Setting up laboratory-based antimicrobial resistance surveillance in low- and middle-income countries: lessons learned from Georgia.

BACKGROUND: Antimicrobial resistance (AMR) is a growing problem worldwide, with an estimated high burden in low- and middle-income countries (LMICs). In these settings, tackling the problem of AMR is often constrained by a lack of reliable surveillance data due to limited use of microbiological diagnostics in clinical practice. OBJECTIVES: The aim of this article is to present an overview of essential elements for setting up an AMR surveillance system in LMICs, to summarize the steps taken to develop such a system in the country of Georgia, and to describe its impact on microbiology laboratories. SOURCES: A literature review of published papers using PubMed and experiences of experts involved in setting up AMR surveillance in Georgia. CONTENT: Basic requirements for implementing a laboratory-based surveillance system in LMICs can be captured under four pillars: (a) governmental support, (b) laboratory capacity and quality management, (c) materials and supplies, and (d) sample collection, data management, analysis and reporting. In Georgia, the World Health Organization Proof-of-Principle project helped to start the collection of AMR surveillance data on a small scale by promoting the use of microbiological diagnostics in clinics, and by providing training and materials for laboratories. Thanks to governmental support and a strong lead by the national reference laboratory, the AMR surveillance network was sustained and expanded after the project ended. IMPLICATIONS: This review describes the Georgian approach in building and expanding a functional AMR surveillance system, considering the elements identified from the literature. The introduction of quality management systems, standardization of guidelines and training paired with targeted capacity building led to improved laboratory standards and management of patients with bloodstream infections. Reliable AMR surveillance data may inform and facilitate policy-making on AMR control. The Georgian experience can guide other countries in the process of building up their national AMR surveillance system.

Effectiveness of 32 versus 20 weeks of prednisolone in leprosy patients with recent nerve function impairment: A randomized controlled trial.

BACKGROUND: While prednisolone is commonly used to treat recent nerve function impairment (NFI) in leprosy patients, the optimal treatment duration has not yet been established. In this "Treatment of Early Neuropathy in Leprosy" (TENLEP) trial, we evaluated whether a 32-week prednisolone course is more effective than a 20-week course in restoring and improving nerve function. METHODS: In this multi-centre, triple-blind, randomized controlled trial, leprosy patients who had recently developed clinical NFI (<6 months) were allocated to a prednisolone treatment regimen of either 20 weeks or 32 weeks. Prednisolone was started at either 45 or 60 mg/day, depending on the patient's body weight, and was then tapered. Throughout follow up, NFI was assessed by voluntary muscle testing and monofilament testing. The primary outcome was the proportion of patients with improved or restored nerve function at week 78. As secondary outcomes, we analysed improvements between baseline and week 78 on the Reaction Severity Scale, the SALSA Scale and the Participation Scale. Serious Adverse Events and the need for additional prednisolone treatment were monitored and reported. RESULTS: We included 868 patients in the study, 429 in the 20-week arm and 439 in the 32-week arm. At 78 weeks, the proportion of patients with improved or restored nerve function did not differ significantly between the groups: 78.1% in the 20-week arm and 77.5% in the 32-week arm (p = 0.821). Nor were there any differences in secondary outcomes, except for a significant higher proportion of Serious Adverse Events in the longer treatment arm. CONCLUSION: In our study, a 20-week course of prednisolone was as effective as a 32-week course in improving and restoring recent clinical NFI in leprosy patients. Twenty weeks is therefore the preferred initial treatment duration for leprosy neuropathy, after which likely only a minority of patients require further individualized treatment.

Early detection of neuropathy in leprosy: a comparison of five tests for field settings.

BACKGROUND: Early detection and treatment of neuropathy in leprosy is important to prevent disabilities. A recent study showed that the Nerve Conduction Studies (NCS) and Warm Detection Thresholds (WDT) tests can detect leprosy neuropathy the earliest. These two tests are not practical under field conditions, however, because they require climate-controlled rooms and highly trained staff and are expensive. We assessed the usefulness of alternative test methods and their sensitivity and specificity to detect neuropathy at an early stage. METHODS: Through a literature search we identified five alternative devices that appeared user-friendly, more affordable, portable and/or battery-operated: the Neuropad®, Vibratip™, NC-Stat®DPNCheck™, NeuroQuick and the Thermal Sensibility Tester (TST), assessing respectively sweat function, vibration sensation, nerve conduction, cold sensation and warm sensation. In leprosy patients in Bangladesh, the posterior tibial and sural nerves that tested normal for the monofilament test and voluntary muscle test were assessed with the NCS and WDT as reference standard tests. The alternative devices were then tested on 94 nerves with abnormal WDT and/or NCS results and on 94 unaffected nerves. Sensitivity and specificity were the main outcomes. RESULTS: The NeuroQuick and the TST showed very good sensitivity and specificity. On the sural nerve, the NeuroQuick had both a sensitivity and a specificity of 86%. The TST had a sensitivity of 83% and a specificity of 82%. Both the NC-Stat®DPNCheck™ and Vibratip™ had a high specificity (88% and 100%), but a low sensitivity (16% and 0%). On the posterior tibial nerve, the NeuroQuick and the TST also showed good sensitivity, but the sensitivity was lower than for the sural nerve. The Neuropad® had a sensitivity of 56% and a specificity of 61%. CONCLUSIONS: The NeuroQuick and TST are good candidates for further field-testing for reliability and reproducibility. The feasibility of production on a larger scale should be examined.

