Skip to main content
PMC home page
PLOS ONE logoLink to PLOS ONE
. 2021 May 6;16(5):e0250804. doi: 10.1371/journal.pone.0250804

Predictors of mortality and loss to follow-up among drug resistant tuberculosis patients in Oromia Hospitals, Ethiopia: A retrospective follow-up study

Demelash Woldeyohannes 1,*, Yohannes Tekalegn 2, Biniyam Sahiledengle 2, Tesfaye Assefa 3, Rameto Aman 2, Zeleke Hailemariam 4, Lillian Mwanri 5, Alemu Girma 6
Editor: Claudia Marotta7
PMCID: PMC8101723  PMID: 33956812

Abstract

Background

Drug resistance tuberculosis (DR-TB) patients’ mortality and loss to follow-up (LTF) from treatment and care is a growing worry in Ethiopia. However, little is known about predictors of mortality and LTF among drug-resistant tuberculosis patients in Oromia region, Ethiopia. The current study aimed to identify predictors of mortality and loss to follow-up among drug resistance tuberculosis patients in Oromia Hospitals, Ethiopia.

Methods

A retrospective follow up study was carried out from 01 November 2012 to 31 December 2017 among DR-TB patients after calculating sample size using single proportion population formula. Mean, median, Frequency tables and bar charts were used to describe patients’ characteristics in the cohort. The Kaplan-Meier curve was used to estimate the probability of death and LTF after the treatment was initiated. The log-rank test was used to compare time to death and time to LTF. The Cox proportional hazard model was used to determine predictors of mortality and LTF after DR-TB diagnosis. The Crude and adjusted Cox proportional hazard ratio was used to measure the strength of association whereas p-value less than 0.05 were used to declare statistically significant predictors.

Result

A total of 406 DR-TB patients were followed for 7084 person-months observations. Among the patients, 71 (17.5%) died and 32 (7.9%) were lost to follow up (LTF). The incidence density of death and LTF in the cohort was 9.8 and 4.5 per 1000 person-months, respectively. The median age of the study participants was 28 years (IQR: 27.1, 29.1). The overall cumulative survival probability of patients at the end of 24 months was 77.5% and 84.5% for the mortality and LTF, respectively. The independent predictors of death was chest radiographic findings (AHR = 0.37, 95% CI: 0.17–0.79) and HIV serostatus 2.98 (95% CI: 1.72–5.19). Drug adverse effect (AHR = 6.1; 95% CI: 2.5, 14.34) and culture test result (AHR = 0.1; 95% CI: 0.1, 0.3) were independent predictors of LTF.

Conclusion

This study concluded that drug-resistant tuberculosis mortality and LTF remains high in the study area. Continual support of the integration of TB/HIV service with emphasis and work to identified predictors may help in reducing drug-resistant tuberculosis mortality and LTF.

Background

Drug resistant tuberculosis (DR-TB) is defined as resistance to any anti-TB drugs. Extensively drug-resistant tuberculosis (XDR-TB) is a subset of DR-TB with additional resistance to a fluoroquinolone and a second-line injectable agent [1].

According to the WHO, there were an estimated 484000 incident cases of DR/RR-TB in the year 2018 worldwide. Globally in 2018, an estimated 3.4% of new cases and 18% of previously treated cases had DR/RR-TB. A global total of 206,030 people with drug- or rifampicin-resistant TB (DR/RR-TB) were detected and notified in 2019, a 10% increase from 186,883 in 2018 [2,3].

The WHO estimates that about 5% of all TB cases progress to DR-TB, from which more than 40% died in 2013. Treating DR- TB and XDR-TB is particularly difficult even in resource-rich countries because the required long term treatment, a minimum of 18–24 months with second-line TB drugs, has significant adverse effects [4].

Drug resistant tuberculosis surveys in 2005 and 2014 and the 2018 WHO TB report in Ethiopia showed that the prevalence of DR-TB respectively, was 1.6%, 2.3%, and 2.7% among new and 11.8%, 17.8%, and 14% among previously treated TB cases [5–7].

Tuberculosis programmes have reported the LTF of two or more consecutive months to contribute to the poor levels of treatment success in DR-TB [5]. Although DR-TB treatment lasting for 20–24 months has shown to achieve a success rate of 50% of patients worldwide, recent advances show that a short course treatment regimen achieves high treatment success [3].

The 2020 WHO report [3] showed 0.71% and 12% respectively, as proportions of new cases and previously treated cases with DR/RR-TB in Ethiopia, making Ethiopia one among the countries with poorest treatment success rate when compared to other member states. Factors including LTF and poor adherence to treatment were reported to contributing to poor treatment outcome in some countries [3].

The Ethiopian Federal Ministry of Health adopted a two armed standardized regimen consisting of an 8-month intensive phase and a 12-month continuation phase. However, few observational studies have been conducted and reveal poor treatment outcomes including loss to follow-up among DR-TB patients [6]. Both patient- and regimen-related factors were associated with loss to follow-up, important information which may guide interventions to improve treatment adherence, particularly in the first 11 months [8]. Studies have also shown that, similar to what happens with drug-susceptible TB patients, the LTF is one of the main problems in the treatment of DR-TB. In a study conducted in Brazil, identified number of determinants to loss to follow-up such as drug toxicity, long duration of treatment, and other social determinants [9].

Previous studies have shown that predictors of DR-TB mortality are: immune-suppression, tuberculosis related complications, malnutrition, HIV/AIDS, smoking cigarette, LTF, tuberculosis treatment history, and diabetes mellitus, for which, some are determined by patients’ social-demographic, behavioural and lifestyle factors [10–12]. As far as is known to us, only one report has been published in Ethiopia to assess risks for mortality among DR-TB patients [13,14].

Limited studies conducted in Ethiopia showed lost to follow-up among DR-TB registered patients for treatment was high in the first 6 months compared to later follow-up months [12], and the incidence of mortality was 7.42/100 person-years follow-up during treatment and most patients died early on the initiation of treatment [15].

Therefore, the current study aimed to assess predictors, time to mortality and loss to follow-up among patients infected with drug resistance tuberculosis in Ethiopia.

Methods

Study design and study area

A retrospective follow up study was carried out from 01 November 2012 to 31 December 2017 among DR-TB patients in hospitals of Oromia regional state, Ethiopia where high prevalence of TB has been reported to be as high as 21.3%. Included hospitals were Metu Karl, Shanen Gibe, Bishoftu, Shashemene, Adama, Chiro, Deder and Nekemt. The 2016 WHO global report puts Ethiopia among countries with high burden of DR-TB, with more than 3,300 cases estimated annually. In 2016, it was estimated that 2.7% (1.5–4.0 of newly notified and 14% (3.6–25) of previously treated TB patients had DR-TB [16].

