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Background Multidrug-resistant tuberculosis (MDR-TB) requires lengthy use of second-line drugs, burdened by many side effects. Hepatitis C virus (HCV) chronic infection increases risk of drug-induced liver injury (DILI) in these patients. Data on MDR-TB patients with concurrent HCV chronic infection treated at the same time with second-line antitubercular drugs and new direct-acting antivirals (DAAs) are lacking. We evaluate if treating at the same time HCV infection and pulmonary MDR-TB is feasible and effective. Cases presentation In this study, we described two cases of patients with pulmonary MDR-TB and concurrent HCV chronic infection cured with DAAs at a Tertiary Infectious Diseases Hospital in Italy. During antitubercular treatment, both patients experienced a DILI before treating HCV infection. After DAAs liver enzymes normalized and HCV RNA was undetectable. Then antitubercular regimen was started according to the institutional protocol, drawn up following WHO MDR-TB guidelines. It was completed without further liver side effects and patients were declared cured from both HCV infection and MDR-TB. Conclusions We suggest to consider treatment of chronic hepatitis C with DAAs as a useful intervention for reintroduction of second-line antitubercular agents in those patients who developed DILI, reducing the risk of treatment interruption when re-exposed to these drugs.

Purpose Multidrug-resistant tuberculosis (MDR-TB) is a major burden to public health in low incidence countries in Europe. The aim of this study was to attempt to have a better insight into the trends of MDR-TB in the metropolitan area of Rome, within the Italian and the foreign-born population, based on microbiological and demographic data. Patients and methods We performed a prospective study, collecting microbiological data based on phenotypic drug-resistant testing (DST) of TB strains consecutively isolated in a referral hospital in Rome, the capital city of a low TB incidence country, over a 6-year period, and correlated them to the geographical origin of patients. This study was carried out in a referral hospital for patients with drug-resistant TB from the whole region. Results Drug-resistance data from 926 patients with a microbiological diagnosis of TB from 2011 to 2016 show a 5.5% rate of MDR-TB, mostly occurring in patients born in a single East European country, that has a high incidence of MDR-TB. The strains isolated from these patients frequently carry additional resistances, leading to an increased risk of developing extensively drug-resistant (XDR) TB. Conclusion In the great metropolitan area of Rome, MDR-TB more frequently occurs in patients who were born in a single country from Eastern Europe known to have high rates of MDR-TB and long-time residents in Italy. Recent immigrants from non-European countries do not appear to contribute to the rates of MDR-TB reported in this article. This knowledge of local TB trends could help improve the measures of surveillance and prevention of disease.

Background: The WHO advised that the impact of COVID-19 pandemic on TB services was estimated to be dramatic due to the disruption of TB services. Methods: A retrospective data collection and evaluation was conducted to include all the patients hospitalized for TB at INMI from 9 March to 31 August 2020 (lockdown period and three months thereafter). For the purpose of the study, data from patients hospitalized in the same period of 2019 were also collected. Results: In the period of March–August 2019, 201 patients were hospitalized with a diagnosis of TB, while in the same period of 2020, only 115 patients, with a case reduction of 43%. Patients with weight loss, acute respiratory failure, concurrent extrapulmonary TB, and higher Timika radiographic scores were significantly more frequently hospitalized during 2020 vs. 2019. The median patient delay was 75 days (IQR: 40–100) in 2020 compared to 30 days (IQR: 10–60) in 2019 (p &lt, 0.01). Diagnostic delays in 2020 remain significant in the multiple logistic model (AOR = 6.93, 95%CI: 3.9–12.3). Conclusions: Our experience suggests that COVID-19 pandemic had an impact on TB patient care in terms of higher diagnostic delay, reduction in hospitalization, and a greater severity of clinical presentations.

BACKGROUND: Essential TB care in the European Union/European Economic Area (EU/EEA) comprises 21 standards for the diagnosis, treatment and prevention of TB that constitute the European Union Standards for Tuberculosis Care (ESTC).METHODS: In 2017, we conducted an audit on TB management and infection control measures against the ESTC standards. TB reference centres in five EU/EEA countries were purposely selected to represent the heterogeneous European TB burden and examine geographic variability.RESULTS: Data from 122 patients, diagnosed between 2012 and 2015 with multidrug-resistant TB (n = 49), extensively drug‐resistant TB (XDR‐TB) (n = 11), pre‐XDR‐TB (n = 29) and drug‐susceptible TB (n = 33), showed that TB diagnosis and treatment practices were in general in agreement with the ESTC.CONCLUSION: Overall, TB management and infection control practices were in agreement with the ESTC in the selected EU/EEA reference centres. Areas for improvement include strengthening of integrated care services and further implementation of patient‐centred approaches.

Background Few data about predictors and outcomes associated with prolonged SARS-CoV-2 RNA shedding (VS) are available. Methods Retrospective study including all patients admitted with COVID-19 in an Italian reference hospital for infectious diseases between March 1 and July 1, 2020. Predictors of viral clearance (VC) and prolonged VS from upper respiratory tract were assessed by Poisson regression and logistic regression analyses. The causal relation between duration of VS and probability of clinical outcomes was evaluated through inverse probability weighted Cox model. Results 536 subjects were included. Median duration of VS from symptoms onset was 18 days (IQR 12-26). The estimated 30-day probability of VC was 70.2% (95%CI:65-75). At multivariable analysis, patients with comorbidities (aIRR = 0.88, p = 0.004), lymphopenia at hospital admission (aIRR = 0.75, p = 0.032) and with moderate/severe respiratory disease (aIRR = 0.42, p 1000 ng/mL at admission (aOR = 1.76, p = 0.035) independently predicted prolonged VS. The achievement of VC doubled the chance of clinical recovery (aHR = 2.17, p

(1) Background: Tuberculosis (TB) is one of the world’s top infectious killers, in fact every year 10 million people fall ill with TB and 1.5 million people die from TB. Vitamins have an important role in vital functions, due to their anti-oxidant, pro-oxidant, anti-inflammatory effects and to metabolic functions. The aim of this review is to discuss and summarize the evidence and still open questions regarding vitamin supplementation as a prophylactic measure in those who are at high risk of Mycobacterium tuberculosis (MTB) infection and active TB; (2) Methods: We conducted a search on PubMed, Scopus, Google Scholar, EMBASE, Cochrane Library and WHO websites starting from March 1950 to September 2021, in order to identify articles discussing the role of Vitamins A, B, C, D and E and Tuberculosis; (3) Results: Supplementation with multiple micronutrients (including zinc) rather than vitamin A alone may be more beneficial in TB. The WHO recommend Pyridoxine (vitamin B6) when high-dose isoniazid is administered. High concentrations of vitamin C sterilize drug-susceptible, MDR and extensively drug-resistant MTB cultures and prevent the emergence of drug persisters; Vitamin D suppresses the replication of mycobacterium in vitro while VE showed a promising role in TB management as a result of its connection with oxidative balance; (4) Conclusions: Our review suggests and encourages the use of vitamins in TB patients. In fact, their use may improve outcomes by helping both nutritionally and by interacting directly and/or indirectly with MTB. Several and more comprehensive trials are needed to reinforce these suggestions.

