Ex vivo cytokine mRNA levels correlate with changing clinical status of ethiopian TB patients and their contacts over time.

There is an increasing body of evidence which suggests that IL-4 plays a role in the pathogenesis of TB, but a general consensus on its role remains elusive. We have previously published data from a cohort of Ethiopian TB patients, their contacts, and community controls suggesting that enhanced IL-4 production is associated with infection with M. tuberculosis, rather than overt disease and that long-term protection in infected community controls is associated with co-production of the IL-4 antagonist IL-4d2, alongside elevated IL-4. Here, for the first time, we compare data on expression of IFN-gamma, IL-4 and IL-4delta2 over time in TB patients and their household contacts. During the follow-up period, the TB patients completed therapy and ceased to display TB-like symptoms. This correlated with a decrease in the relative amount of IL-4 expressed. Over the same period, the clinical status of some of their contacts also changed, with a number developing TB-like symptoms or clinically apparent TB. IL-4 expression was disproportionately increased in this group. The findings support the hypothesis that elevated IL-4 production is generally associated with infection, but that TB disease is associated with a relatively increased expression of IL-4 compared to IFN-gamma and IL-4delta2. However, the data also suggest that there are no clear-cut differences between groups: the immune response over time appears to include changes in the expression of IFN-gamma, IL-4 and IL-4delta2, and it is the relative, not absolute levels of cytokine expression that are characteristic of clinical status

A Randomized Controlled Double Blind Trial of Ciclosporin versus Prednisolone in the Management of Leprosy Patients with New Type 1 Reaction, in Ethiopia.

BACKGROUND: Leprosy Type 1 (T1R) reactions are immune-mediated events leading to nerve damage and preventable disability affecting hands, feet and eyes. Type 1 Reactions are treated with oral corticosteroids. There is little evidence on alternative treatments for patients who do not respond to steroids or experience steroid adverse effects. We report the results of a randomized controlled trial testing the efficacy and adverse effect profile of ciclosporin and prednisolone (CnP) in comparison to prednisolone only (P) in patients with new T1R in Ethiopia. Ciclosporin is a potent immunosuppressant. Outcomes were measured using a clinical severity score, recurrence rate, adverse events and quality of life. RESULTS: Seventy three patients with new T1R were randomized to receive CnP or P for 20 weeks. Recovery rates in skin signs was similar in both groups (91% vs 88%). Improvements in nerve function both, new and old, sensory (66% vs 49%) and motor (75% vs 74%) loss were higher (but not significantly so) in the patients on CnP. Recurrences rates of T1R (85%) were high in both groups, and recurrences occurred significantly earlier (8 weeks) in patients CnP, who needed 10% more additional prednisolone. Serious major and minor adverse events rates were similar in patients in the two treatment arms of the study. Both groups had a significant improvement in their quality of life after the study, measured by the SF-36. CONCLUSIONS: This is the first double-blind RCT assessing ciclosporin, in the management of T1R in Africa. Ciclosporin could be a safe alternative second-line drug for patients with T1R who are not improving with prednisolone or are experiencing adverse events related to prednisolone. This study illustrates the difficulty in switching off leprosy inflammation. Better treatment agents for leprosy patients with reactions and nerve damage are needed

