• False-positive Xpert(®) MTB/RIF assays and previous treatment

      Boyles, T H; Hughes, J; Cox, V; Burton, R; Meintjes, G; Mendelson, M (International Union Against Tuberculosis and Lung Disease, 2015-04)
    • False-positive Xpert(®) MTB/RIF assays in previously treated patients: need for caution in interpreting results.

      Boyles, T H; Hughes, J; Cox, V; Burton, R; Meintjes, G; Mendelson, M (2014-07)
      Xpert(®) MTB/RIF is the initial diagnostic test of choice for tuberculosis (TB). It is not known if false-positive results are more common in previously treated patients. We report four patients with successful treatment for TB up to 5 years previously who presented with respiratory tract infection and were Xpert-positive, but had negative TB cultures and clinical improvement without anti-tuberculosis treatment. We hypothesise that the Xpert results were false-positive due to the presence of dead Mycobacterium tuberculosis bacilli in lungs and sputum. Further work is required to determine the specificity of Xpert in previously treated patients.
    • Feasibility of using Determine TB-LAM to diagnose tuberculosis in HIV-positive patients in programmatic conditions: a multisite study.

      Mathabire Rucker, SC; Cossa, L; Harrison, RE; Mpunga, J; Lobo, S; Kisaka Kimupelenge, P; Mandar Kol'Ampwe, F; Amoros Quiles, I; Molfino, L; Szumilin, E; et al. (Taylor & Francis, 2019-10-15)
      Background: Determine TB-LAM is a urine-based point-of-care assay for diagnosis of tuberculosis (TB). Objective: To assess the feasibility of using LAM to diagnose TB in adult HIV-positive patients in resource-limited settings. Methods: We performed a multi-centric mixed-methods cross-sectional descriptive study in the Democratic Republic of Congo, Malawi, and Mozambique. We used the study and program monitoring tools to estimate user workload, turn-around time (TAT), and proportion of patients with LAM and sputum-based results. We conducted semi-structured interviews to assess the user acceptability of the LAM. Results: The duration of the LAM testing activity per patient was 27 min (IQR 26-29); staff continued with other duties whilst waiting for the result. More patients had a LAM versus a sputum-based result: 168/213 (78.9%) vs 77/213 (36.1%), p < 0.001 in DRC; 691/695 (99.4%) vs 429/695 (61.7%), p < 0.001 in Malawi; and 646/647 (99.8%) vs 262/647 (40.5%), p < 0.001 in Mozambique. The median TAT in minutes when LAM was performed in the consultation room was 75 (IQR 45-188) in DRC, 29 (IQR 27-39) in Malawi, and 36 (IQR 35-41) in Mozambique. In comparison, the overall median TAT for sputum-based tests (smear or GeneXpert) was 2 (IQR 1-3) days. The median time to the first anti-TB drug dose for LAM-positive patients was 155 (IQR 90-504) minutes in DRC and 90 (IQR 60-117) minutes in Mozambique. The overall inter-reader agreement for the interpretation of the LAM result as positive or negative was 98.9%, kappa 0.97 (95%CI 0.96-0.99). Overall, LAM users found the test easy to perform. Major concerns were use of the reading card and the prior requirement of CD4 results before LAM testing. Conclusion: It is feasible to implement the LAM test in low resource settings. The short TAT permitted same day initiation of TB treatment for LAM-positive patients.
    • Feasibility of using teleradiology to improve tuberculosis screening and case management in a district hospital in Malawi.

      Coulborn, R M; Panunzi, I; Spijker, S; Brant, W E; Duran, L T; Kosack, C S; Murowa, M M; Médecins Sans Frontières, PO Box 219, Thyolo, Malawi. msfocb-blantyre-opr@brussels.msf.org (2012-09-01)
      Malawi has one of the world's highest rates of human immunodeficiency virus (HIV) infection (10.6%), and southern Malawi, where Thyolo district is located, bears the highest burden in the country (14.5%). Tuberculosis, common among HIV-infected people, requires radiologic diagnosis, yet Malawi has no radiologists in public service. This hinders rapid and accurate diagnosis and increases morbidity and mortality.
    • Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study

