Frequency of MTB and rifampicin resistance MTB using Xpert-MTB/RIF assay among adult presumptive tuberculosis patients in Tigray, Northern Ethiopia: A cross sectional study

Araya Gebreyesus Wasihun; Tsehaye Asmelash Dejene; Genet Gebrehiwet Hailu

doi:10.1371/journal.pone.0240361

. 2020 Nov 4;15(11):e0240361. doi: 10.1371/journal.pone.0240361

Frequency of MTB and rifampicin resistance MTB using Xpert-MTB/RIF assay among adult presumptive tuberculosis patients in Tigray, Northern Ethiopia: A cross sectional study

Araya Gebreyesus Wasihun ^1,^*, Tsehaye Asmelash Dejene ^1,², Genet Gebrehiwet Hailu ¹

Editor: Shampa Anupurba³

PMCID: PMC7641410 PMID: 33147218

Abstract

Background

Multidrug-resistant tuberculosis (MDR-TB) continues to be a global health problem. Data on rifampicin resistance MTB using Xpert- MTB/RIF assay in Ethiopia, particularly in the study area is limited. The aim of this study was to determine the frequency of MTB and rifampicin resistant-MTB among presumptive tuberculosis patients in Tigray, Northern Ethiopia.

Methods

A multicenter retrospective study was conducted among presumptive TB patients from five governmental hospitals and one comprehensive specialized teaching hospital in Tigray regional state. Records of sputum sample results of presumptive MTB patients with Xpert-MTB/RIF assay from January 2016 to December 2019 were investigated. Data extraction tool was used to collect data from registration books and analyzed using SPSS ver.21 statistical software. Statistical significance was set at p-value ≤ 0.05.

Results

Of the 30,935 presumptive adult TB patients who have provided specimens for TB diagnosis from January 2016 to December 2019, 30,300 (98%) had complete data and were included in this study. More than half, 17,471 (57.7%) were males, and the age of the patients ranged from 18–112 years, with a median age of 40.65 (interquartile 29.4–56.5 years). Majority, 28,996 (95.7%) of the participants were treatment naïve, and 23,965 (79.1%) were with unknown HIV status. The overall frequency of MTB was 2,387 (7.9% (95% CI: 7.6–8.2%); of these, 215 (9% (95% CI: 7.9–10.2%) were rifampicin resistant-MTB. Age (18–29 years), HIV positive and previous TB treatment history were significantly associated with high MTB (p < 0.001), whereas gender (being female) was associated with low MTB (p < 0.001). Likewise, rifampicin resistant-MTB was more prevalent among relapse (p < 0.001) and failure cases (p = 0.025); while age group 30–39 years was significantly associated with lower frequency of rifampicin resistant-MTB (p = 0.008).

Conclusion

Frequency of MTB among tuberculosis presumptive patients was low; however, the problem of rifampicin resistant-MTB among the tuberculosis confirmed patients was high. The high frequency of MTB and RR-MTB among previously treated and HIV positive patients highlights the need for more efforts in TB treatment and monitoring program in the study area.

Introduction

Tuberculosis (TB) is one the top ten causes of mortality and the first killer among infectious diseases worldwide. Multidrug resistant Mycobacterium tuberculosis (MDR-MTB), defined as resistant to at least isoniazid and rifampicin, is a major global health problem. According to the 2019 report of the WHO, globally, an estimated 10.0 million (range, 9.0–11.1 million) people fell ill with TB and about 1.2 million (range, 1.1–1.3 million) TB deaths among HIV-negative people were reported in 2018. Similarly, there were about half a million new cases of rifampicin-resistant TB (of which 78% had multidrug-resistant TB) in the 2018 [1]. Delay in early diagnosis and appropriate treatment initiation, and high prevalence of HIV in resource limited settings made TB and MDR-TB associated morbidity and mortality to be quite high [2, 3].

The WHO endorsed Xpert MTB/RIF assay in 2010, an automated molecular system which detects both DNA of MTB and rifampicin resistance (RR) simultaneously [4]. Rifampicin resistant -MTB (RR-MTB) is a proxy marker for MDR-TB in more than 90% of the cases [5]. Initially, the assay was indicated for patients with TB/HIV co-infection, presumptive MDR-TB and paediatrics TB patients [6]. Three years after its implementation it was recommended for all TB presumptive patients [7]. In Ethiopia Xpert- MTB/RIF assay was implemented in all general and referral hospitals since 2014 [8].

Ethiopia is one of the 30 high TB, TB/HIV and MDR-TB burdened countries with a rank of 15th among the high MDR-TB countries with more than 5800 estimated MDR-TB cases each year [9]. A systematic review from Ethiopia reported that 2.18% of TB treatment naïve and 21.07% of previously treated patients had MDR-TB nationwide [10]. Most studies in Ethiopia used the conventional culture and sensitivity methods not the automated Xpert -MTB/RIF assay. There are few studies in Ethiopia such as: Addis Ababa [11], Amhara regional state [4] and Southern Ethiopia [12] on prevalence of TB and rifampicin resistant MTB (RR-MTB) using Xpert- MTB/RIF assay. However, these studies were far from complete because of their area coverage. For example, the report from the Amhara regional state and south Ethiopia included single hospital each and used small sample size. Similarly, the study conducted in Addis Ababa included 12,414 samples from four health facilities, but this cannot represent the national level prevalence. The limitations of the previous studies calls for more data to be generated from each region with representative sample to forward reasonable findings and recommendations to help policy makers and implementers to plan and design proper intervention strategies to control TB.

In Tigray regional state, a total of 9,594 TB cases were reported in 2015 [13]. There are only two studies on MDR-TB in this region [14, 15]. Both of the studies, however, were done on presumptive MDR-TB patients (failure, relapsed, and who have contact with MDR TB patients) which could not show the magnitude of MTB and RR-MTB among the presumptive TB patients in the region. Hence, addressing this knowledge gap on the prevalence and associated factors of TB and RR-MTB among presumptive adult TB patients in the study area is rational to help policy makers and implementers to plan and design proper intervention to achieve the strategy “End TB by 2035.”

Methods

Study design and study population

Study setting

Tigray Regional state is the North most region of the Federal Democratic Republic of Ethiopia with population size of 6,960,003 with an area of 54, 572.6 km². The capital city of Tigray is Mekelle, located 783 km north of Addis Ababa, the capital of Ethiopia. The region is bordered by Sudan in the west, Eritrea in the north, Afar regional state in the East and Amhara regional state in the South. It is administratively divided into seven Zones and 52 districts (34 rural and 18 urban). In the region, health services are provided by one teaching and specialized hospital, 12 general hospitals, 22 primary hospitals, 204 health centers, 712 health posts [village clinic] and 500 private health facilities. In the region Xpert-MTB/RIF assay for TB diagnosis is given in the general hospitals not the primary hospitals.

A multicenter health facility based retrospective cross sectional study design was used to collect data from January 2016 to December 2019 from five governmental general hospitals. In this study, general hospitals which introduced Xpert since 2016 were included. Thus, from the 10 general hospitals which introduced Xpert-MTB/RIF assay for MTB diagnosis five hospitals, and one comprehensive specialized teaching hospital were included namely: Adigrat, Wukro, Mekelle, Lemelem Karli, Alamata and Ayider comprehensive specialized teaching hospital located in the three zones of the region (Eastern zone, Southern zone and Mekelle special zone. Directly observed treatment, short-course (DOTS) TB treatment services are given in all the health facilities. The region had three MDR-TB treatment initiation centers and 52 treatment follow-up centers (Fig 1).

The source population were all adult patients with clinical signs and symptoms suggestive of MTB and visited the hospitals between January 2016 and December 2019, and gave sputum samples for Xpert MTB/RIF assay. Our study participants were all adult patients (≥18 years) whose data of age, sex, Xpert MTB/RIF results, HIV status and MTB treatment history were recorded in the registration book. Whereas, those children and with any missing information in age, gender, Xpert MTB/RIF results, invalid, indeterminate Xpert MTB/RIF results, HIV status and TB treatment history were excluded from the study.