Chloroquine-resistant Plasmodium vivax malaria in Debre Zeit, Ethiopia

<p>Abstract</p> <p>Background</p> <p><it>Plasmodium vivax </it>accounts for about 40% of all malaria infection in Ethiopia. Chloroquine (CQ) is the first line treatment for confirmed <it>P. vivax </it>malaria in the country. The first report of CQ treatment failure in <it>P. vivax </it>was from Debre Zeit, which suggested the presence of chloroquine resistance.</p> <p>Methods</p> <p>An <it>in vivo </it>drug efficacy study was conducted in Debre Zeit from June to August 2006. Eighty-seven patients with microscopically confirmed <it>P. vivax </it>malaria, aged between 8 months and 52 years, were recruited and treated under supervision with CQ (25 mg/kg over three days). Clinical and parasitological parameters were assessed during the 28 day follow-up period. CQ and desethylchloroquine (DCQ) blood and serum concentrations were determined with high performance liquid chromatography (HPLC) in patients who showed recurrent parasitaemia.</p> <p>Results</p> <p>Of the 87 patients recruited in the study, one was lost to follow-up and three were excluded due to <it>P. falciparum </it>infection during follow-up. A total of 83 (95%) of the study participants completed the follow-up. On enrolment, 39.8% had documented fever and 60.2% had a history of fever. The geometric mean parasite density of the patients was 7045 parasites/μl. Among these, four patients had recurrent parasitaemia on Day 28. The blood CQ plus DCQ concentrations of these four patients were all above the minimal effective concentration (> 100 ng/ml).</p> <p>Conclusion</p> <p>Chloroquine-resistant <it>P. vivax </it>parasites are emerging in Debre Zeit, Ethiopia. A multi-centre national survey is needed to better understand the extent of <it>P. vivax </it>resistance to CQ in Ethiopia.</p

Novel approaches toward the development of an oral post-exposure DNA vaccine for latent tuberculosis using Salmonella typhimurium ΔaroA vector

Tuberculosis remains one of the major causes of global public health problems. There is no effective vaccine for the disease until now. Many reports show that DNA vaccines are promising to induce protection against Mycobacterium tuberculosis (M. tb); however, the efficiency of DNA vaccine is limited due to inadequate delivery systems. Among others, live attenuated bacterial vectors such as Salmonella enterica typhimurium (S. typhimurium) have significant promise as efficient mucosal delivery vehicles for DNA vaccines. In this study, we constructed recombinant attenuated S. typhimurium DNA vaccines carrying genes encoding resuscitation promoting factor (Rpf)-like proteins of M. tb on eukaryotic expression plasmid agianst latent tuberculosis and evaluated the plasmid stability and growth curve assays of the recombinant Salmonella vaccine constructs in vitro. Four Rpf gene fragments (RpfB, RpfC, RpfD, RpfE) associated with latency were amplified from genomic DNA of the H37Rv strain of M. tb, cloned into eukaryotic expression plasmid (pVR1020) and verified by sequencing. In later studies, we will demonstrate the potential use of the Salmonella-mediated DNA constructs as candidate post-exposure vaccines against tuberculosis through testing their immunogenicity and effectiveness for oral delivery in eukaryotic systems.Key words: Latent tuberculosis, resuscitation promoting factor (Rpf), DNA vaccine, recombinant Salmonella typhimurium

Performance of general health workers in leprosy control activities at public health facilities in Amhara and Oromia States, Ethiopia.

BACKGROUND: Leprosy is a chronic infectious disease of public health importance and one of the leading causes of permanent physical disability. Nevertheless, the drop in prevalence following multidrug therapy has resulted in the neglect of leprosy. The annual incidence of leprosy has remained the same in Ethiopia since decades with more than 76% of the reported new cases coming from Oromia and Amhara Regional States. This study was aimed to assess the knowledge, attitude and skill of general health workers in leprosy control activities at public health facilities in Oromia and Amhara Regional States. METHODS: A cross-sectional study was conducted from September 2011 to February 2012 at different public health facilities in selected eight zones in Oromia and Amhara Regional States. A multistage sampling method was used to obtain representative samples. High and low endemic zones for leprosy were included in the study in both regional states. Data were collected from general health workers through a structured self-administered questionnaire and at on-site assessment of their performance. Baseline socio-demographic data, health workers' attitude towards leprosy and their knowledge and skill in the management of leprosy were assessed. Bloom's cut off point was used to describe the knowledge and practical skills of the respondents while Likert's scale was used for attitude assessment. RESULT: A total of 601 general health workers responsible for leprosy control activities at public health facilities were included in knowledge and attitude assessment and 83 of them were subjected to practical evaluation, with on-site observation of how they handle leprosy patients. These included medical doctors (4%), health officers and nurses with Bachelor degree in Science (27%), clinical nurses with diploma (66%) and health assistants (2.8%). The median age of the respondents was 26.0 years and females made up of 45%. Generally the knowledge and skills of the respondents were found to be poor while attitude towards leprosy was positive for the majority of the respondents. The result showed that 519 (86.3%) had poor knowledge. Overall 155 (25.8%) of the respondents had positive attitude towards leprosy while 205 (34.1%) had intermediate (mixed) attitude and 241 (40.1%) had negative attitude to the disease. Among 83 respondents assessed for diagnosis of leprosy only 15(18.0%) diagnosed leprosy correctly. Variation in knowledge and attitude indicated a significant difference (p < 0.05) among different health institutions, professions, gender, in-service training and years of experience. CONCLUSION: The current finding underlines that although leprosy control activities are integrated to the general health services in the country, the knowledge and skills of leprosy diagnosis, treatment and management by health workers was unsatisfactory. Hence, attention should be given to develop training strategies that can improve health worker knowledge and promote better leprosy management at public health facilities. This could be achieved through pre-service and in-service training and giving adequate emphasis to leprosy related practical work and continuous follow- up

