and healthy controls (HC; n = 20). Their sera were analyzed for 40 cytokines/chemokines and activity of adenosine deaminase (ADA) isozymes. A prediction model was designed to differentiate ATB from untreated LTBI using sparse partial least squares (sPLS) and logistic regression analyses. Serum samples of two independent cohorts (national and international) were used for validation.
sPLS regression analyses identified C-C motif chemokine ligand 1 (CCL1), C-reactive protein (CRP), C-X-C motif chemokine ligand 10 (CXCL10), and vascular endothelial growth factor (VEGF) as the most discriminating biomarkers. These markers and ADA(2) activity were significantly increased in ATB compared to untreated LTBI (p ≤ 0.007). Combining CCL1, CXCL10, VEGF, and ADA2 activity yielded a sensitivity and specificity of 95% and 90%, respectively, in differentiating ATB from untreated LTBI. These findings were confirmed in the validation cohort including remotely acquired untreated LTBI participants.
The biomarker signature of CCL1, CXCL10, VEGF, and ADA2 activity provides a promising tool for differentiating patients with ATB from non-treated LTBI individuals.
Introduction
A triple combination of CFTR modulators ELE/TEZ/IVA (elexacaftor/tezacaftor/ivacaftor, Trikafta™) has been evaluated in clinical trials for people with cystic fibrosis (pwCF) and was ...approved to the European and US market. During registration and settling reimbursement in Europe, it could be requested on a compassionate use basis, for patients with advanced lung disease (ppFEV1 < 40).
Aim
The aim of this study is to evaluate 2 years of experience with the clinical and radiological response of ELE/TEZ/IVA in pwCF in a compassionate use setting.
Methods
pwCF who started ELE/TEZ/IVA in a compassionate use setting were prospectively followed with assessment of spirometry, BMI, chest CT, CFQ‐R and sweat chloride concentration (SCC) before start and after 3 months. Furthermore, spirometry, sputum cultures, and BMI were repeated after 1, 6, 12, 18, and 24 months.
Results
Eighteen patients were eligible for this evaluation, nine with F508del/F508del genotype (eight of whom were using dual CFTR modulators) and nine with F508del/minimal function mutation. After 3 months, mean change in SCC was −44.9 (p ≤ 0.001), together with significant improvement in CT (change in Brody score: −28.27 p ≤ 0.001) and CFQ‐R results (change in respiratory domain: +18.8, p = 0.002). After 24 months, ppFEV1 change was +8.89 (p = 0.002), BMI had improved by +1.53 kg/m2 (p ≤ 0.001) and exacerbation rate declined from 5.94 in 24 months before start to 1.17 (p ≤ 0.001) in the 24 months after.
Conclusion
pwCF with advanced lung disease experience relevant clinical benefit after 2 years of treatment with ELE/TEZ/IVA in a compassionate use setting. Structural lung damage, quality of life, exacerbation rate, and BMI improved significantly with treatment. Gain in ppFEV1 is lower compared to the phase III trials that included younger patients with moderately affected lung function.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Highly effective CFTR modulators such as elexacaftor/tezacaftor/ivacaftor (ELE/TEZ/IVA will become available for an increasing number of people with cystic fibrosis (pwCF) in the near future. Before ...the start of this therapy, many questions may arise concerning the expected effects. We assembled the currently available data from the literature about ELE/TEZ/IVA that focused on commonly asked questions from patients. Overall, the literature so far presents a very hopeful prospect of effects, not only on lung function, but also on nutritional status, sinonasal symptoms and quality of life. The effects in patients with pwCF with severe lung damage are also favorable. Treatment is generally well tolerated. In some cases, patient-derived cell models can help in predicting the effects for individual patients.
As part of a prospective study on the safety of TNF-α inhibitor therapy after screening for and treatment of latent tuberculosis infection (LTBI), we report two patients who developed active ...tuberculosis (TB) infection during TNF-α inhibitor therapy, despite negative screening for LTBI. The clinical history is suggestive of a primary infection acquired during travelling to TB-endemic countries. In this lesson of the month we would like to highlight the risk of travelling to TB-endemic areas in patients treated with TNF-α inhibitor therapy. Screening for latent tuberculosis infection is not enough to prevent tuberculosis in patients treated with TNF-α inhibitor therapy.
Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is an opportunistic infection across the tropics. Here, we provide a systematic overview of imported human cases in a ...non-endemic country over a 25-year period.
All 55 Dutch microbiology laboratories were contacted in order to identify all B. pseudomallei positive cultures from 1990 to 2018. A response rate of 100% was achieved. Additionally, a systematic literature search was performed, medical-charts reviewed, and tissue/autopsy specimens were re-assessed.
Thirty-three travelers with melioidosis were identified: 70% male with a median-age of 54 years. Risk factors were present in most patients (n = 23, 70%), most notably diabetes (n = 8, 24%) and cystic fibrosis (n = 3, 9%). Countries of acquisition included Thailand, Brazil, Indonesia, Panama, and The Gambia. Disease manifestations included pneumonia, intra-abdominal abscesses, otitis externa, genitourinary, skin-, CNS-, and thyroid gland infections. Twelve (36%) patients developed sepsis and/or septic shock. Repeat episodes of active infection were observed in five (15%) and mortality in four (12%) patients. Post-mortem analysis showed extensive metastatic (micro)abscesses amongst other sites in the adrenal gland and bone marrow.
The number of imported melioidosis is likely to increase, given rising numbers of (immunocompromised) travelers, and increased vigilance of the condition. This first systematic retrospective surveillance study in a non-endemic melioidosis country shows that imported cases can serve as sentinels to provide information about disease activity in areas visited and inform pre-travel advice and post-travel clinical management.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: The aim of this study was to evaluate the positive predictive value (PPV) of ELISpot in bronchoalveolar lavage (BAL) and pleural fluid for the diagnosis of active tuberculosis (TB) in ...real-life clinical practice, together with the added value of a cut-off >1.0 for the ratio between the extra-sanguineous and systemic interferon-gamma responses in positive samples.
Methods: A retrospective, single-centre study was performed. Patients with positive ELISpot in BAL and pleural fluid were included.
Results: The PPV for TB in patients with positive ELISpot in BAL (n = 40) was 64.9%, which increased to 82.6% for the ESAT-6 panel and 71.4% for the CFP-10 panel after the introduction of a cut-off >1.0 for the ratio between the BAL and blood interferon-gamma responses. In patients with positive ELISpot in pleural fluid (n = 16), the PPV for TB was 85.7%, which increased to 91.7% for the ESAT-6 panel and 92.3% for the CFP-10 panel after the introduction of a cut-off >1.0 for the ratio between the pleural fluid and blood interferon-gamma responses.
Conclusions: This report describes the PPV of ELISpot in BAL and pleural fluid for the diagnosis of active TB in real-life clinical practice. The results indicate the possibility of an increase of the PPV using a cut-off >1.0 for the ratio between the extra-sanguineous and systemic interferon-gamma responses. Further studies are needed to underline this ratio-approach and to evaluate the full diagnostic accuracy of ELISpot in extra-sanguineous fluids like BAL and pleural fluid.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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