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1.  Clinical and Pharmacogenomic Implications of Genetic Variation in a Southern Ethiopian Population 
The pharmacogenomics journal  2014;15(1):101-108.
Africa is home to genetically diverse human populations. We compared the genetic structure of the Wolaita ethnic population from southern Ethiopia (WETH, n=120) with HapMap populations using genome-wide variants. We investigated allele frequencies of 443 clinically and pharmacogenomically relevant genetic variants in WETH compared to HapMap populations. We found that WETH were genetically most similar to the Kenya Maasai and least similar to the Japanese in HapMap. Variant alleles associated with increased risk of adverse reactions to drugs used for treating tuberculosis (rs1799929 and rs1495741 in NAT2), thromboembolism (rs7294, rs9923231 and rs9934438 in VKORC1), and HIV/AIDS and solid tumors (rs2242046 in SLC28A1) had significantly higher frequencies in WETH compared to African ancestry HapMap populations. Our results illustrate that clinically relevant pharmacogenomic loci display allele frequency differences among African populations. We conclude that drug dosage guidelines for important global health diseases should be validated in genetically diverse African populations.
doi:10.1038/tpj.2014.39
PMCID: PMC4277706  PMID: 25069476
pharmacogenomics; global health; tuberculosis; HIV/AIDS; warfarin; Ethiopia
2.  Mapping and Modelling the Geographical Distribution and Environmental Limits of Podoconiosis in Ethiopia 
PLoS Neglected Tropical Diseases  2015;9(7):e0003946.
Background
Ethiopia is assumed to have the highest burden of podoconiosis globally, but the geographical distribution and environmental limits and correlates are yet to be fully investigated. In this paper we use data from a nationwide survey to address these issues.
Methodology
Our analyses are based on data arising from the integrated mapping of podoconiosis and lymphatic filariasis (LF) conducted in 2013, supplemented by data from an earlier mapping of LF in western Ethiopia in 2008–2010. The integrated mapping used woreda (district) health offices’ reports of podoconiosis and LF to guide selection of survey sites. A suite of environmental and climatic data and boosted regression tree (BRT) modelling was used to investigate environmental limits and predict the probability of podoconiosis occurrence.
Principal Findings
Data were available for 141,238 individuals from 1,442 communities in 775 districts from all nine regional states and two city administrations of Ethiopia. In 41.9% of surveyed districts no cases of podoconiosis were identified, with all districts in Affar, Dire Dawa, Somali and Gambella regional states lacking the disease. The disease was most common, with lymphoedema positivity rate exceeding 5%, in the central highlands of Ethiopia, in Amhara, Oromia and Southern Nations, Nationalities and Peoples regional states. BRT modelling indicated that the probability of podoconiosis occurrence increased with increasing altitude, precipitation and silt fraction of soil and decreased with population density and clay content. Based on the BRT model, we estimate that in 2010, 34.9 (95% confidence interval [CI]: 20.2–51.7) million people (i.e. 43.8%; 95% CI: 25.3–64.8% of Ethiopia’s national population) lived in areas environmentally suitable for the occurrence of podoconiosis.
Conclusions
Podoconiosis is more widespread in Ethiopia than previously estimated, but occurs in distinct geographical regions that are tied to identifiable environmental factors. The resultant maps can be used to guide programme planning and implementation and estimate disease burden in Ethiopia. This work provides a framework with which the geographical limits of podoconiosis could be delineated at a continental scale.
Author Summary
Podoconiosis is a neglected tropical disease that results in swelling of the lower legs and feet. It is common among barefoot individuals with prolonged contact with irritant soils of volcanic origin. The disease causes significant social and economic burden. The disease can be prevented by consistent shoe wearing and regular foot hygiene. A pre-requisite for implementation of prevention and morbidity management is information on where the disease is endemic and the identification of priority areas. We undertook nationwide mapping of podoconiosis in Ethiopia covering 1442 communities in 775 districts all over Ethiopia. During the survey, individuals underwent a rapid-format antigen test for diagnosis of lymphatic filariasis and clinical history and physical examination for podoconiosis. A suite of environmental and climatic data and a method called boosted regression tree modelling was used to predict the occurrence of podoconiosis. Our survey results indicated that podoconiosis is more widespread in Ethiopia than previously estimated. The modelling indicated that the probability of podoconiosis occurrence increased with increasing altitude, precipitation and silt fraction of soil and decreased with more clay content and population density. The map showed that in 2010, 34.9 million people lived in areas environmentally suitable for the occurrence of podoconiosis in Ethiopia.
doi:10.1371/journal.pntd.0003946
PMCID: PMC4519246  PMID: 26222887
3.  Low Dietary Diversity and Intake of Animal Source Foods among School Aged Children in Libo Kemkem and Fogera Districts, Ethiopia 
PLoS ONE  2015;10(7):e0133435.
Background
A low dietary diversity score (DDS) and low consumption of food from animal sources (ASF) are among the factors related to malnutrition in school-aged children living in Libo Kemkem and Fogera (Ethiopia).
Objectives
This study aimed to identify associated determinants for low dietary diversity and lack of consumption of ASF.
Methods
In 2009, a cross-sectional survey was carried out in May, at the end of the lean season. Socio-demographic characteristics and diet habits were collected from 886 school-aged children. Additionally, 516 children from rural sites were followed up in the post-harvest season, in December of the same year. Bivariate and multivariable statistical methods were employed to assess low DDS and ASF intake and their association with different factors.
Results
Up to 80% and 60% of school-aged children living in rural and urban sites, respectively, ate ≤ 3 food groups the day before the survey. The percentage of children consuming ASF was significantly higher in urban settings (64% vs 18%). In the rural areas, if the head of the household was male (OR: 1.91; 95%CI: 1.00-3.65) and older than 40 years (OR: 1.56; 95%CI: 1.02-2.38) the child had a lower DDS in the lean season, while differences by socioeconomic indexes were observed in the post-harvest season. Males took more ASF than females in rural settings (OR: 1.73; 95%CI: 1.14-2.62) and differences by socioeconomic indexes were observed in both settings in the lean season, though not in post-harvest survey.
Conclusions
The findings of this study revealed that the diet among school-aged children in Libo Kemkem and Fogera districts lacked diversity, and that the intake of foods from animal sources was low, especially among rural girls. To effectively tackle malnutrition, dietary diversification strategies oriented to the local needs are recommended.
doi:10.1371/journal.pone.0133435
PMCID: PMC4512702  PMID: 26203904
4.  Eco-epidemiology of visceral leishmaniasis in Ethiopia 
Parasites & Vectors  2015;8:381.