Study population and inclusion criteria

The study population involved all DR-TB patients with complete chart, aged 18 years and above enrolled into the adult Tuberculosis clinics in the Oromia Hospitals from 01 November 2012 to 31 December 2017. The period was selected in order to have the nearest five year follow up study period and it was also the period when hospitals in Oromia started the full implementation of standardized formats, documentation and recording systems in a regular manner.

Sample size determination

The sample size was calculated using single population proportion formula after considering the following assumptions: 50% proportion, 95% confidence level (Zα/2 = 1.96), 5% margin of error (d). The final sample size was 423 but the registered DR-TB patients at the study period was 497 and 91 patient charts were incomplete. Hence, we have included 406 patient charts.

Data collection tools and procedures

Data were extracted by using a structured format that was developed from the standard treatment protocol for DR-TB treatment. The checklist sought from individual records, information on patient-related data (Socio demographic characteristics), clinical characteristic, comorbidities, treatment and others.

Selected nurses who worked in TB clinics extracted all DR-TB patients’ data retrospectively (including date of death and LTF) from the hospitals’ registration log books during January 1–30, 2018. Trained data collectors assessed the data quality using a pre-tested data collection tool, and two public health professionals provided continuous supervision and monitoring. Supervisors, data clerks and investigators checked the completeness and consistency of data before and after data entry.

Data analysis

Data were entered into EPI data (version 4.6.0.0) and the analysis was conducted using Statistical package for Social Science (SPSS version 20.0) and Stata (version 14.0). Data were cleaned to remove irrelevant observations before analyses were performed. Median, mean and frequencies (as percentages) were used to describe patients’ characteristics in each cohort. The response variable was survival time, defined as “time in months transpired from the date of initial DR-TB treatment to death/LTF” or, in the case of individuals who did not die/not LTF (censored), “the time in months transpired to LTF. The Kaplan-Meier curve was used to estimate the probability of death and LTF and the median time to death and LTF after the initiation of the DR-TB treatment. The log-rank test was used to compare time to death and LTF between the two groups. The Cox proportional hazard model was used to determine predictors of death and LTF after DR-TB diagnosis. All statistically significant (p < 0.05) variables in the multivariate proportional hazard cox regression model were considered as predictors for mortality and LTF. The crude and adjusted hazard ratio (HR) and its 95% confidence interval (CI) were estimated.

Ethical issues

Ethical approval was obtained from the Review Ethics Committee of the School of Health Science at Madda Walabu University. The data were fully anonymized and name and identifications were not extracted. To preserve patient confidentiality, the identified patients’ data were extracted from medical charts by nurses working in the respective TB clinic.

Result

Socio demographic characteristics

A total of 497 DR-TB patients were registered during the study period. Ninety one (91) patients were excluded due to missing charts, incomplete baseline and follow-up data. The median age of the included participants (406), the median age was 28 (IQR: 27.1, 29) years, and 147 (36.2%) individuals aged between 25–30 years old, made the largest group of participants. Two hundred and thirty nine (58.9%) were males and 41.1% were females. Among males, 41 died and 20 were LTF and individual aged 41 and above years old, recorded the highest death rate (Table 1).

Table 1. Socio-demographic characteristics of drug resistance tuberculosis infected patents in Oromia region, Ethiopia, 2020.

Variables Number (406) Mortality LTF
Event (n = 71) Censored (n = 335) Event (n = 32) Censored(n = 374)
Gender Male 239 (58.9) 41 198 20 219
Female 167 (41.1) 30 137 12 155
Address Urban 261 (64.3) 52 209 18 243
Rural 145 (35.7) 19 126 14 131
Age 19–24 117 (28.8) 15 102 14 103
25–30 147 (36.2) 19 128 7 140
31–40 79 (19.2) 55 55 7 72
≥41 63 (15.5) 50 50 4 59
Open in a new tab

Clinical characteristics of the study participants

Almost all study participants had a diagnosis of pulmonary TBs 397 (97.8%), of which 71 died and 31 were LTF. About 2/3 of DR-TB patients had only rifampicin resistance 260 (64%), of whom 46 died and 23 were LTF. Almost all patients (99.8%), had treatment initiated after the confirmation of TB. Among HIV tested patents, 77 (19.1%) were positive for HIV of which 31 died and 4 were LTF. One tenth 41 (10.1%) of DR-TB patents had comorbidity, of whom 25 died and 7 were LTF. Forty nine (12.1%) DR-TB had unilateral lung cavity, of whom 12 died and 3 were LTF. About 11 (2.7%) patients had any type of addiction, of which 2.8% and 3.1% patients died and LTF respectively. At the beginning of treatment, the majority of patents had BMI ≤ 18 and after treatment a similar number of patients had BMI ≥ 18 (359 (88.4%) and 362 (89.2%) respectively) (Table 2).

Table 2. Clinical characteristics of drug resistance tuberculosis infected patents in Oromia region, Ethiopia, 2020.