Prophylactic low molecular weight heparin (pLMWH) is currently recommended in COVID-19 to reduce the risk of coagulopathy. The aim of this study was to evaluate whether the antinflammatory effects of pLMWH could translate in lower rate of clinical progression in patients with COVID-19 pneumonia.Patients admitted to a COVID-hospital in Rome with SARS-CoV-2 infection and mild/moderate pneumonia were retrospectively evaluated. The primary endpoint was the time from hospital admission to orotracheal intubation/death (OTI/death). A total of 449 patients were included: 39% female, median age 63 (IQR, 50-77) years. The estimated probability of OTI/death for patients receiving pLMWH was: 9.5% (95%CI 3.2-26.4) by day 20 in those not receiving pLMWH vs. 10.4% (6.7-15.9) in those exposed to pLMWH;p-value=0.144. This risk associated with the use of pLMWH appeared to vary by PaO2/FiO2 ratio: aHR 1.40 (95%CI 0.51-3.79) for patients with an admission PaO2/FiO2 < 300 mmHg and 0.27 (0.03-2.18) for those with PaO2/FiO2 >300 mmHg;p-value at interaction test 0.16. pLMWH does not seem to reduce the risk of OTI/death mild/moderate COVID-19 pneumonia, especially when respiratory function had already significantly deteriorated. Data from clinical trials comparing the effect of prophylactic vs. therapeutic dosage of LMWH at various stages of COVID-19 disease are needed.

Data on characteristics of patients with pulmonary NTM in Italy are lacking. The Italian Registry on pulmonary NTM (IRENE) has been set up in April 2017 as a multicenter, prospective, observational, cohort study enrolling consecutive adults with active NTM pulmonary infection or NTM pulmonary disease (NTM-PD) from 48 centers across Italy. Data are collected at baseline with yearly follow-up visits. 500 patients have been enrolled in the registry so far. Median (IQR) age is 67 (55-75) years, 66% are females, median (IQR) BMI is 20 (18-22), and 45% are current/former smokers. 90% have pre-existing lung diseases, including bronchiectasis (66%), COPD (21%), cystic fibrosis (10%) and asthma (8%), 36% have GERD, and 25% at least one risk factor for immunosuppression. 355 (71%) patients met the 2007 ATS/IDSA criteria for NTM-PD. Among them, the most common NTM are M. avium complex (72%) -including M. intracellulare (28%) and M. avium (27%)-, M. abscessus complex (MABc) (13%) -including M. a.abscessus (10%)-, M. xenopi (4%) and M. kansasii (3%). 77% of the patients have cough, 55% sputum production, 51% fatigue, 47% shortness of breath, 37% weight loss, 27% intermittent fever, 26% haemoptysis, and 22% night sweats. In terms of radiology, 21% of the patients have cavitating nodules, 13% large cavities and 58% consolidations. Median (IQR) FEV1%pred. is 77% (59-94). A total of 77% of patients with NTM-PD underwent treatment, including azithromycin/clarithromycin, ethambutol, rifampicin/rifabutin. IRENE has the important role to inform the clinical and scientific communities on the current management of adults with pulmonary NTM in Italy and acts as a national network to increase disease awareness.

Tuberculosis (TB), due to Mycobacterium tuberculosis infection, is still the principal cause of death caused by a single infectious agent. The balance between the bacillus and host defense mechanisms reflects the different manifestations of the pathology. Factors defining this variety are unclear and likely involve both mycobacterial and immunological components. Myeloid derived suppressor cells (MDSC) have been shown to be expanded during TB, but their role in human TB pathogenesis is not clear. We evaluated the frequency of circulating MDSC by flow-cytometry in 19 patients with active TB, 18 with latent TB infection (LTBI), and 12 healthy donors (HD) as control. Moreover, we investigated the capacity of MDSC to modulate the mycobactericidal activity of monocytes. The association between MDSC level and TB chest X-ray severity score was analyzed. We observed that, unlike active TB, polymorphonuclear (PMN)-MDSC are not expanded in LTBI patients, and, by performing a receiver operating characteristic (ROC) curve analysis, we found that PMN-MDSC frequency supported the discrimination between active disease and LTBI. Interestingly, we observed an association between PMN-MDSC levels and the severity of TB disease evaluated by chest X-ray. Specifically, PMN-MDSC frequency was higher in those classified with a low/mild severity score compared to those classified with a high severity score. Moreover, PMN-MDSC can impact mycobacterial growth by inducing ROS production in Bacillus Calmette et Guerin (BCG)-infected monocytes. This effect was lost when tested with M. tuberculosis (MTB), In conclusion, our data indicate that the elevated frequency of PMN-MDSC in IGRA-positive individuals is associated with active TB. Our findings also pointed out a beneficial role of PMN-MDSC during human active TB, most likely associated with the limitation of inflammation-induced tissue damage.

Tuberculosis (TB) is top infectious disease killer caused by a single organismresponsible for 1.5 million deaths in 2018. Both COVID 19 and the pandemic responseare risking to affect control measures for TB and continuity of essential services forpeople affected by this infection in western countries and even more in developingcountries. Knowledges about concomitant pulmonary TB and COVID-19 are extremelylimited. The double burden of these two diseases can have devastating effects. Herewe describe from both the clinical and the immunological point of view a case of apatient with in vitro immune cell anergy affected by bilateral cavitary pulmonary TB andsubsequent COVID-19-associated pneumonia with a worst outcome. COVID-19 can bea precipitating factor in TB respiratory failure and, during ongoing SARS COV 2 pandemic, clinicians must be aware of this possible coinfection in differential diagnosisof patients with active TB and new or worsening chest imaging

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) pandemic has attracted interest because of its global rapid spread, clinical severity, high mortality rate, and capacity to overwhelm healthcare systems [1, 2]. SARS-CoV-2 transmission occurs mainly through droplets, although surface contamination contributes and debate continues on aerosol transmission [3–5].

Background: Tuberculosis (TB) can seriously affect the hematopoietic system, with involvement of both myeloid and lymphoid cell lines as well as plasma components. These hematological changes act as a marker for the diagnosis, prognosis and response to therapy. Methods: We searched PubMed, Scopus, Google Scholar, EMBASE, Cochrane Library and WHO websites from 1950 to May 2021 for papers on the interaction between TB and common and rare hematological manifestation. Results: Hematological reactions in patients with TB are possible in both young and old women and men but seem more frequent in the elderly, and they can be predictors of both diagnosis and worse outcome for TB, regardless of whether it is pulmonary, extra pulmonary or miliary. Even anti-TB therapies can cause hematological adverse events, among which some are serious and rare and can compromise the patient’s recovery pathway to completing treatment. Conclusion: Hematological screening and follow-up, including complete blood count and coagulation, are always necessary both at the diagnosis of TB and during antitubercular treatment in order to monitor hematological parameters. Short therapy regimens for multidrug-resistant TB (MDR-TB) may also be useful for reducing hematological toxicity, especially in contexts where this cannot be monitored. Close monitoring of drug interactions and hematological adverse events is always recommended.