Concerted Efforts to Control or Eliminate Neglected Tropical Diseases: How Much Health Will Be Gained?

BACKGROUND: The London Declaration (2012) was formulated to support and focus the control and elimination of ten neglected tropical diseases (NTDs), with targets for 2020 as formulated by the WHO Roadmap. Five NTDs (lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminths and trachoma) are to be controlled by preventive chemotherapy (PCT), and four (Chagas' disease, human African trypanosomiasis, leprosy and visceral leishmaniasis) by innovative and intensified disease management (IDM). Guinea worm, virtually eradicated, is not considered here. We aim to estimate the global health impact of meeting these targets in terms of averted morbidity, mortality, and disability adjusted life years (DALYs). METHODS: The Global Burden of Disease (GBD) 2010 study provides prevalence and burden estimates for all nine NTDs in 1990 and 2010, by country, age and sex, which were taken as the basis for our calculations. Estimates for other years were obtained by interpolating between 1990 (or the start-year of large-scale control efforts) and 2010, and further extrapolating until 2030, such that the 2020 targets were met. The NTD disease manifestations considered in the GBD study were analyzed as either reversible or irreversible. Health impacts were assessed by comparing the results of achieving the targets with the counterfactual, construed as the health burden had the 1990 (or 2010 if higher) situation continued unabated. PRINCIPLE FINDINGS/CONCLUSIONS: Our calculations show that meeting the targets will lead to about 600 million averted DALYs in the period 2011-2030, nearly equally distributed between PCT and IDM-NTDs, with the health gain amongst PCT-NTDs mostly (96%) due to averted disability and amongst IDM-NTDs largely (95%) from averted mortality. These health gains include about 150 million averted irreversible disease manifestations (e.g. blindness) and 5 million averted deaths. Control of soil-transmitted helminths accounts for one third of all averted DALYs. We conclude that the projected health impact of the London Declaration justifies the required efforts.

Diet-related risk factors for leprosy: a case-control study.

BACKGROUND: Food shortage was associated with leprosy in two recent studies investigating the relation between socioeconomic factors and leprosy. Inadequate intake of nutrients due to food shortage may affect the immune system and influence the progression of infection to clinical leprosy. We aimed to identify possible differences in dietary intake between recently diagnosed leprosy patients and control subjects. METHODS: In a leprosy endemic area of Bangladesh, newly diagnosed leprosy patients and control subjects were interviewed about their socioeconomic situation, health and diet. Dietary intakes were recorded with a 24-hour recall, from which a Dietary Diversity Score (DDS) was calculated. Body Mass Index (BMI) was calculated and Household Food Insecurity Access Scale (HFIAS) was filled out for every participant. Using logistic regression, a univariate, block wise multivariate, and an integrated analysis were carried out. RESULTS: 52 leprosy cases and 100 control subjects were included. Food shortage was more common, dietary diversity was lower and household food insecurity was higher in the patient group. Patients consumed significantly less items from the DDS food groups 'Meat and fish' and 'Other fruits and vegetables.' Lower food expenditure per capita, lower BMI, lower DDS and absence of household food stocks are the main factors associated with an increased risk of having leprosy. CONCLUSION: Low income families have only little money to spend on food and consequently have a low intake of highly nutritious non-rice foods such as meat, fish, milk, eggs, fruits and vegetables. Development of clinical leprosy could be explained by deficiencies of the nutrients that these foods normally provide.

Reliability of clinical nerve function assessment in peripheral neuropathies.

