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BACKGROUND: The tuberculin skin test (TST) has low specificity. QuantiFERON-TB Gold (QFT-G) and T-SPOT.TB are based on interferon (IFN)-gamma responses to Mycobacterium tuberculosis-specific antigens. A novel in-tube format of QFT-G (QFT-GIT) offers logistical advantages. OBJECTIVE: To compare TST, QFT-GIT, and T-SPOT.TB in bacillus Calmette-Guérin unvaccinated contacts and correlate results with measures of recent exposure. METHODS: When a supermarket employee with smear-positive tuberculosis had infected most close contacts, a contact investigation among more than 20,000 customers was performed. We recruited subjects randomly on the day of TST administration (n = 469) and subjects with TST of more than 0 mm on the day of TST reading (n = 316). QFT-GIT and T-SPOT.TB were performed. Demographic data and measures of exposure were collected. TST results were analyzed at a cutoff of 10 or 15 mm. Blood tests were interpreted following the manufacturers' criteria and by varying cutoff levels. RESULTS: Among 785 study participants, TST results were associated with age, whereas positive IFN-gamma responses were significantly associated with cumulative shopping time, most markedly for QFT-GIT. Among participants with a TST of 15 mm or greater, sensitivity of QFT-GIT and T-SPOT.TB was 42.2 and 51.3%, respectively. Interassay agreement was 89.6% (kappa = 0.59). By varying cutoff values, agreement between the IFN-gamma assays was optimal at 93.6% (kappa = 0.71) using a cutoff of 0.20 IU/ml for QFT-GIT and 13 spots for T-SPOT.TB. CONCLUSIONS: Blood test results were associated with exposure, whereas the TST was not. A possible lack of sensitivity of IFN-gamma assays in detecting individuals with TST of 15 mm or greater, despite negative bacillus Calmette-Guérin vaccination status, warrants further investigation into alternative cutoff values. [ABSTRACT FROM AUTHOR]

BACKGROUND: Pneumocystis carinii pneumonia (PCP) occurs in immunocompromised patients without the acquired immunodeficiency syndrome (AIDS). There has been an increasing yearly number of cases of PCP in our patients without AIDS. OBJECTIVE: To determine the nature of the underlying disorder and previous immunosuppressive treatment in patients with PCP without AIDS. METHOD: A study of the charts of 78 such patients admitted to our hospital from 1980 through 1993. RESULTS: The number of PCP cases per year increased during the period studied. All patients had an underlying disorder, either hematologic malignancy (49%), solid organ tumor (4%), vasculitis or other immunologic disorder (22%), or they had undergone renal transplantation (17%) or bone marrow transplantation (9%). Previous immunosuppressive medication consisted of prednisone or other corticosteroids in 72 (92%) of 78 patients, cytotoxic drugs in 55 (71%) of 78 patients, both in 50 (64%) of 78 patients, and none in one patient. Quantification of previous corticosteroid treatment showed a large variability among patients. The overall mortality rate for patients was 35% (27/78). Mortality was significantly higher in patients with a concomitant pulmonary infection (P = .01), an underlying disorder other than that which resulted in renal transplantation (P = .03), mechanical ventilation (P < .001), previous chemotherapy (P = .04), as well as previous cyclophosphamide treatment (P = .01). A trend toward a higher mortality in patients with previous corticosteroid use was detected (P = .06). CONCLUSION: Pneumocystis carinii pneumonia may complicate a variety of immunocompromised states, with considerable mortality. Pneumocystis carinii pneumonia occurred at all levels of immunosuppression; no threshold level could be defined. [ABSTRACT FROM AUTHOR]