      Boehme, C C; Nicol, M P; Nabeta, P; Michael, J S; Gotuzzo, E; Tahirli, R; Gler, M T; Blakemore, R; Worodria, W; Gray, C; et al. (2011-04-18)
      BACKGROUND: The Xpert MTB/RIF test (Cepheid, Sunnyvale, CA, USA) can detect tuberculosis and its multidrug-resistant form with very high sensitivity and specificity in controlled studies, but no performance data exist from district and subdistrict health facilities in tuberculosis-endemic countries. We aimed to assess operational feasibility, accuracy, and effectiveness of implementation in such settings. METHODS: We assessed adults (≥18 years) with suspected tuberculosis or multidrug-resistant tuberculosis consecutively presenting with cough lasting at least 2 weeks to urban health centres in South Africa, Peru, and India, drug-resistance screening facilities in Azerbaijan and the Philippines, and an emergency room in Uganda. Patients were excluded from the main analyses if their second sputum sample was collected more than 1 week after the first sample, or if no valid reference standard or MTB/RIF test was available. We compared one-off direct MTB/RIF testing in nine microscopy laboratories adjacent to study sites with 2-3 sputum smears and 1-3 cultures, dependent on site, and drug-susceptibility testing. We assessed indicators of robustness including indeterminate rate and between-site performance, and compared time to detection, reporting, and treatment, and patient dropouts for the techniques used. FINDINGS: We enrolled 6648 participants between Aug 11, 2009, and June 26, 2010. One-off MTB/RIF testing detected 933 (90·3%) of 1033 culture-confirmed cases of tuberculosis, compared with 699 (67·1%) of 1041 for microscopy. MTB/RIF test sensitivity was 76·9% in smear-negative, culture-positive patients (296 of 385 samples), and 99·0% specific (2846 of 2876 non-tuberculosis samples). MTB/RIF test sensitivity for rifampicin resistance was 94·4% (236 of 250) and specificity was 98·3% (796 of 810). Unlike microscopy, MTB/RIF test sensitivity was not significantly lower in patients with HIV co-infection. Median time to detection of tuberculosis for the MTB/RIF test was 0 days (IQR 0-1), compared with 1 day (0-1) for microscopy, 30 days (23-43) for solid culture, and 16 days (13-21) for liquid culture. Median time to detection of resistance was 20 days (10-26) for line-probe assay and 106 days (30-124) for conventional drug-susceptibility testing. Use of the MTB/RIF test reduced median time to treatment for smear-negative tuberculosis from 56 days (39-81) to 5 days (2-8). The indeterminate rate of MTB/RIF testing was 2·4% (126 of 5321 samples) compared with 4·6% (441 of 9690) for cultures. INTERPRETATION: The MTB/RIF test can effectively be used in low-resource settings to simplify patients' access to early and accurate diagnosis, thereby potentially decreasing morbidity associated with diagnostic delay, dropout and mistreatment. FUNDING: Foundation for Innovative New Diagnostics, Bill & Melinda Gates Foundation, European and Developing Countries Clinical Trials Partnership (TA2007.40200.009), Wellcome Trust (085251/B/08/Z), and UK Department for International Development.
    • Field evaluation of a simple fluorescence method for detection of viable Mycobacterium tuberculosis in sputum specimens during treatment follow-up.

      Schramm, B; Hewison, C; Bonte, L; Jones, W; Camélique, O; Ruangweerayut, R; Swaddiwudhipong, W; Bonnet, M; Epicentre, Paris, France; Médecins Sans Frontières (MSF), Paris, France;International Organization for Migration (IOM), Bangkok, Thailand; Epicentre, Geneva, Switzerlandf (2012-08)
      Simple tuberculosis (TB) treatment monitoring tools are needed. We assessed the performance of fluorescein-diacetate (FDA) smear microscopy for detection of viable Mycobacterium tuberculosis in sputum specimens (n = 288) of TB cases under treatment compared to culture (17.4% culture positivity). FDA sensitivity was moderate (83.7% [95% confidence interval {CI}, 70.3 to 92.6]), and specificity was low (66.1% [59.5 to 72.2]). The good negative predictive value (94.8% [90.1 to 97.8]) and negative likelihood ratio (0.2) suggest using this method to rule out treatment failure in settings without access to culture.
    • Field Evaluation of Near Point of Care Cepheid GeneXpert HIV-1 Qual for Early Infant Diagnosis

