Serum biomarker profile including CCL1, CXCL10, VEGF, and adenosine deaminase activity distinguishes active from remotely acquired latent tuberculosis

IntroductionThere 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.Materials and MethodsThe 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.ResultssPLS 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 ConclusionThe biomarker signature of CCL1, CXCL10, VEGF, and ADA2 activity provides a promising tool for differentiating patients with ATB from non-treated LTBI individuals.Immunogenetics and cellular immunology of bacterial infectious disease

Melioidosis in travelers: An analysis of Dutch melioidosis registry data 1985–2018

Background: 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. Methods: All 5

Clinical Aspects of Immune Responses in Tuberculosis

INTRODUCTION Tuberculosis (TB) is a challenging disease for several reasons. These challenges include the global heterogeneous context, with large differences in incidence and diagnostic facilities. The lack of a gold standard for latent TB infection (LTBI) is another challenge, both for clinical practice and for research. Despite many years of research, the complex host-microbe interaction is still incompletely understood, and difficulties persist in the establishment of a quick and definite diagnosis, especially in extrapulmonary TB. Furthermore, it remains difficult to distinguish the different stages of the disease. In this thesis, we focus on several clinical and immunological aspects of TB and how the immune response against M. tuberculosis could facilitate diagnosis of the different disease manifestations. OBJECTIVES AND METHODS 1. LTBI screening and the development of TB is evaluated in patients treated with TNF-α inhibitor therapy in daily clinical practice. 2. Several applications for Interferon Gamma Release Assays (IGRA) in extra-sanguineous body-fluids are evaluated. a. The positive predictive value (PPV) of TB specific ELISpot in bronchoalveolar lavage (BAL) and pleural fluid in real-life clinical practice is evaluated for the diagnosis of TB, together with an attempt to increase the PPV. b. The two commercial IGRA (ELISpot and Quantiferon) are discussed for application in extra-sanguineous body fluids. c. T-lymphocyte responsiveness to the PPD antigen (ELISpot) is measured in patients with sarcoidosis compared to patients with other causes of interstitial lung disease. d. The feasibility of a PPD-based ELISpot in the urine and bladder fluids of patients with bladder malignancies after treatment with intravesical BCG-instillations is explored. 3. QuantiFERON-TB Gold PLUS together with several potential markers are evaluated for the ability to discriminate between active and latent TB. RESULTS AND CONCLUSIONS 1. None of the patients diagnosed with and treated for LTBI developed TB during TNF-α inhibitor therapy. Two patients with negative LTBI screening developed TB, probably due to travelling to TB-endemic countries during TNF-α inhibitor therapy, which should be mentioned as a risk. 2. IGRA in extra-sanguineous body-fluids is possible with different antigens. a. The PPV of TB-specific ELISpot in BAL and pleural fluid could be increased using a cut-off for the ratio between the extra-sanguineous and systemic interferon-gamma responses. b. TB-specific ELISpot in extra-sanguineous body fluids is preferred above Quantiferon for the diagnosis of TB. c. There is no difference between PPD reactivity in blood and BAL fluid in patients with sarcoidosis compared to patients with other interstitial lung disease. d. IGRA with PPD antigen in urine and bladder fluid is possible, but the clinical value remains uncertain. 3. QuantiFERON-plus does not discriminate between active and latent TB, but adenosine deaminase and I-309 are promising markers for this purpose

Extern juridisch advies inzake Wijziging van de Successiewet 1956 en enige andere belastingwetten (vereenvoudiging bedrijfsopvolgingsregeling en herziening tariefstructuur in de Succiessiewet 1956, alsmede introductie van een regeling voor afgezonderd particulier vermogen in de Wet inkomstenbelasting 2001 en de Successiewet 1956)

Advies aan de Tweede Kamer inzake het Afgezonderd Particulier Vermogen, de in art. 2.14a Wet IB 2001 vervatte toerekeningsfictie en hoe een ander zich verhoudt met belastingverdragen en meer in het bijzonder de jurisprudentie van de Hoge Raad inzake de goede trouw die bij de interpretatie en toepassing van belastingverdragen in acht moet worden genomen jegens andere verdragspartners

Detection of multiple respiratory pathogens during primary respiratory infection: nasal swab versus nasopharyngeal aspirate using real-time polymerase chain reaction.

In this study, we present the multiple detection of respiratory viruses in infants during primary respiratory illness, investigate the sensitivity of nasal swabs and nasopharyngeal aspirates, and assess whether patient characteristics and viral load played a role in the sensitivity. Healthy infants were included at signs of first respiratory tract infection. Paired nasopharyngeal aspirates and nasal swabs were collected. Real-time polymerase chain reaction (PCR) was carried out for 11 respiratory pathogens. Paired nasopharyngeal aspirates and nasal swabs were collected in 98 infants. Rhinovirus (n = 67) and respiratory syncytial virus (n = 39) were the most frequently detected. Co-infection occurred in 48% (n = 45) of the infants. The sensitivity of the nasal swab was lower than the nasopharyngeal aspirate, in particular, for respiratory syncytial virus (51% vs. 100%) and rhinovirus (75% vs. 97%). The sensitivity of the nasal swab was strongly determined by the cycle threshold (CT) value (p /=11). It is concluded that, for community-based studies and surveillance purposes, the nasal swab can be used, though the sensitivity is lower than the aspirate, in particular, for the detection of mild cases of respiratory syncytial virus (RSV) infection.(aut. ref.