Background: Screening for tuberculosis (TB) infection often includes QuantiFERON-TB Gold Plus (QFT) testing. Previous studies showed that two-thirds of patients with negative QFT results just below the cut-off, so-called borderline test results, nevertheless had other evidence of TB infection. This study aimed to identify a biomarker profile by which borderline QFT results due to TB infection can be distinguished from random test variation., Methods: QFT supernatants of patients with a borderline (≥0.15 and <0.35 IU·mL -1 ), low-negative (<0.15 IU·mL -1 ) or positive (≥0.35 IU·mL -1 ) QFT result were collected in three hospitals. Bead-based multiplex assays were used to analyse 48 different cytokines, chemokines and growth factors. A prediction model was derived using LASSO regression and applied further to discriminate QFT-positive Mycobacterium tuberculosis -infected patients from borderline QFT patients and QFT-negative patients RESULTS: QFT samples of 195 patients were collected and analysed. Global testing revealed that the levels of 10 kDa interferon (IFN)-γ-induced protein (IP-10/CXCL10), monokine induced by IFN-γ (MIG/CXCL9) and interleukin-1 receptor antagonist in the antigen-stimulated tubes were each significantly higher in patients with a positive QFT result compared with low-negative QFT individuals (p<0.001). A prediction model based on IP-10 and MIG proved highly accurate in discriminating patients with a positive QFT (TB infection) from uninfected individuals with a low-negative QFT (sensitivity 1.00 (95% CI 0.79-1.00) and specificity 0.95 (95% CI 0.74-1.00)). This same model predicted TB infection in 68% of 87 patients with a borderline QFT result., Conclusions: This study was able to classify borderline QFT results as likely infection-related or random. These findings support additional laboratory testing for either IP-10 or MIG following a borderline QFT result for individuals at increased risk of reactivation TB., Competing Interests: Conflict of interest: T.H.M. Ottenhoff reports grants from NWO-TTW (PI: T.H.M. Ottenhoff), Dutch Government, Technical Sciences; ZonMw (PI: T.H.M. Ottenhoff), Dutch Government (ZonMw); IMI2 HOR2020 VSV EBOPLUS (PI: C.A. Siegrist), European Commission HOR2020 IMI2 Program; NWO-TTW (PI: J. Bouwstra), Dutch Government, Technical Sciences; NWO-TTW (PI: T.H.M. Ottenhoff), Dutch Government, Technical Sciences, NACTAR Program; NWO-Chemical Sciences (PI: A. Minnaard), Dutch Government, Technical Sciences; EC HOR2020 TRANSVAC2 (PI: European Vaccine Initiative (EVI)), European Commission HOR2020 Program; IMI2 EC HOR2020 Respiri-TB (PI: M. Lamers), European Commission HOR2020 IMI2 Program; IMI2 EC HOR2020 Respiri-NTM (PI: M. Lamers), European Commission HOR2020 IMI2 Program; NIH (PI: T.H.M. Ottenhoff); NIH, NIAID, grant: 1RO1AI141315-01A1; EC HOR2020 SMA-TB (PI: C. Vilaplana); European Commission HOR2020 Program; leadership at the Tuberculosis Vaccine Initiative (TBVI; www.tbvi.eu); outside the submitted work. S.A. Joosten reports grants from NIH (PI: T.H.M. Ottenhoff; co-PI: S.A. Joosten); NIH, NIAID, grant: 1RO1AI141315-01A1; outside the submitted work. S.M. Arend reports travel support from Oxford Immunotec, outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2022.)

Background: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great importance in this group, but little is known about the immunogenicity of COVID-19 vaccines in these patients., Objectives: We sought to study humoral and cellular immune responses after mRNA-1273 COVID-19 vaccination in adult patients with IEI., Methods: In a prospective, controlled, multicenter study, 505 patients with IEI (common variable immunodeficiency [CVID], isolated or undefined antibody deficiencies, X-linked agammaglobulinemia, combined B- and T-cell immunodeficiency, phagocyte defects) and 192 controls were included. All participants received 2 doses of the mRNA-1273 COVID-19 vaccine. Levels of severe acute respiratory syndrome coronavirus-2-specific binding antibodies, neutralizing antibodies, and T-cell responses were assessed at baseline, 28 days after first vaccination, and 28 days after second vaccination., Results: Seroconversion rates in patients with clinically mild antibody deficiencies and phagocyte defects were similar to those in healthy controls, but seroconversion rates in patients with more severe IEI, such as CVID and combined B- and T-cell immunodeficiency, were lower. Binding antibody titers correlated well to the presence of neutralizing antibodies. T-cell responses were comparable to those in controls in all IEI cohorts, with the exception of patients with CVID. The presence of noninfectious complications and the use of immunosuppressive drugs in patients with CVID were negatively correlated with the antibody response., Conclusions: COVID-19 vaccination with mRNA-1273 was immunogenic in mild antibody deficiencies and phagocyte defects and in most patients with combined B- and T-cell immunodeficiency and CVID. Lowest response was detected in patients with X-linked agammaglobulinemia and in patients with CVID with noninfectious complications. The assessment of longevity of immune responses in these vulnerable patient groups will guide decision making for additional vaccinations., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objective: In the randomized controlled trial REMAP-CAP, it was shown that next to dexamethasone, the interleukin (IL)-6 receptor antagonist tocilizumab improves outcome, including survival in intensive care unit (ICU)-admitted coronavirus disease 2019 (COVID)-19 patients. Therefore tocilizumab has been added to many COVID-19 treatment guidelines. Because obesity is a risk factor for the development of severe COVID-19, concerns have been raised about overtreatment, as well as undertreatment, through weight-based dosing of tocilizumab. The currently applied dose of 8 mg/kg is based on the use of this drug for other indications, however it has not formally been investigated for COVID-19. In this study, the pharmacokinetics and pharmacodynamics of tocilizumab were investigated in ICU-admitted COVID-19 patients., Methods: This was an open-label, single-centre, observational population pharmacokinetic and descriptive pharmacodynamic evaluation study. Enrolled patients, with polymerase chain reaction-confirmed COVID-19 were admitted to the ICU for mechanical ventilation or high flow nasal canula oxygen support. All patients were 18 years of age or older and received intravenous tocilizumab 8 mg/kg (maximum 800 mg) within 24 h after admission to the ICU and received dexamethasone 6 mg daily as concomitant therapy. For evaluation of the pharmacokinetics and pharmacodynamics of tocilizumab, all time points from day 0 to 20 days after dose administration were eligible for collection. A nonlinear mixed-effects model was developed to characterize the population pharmacokinetic parameters of tocilizumab in ICU-admitted COVID-19 patients. Covariate analysis was performed to identify potential covariates for dose individualization. For the development of alternative dosing schedules, Monte Carlo simulations using the final model were performed., Results: Overall, 29 patients were enrolled between 15 December 2020 and 15 March 2021. A total of 139 tocilizumab plasma samples were obtained covering the pharmacokinetic curve of day 0 to day 20 after tocilizumab initiation. A population pharmacokinetic model with parallel linear and nonlinear clearance (CL) was developed and validated. Average CL was estimated to be 0.725 L/day, average volume of distribution (V d ) was 4.34 L, maximum elimination rate (V max ) was 4.19 μg/day, and concentration at which the elimination pathway is half saturated (K m ) was 0.22 μg/mL. Interindividual variability was identified for CL (18.9%) and V d (21%). Average area under the concentration versus time curve from time zero to infinity of the first dose (AUC inf 1st DOSE ) was 938 [±190] μg/mL*days. All patients had tocilizumab exposure above 1 μg/mL for at least 15 days. Bodyweight-based dosing increases variability in exposure compared with fixed dosing., Conclusions: This study provides evidence to support a fixed dose of tocilizumab 600 mg in COVID-19 patients. Fixed dosing is a safe, logistically attractive, and drug expenses saving alternative compared with the current 8 mg/kg recommendation., (© 2021. The Author(s).)