Inclusion criteria

We included all presumptive TB adult patients (above ≥18 years) with complete record of age, sex, Xpert -MTB/RIF results, HIV status, and TB treatment history. Whereas, children and adults with any missing record on age, gender, Xpert- MTB/RIF results, invalid, indeterminate Xpert MTB/RIF results, HIV status, and TB treatment history were excluded from the study.

Variables

Outcome variable

MTB and RR-MTB among presumptive TB patients.

Independent variables

Age, gender, HIV status and TB treatment history.

Operational definitions

New cases

Patients have never been treated for TB before

Relapse case

Is a TB patient who has become (and remained) culture negative while receiving therapy but after completion of therapy becomes: culture positive again

Lost to follow up

A TB patient who did not start treatment or whose treatment was interrupted for 2 consecutive months or more

Failure case

Is a TB patient whose sputum smear or culture is positive at month 5 or later during treatment

MDR-TB

TB that does not respond to at least isoniazid and rifampicin, the most important first-line anti-TB drugs

Rifampicin-resistant TB (RR-TB)

Defined as resistance to rifampicin detected using genotypic or phenotypic methods with or without resistance to other first-line anti-TB drugs

Data collection

Patients’ socio-demographic characteristics (such as age and sex) and clinical-related data (such as Xpert MTB/RIF results, HIV status, and MTB treatment history) were collected using a structured data extraction sheet from Xpert MTB/RIF paper based registration books in each health facilities.

Laboratory processing

A single sputum sample per patient was used for the diagnosis of TB using Xpert-MTB/RIF assay (Cepheid, Sunnyvale, CA, USA). Briefly, after sputum was collected, it was mixed with sample reagent buffer in 1:2 (sample: sample reagent buffer) volume ratio. Then, closing it tightly, vortexed for 15 seconds and allowed to stand at room temperature for 10 min. It was again vortexed after 10 min and allowed to stand for 5 min, using the Pasteur pipette provided with the kit >2mL of the (just above 2mL mark on pipette) processed sample was put into the Xpert -MTB/RIF cartridge. Then the cartridge with the specimen was loaded to the Xpert machine. Finally, results were collected from the Xpert computer after 2h [16].

HIV testing

Rapid HIV test was done according to the national algorithm of the Federal Ministry of Health of Ethiopia.

Data analysis

After data completeness is checked, data was entered and analyzed using SPSS Version 21. Frequency, mean, range and standard deviation were computed. Chi-square and logistic regression analysis were done to identify the associated factors with MTB and RR-MTB. Significant variables in binary logistic regression were analyzed using multiple logistic regressions to identify variables which had association with MTB and RR-MTB at p ≤ 0.05.

Ethical consideration

Before the study was conducted, ethical clearance was obtained from Aksum University; College of Health Sciences Institutional Review Board (IRB). Besides, a letter of cooperation was written from the Tigray Regional Health Bureau to each study hospitals and permission was obtained accordingly.

Result

Socio-demographic, clinical characteristics and MTB results

Out of the total 30, 935 presumptive adult TB patients who have provided sputum samples for MTB diagnosis, 30,300 (98%) had complete data and were included in this study. More than half 17,471 (57.7%) were males and the median age was 40.65 (interquartile 29.4–56.5 years). The majority, 28,996 (95.7%) and 23,965 (79.1%) of the participants were treatment naïve and with unknown HIV status, respectively. Overall, the frequency of MTB was 2387(7.9%), of those, frequency of RR-MTB was 215 (9%) (Table 1).

Table 1. Socio-demographic, clinical characteristics and MTB result among presumptive adult patients in Eastern, Mekelle and Southern Zones of Tigray, Ethiopia, 2016–2019 (N = 30,300).

Variables	Frequency	%
Gender
Male	17471	57.7
Female	12829	42.3
Age
18–29	7453	24.6
30–39	6300	20.8
40–49	5349	17.7
50–59	4337	14.3
60–69	3749	12.4
70–112	3112	10.3
HIV Status
Positive	2675	8.8
Negative	3660	12.1
Unknown	23965	79.1
TB Treatment History
New case	28996	95.7
Relapse	1222	4
Lost	25	0.1
Failure	57	0.2
MTB Result
Detected	2387	7.9
Not detected	27913	92.1
RR_MTB Result (N = 2,387)
RR _MTB detected	215	9
RR _MTB not detected	2172	91

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RR = rifampicin resistance.

Associated risk factors of MTB infections

In this study, females were 14% times less likely [Adjusted Odds Ratio (AOR) = 0.86; 95% CI = 0.79, 0.94, p < 0.001] to have MTB compared to males. The odds of having MTB showed a decreasing trend by age. Patients whose age was greater than 29 years were less likely to have MTB compared to 18–29 years [p < 0.001]. Likewise, HIV positive patients were 1.54 times [AOR: 1.54; 95% CI: 1.33–1.72, p < 0.001]. The odds of MTB was higher among previously treated patients [p < 0.001] [Table 2].

Table 2. Frequency of MTB by gender, age, treatment history, and HIV status in Eastern, Mekelle and Southern Zones of Tigray, Ethiopia, 2016–2019 (N = 30, 300).

Variables	MTB Pos. N (%)	MTB Neg. N (%)	COR (95% CI)	P value	AOR (95%CI)	P value
Gender
Male	1457(61)	16014(57.4)	Ref		Ref
Female	930 (39)	11899(42.6)	0.86(0.79–0.94)	<0.001^*	0.86(0.79–0.94)	<0.001^*
Age
18–29	940(39.4)	6513(23.3)	Ref		Ref
30–39	580(24.3)	5720(20.5)	0.7(0.63–0.78)	<0.001^*	0.7(0.63–0.78)	<0.001^*
40–49	388(16.3)	4961(17.8)	0.54(0.48–0.61)	<0.001^*	0.54(0.47–0.61)	<0.001^*
50–59	239(10)	4098(14.7)	0.4(0.35–0.47)	<0.001^*	0.4(0.35–0.47)	<0.001^*
60–69	144(6)	3605(12.9)	0.28(0.23–0.33)	<0.001^*	0.28(0.18–0.27)	<0.001^*
70–112	96(4)	3016(10.8)	0.22(0.22–0.18)	<0.001^*	0.22(0.18–0.27)	<0.001^*
HIV status (n = 665)
Positive	288(12.1)	2387(89.2)	1. 56 (1.37–1.78)	<0.001^*	1.54(1.33–1.72)	<0.001^*
Negative	377(15.8)	3283(11.8)	Ref		Ref
TB Treatment History
New cases	2195(92)	26801(96)	Ref		Ref
Relapse	168(7)	1054(3.8)	1.95(1.6–2.3)	<0.001^*	2.0(1.69–2.36)	<0.001^*
Lost	7(0.3)	18(0.1)	4.75(1.98–11.4)	<0.001^*	5.21(2.1–12.8)	<0.001^*
Failure	17(0.7)	40(0.1)	5.2(2.94–9.17)	<0.001^*	5.4(3.0–9.7)	<0.001^*

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*: Statistically significant.

Associated risk factors of RR-MTB

Of the total 2,387 MTB confirmed patients, 215 (9%) of them were infected by RR-MTB. Patients whose age was between 30–39 years were 49% times less likely to have RR-MTB [AOR = 0.51; 95% CI = 0.31, 0.84, p = 0.008] compared to the age groups of 18–29 years. On the other hand, RR-MTB was significantly prevalent among relapse cases [AOR = 3.26; 95% CI = 2.14, 4.97, p < 0.001] and failure cases [AOR = 3.75; 95% CI = 1.18, 11.92, p = 0.025] [Table 3].

Table 3. Frequency of RR-MTB among adult TB patients by sex, age, treatment history and HIV status in Eastern, Mekelle and Southern Zones of Tigray, Ethiopia, 2016–2019 (N = 2,387).

