The Open Microbiology Journal




ISSN: 1874-2858 ― Volume 13, 2019
RESEARCH ARTICLE

Use of Xpert MTB/RIF for the Identification of TB and Drug Resistance Among Smear-Negative and Re-Treatment Cases in Rural Areas of Ethiopia



Mesfin Worku1, *, Mulualem Agonafir2, Mubarek A. Yassin2, Mohammed A. Yassin3, Daniel G. Datiko2, Sally Theobald4, Luis E. Cuevas4
1 School of Medical Laboratory Sciences, College of Medicine and Health Science, Hawassa University, Hawassa, Ethiopia
2 REACH Ethiopia, Ethiopia
3 Global Fund to Fight AIDS Tuberculosis and Malaria, Geneva, Switzerland
4 Liverpool School of Tropical Medicine, Liverpool, United Kingdom

Abstract

Introduction:

Tuberculosis (TB) remains a leading infectious cause of morbidity and mortality worldwide. A key contributor to this burden is poor diagnosis as only 60% of new pulmonary tuberculosis (TB) cases in Africa are ever detected. Therefore, this study aimed to assess the feasibility of Xpert MTB/RIF test implementation in the region, and the performance of the assay to increase case detection on the selected rural health care setting.

Objective:

To assess the feasibility of Xpert MTB/RIF test implementation in the rural health care setting in Southern Ethiopia.

Methods:

Two Xpert MTB/RIF machines were brought in 2012 through TB REACH project. It was placed at Yirgalem hospital and at Aletawondo health centre. The instruments were installed after formal training was provided to laboratory technologists for three days. We collected sputum sample from participants who repeatedly had negative smear microscopy and those who had not responded to first-line anti-TB drugs.

Result:

Of the total participants tested, 1828 have valid result (MTB-, MTB+/RIF-, MTB+/RIF+, MTB+/RIF Indeterminate). From the participants with valid results, 217 (11.9%) were Xpert-positive of which were 165 (9.0%) RIF-negative, 6 (0.3%) RIF-indeterminate and 46 (2.5%) RIF-positive. Among TB suspects with previous treatment history and positive by Xpert, RIF resistance was detected in 10 (2.2%). From the new TB suspects with positive Xpert, RIF resistance was detected in 29 (2.7%). All cases identified were linked with TB/MDR-TB treatment centers.

Conclusion:

Xpert provides an additional tool for the diagnosis of TB and drug resistance, with almost 12% of new and retreatment cases obtaining information that is useful for clinical management. To enhance its efficient utilisation, operational challenges should be minimized particularly in relation to availing robust alternative power source.

Keyword: Xpert, Tuberculosis, SNNPR, Operational challenges, Negative smear microscopy, TB/MDR-TB.


Article Information


Identifiers and Pagination:

Year: 2019
Volume: 13
First Page: 188
Last Page: 192
Publisher Id: TOMICROJ-13-188
DOI: 10.2174/1874285801913010188

Article History:

Received Date: 23/01/2019
Revision Received Date: 16/05/2019
Acceptance Date: 22/05/2019
Electronic publication date: 30/06/2019
Collection year: 2019

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© 2019 Worku et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at theSchool of Medical Laboratory Sciences, College of Medicine and Health Science, Hawassa University, Hawassa, Ethiopia; Tel: +251911904261; Emails: mesfinwh@gmail.com




1. INTRODUCTION

Tuberculosis (TB) remains a leading infectious cause of morbidity and mortality worldwide. In 2013, there were 9.0 million new TB cases, 1.5 million TB deaths and over 36% of all cases remained undetected. The African Region had approximately one quarter of the world’s cases, and the highest rates of cases and deaths relative to its population [1World Health Organization. Global tuberculosis report 2018.].

A key contributor to this burden of morbidity and mortality is poor diagnosis as only 60% of new pulmonary tuberculosis (TB) cases in Africa are ever detected [2World Health Organization. Global tuberculosis report 2016.]. The case detection rate of TB in Ethiopia remains low (62 /100000) [1World Health Organization. Global tuberculosis report 2018.] and this inadequate case detection reflects, in part, the limitations of the diagnostic used, with sputum smear microscopy remaining the mainstay of TB diagnosis in countries with limited resources [3Walker D, McNerney R, Mwembo MK, Foster S, Tihon V, Godfrey-Faussett P. An incremental cost-effectiveness analysis of the first, second and third sputum examination in the diagnosis of pulmonary tuberculosis. Int J Tuberc Lung Dis 2000; 4(3): 246-51.
[PMID: 10751071]
-5Steingart KR, Ramsay A, Pai M. Optimizing sputum smear microscopy for the diagnosis of pulmonary tuberculosis. Expert Rev Anti Infect Ther 2007; 5(3): 327-31.
[http://dx.doi.org/10.1586/14787210.5.3.327] [PMID: 17547496]
].