Objective: To make an informed viewpoint on the usefulness of Tuberculin Skin test (TST) compared to Interferon Gamma Release Assays (IGRAs) for diagnosis of Latent TB Infection (LTBI) in different geographical settings. Methods: We reviewed the current literature on TST compared to IGRA, including national implementation of WHO LTBI recommendations and retrospective data over the past 7 years at the National Institute for Infectious Diseases “L. Spallanzani” as indirect indicator of usage of both tests under actual programmatic conditions. Results: Current national guidelines vary considerably, reflecting the uncertainty and rapidly evolving evidence about the potential use of these tests. Data from Institute “L. Spallanzani” showed IGRA concordance in TST positive subjects only in 54.74% of subjects, while there was strong concordance between two tests in TST negative subjects (93.78%). Conclusion: Neither IGRAs nor TST can distinguish active TB from LTBI. TST will continue to be clinically useful in low and high TB endemic areas until more accurate and predictive tests will become available. Clinical judgment remains fundamental in choosing between IGRA/TST tests and interpreting their results. Keywords: Tuberculin skin test, TST, Interferon-γ release assays, IGRA, Tuberculosis, Quantiferon, TB, Latent TB, LTBI

Background. The growing burden of diabetes mellitus (DM) is posing a threat to global tuberculosis (TB) control. DM triples the risk of developing TB, modifies the presenting features of pulmonary TB, and worsens TB treatment outcomes. We aimed to analyze the prevalence of DM among TB patients and to describe the characteristics and clinical presentation of TB-DM patients in Europe. Methods. We performed a cross-sectional survey on the prevalence of DM among consecutively diagnosed adult TB patients in 11 European TB referral centers located in France, Germany, Greece, Italy, Russia, Slovakia, Spain, and the United Kingdom over the period 2007-2015. We also selected DM-TB cases and TB only controls with a 1:3 ratio to perform a case-control analysis, including patients selected from the countries mentioned above plus Norway and Ukraine. Results. Among 3143 TB enrolled patients, DM prevalence overall was 10.7% and ranged from 4.4% in Greece to 28.5% in the United Kingdom. Patients' median ages ranged from 36 to 49 years, and all centers had >60% males; the proportion of foreign-born patients varied widely across sites. In the case-control study, DM was independently associated with older age and, among older patients, with being foreign-born. Among patients with pulmonary involvement, cavities on chest imaging were more frequently observed among those with DM. Conclusions. Diabetes mellitus represents a challenge for TB control in Europe, especially in foreign-born and in elderly patients. Specific screening strategies should be evaluated., This work was supported in part by Fondi 5x1000 and Ricerca Corrente to National Institute for Infectious Diseases L. Spallanzani – Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS).

Objectives To examine whether specific T-cell-responses to SARS-CoV-2 peptides can be detected in COVID-19 using a whole-blood experimental setting, which may be further explored as potential diagnostic tool. Methods We evaluated IFN-γ levels after stimulating whole-blood with spike and remainder-antigens peptides megapools (MP) derived from SARS-CoV-2 sequences; IL-1β, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17A, eotaxin, basic FGF, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF, RANTES, TNF-α, VEGF were also evaluated. Results IFN-γ-response to spike and remainder-antigens MPs was significantly increased in 35 COVID-19-patients compared to 29 “NO COVID-19”-individuals (medians spike-MP: 0.26 vs 0, p=0.0002; medians remainder-antigens-MP: 0.07 vs 0.02; p=0.02). This response was detected independently of patients’ clinical parameters. IFN-γ-response to SARS-CoV-2-unrelated antigens CMV and SEB was similar in COVID-19 compared to NO-COVID-19-invididuals (median CMV: 3.46 versus 5.28, p=0.16; median SEB: 12.68 versus 15.05; p=0.1). In response to spike-MPs in COVID-19- compared to “NO COVID-19”-individuals, we found significant higher median of IL-2 (50.08 vs 0, p=0.0018), IFN-γ (90.16 vs 0, p=0.01), IL-4 (0.52 vs 0, p=0.03), IL-13 (0.84 vs 0, p=0.007) and MCP-1 (4602 vs 359.2, p=0.05). Conclusions Immune response to SARS-CoV-2 peptides in a whole-blood assay is associated to COVID-19 and it is characterized by both Th1 and Th2 profile. This experimental approach may be useful for developing new T-cell based diagnostic tests for disease and vaccine settings., Graphical abstract Image 1

No large study to date has ever evaluated the effectiveness, safety and tolerability of imipenem/clavulanateversusmeropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to compare the therapeutic contribution of imipenem/clavulanateversusmeropenem/clavulanate added to background regimens to treat MDR- and XDR-TB cases.84 patients treated with imipenem/clavulanate-containing regimens showed a similar median number of antibiotic resistances (8versus8) but more fluoroquinolone resistance (79.0%versus48.9%, pversus49.0%, p=0.01) in comparison with 96 patients exposed to meropenem/clavulanate-containing regimens. Patients were treated with imipenem/clavulanate- and meropenem/clavulanate-containing regimens for a median (interquartile range) of 187 (60–428)versus85 (49–156) days, respectively.Statistically significant differences were observed on sputum smear and culture conversion rates (79.7%versus94.8%, p=0.02 and 71.9%versus94.8%, pversus77.5%, p=0.03). Adverse events to imipenem/clavulanate and meropenem/clavulanate were reported in 5.4% and 6.5% of cases only.Our study suggests that meropenem/clavulanate is more effective than imipenem/clavulanate in treating MDR/XDR-TB patients.

Introduction: In 2010, a clinical audit on tuberculosis (TB) management in the European Union and European Economic Area (EU/EEA) identified important gaps between international standards of care and the management of TB patients, particularly for those with multidrug- or extensively drug resistant tuberculosis (MDR/XDR-TB). The results informed the development of the European Union Standards for TB Care (ESTC). Objective: We conducted a new audit aiming at assessing if TB management, including infection control measures, in EU/EEA clinical care centres was consistent with the ESTC. Methods: TB reference hospitals in five EU/EEA countries were purposely selected. In each hospital a maximum of 40 medical records of consecutive confirmed TB cases, diagnosed between 2012 and 2014, were reviewed. Ethical approval was obtained if required by the local legislation. Results: Data from 122 patients with XDR-TB (n= 11), pre-XDR-TB (n= 29) MDR-TB (n= 49), and drug-susceptible TB (n= 33) showed that TB diagnosis and treatment were according to the ESTC. Treatment outcomes were duly registered and hospitals reached the target for treatment success (75-100%) for patients with drug-resistant TB. All TB patients were offered, and subsequently accepted, HIV testing and counselling. However, antiretroviral treatment was not immediately offered to all TB patients co-infected with HIV. Infection control procedures were properly implemented. Therapeutic drug monitoring and routine genetic typing of TB strains, although not considered a standard in the ESTC, were used in some EU/EEA settings. Conclusions: Overall, selected EU/EEA reference centres reported good adherence to the ESTC.