Variables	RR-MTB N (%)	Not RR-MTB N (%)	COR (95% CI)	P value	AOR (95%CI)	P value
Gender
Male	125(58.1)	1332(61.3)	Ref		Ref
Female	90(41.9)	840(38.7)	1.1(0.86–1.52)	0.36	1.1(0.82–1.46)	0.54
Age
18–29	90(41.9)	850(39.1)	Ref		Ref
30–39	58(27)	522(24)	1.1(0.74–1.5)	0.79	0.51(0.31–0.84)	0.008*
40–49	21(9.8)	367(16.9)	0.54(0.33–1.82)	0.14	0.51 (0.45–1.30)	0.19
50–59	32(14.9)	207(9.5)	1.5(0.95–2.25)	0.085	0.64(0.32–1.3)	0.22
60–69	9(4.2)	135(6.2)	0.6(0.31–1.3)	0.20	0.47(0.19–1.2)	0.12
70–112	5(2.5)	91(4.2)	0.52(0.21–1.3)	0.17	0.65(0.33–1.34)	0.29
HIV status (n = 55)
Positive	17(7.9)	271(12.5)	0.62(0.37–1.03)	0.06	0.53(0.31–0.9)	0.064
Negative	38(17.7)	339(15.6)	Ref		Ref
TB Treatment History
New case	176(81.9)	2019(93)	Ref		Ref
Relapse	34(15.8)	134(6.2)	2.9(1.94–4.37)	<0.001*	3.26(2.14–4.97)	<0.001*
Lost	1(0.5)	6(0.3)	1.9(.23-15-97)	0.55	1.7(0.19–14.52)	0.63
Failure	4(1.9)	13(0.6)	3.5(1.2–10.94)	0.029	3.75(1.18–11.9)	0.025*

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*: Statistically significant.

Frequency of MTB and RR- MTB by study years

Fig 2 compares the frequency of MTB and RR-MTB by study years. The number of MTB suspected patients who visited the hospitals increased from 3281 in 2016 to 11023 in 2018. Similarly, the absolute number of MTB positive has also increased from 408 in 2016 to 793 in 2018. However, the actual of percent of MTB frequency significantly decreased from (12.4%) in 2016 to (6.8%) in 2019 (p < 0.001, data not shown). Similarly though the absolute number of RR-MTB positive cases shows an increment from 42 in 2016 to 65 in 2018, it was not statistically significant (p > 0.05) [Fig 2].

Discussion

Availability of local epidemiological data on MTB and RR-MTB and identification of potentially predisposing factors is of paramount to design appropriate intervention strategies to control MTB. Overall, the frequency of MTB and RR-MTB in this study were 7.9% and 9%, respectively. MTB frequency (7.9%) in this study was more or less comparable with previous reports from Addis Ababa, [17] and Amhara region, [18]. However, our result was lower than studies conducted in Addis Ababa [11, 19], Southern Ethiopia [12], Somali region [20], Tigray region [15] and Oromia region [21], Amhara region [4, 22, 23], Congo [24], South Africa [25], Togo [26], Nigeria [27, 28], Korea [29], Pakistan [30], India [27, 31–34] and China [35]. However, our frequency was higher than the study conducted in Oromia region [36].

Possible reasons for the variations could be due to differences in methodological techniques (culture vs Xpert), study participants, study period, sample size, geography and TB control and prevention practices. For example, the high TB frequency in South Ethiopia [12], Oromia region [21], Amhara region [23], Tigray region [15], Congo [24], India [33] and Togo [26] was because their study participants were MDR presumptive patients (relapse, defaulter, lost and failure) unlike this study which included TB presumptive patients. Another possible reason for the high MTB recovery in the other studies such as Oromia region [36], Amhara region, [22], and Nigeria [28], used small sample size (small sampling could artificially generate higher prevalence rate).

The high prevalence of MTB in the studies from Somalia region [20], Pakistan [30], Bangladesh [37], India [32] and Togo [26] compared to our results reflects the higher disease burden in these countries. It could be due to the fact that their early reporting period, which was 2011 to 2014 where Xpert was initially indicated for patients with TB/HIV co-infection, presumptive MDR-TB and paediatrics TB patients. Whereas, this study was carried out from 2016 to 2019 where the method was used to all presumptive MTB patients.

The age range of our study participants was 18–112 years. Of these, participants whose age was 29 years or greater were less infected by MTB compared to the 18–29 years age groups (p< 0.05). Though there is no clear cut value for age, other studies reported higher prevalence in different age groups: 16–30 years [12], 25–34 years [22], while others reported no association between age and TB infection [2, 11, 21, 27]. Females were 14% times less likely [AOR = 0.86; 95% CI = 0.79, 0.94, p< 0.001] to have TB compared to males which was supported by other studies [4], Philippines [38] and North Sudan [36]. This could be probably due to males usually spending less time at home and have more frequent contacts with TB patients while females usually stay at home. Hence this could put males at more exposure to the disease [39].

On the other hand, previously treated patients (failure, relapse and lost to follow up) were more infected by MTB compared to new cases which was in line with a report by Adane et al [22]. The high TB prevalence in the previously treated highlights the need to give due attention in the DOT program as this may indicate high TB transmission to new TB cases in the community and in the case of relapse, the lack of TB treatment monitoring and control.

The distribution of RR-MTB is a big health problem in the study population. The frequency of RR-MTB (9%) in our study is in line with previous reports from Addis Ababa [11, 17], Amhara region, [4], Nigeria [27, 40], Korea [30], and India [32–34]. However, our frequency is lower than previous similar studies conducted in other parts of Ethiopia: Oromia region [21], Amhara region [23], Tigray region [14, 15], Congo [24], Nigeria [28], Togo [26], Russia [41], India [34], Bangladesh [37], Pakistan [31] and China [35]. Others have reported lower RR- TB prevalence in Southern Ethiopia [12], Amhara region [22], and Addis Ababa [19].

Possible reasons for the differences in the RR-MTB results could be due to variations in geography, methodology (sample size, method of diagnosis, study participants), study setting, study period and TB control practice. The high RR-MTB prevalence in Oromia region [21], Amhara region [23], Tigray region [15], Congo [24], India [33] and Togo [26] is due to the fact their study participants were suspected of MDR-TB (relapse, defaulter, lost and failure) unlike the presumptive TB patients which are included in this study. Low RR-MTB in study by Hamusse et al [36], could be due to the fact that the study was a community based study, not health service based one. The high RR-MTB reports from Somali region [20], Pakistan [31], Bangladesh [37], India [27] and Togo [26] compared to this report might be due to the difference in the study period and the scope to use Xpert for TB diagnosis. These studies were conducted between 2011 and 2014, where Xpert assay was indicated only for patients with presumptive MDR-TB. This study however, included data from 2016 to 2019 where Xpert-MTB/RIF Assay was recommended for all TB suspected patients.

In the present study, gender was not associated with RR-MTB; however, others [11, 23, 41] have indicated more RR-MTB among females compared to males. In contrary to this, other studies have reported more RR-MTB infection among males [14, 27, 40]. Similarly, age groups of 30–39 years in this study were less infected by RR-MTB compared to the other age group which was similar to other studies [23, 40]. The other associated factor with RR-MTB in this study was previous TB treatment. This is in agreement with previous reports [11, 21, 23, 27, 41]. The strong association of rifampicin resistance MTB with previous treatment highlights the need for coordinated work of stake holders so as to improve the monitoring of treatment to reduce the emergence of circulating drug resistant MTB strains in the community.

This study has also tried to see the trend of MTB and RR-MTB through time. Accordingly, a significant decrease in the percentage of MTB frequency while the actual number of MTB detection increases show that the regional government and stakeholders have to perform well to tackle tuberculosis in the region. Though it was not statistically significant, the absolute number of RR-MTB positive cases shows an increment from 2016 to 2018.

This multicenter health facility based study was held in Tigray regional state and collected a large sample size. This is believed to give an updated information on the frequency of TB and RR-MTB to the regional and national governments. However, this study has limitations. First, the study was carried out only in one region of the nation (Tigray); the economic and regional disparities limited the generalization of the result. Second, we couldn’t do microbiological confirmation of the Xpert positive MTB and RR-MTB, phenotypic rifampicin resistance and resistance to other anti-TB drugs because of the retrospective nature of the study. Third, we could not get information on contact history of MDR -TB and TB, education, and living conditions of patients; thus, we were unable to show the associations between these factors with our outcome variables.

