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

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

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

Concurrent evaluation of cytokines improves the accuracy of antibodies against Mycobacterium tuberculosis antigens in the diagnosis of active tuberculosis

Data availability statement: All the important data relevant to this study was reported in the manuscript. Any additional data will be made available upon request from the corresponding author.Copyright © 2022 The Authors. Background: Antibodies against mycobacterial proteins are highly specific, but lack sensitivity, whereas cytokines have been shown to be sensitive but not very specific in the diagnosis of tuberculosis (TB). We assessed combinations between antibodies and cytokines for diagnosing TB. Methods: Immuoglubulin (Ig) A and IgM antibody titres against selected mycobacterial antigens including Apa, NarL, Rv3019c, PstS1, LAM, “Kit 1” (MTP64 and Tpx)”, and “Kit 2” (MPT64, Tpx and 19 kDa) were evaluated by ELISA in plasma samples obtained from individuals under clinical suspicion for TB. Combinations between the antibody titres and previously published cytokine responses in the same participants were assessed for diagnosing active TB. Results: Antibody responses were more promising when used in combination (AUC of 0.80), when all seven antibodies were combined. When anti-“Kit 1”-IgA levels were combined with five host cytokine biomarkers, the AUC increased to 97% (92–100%) with a sensitivity of 95% (95% CI, 73–100%), and specificity of 88.5% (95% CI, 68.7–97%) achieved after leave-one-out cross validation. Conclusion: When used in combination, IgA titres measured with ELISA against multiple Mycobacterium tuberculosis antigens may be useful in the diagnosis of TB. However, diagnostic accuracy may be improved if the antibodies are used in combination with cytokines.This work was part of the EDCTP1 programme supported by the European Union (grant number IP_2009_32040, AE-TBC; awarded to GW). The project was also supported by the South African Government through the National Research Foundation (NRF, awarded to NC) and the South African Medical Research Council (SAMRC, postgraduate scholarship to RJ)

Validation of bleach-treated smears for the diagnosis of pulmonary tuberculosis

SETTING: Health centres in Awassa, southern Ethiopia. DESIGN: Consecutive patients visiting health centre laboratories for the evaluation of suspected pulmonary tuberculosis (TB) between June and September 2006 were investigated. On-the-spot, morning and second on-the-spot sputum samples were pooled for each patient. Direct smears were stained with hot Ziehl-Neelsen (ZN) technique and aliquots cultured for mycobacteria on Lowenstein-Jensen media. The remaining sputum was treated with household bleach, aliquoted and processed with short-term digestion, centrifugation and sedimentation techniques, and stained with ZN. RESULTS: Acid-fast bacilli were detected in respectively 126 (25%), 141 (28%), 169 (34%) and 198 (40%) of the 497 pooled sputum samples processed by the direct, short-term, sedimentation and centrifugation techniques (P < 0.001). The sensitivity of the direct, short-term, sedimentation and centrifugation techniques was respectively 51.1%, 53.2%, 57.6% and 63.6%. The difference between the direct smear and centrifugation (P < 0.001) or sedimentation (P < 0.005) methods was significant. The specificity of the direct, short-term digestion, sedimentation and centrifugation techniques was respectively 97%, 93%, 86.5% and 80.8%. CONCLUSIONS: Bleach treatment of sputum and centrifugation significantly improves the sensitivity of smear microscopy for the diagnosis of TB in a health centre in a high TB burden area. It is more sensitive, but possibly less specific, than other bleach methods

Diagnosis of tuberculous lymphadenitis in Ethiopia: correlation with culture, histology and HIV status

Butajira, Southern Ethiopia. To compare the diagnostic capacity of the clinical criteria for tuberculous lymphadenitis (TBLN) with histological and/or culture results and to assess the association of human immunodeficiency virus (HIV) with tuberculosis (TB) lymphadenitis. Patients (n=171) were included in the study from October 2005 until July 2006 at Butajira Hospital. Laboratory tests were performed to confirm TBLN. HIV status was identified in TBLN patients and retrospectively in 1608 healthy individuals. A total of 136/161 (84.5%) patients were diagnosed with TBLN by histology. TBLN was culture-confirmed in 107/156 (68.6%) patients. The sensitivity, specificity, positive and negative predictive values of histology were respectively 92.5%, 49%, 79.8% and 75% when compared to culture as gold standard. Patients positive for TBLN by cytology and Ziehl-Neelsen (ZN) were also positive by histology and culture. Among the 143 confirmed TBLN patients, nine (6.3%) were HIV-positive. Of the 1608 healthy individuals, 77 (4.8%) were HIV-positive. Younger age (P=0.0001), female sex (P=0.016), not being married (P=0.0001) and illiteracy (P=0.016) showed a strong association with HIV in healthy individuals. Clinical criteria alone over-diagnosed TBLN by 15.4% compared to histological and/or bacteriological results. The HIV prevalence in TBLN patients and healthy individuals was the sam