The phosphoinositide-3-kinase (PI3K) family plays a major role in cell signaling and is predominant in leukocytes. Gain-of-function (GOF) mutations in the PIK3CD gene lead to the development of activated PI3Kδ syndrome (APDS), a rare primary immunodeficiency disorder. A subset of APDS patients also displays neurodevelopmental delay symptoms, suggesting a potential role of PIK3CD in cognitive and behavioural function. However, the extent and nature of the neurodevelopmental deficits has not been previously quantified. Here, we assessed the cognitive functions of two APDS patients, and investigated the causal role of the PIK3CD GOF mutation in neurological deficits using a murine model of this disease. We used p110δ E1020K knock-in mice, harbouring the most common APDS mutation in patients. We found that APDS patients present with visuomotor deficits, exacerbated by autism spectrum disorder comorbidity, whereas p110δ E1020K mice exhibited impairments in motor behaviour, learning and repetitive behaviour patterning. Our data indicate that PIK3CD GOF mutations increase the risk for neurodevelopmental deficits, supporting previous findings on the interplay between the nervous and the immune system. Further, our results validate the knock-in mouse model, and offer an objective assessment tool for patients that could be incorporated in diagnosis and in the evaluation of treatments., Competing Interests: We declare that one of the authors (PMH) has received grants and research support from Takeda, CSL Behring, Abbvie, Lamepro, Novartis Nederland, and honoraria or consultation fees from UCB Pharma. All the other authors have no conflict of interest to declare., (© 2021 The Authors.)

Screening for latent tuberculosis infection (LTBI) is indicated before immunosuppressive therapies but is complicated by lack of a gold standard and limited by, e.g., immunosuppression. This study aimed to investigate a series of patients diagnosed with LTBI during screening before immunosuppressive therapy, describing how the use of diagnostic tests and treatment evolved over time. This retrospective cohort study included all individuals diagnosed with LTBI during screening before intended immunosuppressive therapy in a tertiary care hospital between January 2000 and December 2017. Evidence for LTBI, including history, tuberculin skin test (TST), QuantiFERON (QFT) result and suggestive lesions on chest radiography (CXR), and CT scan if available, was analyzed. The study included 295 individuals with LTBI, with median follow-up of 3.8 years (IQR 1.7-7.4 years). During screening, TST, QFT, and CXR were positive in 80.8%, 53.4%, and 22.7%, respectively. Chest CT revealed lesions associated with past tuberculosis infection in around 70%, significantly more frequent than CXR. In patients diagnosed with LTBI, we observed that the use of TST declined over time whereas the use of QFT increased, and that isoniazid was replaced with rifampicin as preferential treatment. Preventive treatment was started in 82.3%, of whom 88.6% completed treatment. During follow-up, no individuals developed active tuberculosis. The diagnosis of LTBI was based on history, TST, QFT, and/or CXR in nearly every possible combination, but mostly on TST and QFT. The most striking trends were the decreased use of TST, increased use of QFT, and the replacement of isoniazid with rifampicin for treatment.