Visceral leishmaniasis (VL, Kala-azar) is one of the growing public health challenges in Ethiopia with over 3.2 million people at risk and estimated up to 4000 new cases per year. Historically, VL was known as the diseases of the lowlanders; in the lower and upper Kola agro-ecological zones of Ethiopia. The 2005–07 out breaks in highlands of Libo Kemkem and Fogera, in the Woina Degas, that affected thousands and claimed the life of hundreds misdiagnosed as drug resistance malaria marked that VL is no more the problem of the lowlanders. The Kola (lower and upper) and the Woina Dega are the most productive agroecological zones, supporting both the ongoing and planned expansions of large or small scale agriculture and/or agriculture based industries. Thus, the (re)emergence of VL is not only a public health and social problem but also have a direct implication on the country’s economy and further development. Thus is high time for its control and/or elimination. Yet, the available data seem incomplete to plan for a cost-effective and efficient VL control strategy: there is a need to update data on vector behaviour in specific ecosystems and the roles of domestic animals need to be ascertained. The effectiveness and social acceptability of available vector control tools need be evaluated. There is a need for identifying animal reservoir(s), or establish the absence of zoonosis in Ethiopia. The planning of prevention of (re)emergence and spread of VL to areas adjacent to endemic foci need be supported with information from spatio-temporal mapping. In affected communities, available data showed that their knowledge about VL is generally very low. Thus, well designed studies to identify risk factors, as well as better tools for social mobilization with the understanding of their knowledge, aptitude and practice towards VL are necessary.
doi:10.1186/s13071-015-0987-y
PMCID: PMC4506599  PMID: 26187584
5.  Identification of large variation in pfcrt, pfmdr-1 and pfubp-1 markers in Plasmodium falciparum isolates from Ethiopia and Tanzania 
Malaria Journal  2015;14:264.
Background
Plasmodium falciparum resistance to anti-malarials is a major drawback in effective malaria control and elimination globally. Artemisinin-combination therapy (ACT) is currently the key first-line treatment for uncomplicated falciparum malaria. Plasmodium falciparum genetic signatures at pfmdr-1, pfcrt, and pfubp-1 loci are known to modulate in vivo and in vitro parasite response to ACT. The objective of this study was to assess the distribution of these resistance gene markers in isolates collected from different malaria transmission intensity in Ethiopia and Tanzania.
Methods
Plasmodium falciparum clinical isolates were collected from different regions of Ethiopia and Tanzania. Genetic polymorphisms in the genes pfcrt, pfmdr-1 and pfubp-1 were analysed by PCR and sequencing. Frequencies of the different alleles in the three genes were compared within and between regions, and between the two countries.
Results
The majority of the isolates from Ethiopia were mutant for the pfcrt 76 and wild-type for pfmdr-1 86. In contrast, the majority of the Tanzanian samples were wild-type for both pfcrt and pfmdr-1 loci. Analysis of a variable linker region in pfmdr-1 showed substantial variation in isolates from Tanzania as compared to Ethiopian isolates that had minimal variation. Direct sequencing of the pfubp-1 region showed that 92.8% (26/28) of the Ethiopian isolates had identical genome sequence with the wild type reference P. falciparum strain 3D7. Of 42 isolates from Tanzania, only 13 (30.9%) had identical genome sequences with 3D7. In the Tanzanian samples, 10 variant haplotypes were identified.
Conclusion
The majority of Ethiopian isolates carried the main marker for chloroquine (CQ) resistance, while the majority of the samples from Tanzania carried markers for CQ susceptibility. Polymorphic genes showed substantially more variation in Tanzanian isolates. The low variability in the polymorphic region of pfmdr-1 in Ethiopia may be a consequence of low transmission intensity as compared to high transmission intensity and large variations in Tanzania.
doi:10.1186/s12936-015-0783-3
PMCID: PMC4495614  PMID: 26152336
Malaria; Plasmodium falciparum; pfcrt; pfmdr-1; pfubp-1; Ethiopia; Tanzania
6.  Prevalence and drug resistance profile of Mycobacterium tuberculosis isolated from pulmonary tuberculosis patients attending two public hospitals in East Gojjam zone, northwest Ethiopia 
BMC Public Health  2015;15:572.
Background
The spread of multidrug-resistant tuberculosis (MDR-TB) strains has become a challenge to the global TB control and prevention program. In Ethiopia, particularly in rural areas, information on drug-resistant TB is very limited. In this study, we determined the drug resistance patterns of Mycobacterium tuberculosis (M. tuberculosis) isolates from pulmonary TB patients attending two public hospitals in the East Gojjam zone of northwest Ethiopia.
Methods
A cross-sectional study was conducted between May 2011 and January 2012 using Region of difference-9 (RD9) typing for the identification of species mycobacterium. Drug susceptibility testing (DST) of M. tuberculosis isolates to the first-line drugs: isoniazid, rifampicin, ethambutol and streptomycin was performed by the indirect proportion method on Middle brook 7H10 Agar media.
Results
Out of 385 pulmonary TB suspects studied, 124 (32.2 %) were culture positive among which 120 were M. tuberculosis strains. Susceptibility testing was performed for 89 isolates. Resistance to at least one drug was 15.58 % ([12/77], 95 % CI: 7.48-23.68) among newly diagnosed and 50.0 % ([6/12], 95 % CI: 21.71-78.29) among previously treated cases. Resistance among newly diagnosed patients was most common for streptomycin 5.19 % (4/77) and ethambutol 5.19 % (4/77) followed by rifampicin 3.89 % (3/77). Among retreatment cases, isoniazid resistance was most frequent in which 33.33 % (4/12) of the isolates were resistant. MDR prevalence was 1.29 % (1/77) for newly diagnosed and 16.67 % (2/12) for retreatment cases. In a multivariate logistic regression analysis, age group of 25–34 years (adjusted OR = 4.24; 95 % CI: 1.02-17.5; P = 0.046) and previous history of treatment (adjusted OR = 5.42; 95 % CI: 1.56-27.49; P = 0.01) were independently associated with anti-TB drug resistance.
Conclusions
In general, the magnitude of anti-TB drug resistance including MDR-TB was comparable to previous studies in other areas of Ethiopia. However, rifampicin resistance was high, which could suggest the potential for a rise in the incidence of MDR. Therefore, re-enforcing TB control programs should be considered by the concerned public health authorities.
doi:10.1186/s12889-015-1933-9
PMCID: PMC4473837  PMID: 26092570
Mycobacterium tuberculosis; Drug resistance; MDR-TB; Ethiopia
7.  Admixture mapping of tuberculosis and pigmentation-related traits in an African–European hybrid cattle population 
Frontiers in Genetics  2015;6:210.