Variables Number (406) Mortality LTF
Event (n = 71) Censored (n = 335) Event (n = 32) Censored (n = 374)
Site of TB infection Pulmonary 397 (97.8%) 71 326 31 366
Extra pulmonary 9 (2.2%) 0 9 1 8
Type of resistance RR-Rifampicin 260 (64%) 46 214 23 237
M-MDR 143(35.2%) 24 119 135 8
X-XDR 3 (0.7%) 1 2 2 1
Smear result at zero month Positive 276 (68%) 46 230 16 260
Negative 62 (15.3%) 6 56 10 52
Not done/result not available 68 (16.7%) 19 49 6 62
Culture result at start Positive 252 (62.1%) 34 218 19 233
Negative 40 (9.9%) 2 38 3 37
Not done/result not available 114 (28.1%) 35 79 10 104
Culture result at the end of treatment Positive 18 (4.4%) 7 11 3 15
Negative 322 (79.3%) 30 292 15 307
Not done/result not available 66 (16.3%) 34 32 14 52
Smear result at the end of treatment Positive 14 (3.4%) 7 7 2 12
Negative 339(83%) 35 304 20 319
Not done/result not available 53 (13.1%) 29 24 10 43
Diagnostic method Xpert/MTB/TB/RIF 316 (77.8%) 61 255 20 296
LPA 68 (16.7%) 9 59 8 60
Culture 3 (0.7%) 0 3 0 3
Others 19 (4.7%) 1 18 4 15
Reason for entering MDR treatment Bacteriological confirmed 405 (99.8%) 71 334 32 373
Clinically diagnosed 1 (0.2%) 0 1 0 1
HIV tested Yes 402(99%) 70 332 32 370
No 2(4%) 1 3 0 4
HIV test result Reactive 77 (19.1%) 31 46 4 73
None reactive 326 (80.9%) 39 287 28 298
ART started Yes 30(98.8%) 30 45 3 72
No 1(3.2%) 1 1 1 1
Co-infections Yes 41 (10.1%) 16 25 7 34
No 365 (89.9%) 55 310 25 340
Chronic diseases Yes 12 (3%) 4 8 2 10
No 394 (97%) 67 327 30 364
Drug Adverse effect Yes 40 (9.9%) 5 35 9 31
No 366 (90.1%) 66 300 23 343
Treatment regimen Standard 401 (98.9%) 70 331 31 370
Individualized 5 (1.2%) 1 4 1 4
Steroid use Yes 8 (2%) 2 6 0 8
No 140 (34.5%) 24 116 6 134
Unknown 258 (63.5%) 45 213 26 232
Chest radiographic finding Unilateral Cavity 49 (12.1%) 12 37 3 46
Bilateral Cavity 28 (6.9%) 9 19 4 24
Abnormality without cavity 128 (31.5%) 11 117 7 121
Massive effusion 24 (5.9%) 6 18 3 21
Others 177 (43.6%) 33 144 15 162
Any type of addiction Yes 11 (2.7%) 2 9 1 10
No 395 (97.3%) 69 326 31 364
BMI at start of treatment 18 359 (88.4%) 67 292 30 329
>18 47 (11.6%) 4 43 2 45
BMI at end of treatment = <18 44 (10.8%) 10 34 4 40
>18 362 (89.2%) 61 301 28 334
Open in a new tab

Magnitude and time to mortality and loss to follow up

Of the 406 study participants, 275 (67.7%) were cured, 71(17.5%) died, 32 (7.9%) LTF and the treatment failed in 13 (3.2%). (Fig 1) The incidence density of death in the cohort was 9.8 per 1000 person-months. The incidence density of loss to follow up in the cohort was 4.5 per 1000 person-months.

Fig 1. Treatment outcomes of drug resistance tuberculosis infected patents in Oromia region, Ethiopia, 2020.

Fig 1

Open in a new tab

Survival probability of DR-TB patients for mortality

A total of 406 DR-TB patients were followed for a minimum of 1 month and for a maximum of 24 months with mean follow up period of 21 months (CI: 20.4, 21.7) and contributed 7084 person months observations. The cumulative survival probability of patients at the end of 9 months was 87.4%, at the end of 19 months was 83.3%, and at the end of 24 months was 77.5% (Fig 2). For loss to follow-up, they had follow up for a minimum of one months and maximum of 23 months on follow up with mean follow up period of 22 months. The cumulative survival probability of patients at the end of 8 months was 96.5%, at the end of 19 months was 94.3%, and at the end of 24 months was 84.5% (Fig 3). Kaplan-Meier analysis revealed that LTF was higher in patients who were HIV-infected compared to non-infected (Fig 4). Additionally, patients with co infection had lower survival probability than their counterparts (Fig 5).

Fig 2. Kaplan–Meier survival estimate for mortality of drug resistance tuberculosis infected patents in Oromia region, Ethiopia, 2020.

Fig 2

Open in a new tab

Fig 3. Kaplan–Meier survival estimate for loss to follow up of drug resistance tuberculosis infected patents in Oromia region, Ethiopia, 2020.

Fig 3

Open in a new tab

Fig 4. Kaplan–Meier survival estimate for LTF of drug resistance tuberculosis infected patents for HIV reactive and non-reactive patients in Oromia region, Ethiopia, 2020.

Fig 4

Open in a new tab

Fig 5. Kaplan–Meier survival estimate for mortality of drug resistance tuberculosis infected patents for patients with co morbidity and without co morbidity in Oromia region, Ethiopia, 2020.

Fig 5

Open in a new tab

Predictors of time to mortality and loss to follow up

According to multivariate Cox proportional hazard regression analysis model, two variables were found to be independent predictors for the mortality during the DR-TB patients’ treatment, include chest radiographic finding and HIV sero status. The risk of death decreased by 63% in patients with normal chest radiographic finding compared to chest radiographic with massive effusion (AHR = 0.37, 95% CI: 0.17–0.79). With regards to HIV sero status, HIV positive DR-TB patients had three times higher risk of death compared to their counterpart, 2.98 (95% CI: 1.72–5.19) (Table 3). Patients who had drug adverse effect were six times at higher risk of LTF compared to patients who had no adverse drug effect (AHR = 6.1; 95% CI = 2.5, 14.34). Moreover, those who had negative culture result were 90% less likely to record LTF compared to patients had no culture done [AHR = 0.1; 95% CI: 0.1, 0.3] (Table 4).

Table 3. Predictors of mortality among drug resistance tuberculosis infected patents in Oromia region, Ethiopia, 2020.

Variables No. at risk No. of death CHR (95% CI) AHR (95% CI)
Address Urban 261 52 1.5(0.1, 2.6) 1.06(0.62, 1.83)
Rural 145 19 1 1
HIV sero status Positive 2 1 3.9(2.4, 6.2) 2.98(1.72, 5.19)*
Negative 402 70 1 1
Confection Yes 41 16 2.9(1.7, 5.2) 1.616(0.82, 3.20)
No 365 55 1 1
Chronic diseases Yes 12 4 1.9 (0.7, 5.3) 2.57(0.88, 7.51)
No 394 67 1 1
Drug adverse effect Yes 40 5 0.7(0.3, 1.7) 0.65(0.26, 1.65)
No 366 66 1 1
Chest radiographic finding Massive effusion 49 12 1 1
Bilateral Cavity 28 9 1.3(0.7, 2.5) 1.60(0.79, 3.24)
Abnormality without cavity 128 11 1.9(0.9, 3.9) 2.09(0.95, 4.66)
Normal 24 6 0.4(0.2, 0.8) 0.37(0.17, 0.79)*
Unilateral Cavity 177 33 1.3(0.6, 3.2) 1.10 (0.44, 2.76)
BMI at start of treatment = <18 44 10 2.5(0.9, 6.9) 1.7(0.83, 3.51)
>18 362 61 1 1
BMI at end of treatment = <18 359 67 1.3(0.7, 2.6) 1.88(0.65, 5.49)
>18 47 4 1 1
Open in a new tab

Notes:

*Significant at p<0.05.