Introduction: Poor knowledge retention is a persistent problem among medical students. This challenging issue may be addressed by optimizing frequently used instructional designs, such as lectures. Guided by neuroscientific literature, we designed a spaced learning lecture in which the educator repeats the to-be-learned information using short temporal intervals. We investigated if this modified instructional design could enhance students' retention., Materials and Methods: Second-year medical students ( n = 148) were randomly allocated to either the spaced lecture or the traditional lecture. The spaced lecture consisted of three 15-min instructional periods, separated by 5-min intervals. A short summary of the preceding information was provided after each interval. The traditional lecture encompassed the same information including the summary in the massed format, thus without the intervals. All students performed a baseline knowledge test 2 weeks prior to the lectures and students' knowledge retention was assessed 8 days after the lectures., Results: The average score on the retention test ( α = 0.74) was not significantly different between the spaced lecture group (33.8% ± 13.6%) and the traditional lecture group (31.8% ± 12.9%) after controlling for students' baseline-test performance ( F (1,104) = 0.566, p = 0.458). Students' narrative comments showed that the spaced lecture format was well-received and subjectively benefitted their attention-span and cognitive engagement., Discussion and Conclusion: We were unable to show increased knowledge retention after the spaced lecture compared with the traditional lecture. Based on these findings, we provide recommendations for further research. Ultimately, we aim for optimized spaced learning designs to facilitate learning in the medical curriculum and to help educate health professionals with a solid knowledge base., Competing Interests: Conflict of InterestThe authors declare that they have no conflict of interest., (© The Author(s) 2020.)

Objective: Current guidelines recommend screening for latent tuberculosis infection (LTBI) with a tuberculin skin test (TST) or interferon gamma release assay (IGRA), or both. Many also recommend chest radiography (CXR), although its added value is uncertain. This systematic review assessed the prevalence of abnormalities suggestive of LTBI on CXR (LTBI-CXR lesions) and evaluated the strength of the association., Method: We searched 4 databases up to September 2017 and systematically reviewed cross-sectional and cohort studies reporting LTBI-CXR lesions in individuals with a positive TST or IGRA, or both, result. Prevalence estimates were pooled using random effects models and odds ratios (ORs) were used to calculate risk estimates., Results: In the 26 included studies, the pooled proportion of individuals with LTBI having LTBI-CXR lesions was 0.15 (95% confidence interval [CI], 0.12-0.18]. In 16 studies that reported on individuals with LTBI and uninfected controls, LTBI-CXR lesions were associated with a positive TST result ≥ 5 mm or ≥ 10 mm (OR, 2.45; 95% CI, 1.00-5.99; and OR, 2.06; 95% CI, 1.38-3.09, respectively) and with a positive QuantiFERON result (OR, 1.99; 95% CI, 1.17-3.39) compared to CXR in uninfected controls. Although few studies reported specified lesions, calcified nodules were most frequently reported in individuals with LTBI (proportion, 0.07; 95% CI, 0.02-0.11)., Conclusions: Lesions on CXR suggestive of previous infection with Mycobacterium tuberculosis were significantly associated with positive tests for LTBI, although the sensitivity was only 15%. This finding may have added value when detection of past LTBI is important but immunodiagnostic tests may be unreliable., (© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Several radiological features have been reported in association with latent tuberculosis infection (LTBI) but it has not been studied which are specific. The aim of this study was to evaluate allegedly characteristic abnormalities on chest radiography (CXR) in patients with LTBI compared to uninfected controls., Methods: From 236 patients tested with QuantiFERON-TB Gold In-Tube (QFT), the CXR was re-evaluated in a blinded fashion for fibrotic scarring, (non-)calcified nodules and pleural thickening. LTBI was defined as presence of a positive QFT result and/or positive tuberculin skin test result stratified by Bacille Calmette-Guérin-vaccination status., Results: Any predefined abnormality of LTBI was observed in 116/236 (49.2%) patients, the frequency not being different between groups. However, the specificity for LTBI of a fibrotic scar ≥ 2 cm 2 was 100% [95% CI: 92.0%-100%] and of a calcified nodule ≥1.5 mm was 95.7% [95% CI: 85.2%-99.5%]. The frequency of non-calcified nodules and pleural thickening did not differ between groups., Conclusion: Only a fibrotic scar ≥ 2 cm 2 and/or a calcified nodule ≥1.5 mm were significantly associated with LTBI. This finding is clinically relevant mainly in patients who are at significant risk of TB reactivation and in whom indirect diagnostic tests may be unreliable., (© 2019 The Authors.)