Admixture mapping affords a powerful approach to genetic mapping of complex traits and may be particularly suited to investigation in cattle where many breeds and populations are hybrids of the two divergent ancestral genomes, derived from Bos taurus and Bos indicus. Here we design a minimal genome wide SNP panel for tracking ancestry in recent hybrids of Holstein–Friesian and local Arsi zebu in a field sample from a region of high bovine tuberculosis (BTB) endemicity in the central Ethiopian highlands. We first demonstrate the utility of this approach by mapping the red coat color phenotype, uncovering a highly significant peak over the MC1R gene and a second peak with no previously known candidate gene. Secondly, we exploit the described differential susceptibility to BTB between the ancestral strains to identify a region in which Bos taurus ancestry associates, at suggestive significance, with skin test positivity. Interestingly, this association peak contains the toll-like receptor gene cluster on chromosome 6. With this work we have shown the potential of admixture mapping in hybrid domestic animals with divergent ancestral genomes, a recurring condition in domesticated species.
doi:10.3389/fgene.2015.00210
PMCID: PMC4467177  PMID: 26124773
Bos taurus; Bos indicus; SNPs; admixture mapping; Mycobacterium bovis
8.  Prevalence of Tuberculosis, Drug Susceptibility Testing, and Genotyping of Mycobacterial Isolates from Pulmonary Tuberculosis Patients in Dessie, Ethiopia 
Due to their initially seemingly high cost, timely diagnosis and effective treatment of tuberculosis (TB) are usually hampered by lack or shortage of resources in many high TB burden countries. However, the benefits of effective treatment can eventually outweigh those of empirical treatment. Here, a cross-sectional study was conducted on samples from smear-positive new and retreatment TB patients. Data on sociodemographic and HIV status were collected. Samples were cultured for identification, conventional drug sensitivity testing, and molecular typing by deletion typing and spoligotyping. The results showed the youth were disproportionately affected. New cases were being treated following general treatment guidelines only. Monoresistance or multiple drug resistance was found in 16.5% of new patients. Spoligotyping showed that there were 44 patterns with families H3 and T1 (lineage 4) and CAS-Delhi (lineage 3) being dominant. Some rare patterns from lineage 7 were also found. Spoligotype pattern, HIV positivity, and previous treatment were not associated with drug resistance. That the vast majority of the patients were new cases and young and the large number of these patients with mono- or multiple drug resistance indicate that most TB cases are due to recent transmissions and that urgent actions are needed to curb the transmissions.
doi:10.1155/2015/215015
PMCID: PMC4477223  PMID: 26180642
9.  Polymorphisms in chloroquine resistance-associated genes in Plasmodium vivax in Ethiopia 
Malaria Journal  2015;14:164.
Background
Evidence for decreasing chloroquine (CQ) efficacy against Plasmodium vivax has been reported from many endemic countries in the world. In Ethiopia, P. vivax accounts for 40% of all malaria cases and CQ is the first-line drug for vivax malaria. Mutations in multidrug resistance 1 (pvmdr-1) and K10 insertion in the pvcrt-o genes have been identified as possible molecular markers of CQ-resistance (CQR) in P. vivax. Despite reports of CQ treatment failures, no data are currently available on the prevalence of molecular markers of P. vivax resistance in Ethiopia. The objective of this study was to determine the prevalence of mutations in the pvmdr-1 and K10 insertion in the pvcrt-o genes.
Methods
A total of 36 P. vivax clinical isolates were collected from West Arsi district in Ethiopia. Sequencing was used to analyse polymorphisms of the pvcrt-o and pvmdr-1 genes.
Results
Sequencing results of the pvmdr-1 fragment showed the presence of two non-synonymous mutations at positions 976 and 1076. The Y → F change at codon 976 (TAC → TTC) was observed in 21 (75%) of 28 the isolates while the F → L change (at codon 1076), which was due to a single mutation (TTT → CTT), was observed in 100% of the isolates. Of 33 samples successfully amplified for the pvcrt-o, the majority of the isolates (93.9%) were wild type, without K10 insertion.
Conclusions
High prevalence of mutations in candidate genes conferring CQR in P. vivax was identified. The fact that CQ is still the first-line treatment for vivax malaria, the significance of mutations in the pvcrt-o and pvmdr-1 genes and the clinical response of the patients’ to CQ treatment and whether thus an association exists between point mutations of the candidate genes and CQR requires further research in Ethiopia.
doi:10.1186/s12936-015-0625-3
PMCID: PMC4404130  PMID: 25889237
Chloroquine resistance; Mutations; Plasmodium vivax; Pvcrt-o; Pvmdr-1
10.  Investigation of the high rates of extrapulmonary tuberculosis in Ethiopia reveals no single driving factor and minimal evidence for zoonotic transmission of Mycobacterium bovis infection 
BMC Infectious Diseases  2015;15:112.
Background
Ethiopia, a high tuberculosis (TB) burden country, reports one of the highest incidence rates of extra-pulmonary TB dominated by cervical lymphadenitis (TBLN). Infection with Mycobacterium bovis has previously been excluded as the main reason for the high rate of extrapulmonary TB in Ethiopia.
Methods
Here we examined demographic and clinical characteristics of 953 pulmonary (PTB) and 1198 TBLN patients visiting 11 health facilities in distinct geographic areas of Ethiopia. Clinical characteristics were also correlated with genotypes of the causative agent, Mycobacterium tuberculosis.
Results
No major patient or bacterial strain factor could be identified as being responsible for the high rate of TBLN, and there was no association with HIV infection. However, analysis of the demographic data of involved patients showed that having regular and direct contact with live animals was more associated with TBLN than with PTB, although no M. bovis was isolated from patients with TBLN. Among PTB patients, those infected with Lineage 4 reported “contact with other TB patient” more often than patients infected with Lineage 3 did (OR = 1.6, CI 95% 1.0-2.7; p = 0.064). High fever, in contrast to low and moderate fever, was significantly associated with Lineage 4 (OR = 2.3; p = 0.024). On the other hand, TBLN cases infected with Lineage 4 tended to get milder symptoms overall for the constitutional symptoms than those infected with Lineage 3.
Conclusions
The study suggests a complex role for multiple interacting factors in the epidemiology of extrapulmonary TB in Ethiopia, including factors that can only be derived from population-based studies, which may prove to be significant for TB control in Ethiopia.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-0846-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12879-015-0846-7
PMCID: PMC4359574  PMID: 25886866
Mycobacterium; Tuberculosis; Bovis; Pulmonary; Extrapulmonary; Lymphadenitis; Zoonotic; Ethiopia
11.  Mycobacterium tuberculosis Lineage 7 Strains Are Associated with Prolonged Patient Delay in Seeking Treatment for Pulmonary Tuberculosis in Amhara Region, Ethiopia 
Journal of Clinical Microbiology  2015;53(4):1301-1309.