Conclusion

The frequency of MTB and RR-MTB in this study were 7.9% and 9%, respectively. Age (18–29 years), HIV positive and previous TB treatment history were significantly associated with high MTB, whereas gender (being female) was associated with low MTB. While rifampicin resistant-MTB was more prevalent among relapse and failure cases; it was lower among the age group of 30–39 years. The strong association MTB and RR-MTB with previous treatment highlights the need for more attention in TB treatment and monitoring program in the study area. Though frequency of MTB shows a decreasing trend over the study period, the prevalence still shows that more works should be done to further combat MTB associated morbidities and mortalities in the study area.

Acknowledgments

We would like to thank all the hospital directors and laboratory staff of the study hospitals for their co-operation in allowing the researchers to access the records and extract the data.

Abbreviations

HIV: Human immunodeficiency virus
MDR-TB: Multidrug resistant tuberculosis
MTB: Mycobacterium tuberculosis
RR: Rifampicin resistant tuberculosis
TB: Tuberculosis
WHO: World Health Organization
DOTS: Directly observed treatment, short-course

Data Availability

All relevant data are within the manuscript.

Funding Statement

No funding was obtained from any funding organizer to run the research.

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PLoS One. doi: 10.1371/journal.pone.0240361.r001

Decision Letter 0

Shampa Anupurba

8 Jun 2020

PONE-D-20-09432

MTB and Rifampicin Resistance TB using Gene-Xpert-MTB/RIF Assay among Adult Presumptive Tuberculosis Patients in Tigray, Northern Ethiopia: a cross sectional study

PLOS ONE

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Despite you try TO deal with the current national and global issue, the drug resistance TB, but your manuscript is not well written. I presented some of my comments, but many still left,

General comments

- Your writing is not consistent terms. E,g since xpert detect only mycobacterium tuberculosis it should be written as “RR_MTB,” but you randomly wrote as RR-TB, RR-MTB. It should be consistent though out the manuscript

- There may vocabulary / grammar errors. Incases MTP instead MTB

- You use your non standard terminologies: RR-TB positive AND RR-TB negative (table 1). RR_MTB DETECTED OR RR_MTB NOT DETECTED

- The texts/ paragraph with our references e.g “….Most studies in Ethiopia used the conventional culture and sensitivity methods not the automated Xpert MTB/RIF assay…” (Introduction). There are also reliable references. E.g there reference for population size of 6,960,000 of the region is the study from south Africa “Group Accuracy of the Xpert MTB / RIF test for the diagnosis of pulmonary tuberculosis in children admitted to hospital in Cape Town , South Africa : a descriptive study” . All the reference should be checked and reliable

Abstract

1. Part of the conclusion is not drawn from your data. In cases you try to highlights the need of a coordinated work in health education despite your data not support it

Methodology

1. The study setting is confusing : your describe that there 12 general hospitals, 22 primary hospitals,…… in the region” . You collect data from the five general hospitals and one compressive hospital. On the parag 3 you’re said “There are two general hospitals and one primary hospital which are not included in the study”.

2. Inclusion criteria;-despite you used secondary data (log book) but you exclude children and sample other than the sputum. Why ?

3. Laboratory Processing: it says “Samples were collected before the patients started anti-TB treatment” but on your result there are patents with failure and lost who already on treatment but sample collected for the indication probably as per national protocol

4. HIV testing: you describe the algorithm which could potential be modified as per the change in technology without reference.

5. Quality control: “… the researchers checked and confirmed that the Gene Xpert MTB/RIF assay was done using standard operating procedures”. How it possible for the secondary data? You can obtain SOP but how you know whether they followed or not. Such unnecessary should be modified

Result

1. Sociology-demographic, Clinical characteristics and TB results

- Using median instead of the mean is more appropriate for your study as the age range 18-112, which seems having extreme age like 112.

- The writing style not consistent. E.g (17,471; 57.7 %), 28,996 (95.7 %), 7.9 %

2. Associated Risk Factors of MTB or RR_ MTB Infections

- Interpretation of the statistical finding wrong. E.G for AOR of 0.86, your describe as “…females were 86 % times less likely to be infected by TB compared to males”. Rather is should be … female has 26% less likely infected by TB compared to males”. Many other examples found in your result section while you interpreted the associated Risk Factors of for MTB AND RR –TB. This misleading interpretation also reflected in your discussion part.

Reviewer #2: Abstract

Methods

- The authors may delete the period when the data extraction was done (Oct - Dec 2019) given that have also included the focus period Jan 2016 - Dec 2019.

Results

- The authors mention "high TB infection" which is confusing and yet the study focused on MTB (TB) and RR TB (MDR TB).

- The interpretation of the first part of the statement "Likewise rifampicin resistant was more prevalent .....(p<0.05) should be aligned to table 3 findings.

Conclusion

-The authors need to include a statement on whether the prevalence was high or low - this may eliminate the repetition of figures which are already listed under the results section.

- The final recommendation listed is not clear

Main text

Introduction

- Reference 1 - There is a more recent global TB report 2019

- Paragraph 2 - There are 30 MDR TB high burden countries - The authors should replace reference 9 with a more recent reference

- The text listed in paragraph 2 is not clear and requires revision

Study setting

- The authors include detailed geographical information such as longitude and latitude which may not be relevant and can be deleted.

- The authors may delete the period when the data extraction was done (Oct - Dec 2019) given that have also included the focus period Jan 2016 - Dec 2019.

- The text on the selected and non selected sites can be shortened. This will make it easier to understand.

Inclusion criteria

- Include "presumptive TB" before adult patients - this is the study population

Outcome variables

- Delete prevalence. Outcome variable is TB and RR TB

Data collection

- It is not clear whether the patient records were paper based or electronic.

Ethical consideration

- This text can be shortened

Results

Table 1

- The total for the variables under TB treatment history is (41,300) is more than the sample size (30,300). The figures need to be verified

Associated risk factors for MTB infections

- The authors use "infected by TB" which may confuse the reader. They may consider using "TB" e.g. ...."less likely to have TB" as opposed to "less likely to be infected by TB"

- The authors do not need to list all the odds for the different age groups since they are reflected in table 2. The odds show a decreasing trend and can be summarized as such.

- The authors do not need to list all the odds for the "TB treatment history" groups since they are reflected in table 2. This may be summarized by mentioning that the odds of TB were higher among previously treated patients.

Table 2

- Column proportions would be more informative especially when comparing proportions across the independent variable groups by the outcome variable.

Table 3

- Column proportions would be more informative especially when comparing proportions across the independent variable groups by the outcome variable.

- Does changing "HIV negative" to the ref group in the bi-variate and multi-variate analysis change the results. It would be good to run the analysis for comparison.

Prevalence of MTB and RR-TB by years

- Figure 2 - Does "total patients refer to "presumptive TB"? This should be clarified

- While the authors state that the prevalence of TB has reduced over time, it is important to also make a comment on the absolute numbers which have increased over time. The numbers for RR TB are not included on the figure.

Discussion

- Paragraph 2 - The authors list that their findings are more or less comparable and then include contradicting statements thereafter. They list all the proportions for the various studies in reference which might not be necessary. The authors may include a summary statement and simply quote the references.

Paragraph 2 - Text can be reduced. Authors list all proportions from other studies which makes the text really long. The authors may include a summary statement and simply quote the references.

- Paragraph 2 - It is not clear why the authors compare their findings to a study conducted in Uganda (29) which focused on children. They excluded children. Furthermore, the two populations differ in disease patterns which would also . It makes more sense for the authors to limit the comparison to adult studies.

- Paragraph 3 - The high prevalence of TB in studies from Somalia, Pakistan, Bangladesh..... reflects the higher disease burden in these countries.

- Paragraph 3 - See comments above on "TB infection" and "more infected by TB"

Conclusion

- See comments above (abstract)

Reviewer #3: Comments to the Author

Manuscript Number: PONE-D-20-09432

Title: MTB and Rifampicin Resistance TB using Gene-Xpert-MTB/RIF Assay among Adult Presumptive Tuberculosis Patients in Tigray, Northern Ethiopia: a cross sectional study

This is an interesting study that potentially represents the prevalence of tuberculosis and multidrug resistant tuberculosis in in Tigray, Northern Ethiopia. This study also giving information about increasing trend of multiple drug resistance against TB which an alrming condition.

General comments

This study is well described, however there are certain limitations in the study that need to be addressed.