Serodiagnosis of tuberculous lymphadenitis using a combination of antigens

BACKGROUND The diagnosis of extra-pulmonary tuberculosis (EPTB) by conventional methods such as culture and microscopy has low sensitivity and requires an invasive procedure. A simple rapid serological test would be of great value. METHODS Six antigens (ESAT-6, Ag85A, TB10.4, Rv3881c, lipoarabinomannan (LAM) and Ara6-BSA) were tested in an ELISA to detect antigen specific IgG and IgM antibodies in sera from 54 culture and histology-confirmed tuberculous lymphadenitis (TBLN) patients, among whom four were HIV seropositive, sera from 25 smear positive pulmonary tuberculosis (PTB) patients, 15 culture and histology-negative lymphadenitis (non-TBLN) patients (n=15) and 22 healthy controls (HCs). RESULTS The sensitivities of the antigens for the detection of IgG in sera of TBLN patients ranged from 4 to 30 %. Specificities ranged from 91 to 100 % with sera from HCs. Sensitivities of the antigens for detection of IgM ranged from 0 to 15 % and specificities ranged from 91 to 100 %. LAM was the most potent antigen followed by ESAT-6 and Rv3881c for detection of IgG. However, the sensitivity for antigen specific IgG antibody detection was improved when LAM was combined with ESAT-6 and Rv3881c.The sensitivity was 54 % and the specificity 91 %. CONCLUSIONS The study suggests that the combined use of LAM, ESAT-6 and Rv3881c for the detection of IgG in sera of TBLN patients could be a supplement to microscopy of fine- needle aspirate (FNA) to diagnose EPTB

Serodiagnosis of tuberculous lymphadenitis using a combination of antigens

BACKGROUND The diagnosis of extra-pulmonary tuberculosis (EPTB) by conventional methods such as culture and microscopy has low sensitivity and requires an invasive procedure. A simple rapid serological test would be of great value. METHODS Six antigens (ESAT-6, Ag85A, TB10.4, Rv3881c, lipoarabinomannan (LAM) and Ara6-BSA) were tested in an ELISA to detect antigen specific IgG and IgM antibodies in sera from 54 culture and histology-confirmed tuberculous lymphadenitis (TBLN) patients, among whom four were HIV seropositive, sera from 25 smear positive pulmonary tuberculosis (PTB) patients, 15 culture and histology-negative lymphadenitis (non-TBLN) patients (n=15) and 22 healthy controls (HCs). RESULTS The sensitivities of the antigens for the detection of IgG in sera of TBLN patients ranged from 4 to 30 %. Specificities ranged from 91 to 100 % with sera from HCs. Sensitivities of the antigens for detection of IgM ranged from 0 to 15 % and specificities ranged from 91 to 100 %. LAM was the most potent antigen followed by ESAT-6 and Rv3881c for detection of IgG. However, the sensitivity for antigen specific IgG antibody detection was improved when LAM was combined with ESAT-6 and Rv3881c.The sensitivity was 54 % and the specificity 91 %. CONCLUSIONS The study suggests that the combined use of LAM, ESAT-6 and Rv3881c for the detection of IgG in sera of TBLN patients could be a supplement to microscopy of fine- needle aspirate (FNA) to diagnose EPTB.Immunogenetics and cellular immunology of bacterial infectious disease

Prevalence of bovine tuberculosis in pastoral cattle herds in the Oromia region, southern Ethiopia

A cross-sectional study of bovine tuberculosis (BTB) was conducted in pastoral cattle herds in southern Ethiopia, from February to August 2008 using the comparative intradermal tuberculin test. The prevalence of BTB and the risk factors for having positive reactor herds were assessed in four pastoral associations in two districts of southern Ethiopia, namely Goro-Dola with 242 cattle in 16 herds and Liben with 231 cattle in 15 herds. A herd was considered positive if there was at least one reactor animal in a herd. The test results were interpreted based on the Office Internationale des Epizooties recommended 4-mm and a recently suggested 2-mm cut-off. The apparent individual animal prevalence of tuberculin reactors was 5.5% (95% confidence interval (CI), 4.0-8.0%) and 7.0% (95% CI, 5.0-10.0%), whereas the true prevalence estimate was 4.4% (95% CI, 0.8-8.0%) and 6.1% (95% CI, 2.6-9.5%), when using the 4-mm and the 2-mm cut-offs, respectively. The overall herd apparent prevalence of tuberculin reactor animals was 41.9% (95% CI, 24.9-60.9%) and 48.4% (95% CI, 30.2-66.9%) with the 4-mm and 2-mm cut-offs, respectively. A positive tuberculin test was associated with the age of animals and the main drinking water sources during dry seasons. In order to investigate the public health risks and the epidemiological importance of BTB in the area, we recommend to include other livestock species (camels and goats) as well as humans in future studie