      Opollo, VS; Nikuze, A; Ben-Farhat, J; Anyango, E; Humwa, F; Oyaro, B; Wanjala, S; Omwoyo, W; Majiwa, M; Akelo, V; et al. (Public Library of Science, 2018-12-27)
      Access to point-of-care HIV testing shortens turn-around times, time to diagnosis and reduces loss to follow-up hence minimizing barriers to early linkage to care and treatment among HIV infected infants. Currently samples for early infant HIV diagnosis are sent to centralized testing facilities which are few and located only at specific regions in Kenya. However, there are Point of Care (POC) early infant diagnosis [EID] technologies elsewhere such as SAMBA and ALERE-Q that are yet to be evaluated in Kenya despite the urgent need for data to inform policy formulation regarding EID. The Cepheid GeneXpert HIV-1 Qual (GeneXpert) technology for POC EID offers a great opportunity to minimize HIV associated morbidity, mortality and loss to follow-up through decentralization of early infant HIV testing to the clinics. This technology also allows for same-day results thus facilitating prompt linkage to care.
    • Field research in humanitarian medical programmes. Treatment of a cohort of tuberculosis patients using the Manyatta regimen in a conflict zone in South Sudan.

      Keus, K; Houston, S; Melaku, Y; Burling, S; Médecins Sans Frontières-Holland, Max Euweplein 40, PO Box 10014, 1001 EA Amsterdam, The Netherlands. (Elsevier, 2008-01-31)
      This is a descriptive report of a pilot project of tuberculosis (TB) treatment in a conflict zone. A TB programme was implemented by Médecins Sans Frontières(MSF)-Holland in a semi-nomadic population in a very insecure and underdeveloped area of Upper Nile province in Southern Sudan. Outcome measures were operational feasibility, default rate, and sputum smear conversion at 4 months. A cohort of TB patients was admitted over a 10-week period (July-September 2001). Adherence strategy, project implementation, and and contingency planning were adapted to local conditions. The treatment regimen (4 HRZE [4-month daily supervised regimen] followed by 3EH or 3TH [3-month unsupervised regimen]: isoniazid (H), rifampicin (R), pyrazinamide (Z), ethambutol (E) and thiacetazone (T)) was a variant on the Manyatta regimen developed for semi-nomads in Kenya. Of 163 patients, 84 (52%) were children aged < 15 years. Lymph node TB comprised 34% and spinal TB 15% of all patients. Among adults, 41% had smear-positive pulmonary disease. Only 1 patient (0.6%) defaulted. All sputum smear-positive patients who completed 4 months of therapy converted to smear-negative, although 2 were subsequently found to have relapsed. TB in complex emergency situations is an underrecognized priority. Using an approach adapted especially to this setting, TB treatment was successfully implemented with minimal risk of promoting drug resistance, in an unstable setting.
    • The 'frozen state' of drug-resistant tuberculosis: notes from the field in Abkhazia

      Majumdar, S; O'Brien, D; Hurtado, N; Hewison, C; du Cros, P; Department of Infectious Diseases, Alfred Hospital, Melbourne, Victoria, Australia; Department of Infectious Diseases, Geelong Hospital, Melbourne, Victoria, Australia; Department of Infectious Diseases, Royal Melbourne Hospital and University of Melbourne, Melbourne, Victoria, Australia; Médecins Sans Frontières, Amsterdam, the Netherlands; Medical Department, Médecins Sans Frontières, Paris, France; Manson Unit, Médecins Sans Frontières, London, UK (Wiley-Blackwell, 2011-12-08)
    • Further evidence of Mycobacterium tuberculosis in the sputum of culture-negative pulmonary tuberculosis suspects using an ultrasensitive molecular assay.