Accurate and rapid detection of TB and drug resistant-TB is vital to improve patient outcomes, increase the cure rate and decrease mortality [6Policy Framework WHO. 2010 World Health Organization Policy framework for implementing new tuberculosis diagnostics 2011.]. In 2010, WHO endorsed a rapid, automated, cartridge-based nucleic acid amplification test (NAAT), the Xpert MTB/RIF assay (Cepheid, Sunnyvale, USA), that simultaneously detects the presence of TB and genetic markers of rifampicin (RIF) resistance.The assay has high sensitivity (89%) and specificity (99%) for pulmonary TB detection [7Denkinger CM, Schumacher SG, Boehme CC, Dendukuri N, Pai M, Steingart KR. Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis. Eur Respir J 2014; 44(2): 435-46.
[http://dx.doi.org/10.1183/09031936.00007814] [PMID: 24696113]
].

The Ethiopian TB control program uses a passive strategy to identify cases of TB and patients are mostly identified when they attend curative and diagnostic services. To complement this approach, we have implemented a community-based approach in which health extension workers (HEWs) conduct house to house visits to identify individuals with chronic cough or, collect sputum for examination, which is collected by supervisors and examined at the nearby designated microscopy centre, as described in Yasin et al. 2013 [8Yassin MA, Datiko DG, Tulloch O, et al. Innovative community-based approaches doubled tuberculosis case notification and improve treatment outcome in Southern Ethiopia. PLoS One 2013; 8(5)e63174
[http://dx.doi.org/10.1371/journal.pone.0063174] [PMID: 23723975]
]. The approach increased case notification and improved treatment uptake.

To optimise the identification of patients, we also implemented the Xpert MTB/RIF platform at two selected sites in the Southern Nations, Nationalities and Peoples Region (SNNPR).

2. MATERIALS AND METHODS

2.1. Settings

Yirgalem Hospital is a tertiary health care hospital serving the population of south nations and nationalities (SNNPR). About 15 million populations are getting service by the hospital from South Nation and Nationalities Region (SNNPR) and the neighbor Oromia region. The hospital is located 317 km south from capital Addis Ababa and 45 km from Hawassa town. In the hospital a Directly Observed Therapy; Short-Course (DOTS) clinic is operating under the National Tuberculosis and LeprosyControl Program (NTLCP) of Ethiopia, under which the diagnosis of pulmonary TB is followed by an examination of three sputum smears (spot morning spot) by Zihel –Nielsen staining method for acid-fast bacilli (AFB). Chest radiographs and pathological investigations are also used to support the diagnosis. Patients diagnosed with tuberculosis are referred to the DOTS clinic where they are registered and treated according to the national TLCP guideline (Ministry of Health of Ethiopia (MOH)

2.2. Study Design

We conducted a prospective study to evaluate the diagnostic ability of Xpert MTB/RIF in identifying patients with pulmonary TB in children with the Human Immunodeficiency Virus (HIV), children, patients who repeatedly had negative smear microscopy and those who had not responded to first-line anti-TB drugs and were suspected to have drug resistance. The study was conducted in 19 rural districts of Sidama zone of the SNNPR with a predominantly farming subsistence population. Two Xpert MTB/RIF machines were brought in 2012 through TB REACH project. The platform was the first of its kind to be used in rural health facility settings of the nation. It was placed at Yirgalem hospital, one of the oldest hospitals found in the country, and at Aletawondo health centre. The hospital serves people of 19 rural districts, two administrative towns and areas bordering the Sidama zone. Similarly, the two machines were assumed to provide service to the Sidama zone and bordering area.

2.3. Training

The instruments were installed after formal training that included theoretical and hands-on practice was provided to laboratory technologists for three days. A separate laboratory register was prepared to simultaneously keep the results and patient details in a hard copy. As a follow-up, frequent supervisions were conducted and on-site refresher trainings were provided on troubleshooting, maintenance and data management.