Rationale: Multidrug-resistant tuberculosis (MDR-TB) is a major burden to public health in Europe. Reported treatment success rates are around 50% or less, and cure rates are even lower.Objectives: To document the management and treatment outcome in patients with MDR-TB in Europe.Methods: We performed a prospective cohort study, analyzing management and treatment outcomes stratified by incidence of patients with MDR-TB in Europe. Treatment outcomes were compared by World Health Organization and alternative simplified definitions by the Tuberculosis Network European Trialsgroup (TBNET).Measurements and Main Results: A total of 380 patients with MDR-TB were recruited and followed up between 2010 and 2014 in 16 European countries. Patients in high-incidence countries compared with low-incidence countries were treated more frequently with standardized regimen (83.2% vs. 9.9%), had delayed treatment initiation (median, 111 vs. 28 d), developed more additional drug resistance (23% vs. 5.8%), and had increased mortality (9.4% vs. 1.9%). Only 20.1% of patients using pyrazinamide had proven susceptibility to the drug. Applying World Health Organization outcome definitions, frequency of cure (38.7% vs. 9.7%) was higher in high-incidence countries. Simplified outcome definitions that include 1 year of follow-up after the end of treatment showed similar frequency of relapse-free cure in low-(58.3%), intermediate-(55.8%), and high-incidence (57.1%) countries, but highest frequency of failure in high-incidence countries (24.1% vs. 14.6%).Conclusions: Conventional standard MDR-TB treatment regimens resulted in a higher frequency of failure compared with individualized treatments. Overall, cure from MDR-TB is substantially more frequent than previously anticipated, and poorly reflected by World Health Organization outcome definitions.

The International Standards for Tuberculosis Care define the essential level of care for managing patients who have or are presumed to have tuberculosis, or are at increased risk of developing the disease. The resources and capacity in the European Union (EU) and the European Economic Area permit higher standards of care to secure quality and timely TB diagnosis, prevention and treatment. On this basis, the European Union Standards for Tuberculosis Care (ESTC) were published in 2012 as standards specifically tailored to the EU setting. Since the publication of the ESTC, new scientific evidence has become available and, therefore, the standards were reviewed and updated.A panel of international experts, led by a writing group from the European Respiratory Society (ERS) and the European Centre for Disease Prevention and Control (ECDC), updated the ESTC on the basis of new published evidence. The underlying principles of these patient-centred standards remain unchanged. The second edition of the ESTC includes 21 standards in the areas of diagnosis, treatment, HIV and comorbidities, and public health and prevention.The ESTC target clinicians and public health workers, provide an easy-to-use resource and act as a guide through all the required activities to ensure optimal diagnosis, treatment and prevention of TB.

Summary There are still no reliable tests to distinguish active tuberculosis (TB) from latent TB infection (LTBI). Assessment of CD27 modulation on CD4 + T-cells has been suggested as a tool to diagnose different TB stages. Objectives To use several cytometric approaches to evaluate CD27 expression on Mycobacterium tuberculosis (Mtb)-specific CD4 + T-cells to differentiate TB stages. Methods 55 HIV-uninfected subjects were enrolled: 13 active TB; 12 cured TB; 30 LTBI. Whole blood was stimulated with RD1-proteins or Cytomegalovirus-lysate (CMV). Interferon (IFN)-γ response was evaluated by cytometry. The proportion of CD27 −/+ within the IFN-γ + CD4 + T-cells or RATIO of the CD27-median fluorescence intensity (MFI) of CD4 + T-cells over the CD27 MFI of IFN-γ + CD4 + T-cells was evaluated. Results The greatest diagnostic accuracy in discriminating active TB vs. LTBI or cured TB was reached by evaluating the CD27 + CD45RA − cells within the IFN-γ + CD4 + T-cell subset (76.92 sensitivity for both, and 90% and 91.67% specificity, respectively), although the use of the CD27 MFI RATIO allows for stricter data analysis, independent of the operator. Conclusions the study of CD27 expression using different approaches, whether it involves evaluation of CD45RA expression or not, is a robust biomarker for discriminating TB stages.

Introduction: Well designed studies on BQ used programmatically to treat M/XDR tuberculosis (TB) are lacking. The aim of this study is to evaluate effectiveness and safety of BQ in a large retrospective, observational study conducted in 25 centres in 15 countries on 5 continents. Methods: Bacteriological conversion rates, treatment outcomes (WHO definitions) and adverse events observed in confirmed MDR-TB BQ-treated patients were analysed. Results: 428 MDR-TB cases (representing 10-100% of all national cases treated from January 2007 to March 2015) were enrolled: median age (IQR): 35 years (27-44); 61.3% males; 22.1% HIV-positive; 45.6% XDR-TB. The median (IQR) number of hospital admission days was 179 (92-280) and exposure to BQ 168 days (86-180). 5 cases received both BQ and delamanid. Treatment regimens included linezolid (82.0% of cases), moxifloxacin (53.7%) and carbapenems (15.7%). Sputum smear (SS) and culture (C) conversion rates were at 30 days 63.6 and 30.1%; at 60 days 81.1 and 56.7%; at 90 days 85.5 and 80.5% and the end of treatment 90.0 and 91.8%, respectively. The time to SS and C conversion was 34 (30-60) and 60 (33-90) days. Out of 246 cases completing treatment, 71.1% achieved success (62.2% cured; 8.9% treatment completed), 13.4% died, 8.1% failed and 7.3% were lost to follow-up. 51/428 (11.2%) cases interrupted BQ for any reason, 23/428 permanently (5.4%; 16/428 -1.4% - because of cardiologic disorders). Conclusions: The results of this study, the largest ever done, indicate that BQ-containing regimens used at the programmatic level achieve satisfactory outcomes and bacteriological conversion rates even with a significant proportion of XDR-TB cases.

