Bacteriologically confirmed extrapulmonary tuberculosis and the associated risk factors among extrapulmonary tuberculosis suspected patients in Ethiopia: A systematic review and meta-analysis

Getu Diriba; Ayinalem Alemu; Kirubel Eshetu; Bazezew Yenew; Dinka Fikadu Gamtesa; Habteyes Hailu Tola

doi:10.1371/journal.pone.0276701

. 2022 Nov 23;17(11):e0276701. doi: 10.1371/journal.pone.0276701

Bacteriologically confirmed extrapulmonary tuberculosis and the associated risk factors among extrapulmonary tuberculosis suspected patients in Ethiopia: A systematic review and meta-analysis

Getu Diriba ^1,^*, Ayinalem Alemu ^1,², Kirubel Eshetu ³, Bazezew Yenew ¹, Dinka Fikadu Gamtesa ¹, Habteyes Hailu Tola ¹

Editor: Elizabeth S Mayne⁴

PMCID: PMC9683558 PMID: 36417408

Abstract

Background

The actual burden of bacteriologically confirmed extrapulmonary tuberculosis (EPTB) and risk factors in Ethiopia is not well known due to the lack of a strong surveillance system in Ethiopia. Thus, this study was conducted to estimate the pooled prevalence of bacteriologically confirmed EPTB and the associated risk factors among persons suspected to have non-respiratory tuberculosis in Ethiopia.

Methods

A systematic review and meta-analysis of published studies reporting the prevalence of EPTB from searched electronic databases; Science Direct, PubMed, and Google Scholar was estimated spread across the research periods, nationally, and in different areas, using a fixed-effects model. We used I² to analyze heterogeneity in the reported prevalence of bacteriologically confirmed extrapulmonary tuberculosis.

Results

After reviewing 938 research articles, 20 studies (19 cross-sectional and 1 retrospective) from 2003 to 2021 were included in the final analyses. The pooled prevalence of bacteriologically confirmed EPTB was 43% (95%CI; 0.34–0.52, I² = 98.45%). The asymmetry of the funnel plot revealed the presence of publication bias. Specifically the pooled prevalence of bacteriologically confirmed EPTB based on smear microscopy, Xpert MTB/RIF assay, and culture were 22% (95%CI; 0.13–0.30, I² = 98.56%), 39% (95%CI; 0.23–0.54, I² = 98.73%) and 49% (95%CI; 0.41–0.57, I² = 96.43%) respectively. In this study, a history of pulmonary tuberculosis (PTB) contact with PTB patients, contact with live animals, consumption of raw milk, HIV-positive, male, and lower monthly income, were found to be independently associated with bacteriologically confirmed EPTB.

Conclusion

Ethiopia has a high rate of bacteriologically confirmed EPTB. A history of previous PTB, being HIV-positive and having contact with PTB patients were the most reported risk factors for EPTB in the majority of studies. Strengthening laboratory services for EPTB diagnosis should be given priority to diagnose EPTB cases as early as possible.

Introduction

Pulmonary tuberculosis (PTB), which affects the lungs, accounts for 85% of all reported tuberculosis cases globally [1]. However, extrapulmonary tuberculosis (EPTB), which affects parts of the body other than the lung is becoming a major concern in TB prevention and control efforts [2]. The prevalence of EPTB among notified TB cases in the African region in the 2018 global report was 16%, which is the second-highest next to the Eastern Mediterranean region (24%), which is more than the global prevalence of EPTB (15%). The lowest prevalence was reported in the Western Pacific region (8%) [3]. EPTB is assumed to be produced by the spread of bacteria through the bloodstream from a primary focus in the lung, and hence represents a disseminated form of tuberculosis. EPTB most commonly affects the lymph nodes, abdomen, pleura, bones, and meninges, but the prevalence varies with age, sex, and geographic location [4].

Extrapulmonary TB remains a critical concern both in developing and developed countries. EPTB accounts for 15% to 30% of all tuberculosis cases [5,6]. In persons with HIV/AIDS and other immunocompromised states, it is a prevalent opportunistic infection [7]. In Ethiopia, there is a scarcity of evidence on bacteriological diagnosis and evaluation of EPTB.