Table 4. Predictors of LTF among drug resistance tuberculosis infected patents in Oromia region, Ethiopia, 2020.

Variable No. at risk No. of LTF CHR (95% CI) AHR (95% CI)
Address Urban 261 18 0.6 (0.3, 1.2) 0.5 (0.3, 1.2)
Rural 145 14 1 1
Confection Yes 41 7 3.1(1.3, 7.1) 1.6 (0.6, 3.8)
No 365 25 1 1
Drug A/E Yes 40 9 4.1(1.9, 8.8) 6.1 (2.5, 14.34)*
No 366 23 1 1
Steroid use Yes 8 0
No 140 6
Unknown 258 26
BMI at start = <18 44 30 2.8(0.7, 11.8) 1.5 (0.3, 6.7)
>18 362 2 1 1
Sex Male 239 20 1.2(0.6, 2.5) 1.5 (0.6, 3.2)
Female 167 12 1 1
Culture at end Positive 18 3 0.6(0.2, 1.9) 1.0 (0.3, 3.9)
Negative 322 15 0.13(0.06, 0.28) 0.1 (0.1, 0.3)
Not done/result not available 66 14 1 1
Open in a new tab

Notes:

*Significant at p<0.05.

Discussion

This study was designed to assess the incidence rate and to identify the predictors of mortality and lost to follow-up among DR-TB patients attending their treatment at the Oromia Hospitals, Ethiopia. A total of 406 DR-TB patients were followed and produced 7084 person-months observations and 71 (17.5%) died. This finding was higher than a study conducted in Dangila and agreed with a systematic review and meta-analysis conducted in Ethiopia [17,18].

The patients who were LTF would have not completed their treatment regime, resulting in serious public health problems because these patients are at higher risk of extra DR-TB and transmission to the community [19]. In this study, 32 (7.9%) for DR-TB treatment enrolled patents were LTF. Similar high rate of LTF among DR-TB patients has been demonstrated in a systematic review and other studies conducted in China, Pakistan, and Brazil [20–23], together illustrating the immense challenges in achieving completion of currently recommended treatment regimens for DR-TB. In this study LTF rate was also substantially higher than the WHO recommended target of 5% [24], which implies the need to demand for more comprehensive approaches to reduce LTF among DR-TB patients by targeting those risk factors for treatment interruptions.

The incidence density of LTF in the current study cohort was 4.5 per 1000 person-months. This finding was lower than a study conducted in Northern part of Ethiopia and higher than a study conducted in St. Peter’s specialized Tuberculosis treatment hospital in Ethiopia [13,25]. We hypothesise that this variation could possibly be due to differences, including in the sample size, study population, treatment guideline, and regimens.

The incidence density of death in the cohort was 9.8 per 1000 person-months. This finding was higher than a study conducted in Amhara region as well as a study conducted in nationwide in Ethiopia [12,26]. The possible explanation for this might be due to the difference in the follow-up periods, because the longer follow up periods have the probability of decreasing the occurrence of events.

The risk of death decreased by 63% in patients with normal chest radiographic findings compered to chest radiographic finding with massive effusion. This finding was consistent with previous studies conducted in Tanzania and central Ethiopia [15,27]. The lower respiratory tract infections are known to have consequences including the accumulation of inflammatory exudate in the alveoli, resulting in reduced oxygen exchange and respiratory insufficiency, and the DR-TB patients with clinical complications experience longer recovery times and poor response to anti TB-medications [28,29].

In this study, HIV positive DR-TB patients had 2.98 times higher risk of death compared to the HIV negative DR-TB, findings which are consistent with studies conducted in other sites including: Amhara region, Dangila, St. Peter’s specialized Tuberculosis hospital in Ethiopia, eastern and central Africa, and in Ethiopia, Eastern Europe, Brazil, Peru, Nigeria [12,17,25,26,30–34]. The high mortality rate of DR-TB patients among HIV positive participants might be due to the synergistic effects of the two co-infections, i.e. HIV and DR-TB. Because DR-TB patients receive treatment for a minimum of two years, they might experience serious drug adverse effects and toxicities due to the high burden of pills, which may result in poor adherence to treatment and poorer overall patients’ poor outcome. Coupled with the known higher rate of smear negative in HIV positive patients, the diagnosis of DR-TB in HIV positive patients is said to difficult as may be confused with other pulmonary or systemic infections. These interactions, can result in misdiagnosis or delays in a diagnosis and leading to higher morbidity and mortality [35,36].

Patients who had drug adverse effect were six times higher risk of LTF compared to patients who had no adverse drug effect. This finding was consistent with studies that were conducted in the Philippines, Pakistan, Tajikistan, Georgia, and a systematic review and Meta-analysis [8,21,37–39]. These findings support the knowledge that an association exists between LTF and individuals taking DR-TB drugs since second line drugs are more toxic and more likely to cause severe side effects.

Drug resistance Tuberculosis patients who had negative culture result at the end of initiation phase were 90% less likely to be LTF compared to patients who had no culture undertaken. This seems to be promising result as at the end of initiation phase could motivate patients to finish treatment, and thus a possibility of positive outcome.

Limitations of the study

As a limitation, this study did not considered some predictors such as viral load, liver function and renal function tests because it was conducted using secondary data that have missing records. Additionally, there could also be underestimation of the mortality incidence rate and LTF due to record problems.

Conclusion and recommendation

Our findings point to some risk factors related to mortality and loss to follow-up, which are public health problems that contribute to worsening DR-TB treatment. It is important for TB control programs and health professionals to identify predictors in patients with increased risk of loss to follow-up and to adopt specific strategies to address this problem and prevent death. Continual support of the integration of TB/HIV service with emphasis and further work on identified predictors may help in reducing DR-TB mortality and LTF.

Supporting information

S1 Data. Available data for predictors of mortality and loss to follow-up among drug resistant tuberculosis patients in Oromia Hospitals, Ethiopia.

(SAV)

Click here for additional data file. (34.9KB, sav)

Data Availability

The data underlying this study are accessible via BioStudies database (accession number S-BSST624): http://helpdesk.ebi.ac.uk/Ticket/Display.html?id=494263https://www.ebi.ac.uk/biostudies/studies/S-BSST624?query=S-BSST624.