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Clarithromycin had a good tolerability and safety profile as assessed in MDR-TB patients receiving prolonged treatment http://ow.ly/r8Jh306Ac0u

HIV-positive patients with MDR-TB demonstrate a very low proportion of relapse-free curehttp://ow.ly/r9sk30bqLBP

Action on social determinants is a main component of the World Health Organization End Tuberculosis (TB) Strategy. The aim of the study was to collect information on socioeconomic characteristics and biomedical risk factors in migrant TB patients in Italy and compare it with data collected among Italian TB patients. A cross-sectional study was conducted among TB patients aged 18 years over a 12-months enrolment period in 12 major Italian hospitals. Information on education, employment, housing and income was collected, and European Union Statistics on Income and Living Conditions index was used to assess material deprivation. Among migrants, we also analyzed factors associated with severe material deprivation. Migrants were compared with younger (18–64 years) and older (65+ years) Italians patients. Out of 755 patients enrolled (with a median age of 42 years, interquartile range: 31–53), 65% were migrants. Pulmonary, microbiologically confirmed, and new cases were 80%, 73%, and 87% respectively. Prevalence of co-morbidities (i.e. diabetes, chronic kidney disease, neoplastic diseases and use of immunosuppressive drugs) was lower among migrants compared to Italian TB patients, while indicators of socioeconomic status, income and housing conditions were worst in migrants. Forty-six percent of migrants were severely deprived vs. 9% of Italians (p

The World Health Organization (WHO) recommends that countries implement pharmacovigilance and collect information on active drug safety monitoring (aDSM) and management of adverse events.The aim of this prospective study was to evaluate the frequency and severity of adverse events to anti-tuberculosis (TB) drugs in a cohort of consecutive TB patients treated with new (i.e. bedaquiline, delamanid) and repurposed (i.e. clofazimine, linezolid) drugs, based on the WHO aDSM project. Adverse events were collected prospectively after attribution to a specific drug together with demographic, bacteriological, radiological and clinical information at diagnosis and during therapy. This interim analysis included patients who completed or were still on treatment at time of data collection.Globally, 45 centres from 26 countries/regions reported 658 patients (68.7% male, 4.4% HIV co-infected) treated as follows: 87.7% with bedaquiline, 18.4% with delamanid (6.1% with both), 81.5% with linezolid and 32.4% with clofazimine. Overall, 504 adverse event episodes were reported: 447 (88.7%) were classified as minor (grade 1–2) and 57 (11.3%) as serious (grade 3–5). The majority of the 57 serious adverse events reported by 55 patients (51 out of 57, 89.5%) ultimately resolved. Among patients reporting serious adverse events, some drugs held responsible were discontinued: bedaquiline in 0.35% (two out of 577), delamanid in 0.8% (one out of 121), linezolid in 1.9% (10 out of 536) and clofazimine in 1.4% (three out of 213) of patients. Serious adverse events were reported in 6.9% (nine out of 131) of patients treated with amikacin, 0.4% (one out of 221) with ethionamide/prothionamide, 2.8% (15 out of 536) with linezolid and 1.8% (eight out of 498) with cycloserine/terizidone.The aDSM study provided valuable information, but implementation needs scaling-up to support patient-centred care.

RationaleTreatment of multi-drug resistant Tuberculosis (MDR-TB) is challenging because it mostly relies on drugs with lower efficacy and greater toxicity than those used for drug-susceptible TB.ObjectivesAim of the study was to describe the frequency and type of adverse drug reactions in a cohort of MDR-TB patients and their potential impact on treatment outcome.MethodsWe conducted a retrospective study in a cohort of MDR-TB patients enrolled at a tertiary referral hospital in Italy from January 2008 to December 2016. The records of patients were reviewed for epidemiological, clinical, microbiological and adverse drug reactions data.ResultsSeventy-four MDR-TB patients (mean age 32 years, 58.1% males, 2 XDR, 12 pre-XDR TB) were extracted from the Institute data base and included in the retrospective study cohort in the evaluation period (January 2008-December 2016). Median length of treatment duration was 20 months (IQR 14-24). Treatment outcome was successful in 57 patients (77%; 51 cured, 6 treatment completed); one patient died and one failed (2.7% overall); 15 patients were lost to follow-up (20.3%). Sixty-six (89.2%) presented adverse drug reactions during the whole treatment period. Total number of adverse drug reactions registered was 409. Three hundred forty-six (84.6%) were classified as adverse events (AEs) and 63 (15.4%) were serious AEs (SAEs). One third of the total adverse drug reactions (134/409; 32.8%) was of gastrointestinal origin, followed by 47/409 (11.5%) ototoxic drug reactions, thirty-five (8.6%) regarded central nervous system and 33 (8.1%) affected the liver. All 63 SAEs required treatment suspension with 61 SAEs out of 63 (96.8%) occurring during the first six months of treatment. Factors associated with unsuccessful treatment outcome were smoking (p = 0.039), alcohol abuse (p = 0.005) and homeless condition (p = 0.044). Neither the number of antitubercular drugs used in different combinations nor the number of AEs showed significant impact on outcome. Patients who completed the treatment experienced a greater number of AEs and SAEs (p < 0.001) if compared to lost to follow-up patients.ConclusionsOur data demonstrate that, despite the high frequency of adverse drug reactions and long term therapy, the clinical management of MDR-TB patients in a referral center could reach successful treatment according to WHO target, by implementing active and systematic clinical and laboratory assessment to detect, report and manage suspected and confirmed adverse drug reactions.

Summary Objectives Controversial results were reported on the role of polyfunctional T-cells in tuberculosis (TB). Our aim was to simultaneously characterize the Mycobacterium tuberculosis (Mtb)-specific immune response as cytokine production and memory phenotype by flow cytometry after in vitro stimulation with region of difference 1 ("RD1") recombinant proteins (ESAT-6 and CFP-10) in patients at different TB stage in a low TB endemic country. To assess the specificity of these findings, we evaluated the response to cytomegalovirus (CMV), an unrelated antigen. Methods We enrolled subjects with active TB, cured TB, latent TB infection (LTBI). Cytokine and phenotype profiles of T-cells from whole blood stimulated with "RD1" proteins and CMV were characterized by multi-parametric flow cytometry. Results Bifunctional IFNγ + TNFα + CD4 + T-cells and effector memory phenotype significantly associated with active TB compared to the LTBI group ( p = 0.008, at least p ≤ 0.009 respectively) whereas "RD1"-T-cell response in cured TB and LTBI was characterized by a central memory phenotype (at least p ≤ 0.013 and p ≤ 0.004 respectively vs active TB). In contrast, response to CMV antigen was not associated with a TB-specific status. Conclusion We identified qualitative associations between Mtb -specific T-cell and TB status in terms of functional capacity and memory status. These immune correlates may be helpful to trace natural history of TB.

Background: Meropenem/clavulanate (MC) has been prescribed to treat MDR/XDR-TB cases, although limited scientific evidence exists. Aim: To retrospectively evaluate the effectiveness, safety, and tolerability of MC added to build an optimal regimen when treating MDR/XDR-TB patients. Methods: An observational, retrospective, cohort study was performed in 5 countries across Europe and South America, where consecutive patients with bacteriologically proven MDR-TB were recruited and divided by MC exposure. Information on demographic, epidemiological, microbiological, and clinical variables were collected from the clinical files using standardized e-forms. Results: A cohort of 264 MDR-TB patients was established: 96 patients were treated with MC-containing regimens and 168 without. Only thirteen (5.2%) were HIV-infected. The proportion of XDR-TB was higher in those exposed to MC-containing regimens (49.0% vs. 6.0%), as was the median (IQR) number of antibiotic resistances (8[6-9] vs 5[4-6]). Sputum smear and culture conversion rates were not statistically different in MDR-TB cases exposed and not exposed to MC-containing regimens, including the XDR-TB subgroup (88.0% vs. 100.0%, P=1.00, and 88.0% vs. 100.0%, P=1.00, respectively). Only 6 MC-related adverse events were reported. In 4 cases, MC was re-started after interruption Conclusion: MC-containing regimens can help achieve sputum culture conversion in MDR/XDR-TB cases with no significant toxicity. This study suggests a potential added value of MC in severe forms of drug-resistant TB when an optimal regimen can not be built with available drugs.