2.4. Source of Sputum Specimen

We collected sputum sample from patients with pulmonary TB in children with the Human Immunodeficiency Virus (HIV), children, patients who repeatedly had negative smear microscopy and those who had not responded to first-line anti-TB drugs and were suspected to have drug resistance to see detection rate of Xpert MTB/RIF testing machine.

2.5. Study Procedures

Health Extension Workers (HEWs) interviewed and enrolled study presumptive TB patients who have consented using a structured questionnaire for demographic, clinical and epidemiological data that is provided by the national TB control program. Before collecting the first specimen, interviews were conducted by field supervisors.

2.6. Sample Collection and Processing

3–5ml of sputum was spat carefully by each participant into a wide-mouthed, unbreakable, leak-proof container and closed the lid tightly. The sample was placed in re-sealable plastic bag kept in a cold chain and finally transported to the Xpert MTB/RIF testing sites in less than 24 hours.

2.7. Gene Xpert Testing

The Xpert MTB/RIF assay was performed according to the manufacturer’s instructions. A sputum sample reagent buffer containing NaOH and isopropanol was added at 2:1 ratio to the untreated sputum ensuring a final volume of at least 2 ml. Manually agitated and kept for 10 min at room temperature, then shaken again and kept for 5 min; 2 ml of the inactivated material was transferred to the cartridge containing the wash buffer, reagents for lyophilized DNA extraction and PCR amplification, and fluorescent detection probes. The cartridge was placed in the test platform of the instrument. Results wereautomatically generated within 2 h and reported as M. TB-negative or - positive (with semi-quantification) and RIF sensitive or resistant.

2.8. Data Analysis

Data was exported from the instrument to an MS Excel sheet and analyzed using SPSS version 20 (SPSS, Inc., Chicago, USA). Proportions were computed and Chi-square test was applied to assess group differences. P values<0.05 were considered significant.

2.9. Ethics Approval

The operational research was conducted under routine National TB Programme and implemented by TB programme coordinators and health workers in the public health sector. Therefore, ethical clearance was not required for the research. However, we have obtained informed consent from the study participants. Study participants who were diagnosed to have TB were started on anti-Tb treatment as per the National Guideline. We have offered advice to patients who were negative by the test to undergo further medical examination [16MoH. 2014.].

3. RESULTS

From March 2012- April 2014, Xpert MTB/RIF test was utilized to diagnose TB among 2024 presumptive TB cases. The participant composition involved 1098 (54.2%) female, 926 (46.8%) male and 108(5.3%) paediatric presumptive TB cases. Majority of the participants were married (80%), had no formal education 1173 (83.1%) and had the previous history of TB treatment1186 (69.9%)

In addition to chronic cough for 8 weeks and above 1270 (76.3%), the participants had clinical symptoms such as fever 1778 (94.9%), weight loss 1750 (94.3%), night sweating 1820 (97.1%), loss of appetite 1752 (93.6%) and chest pain 1790 (95.3%). From the participants who had x-ray and HIV tests performed, 65 (18.1%) had abnormal x-ray suggestive of TB and 35 (5.2%) were HIV positive, respectively.

Of the total participants tested, 1798 (88.8%) have valid result (MTB-, MTB+/RIF-, MTB+/RIF+, MTB+/RIF Indeterminate). The remaining 226(11.2%) had failed tests (error, invalid or no result). From the participants with valid results, 217 (11.9%) were Xpert-positive of which were 161 (8.0%) RIF-negative, 6 (0.3%) RIF-indeterminate and 45 (2.2%) RIF-positive (Table 1).

Table 1
Xpert results for the detection of M. tuberculosis in Southern Ethiopia.


Among TB suspects with previous treatment history and positive by Xpert, RIF resistance was detected in 11 (2.0%). From the new TB suspects with positive Xpert, RIF resistance was detected in 34 (2.7%) Table 2. All cases identified were linked with TB/MDR-TB treatment centres.

The majority of 169 (79.3%) TB cases detected were in the age group 15-44 years. The number of TB cases detected among participants with no previous TB contact history is twice that of the participants with contact history. Similarly, the number of cases detected among participants with no previous treatment history was twice that of participants with previous treatment history. More males (114) were detected than females (Table 3).

Table 2
The proportion of Xpert positivity and rifampicin resistance in previously treated cases.