Title: Title is not matched with study. Title could be better like “ Frequency of MTB and Rifampicin Resistance TB using Xpert-MTB/RIF Assay among Adult Presumptive Tuberculosis Patients in Tigray, Northern Ethiopia: a cross sectional study” instead of “MTB and Rifampicin Resistance TB using Gene-Xpert-MTB/RIF Assay among Adult Presumptive Tuberculosis Patients in Tigray, Northern Ethiopia: a cross sectional study”

Abstract:

� This is not Prevalence study so replace prevalence words by frequency

� Replace Gene-Xpert-MTB/RIF Assay by Xpert-MTB/RIF Assay

Methods:

� Please correct timing of study because you wrote October 2019 to December 2019 in one line and January 2016 to December 2019 in other line.

Results:

� Line number 6, Please write number out of total and then write percentage in bracket. For example you wrote in line number 3, 17,471 (57.7 %) were males.

� It would be better if you shows the significant value with males and previous history that how much it is significant

Conclusion: Don’t start paragraph with number like 7.9%

Introduction:

� It would be better if you define 1st susceptible and resistant tuberculosis, Rifampecin resistant and then MDR-TB.

You can help from this article (Javaid A, Ullah I, Masud H, Basit A, Ahmad W, Butt ZA, Qasim M. Predictors of poor treatment outcomes in multidrug-resistant tuberculosis patients: a retrospective cohort study. Clinical Microbiology and Infection. 2018 Jun 1;24(6):612-7).

� Paragraph 3, line 6. Write RR-TB in full instead of abbreviation 1st and check thought out the manuscript.

Materials and Methods

� Please make a table or box and write all the definition like Variables, outcomes relapse, failure, relapse etc

Results:

� Please go through overall papers as some paragraphs are confusing and not clear. Rephrase it like “According to the results of this study, the overall, prevalence of TB and RR- TB were 7.9 % and 9 %, respectively” and “As can be seen in Table 2, females were 86 % times less likely [Adjusted Odds Ratio (AOR) =0.86; 95 % CI= 0.79, 0.94, p= 0.000] to be infected by TB compared to males.

Discussion:

� Discussion is overall good but need to be slightly modify it by grammatically

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Dr Irfan Ullah

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PLoS One. 2020 Nov 4;15(11):e0240361. doi: 10.1371/journal.pone.0240361.r002

Author response to Decision Letter 0

28 Jul 2020

Point-By-Point Response Letter to Reviewers Comments

Dear Editor,

Greetings,

First and foremost, we thank you for giving us the chance to revise our manuscript. We really appreciate the interest of the reviewers to our paper, and their critical and important comments which made us learn a lot. We have revised the manuscript and reviewers’ comments and questions are addressed in highlighted in the revised manuscript.

Kind regards,

Araya GebreyesusWsihun, on behalf of the research members.

Reviewer #1:

Dear Reviewer,

I, on behalf of the team would like to thank you for reviewing our manuscript critically and in a detail way. Your constructive comments not only help us enrich the manuscript, but also made us learn a lot on how one should review articles. We have tried to address your comments as much as we could. Thank you once again for making us learn.

Reviewer’s general comments

Despite you try TO deal with the current national and global issue, the drug resistance TB, but your manuscript is not well written. I presented some of my comments, but many still left,- Your writing is not consistent terms. E,g since xpert detect only mycobacterium tuberculosis it should be written as “RR_MTB,” but you randomly wrote as RR-TB, RR-MTB. It should be consistent though out the manuscript

Author’s response: Corrected.

- Reviewer’s comments: There may vocabulary / grammar errors. Incases MTP instead MTB

Author’s response: Corrected.

- Reviewer’s comments: You use your nonstandard terminologies: RR-TB positive AND RR-TB negative (table 1). RR_MTB DETECTED OR RR_MTB NOT DETECTED

Author’s response: Corrected.

Reviewer’s comments: The texts/ paragraph with our references e.g “….Most studies in Ethiopia used the conventional culture and sensitivity methods not the automated Xpert MTB/RIF assay…” (Introduction). There are also reliable references. E.g there reference for population size of 6,960,000 of the region is the study from south Africa “Group Accuracy of the Xpert MTB / RIF test for the diagnosis of pulmonary tuberculosis in children admitted to hospital in Cape Town , South Africa : a descriptive study” . All the reference should be checked and reliable

Author’s response: Thank you very much for your comments and reference you provided. However, our statement is specific to Ethiopia; not referring to Africa or broader studies. As can be seen, in the discussion part, we have compared our result with similar studies on Xpert for other parts.

Abstract

Reviewer’s comments: Part of the conclusion is not drawn from your data. In cases you try to highlights the need of a coordinated work in health education despite your data not support it

Author’s response: Corrected.

Methodology

Reviewer’s comments: The study setting is confusing: your describe that there 12 general hospitals, 22 primary hospitals, in the region”. You collect data from the five general hospitals and one compressive hospital. On the page 3 you’re said “There are two general hospitals and one primary hospital which are not included in the study”.

Author’s response: Corrected

Reviewer’s comments: 2. Inclusion criteria;-despite you used secondary data (log book) but you exclude children and sample other than the sputum. Why?

Author’s response: Thank you very much for raising very important question. Given our objective was to determine prevalence of pulmonary TB among adults, where TB is more prevalent, we did not include children and other samples. But as you pretty mentioned, we believe their inclusion could have given some additional information on RR-MTB and MTB in the study area.

Reviewer’s comments: 3. Laboratory Processing: it says “Samples were collected before the patients started anti-TB treatment” but on your result there are patents with failure and lost who already on treatment but sample collected for the indication probably as per national protocol

Author’s response: Thank you very much for such constructive comments indeed. We have removed such controverting sentence and corrected accordingly.

Reviewer’s comments: 4. HIV testing: you describe the algorithm which could potential be modified as per the change in technology without reference.

Author’s response: Thank you for your important comment. We have now corrected and rewritten as: Rapid HIV test was done according to the national algorithm of the Federal Ministry of Health of Ethiopia.

Reviewer’s comments: 5. Quality control: “… the researchers checked and confirmed that the Gene Xpert MTB/RIF assay was done using standard operating procedures”. How it possible for the secondary data? You can obtain SOP but how you know whether they followed or not. Such unnecessary should be modified

Author’s response: As you clearly mentioned, it is possible to get the SOP and we indeed obtained it, but it is not possible to confirm whether or not followed. Hence we corrected such ambiguity sentences in the revised version as per the given comments.

Result

Reviewer’s comments: 1. Sociology-demographic, Clinical characteristics and TB results

Using median instead of the mean is more appropriate for your study as the age range 18-112, which seems having extreme age like 112.

Author’s response: Though there are age outliers, age distribution in the histogram shows normal distribution, hence we used the mean. But as per your comment, we changed to median which was 40.65 (interquartile 29.4 -56.5 years).

Reviewer’s comments: The writing style not consistent. E.g (17,471; 57.7 %), 28,996 (95.7 %), 7.9 %

Author’s response: Corrected as N (%).

2. Associated Risk Factors of MTB or RR_ MTB Infections

Reviewer’s comments: - Interpretation of the statistical finding wrong. E.G for AOR of 0.86, your describe as “…females were 86 % times less likely to be infected by TB compared to males”. Rather is should be … female has 26% less likely infected by TB compared to males”. Many other examples found in your result section while you interpreted the associated Risk Factors of for MTB AND RR –TB. This misleading interpretation also reflected in your discussion part.

Author’s response: Thank you very much. We have corrected the error in interpretation.

Reviewer #2: Abstract

Dear Reviewer,

Methods

Reviewer’s comments: - The authors may delete the period when the data extraction was done (Oct - Dec 2019) given that have also included the focus period Jan 2016 - Dec 2019.

Author’s response: Thank you for your critical comments, we have deleted.

Results

Reviewer’s comments: - The authors mention "high TB infection" which is confusing and yet the study focused on MTB (TB) and RR TB (MDR TB).

Author’s response: Corrected.

Reviewer’s comments: - The interpretation of the first part of the statement "Likewise rifampicin resistant was more prevalent .....(p<0.05) should be aligned to table 3 findings.

Author’s response: Corrected as per the recommendation.

Conclusion

Reviewer’s comments: -The authors need to include a statement on whether the prevalence was high or low - this may eliminate the repetition of figures which are already listed under the results section.