Recent genotyping studies of Mycobacterium tuberculosis in Ethiopia have reported the identification of a new phylogenetically distinct M. tuberculosis lineage, lineage 7. We therefore investigated the genetic diversity and association of specific M. tuberculosis lineages with sociodemographic and clinical parameters among pulmonary TB patients in the Amhara Region, Ethiopia. DNA was isolated from M. tuberculosis-positive sputum specimens (n = 240) and analyzed by PCR and 24-locus mycobacterial interspersed repetitive unit–variable-number tandem-repeat (MIRU-VNTR) analysis and spoligotyping. Bioinformatic analysis assigned the M. tuberculosis genotypes to global lineages, and associations between patient characteristics and genotype were evaluated using logistic regression analysis. The study revealed a high diversity of modern and premodern M. tuberculosis lineages, among which approximately 25% were not previously reported. Among the M. tuberculosis strains (n = 138) assigned to seven subgroups, the largest cluster belonged to the lineage Central Asian (CAS) (n = 60; 26.0%), the second largest to lineage 7 (n = 36; 15.6%), and the third largest to the lineage Haarlem (n = 35; 15.2%). Four sublineages were new in the MIRU-VNTRplus database, designated NW-ETH3, NW-ETH1, NW-ETH2, and NW-ETH4, which included 24 (10.4%), 18 (7.8%), 8 (3.5%), and 5 (2.2%) isolates, respectively. Notably, patient delay in seeking treatment was significantly longer among patients infected with lineage 7 strains (Mann-Whitney test, P < 0.008) than in patients infected with CAS strains (adjusted odds ratio [AOR], 4.7; 95% confidence interval [CI], 1.6 to 13.5). Lineage 7 strains also grew more slowly than other M. tuberculosis strains. Cases of Haarlem (OR, 2.8; 95% CI, 1.2 to 6.6) and NW-ETH3 (OR, 2.8; 95% CI, 1.0 to 7.3) infection appeared in defined clusters. Intensified active case finding and contact tracing activities in the study region are needed to expedite diagnosis and treatment of TB.
doi:10.1128/JCM.03566-14
PMCID: PMC4365194  PMID: 25673798
12.  Epidemiology and individual, household and geographical risk factors of podoconiosis in Ethiopia: results from the first nationwide mapping 
Although podoconiosis is one of the major causes of tropical lymphoedema and is endemic in Ethiopia its epidemiology and risk factors are poorly understood. Individual level data for 129,959 individuals from 1,315 communities in 659 woreda (districts) were collected for nationwide integrated survey of lymphatic filariasis and podoconiosis. Blood samples were tested for circulating Wuchereria bancrofti antigen using immunochromatographic card tests. A clinical algorithm was used to reach a diagnosis of podoconiosis by excluding other potential causes of lymphoedema of the lower limb. Bayesian multilevel models were used to identify individual and environmental risk factors. Overall, 8,110 of 129,959 (6.2%, 95% confidence interval [CI] 6.1 - 6.4%) surveyed individuals were identified with lymphoedema of the lower limb, of whom 5,253 (4.0%, 95% CI 3.9 - 4.1%) were confirmed to be podoconiosis cases. In multivariable analysis, being female, older, unmarried, washing the feet less frequently than daily, and being semiskilled or unemployed were significantly associated with increased risk of podoconiosis. Attending formal education and living in a house with a covered floor were associated with decreased risk of podoconiosis. Podoconiosis exhibits marked geographical variation across Ethiopia, with variation in risk associated with variation in rainfall, enhanced vegetation index and altitude.
doi:10.4269/ajtmh.14-0446
PMCID: PMC4288951  PMID: 25404069
podoconiosis; mapping; non-filarial elephantiasis; lymphoedema; Ethiopia
13.  Epidemiology and Individual, Household and Geographical Risk Factors of Podoconiosis in Ethiopia: Results from the First Nationwide Mapping 
Although podoconiosis is one of the major causes of tropical lymphoedema and is endemic in Ethiopia its epidemiology and risk factors are poorly understood. Individual-level data for 129,959 individuals from 1,315 communities in 659 woreda (districts) were collected for a nationwide integrated survey of lymphatic filariasis and podoconiosis. Blood samples were tested for circulating Wuchereria bancrofti antigen using immunochromatographic card tests. A clinical algorithm was used to reach a diagnosis of podoconiosis by excluding other potential causes of lymphoedema of the lower limb. Bayesian multilevel models were used to identify individual and environmental risk factors. Overall, 8,110 of 129,959 (6.2%, 95% confidence interval [CI] 6.1–6.4%) surveyed individuals were identified with lymphoedema of the lower limb, of whom 5,253 (4.0%, 95% CI 3.9–4.1%) were confirmed to be podoconiosis cases. In multivariable analysis, being female, older, unmarried, washing the feet less frequently than daily, and being semiskilled or unemployed were significantly associated with increased risk of podoconiosis. Attending formal education and living in a house with a covered floor were associated with decreased risk of podoconiosis. Podoconiosis exhibits marked geographical variation across Ethiopia, with variation in risk associated with variation in rainfall, enhanced vegetation index, and altitude.
doi:10.4269/ajtmh.14-0446
PMCID: PMC4288951  PMID: 25404069
14.  Micronutrient Deficiencies and Related Factors in School-Aged Children in Ethiopia: A Cross-Sectional Study in Libo Kemkem and Fogera Districts, Amhara Regional State 
PLoS ONE  2014;9(12):e112858.
Introduction
The present study describes the distribution of selected micronutrients and anaemia among school-aged children living in Libo Kemkem and Fogera (Amhara State, Ethiopia), assessing differences by socio-demographic characteristics, health status and dietary habits.
Methods
A cross-sectional survey was carried out during May–December 2009. Socio-demographic characteristics, health status and dietary habits were collected. Biomarkers were determined for 764 children. Bivariate and multivariable statistical methods were employed to assess micronutrient deficiencies (MD), anaemia, and their association with different factors.
Results
More than two thirds of the school-aged children (79.5%) had at least one MD and 40.5% had two or more coexisting micronutrient deficiencies. The most prevalent deficiencies were of zinc (12.5%), folate (13.9%), vit A (29.3%) and vit D (49%). Anaemia occurred in 30.9% of the children. Children living in rural areas were more likely to have vit D insufficiency [OR: 5.9 (3.7–9.5)] but less likely to have folate deficiency [OR: 0.2 (0.1–0.4)] and anaemia [OR: 0.58 (0.35–0.97)]. Splenomegaly was positively associated with folate deficiency and anaemia [OR: 2.77 (1.19–6.48) and 4.91 (2.47–9.75)]. Meat and fish consumption were inversely correlated with zinc and ferritin deficiencies [OR: 0.2 (0.1–0.8) and 0.2 (0.1–0.9)], while oil consumption showed a negative association with anaemia and deficiencies of folate and vitamin A [0.58 (0.3–0.9), OR: 0.5 (0.3–0.9) and 0.6 (0.4–0.9)]. Serum ferritin levels were inversely correlated to the presence of anaemia (p<0.005).