      Guillermo, M; Solange, V; Orr, B; White, L; Gaeddert, M; Miller, NS; Mpeirwe, M; Orikiriza, P; Mwanga-Amumpaire, J; Boum, Y; et al. (Elsevier, 2019-03-23)
      BACKGROUND: Rapid diagnosis of pulmonary tuberculosis (TB) is critical to TB control. However, many patients with paucibacillary TB disease remain undiagnosed. Current TB elimination goals require new tools to diagnose early disease. We evaluated performance of the Totally Optimized PCR (TOP) TB assay, a novel ultrasensitive molecular test. METHODS: We assessed analytical specificity against nontuberculous mycobacteria (NTM), and estimated the diagnostic accuracy of TOP in a pilot study in Brazil (n = 46) and a cross-sectional study in Boston (n = 60). We compared TOP results to culture and a composite reference standard (CRS). RESULTS: TOP exhibited no cross-reactivity against NTM. We tested 132 respiratory specimens from 106 patients with suspected pulmonary TB. The pilot demonstrated feasibility and 100% (95% CI 85-100) sensitivity in predominantly smear-positive specimens; TOP's specificity against solid media culture was low (58%, 37-77) but improved against a CRS (93%, 68-100). Similarly, when using the CRS in the Boston study, TOP (88%, 1-99) had greater sensitivity than solid or liquid media culture (25%, 3-65) and similar specificity (both 100%, 93-100). CONCLUSIONS: The TOP assay enables detection of M. tuberculosis in culture-negative paucibacillary disease. While the use of TOP for the diagnosis of paucibacillary disease will require further clinical validation, its high sensitivity indicate a more immediate utility as a rule out TB test.
    • GeneXpert and Community Health Workers Supported Patient Tracing for Tuberculosis Diagnosis in Conflict-Affected Border Areas in India

      Isaakidis, P; Ferlazzo, G; Das, M; Pasupuleti, D; Sloan, S; Hossain, F; Kalon, S; Mansoor, H; Rao, S (MDPI AG, 2019-12-21)
      Abstract: Médecins Sans Frontières (MSF) has been providing diagnosis and treatment for patients with tuberculosis (TB) via mobile clinics in conflict-affected border areas of Chhattisgarh, India since 2009. The study objectives were to determine the proportion of patients diagnosed with TB and those who were lost-to-follow-up (LTFU) prior to treatment initiation among patients with presumptive TB between April 2015 and August 2018. The study also compared bacteriological confirmation and pretreatment LTFU during two time periods: a) April 2015–August 2016 and b) April 2017–August 2018 (before and after the introduction of GeneXpert as a first diagnostic test). Community health workers (CHW) supported patient tracing. This study was a retrospective analysis of routine program data. Among 1042 patients with presumptive TB, 376 (36%) were diagnosed with TB. Of presumptive TB patients, the pretreatment LTFU was 7%. Upon comparing the two time-periods, bacteriological confirmation increased from 20% to 33%, while pretreatment LTFU decreased from 11% to 4%. TB diagnosis with GeneXpert as the first diagnostic test and CHW-supported patient tracing in a mobile-clinic model of care shows feasibility for replication in similar conflict-affected, hard to reach areas.
    • GeneXpert and Community Health Workers Supported Patient Tracing for Tuberculosis Diagnosis in Conflict-Affected Border Areas in India.

      Das, M; Pasupuleti, D; Rao, S; Sloan, S; Mansoor, H; Kalon, S; Hossain, F; Ferlazzo, G; Isaakidis, P (MDPI AG, 2019-12-21)
      Médecins Sans Frontières (MSF) has been providing diagnosis and treatment for patients with tuberculosis (TB) via mobile clinics in conflict-affected border areas of Chhattisgarh, India since 2009. The study objectives were to determine the proportion of patients diagnosed with TB and those who were lost-to-follow-up (LTFU) prior to treatment initiation among patients with presumptive TB between April 2015 and August 2018. The study also compared bacteriological confirmation and pretreatment LTFU during two time periods: a) April 2015–August 2016 and b) April 2017–August 2018 (before and after the introduction of GeneXpert as a first diagnostic test). Community health workers (CHW) supported patient tracing. This study was a retrospective analysis of routine program data. Among 1042 patients with presumptive TB, 376 (36%) were diagnosed with TB. Of presumptive TB patients, the pretreatment LTFU was 7%. Upon comparing the two time-periods, bacteriological confirmation increased from 20% to 33%, while pretreatment LTFU decreased from 11% to 4%. TB diagnosis with GeneXpert as the first diagnostic test and CHW-supported patient tracing in a mobile-clinic model of care shows feasibility for replication in similar conflict-affected, hard to reach areas.
    • Global programmatic use of bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis

      Cox, V; Brigden, G; Crespo, RH; Lessem, E; Lynch, S; Rich, ML; Waning, B; Furin, J (International Union Against Tuberculosis and Lung Disease, 2018-04-01)
      The World Health Organization recommended two new drugs, bedaquiline (BDQ) and delamanid (DLM), for the treatment of multidrug-resistant tuberculosis (MDR-TB) in 2013 and 2014, respectively. An estimated one third of patients with MDR-TB would benefit from the inclusion of these drugs in their treatment regimens.
    • Hepple - Microscopy compared to culture for the diagnosis of Tuberculosis in Induced Sputum samples; a systematic review

      Hepple, P; Ford, N; McNerney, R; Manson Unit, Médecins Sans Frontières, London, UK. pamela.hepple@london.msf.org (2012-03-07)
      Resource-limited settings rely on sputum examination using microscopy to diagnose tuberculosis (TB); however, the sensitivity of the test is poor and case detection rates are low. Sputum induction is proposed as a way to improve sample collection and enhance test sensitivity.
    • High Activation of γδ T Cells and the γδ2 T-Cell Subset Is Associated With the Onset of Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome, ANRS 12153 CAPRI NK.

      Polidy, P; Nouhin, J; Ratana, M; Madec, Y; Borand, L; Marcy, O; Laureillard, D; Fernandez, M; Barre-Sionussi, F; Weiss, L; et al. (Frontiers Media, 2019-08-09)
      Background: Human Immunodeficiency Virus 1 (HIV-1) and Mycobacterium Tuberculosis (Mtb) co-infected patients are commonly at risk of immune reconstitution inflammatory syndrome (IRIS) when initiating antiretroviral treatment (ART). Evidence indicates that innate immunity plays a role in TB-IRIS. Here, we evaluate the phenotype of Gamma-delta (γδ) T cells and invariant Natural Killer (iNK) T cells in tuberculosis-associated IRIS. Methods: Forty-eight HIV+/TB+ patients (21 IRIS) and three control groups: HIV-/TB- (HD, n = 11), HIV+/TB- (n = 26), and HIV-/TB+ (n = 22) were studied. Samples were taken at ART initiation (week 2 of anti-tuberculosis treatment) and at the diagnosis of IRIS for HIV+/TB+; before ART for HIV+/TB-, and at week 2 of anti-tuberculosis treatment for HIV-/TB+ patients. γδ T cells and Invariant natural killer T (iNKT) cells were analyzed by flow cytometry. Results: Before ART, IRIS, and non-IRIS patients showed a similar proportion of γδpos T and iNKT cells. HLA-DR on γδpos T cells and δ2posγδpos T cells was significantly higher in TB-IRIS vs. non-IRIS patients and controls (p < 0.0001). NKG2D expression on γδpos T cells and the δ2posγδpos T cell subset was lower in HIV+/TB+ patients than controls. CD158a expression on γδpos T cells was higher in TB-IRIS than non-IRIS (p = 0.02), HIV+/TB-, and HIV-/TB- patients. Conclusion: The higher activation of γδposT cells and the γδ2posγδpos T cell subset suggests that γδ T cells may play a role in the pathogenesis of TB-IRIS.
    • High adherence to anti-tuberculosis treatment among patients attending a hospital and slum health centre in Nairobi, Kenya

      Raguenaud, M E; Zachariah, R; Massaquoi, M; Ombeka, V; Ritter, H; Chakaya, J; Medecins Sans Fronteres (Taylor & Francis, 2008-10-22)
      We conducted a study among patients with tuberculosis (TB) attending two health facilities - a hospital and a slum health centre - in Nairobi, in order to: (a) assess adherence to anti-TB treatment; and (b) identify reasons for non-adherence. Urine Isoniazid (INH), used as a proxy for overall adherence, was detected in 142 (97%) (95% CI 92-99) of the 147 patients involved in the study. Five patients had no INH detected in urine and had run out of pills within the previous three days. The reasons included: not having enough pills to last until the next appointment date (1); and losing some pills (1). Anti-TB treatment adherence is high, and is reassuring information as Kenya plans to change to a superior first-line regimen based on rifampicin throughout the course of anti-TB treatment. Providing patients with a three-day "excess stock" of pills would provide a "safety net" for continued treatment.
    • High initial default in patients with smear-positive pulmonary tuberculosis at a regional hospital in Accra, Ghana