INTRODUCTION: Sensory and/or motor nerve function impairment as a consequence of neuropathy is often assessed using electroneurophysiological tests. However, in low-resource countries where the required equipment is rarely available, manual muscle strength testing (MMST) and monofilament testing (MFT) offer very reliable alternatives. In six leprosy programmes in four Asian countries, a multi-centre randomised clinical trial (RCT) was carried out to assess the effect of corticosteroids on neuropathy in leprosy-affected people. The sensory and motor nerve function was tested using MMST and MFT, including new test sites for the sural and radial cutaneous nerves (MFT) and the posterior tibial and common peroneal nerves (MMST). The reliability studies of the MMST and MFT tests of the TENLEP (Treatment of Early Neuropathy in LEProsy) trials are presented here. METHODS: Two assessors in each centre independently used the MFT and MMST in 30 leprosy-affected people. RESULTS: Reliability is good to very good for MFT in nearly all nerves. MMST also shows good to very good agreement, with a few exceptions. CONCLUSION: Our study confirms that MMST and MFT can be performed reliably, and that the new tests also have acceptable reliability.

Normal threshold values for a monofilament sensory test in sural and radial cutaneous nerves in Indian and Nepali volunteers.

The monofilament test (MFT) is a reliable method to assess sensory nerve function in leprosy and other neuropathies. Assessment of the radial cutaneous and sural nerves, in addition to nerves usually tested, can help improve diagnosis and monitoring of nerve function impairment (NFI). To enable the detection of impairments in leprosy patients, it is essential to know the monofilament threshold of these two nerves in normal subjects. The radial cutaneous, sural, ulnar, median and posterior tibial nerves of 245 volunteers were tested. All nerves were tested at three sites on both left and right sides. Normal monofilament thresholds were calculated per test-site and per nerve. We assessed 490 radial cutaneous and 482 sural nerves. The normal monofilament was 2 g (Filament Index Number (FIN) 4.31) for the radial cutaneous and 4 g (FIN 4.56) for the sural nerve, although heavy manual laborers demonstrated a threshold of 10 g (FIN 5.07) for the sural nerve. For median and ulnar nerves, the 200 mg (FIN 3.61) filament was confirmed as normal while the 4 g (FIN 4.56) filament was normal for the posterior tibial. Age and occupation have an effect on the mean touch sensitivity but do not affect the normal threshold for the radial cutaneous and sural nerves. The normal thresholds for the radial cutaneous and sural nerves are determined as the 2 g (FIN 4.31) and the 4 g (FIN 4.56) filaments, respectively. The addition of the radial cutaneous and sural nerve to sensory nerve assessment may improve the diagnosis of patients with impaired sensory nerve function.

Two randomized controlled clinical trials to study the effectiveness of prednisolone treatment in preventing and restoring clinical nerve function loss in leprosy: the TENLEP study protocols.

BACKGROUND: Nerve damage in leprosy often causes disabilities and deformities. Prednisolone is used to treat nerve function impairment (NFI). However, optimal dose and duration of prednisolone treatment has not been established yet. Besides treating existing NFI it would be desirable to prevent NFI. Studies show that before NFI is clinically detectable, nerves often show subclinical damage. Within the 'Treatment of Early Neuropathy in LEProsy' (TENLEP) study two double blind randomized controlled trials (RCT) will be carried out: a trial to establish whether prednisolone treatment of 32 weeks duration is more effective than 20 weeks in restoring nerve function in leprosy patients with clinical NFI (Clinical trial) and a trial to determine whether prednisolone treatment of early sub-clinical NFI can prevent clinical NFI (Subclinical trial). METHODS: Two RCTs with a follow up of 18 months will be conducted in six centers in Asia. In the Clinical trial leprosy patients with recent (< 6 months) clinical NFI, as determined by Monofilament Test and Voluntary Muscle Test, are included. The primary outcomes are the proportion of patients with restored or improved nerve function. In the Subclinical trial leprosy patients with subclinical neuropathy, as determined by Nerve Conduction Studies (NCS) and/or Warm Detection Threshold (WDT), and without any clinical signs of NFI are randomly allocated to a placebo group or treatment group receiving 20 weeks prednisolone. The primary outcome is the proportion of patients developing clinical NFI. Reliability and normative studies are carried out before the start of the trial. DISCUSSION: This study is the first RCT testing a prednisolone regimen with a duration longer than 24 weeks. Also it is the first RCT assessing the effect of prednisolone in the prevention of clinical NFI in patients with established subclinical neuropathy. The TENLEP study will add to the current understanding of neuropathy due to leprosy and provide insight in the effectiveness of prednisolone on the prevention and recovery of NFI in leprosy patients. In this paper we present the research protocols for both Clinical and Subclinical trials and discuss the possible findings and implications. TRIAL REGISTRATION: Netherlands Trial Register: NTR2300 Clinical Trial Registry India: CTRI/2011/09/002022.