P109 The impact of tb nice guidance on resource capacity and contact screening outcomes: a retrospective, observational study within a central london tb centre

Introduction and objectives: Recently published NICE guidance has significantly expanded the approach to adult tuberculosis (TB) contact screening by recommending tuberculin skin testing (TST) for pulmonary and laryngeal contacts only, increasing the age threshold for screening and treatment to 65 years and defining a positive TST as induration ≥5 mm, regardless of BCG vaccination status. Interferon Gamma Release Assay (IGRA) is recommended only in situations where more evidence of infection is needed. Our institution has previously adopted an approach comprising a chest radiograph, TST and IGRA. The aim of our study was to evaluate the impact of NICE guidance on screening outcomes and resource capacity by applying the criteria to a well-defined historic cohort of TB contacts. Methods: This was a retrospective, observational study carried out at a central London teaching hospital. The study population comprised 593 consecutive, adult TB contacts screened between 1/1/2008 and 31/12/2010. Data was collected through a retrospective review of TST and IGRA tests. Results: Of the 593 contacts screened, 358 pulmonary contacts had TST and IGRA results. 56% had a TST ≥5 mm, regardless of BCG status, qualifying them for treatment as per the new NICE guidance. Of these, 61% were IGRA negative (discordant) and may therefore include false positive diagnoses, resulting in the potential for over treatment. In those with TST 5–14 mm, discordance rises to 84%. Conversely, 6% of those with TST < 5 mm are IGRA positive representing potentially missed cases. 16% of screened individuals were contacts of extra pulmonary TB. Not screening this group would reduce the demand for outpatient appointments by 151* in our cohort. In contrast, testing contacts > 35 years would require capacity for an additional 165* appointments. Furthermore, there were 162 additional LTBI cases in comparison to previous guidance requiring an additional 648* appointments. 72% of this group were IGRA negative. (*Approximate) Conclusions: Our results show the revised guidance will require increased resource capacity largely due to more patients being classified as having latent TB. In addition to workforce planning to meet these demands, further debate is needed to decide if this new approach truly reduces the incidence of active TB or results in unnecessary treatment

Evaluation of serum inflammatory biomarkers as predictors of treatment outcome in pulmonary tuberculosis

Objective: To evaluate C-reactive protein (CRP), globulin and white blood cell (WBC) count as predictors of treatment outcome in pulmonary tuberculosis (PTB).Methods: An observational study of patients with active PTB was conducted at a tertiary centre. All patients had serum CRP, globulin and WBC measured at baseline and at 2 months following commencement of treatment. The outcome of interest was requirement for extension of treatment beyond 6 months.Results: There were 226 patients included in the study. Serum globulin 45 g/l was the only baseline biomarker evaluated that independently predicted requirement for treatment extension (OR 3.42, 95%CI 1.597.32, P 0.001). An elevated globulin level that failed to normalise at 2 months was also associated with increased requirement for treatment extension (63.9% vs. 5.1%, P 0.001), and had a low negative likelihood ratio (0.07) for exclusion of requirement for treatment extension. On multivariable analysis, an elevated globulin that failed to normalise at 2 months was independently associated with requirement for treatment extension (OR 6.13, 95%CI 2.2316.80, P 0.001).Conclusions: Serum globulin independently predicts requirement for treatment extension in PTB and outperforms CRP and WBC as a predictive biomarker. Normalisation of globulin at 2 months following treatment commencement is associated with low risk of requirement for treatment extension.</p

Natural variation in immune responses to neonatal mycobacterium bovis bacillus calmette-guerin (BCG) vaccination in a cohort of Gambian infants

Background There is a need for new vaccines for tuberculosis (TB) that protect against adult pulmonary disease in regions where BCG is not effective. However, BCG could remain integral to TB control programmes because neonatal BCG protects against disseminated forms of childhood TB and many new vaccines rely on BCG to prime immunity or are recombinant strains of BCG. Interferon-gamma (IFN-) is required for immunity to mycobacteria and used as a marker of immunity when new vaccines are tested. Although BCG is widely given to neonates IFN- responses to BCG in this age group are poorly described. Characterisation of IFN- responses to BCG is required for interpretation of vaccine immunogenicity study data where BCG is part of the vaccination strategy. Methodology/Principal Findings 236 healthy Gambian babies were vaccinated with M. bovis BCG at birth. IFN-, interleukin (IL)-5 and IL-13 responses to purified protein derivative (PPD), killed Mycobacterium tuberculosis (KMTB), M. tuberculosis short term culture filtrate (STCF) and M. bovis BCG antigen 85 complex (Ag85) were measured in a whole blood assay two months after vaccination. Cytokine responses varied up to 10 log-fold within this population. The majority of infants (89-98% depending on the antigen) made IFN- responses and there was significant correlation between IFN- responses to the different mycobacterial antigens (Spearman’s coefficient ranged from 0.340 to 0.675, p=10-6-10-22). IL-13 and IL-5 responses were generally low and there were more non-responders (33-75%) for these cytokines. Nonetheless, significant correlations were observed for IL-13 and IL-5 responses to different mycobacterial antigens Conclusions/Significance Cytokine responses to mycobacterial antigens in BCG-vaccinated infants are heterogeneous and there is significant inter-individual variation. Further studies in large populations of infants are required to identify the factors that determine variation in IFN- responses