Funding Statement

The authors received no specific funding for this work.

References

  • 1.Nahid P, Mase SR, Migliori GB, Sotgiu G, Bothamley GH, Brozek JL, et al. Treatment of drug-resistant tuberculosis. An official ATS/CDC/ERS/IDSA clinical practice guideline. American journal of respiratory and critical care medicine. 2019;200(10):e93–e142. 10.1164/rccm.201909-1874ST [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Branigan D. THE RIGHT TO QUALITY TB DIAGNOSTIC TESTING.
  • 3.Organization WH. Global tuberculosis report 2020. Global tuberculosis report 20202020.
  • 4.Mollel EW, Chilongola JO. Predictors for mortality among multidrug-resistant tuberculosis patients in Tanzania. Journal of tropical medicine. 2017;2017. 10.1155/2017/9241238 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Organization WH. World Health Organization Global tuberculosis repot 2013. Gevena: World Health Organization. 2013.
  • 6.Eshetie S, Alebel A, Wagnew F, Geremew D, Fasil A, Sack U. Current treatment of multidrug resistant tuberculosis in Ethiopia: an aggregated and individual patients’ data analysis for outcome and effectiveness of the current regimens. BMC Infectious Diseases. 2018;18(1):486. 10.1186/s12879-018-3401-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Eshetu L, Beniam F, Abebaw K, Muluwork G, Zelalem Y, Ribka F. Second round anti-tuberculosis drug resistance surveillance in Ethiopia. 2014.
  • 8.Walker IF, Shi O, Hicks JP, Elsey H, Wei X, Menzies D, et al. Analysis of loss to follow-up in 4099 multidrug-resistant pulmonary tuberculosis patients. European Respiratory Journal. 2019;54(1):1800353. 10.1183/13993003.00353-2018 [DOI] [PubMed] [Google Scholar]
  • 9.Viana PVdS, Redner P, Ramos JP. Factors associated with loss to follow-up and death in cases of drug-resistant tuberculosis (DR-TB) treated at a reference center in Rio de Janeiro, Brazil. Cadernos de saude publica. 2018;34:e00048217. 10.1590/0102-311X00048217 [DOI] [PubMed] [Google Scholar]
  • 10.Gandhi NR, Andrews JR, Brust JC, Montreuil R, Weissman D, Heo M, et al. Risk factors for mortality among MDR-and XDR-TB patients in a high HIV prevalence setting. The International Journal of Tuberculosis and Lung Disease. 2012;16(1):90–7. 10.5588/ijtld.11.0153 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Brust JC, Gandhi NR, Carrara H, Osburn G, Padayatchi N. High treatment failure and default rates for patients with multidrug-resistant tuberculosis in KwaZulu-Natal, South Africa, 2000–2003. The international journal of tuberculosis and lung disease. 2010;14(4):413–9. [PMC free article] [PubMed] [Google Scholar]
  • 12.Ketema DB, Alene M, Assemie MA, Yismaw L, Merid MW. Risk factors for mortality among drug-resistant tuberculosis patients registered for drug-resistant treatment in Amhara region, Ethiopia: a historical cohort study. Archives of Public Health. 2020;78(1):1–9. 10.1186/s13690-020-00448-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Kassa GM, Teferra AS, Wolde HF, Muluneh AG, Merid MW. Incidence and predictors of lost to follow-up among drug-resistant tuberculosis patients at University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia: a retrospective follow-up study. BMC Infectious Diseases. 2019;19(1):817. 10.1186/s12879-019-4447-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Di Gennaro F., et al. (2017). “Social determinants of therapy failure and multi drug resistance among people with tuberculosis: A review.” Tuberculosis 103: 44–51. 10.1016/j.tube.2017.01.002 [DOI] [PubMed] [Google Scholar]
  • 15.Kassa GM, Tadesse A, Gelaw YA, Alemayehu TT, Tsegaye AT, Tamirat KS, et al. Predictors of mortality among multidrug-resistant tuberculosis patients in central Ethiopia: a retrospective follow-up study. Epidemiology & Infection. 2020;148. 10.1017/S0950268820002514 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Zewdie O, Dabsu R, Kifle E, Befikadu D. Rifampicin-Resistant Multidrug-Resistant Tuberculosis Cases in Selected Hospitals in Western Oromia, Ethiopia: Cross-Sectional Retrospective Study. Infection and Drug Resistance. 2020;13:3699. 10.2147/IDR.S274589 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Birlie A, Tesfaw G, Dejene T, Woldemichael K. Time to death and associated factors among tuberculosis patients in Dangila Woreda, Northwest Ethiopia. PLoS One. 2015;10(12):e0144244. 10.1371/journal.pone.0144244 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Alemu A, Bitew ZW, Worku T. Poor treatment outcome and its predictors among drug-resistant tuberculosis patients in Ethiopia: a systematic review and meta-analysis. International Journal of Infectious Diseases. 2020. 10.1016/j.ijid.2020.05.087 [DOI] [PubMed] [Google Scholar]
  • 19.Millett E, Noel D, Mangtani P, Abubakar I, Kruijshaar M. Factors associated with being lost to follow-up before completing tuberculosis treatment: analysis of surveillance data. Epidemiology & Infection. 2013;141(6):1223–31. 10.1017/S095026881200163X [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Toczek A, Cox H, Du Cros P, Cooke G, Ford N. Strategies for reducing treatment default in drug-resistant tuberculosis: systematic review and meta-analysis. The International Journal of Tuberculosis and Lung Disease. 2013;17(3):299–307. 10.5588/ijtld.12.0537 [DOI] [PubMed] [Google Scholar]
  • 21.Kanwal S, Akhtar AM. Risk Factors Associated with Lost to follow up among Multidrug Resistance Tuberculosis Patients Registered for Treatment in Programmatic Management of Drug Resistant Tuberculosis Sites of Punjab, Pakistan. Journal of Biostatistics and Epidemiology. 2020;6(3):162–9. [Google Scholar]
  • 22.Alene KA, Yi H, Viney K, McBryde ES, Yang K, Bai L, et al. Treatment outcomes of patients with multidrug-resistant and extensively drug resistant tuberculosis in Hunan Province, China. BMC Infectious Diseases. 2017;17(1):573. 10.1186/s12879-017-2662-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Redner P, Ramos JP. Factors associated with loss to follow-up and death in cases of drug-resistant tuberculosis (DR-TB) treated at a reference center in. Cad Saúde Pública. 2018;34(5):e00048217. 10.1590/0102-311X00048217 [DOI] [PubMed] [Google Scholar]
  • 24.Organization WH. Roadmap to prevent and combat drug-resistant tuberculosis: the consolidated action plan to prevent and combat multidrug-and extensively drug-resistant tuberculosis in the WHO European region, 2011–2015: World Health Organization. Regional Office for Europe; 2011.
  • 25.Getachew T, Bayray A, Weldearegay B. Survival and predictors of mortality among patients under multi-drug resistant tuberculosis treatment in Ethiopia: St. Peter’s specialized tuberculosis hospital, Ethiopia. Int J Pharm Sci Res. 2013;4(2):776. [Google Scholar]
  • 26.Shimbre MS, Degaga TS, Hebo SH, Zerdo Z, Girum T, Teshome T. Survival and predictors of mortality from multidrug resistant tuberculosis (MDR-TB) among patients treated at MDR-TB Referal Hospitals in Ethiopia: A retrospective cohort study. Journal of Public Health and Epidemiology. 2020;12(1):13–21. [Google Scholar]
  • 27.Leveri TH, Lekule I, Mollel E, Lyamuya F, Kilonzo K. Predictors of treatment outcomes among multidrug resistant tuberculosis patients in Tanzania. Tuberculosis Research and Treatment. 2019;2019. 10.1155/2019/3569018 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Limenih YA, Workie DL. Survival analysis of time to cure on multi-drug resistance tuberculosis patients in Amhara region, Ethiopia. BMC public health. 2019;19(1):165. 10.1186/s12889-019-6500-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Zhang Q, Wu Z, Zhang Z, Sha W, Shen X, Xiao H. Efficacy and effect of free treatment on multidrug-resistant tuberculosis. Experimental and therapeutic medicine. 2016;11(3):777–82. 10.3892/etm.2015.2966 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Gebre T, Hordofa MA, Birhanu MY, Siferih M, Leshargie CT. Time to death and its predictors among adult with drug-resistance tuberculosis patients, in Eastern and East-Central Ethiopia, 2012–2018: A retrospective cohort study. 2019.
  • 31.Balabanova Y, Ignatyeva O, Fiebig L, Riekstina V, Danilovits M, Jaama K, et al. Survival of patients with multidrug-resistant TB in Eastern Europe: what makes a difference? Thorax. 2016;71(9):854–61. 10.1136/thoraxjnl-2015-207638 [DOI] [PubMed] [Google Scholar]
  • 32.Gayoso R, Dalcolmo M, Braga JU, Barreira D. Predictors of mortality in multidrug-resistant tuberculosis patients from Brazilian reference centers, 2005 to 2012. Brazilian Journal of Infectious Diseases. 2018;22(4):305–10. 10.1016/j.bjid.2018.07.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Chung-Delgado K, Guillen-Bravo S, Revilla-Montag A, Bernabe-Ortiz A. Mortality among MDR-TB cases: comparison with drug-susceptible tuberculosis and associated factors. PloS one. 2015;10(3):e0119332. 10.1371/journal.pone.0119332 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Bajehson M, Musa BM, Gidado M, Nsa B, Sani U, Habibu AT, et al. Determinants of mortality among patients with drug-resistant tuberculosis in northern Nigeria. PloS one. 2019;14(11):e0225165. 10.1371/journal.pone.0225165 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Matteelli A, Centis R, D’Ambrosio L, Sotgiu G, Tadolini M, Pontali E, et al. WHO strategies for the programmatic management of drug-resistant tuberculosis. Expert review of respiratory medicine. 2016;10(9):991–1002. 10.1080/17476348.2016.1199278 [DOI] [PubMed] [Google Scholar]
  • 36.Organization WH. Global tuberculosis control and patient care. A ministerial meeting of high M/XDR-TB burden countries. Beijing, China, 1–3 April 2009.
  • 37.Tupasi TE, Garfin AMCG, Kurbatova EV, Mangan JM, Orillaza-Chi R, Naval LC, et al. Factors associated with loss to follow-up during treatment for multidrug-resistant tuberculosis, the Philippines, 2012–2014. Emerging infectious diseases. 2016;22(3):491. 10.3201/eid2203.151788 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Wohlleben J, Makhmudova M, Saidova F, Azamova S, Mergenthaler C, Verver S. Risk factors associated with loss to follow-up from tuberculosis treatment in Tajikistan: a case-control study. BMC Infectious Diseases. 2017;17(1):543. 10.1186/s12879-017-2655-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Kuchukhidze G, Kumar A, De Colombani P, Khogali M, Nanava U, Blumberg H, et al. Risk factors associated with loss to follow-up among multidrug-resistant tuberculosis patients in Georgia. Public Health Action. 2014;4(2):S41–S6. 10.5588/pha.14.0048 [DOI] [PMC free article] [PubMed] [Google Scholar]