4. DISCUSSION

Using Xpert has high sensitivity and specificity in detecting MTB in both smear negative and positive among clinical specimens [7Denkinger CM, Schumacher SG, Boehme CC, Dendukuri N, Pai M, Steingart KR. Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis. Eur Respir J 2014; 44(2): 435-46.
[http://dx.doi.org/10.1183/09031936.00007814] [PMID: 24696113]
, 9Iram S, Zeenat A, Hussain S, Wasim Yusuf N, Aslam M. Rapid diagnosis of tuberculosis using Xpert MTB/RIF assay - Report from a developing country. Pak J Med Sci 2015; 31(1): 105-10.
[http://dx.doi.org/10.12669/pjms.311.6970] [PMID: 25878624]
, 10Moure R, Muñoz L, Torres M, Santin M, Martín R, Alcaide F. Rapid detection of Mycobacterium tuberculosis complex and rifampin resistance in smear-negative clinical samples by use of an integrated real-time PCR method. J Clin Microbiol 2011; 49(3): 1137-9.
[http://dx.doi.org/10.1128/JCM.01831-10] [PMID: 21191053]
] more specifically could be used as a routine method in screening smear-negative patients with high suspicion of TB [9Iram S, Zeenat A, Hussain S, Wasim Yusuf N, Aslam M. Rapid diagnosis of tuberculosis using Xpert MTB/RIF assay - Report from a developing country. Pak J Med Sci 2015; 31(1): 105-10.
[http://dx.doi.org/10.12669/pjms.311.6970] [PMID: 25878624]
]. We report a high prevalence of MTB+ as high as 11.2% in remote and rural settings in Ethiopia more among women. This was attributable to the reduced barriers to services through community-based intervention [8Yassin MA, Datiko DG, Tulloch O, et al. Innovative community-based approaches doubled tuberculosis case notification and improve treatment outcome in Southern Ethiopia. PLoS One 2013; 8(5)e63174
[http://dx.doi.org/10.1371/journal.pone.0063174] [PMID: 23723975]
, 11Datiko DG, Lindtjørn B. Health extension workers improve tuberculosis case detection and treatment success in southern Ethiopia: A community randomized trial. PLoS One 2009; 4(5)e5443
[http://dx.doi.org/10.1371/journal.pone.0005443] [PMID: 19424460]
]. A similar study conducted in Benin supported that The Xpert MTB/RIF test has superior performance for rapid diagnosis of Mycobacterium tuberculosis over existing AFB smear microscopy [17Ochei K, Chinedum A, Emwiomwan O, Emmanuel I, Aminu B. Comparative Analysis of Ziehl-Neelsen and Genexpert Techniques for the Diagnosis of Tuberculosis in Human Immuno-Deficiency Virus Positive Patients in Benin City. Ann Clin Lab Res 2017; 5(4): 208.]. Another similar study conducted somewhere else indicated that GeneXpert has a higher sensitivity than AFB smear microscopy in respiratory samples. GeneXpert can be a useful tool for early diagnosis of patients with high clinical suspicion of pulmonary tuberculosis [18Agrawal M, Bajaj A, Bhatia V, Dutt S. Comparative Study of GeneXpert with ZN Stain and Culture in Samples of Suspected Pulmonary Tuberculosis. J Clin Diagn Res 2016; 10(5): DC09-12.
[http://dx.doi.org/10.7860/JCDR/2016/18837.7755] [PMID: 27437 212]
]. Another study report in Nigeria indicated that Xpert gene assay methods in TB/MDRTB diagnosis in their facility reveal high positive TB and Rifampicin resistance [19Okonkwo RC, Onwunzo MC, Chukwuka CP, et al. The use of the Gene Xpert mycobacterium tuberculosis/rifampicin (mtb/rif) assay in detection of multi-drug resistant tuberculosis (mdrtb) in Nnamdi Azikiwe University Teaching Hospital, Nnewi, Nigeria Journal of HIV and Retro virus 2017; 3(1)
[http://dx.doi.org/0.21767/2471-9676.100028]
].

Furthermore, the majority of the cases were aged between 15-44 years which are economically productive workforce [12Frieden TR, Sterling TR, Munsiff SS, Watt CJ, Dye C. Tuberculosis. Lancet 2003; 362(9387): 887-99.
[http://dx.doi.org/10.1016/S0140-6736(03)14333-4] [PMID: 136789 77]
].