A novel electrochemical process for the recovery and recycling of ferric chloride from precipitation sludge

During wastewater treatment and drinking water production, significant amounts of ferric sludge (comprising ferric oxy-hydroxides and FePO4) are generated that require disposal. This practice has a major impact on the overall treatment cost as a result of both chemical addition and the disposal of the generated chemical sludge. Iron sulfide (FeS) precipitation via sulfide addition to ferric phosphate (FePO4) sludge has been proven as an effective process for phosphate recovery. In turn, iron and sulfide could potentially be recovered from the FeS sludge, and recycled back to the process. In this work, a novel process was investigated at lab scale for the recovery of soluble iron and sulfide from FeS sludge. Soluble iron is regenerated electrochemically at a graphite anode, while sulfide is recovered at the cathode of the same electrochemical cell. Up to 60±18% soluble Fe and 46±11% sulfide were recovered on graphite granules for up-stream reuse. Peak current densities of 9.5±4.2Am-2 and minimum power requirements of 2.4±0.5kWhkgFe-1 were reached with real full strength FeS suspensions. Multiple consecutive runs of the electrochemical process were performed, leading to the successful demonstration of an integrated process, comprising FeS formation/separation and ferric/sulfide electrochemical regeneration

Neurofibromatosis Type 1: Optimizing Management with a Multidisciplinary Approach

Shaan Lalvani, Rebecca M Brown Department of Neurology, The Mount Sinai Hospital, New York, NY, USACorrespondence: Rebecca M Brown, MD, PhD, The Mount Sinai Hospital, Department of Neurology, 1216 5th Avenue, New York, NY, 10029, USA, Tel +1 2128248579, Email [email protected]: Neurofibromatosis Type I (NF1) is a complex genetic condition that affects multiple organ systems and presents a unique set of challenges for clinicians in its management. NF1 is a tumor predisposition syndrome that primarily affect the peripheral and central nervous systems via the impact of haploinsufficiency upon neural crest lineage cells including Schwann cells, melanocytes, fibroblasts, etc. NF1 can further lead to pathology of the skin, bones, visual system, and cardiovascular system, all of which can drastically reduce a patient’s quality of life (QOL). This review provides a comprehensive examination of the many specialties required for the care of patients with Neurofibromatosis Type 1 (NF1). We delve into the pathogenesis and clinical presentation of NF1, highlighting its diverse manifestations and the challenges they pose in management. The review underscores the importance of a multidisciplinary approach to NF1, emphasizing how such an approach can significantly improve patient outcomes and overall QOL. Central to this approach is the role of the NF expert, who guides a multidisciplinary team (MDT) comprising healthcare professionals from many areas of expertise. The MDT collaboratively addresses the multifaceted needs of NF1 patients, ensuring comprehensive and personalized care. This review highlights the need for further investigation to optimize the workflow for NF1 patients in an MDT setting, and to improve implementation and efficacy.Keywords: multisystemic, multidisciplinary team, quality of life, neurofibromatosis, NF expert, NF1, tumor predisposition syndrom

Progress in interferon-gamma release assay development and applications: an unfolding story of translational research.

The introduction of blood-based tests for M. tuberculosis (Mtb) infection approximately 15 years ago was a turning point for diagnosis of latent tuberculosis (TB). Interferon-gamma release assays (IGRAs), which measure Mtb antigen-specific T cell responses, include the ELISpot-based T-SPOT.TB (Oxford Immunotec, Abingdon, UK) and the ELISA-based QuantiFERON Gold In-Tube (QFT-GIT; Qiagen, Hilden, Germany)

Modulation of the immune response to Mycobacterium tuberculosis during malaria/M. tuberculosis co-infection