Intravesical bacillus Calmette-Guérin (BCG) is widely used for high-risk, non-muscle-invasive bladder cancer. This report describes four cases that illustrate the spectrum of BCG-induced complications, varying from granulomatous prostatitis to sepsis. There is considerable debate regarding whether inflammation or infection is the predominant mechanism in the pathogenesis of BCG disease. In two patients with a systemic illness, the symptoms first resolved after adding prednisone, indicating a principal role for inflammation in systemic disease. In vitro testing of T-cell responses and a mycobacterial growth inhibition assay were performed for these patients with systemic disease. The patient with mild symptoms showed more effective in vitro growth reduction of BCG, while the patient with sepsis and organ involvement had high T-cell responses but ineffective killing. While these findings are preliminary, it is believed that immunological assays, as described in this report, may provide a better insight into the pathogenesis of BCG disease in individual patients, justifying further research., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: QuantiFERON (QFT) results near the cut-off are subject to debate. We aimed to investigate which borderline QFT results were due to Mycobacterium tuberculosis (Mtb)-specific responses or to test variability., Methods: In a contact investigation, tuberculin skin test (TST), QFT and T-SPOT.TB (T-SPOT) were performed in 785 BCG-unvaccinated contacts. Contacts with a low-negative (<0.15), borderline (0.15-0.35), low-positive (0.35-0.70) or high-positive QFT (≥0.70 IU/mL) were compared with respect to exposure, TST and T-SPOT results. Development of active tuberculosis was assessed., Results: Borderline QFT results occurred in threefold excess over test variability (p = 0.0027). In contacts with low-negative, borderline or positive QFT results, a positive TST occurred in 24.9%, 62.1% and 91.4% (p < 0.0001) and a positive T-SPOT result in 6.3%, 41.3% and 86.4%, respectively (p < 0.0001). Two-third (20/29) of contacts with a borderline and 14/16 (88%) with a low-positive QFT had a positive TST and/or T-SPOT, indicating probable Mtb-infection. During 12 years of follow-up, seven patients were diagnosed with active tuberculosis, two of whom after a low-positive QFT., Conclusions: In this study, most borderline and low-positive QFT results were Mtb-specific, showing the biological significance of a borderline QFT. The clinical relevance, however, will be most distinct in patients who are or will be immunocompromised., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Hepatic tuberculosis (TB) shows non-specific symptoms, and liver imaging may provide diagnostic clues. Here we describe a series of patients with hepatic TB showing characteristic radiological findings., Methods: Single-centre retrospective evaluation of patients with hepatic TB diagnosed over a period of 16 years who underwent ultrasound, computed tomography (CT) and/or magnetic resonance imaging (MRI). Hepatic lesions were classified as miliary, nodular, serohepatic or cholangitis., Results: Of 14 patients with hepatic TB, five were co-infected with the human immunodeficiency virus. All patients had additional extrahepatic TB localisations. An interferon-gamma release assay was performed in 11/14 patients, ultrasound and CT were available for all patients and MRI for four. Observed patterns were miliary (n = 6) with multiple nodules < 2 cm; nodular (n = 5), characterised by a variable number of nodules (2-7 cm); and serohepatic (n = 3), with multiple nodular subcapsular lesions with a thin, smooth wall. Shared findings were hypoechoic lesions on ultrasound, hypodense lesions with ring enhancement on CT, while MRI lesions were hypointense on T1- and hyperintense on T2-weighted images., Conclusions: Ultrasound, CT and MRI can independently contribute to detection of hepatic TB. While a miliary pattern or calcifications are characteristic, no pattern is completely pathognomonic and the diagnosis depends on microbiological evidence. Particularly in risk groups, characteristic radiological findings may prompt targeted diagnostic work-up.

Background: Measurement of rifampin levels is not part of routine practice. However, low levels are associated with failure of tuberculosis treatment. The clinical relevance of serum levels in daily practice is unclear. The objective was to evaluate rifampin serum concentrations and factors associated with insufficient concentrations., Methods: Patients with at least one rifampin concentration drawn 3 hours after intake (C3) between 2005 and 2014 were included. Data on demographic and clinical characteristics were collected, including side effects and dose adjustments. Two different criteria were used to define adequate concentrations (criterion 1: C3 a nd C 6 ≥ 3 mg/l; criterion 2: C3 or C6 ≥ 5 mg/l)., Results: Of 63 patients, 66% and 76% had a sufficient level according to criterion 1 or 2, respectively. C3 exceeded C6 in most patients, while a late maximum was significantly associated with diabetes mellitus (p = 0.003). A dose adjustment was made in 19% of cases, more frequently in patients with insufficient levels (p = 0.02) or with ≥ 2 side effects (p = 0.03)., Conclusion: Rifampin levels varied but were mostly adequate and a single measurement at 3 hours after intake provided the required information in most cases, indicating that full AUC0-24 measurements could be limited to specific situations.

The lack of defined correlates of protection hampers development of vaccines against tuberculosis (TB). In vitro mycobacterial outgrowth assays are thought to better capture the complexity of the human host/Mycobacterium tuberculosis (Mtb) interaction. Here, we used a mycobacterial growth inhibition assay (MGIA) based on peripheral blood mononuclear cells to investigate the capacity to control outgrowth of bacille Calmette-Guérin (BCG). Interestingly, strong control of BCG outgrowth was observed almost exclusively in individuals with recent exposure to Mtb, but not in (long-term) latent TB infection, and only modestly in BCG vaccinees. Mechanistically, control of mycobacterial outgrowth strongly correlated with the presence of a CD14dim monocyte population, but also required the presence of T cells. The nonclassical monocytes produced CXCL10, and CXCR3 receptor blockade inhibited the capacity to control BCG outgrowth. Expression of CXCR3 splice variants was altered in recently Mtb-exposed individuals. Cytokines previously associated with trained immunity were detected in MGIA supernatants, and CXCL9, CXCL10, and CXCL11 represent new markers of trained immunity. These data indicate that CXCR3 ligands are associated with trained immunity and are critical factors in controlling mycobacterial outgrowth. In conclusion, control of mycobacterial outgrowth early after exposure to Mtb is the result of trained immunity mediated by a CXCL10-producing nonclassical CD14dim monocyte subset.