Ethiopia is one of the five African countries listed as countries with a high number of missed cases [1World Health Organization. Global tuberculosis report 2018.]. The innovative community-based approach practiced in the SNNP regional state of Ethiopia had demonstrated the detection of more TB cases [8Yassin MA, Datiko DG, Tulloch O, et al. Innovative community-based approaches doubled tuberculosis case notification and improve treatment outcome in Southern Ethiopia. PLoS One 2013; 8(5)e63174
[http://dx.doi.org/10.1371/journal.pone.0063174] [PMID: 23723975]
]. Moreover, the introduction of rapid and highly sensitive ‘point of care’ diagnostic tools such as Xpert could avert events that could occur as a result of the use of less sensitive methods thereby increasing case notification. This study demonstrated that Xpert picks a significant proportion of TB cases in rural settings where AFB smear microscopy is the cornerstone of TB diagnosis and other more sensitive diagnostic tools such as culture are scarce In the current study, Xpert was able to detect 11.9% TB cases (of which 1% children) that were otherwise missed by smear microscopy. Similarly, a study conducted in Pakistan has revealed that Xpert was able to detect 10-15% more cases than ZN microscopy in smear-negative cases [9Iram S, Zeenat A, Hussain S, Wasim Yusuf N, Aslam M. Rapid diagnosis of tuberculosis using Xpert MTB/RIF assay - Report from a developing country. Pak J Med Sci 2015; 31(1): 105-10.
[http://dx.doi.org/10.12669/pjms.311.6970] [PMID: 25878624]
].

Table 3
TB Risk factors and Xpert positivity among participants.


In this study of 1798 (88.8%) valid results (MTB-, MTB+/RIF-, MTB+/RIF+, MTB+/RIF Indeterminate), 45 (2.2%) were with rifampicin resistance TB. This finding is comparable to a similar study conducted in Nigeria (1.4%) [19Okonkwo RC, Onwunzo MC, Chukwuka CP, et al. The use of the Gene Xpert mycobacterium tuberculosis/rifampicin (mtb/rif) assay in detection of multi-drug resistant tuberculosis (mdrtb) in Nnamdi Azikiwe University Teaching Hospital, Nnewi, Nigeria Journal of HIV and Retro virus 2017; 3(1)
[http://dx.doi.org/0.21767/2471-9676.100028]
]. However, another similar study conducted elsewhere reported a higher rate of rifampicin resistance TB (25.23%) [21Nourjahan L, Akram H, Jannatu F, Mominur R. GeneXpert MTB/RIF assay for rapid identification of mycobacterium tuberculosis and rifampicin resistance directly from sputum sample. J Enam Med Col 2017; 7(2): 86-9.
[http://dx.doi.org/10.3329/jemc.v7i2.32653]
]. The probable reason attributed to this variation could be the sample size used and the geographic variation. The majority were initiated on MDR-TB treatment except few who were deceased at the initial stages of the Xpert implementation [6Policy Framework WHO. 2010 World Health Organization Policy framework for implementing new tuberculosis diagnostics 2011., 13Yoon C, Cattamanchi A, Davis JL, et al. Impact of Xpert MTB/RIF testing on tuberculosis management and outcomes in hospitalized patients in Uganda. PLoS One 2012; 7(11)e48599
[http://dx.doi.org/10.1371/journal.pone.0048599] [PMID: 23139799]
, 14Bygrave H, Simons S, Munyaradzi D, Nyagadza B. Implementing Xpert® MTB/RIF in rural Zimbabwe: impact on diagnosis of smear-negative TB and time-to-initiation of TB treatment in smear-negative patients co-infected with HIV. Abstract In: XIX International AIDS Conference; Washington DC, USA. 2012.2012.].

In our study, over 75.6% (34/45) of the cases identified as having rifampicin resistance had no history of previous TB treatment and this underlines the importance of rapid resistance testing in patients with no history of TB. This indicated that Xpert MTB/RIF has an added value in detecting MTB and drug resistance that facilitated and supported the community-based intervention in the study site. This is also supported by a study entitled “The implementation of Xpert MTB/RIF assay for diagnosis of tuberculosis “conducted in Nepal [15Osman M, Simpson JA, Caldwell J, Bosman M, Nicol MP. GeneXpert MTB/RIF version G4 for identification of rifampin-resistant tuberculosis in a programmatic setting. J Clin Microbiol 2014; 52(2): 635-7.
[http://dx.doi.org/10.1128/JCM.02517-13] [PMID: 24478501]
, 20Joshi B, Lestari T, Graham SM, et al. The implementation of Xpert MTB/RIF assay for diagnosis of tuberculosis in Nepal: A mixed-methods analysis. PLoS One 2018; 13(8)e0201731
[http://dx.doi.org/10.1371/journal.pone.0201731] [PMID: 30096174]
].