Author’s response: We have corrected.

Reviewer’s comments: - The final recommendation listed is not clear

Author’s response: Made clear in the revised manuscript

Main text

Introduction

Reviewer’s comments: - Reference 1 - There is a more recent global TB report 2019

Author’s response: We have use the 2019 reference.

Reviewer’s comments: - Paragraph 2 - There are 30 MDR TB high burden countries - The authors should replace reference 9 with a more recent reference

Author’s response: Corrected.

Reviewer’s comments: - The text listed in paragraph 2 is not clear and requires revision

Author’s response: Corrected

Study setting

Reviewer’s comments: - The authors include detailed geographical information such as longitude and latitude which may not be relevant and can be deleted.

Author’s response: Deleted.

Reviewer’s comments: - The authors may delete the period when the data extraction was done (Oct - Dec 2019) given that have also included the focus period Jan 2016 - Dec 2019.

Author’s response: Deleted

Reviewer’s comments: - The text on the selected and non-selected sites can be shortened. This will make it easier to understand.

Author’s response: Shortened

Inclusion criteria

Reviewer’s comments: - Include "presumptive TB" before adult patients - this is the study population

Author’s response: Included

Outcome variables

Reviewer’s comments: - Delete prevalence. Outcome variable is TB and RR TB

Author’s response: Deleted.

Data collection

Reviewer’s comments: - It is not clear whether the patient records were paper based or electronic.

Author’s response: Corrected as paper based (registration books)

Ethical consideration

Reviewer’s comments: - This text can be shortened

Author’s response: Corrected.

Results

Table 1

Reviewer’s comments: - The total for the variables under TB treatment history is (41,300) is more than the sample size (30,300). The figures need to be verified

Author’s response: Thank you for your critical reviewing our paper. There was type error where ‘ 2’ was added. Now corrected.

Associated risk factors for MTB infections

Reviewer’s comments: - The authors use "infected by TB" which may confuse the reader. They may consider using "TB" e.g. ...."less likely to have TB" as opposed to "less likely to be infected by TB"

Author’s response: Corrected as per the comments throughout the manuscript.

Reviewer’s comments: - The authors do not need to list all the odds for the different age groups since they are reflected in table 2. The odds show a decreasing trend and can be summarized as such.

Author’s response: We have corrected and put in summary.

Reviewer’s comments: - The authors do not need to list all the odds for the "TB treatment history" groups since they are reflected in table 2. This may be summarized by mentioning that the odds of TB were higher among previously treated patients.

Author’s response: Summarized.

Table 2

Reviewer’s comments: - Column proportions would be more informative especially when comparing proportions across the independent variable groups by the outcome variable.

Author’s response: Changed to column proportions

Table 3

Reviewer’s comments: - Column proportions would be more informative especially when comparing proportions across the independent variable groups by the outcome variable.

Author’s response: Changed to column proportions

Reviewer’s comments: Does changing "HIV negative" to the ref group in the bi-variate and multi-variate analysis change the results. It would be good to run the analysis for comparison.

Author’s response: Changed and reanalyzed as per the given comments

Prevalence of MTB and RR-TB by years

Reviewer’s comments: - Figure 2 - Does "total patients refer to "presumptive TB"? This should be clarified

Author’s response: Yes, and we have corrected in the figure.

Reviewer’s comments: While the authors state that the prevalence of TB has reduced over time, it is important to also make a comment on the absolute numbers which have increased over time. The numbers for RR TB are not included on the figure.

Author’s response: We have corrected, and figure are put as number.

Discussion

Reviewer’s comments: - Paragraph 2 - The authors list that their findings are more or less comparable and then include contradicting statements thereafter. They list all the proportions for the various studies in reference which might not be necessary. The authors may include a summary statement and simply quote the references.

Author’s response: Corrected.

Reviewer’s comments: Paragraph 2 - Text can be reduced. Authors list all proportions from other studies which makes the text really long. The authors may include a summary statement and simply quote the references.

Author’s response: Shortened by deleting the figures.

Reviewer’s comments: - Paragraph 2 - It is not clear why the authors compare their findings to a study conducted in Uganda (29) which focused on children. They excluded children. Furthermore, the two populations differ in disease patterns which would also. It makes more sense for the authors to limit the comparison to adult studies.

Author’s response: We have deleted the comparison made with children from Uganda

Reviewer’s comments: - Paragraph 3 - The high prevalence of TB in studies from Somalia, Pakistan, Bangladesh..... reflects the higher disease burden in these countries.

Author’s response: Corrected.

Reviewer’s comments: - Paragraph 3 - See comments above on "TB infection" and "more infected by TB"

Author’s response: Corrected.

Conclusion

Reviewer’s comments: - See comments above (abstract)

Author’s response: Corrected.

Reviewer #3:

Dear Reviewer,

Manuscript Number: PONE-D-20-09432

Title: MTB and Rifampicin Resistance TB using Gene-Xpert-MTB/RIF Assay among Adult Presumptive Tuberculosis Patients in Tigray, Northern Ethiopia: a cross sectional study

General comments

This study is well described, however there are certain limitations in the study that need to be addressed.

Reviewer’s comments: Title: Title is not matched with study. Title could be better like “ Frequency of MTB and Rifampicin Resistance TB using Xpert-MTB/RIF Assay among Adult Presumptive Tuberculosis Patients in Tigray, Northern Ethiopia: a cross sectional study” instead of “MTB and Rifampicin Resistance TB using Gene-Xpert-MTB/RIF Assay among Adult Presumptive Tuberculosis Patients in Tigray, Northern Ethiopia: a cross sectional study”

Author’s response: Thank you for your constructive comments. We have changed as per the comments.

Abstract:

Reviewer’s comments: � This is not Prevalence study so replace prevalence words by frequency

Author’s response: Replaced.

Reviewer’s comments: � Replace Gene-Xpert-MTB/RIF Assay by Xpert-MTB/RIF Assay

Author’s response: Replaced throughout the paper

Methods:

Reviewer’s comments: � Please correct timing of study because you wrote October 2019 to December 2019 in one line and January 2016 to December 2019 in other line.

Author’s response: Corrected.

Results:

Reviewer’s comments: � Line number 6, Please write number out of total and then write percentage in bracket. For example you wrote in line number 3, 17,471 (57.7 %) were males.

Author’s response: Corrected as N (%).

Reviewer’s comments: � It would be better if you shows the significant value with males and previous history that how much it is significant

Author’s response: Corrected.

Reviewer’s comments: Conclusion: Don’t start paragraph with number like 7.9%

Author’s response: Corrected

Introduction:

Reviewer’s comments: � It would be better if you define 1st susceptible and resistant tuberculosis, Rifampecin resistant and then MDR-TB.

Author’s response: we have defined MDR-TB in the introduction, we have also added Operational definition part in the methods.

Reviewer’s comments: � Paragraph 3, line 6. Write RR-TB in full instead of abbreviation 1st and check thought out the manuscript.

Author’s response: Written.

Materials and Methods

Reviewer’s comments: � Please make a table or box and write all the definition like Variables, outcomes relapse, failure, relapse etc

Author’s response: Included in the operational definition.

Results:

� Reviewer’s comments: Please go through overall papers as some paragraphs are confusing and not clear. Rephrase it like “According to the results of this study, the overall, prevalence of TB and RR- TB were 7.9 % and 9 %, respectively” and “As can be seen in Table 2, females were 86 % times less likely [Adjusted Odds Ratio (AOR) =0.86; 95 % CI= 0.79, 0.94, p= 0.000] to be infected by TB compared to males.

Discussion:

Author’s response: Corrected.

Reviewer’s comments: Discussion is overall good but need to be slightly modify it by grammatically

Author’s response: Improved.

PLoS One. doi: 10.1371/journal.pone.0240361.r003

Decision Letter 1

Shampa Anupurba

20 Aug 2020

PONE-D-20-09432R1

Frequency of MTB and Rifampicin Resistance MTB using Xpert-MTB/RIF Assay among Adult Presumptive Tuberculosis Patients in Tigray, Northern Ethiopia: a cross sectional study

PLOS ONE

Dear Dr. Wasihun,

In addition to the reviewer's comment, I noticed that you have missed out the following:

1. "You use your non standard terminologies: RR-TB positive AND RR-TB negative (table 1). RR_MTB DETECTED OR RR_MTB NOT DETECTED"-same changes should be made with respect to MTB DETECTED/NOT DETECTED

2. "Part of the conclusion is not drawn from your data. In cases you try to highlights the need of a coordinated work in health education despite your data not support it".This has been omitted from the abstract,but is still present in the conclusion of the manuscript.