Tuberculosis (TB) causes significant morbidity and mortality on a global scale. The African region has 24% of the world's TB cases. TB overlaps with other infectious diseases such as malaria and HIV, which are also highly prevalent in the African region. TB is a leading cause of death among HIV-positive patients and co-infection with HIV and TB has been described as a syndemic. In view of the overlapping epidemiology of these diseases, it is important to understand the dynamics of the immune response to TB in the context of co-infection. We investigated the cytokine response to purified protein derivative (PPD) in peripheral blood mononuclear cells from TB patients co-infected with HIV or malaria and compared it to that of malaria- and HIV-free TB patients. A total of 231 subjects were recruited for this study and classified into six groups; untreated TB-positive, TB positive subjects on TB drugs, TB- and HIV-positive, TB- and malaria-positive, latent TB and apparently healthy control subjects. Our results demonstrate maintenance of interferon (IFN)-γ production in HIV and malaria co-infected TB patients in spite of lower CD4 counts in the HIV-infected cohort. Malaria co-infection caused an increase in the production of the T helper type 2 (Th2)-associated cytokine interleukin (IL)-4 and the anti-inflammatory cytokine IL-10 in PPD-stimulated cultures. These results suggest that malaria co-infection diverts immune response against M. tuberculosis towards a Th-2/anti-inflammatory response which might have important consequences for disease progression

Uloga testova otpuštanja interferona gama u nadzoru nad tuberkulozom

Tuberculosis is still one of the major global public health threats. Countries with low incidence must focus on exhausting the reservoir of future cases by preventing reactivation. Therefore, it is important to identify and effectively treat those individuals who have latent tuberculosis infection and who may develop active disease. The tuberculin skin test has been the standard for detection of immune response against M. tuberculosis since the beginning of the 20th century. The new millennium has brought advancement in the diagnosis of latent tuberculosis infection. The name of the new blood test is interferon-gamma release assay (IGRA). Croatia is a middle-incidence country with a long decreasing trend and developed tuberculosis control. To reach low incidence and finally eliminate tuberculosis, its tuberculosis programme needs a more aggressive approach that would include intensive contact investigation and treatment of persons with latent tuberculosis infection. This article discusses the current uses of IGRA and its role in tuberculosis control.Tuberkuloza je i danas jedan od vodećih javnozdravstvenih problema. Zemlje s niskom incidencijom fokusiraju se na iscrpljivanje rezervoara budućih slučajeva sprječavanjem reaktivacije bolesti. To se odnosi na traženje i učinkovito liječenje infi ciranih osoba, primarno onih koje su u riziku od obolijevanja nakon infekcije. Tuberkulinski test je od početka 20. stoljeća bio standard u otkrivanju imunosnog odgovora na kontakt s Mycobacterium tuberculosis. Novo tisućljeće donijelo je određeni napredak u obliku novih testova za dijagnozu latentne tuberkulozne infekcije, krvne testove otpuštanja interferona gama. Hrvatska je zemlja srednje incidencije tuberkuloze s dugogodišnjim silaznim trendom i razvijenim protutuberkuloznim aktivnostima. U težnji prema niskoj incidenciji i u konačnici eliminaciji tuberkuloze potrebne su opsežnije aktivnosti unutar državnog programa nadzora nad tuberkulozom, uključujući intenzivnu obradu kontakata i probir na postojanje latentne tuberkulozne infekcije. Ovaj rad razmatra trenutačnu uporabu IGRE (engl. interferon - gamma release assay) i njezinu ulogu u nadzoru nad tuberkulozom

Mixed Th1 and Th2 Mycobacterium tuberculosis-specific CD4 T cell responses in patients with active pulmonary tuberculosis from Tanzania.

Mycobacterium tuberculosis (Mtb) and helminth infections elicit antagonistic immune effector functions and are co-endemic in several regions of the world. We therefore hypothesized that helminth infection may influence Mtb-specific T-cell immune responses. We evaluated the cytokine profile of Mtb-specific T cells in 72 individuals with pulmonary TB disease recruited from two Sub-Saharan regions with high and moderate helminth burden i.e. 55 from Tanzania (TZ) and 17 from South Africa (SA), respectively. We showed that Mtb-specific CD4 T-cell functional profile of TB patients from Tanzania are primarily composed of polyfunctional Th1 and Th2 cells, associated with increased expression of Gata-3 and reduced expression of T-bet in memory CD4 T cells. In contrast, the cytokine profile of Mtb-specific CD4 T cells of TB patients from SA was dominated by single IFN-γ and dual IFN-γ/TNF-α and associated with TB-induced systemic inflammation and elevated serum levels of type I IFNs. Of note, the proportion of patients with Mtb-specific CD8 T cells was significantly reduced in Mtb/helminth co-infected patients from TZ. It is likely that the underlying helminth infection and possibly genetic and other unknown environmental factors may have caused the induction of mixed Th1/Th2 Mtb-specific CD4 T cell responses in patients from TZ. Taken together, these results indicate that the generation of Mtb-specific CD4 and CD8 T cell responses may be substantially influenced by environmental factors in vivo. These observations may have major impact in the identification of immune biomarkers of disease status and correlates of protection