Conclusion
There is a high prevalence of vitamin A deficiency and vitamin D insufficiency and a moderate prevalence of zinc and folate deficiencies in school-aged children in this area. The inverse association of anaemia and serum ferritin levels may be due to the presence of infectious diseases in the area. To effectively tackle malnutrition, strategies should target not only isolated micronutrient supplementation but also diet diversification.
doi:10.1371/journal.pone.0112858
PMCID: PMC4278675  PMID: 25546056
15.  Immunocytochemical detection of Mycobacterium Tuberculosis complex specific antigen, MPT64, improves diagnosis of tuberculous lymphadenitis and tuberculous pleuritis 
BMC Infectious Diseases  2014;14:585.
Background
A rapid, sensitive and accurate laboratory diagnosis is of prime importance in suspected extrapulmonary tuberculosis (EPTB) cases. However, traditional techniques for the detection of acid-fast bacilli have limitations. The aim of the study was to evaluate the diagnostic value of immunocytochemical staining for detection of Mycobacterium tuberculosis complex specific antigen, MPT64, in aspirates from pleural effusions and lymph nodes, the most common presentations of EPTB.
Method
A cross-sectional study was conducted by including patients at Tikur Anbessa Specialized Hospital and the United Vision Medical Services from December 2011 to June 2012. Lymph node aspirates and pleural fluid samples were collected and analyzed from a total of 51 cases (26 tuberculous (TB) pleuritis and 25 TB lymphadenitis) and 67 non-TB controls. Each specimen was subjected to Ziehl-Neelsen (ZN) staining, culture on Lowenstein– Jensen (LJ) medium, cytological examination, Polymerase Chain Reaction (PCR) using IS1081gene sequence as a primer and immunocytochemistry (ICC) with polyclonal anti-MPT64 antibody. All patients were screened for HIV.
Result
ICC was positive in 38 of 51 cases and in the 7 of 67 controls giving an overall sensitivity and specificity of 74.5% and 89.5%, respectively. Using IS1081-PCR as a reference method, the sensitivity and specificity, positive and negative predictive value of ICC was 88.1%, 89.5%, 82.2% and 93.2%, respectively. The case detection rate increased from 13.7% by ZN stain to 19.6% by LJ culture, to 66.7% by cytology and 74.5% by ICC.
Conclusion
Immunocytochemistry with anti-MPT64 antigen improved detection of TB in pleural effusion and lymph node aspirates. Further studies using monoclonal antibodies on samples from other sites of EPTB is recommended to validate this relatively simple diagnostic method for EPTB.
doi:10.1186/s12879-014-0585-1
PMCID: PMC4262190  PMID: 25421972
Tuberculous lymphadenitis; Tuberculous pleural effusion; M. tuberculosis; ICC; MPT64 antigen
16.  Cross-Sectional Study of Malnutrition and Associated Factors among School Aged Children in Rural and Urban Settings of Fogera and Libo Kemkem Districts, Ethiopia 
PLoS ONE  2014;9(9):e105880.
Introduction
Little information is available on malnutrition-related factors among school-aged children ≥5 years in Ethiopia. This study describes the prevalence of stunting and thinness and their related factors in Libo Kemkem and Fogera, Amhara Regional State and assesses differences between urban and rural areas.
Methods
In this cross-sectional study, anthropometrics and individual and household characteristics data were collected from 886 children. Height-for-age z-score for stunting and body-mass-index-for-age z-score for thinness were computed. Dietary data were collected through a 24-hour recall. Bivariate and backward stepwise multivariable statistical methods were employed to assess malnutrition-associated factors in rural and urban communities.
Results
The prevalence of stunting among school-aged children was 42.7% in rural areas and 29.2% in urban areas, while the corresponding figures for thinness were 21.6% and 20.8%. Age differences were significant in both strata. In the rural setting, fever in the previous 2 weeks (OR: 1.62; 95% CI: 1.23–2.32), consumption of food from animal sources (OR: 0.51; 95% CI: 0.29–0.91) and consumption of the family's own cattle products (OR: 0.50; 95% CI: 0.27–0.93), among others factors were significantly associated with stunting, while in the urban setting, only age (OR: 4.62; 95% CI: 2.09–10.21) and years of schooling of the person in charge of food preparation were significant (OR: 0.88; 95% CI: 0.79–0.97). Thinness was statistically associated with number of children living in the house (OR: 1.28; 95% CI: 1.03–1.60) and family rice cultivation (OR: 0.64; 95% CI: 0.41–0.99) in the rural setting, and with consumption of food from animal sources (OR: 0.26; 95% CI: 0.10–0.67) and literacy of head of household (OR: 0.24; 95% CI: 0.09–0.65) in the urban setting.
Conclusion
The prevalence of stunting was significantly higher in rural areas, whereas no significant differences were observed for thinness. Various factors were associated with one or both types of malnutrition, and varied by type of setting. To effectively tackle malnutrition, nutritional programs should be oriented to local needs.
doi:10.1371/journal.pone.0105880
PMCID: PMC4179248  PMID: 25265481
17.  Potential of cell-free supernatants from cultures of selected lactic acid bacteria and yeast obtained from local fermented foods as inhibitors of Listeria monocytogenes, Salmonella spp. and Staphylococcus aureus 
BMC Research Notes  2014;7:606.
Background
Food-borne infections cause huge economic and human life losses worldwide. The most common contaminants of foods include Listeria monocytogenes Salmonellae and Staphylococcus aureus. L. monocytogenes is most notorious due to its tolerance to common food preservation methods and the risks it poses, including higher fatality rates. Safer, more efficacious control methods are thus needed. Along with food-borne pathogens, lactic acid bacteria (LAB) can also be found in foods. Some LAB isolates inhibit pathogenic bacteria by various mechanisms, including by production of antimicrobial metabolites.
Methods
The potential of cell-free culture supernatants (CFS) derived from broth cultures of selected local LAB and yeast isolates, some of which were subjected to various treatments, were tested for inhibition of L. monocytogenes, Salmonella spp. and S. aureus in in vitro culture by incorporating various proportions of the CFSs into the growth medium concurrently with inoculation (co-cultures) or following limited proliferation after inoculation of the pathogens (delayed cultures). The effects of the CFSs on various growth parameters were assessed.
Results
CFS from the LAB isolates were strongly inhibitory when co-cultured. The inhibitory activities were stable following heat or protease treatment of the CFSs. Inhibitory activity was dependent primarily on active substance(s) secreted into the supernatant. In all co-cultures, CFS proportion-dependent progressive decrease in the number of colonies was observed and both growth rates and number of generations were reduced with significantly fewer numbers of colony forming units, whereas generation times were significantly increased compared to those of controls. Transfer from co-cultures to fresh broth showed inhibited cultures contained bacteria that can re-grow, indicating the presence of viable bacteria that are undetectable by culture. Growth rates in CFS-treated delayed cultures were also reduced to varying degrees with the number of colonies in some cultures being significantly less than the corresponding control values. CFSs were active against both Gram-positive and –negative bacteria.