Decision Letter 0

Claudia Marotta

17 Mar 2021

PONE-D-21-04578

Predictors of Mortality and Loss to Follow-up among Drug Resistant Tuberculosis Patients in Ethiopia: A Retrospective Follow-up Study

PLOS ONE

Dear Dr. Demelash Woldeyohannes,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by 22 March. 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'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Claudia Marotta

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide-

3. Thank you for stating the following financial disclosure:

"The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

At this time, please address the following queries:

  1. Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution.

  2. State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

  3. If any authors received a salary from any of your funders, please state which authors and which funders.

  4. If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.”

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

4. In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study, including: a) whether all data were fully anonymized before you accessed them; b) the date range (month and year) during which patients' medical records were accessed; c) the date range (month and year) during which patients whose medical records were selected for this study sought treatment. If the ethics committee waived the need for informed consent, or patients provided informed written consent to have data from their medical records used in research, please include this information.

5. You indicated that you had ethical approval for your study. In your Methods section, please ensure you have also stated whether you obtained consent from parents or guardians of the minors included in the study or whether the research ethics committee or IRB specifically waived the need for their consent.

6.Thank you for submitting the above manuscript to PLOS ONE. During our internal evaluation of the manuscript, we found some minor occurrences of overlapping text with the following previous publication(s), some of which you are an author, which needs to be addressed:

- https://doi.org/10.1590/0102-311X00048217

- https://doi.org/10.1186/1471-2334-13-297

We would like to make you aware that copying extracts from previous publications word-for-word, especially outside the methods section, is unacceptable. In addition, the reproduction of text from published reports has implications for the copyright that may apply to the publications.