We report two unrelated cases of tenosynovitis caused by Mycobacterium malmoense in kidney transplant recipients. Both patients received immunosuppression and were referred to our tertiary hospital because of persisting complaints lasting >6 months not responding to corticosteroids or surgery. The mycobacterial cultures were positive for the slow-growing M. malmoense after several weeks of incubation. The patient in Case 1 was treated with a combination of surgical debridement and antibiotics, whereas the patient in Case 2 was only treated surgically. Both cases illustrate the doctor's delay in diagnosing mycobacterial infections, and remind us that nontuberculous mycobacterial infections should be part of the differential diagnosis of tenosynovitis, especially in immunocompromised patients., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We present a case of donor-derived tuberculosis after liver transplantation, in which the donor origin of the Mycobacterium tuberculosis isolate was made most likely by DNA fingerprinting. Screening for latent tuberculosis of transplant donors originating from high endemic areas with an ex-vivo interferon-gamma release assay should be considered.

The diagnosis of a latent tuberculosis infection (LTBI) is based on detection of immunity against Mycobacterium tuberculosis (Mtb). The tuberculin skin test (TST), the Quantiferon (QFT) and a prolonged lymphocyte stimulation test using either ESAT-6/CFP-10 (LST-EC) or PPD (LST-PPD) were evaluated in a cohort of 495 individuals, suspected to have LTBI, in a low endemic country. While the TST and LST-PPD were both positive in the majority (75%) of individuals, only one third responded in the LST-EC and in the QFT. The choice for LTBI treatment was significantly associated with ESAT6/CFP10 recognition, however the LST-EC detected considerably more individuals (21%) with immunity against Mtb, who might also be at risk for development of active TB, although none of them did during follow up. Follow-up for 2 years showed 7% conversions and 32% reversions for the QFT. The LST-EC showed higher conversion rates (∼45%), although the percentage of individuals positive in the LST-EC did not change significantly within the follow-up period. LTBI treatment did not alter immune recognition of Mtb antigens. In conclusion, the sensitivity of tests for detection of cellular immunity to Mtb specific antigens depends on test methodology and may vary considerably over time in a low endemic region., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

While postnatal toxoplasmosis in immune-competent patients is generally considered a self-limiting and mild illness, it has been associated with a variety of more severe clinical manifestations. The causal relation with some manifestations, e.g. myocarditis, has been microbiologically proven, but this is not unequivocally so for other reported associations, such as with epilepsy. We aimed to systematically assess causality between postnatal toxoplasmosis and epilepsy in immune-competent patients. A literature search was performed. The Bradford Hill criteria for causality were used to score selected articles for each component of causality. Using an arbitrary but defined scoring system, the maximal score was 15 points (13 for case reports). Of 704 articles, five case reports or series and five case-control studies were selected. The strongest evidence for a causal relation was provided by two case reports and one case-control study, with a maximal causality score of, respectively, 9/13, 10/13 and 10/15. The remaining studies had a median causality score of 7 (range 5-9). No selection bias was identified, but 6/10 studies contained potential confounders (it was unsure whether the infection was pre- or postnatal acquired, or immunodeficiency was not specifically excluded). Based on the evaluation of the available literature, although scanty and of limited quality, a causal relationship between postnatal toxoplasmosis and epilepsy seems possible. More definite proof requires further research, e.g. by performing Toxoplasma serology in all de novo epilepsy cases.

Background: Between 1994 and 2009, incidence rates of general practitioner (GP) consultations for tick bites and erythema migrans, the most common early manifestation of Lyme borreliosis, have increased substantially in the Netherlands. The current article aims to estimate and validate the incidence of GP-reported Lyme carditis in the Netherlands., Methods: We sent a questionnaire to all GPs in the Netherlands on clinical diagnoses of Lyme borreliosis in 2009 and 2010. To validate and adjust the obtained incidence rate, medical records of cases of Lyme carditis reported by GPs in this incidence survey were reviewed and categorised according to likelihood of the diagnosis of Lyme carditis., Results: Lyme carditis occurred in 0.2 % of all patients with GP-reported Lyme borreliosis. The adjusted annual incidence was six GP-reported cases of Lyme carditis per 10 million inhabitants, i.e. approximately ten cases per year in 2009 and 2010., Conclusions: We report the first incidence estimate for Lyme carditis in the Netherlands, validated by a systematic review of the medical records. Although Lyme carditis is an uncommon manifestation of Lyme borreliosis, physicians need to be aware of this diagnosis, in particular in countries where the incidence of Lyme borreliosis has increased during the past decades.