Conclusions
Active metabolites produced and secreted by LAB into the growth medium were effective in inhibiting the tested pathogens. Early addition of the CFSs was necessary for significant inhibition to occur. Further studies will help make these findings applicable to food safety.
doi:10.1186/1756-0500-7-606
PMCID: PMC4167124  PMID: 25190588
Lactic acid bacteria; Listeria monocytogenes; Salmonella; Staphylococcus aureus; Inhibition; Cell-free supernatant; Inhibition
18.  Integrated mapping of lymphatic filariasis and podoconiosis: lessons learnt from Ethiopia 
Parasites & Vectors  2014;7:397.
Background
The World Health Organization (WHO), international donors and partners have emphasized the importance of integrated control of neglected tropical diseases (NTDs). Integrated mapping of NTDs is a first step for integrated planning of programmes, proper resource allocation and monitoring progress of control. Integrated mapping has several advantages over disease specific mapping by reducing costs and enabling co-endemic areas to be more precisely identified. We designed and conducted integrated mapping of lymphatic filariasis (LF) and podoconiosis in Ethiopia; here we present the methods, challenges and lessons learnt.
Methods
Integrated mapping of 1315 communities across Ethiopia was accomplished within three months. Within these communities, 129,959 individuals provided blood samples that were tested for circulating Wuchereria bancrofti antigen using immunochromatographic card tests (ICT). Wb123 antibody tests were used to further establish exposure to LF in areas where at least one ICT positive individual was detected. A clinical algorithm was used to reliably diagnose podoconiosis by excluding other potential causes of lymphoedema of the lower limb.
Results
A total of 8110 individuals with leg swelling were interviewed and underwent physical examination. Smartphones linked to a central database were used to collect data, which facilitated real-time data entry and reduced costs compared to traditional paper-based data collection approach; their inbuilt Geographic Positioning System (GPS) function enabled simultaneous capture of geographical coordinates. The integrated approach led to efficient use of resources and rapid mapping of an enormous geographical area and was well received by survey staff and collaborators. Mobile based technology can be used for such large scale studies in resource constrained settings such as Ethiopia, with minimal challenges.
Conclusions
This was the first integrated mapping of podoconiosis and LF globally. Integrated mapping of podoconiosis and LF is feasible and, if properly planned, can be quickly achieved at nationwide scale.
Electronic supplementary material
The online version of this article (doi:10.1186/1756-3305-7-397) contains supplementary material, which is available to authorized users.
doi:10.1186/1756-3305-7-397
PMCID: PMC4153915  PMID: 25164687
Integrated; Mapping; Lymphedema; Elephantiasis; Lymphatic filariasis; Podoconiosis; Ethiopia
19.  A 24-well plate assay for simultaneous testing of first and second line drugs against Mycobacterium tuberculosis in a high endemic setting 
BMC Research Notes  2014;7:512.
Background
Early detection of drug resistance is one of the priorities of tuberculosis (TB) control programs as drug resistance is increasing. New molecular assays are only accessible for a minority of the second line drugs and their availability in high endemic settings is also hampered by high cost and logistic challenges. Therefore, we evaluated a previously developed method for drug susceptibility testing (DST) including both first- and second line anti-TB drugs for use in high endemic areas.
Results
Baseline mycobacterial isolates from 78 consecutive pulmonary TB patients from Addis Ababa, Ethiopia who were culture positive for Mycobacterium tuberculosis at the end of a two-month directly observed treatment short course (DOTS) were included. The isolates were simultaneously tested for isoniazid, rifampicin, ethambutol, streptomycin, amikacin, kanamycin, capreomycin, ofloxacin, moxifloxacin, ethionamide and para-aminosalicylic acid susceptibility using the indirect proportion method adopted for 24-well agar plates containing Middlebrook 7H10 medium. Applying the 24-well plate assay, 43 (55.1%) isolates were resistant to one or more of the first line drugs tested (isoniazid, rifampicin and ethambutol). MDR-TB was identified in 20.5% of this selected group and there was a perfect correlation for rifampicin resistance with the results from the genotype MTBDRplus assay. All isolates were susceptible to aminoglycosides and fluoroquinolones in agreement with the genotype MTBDRsl assay. The only tested second line drug associated to resistance was ethionamide (14.1% resistant). The method was reproducible with stable results for internal controls (one multi-drug resistant (MDR) and one pan-susceptible strain (H37Rv) and DST results could be reported at two weeks.
Conclusions
The 24-well plate method for simultaneous DST for first- and second line drugs was found to be reproducible and correlated well to molecular drug susceptibility tests. It is likely to be useful in high-endemic areas for surveillance as well as for the detection of second line drug resistance in targeted groups such as in those who fail empirical MDR treatment.
doi:10.1186/1756-0500-7-512
PMCID: PMC4267144  PMID: 25108648
Susceptibility testing; Epidemiological cut off value (ECOFF); Multi drug resistant (MDR) tuberculosis; Ethiopia
20.  Return of chloroquine-sensitive Plasmodium falciparum parasites and emergence of chloroquine-resistant Plasmodium vivax in Ethiopia 
Malaria Journal  2014;13:244.
Background
Increased resistance by Plasmodium falciparum parasites led to the withdrawal of the antimalarial drugs chloroquine and sulphadoxine-pyrimethamine in Ethiopia. Since 2004 artemether-lumefantrine has served to treat uncomplicated P. falciparum malaria. However, increasing reports on delayed parasite clearance to artemisinin opens up a new challenge in anti-malarial therapy. With the complete withdrawal of CQ for the treatment of Plasmodium falciparum malaria, this study assessed the evolution of CQ resistance by investigating the prevalence of mutant alleles in the pfmdr1 and pfcrt genes in P. falciparum and pvmdr1 gene in Plasmodium vivax in Southern and Eastern Ethiopia.
Methods
Of the 1,416 febrile patients attending primary health facilities in Southern Ethiopia, 329 febrile patients positive for P. falciparum or P. vivax were recruited. Similarly of the 1,304 febrile patients from Eastern Ethiopia, 81 febrile patients positive for P. falciparum or P. vivax were included in the study. Of the 410 finger prick blood samples collected from malaria patients, we used direct sequencing to investigate the prevalence of mutations in pfcrt and pfmdr1. This included determining the gene copy number in pfmdr1 in 195 P. falciparum clinical isolates, and mutations in the pvmdr1 locus in 215 P. vivax clinical isolates.