Please revise the manuscript to quote or rephrase the duplicated text and cite your sources for text outside the methods section. Please note that further consideration is dependent on the submission of a manuscript that addresses these concerns about the overlap in text with published work.

Additional Editor Comments:

dear Auhtors follow reviewer suggestions to improve your paper

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

Reviewers' comments:

Reviewer's Responses to Questions

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: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: 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: This paper evaluated the incidence and predictors of mortality and lost to follow-up among Rifampin resistant TB patients in a state of Ethiopia. RR/MDR-TB is a major public health problem all over the world. The authors presented us the severity and poor outcome of RR/MDR-TB in Oromia regional state of Ethiopia which is common in many high burden countries. The article could help the readers to update the factors for the treatment outcome in this country. However, there some questions need to be addressed for this paper.

1. The definition for DR-TB was not correctly described in the background. Drug resistant tuberculosis (DR-TB) was referred to resistance to any anti-TB drugs, and resistance to at least Isoniazid (H) and rifampin(R) was defined as MDR-TB according to WHO. The definition needs to be clear for the entire study.

2. The study was only conducted in in a state of Ethiopia, thus cannot represent the whole country of Ethiopia. The title and conclusion of the article should be more precisely set and described.

3. Although the study had been approved by the ethics committee, it had used the patient retrospective data which the patient consent exempt is also needed for the study. Was it also approved by the committee?

4. According to the study, 91 patients were excluded due to missing charts, incomplete baseline and follow-up data. How many patients among these excluded group died or LTF? Because the poor outcome could also cause the missing of data.

5. Page 8, line 5, there was a mistake of “of which 7 died…”. It should be 71 died.

Reviewer #2: I read with great interest this paper.Demelash Woldeyohannes and colleague wrote on important global health problem: Predictors of Mortality and Loss to Follow-up among Drug Resistant Tuberculosis in high burden setting.

Below my suggestions:

1. Introduction: well that article show data on TB global burden data of TB Report 2020. Add the role of social determinants of health in worst outcome of TB, therapy failure and onset on TB MDR (see and cite Social determinants of therapy failure and multi drug resistance among people with tuberculosis: A review. Tuberculosis (Edinb). 2017 Mar;103:44-51. doi: 10.1016/j.tube.2017.01.002.2. Methods: clear. Correct tuberculosis in TB or Tuberculosis.

3. Results: no suggestions

4. Discussion: discuss better the role of age (Active Pulmonary Tuberculosis in Elderly Patients: A 2016-2019 Retrospective Analysis from an Italian Referral Hospital. Antibiotics (Basel) in worse outcome and onset adverse events and how they need more medical attention and the role of comorbidity exspecially diabetes (Diabetes in active tuberculosis in low-income countries: to test or to take care? Lancet Glob Health. 2019 Jun;7(6):e707. doi: 10.1016/S2214-109X(19)30173-1. PMID: 31097272.). In fact, Many factors contribute to the lack of efficacy in contain- ing TB, as social determinants of health (SDH) and con- comitance of other co-morbidities, such as co-infections (in particular with HIV) and non-communicable diseases, such as diabetes mellitus (DM). Furthermore, TB and DM remain serious public health problems particularly in low‐ and middle‐income countries. The coexistence of these two conditions is an example of a bidirectional association between a communicable and non‐communicable disease that increases the dual burden of DM and TB(see and cite Pizzol D, et al. Prevalence of diabetes mellitus in newly diagnosed pulmonary tuberculosis in Beira, Mozambique. Afr Health Sci. 2017 Sep;17(3):773-779. )

Compare better your data with other data from low income country anger high burden of Tb (es Mozambique) (Predictors of therapy failure in newly diagnosed pulmonary tuberculosis cases in Beira, Mozambique. BMC Res Notes. 2018 Feb 5;11(1):99. doi: 10.1186/s13104-018-3209-9. PMID: 29402317; PMCID: PMC5800087)

**********

6. 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.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Francesco Di Gennaro

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 May 6;16(5):e0250804. doi: 10.1371/journal.pone.0250804.r002

Author response to Decision Letter 0

12 Apr 2021

Responses for the comments from reviewers

We are very grateful to the editor and reviewers for their valuable comments and we believe that the revised manuscript is much stronger as a result of their feedback.

Dear Editor and reviewers:

Thank you for the opportunity to revise our manuscript “Predictors of Mortality and Loss to Follow-up among Drug Resistant Tuberculosis Patients in Ethiopia: A Retrospective Follow-up Study” (PONE-D-21-04578) for publication by PLOS ONE.

We have addressed the Editors’ and reviewers’ comments in our responses and incorporated related changes into the manuscript. For convenience, the reviewers’ comments are in black and our responses are in blue.

The primary changes made to the study include: Editing of the manuscript to improve clarity and consistency

Additional requirements

1. Please ensure that your manuscript meets PLOS ONE's style requirements

Response: Thank you very much for reminding us to stick on the guideline, the revised manuscript meets PLOS ONE's style requirements

2. Regarding data availability

Response: Thank you very much for flagging this point, all data are fully available without restriction

3. Regarding financial disclosure

Response: “The authors received no specific funding for this work.”

4. Regarding ethics statement

Response: We have addressed the revised point regarding the ethics statement in the revised manuscript and cover letter.

5. Please ensure you have also stated whether you obtained consent from parents or guardians of the minors included in the study or whether the research ethics committee or IRB specifically waived the need for their consent.

Response: This study didn’t included the minors

6. Minor occurrences of overlapping text with the following previous publication:

Response: We are grateful to the editor comments; we have paraphrased the overlapping statements

Reviewer #1:

1.1. The definition for DR-TB was not correctly described in the background. Drug resistant tuberculosis (DR-TB) was referred to resistance to any anti-TB drugs, and resistance to at least Isoniazid (H) and rifampin(R) was defined as MDR-TB according to WHO. The definition needs to be clear for the entire study.

Response: We are grateful to the reviewer comments; we made a correction in background of the study

1.2. The study was only conducted in in a state of Ethiopia, thus cannot represent the whole country of Ethiopia. The title and conclusion of the article should be more precisely set and described.

Response: We thank the reviewer for catching this. We made correction on the title of the study

1.3. Although the study had been approved by the ethics committee, it had used the patient retrospective data which the patient consent exempt is also needed for the study. Was it also approved by the committee?

Response: Yes, the ethical approval was received after the considering these issues

1.4. According to the study, 91 patients were excluded due to missing charts, incomplete baseline and follow-up data. How many patients among these excluded group died or LTF? Because the poor outcome could also cause the missing of data.