INTRODUCTION: Among the IFN-g release assays (IGRA), QuantiFERON-TB Plus (QFT-Plus) is a new generation of QuantiFERON TB Gold In tube (QFT-IT) which includes an additional antigen tube (TB2). The TB1 tube contains ESAT-6 and CFP-10 derived peptides (TB-7.7, present in QFT-GIT, has been removed), designed to induce a specific response from CD4 + T-cells. The TB2 contains newly designed shorter peptides able to stimulate IFN-g production by both CD4 + and CD8 + T-cells. IGRAs are designed for latent tuberculosis infection (LTBI); however active TB diagnosis is used to compare test accuracy in the absence of a gold-standard test for LTBI. AIM: To evaluate by cytometry the specific response to QFT-Plus by both CD4 + and CD8 + T-cells in patients with active TB and LTBI. RESULTS: we enrolled 19 HIV-uninfected patients, 9 with active TB microbiologically diagnosed, 10 LTBI (defined by positivity to QFT-IT). Among the active TB, in TB1 the proportion of CD4 and CD8 response was 78% and 22% respectively whereas for TB2 the proportion of CD4 and CD8 response was 78% and 100% respectively; among the LTBI in TB1 the proportion of CD4 or CD8 response was 90% and 20% respectively whereas for TB2 the proportion of CD4 or CD8 response was 80% and 30% respectively. Analysing the responses within the TB2, a significantly higher proportion of CD8 responses was found in those with active TB compared to LTBI (p=0.05). CONCLUSIONS: this is the first report in which the analysis of the specific CD4 and CD8 response to QFT-Plus is done by cytometry. The response to the tube called TB2 is specifically associated to a CD8 response and is significantly associated to active TB.

Background: Carbapenems are used to treat MDR/XDR-TB cases in order to build a robust regimen, however limited evidence of their effectiveness exists. Aim: To compare the therapeutic contribution of imipenem and amoxicillin/clavulanate (IC) vs. meropenem and amoxicillin/clavulanate (MC) added to background regimens to treat MDR/XDR-TB cases. Methods: An observational, retrospective, cohort study was performed in 5 centres in Europe and South America, consecutive adult patients with bacteriologically proven MDR-TB were recruited and divided by MC and IC exposure. Demographic, epidemiological, microbiological, and clinical variables were collected using standardized e-forms. Results: A cohort of 180 MDR-TB patients were enrolled: 84 and 96 were treated with IC and MC respectively. Both groups had similar median number of antibiotic resistances (8 vs. 8) but more fluoroquinolone resistance (79.0% vs. 48.9% ; p-value: Conclusion: Our study suggests that MC is safe and more effective than IC in treating M/XDR-TB patients.

Background: MDR-TB is emerging as a major challenge for tuberculosis control programs.In Italy the proportion of MDR-TB reported during 2013 was 3.3%; unfortunately, treatment outcomes in MDR-TB patients are poorly documented. Aim: To evaluate the outcomes of MDR-TB patients treated at the National Institute of Infectious Disease (INMI), a referral hospital for Infectious Diseases in Italy. Methods: 74 MDR-TB patients diagnosed between 2008 and 2015 were consecutively enrolled in an observational retrospective cohort study. All patients were treated according WHO guidelines. Results: The patients (median age 35.8 yr) were mainly male (63.5%) and foreign born (87.2%). Among 74 patients, 2 were extensively drug-resistant (XDR) cases, 2 patients were HIV-coinfected,and 45 (61.0%) were newly diagnosed. Fifty-eight (78.4%) cases were pulmonary sputum smear-positive. 51% of patients were transferred in from units of other regions of central and southern Italy. Among 57 patients who completed treatment in the study period, 68.4 % achieved treatment success, 22.8% were lost to follow up, 3% were transferred out and 1.8% died. Conclusion: Monitoring the treatment outcome of MDR-TB is essential to evaluate the effectiveness of interventions and to identify potential barriers for TB control. In our cohort MDR-TB is mainly related to the immigration of patients from countries with a high TB prevalence with a high proportion of new cases. Data show that, in a referral center for the treatment of MDR-TB, success rates close to the target defined by WHO can be achieved, even if actions are required to reduce the high proportion of patients lost to follow-up.

Treatment of multidrug-resistant tuberculosis (MDR-TB) cases is challenging because it relies on second-line drugs that are less potent and more toxic than those used in the clinical management of drug-susceptible TB. Moreover, treatment outcomes for MDR-TB are generally poor compared to drug sensitive disease, highlighting the need for of new drugs. For the first time in more than 50 years, two new anti-TB drugs were approved and released. Bedaquiline is a first-in-class diarylquinoline compound that showed durable culture conversion at 24 weeks in phase IIb trials. Delamanid is the first drug of the nitroimidazole class to enter clinical practice. Similarly to bedaquiline results of phase IIb studies showed increased sputum-culture conversion at 2 months and better final treatment outcomes in patients with MDR-TB. Among repurposed drugs linezolid and carbapenems may represent a valuable drug to treat cases of MDR and extensively drugresistant TB. The recommended regimen for MDR-TB is the combination of at least four drugs to which M. tuberculosis is likely to be susceptible for the duration of 20 months. Drugs are chosen with a stepwise selection process through five groups on the basis of efficacy, safety, and cost. Clinical phase III trials on new regimen are ongoing that could prove transformative against MDR-TB, by being shorter (six months), simpler (an alloral regimen) and safer than current standard therapy. It is fundamental that the adoption of the new drugs is done responsibly to avoid inappropriate use. Concentration of inpatient MDR-TB treatment in specialized centers could be considered in countries with low numbers of cases in order to provide appropriate clinical case management and to prevent emergence of drug resistance.

In Italy tuberculosis (TB) is largely concentrated in vulnerable groups such as migrants and in urban settings. We analyzed three TB case finding interventions conducted at primary centers and mobile clinics for regular/ irregular immigrants and refugees/asylum seekers performed over a four-year period (November 2009-March 2014) at five different sites in Rome and one site in Milan, Italy. TB history and presence of symptoms suggestive of active TB were investigated by verbal screening through a structured questionnaire in migrants presenting for any medical condition to out-patient and mobile clinics. Individuals reporting TB history or symptoms were referred to a TB clinic for diagnostic workup. Among 6347 migrants enrolled, 891 (14.0%) reported TB history or symptoms suggestive of active TB and 546 (61.3%) were referred to the TB clinic. Of them, 254 (46.5%) did not present for diagnostic evaluation. TB was diagnosed in 11 individuals representing 0.17% of those screened and 3.76% of those evaluated. The overall yield of this intervention was in the range reported for other TB screening programs for migrants, although we recorded an unsatisfactory adherence to diagnostic workup. Possible advantages of this intervention include low cost and reduced burden of medical procedures for the screened population.