We were not able to corroborate the rifampicin-resistant results with phenotypic drug susceptibility method which is considered as the golden standard. This was the limitation of the current study. Despite the mentioned problems of implementation and limitation of the study, it was possible to demonstrate the usefulness of Xpert in increasing case detection and confirming drug resistance in resource-limited settings such as ours. The findings of this study will be additional input to further optimize the implementation of the tool in other sites by the control program.

CONCLUSION

As a conclusion, Gene Xpert can be a valuable diagnostic tool in patients of suspected Pulmonary Tuberculosis either AFB smear negative or positive due to its rapidity and synchronized detection of Rifampicin resistance especially advantageous in a patient with MDR and HIV associated tuberculosis. However, cost-effectiveness of GeneXpert especially cartridge and realization of continuous supply of electric power in low-income countries like Ethiopia with a high prevalence of tuberculosis needs special emphasis.

LIST OF ABBREVIATIONS

FMoH = Federal Ministry of Health of Ethiopia
MDR-TB = multidrug resistant tuberculosis
MTB+ = Mycobacterium tuberculosis positive
MTB- = Mycobacterium tuberculosis negative
RIF- = Refampicin

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Not applicable.

HUMAN AND ANIMAL RIGHTS

No animals/humans were used for studies that are the basis of this research.

CONSENT FOR PUBLICATION

We have obtained informed consent from the study participants. Study participants who were diagnosed to have TB were started on anti-Tb treatment as per the National Guideline.

AVAILABILITY OF DATA AND MATERIALS

The data used for the analysis of the current study are available from the corresponding author on reasonable request.

FUNDING

The study was funded by TB REACH Initiative of the Stop TB Partnership. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

AUTHORS’ CONTRIBUTIONS

DGD, LEC, Mohammed AY and ST conceived the study. Mubarek AY and MAC lead the field work. DGD, LEC, Mohammed AY and MW did the data analyses and write up of the manuscript. All authors have approved the final submitted manuscript.

ACKNOWLEDGEMENTS

We are grateful to the field supervisors, HEWsand laboratory technologists for their support. We also thank the Ministry of Health of Ethiopia, Southern Region Health Bureau, Sidama Zone Health Department, Aletawondo District Health Bureau and Yirgalem hospital.