Response: Thank you very much, 91 patent (missing) charts not included outcomes

1.5. Page 8, line 5, there was a mistake of “of which 7 died…”. It should be 71 died.

Response: Thank you for flagging this, we effected in the manuscript (Result section, line 5, page 8)

Reviewer #2

2.1. Introduction: well that article show data on TB global burden data of TB Report 2020. Add the role of social determinants of health in worst outcome of TB, therapy failure and onset on TB MDR (see and cite Social determinants of therapy failure and multi drug resistance among people with tuberculosis: A review. Tuberculosis (Edinb). 2017 Mar;103:44-51. doi: 10.1016/j.tube.2017.01.002.2.

Response: We are grateful to the Reviewer for this comments, we have considered the factors and cited manuscript

2.2. Methods: clear. Correct tuberculosis in TB or Tuberculosis.

Response: We thank the reviewer for catching this. We made correction in the whole document

2.3. Results: no suggestions

2.4. Discussion: discuss better the role of age (Active Pulmonary Tuberculosis in Elderly Patients: A 2016-2019 Retrospective Analysis from an Italian Referral Hospital. Antibiotics (Basel) in worse outcome and onset adverse events and how they need more medical attention and the role of comorbidity exspecially diabetes (Diabetes in active tuberculosis in low-income countries: to test or to take care? Lancet Glob Health. 2019 Jun;7(6):e707. doi: 10.1016/S2214-109X(19)30173-1. PMID: 31097272.). In fact, Many factors contribute to the lack of efficacy in contain- ing TB, as social determinants of health (SDH) and con- comitance of other co-morbidities, such as co-infections (in particular with HIV) and non-communicable diseases, such as diabetes mellitus (DM). Furthermore, TB and DM remain serious public health problems particularly in low‐ and middle‐income countries. The coexistence of these two conditions is an example of a bidirectional association between a communicable and non‐communicable disease that increases the dual burden of DM and TB (see and cite Pizzol D, et al. Prevalence of diabetes mellitus in newly diagnosed pulmonary tuberculosis in Beira, Mozambique. Afr Health Sci. 2017 Sep;17(3):773-779.)

Response: We are grateful to the reviewer comments; our study included co infection such as HIV but it didn’t included non-communicable disease specifically diabetes mellitus and role of age. We take these concerns as the limitations of the study.

2.5. Compare better your data with other data from low income country anger high burden of Tb (es Mozambique) (Predictors of therapy failure in newly diagnosed pulmonary tuberculosis cases in Beira, Mozambique. BMC Res Notes. 2018 Feb 5;11(1):99. doi: 10.1186/s13104-018-3209-9. PMID: 29402317; PMCID: PMC5800087)

Response: Thank you very much for flagging this. The outcome variable for the study conducted in Zimbabwe was therapy failure our study outcome variable were mortality and Loss to follow up, hence we unable to compare and contrast with our study findings.

Please contact me again if additional information and editing required

Kind regards,

Demelash Woldeyohannes

The second Responses for the comments from editor and reviewers

We are very grateful to the editor and reviewers for their valuable comments and we believe that the revised manuscript is much stronger as a result of their feedback.

Dear Editor and reviewers:

Thank you for the opportunity to revise our manuscript “Predictors of Mortality and Loss to Follow-up among Drug Resistant Tuberculosis Patients in Oromia Hospitals, Ethiopia: A Retrospective Follow-up Study” (PONE-D-21-04578R1) for publication by PLOS ONE.

We have addressed the Editors’ and reviewers’ comments in our responses and incorporated related changes into the manuscript. For convenience, the reviewers’ comments are in black and our responses are in blue.

The primary changes made to the study include: Editing of the manuscript to improve clarity and consistency

1. According to Table 1, the study included data from minors (age <18). In your Methods section, please ensure you have also stated whether you obtained consent from parents or guardians of the minors included in the study or whether the research ethics committee or IRB specifically waived the need for parental consent.

Responses: Thank very much for flagging this: Under age 18 study participants were included due to editorial problem. They are under age category of 19 to 24.

2. Please amend the title either on the online submission form or in your manuscript so that they are identical.

Responses: We made correction

3. Please ensure that you refer to Figure 2 and Figure 3 in your text as, if accepted, production will need this reference to link the reader to the figures.

Responses: We made correction

4. Please upload a copy of Supporting Information Table S1 - S4 which you refer to in your text.

Responses: We made correction

5. Thank you for updating your data availability statement. You note that your data are available within the Supporting Information files, but no such files have been included with your submission. At this time we ask that you please upload your minimal data set as a Supporting Information file, or to a public repository such as Figshare or Dryad. Please also ensure that when you upload your file you include separate captions for your supplementary files at the end of your manuscript.

Responses: We have uploaded as supplementary file

Attachment

Submitted filename: Responses to reviewers 2.docx

Click here for additional data file. (16.2KB, docx)

Decision Letter 1

Claudia Marotta

14 Apr 2021

Predictors of Mortality and Loss to Follow-up among Drug Resistant Tuberculosis Patients in Oromia Hospitals, Ethiopia: A Retrospective Follow-up Study

PONE-D-21-04578R1

Dear Dr. Demelash Woldeyohannes,

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,

Claudia Marotta

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

congratulations

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

Reviewer #2: All comments have been addressed

**********

2. 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: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. 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: (No Response)

Reviewer #2: (No Response)

**********

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.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Acceptance letter

Claudia Marotta

19 Apr 2021

PONE-D-21-04578R1

Predictors of Mortality and Loss to Follow-up among Drug Resistant Tuberculosis Patients in Oromia Hospitals, Ethiopia: A Retrospective Follow-up Study

Dear Dr. Woldeyohannes:

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. Claudia Marotta

Academic Editor

PLOS ONE

Associated Data

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

    Supplementary Materials

    S1 Data. Available data for predictors of mortality and loss to follow-up among drug resistant tuberculosis patients in Oromia Hospitals, Ethiopia.

    (SAV)

    Click here for additional data file. (34.9KB, sav)
    Attachment

    Submitted filename: Responses to reviewers 2.docx

    Click here for additional data file. (16.2KB, docx)

    Data Availability Statement

    The data underlying this study are accessible via BioStudies database (accession number S-BSST624): http://helpdesk.ebi.ac.uk/Ticket/Display.html?id=494263https://www.ebi.ac.uk/biostudies/studies/S-BSST624?query=S-BSST624.

    Articles from PLoS ONE are provided here courtesy of PLOS

    RESOURCES