SETTING A tuberculosis (TB) referral centre in Rome, Italy. OBJECTIVE To identify demographic and epidemiological characteristics associated with diabetes mellitus (DM) among patients with TB and to compare the clinical presentation of TB and TB-DM in the light of the growing worldwide burden of DM. DESIGN We performed a retrospective study of TB cases diagnosed from 2007 to 2012. RESULTS Among 971 TB patients, 723 were foreign-born and 63 (6.5%) had DM. DM prevalence was 12.7% (8/63) among those born in countries with DM prevalence ⩾8%, 4.7% (31/660) among patients from countries with DM prevalence

Blood-based biomarkers tests are attractive alternative for diagnosing tuberculosis to assays depending on mycobacteria detection. Given several immunological markers we used logistic regression to model the probability of active tuberculosis in a cohort of patients with active or latent tuberculosis, showing an increased accuracy in distinguishing active from latent tuberculosis.

No large study has ever evaluated the efficacy, safety and tolerability of meropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to evaluate the therapeutic contribution, effectiveness, safety and tolerability profile of meropenem/clavulanate added to a background regimen when treating MDR- and XDR-TB cases.Patients treated with a meropenem/clavulanate-containing regimen (n=96) showed a greater drug resistance profile than those exposed to a meropenem/clavulanate-sparing regimen (n=168): in the former group XDR-TB was more frequent (49% versus 6.0%, pversus 5 (4–6)). Patients were treated with a meropenem/clavulanate-containing regimen for a median (IQR) of 85 (49–156) days.No statistically significant differences were observed in the overall MDR-TB cohort and in the subgroups with and without the XDR-TB patients; in particular, sputum smear and culture conversion rates were similar in XDR-TB patients exposed to meropenem/clavulanate-containing regimens (88.0% versus 100.0%, p=1.00 and 88.0% versus 100.0%, p=1.00, respectively). Only six cases reported adverse events attributable to meropenem/clavulanate (four of them then restarting treatment).The nondifferent outcomes and bacteriological conversion rate observed in cases who were more severe than controls might imply that meropenem/clavulanate could be active in treating MDR- and XDR-TB cases.

Simon Tiberi, Giovanni Sotgiu, Lia D’Ambrosio, Rosella Centis, Marcos Abdo Arbex, Edith Alarcon Arrascue, Jan Willem Alffenaar, Jose A. Caminero, Mina Gaga, Gina Gualano, Alena Skrahina, Ivan Solovic, Giorgia Sulis, Marina Tadolini, Valentina Alarcon Guizado, Saverio De Lorenzo, Aurora Jazmin Roby Arias, Anna Scardigli, Onno W. Akkerman, Alena Aleksa, Janina Artsukevich, Vera Avchinko, Eduardo Henrique Bonini, Felix Antonio Chong Marin, Lorena Collahuazo Lopez, Gerard de Vries, Simone Dore, Heinke Kunst, Alberto Matteelli, Charalampos Moschos, Fabrizio Palmieri, Apostolos Papavasileiou, Marie-Christine Payen, Andrea Piana, Antonio Spanevello, Dante Vargas Vasquez, Pietro Viggiani, Veronica White, Alimuddin Zumla and Giovanni Battista Migliori

Evaluation of drug resistances is needed to identify candidates for the shorter regimen in MDR-TB hot spots http://ow.ly/wZV33022VXt

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Objective/Background Interferon (IFN)-γ release assays (IGRA) are designed for diagnosing tuberculosis (TB) infection. The new IGRA, QuantiFERON-TB Plus (QFT-Plus), is based on the enzyme-linked immunosorbent assay detection of IFN-γ after stimulation with Mycobacterium tuberculosis TB1 and TB2 antigens. TB1 elicits a cellular-mediated immune (CMI) response by CD4 T cells, and TB2 contains peptides recognized by both CD4 and CD8 T cells. The aim of the study is to characterize the CMI to QFT-Plus peptides in active TB and latent TB infection (LTBI) at baseline and during or after specific treatment (follow-up). Methods We enrolled 7 individuals with active TB and 11 individuals with LTBI at baseline and followed them during the treatment, either for active diseases or preventive therapy. Peripheral blood mononuclear cells were stimulated with QFT-Plus antigens (TB1, TB2, and mitogen). Cytokine profile (IFN-γ, tumor necrosis factor-α, interleukin-2) and phenotype (CD45RA, CD27) of CD4 and CD8 T cells were characterized by flow cytometry. Results All the individuals responded to mitogen. CD4 T-cell responses to TB1 and TB2 were similar in both individuals with active TB and those with LTBI evaluated over time. Differently, we found a higher number of TB2-associated CD8 T-cell responders in individuals with active TB than in those with LTBI. For individuals with active TB, there was no change in the specific response overtime. Differently, in individuals with LTBI, the number of CD8 responders to QFT-Plus antigens increased during preventive treatment (TB1 = 5/11 [45%], TB2 = 5/11 [45%]) compared with that at the time of enrolment (TB1 = 1/11 [9%], TB2 = 1/11 [9%]). Moreover, we analyzed the effector memory profile of T cells responding to QFT-Plus antigens. The largest component of antigen-specific CD4 T cells (65%) had a central memory (CD45RA−CD27+) phenotype at enrolment and during follow-up. In contrast, specific CD8 T cells, which were analyzed only at follow-up because they were almost absent at baseline, were characterized by a large component with naive (CD45RA+CD27+) phenotype (40%) and a minor component with central memory (25%) features. Conclusion To our knowledge, this is the first report characterizing CD4 and CD8 T-cell responses of individuals with active TB and with LTBI, followed overtime, to QFT-Plus antigens by flow cytometry. The results, although preliminary, may help in identifying better tools for monitoring therapy, especially in those with LTBI undergoing preventive treatment.