This study aimed to estimate the risk of progression to active tuberculosis (TB) within 2 yrs after entry in newly arriving immigrants who were screened with the QuantiFERON®-TB Gold In-Tube assay (QFT-GIT; Cellestis, Carnegie, Australia). In a case-base design, we determined the prevalence QFT-GIT-positive subjects among a representative sample of immigrants aged ≥ 18 yrs who arrived between April 2009 and March 2011 (the base cohort). Active TB patients (cases) within 2 yrs post-arrival in 2005, 2006 or 2007 were extracted from the Netherlands Tuberculosis Register. The risk of progression to active TB was estimated using Bayesian analyses to adjust for the sensitivity of QFT-GIT. Among the base cohort, 20% of 1,468 immigrants were QFT-GIT positive. Stratified by TB incidence in the person's country of origin as low (<100 cases per 100,000 population), intermediate (100-199 cases per 100,000) or high (≥ 200 cases per 100,000), the risk of progression to active TB per 100,000 arriving immigrants if QFT-GIT positive (95% credibility interval) was 456 (95% CI 307-589), 590 (397-762) and 386 (259-499), respectively, compared with 18 (0-46), 38 (0-97) and 28 (0-71) if QFT-GIT negative. Screening newly arriving immigrants with QFT-GIT contributes to detecting those at high risk of subsequent TB reactivation within 2 yrs after entry, which offers opportunities for prevention by targeted interventions.

Setting: After the diagnosis of a case of tuberculosis (TB), contact tracing is directed by the risk of transmission, for which sputum acid-fast bacilli (AFB) staining results are highly relevant. Limited data are available on the effect of the degree of acid-fast positivity, of a polymerase chain reaction (PCR) result or of bronchoalveolar lavage (BAL) fluid results on the risk of transmission., Objectives: To investigate factors associated with TB transmission, focusing on quantitative sputum smear results., Design: Retrospective study of contact investigations performed over a period of 5 years in a Dutch Municipal Health Service among all index patients with TB, and the tuberculin skin test and chest radiography results in contacts. Three definitions of transmission were used: ≥ 1 or ≥ 5 contacts with positive TST or active TB in contacts., Results: The highest (+4/+5) sputum AFB grades were associated with the highest relative risk (≥ 8) of extensive transmission or active TB among contacts. Novel risk factors observed were employment or school attendance, positive PCR of sputum and positive AFB staining of BAL fluid. Pulmonary symptoms, infiltrate or cavity and positive AFB sputum stain were also associated with transmission, confirming previous studies., Conclusion: The risk factors observed in this study may aid in the extension of contact investigations.

Tuberculosis (TB) is a possible complication of solid organ and hematopoietic stem cell transplantation. The identification of candidates for preventive chemotherapy is an effective intervention to protect transplant recipients with latent infection with Mycobacterium tuberculosis from progressing to active disease. The best available proxy for diagnosing latent infection with M. tuberculosis is the identification of an adaptive immune response by the tuberculin skin test or an interferon-γ based ex vivo assay. Risk assessment in transplant recipients for the development of TB depends on, among other factors, the locally expected underlying prevalence of infection with M. tuberculosis in the target population. In areas of high prevalence, preventive chemotherapy for all transplant recipients may be justified without immunodiagnostic testing while in areas of medium and low prevalence, preventive chemotherapy should only be offered to candidates with positive M. tuberculosis-specific immune responses. The diagnosis of TB in transplant recipients can be challenging. Treatment of TB is often difficult due to substantial interactions between anti-TB drugs and immunosuppressive medications. This management guideline summarises current knowledge on the prevention, diagnosis and treatment of TB related to solid organ and hematopoietic stem cell transplantation and provides an expert consensus on questions where scientific evidence is still lacking.

Immune thrombocytopenic purpura (ITP) is a multicausal disease. In the majority of cases, autoimmune antibodies against thrombocytes and other autoimmune processes play a role. However, in about 20% of cases an underlying cause can be identified. Recently, Helicobacter pylori infection was recognized as one of these underlying causes. We present two patients with ITP in whom a significant increase of thrombocytes occurred after eradication of H. pylori. In the first patient, a 75-year-old man, experimental therapy was withheld. The second patient, a 47-year-old man, never received immunosuppressive medication. H. pylori screening and eradication should be standard practice in the work up of a patient with thrombocytopenia. Despite the lack of clear pathophysiological understanding, in a minority of ITP cases there is evidence of a correlation between H. pylori infection and ITP. Tests and treatment are non-invasive, cheap and without major side-effects. In the event of a platelet response, expensive immunosuppressive treatment with significant side effects may be avoided.