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

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.; 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.; 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.; 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

Comparison of Efficacy and Safety of Ciclosporin to Prednisolone in the Treatment of Erythema Nodosum Leprosum: Two Randomised, Double Blind, Controlled Pilot Studies in Ethiopia.

BACKGROUND: Erythema Nodosum Leprosum (ENL) is a serious complication of leprosy. It is normally treated with high dose steroids, but its recurrent nature leads to prolonged steroid usage and associated side effects. There is little evidence on the efficacy of alternative treatments for ENL, especially for patients who have become steroid resistant or have steroid side effects. These two pilot studies compare the efficacy and side effect profile of ciclosporin plus prednisolone against prednisolone alone in the treatment of patients with either new ENL or chronic and recurrent ENL. METHODS AND RESULTS: Thirteen patients with new ENL and twenty patients with chronic ENL were recruited into two double-blinded randomised controlled trials. Patients were randomised to receive ciclosporin and prednisolone or prednisolone treatment only. Patients with acute ENL had a delay of 16 weeks in the occurrence of ENL flare-up episode, with less severe flare-ups and decreased requirements for additional prednisolone. Patients with chronic ENL on ciclosporin had the first episode of ENL flare-up 4 weeks earlier than those on prednisolone, as well as more severe ENL flare-ups requiring 2.5 times more additional prednisolone. Adverse events attributable to prednisolone were more common that those attributable to ciclosporin. CONCLUSIONS: This is the first clinical trial on ENL management set in the African context, and also the first trial in leprosy to use patients' assessment of outcomes. Patients on ciclosporin showed promising results in the management of acute ENL in this small pilot study. But ciclosporin, did not appear to have a significant steroid-sparing effects in patients with chronic ENL, which may have been due to the prolonged use of steroids in these patients in combination with a too rapid decrease of steroids in patients given ciclosporin. Further research is needed to determine whether the promising results of ciclosporin in acute ENL can be reproduced on a larger scale

Anti-Tuberculosis Therapy-Induced Hepatotoxicity among Ethiopian HIV-Positive and Negative Patients

Background: To assess and compare the prevalence, severity and prognosis of anti-TB drug induced hepatotoxicity (DIH) in HIV positive and HIV negative tuberculosis (TB) patients in Ethiopia. Methodology/Principal Findings: In this study, 103 HIV positive and 94 HIV negative TB patients were enrolled. All patients were evaluated for different risk factors and monitored biochemically and clinically for development of DIH. Sub-clinical hepatotoxicity was observed in 17.3 % of the patients and 8 out of the 197 (4.1%) developed clinical hepatotoxicity. Seven of the 8 were HIV positive and 2 were positive for HBsAg. Conclusions/Significance: Sub-clinical hepatotoxicity was significantly associated with HIV co-infection (p = 0.002), concomitant drug intake (p = 0.008), and decrease in CD4 count (p = 0.001). Stepwise restarting of anti TB treatment was also successful in almost all the patients who developed clinical DIH. We therefore conclude that anti-TB DIH is a major problem in HIV-associated TB with a decline in immune status and that there is a need for a regular biochemical and clinical follow up for those patients who are at risk