Please submit your revised manuscript by Oct 04 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Shampa Anupurba, MD

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: No

**********

6. Review Comments to the Author

Reviewer #1: Thank you for dressing most of my comments and suggestions in the first draft. I have seen good improvement in the manuscript. However, I have some mirror correction

Abstract

1. Change the mean to the median in the abstract, to make it consistent

2. Change “The overall frequency of TB was…” to “The overall frequency of MTB was…’’. Pleases use MTB as Xpert MTB/RIF detects only MTB and its RIF resistant strain but not other species of tuberculosis. Make it consistent in part too

Introduction

1. “Its drug-resistant strain called multidrug-resistant mycobacterium tuberculosis (MDR-MTB)….”. This sentence looks confusing as mycobacterium tuberculosis, not the only MDR strain. Please modify it

2. Last paragraph… ‘’ Besides, they were done using culture and drug susceptibility testing methods….’’.I think this is no limitation rather it is good as it detects other species/strain of TB. Good to modify or remove it

Methods

1. Outcome variable: not “TB and RR-MTB among presumptive TB patients” rather MTB and RR-MTB among presumptive TB patients

2. Operational definition

o MDR-TB: is not “Isolate of M. tuberculosis…..” Not only M. tuberculosis, why other species? modify it

o Rifampicin-resistant TB (RR-MTB) change to : Rifampicin-resistant TB (RR-TB)

Result

Associated Risk Factors of MTB Infections

1 “………1.46 times [AOR= 1.46; 95% CI =1.29, 1.57, p <0.001] times more likely to have………” correct as “………1.46 times [AOR= 1.46; 95% CI =1.29, 1.57, p <0.001] more likely to have………”

2 Change TB to MTB

3. Frequency of MTB and RR- MTB by study years

1. Change “Figure 2 compares the frequency of TB and RR-MTB by study years” to Figure 2 compares the frequency of MTB and RR-MTB by study years. Please do the same for others in this paragraph. Do mix TB and MTB

Discussion

1. The same research finding “Addis Ababa, [17]” in opposite comparation. ‘MTB frequency (7.9%) in this study was more or less comparable with previous reports from Addis Ababa, [17]……………………..”. “However, our frequency was higher than studies conducted in Addis Ababa [17]”. please modify the reference “17’’

2. . change ‘’For Example……” , For example,

3. The sentence (paragraph 4) is opposite to you finding “Of these, participants whose age was 29 years or greater were more infected by TB compared to the 18-29 years age groups (p< 0.05).” pleases modify it

4. Whereas, this study was carried out from 2016 to 2019 where the method was used to all presumptive TB patients. This sentence repeated pleases good to explain with other explanation

5. Correct 3039 to 30-39

6. “Accordingly, the number of TB suspected patients who visited the hospitals significantly increased from 3281 in 2016 to 11023 in 2018. Similarly, the absolute number of TB positive patients has also increased from 408 in 2016 to 793 in 2018. However, the actual percent of TB frequency showed a significant decrease from (12.4%) in 2016 to (6.8%) in 2019” this is the direct copy of the result, pleases do not repeat/ copy rather discuss the concept. for example, the concept can be summerazised like this “A significant decrease in the percentage of MTB frequency while the actual number of TB detection increases show that the regional government and stakeholders have to perform well to tackle tuberculosis in the region

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

PLoS One. 2020 Nov 4;15(11):e0240361. doi: 10.1371/journal.pone.0240361.r004

Author response to Decision Letter 1

27 Aug 2020

Point-By-Point Response Letter to Reviewers Comments

Dear Editor,

Greetings,

First and foremost, we thank for giving a chance to revise our paper. We really appreciate the interest of the reviewers to our paper, and we also appreciate for their critical and important comments and recommendations. We have revised the manuscript and reviewer’s comments and questions are addressed in highlighted in the revised manuscript.

Kind regards,

Araya Gebreyesus Wsihun (PhD)

Editor’s comment

In addition to the reviewer's comment, I noticed that you have missed out the following:

1. "You use your nonstandard terminologies: RR-TB positive AND RR-TB negative (table 1). RR_MTB DETECTED OR RR_MTB NOT DETECTED"-same changes should be made with respect to MTB DETECTED/NOT DETECTED

Response: Corrected

2. "Part of the conclusion is not drawn from your data. In cases you try to highlights the need of a coordinated work in health education despite your data not support it". This has been omitted from the abstract, but is still present in the conclusion of the manuscript.

Response: Now corrected

Reviewer #1: Thank you for dressing most of my comments and suggestions in the first draft. I have seen good improvement in the manuscript. However, I have some mirror correction

Abstract

1. Change the mean to the median in the abstract, to make it consistent

Response: Changed

Response: Corrected

Introduction

Response: Corrected

Response: Removed

Methods

1. Outcome variable: not “TB and RR-MTB among presumptive TB patients” rather MTB and RR-MTB among presumptive TB patients

Response: Corrected

2. Operational definition

o MDR-TB: is not “Isolate of M. tuberculosis ” Not only M. tuberculosis, why other species? modify it

Response: Modified

o Rifampicin-resistant TB (RR-MTB) change to : Rifampicin-resistant TB (RR-TB)

Response: Corrected

Result

Associated Risk Factors of MTB Infections

Response: Corrected

2 Change TB to MTB

Response: Changed

3. Frequency of MTB and RR- MTB by study years

Response: Corrected

Discussion

1. The same research finding “Addis Ababa, [17]” in opposite cooperation. ‘MTB frequency (7.9%) in this study was more or less comparable with previous reports from Addis Ababa, [17]……………………..”. “However, our frequency was higher than studies conducted in Addis Ababa [17]”. please modify the reference “17’’

Response: Corrected

2. Change ‘’For Example……” , For example,

Response: Changed

Response: Modified

4. Whereas, this study was carried out from 2016 to 2019 where the method was used to all presumptive TB patients. This sentence repeated pleases good to explain with other explanation

Response: Corrected

5. Correct 3039 to 30-39

Response: Corrected

Response: summarized as per the comment

PLoS One. doi: 10.1371/journal.pone.0240361.r005

Decision Letter 2

Shampa Anupurba

10 Sep 2020

PONE-D-20-09432R2

Frequency of MTB and Rifampicin Resistance MTB using Xpert-MTB/RIF Assay among Adult Presumptive Tuberculosis Patients in Tigray, Northern Ethiopia: a cross sectional study

PLOS ONE

Dear Dr. Wasihun,

Please submit your revised manuscript by Oct 25 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Shampa Anupurba, MD

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Mycobacterium tuberculosis should be mentioned as italics throughout the manuscript.

Abstract- Background 1st line-Delete 'Mycobacterium tuberculosis (MTB) and its'

Abstract- 4th line under Results- Please write median age 'of' 40.65 instead of 'was'

Abstract- Results-HIV unknown status cannot be associated with high MTB. This does not carry any meaning and should also be deleted from the entire manuscript.The statistical significance may not be shown in Table 1.

Methods- Study Setting- Delete 'the' in the sentence 'In this study, general hospitals which introduced Xpert since the 2016 were included.'

'intermediate' Xpert MTB/RIF results should be changed to 'indeterminate' throughout the manuscript.

Inclusion criteria- 'We include all presumptive TB'- change include to included

Table 1- Under MTB result, mention detected or not detected instead of positive /negative.

Discussion- 2nd para,6th line- 'unlike to this study'-delete 'to'

3rd para, 2nd line-'compared to our results which reflects the' delete 'which'

5th para,1st line-'On the other hand, previous treated patients'- write 'previously'

7th para, 2nd line-write geography instead of geographical

'This study; however, included data from 2016 and 2019'- replace 'and' by 'to', delete semi colon

'Xpert-MTB/RIF Assay is recommended to all TB suspected patients'- replace 'is' by 'was'. Also, delete 'with less likelihood of

having RR-MTB as the MDR-TB suspected patients used in the other studies'.