New TB vaccines are urgently needed because of the apparent lack of effect of the BCG vaccine on rates of adult contagious pulmonary tuberculosis and the risk of disseminated BCG disease in immunocompromised individuals. Since BCG appears to protect children, the primary target for vaccine development is a booster vaccine for adults but such vaccines ideally need to be able to efficiently prime mycobacterially naïve individuals as well as boost individuals previously vaccinated with BCG and those latently infected with TB. Protective immunity against Mycobacterium tuberculosis depends mainly on the generation of a Th1-type cellular immune response characterized by interferon-gamma (IFN-γ) production. In the present study, we monitored safety and IFN-γ responses in healthy BCG-vaccinated and prior or latently TB-infected individuals receiving a novel vaccine composed of the fusion protein Ag85B-ESAT-6 combined with the adjuvant IC31(®), administered at 0 and 2 months. Vaccination caused few local or systemic adverse effects besides transient soreness at the injection site, but it elicited strong antigen-specific T cell responses against Ag85B-ESAT-6 and both the Ag85B and ESAT-6 components, that could be augmented by second vaccination. The strong responses persisted through 32 weeks of follow-up, indicating the induction of a persistent memory response in the vaccine recipients., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The authors determined the positive predictive value (PPV) for progression to tuberculosis (TB) of two interferon-gamma release assays (IGRAs), QuantiFERON-TB Gold In-tube (QFT-GIT) and T-SPOT.TB, and the tuberculin skin test (TST) in immigrants contacts. Immigrant close contacts of sputum smear-positive TB patients were included when aged > or =16 yrs and their TST result was > or =5 mm 0 or 3 months after diagnosis of the index patient. Contacts were followed for the next 2 yrs for development of TB disease. Of 339 immigrant contacts with TST > or =5 mm, 324 and 299 had valid results of QFT-GIT and T-SPOT.TB, respectively. Nine contacts developed active TB. One patient had not been tested with TST, while another patient had not been tested with QFT-GIT and T-SPOT.TB. The PPV for progression to TB during this period was 9/288 = 3.1% (95% CI 1.3-5.0%) for TST > or =10 mm, 7/184 = 3.8% (95% CI 1.7-5.9%) for TST > or =15 mm, 5/178 = 2.8% (95% CI 1.0-4.6%) for QFT-GIT and 6/181 = 3.3% (95% CI 1.3-5.3%) for T-SPOT.TB. Sensitivity was 100%, 88%, 63% and 75%, respectively. The predictive values of QFT-GIT, T-SPOT.TB and TST for progression to TB disease among immigrant close contacts were comparable.

Treatment of latent Mycobacterium tuberculosis infection on the basis of the tuberculin skin test (TST) result is inaccurate due to the false-positive TST results that occur after Mycobacterium bovis BCG vaccination or exposure to nontuberculous mycobacteria (NTM). Gamma interferon release assays (IGRAs) are based on M. tuberculosis-specific antigens. In a previous study among BCG-naïve military employees, a positive TST result after deployment was mostly associated with a negative IGRA result, suggesting exposure to NTM. Data regarding the kinetics of IGRAs are limited and controversial. The present study aimed to reassess the rate of false-positive TST results and to evaluate the kinetics of the Quantiferon TB Gold In-Tube assay (QFT-Git) in military personnel with a positive TST result. QFT-Git was performed at the time of inclusion in the study and was repeated after 2, 6, 12, and 18 or 24 months. Of 192 participants, 17 were recruits and 175 were screened after deployment (n = 169) or because of travel or health care work. Baseline positive QFT-Git results were observed in 7/17 (41.2%) and 12/174 (6.9%) participants, respectively. During follow-up, a negative QFT-Git result remained negative in 163/165 (98.8%) participants. Of 18 subjects with an initial positive QFT-Git result, reversion to a negative result occurred in 1/6 (16%) recruits, whereas it occurred in 8/12 (66%) subjects after deployment or with other risk factors (P = 0.046). The quantitative result was significantly lower in subjects with reversion than in those with consistent positive results (P = 0.017). This study confirmed a low rate of positive QFT-Git results among military personnel with a positive TST result after deployment, supporting the hypothesis of exposure to NTM. Reversion of the majority of initially low-positive QFT-Git results indicates that QFT-Git may be useful for the diagnosis of later reinfections.

Though widely used, the BCG vaccine has had little apparent effect on rates of adult pulmonary tuberculosis. Moreover, the risk of disseminated BCG disease in immunocompromised individuals means that improved TB vaccines ideally need to be able to efficiently prime mycobacterially-naïve individuals as well as boost individuals previously vaccinated with BCG. Protective immunity against Mycobacterium tuberculosis is thought to depend on the generation of a Th1-type cellular immune response characterized by interferon-gamma (IFN-gamma) production. In the present study, we monitored safety and IFN-gamma responses in healthy TB-naïve humans receiving an entirely novel vaccine, composed of the fusion protein Ag85B-ESAT-6, administered at 0 and 2 months either as recombinant protein alone or combined with two concentrations of the novel adjuvant IC31. Vaccination did not cause local or systemic adverse effects besides transient soreness at the injection site, but it elicited strong antigen-specific T cell responses against H1 and both the Ag85B and the ESAT-6 components. These strong responses persisted through 2.5 years of follow-up, indicating the induction of a substantial memory response in the vaccine recipients., ((c) 2010 Elsevier Ltd. All rights reserved.)