Results
The pfcrt K76 CQ-sensitive allele was observed in 84.1% of the investigated P.falciparum clinical isolates. The pfcrt double mutations (K76T and C72S) were observed less than 3%. The pfcrt SVMNT haplotype was also found to be present in clinical isolates from Ethiopia. The pfcrt CVMNK-sensitive haplotypes were frequently observed (95.9%). The pfmdr1 mutation N86Y was observed only in 14.9% compared to 85.1% of the clinical isolates that carried sensitive alleles. Also, the sensitive pfmdr1 Y184 allele was more common, in 94.9% of clinical isolates. None of the investigated P. falciparum clinical isolates carried S1034C, N1042D and D1246Y pfmdr1 polymorphisms. All investigated P. falciparum clinical isolates from Southern and Eastern Ethiopia carried only a single copy of the mutant pfmdr1 gene.
Conclusion
The study reports for the first time the return of chloroquine sensitive P. falciparum in Ethiopia. These findings support the rationale for the use of CQ-based combination drugs as a possible future alternative.
doi:10.1186/1475-2875-13-244
PMCID: PMC4230645  PMID: 24964730
Malaria; Plasmodium falciparum; Plasmodium vivax; Ethiopia; pfcrt; pfmdr1; pvmdr1; pfmdr1 gene copy number
21.  Combination of gene expression patterns in whole blood discriminate between tuberculosis infection states 
BMC Infectious Diseases  2014;14:257.
Background
Genetic factors are involved in susceptibility or protection to tuberculosis (TB). Apart from gene polymorphisms and mutations, changes in levels of gene expression, induced by non-genetic factors, may also determine whether individuals progress to active TB.
Methods
We analysed the expression level of 45 genes in a total of 47 individuals (23 healthy household contacts and 24 new smear-positive pulmonary TB patients) in Addis Ababa using a dual colour multiplex ligation-dependent probe amplification (dcRT-MLPA) technique to assess gene expression profiles that may be used to distinguish TB cases and their contacts and also latently infected (LTBI) and uninfected household contacts.
Results
The gene expression level of BLR1, Bcl2, IL4d2, IL7R, FCGR1A, MARCO, MMP9, CCL19, and LTF had significant discriminatory power between sputum smear-positive TB cases and household contacts, with AUCs of 0.84, 0.81, 0.79, 0.79, 0.78, 0.76, 0.75, 0.75 and 0.68 respectively. The combination of Bcl2, BLR1, FCGR1A, IL4d2 and MARCO identified 91.66% of active TB cases and 95.65% of household contacts without active TB. The expression of CCL19, TGFB1, and Foxp3 showed significant difference between LTBI and uninfected contacts, with AUCs of 0.85, 0.82, and 0.75, respectively, whereas the combination of BPI, CCL19, FoxP3, FPR1 and TGFB1 identified 90.9% of QFT- and 91.6% of QFT+ household contacts.
Conclusions
Expression of single and especially combinations of host genes can accurately differentiate between active TB cases and healthy individuals as well as between LTBI and uninfected contacts.
doi:10.1186/1471-2334-14-257
PMCID: PMC4041060  PMID: 24885723
22.  Field-Evaluation of a New Lateral Flow Assay for Detection of Cellular and Humoral Immunity against Mycobacterium leprae 
Background
Field-applicable tests detecting asymptomatic Mycobacterium leprae (M. leprae) infection or predicting progression to leprosy, are urgently required. Since the outcome of M. leprae infection is determined by cellular- and humoral immunity, we aim to develop diagnostic tests detecting pro-/anti-inflammatory and regulatory cytokines as well as antibodies against M. leprae. Previously, we developed lateral flow assays (LFA) for detection of cytokines and anti-PGL-I antibodies. Here we evaluate progress of newly developed LFAs for applications in resource-poor settings.
Methods
The combined diagnostic value of IP-10, IL-10 and anti-PGL-I antibodies was tested using M. leprae-stimulated blood of leprosy patients and endemic controls (EC). For reduction of the overall test-to-result time the minimal whole blood assay time required to detect distinctive responses was investigated. To accommodate LFAs for field settings, dry-format LFAs for IP-10 and anti-PGL-I antibodies were developed allowing storage and shipment at ambient temperatures. Additionally, a multiplex LFA-format was applied for simultaneous detection of anti-PGL-I antibodies and IP-10. For improved sensitivity and quantitation upconverting phosphor (UCP) reporter technology was applied in all LFAs.
Results
Single and multiplex UCP-LFAs correlated well with ELISAs. The performance of dry reagent assays and portable, lightweight UCP-LF strip readers indicated excellent field-robustness. Notably, detection of IP-10 levels in stimulated samples allowed a reduction of the whole blood assay time from 24 h to 6 h. Moreover, IP-10/IL-10 ratios in unstimulated plasma differed significantly between patients and EC, indicating the feasibility to identify M. leprae infection in endemic areas.
Conclusions
Dry-format UCP-LFAs are low-tech, robust assays allowing detection of relevant cytokines and antibodies in response to M. leprae in the field. The high levels of IP-10 and the required shorter whole blood assay time, render this cytokine useful to discriminate between leprosy patients and EC.
Author Summary
Leprosy is one of the six diseases considered by WHO as a major threat in developing countries and often results in severe, life-long disabilities and deformities due to delayed diagnosis. Early detection of Mycobacterium leprae (M. leprae) infection, followed by effective interventions, is considered vital to interrupt transmission. Thus, field-friendly tests that detect asymptomatic M. leprae infection are urgently required. The clinical outcome after M. leprae infection is determined by the balance of pro- and anti-inflammatory cytokines and antibodies in response to M. leprae. In this study, we developed lateral flow assays (LFA) for detection of pro-inflammatory (IP-10) vs. anti-inflammatory/regulatory (IL-10) cellular immunity as well as antibodies against M. leprae and evaluated these in a field setting in Ethiopia using lightweight, portable readers. We show that detection of IP-10 allowed a significant reduction of the overall test-to-result time from 24 h to 6 h. Moreover, IP-10/IL-10 ratios in unstimulated plasma differed significantly between patients and EC, which can provide means to identify M. leprae infection. Thus, the LFAs are low-tech, robust assays that can be applied in resource-poor settings measuring immunity to M. leprae and can be used as tools for early diagnosis of leprosy leading to timely treatment and reduced transmission.
doi:10.1371/journal.pntd.0002845
PMCID: PMC4014418  PMID: 24810599
23.  Knowledge, Attitudes and Practices Related to Visceral Leishmaniasis in Rural Communities of Amhara State: A Longitudinal Study in Northwest Ethiopia 
Background
In the northwest of Ethiopia, at the South Gondar region, there was a visceral leishmaniasis (VL) outbreak in 2005, making the disease a public health concern for the regional health authorities ever since. The knowledge on how the population perceives the disease is essential in order to propose successful control strategies.