REFERENCES

[1] World Health Organization. Global tuberculosis report 2018.
[2] World Health Organization. Global tuberculosis report 2016.
[3] Walker D, McNerney R, Mwembo MK, Foster S, Tihon V, Godfrey-Faussett P. An incremental cost-effectiveness analysis of the first, second and third sputum examination in the diagnosis of pulmonary tuberculosis. Int J Tuberc Lung Dis 2000; 4(3): 246-51.
[PMID: 10751071]
[4] Mathew P, Kuo YH, Vazirani B, Eng RH, Weinstein MP. Are three sputum acid-fast bacillus smears necessary for discontinuing tuberculosis isolation? J Clin Microbiol 2002; 40(9): 3482-4.
[PMID: 12202598]
[5] Steingart KR, Ramsay A, Pai M. Optimizing sputum smear microscopy for the diagnosis of pulmonary tuberculosis. Expert Rev Anti Infect Ther 2007; 5(3): 327-31.
[http://dx.doi.org/10.1586/14787210.5.3.327] [PMID: 17547496]
[6] Policy Framework WHO. 2010 World Health Organization Policy framework for implementing new tuberculosis diagnostics 2011.
[7] Denkinger CM, Schumacher SG, Boehme CC, Dendukuri N, Pai M, Steingart KR. Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis. Eur Respir J 2014; 44(2): 435-46.
[http://dx.doi.org/10.1183/09031936.00007814] [PMID: 24696113]
[8] Yassin MA, Datiko DG, Tulloch O, et al. Innovative community-based approaches doubled tuberculosis case notification and improve treatment outcome in Southern Ethiopia. PLoS One 2013; 8(5)e63174
[http://dx.doi.org/10.1371/journal.pone.0063174] [PMID: 23723975]
[9] Iram S, Zeenat A, Hussain S, Wasim Yusuf N, Aslam M. Rapid diagnosis of tuberculosis using Xpert MTB/RIF assay - Report from a developing country. Pak J Med Sci 2015; 31(1): 105-10.
[http://dx.doi.org/10.12669/pjms.311.6970] [PMID: 25878624]
[10] Moure R, Muñoz L, Torres M, Santin M, Martín R, Alcaide F. Rapid detection of Mycobacterium tuberculosis complex and rifampin resistance in smear-negative clinical samples by use of an integrated real-time PCR method. J Clin Microbiol 2011; 49(3): 1137-9.
[http://dx.doi.org/10.1128/JCM.01831-10] [PMID: 21191053]
[11] Datiko DG, Lindtjørn B. Health extension workers improve tuberculosis case detection and treatment success in southern Ethiopia: A community randomized trial. PLoS One 2009; 4(5)e5443
[http://dx.doi.org/10.1371/journal.pone.0005443] [PMID: 19424460]
[12] Frieden TR, Sterling TR, Munsiff SS, Watt CJ, Dye C. Tuberculosis. Lancet 2003; 362(9387): 887-99.
[http://dx.doi.org/10.1016/S0140-6736(03)14333-4] [PMID: 136789 77]
[13] Yoon C, Cattamanchi A, Davis JL, et al. Impact of Xpert MTB/RIF testing on tuberculosis management and outcomes in hospitalized patients in Uganda. PLoS One 2012; 7(11)e48599
[http://dx.doi.org/10.1371/journal.pone.0048599] [PMID: 23139799]
[14] Bygrave H, Simons S, Munyaradzi D, Nyagadza B. Implementing Xpert® MTB/RIF in rural Zimbabwe: impact on diagnosis of smear-negative TB and time-to-initiation of TB treatment in smear-negative patients co-infected with HIV. Abstract In: XIX International AIDS Conference; Washington DC, USA. 2012.2012.
[15] Osman M, Simpson JA, Caldwell J, Bosman M, Nicol MP. GeneXpert MTB/RIF version G4 for identification of rifampin-resistant tuberculosis in a programmatic setting. J Clin Microbiol 2014; 52(2): 635-7.
[http://dx.doi.org/10.1128/JCM.02517-13] [PMID: 24478501]
[16] MoH. 2014.
[17] Ochei K, Chinedum A, Emwiomwan O, Emmanuel I, Aminu B. Comparative Analysis of Ziehl-Neelsen and Genexpert Techniques for the Diagnosis of Tuberculosis in Human Immuno-Deficiency Virus Positive Patients in Benin City. Ann Clin Lab Res 2017; 5(4): 208.
[18] Agrawal M, Bajaj A, Bhatia V, Dutt S. Comparative Study of GeneXpert with ZN Stain and Culture in Samples of Suspected Pulmonary Tuberculosis. J Clin Diagn Res 2016; 10(5): DC09-12.
[http://dx.doi.org/10.7860/JCDR/2016/18837.7755] [PMID: 27437 212]
[19] Okonkwo RC, Onwunzo MC, Chukwuka CP, et al. The use of the Gene Xpert mycobacterium tuberculosis/rifampicin (mtb/rif) assay in detection of multi-drug resistant tuberculosis (mdrtb) in Nnamdi Azikiwe University Teaching Hospital, Nnewi, Nigeria Journal of HIV and Retro virus 2017; 3(1)
[http://dx.doi.org/0.21767/2471-9676.100028]
[20] Joshi B, Lestari T, Graham SM, et al. The implementation of Xpert MTB/RIF assay for diagnosis of tuberculosis in Nepal: A mixed-methods analysis. PLoS One 2018; 13(8)e0201731
[http://dx.doi.org/10.1371/journal.pone.0201731] [PMID: 30096174]
[21] Nourjahan L, Akram H, Jannatu F, Mominur R. GeneXpert MTB/RIF assay for rapid identification of mycobacterium tuberculosis and rifampicin resistance directly from sputum sample. J Enam Med Col 2017; 7(2): 86-9.
[http://dx.doi.org/10.3329/jemc.v7i2.32653]
[22] Joshi B, Lestari T, Graham SM, et al. The implementation of Xpert MTB/RIF assay for diagnosis of tuberculosis in Nepal: A mixed-methods analysis. PLoS One 2018; 13(8)e0201731
[http://dx.doi.org/10.1371/journal.pone.0201731] [PMID: 30096174]

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Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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