      Afutu, F K; Zachariah, R; Hinderaker, S G; Ntoah-Boadi, H; Obeng, E A; Bonsu, F A; Harries, A D (2012-08)
    • High Prevalence of Infection and Low Incidence of Disease in Child Contacts of Patients with Drug-resistant Tuberculosis: a Prospective Cohort Study

      Huerga, H; Sanchez-Padilla, E; Melikyan, N; Atshemyan, H; Hayrapetyan, A; Ulumyan, A; Bastard, M; Khachatryan, N; Hewison, C; Varaine, F; et al. (BMJ, 2018-12-06)
      We aimed to measure the prevalence and incidence of latent tuberculosis infection (LTBI) and tuberculosis (TB) disease in children in close contact with patients with drug-resistant TB (DR-TB) in a country with high DR-TB prevalence.
    • High prevalence of infection and low incidence of disease in child contacts of patients with drug-resistant tuberculosis: a prospective cohort study

      Huerga, H; Sanchez-Padilla, E; Melikyan, N; Atshemyan, H; Hayrapetyan, A; Ulumyan, A; Bastard, M; Khachatryan, N; Hewison, C; Varaine, F; et al. (The BMJ, 2019-07)
      Objective We aimed to measure the prevalence and incidence of latent tuberculosis infection (LTBI) and tuberculosis (TB) disease in children in close contact with patients with drug-resistant TB (DR-TB) in a country with high DR-TB prevalence. Design and setting This is a prospective cohort study of paediatric contacts of adult patients with pulmonary DR-TB in Armenia. Children were screened using tuberculin skin test, interferon-gamma release assay and chest X-ray at the initial consultation, and were reassessed every 3–6 months for a period of 24 months. Children did not receive preventive treatment. Main outcome measures Prevalence and incidence of LTBI and TB disease; factors associated with prevalent LTBI. Results At initial evaluation, 3 of the 150 children included were diagnosed with TB disease (2.0%). The prevalence of LTBI was 58.7%. The incidence of LTBI was 19.9 per 100 children per year, and was especially high during the first 6 months of follow-up (33.3 per 100 children per year). No additional cases with incident disease were diagnosed during follow-up. After adjustment, prevalent LTBI was significantly associated with the child’s age, sleeping in the same house, higher household density, the index case’s age, positive smear result and presence of lung cavities. Conclusions Children in close contact with patients with DR-TB or in contact with very contagious patients had an increased risk of prevalent LTBI. Although none of the children developed TB disease during a 2-year follow-up period, screening for symptoms of TB disease, based on the prevalence of disease at recruitment, together with follow-up and repeated testing of non-infected contacts, is highly recommended in paediatric contacts of patients with DR-TB.
    • High prevalence of multidrug-resistant tuberculosis, Swaziland, 2009-2010

      Sanchez-Padilla, E; Dlamini, T; Ascorra, A; Rüsch-Gerdes, S; Tefera, Z D; Calain, P; de la Tour, R; Jochims, F; Richter, E; Bonnet, M; et al. (Center for Disease Control, 2012-01)
      In Africa, although emergence of multidrug-resistant (MDR) tuberculosis (TB) represents a serious threat in countries severely affected by the HIV epidemic, most countries lack drug-resistant TB data. This finding was particularly true in the Kingdom of Swaziland, which has the world's highest HIV and TB prevalences. Therefore, we conducted a national survey in 2009-2010 to measure prevalence of drug-resistant TB. Of 988 patients screened, 420 new case-patients and 420 previously treated case-patients met the study criteria. Among culture-positive patients, 15.3% new case-patients and 49.5% previously treated case-patients harbored drug-resistant strains. MDR TB prevalence was 7.7% and 33.8% among new case-patients and previously treated case-patients, respectively. HIV infection and past TB treatment were independently associated with MDR TB. The findings assert the need for wide-scale intervention in resource-limited contexts such as Swaziland, where diagnostic and treatment facilities and health personnel are lacking.