[Note: HTML markup is below. Please do not edit.]

PLoS One. 2020 Nov 4;15(11):e0240361. doi: 10.1371/journal.pone.0240361.r006

Author response to Decision Letter 2

12 Sep 2020

Point-by-point response letter to Editor’s comments

Dear Dr. Shampa Anupurba,

Warm greetings,

First and foremost, we thank for giving a chance to revise our paper. We really appreciate the interest of the editor to our paper, and we also appreciate for the critical and important comments and recommendations. We have revised the manuscript and editor’s comments in highlighted in the revised manuscript.

Kind regards,

Araya Gebreyesus Wasihun (PhD)

Editor’s comment: Mycobacterium tuberculosis should be mentioned as italics throughout the manuscript.

Response: Done

Editor’s comment: Abstract- Background 1st line-Delete 'Mycobacterium tuberculosis (MTB) and its'

Response: Done

Editor’s comment: Abstract- 4th line under Results- Please write median age 'of' 40.65 instead of 'was'

Response: Done

Editor’s comment: Abstract- Results-HIV unknown status cannot be associated with high MTB. This does not carry any meaning and should also be deleted from the entire manuscript. The statistical significance may not be shown in Table 1.

Response: Dear Editor, we really thank you for the critical comment. Patients with unknown HIV status means that there was no any data on HIV result in the registration book for the patient. Which means the patient may be positive or negative. Again in table one HIV positivity was associated with high MTB. Though we cannot be sure, the HIV result of the patients might be positive. Now we deleted the row for Unknown and we made the regression analysis between the HIV positive and Negative in both tables as (n=655 for table 2) and (n=55 for table 3).

Editor’s comment: Methods- Study Setting- Delete 'the' in the sentence 'In this study, general hospitals which introduced Xpert since the 2016 were included.'

Response: Deleted

Editor’s comment: 'Intermediate' Xpert MTB/RIF results should be changed to 'indeterminate' throughout the manuscript.

Response: Changed

Editor’s comment: Inclusion criteria- 'We include all presumptive TB'- change include to included

Response: Changed

Editor’s comment: Table 1- Under MTB result, mention detected or not detected instead of positive /negative.

Response: Done

Editor’s comment: Discussion- 2nd para,6th line- 'unlike to this study'-delete 'to'

Response: Deleted

Editor’s comment: 3rd para, 2nd line-'compared to our results which reflects the' delete 'which'

Response: Deleted

Editor’s comment: 5th para,1st line-'On the other hand, previous treated patients'- write 'previously'

Response: Done

Editor’s comment: 7th para, 2nd line-write geography instead of geographical

Response: Done

Editor’s comment: 'This study; however, included data from 2016 and 2019'- replace 'and' by 'to', delete semi colon

Response: Replaced and deleted

Editor’s comment: 'Xpert-MTB/RIF Assay is recommended to all TB suspected patients'- replace 'is' by 'was'. Also, delete 'with less likelihood of having RR-MTB as the MDR-TB suspected patients used in the other studies'.

Response: Replaced and deleted

PLoS One. doi: 10.1371/journal.pone.0240361.r007

Decision Letter 3

Shampa Anupurba

23 Sep 2020

PONE-D-20-09432R3

Frequency of MTB and Rifampicin Resistance MTB using Xpert-MTB/RIF Assay among Adult Presumptive Tuberculosis Patients in Tigray, Northern Ethiopia: a cross sectional study

PLOS ONE

Dear Dr. Wasihun,

The manuscript has been thoroughly revised. However there are a few minor corrections

Introduction: 1st para, 2nd line- Write Mycobacterium tuberculosis instead of mycobacterium tuberculosis

Inclusion criteria: indeterminate instead of intermediate (Had been pointed out earlier)

Discussion: 2nd para 6th line- delete 'to' in unlike to this study.(Had been pointed out earlier)

7th para, last line - 'MTB/RIF Assay was recommended to all TB suspected patients' replace 'to' by 'for'

Please submit your revised manuscript by Nov 07 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Shampa Anupurba, MD

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

PLoS One. 2020 Nov 4;15(11):e0240361. doi: 10.1371/journal.pone.0240361.r008

Author response to Decision Letter 3

24 Sep 2020

Point-by-point response letter to Editor’s comments

Dear Editor,

Warm greeting,

Kind regards,

Araya Gebreyesus Wasihun (PhD)

Editor’s comment:

The manuscript has been thoroughly revised. However there are a few minor corrections

Editor’s comment: Introduction: 1st para, 2nd line- Write Mycobacterium tuberculosis instead of mycobacterium tuberculosis

Response: Corrected

Editor’s comment: Inclusion criteria: indeterminate instead of intermediate (Had been pointed out earlier)

Response: Corrected

Discussion:

Editor’s comment: 2nd para 6th line- delete 'to' in unlike to this study.(Had been pointed out earlier)

Response: Deleted

Editor’s comment: 7th para, last line - 'MTB/RIF Assay was recommended to all TB suspected patients' replace 'to' by 'for'

Response: Replaced

PLoS One. doi: 10.1371/journal.pone.0240361.r009

Decision Letter 4

Shampa Anupurba

25 Sep 2020

Frequency of MTB and Rifampicin Resistance MTB using Xpert-MTB/RIF Assay among Adult Presumptive Tuberculosis Patients in Tigray, Northern Ethiopia: a cross sectional study

PONE-D-20-09432R4

Dear Dr. Wasihun,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Shampa Anupurba, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0240361.r010

Acceptance letter

Shampa Anupurba

30 Sep 2020

PONE-D-20-09432R4

Frequency of MTB and Rifampicin Resistance MTB using Xpert-MTB/RIF Assay among Adult Presumptive Tuberculosis Patients in Tigray, Northern Ethiopia: a cross sectional study

Dear Dr. Wasihun:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Shampa Anupurba

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Attachment

Submitted filename: Rif comment.docx

Click here for additional data file.^{(15.9KB, docx)}

Data Availability Statement

All relevant data are within the manuscript.

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PERMALINK

Frequency of MTB and rifampicin resistance MTB using Xpert-MTB/RIF assay among adult presumptive tuberculosis patients in Tigray, Northern Ethiopia: A cross sectional study

Araya Gebreyesus Wasihun

Tsehaye Asmelash Dejene

Genet Gebrehiwet Hailu

Roles

Abstract

Background

Methods

Results

Conclusion

Introduction

Methods

Study design and study population

Study setting

Fig 1. Map of the study area.

Inclusion criteria

Variables

Outcome variable

Independent variables

Operational definitions

New cases

Relapse case

Lost to follow up

Failure case

MDR-TB

Rifampicin-resistant TB (RR-TB)

Data collection

Laboratory processing

HIV testing

Data analysis

Ethical consideration

Result

Socio-demographic, clinical characteristics and MTB results

Table 1. Socio-demographic, clinical characteristics and MTB result among presumptive adult patients in Eastern, Mekelle and Southern Zones of Tigray, Ethiopia, 2016–2019 (N = 30,300).

Associated risk factors of MTB infections

Table 2. Frequency of MTB by gender, age, treatment history, and HIV status in Eastern, Mekelle and Southern Zones of Tigray, Ethiopia, 2016–2019 (N = 30, 300).

Associated risk factors of RR-MTB

Table 3. Frequency of RR-MTB among adult TB patients by sex, age, treatment history and HIV status in Eastern, Mekelle and Southern Zones of Tigray, Ethiopia, 2016–2019 (N = 2,387).

Frequency of MTB and RR- MTB by study years

Fig 2. Frequency of MTB and RR- MTB by study years.

Discussion

Conclusion

Acknowledgments

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Shampa Anupurba

Roles

Author response to Decision Letter 0

Decision Letter 1

Shampa Anupurba

Roles

Author response to Decision Letter 1

Decision Letter 2

Shampa Anupurba

Roles

Author response to Decision Letter 2

Decision Letter 3

Shampa Anupurba

Roles

Author response to Decision Letter 3

Decision Letter 4

Shampa Anupurba

Roles

Acceptance letter

Shampa Anupurba

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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