BACKGROUND AND OBJECTIVES: Tuberculosis (TB) is a leading cause of death in HIV-infected patients worldwide. We aimed to study clinical characteristics and outcome of 1075 consecutive patients diagnosed with HIV/TB from 2004 to 2006 in Europe and Argentina. METHODS: One-year mortality was assessed in patients stratified according to region of residence, and factors associated with death were evaluated in multivariable Cox models. RESULTS: At TB diagnosis, patients in Eastern Europe had less advanced immunodeficiency, whereas a greater proportion had a history of intravenous drug use, coinfection with hepatitis C, disseminated TB, and infection with drug-resistant TB (P < 0.0001). In Eastern Europe, fewer patients initiated TB treatment containing at least rifamycin, isoniazid, and pyrazinamide or combination antiretroviral therapy (P < 0.0001). Mortality at 1 year was 27% in Eastern Europe, compared with 7, 9 and 11% in Central/Northern Europe, Southern Europe, and Argentina, respectively (P < 0.0001). In a multivariable model, the adjusted relative hazard of death was significantly lower in each of the other regions compared with Eastern Europe: 0.34 (95% confidence interval 0.17-0.65), 0.28 (0.14-0.57), 0.34 (0.15-0.77) in Argentina, Southern Europe and Central/Northern Europe, respectively. Factors significantly associated with increased mortality were CD4 cell count less than 200 cells/μl [2.31 (1.56-3.45)], prior AIDS [1.74 (1.22-2.47)], disseminated TB [2.00 (1.38-2.85)], initiation of TB treatment not including rifamycin, isoniazid and pyrazinamide [1.68 (1.20-2.36)], and rifamycin resistance [2.10 (1.29-3.41)]. Adjusting for these known confounders did not explain the increased mortality seen in Eastern Europe. CONCLUSION: The poor outcome of patients with HIV/TB in Eastern Europe deserves further study and urgent public health attention. © 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Background Five known human coronaviruses infect the human respiratory tract: HCoV-OC43, HCoV-229E, SARS-CoV, HCoV-NL63 and HCoV-HKU1. Objectives To evaluate the prevalence of HCoV-NL63 in hospitalized adult patients and to perform molecular characterization of Italian strains. Study Design HCoV-NL63 was sought by RT-PCR in 510 consecutive lower respiratory tract (LRT) samples, collected from 433 Central-Southern Italy patients over a 1-year period. Phylogenetic analysis was performed by partial sequencing of S and ORF1a. Additional S sequences from Northern Italy were included in the phylogenetic trees. Results HCoV-NL63 was detected in 10 patients (2.0%) with symptomatic respiratory diseases, mainly during winter. Phylogenetic analysis indicated a certain degree of heterogeneity in Italian isolates. The ORF1a gene clustering in phylogenetic trees did not match with that of the S gene. Conclusions As observed by others, HCoV-NL63 is often associated with another virus. Phylogenetic characterization of HCoV-NL63 circulating in Italy indicates that this virus circulates as a mixture of variant strains, as observed in other countries.

Background: There is still not reliable tests to distinguish active tuberculosis (TB) from latent TB infection (LTBI) by an immune diagnostic test. QuantiFERON TB Gold (QFT) is used for LTBI diagnosis; however this test does not distinguish between LTBI and active TB. Recently, cytometric studies from high TB endemic countries showed an association of low CD27 level on circulating Mtb-specific CD4 T-cells with active TB. No studies using a similar approach have been conducted in Europe, nor studies have been performed using whole blood. Aim: To validate in a low TB endemic country as Italy, if the modulation of CD27 in whole blood is a tool to discriminate, among QFT-IT-positive patients, active TB from LTBI. Methods: 107 HIV-uninfected QFT-IT-positive subjects were enrolled: 21 active TB; 20 cured TB; 66 LTBI. Whole blood was stimulated with RD1 proteins. Interferon (IFN)γ response was evaluated by cytometry. The data were presented as RATIO of the Median Fluorescence Intensity (MFI) of CD27 + CD4 + T-cells over the MFI of CD27 + IFNγ + CD4 + T-cells. Results: Active TB patients showed higher RATIO to RD1 antigens compared to LTBI (p=0.0005). We performed a ROC analysis to evaluate the potential of CD27 MFI RATIO for TB diagnostics comparing TB and LTBI. We found a significant area under the curve (AUC) (AUC 0.84; 95% CI, 0.68-0.99, p=0.0004) and a cut-off of 3.19 to predict active TB with 61.54% sensitivity (95% CI, 31.58% to 86.14%) and 96.67% specificity (95% CI, 82.78% to 99.92%). Conclusions: This study proposes a cytometric tool based on the modulation of CD27 + CD4 + IFNγ + T-cells in whole blood that may allow to distinguish TB disease from LTBI in a low TB endemic country.

Background: There is still not reliable tests to distinguish active tuberculosis (TB) from latent TB infection (LTBI) by an immune diagnostic test. QuantiFERON TB Gold (QFT) is used for LTBI diagnosis; however this test does not distinguish between LTBI and active TB. Recently, assays based on the response to antigens of latency as HBHA or Rv2628, or evaluation on RD1-specific T cells by cytometry of the modulation of the effector memory/central memory status has been evaluated. Aim: To evaluate in a low TB endemic country as Italy, the accuracy to discriminate active TB from LTBI using several immune diagnostic tests based on different TB antigens and on the modulation of the T cell effector memory status. Methods: Evaluation of the accuracy to distinguish active TB from LTBI in several cohorts of QFT-IT-positive subjects either HIV-uninfected (107) or HIV-infected subjects (27) with active TB, LTBI or enrolled as cured TB. Whole blood or peripheral blood cells were stimulated with RD1 and latency antigens. Interferon (IFN)-γ response was evaluated by ELISA and mono-polyfunctional cytokine expression (IFN-γ, IL-2, TNF-α) and differentiation markers by cytometry. Results: To predict active TB we used the combination of the different experimental-immune-based approaches by logistic regression followed by ROC analysis (AUC 0.96; 95% CI, 0.87-0.99, p Conclusions: This study proposes that a combination of several experimental approaches may help to distinguish TB disease from LTBI in a low TB endemic country.

Large studies on bedaquiline used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) are lacking. This study aimed to evaluate the safety and effectiveness of bedaquiline-containing regimens in a large, retrospective, observational study conducted in 25 centres and 15 countries in five continents.428 culture-confirmed MDR-TB cases were analysed (61.5% male; 22.1% HIV-positive, 45.6% XDR-TB). MDR-TB cases were admitted to hospital for a median (interquartile range (IQR)) 179 (92–280) days and exposed to bedaquiline for 168 (86–180) days. Treatment regimens included, among others, linezolid, moxifloxacin, clofazimine and carbapenems (82.0%, 58.4%, 52.6% and 15.3% of cases, respectively).Sputum smear and culture conversion rates in MDR-TB cases were 63.6% and 30.1%, respectively at 30 days, 81.1% and 56.7%, respectively at 60 days; 85.5% and 80.5%, respectively at 90 days and 88.7% and 91.2%, respectively at the end of treatment. The median (IQR) time to smear and culture conversion was 34 (30–60) days and 60 (33–90) days. Out of 247 culture-confirmed MDR-TB cases completing treatment, 71.3% achieved success (62.4% cured; 8.9% completed treatment), 13.4% died, 7.3% defaulted and 7.7% failed. Bedaquiline was interrupted due to adverse events in 5.8% of cases. A single case died, having electrocardiographic abnormalities that were probably non-bedaquiline related.Bedaquiline-containing regimens achieved high conversion and success rates under different nonexperimental conditions.

In this article we describe an integrated model for the evaluation and risk management of tuberculosis (TB) infection and active TB in socially disadvantaged populations in the city of Rome. We describe and discuss the clinical evaluation procedures performed and the data collection forms used; these tools are useful for the epidemiologic surveillance and clinical management of patients, particularly high risk patients such as the homeless.