Methodology/Principal findings
Two surveys on VL knowledge, attitudes and practices were conducted at the beginning (May 2009) and at the end (February 2011) of a VL longitudinal study carried out in rural communities of Libo Kemkem and Fogera, two districts of the Amhara Regional State. Results showed that VL global knowledge was very low in the area, and that it improved substantially in the period studied. Specifically, from 2009 to 2011, the frequency of proper knowledge regarding VL signs and symptoms increased from 47% to 71% (p<0.0001), knowledge of VL causes increased from 8% to 25% (p<0.0001), and knowledge on VL protection measures from 16% to 55% (p<0.0001). Moreover, the improvement observed in VL knowledge was more marked among the families with no previous history of VL case. Finally, in 2011 more than 90% of the households owned at least an impregnated bed net and had been sprayed, and attitudes towards these and other protective measures were very positive (over 94% acceptance for all of them).
Conclusions/Significance
In 2009 the level of knowledge regarding VL was very low among the rural population of this area, although it improved substantially in the study period, probably due to the contribution of many actors in the area. VL patients and relatives should be appropriately informed and trained as they may act as successful health community agents. VL risk behavioural patterns are subject to change as attitudes towards protective measures were very positive overall.
Author Summary
Visceral leishmaniasis (VL) is a vector borne disease that can be fatal if left untreated. In northern Ethiopia there was a VL outbreak in 2005, making the disease a public health challenge ever since. In order to promote the participation of communities in the control of the disease, it is essential to know how they perceive the disease and its management. There is a paucity of studies dealing with the knowledge, attitudes and practices (KAP) towards VL in the world in general and in rural Ethiopia in particular. We conducted two KAP studies at the beginning and at the end of a VL longitudinal study carried out between 2009 and 2011. The project included VL community talks and sensitization, and there were other interventions implemented by different actors in this period. Our results showed that, among the rural communities surveyed, the knowledge regarding signs and symptoms, causes, and protective measures of the disease was very low. However, it improved substantially in the period studied, suggesting that knowledge was subject to change by community interventions. It also showed that VL patients and relatives can act as successful health agents and that the population had positive attitudes towards the implementation of preventive actions.
doi:10.1371/journal.pntd.0002799
PMCID: PMC3990515  PMID: 24743328
24.  Prevalence and Drug Resistance Patterns of Mycobacterium tuberculosis among New Smear Positive Pulmonary Tuberculosis Patients in Eastern Ethiopia 
The study aimed at determining the prevalence and drug resistance patterns of Mycobacterium tuberculosis among new smear positive pulmonary tuberculosis patients visiting TB diagnosis and treatment facilities at selected health facilities in eastern Ethiopia. A cross-sectional study was conducted between October 2011 and May 2013. A total of 408 new adult pulmonary TB patients (≥ 18 years) were enrolled in this study. Three consecutive sputum samples (spot, morning, and spot) were collected from each patient and transported to the Armauer Hansen Research Institute TB laboratory located in Addis Ababa for culture on Lowenstein Jensen slant media. DST was performed on 357 (87.5%) of the patient samples for isoniazid (H), rifampicin (R), ethambutol (E), and streptomycin (S) using the standard proportion method. The rate of resistance to any one drug was 23%. Any resistance to H, S, R, and E was 14%, 11.5%, 2.8%, and 0.3%, respectively. The highest proportion of monoresistance was observed against H (9.5%). MDRTB was detected in 1.1% of the patients. Any drug resistance was associated with HIV infection (COR = 3.7, 95% CI 1.905–7.222) (P = 0.000). Although the prevalence of MDRTB is relatively low in the study area, high prevalence of H resistance is a serious concern demanding close monitoring. Expanding diagnostic capacity for mycobacterial culture and DST is a vital step in this regard.
doi:10.1155/2014/753492
PMCID: PMC4009208  PMID: 24834351
25.  T-Cell Regulation in Lepromatous Leprosy 
Regulatory T (Treg) cells are known for their role in maintaining self-tolerance and balancing immune reactions in autoimmune diseases and chronic infections. However, regulatory mechanisms can also lead to prolonged survival of pathogens in chronic infections like leprosy and tuberculosis (TB). Despite high humoral responses against Mycobacterium leprae (M. leprae), lepromatous leprosy (LL) patients have the characteristic inability to generate T helper 1 (Th1) responses against the bacterium. In this study, we investigated the unresponsiveness to M. leprae in peripheral blood mononuclear cells (PBMC) of LL patients by analysis of IFN-γ responses to M. leprae before and after depletion of CD25+ cells, by cell subsets analysis of PBMC and by immunohistochemistry of patients' skin lesions. Depletion of CD25+ cells from total PBMC identified two groups of LL patients: 7/18 (38.8%) gained in vitro responsiveness towards M. leprae after depletion of CD25+ cells, which was reversed to M. leprae-specific T-cell unresponsiveness by addition of autologous CD25+ cells. In contrast, 11/18 (61.1%) remained anergic in the absence of CD25+ T-cells. For both groups mitogen-induced IFN-γ was, however, not affected by depletion of CD25+ cells. In M. leprae responding healthy controls, treated lepromatous leprosy (LL) and borderline tuberculoid leprosy (BT) patients, depletion of CD25+ cells only slightly increased the IFN-γ response. Furthermore, cell subset analysis showed significantly higher (p = 0.02) numbers of FoxP3+ CD8+CD25+ T-cells in LL compared to BT patients, whereas confocal microscopy of skin biopsies revealed increased numbers of CD68+CD163+ as well as FoxP3+ cells in lesions of LL compared to tuberculoid and borderline tuberculoid leprosy (TT/BT) lesions. Thus, these data show that CD25+ Treg cells play a role in M. leprae-Th1 unresponsiveness in LL.
Author Summary
Leprosy is a curable infectious disease caused by Mycobacterium leprae (M. leprae) that affects the skin and peripheral nerves. It is manifested in different forms ranging from self-healing, tuberculoid leprosy (TT) with low bacillary load and high cellular immunity against M. leprae, to lepromatous leprosy (LL) with high bacillary load and high antibody titers to M. leprae antigens. However, LL patients have poor cell mediated response against M. leprae leading to delayed clearance of the bacilli. A possible explanation for this bacterial persistence could lie in the presence of more regulatory cells at infection sites and in peripheral blood. This study shows the recovery of the cell mediated response by depletion of CD25+ cells in a subset of LL patients, while another patient subset was not affected similarly. Moreover, an increased frequency of FoxP3+ T cells together with anti-inflammatory macrophages was observed in LL patients' skin biopsies. Thus, these data show that CD25+ Treg cells play a role in M. leprae-unresponsiveness in leprosy patients.
doi:10.1371/journal.pntd.0002773
PMCID: PMC3983090  PMID: 24722473

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