Russell Dacombe

Combination of cytokine responses indicative of latent TB and active TB in Malawian adults.

Background An IFN-γ response to M. tuberculosis-specific antigens is an effective biomarker for M. tuberculosis infection but it cannot discriminate between latent TB infection and active TB disease. Combining a number of cytokine/chemokine responses to M. tuberculosis antigens may enable differentiation of latent TB from active disease. Methods Asymptomatic recently-exposed individuals (spouses of TB patients) were recruited and tuberculin skin tested, bled and followed-up for two years. Culture supernatants, from a six-day culture of diluted whole blood samples stimulated with M. tuberculosis-derived PPD or ESAT-6, were measured for IFN-γ, IL-10, IL-13, IL-17, TNF-α and CXCL10 using cytokine ELISAs. In addition, 15 patients with sputum smear-positive pulmonary TB were recruited and tested. Results Spouses with positive IFN-γ responses to M. tuberculosis ESAT-6 (>62.5 pg/mL) and TB patients showed high production of IL-17, CXCL10 and TNF-α. Higher production of IL-10 and IL-17 in response to ESAT-6 was observed in the spouses compared with TB patients while the ratios of IFN-γ/IL-10 and IFN-γ/IL-17 in response to M. tuberculosis-derived PPD were significantly higher in TB patients compared with the spouses. Tuberculin skin test results did not correlate with cytokine responses. Conclusions CXCL10 and TNF-α may be used as adjunct markers alongside an IFN-γ release assay to diagnose M. tuberculosis infection, and IL-17 and IL-10 production may differentiate individuals with LTBI from active TB.

Resistance to first-line tuberculosis drugs in three cities of Nigeria

Objectives  To determine the levels of resistance to first‐line tuberculosis drugs in three cities in three geopolitical zones in Nigeria.

New Policies, New Technologies : Modelling the Potential for Improved Smear Microscopy Services in Malawi

Background To quantify the likely impact of recent WHO policy recommendations regarding smear microscopy and the introduction of appropriate low-cost fluorescence microscopy on a) case detection and b) laboratory workload. Methodology/Principal Findings An audit of the laboratory register in an urban hospital, Lilongwe, Malawi, and the application of a simple modelling framework. The adoption of the new definition of a smear-positive case could directly increase case detection by up to 28%. Examining Ziehl-Neelsen (ZN) sputum smears for up to 10 minutes before declaring them negative has previously been shown to increase case detection (over and above that gained by the adoption of the new case definition) by 70% compared with examination times in routine practice. Three times the number of staff would be required to adequately examine the current workload of smears using ZN microscopy. Through implementing new policy recommendations and LED-based fluorescence microscopy the current laboratory staff complement could investigate the same number of patients, examining auramine-stained smears to an extent that is equivalent to a 10 minutes ZN smear examination. Conclusions/Significance Combined implementation of the new WHO recommendations on smear microscopy and LED-based fluorescence microscopy could result in substantial increases in smear positive case-detection using existing human resources and minimal additional equipment.

The Impact of a Line Probe Assay Based Diagnostic Algorithm on Time to Treatment Initiation and Treatment Outcomes for Multidrug Resistant TB Patients in Arkhangelsk Region, Russia

Background In the Arkhangelsk region of Northern Russia, multidrug-resistant (MDR) tuberculosis (TB) rates in new cases are amongst the highest in the world. In 2014, MDR-TB rates reached 31.7% among new cases and 56.9% among retreatment cases. The development of new diagnostic tools allows for faster detection of both TB and MDR-TB and should lead to reduced transmission by earlier initiation of anti-TB therapy. Study Aim The PROVE-IT (Policy Relevant Outcomes from Validating Evidence on Impact) Russia study aimed to assess the impact of the implementation of line probe assay (LPA) as part of an LPA-based diagnostic algorithm for patients with presumptive MDR-TB focusing on time to treatment initiation with time from first-care seeking visit to the initiation of MDR-TB treatment rather than diagnostic accuracy as the primary outcome, and to assess treatment outcomes. We hypothesized that the implementation of LPA would result in faster time to treatment initiation and better treatment outcomes. Methods A culture-based diagnostic algorithm used prior to LPA implementation was compared to an LPA-based algorithm that replaced BacTAlert and Löwenstein Jensen (LJ) for drug sensitivity testing. A total of 295 MDR-TB patients were included in the study, 163 diagnosed with the culture-based algorithm, 132 with the LPA-based algorithm. Results Among smear positive patients, the implementation of the LPA-based algorithm was associated with a median decrease in time to MDR-TB treatment initiation of 50 and 66 days compared to the culture-based algorithm (BacTAlert and LJ respectively, p<0.001). In smear negative patients, the LPA-based algorithm was associated with a median decrease in time to MDR-TB treatment initiation of 78 days when compared to the culture-based algorithm (LJ, p<0.001). However, several weeks were still needed for treatment initiation in LPA-based algorithm, 24 days in smear positive, and 62 days in smear negative patients. Overall treatment outcomes were better in LPA-based algorithm compared to culture-based algorithm (p = 0.003). Treatment success rates at 20 months of treatment were higher in patients diagnosed with the LPA-based algorithm (65.2%) as compared to those diagnosed with the culture-based algorithm (44.8%). Mortality was also lower in the LPA-based algorithm group (7.6%) compared to the culture-based algorithm group (15.9%). There was no statistically significant difference in smear and culture conversion rates between the two algorithms. Conclusion The results of the study suggest that the introduction of LPA leads to faster time to MDR diagnosis and earlier treatment initiation as well as better treatment outcomes for patients with MDR-TB. These findings also highlight the need for further improvements within the health system to reduce both patient and diagnostic delays to truly optimize the impact of new, rapid diagnostics.

Married to M.tuberculosis: risk of infection and disease in spouses of smear positive tuberculosis patients

Objectives  To quantify the risk of infection and disease in spouses of tuberculosis patients and the extent to which intervention could reduce the risk in this highly exposed group.

The hidden costs of installing Xpert machines in a tuberculosis high-burden country: experiences from Nigeria.

Introduction Since the endorsement of GeneXpert MTB/RIF by the WHO, many countries have embarked on implementing this technology. Objective: We outline the cost of installing GeneXpert in district hospitals in Abuja, Nigeria. Methods We prospectively documented costs related to the installation of GeneXpert at five sites. Costs were collected from receipts received from suppliers and normalized to USD 2012 values. Results Costs were often identified after initiating installation for many reasons. Installation varied widely between sites with sufficient space and power supply; sites with insufficient space or power supply and costs not directly associated with site installation. The basic cost for installation was USD 2,621.98 per machine. Sites that required additional space cost close to USD 7,000.00. Conclusion Space and power requirements have a significant effect on installation costs. Countries need to carefully consider the placement of Xpert machines based on the quality and size of the available infrastructure.

Developments in Impact Assessment of New Diagnostic Algorithms for Tuberculosis Control

A modified presentation of the impact assessment framework is proposed that improves accessibility while continuing to provide a checklist of the evidence needed to support policy decisions on the implementation of new tools for the diagnosis of tuberculosis.

Infectious disease burden in Gujarat (2005–2011): comparison of selected infectious disease rates with India

Background India is known to be endemic to numerous infectious diseases. The infectious disease profile of India is changing due to increased human environmental interactions, urbanisation and climate change. There are also predictions of explosive growth in infectious and zoonotic diseases. The Integrated Disease Surveillance Project (IDSP) was implemented in Gujarat in 2004. Methods We analysed IDSP data on seven laboratory confirmed infectious diseases from 2005–2011 on temporal and spatial trends and compared this to the National Health Profile (NHP) data for the same period and with other literature. We chose laboratory cases data for Enteric fever, Cholera, Hepatitis, Dengue, Chikungunya, Measles and Diphtheria in the state since well designed vertical programs do not exist for these diseases. Statistical and GIS analysis was done using appropriate software. Results Our analysis shows that the existing surveillance system in the state is predominantly reporting urban cases. There are wide variations among reported cases within the state with reports of Enteric fever and Measles being less than half of the national average, while Cholera, Viral Hepatitis and Dengue being nearly double. Conclusions We found some limitations in the IDSP system with regard to the number of reporting units and cases in the background of a mixed health system with multiplicity of treatment providers and payment mechanisms. Despite these limitations, IDSP can be strengthened into a comprehensive surveillance system capable of tackling the challenge of reversing the endemicity of these diseases and preventing the emergence of others.

FluoroType MTB system for the detection of pulmonary tuberculosis

Diagnosis continues to be a major barrier for the control of tuberculosis (TB), especially in low- and middle-income countries (LMIC) [1]. The number of platforms for the molecular diagnosis of TB have increased in recent years and they can provide test results more rapidly than culture. Molecular assays are increasingly being used as alternative or adjunct methods to culture and smear microscopy, and modern systems seek to partially or fully automate the DNA extraction and amplification steps, increasing their suitability for resource-limited laboratories. One of these platforms, the GeneXpert MTB/RIF (Cepheid, USA), has a sensitivity of roughly 85% compared to culture [2] and has seen significant uptake in developing countries [3]. However, as a fully closed system, the DNA extracted during the process cannot be used for further downstream drug susceptibility testing (DST), which is crucial for patients with suspected drug-resistant TB. FluoroType MTB is a sensitive test for TB but specificity is low compared with fully integrated molecular systems http://ow.ly/WhEO30b1luY

Testing Pooled Sputum with Xpert MTB/RIF for Diagnosis of Pulmonary Tuberculosis To Increase Affordability in Low-Income Countries

ABSTRACT Tuberculosis (TB) is a global public health problem, with the highest burden occurring in low-income countries. In these countries, the use of more sensitive diagnostics, such as Xpert MTB/RIF (Xpert), is still limited by costs. A cost-saving strategy to diagnose other diseases is to pool samples from various individuals and test them with single tests. The samples in positive pool samples are then retested individually to identify the patients with the disease. We assessed a pooled testing strategy to optimize the affordability of Xpert for the diagnosis of TB. Adults with presumptive TB attending hospitals or identified by canvassing of households in Abuja, Nigeria, were asked to provide sputum for individual and pooled (4 per pool) testing. The agreement of the results of testing of individual and pooled samples and costs were assessed. A total of 738 individuals submitted samples, with 115 (16%) being Mycobacterium tuberculosis positive. Valid Xpert results for individual and pooled samples were available for 718 specimens. Of these, testing of pooled samples detected 109 (96%) of 114 individual M. tuberculosis-positive samples, with the overall agreement being 99%. Xpert semiquantitative M. tuberculosis levels had a positive correlation with the smear grades, and the individual sample-positive/pooled sample-negative results were likely due to the M. tuberculosis concentration being below the detection limit. The strategy reduced cartridge costs by 31%. Savings were higher with samples from individuals recruited in the community, where the proportion of positive specimens was low. The results of testing of pooled samples had a high level of agreement with the results of testing of individual samples, and use of the pooled testing strategy reduced costs and has the potential to increase the affordability of Xpert in countries with limited resources.