Extrapulmonary tuberculosis is difficult to diagnose for a variety of reasons. Many types of EPTB necessitate invasive diagnostic sampling, which can be dangerous to the patient and expensive. Because most types of EPTB are paucibacillary (TB disease caused by a limited number of bacteria), detection by smear microscopy is less sensitive. This particularly affects resource-limited settings, where the more sensitive methods of mycobacterial culture examination are not widely available. Culture has its own set of drawbacks such as a very long turnaround time and necessitating a well-equipped biosafety laboratory [8]. Molecular methods are a quick and sensitive procedure that only requires a small amount of sample and may be used on killed bacteria; however, they require highly trained technologists and can be expensive [9]. As a result of these challenges, EPTB is frequently diagnosed solely based on clinical suspicion, and many people are given the incorrect diagnosis, resulting in needless TB treatment or poor outcomes from untreated EPTB. Even in tertiary health care facilities, the majority of patients had started anti-tuberculosis therapy without bacteriological evidence. These people were misdiagnosed or received therapy too late, and they overestimated the scale of the problem at the community level [10]. In Ethiopia, there are few data on bacteriologically confirmed EPTB among suspected EPTB cases. There is no comprehensive review and meta-analysis of the current research to determine the prevalence of bacteriologically confirmed EPTB among EPTB suspects and its risk factors are poorly understood. s. As a result, this study aimed to investigate the prevalence of bacteriologically confirmed EPTB and the associated risk factors amongst persons suspected to have non-respiratory TB in Ethiopia.

Materials and methods

Search strategy

We systematically searched electronic databases such as MEDLINE (PubMed), Science Direct, and grey literature sources such as Google Scholar and Google for articles published in the English language. We used key terms such as “Tuberculosis lymph node”, “Tuberculosis cardiovascular”, “Tuberculosis central nervous system”, “Tuberculosis cutaneous”, “Tuberculosis endocrine”, “Tuberculosis gastrointestinal”, “Tuberculosis hepatic”, “Tuberculosis ocular”, “Tuberculosis osteoarticular”, “Tuberculosis pleura”, “Tuberculosis splenic”, “Tuberculosis urogenital”, and “Ethiopia” both in MeSH and free text.

Eligibility criteria

We included studies that reported the prevalence of EPTB in Ethiopia. Observational studies, such as cohort (prospective or retrospective) and cross-sectional studies, were included. Studies that were written in English and published before October 26, 2021 (the last date of the searching date), were considered. The studies were included regardless of the diagnostic methods used. The articles without a journal name and/or authors, conference proceedings or presentations, and reviews were excluded from the final analysis.

Data extraction

We created a data extraction sheet using a Microsoft Excel® 2010 worksheet. Two independent authors (GD, AA) extracted data including study period, study setting (community or facility-based), study site, test method, sample size, and the number of positive patients. The third author (DF) resolved the inconsistencies that arose between the two authors. To ensure consistency, another co-author (HHT) independently examined the extracted data.

Operational definition

In this meta-analysis, the WHO definition of a positive test result was applied. This states that a positive diagnostic test result using smear microscopy, culture, and Xpert MTM/RIF tests are bacteriological confirmation of EPTB [11].

Risk of bias assessment and study quality

Two authors (GD and DF) independently assessed the quality of the studies using the Newcastle-Ottawa quality assessment scale adapted for cross-sectional studies [12]. The tool has three components: selection, comparability, and outcome/exposure. The selection part is scored from zero to five stars, and the comparability is scored from zero to two stars. The outcome is scored from zero to three stars. To minimize the subjective interpretation of bias from scoring two reviewers (GD and DF) assessed the quality of individual studies. Furthermore, when the disagreements that occurred throughout the quality grading process were settled by consulting a third author (AA) [12]. We used I² to analyze heterogeneity in reported prevalence [13,14]. A funnel plot was also used to investigate the presence of publication bias. The presence of publication bias was determined using a funnel plot. By showing funnel plots with the logarithms of effect size and their standard errors, we were able to quantify publication bias.

Statistical analysis

For statistical analysis, STATA® 14 Stata Corp LLC, Texas, USA software was employed. We estimated the pooled prevalence of bacteriologically confirmed EPTB and a 95% confidence interval using a fixed-effect meta-analysis model. The ’metaprop’ command in STATA 14 was used to determine the pooled prevalence of bacteriologically confirmed EPTB in all patients with EPTB. The distributional information of EPTB was displayed using a forest plot. The pooled effect estimate on the prevalence of bacteriologically confirmed EPTB cases was based on a subgroup analysis of publications comparing culture, smear microscopy, and Xpert MTB/RIF assay methods.

Ethical consideration and consent

Since this study is based on previously published articles ethical approval is not applicable.

Result

Study selection

The three electronic databases yielded a total of 938 articles, which were then imported into an Endnote X8 citation manager, and 173 duplicates were removed. Next, 722 articles were screened by title and abstract. Around 43 articles that passed the first stage were assessed through a full-text review. During this review, the study subjects, study design, study quality, and outcome were considered. Because of this reason 23 articles were removed. Finally, 20 articles became eligible for data extraction The recommended reporting items for systematic reviews and meta-analysis (PRISMA) flow diagram were used to complete the overall screening (Fig 1).

Characteristics of the studies included in the review

Of the total of 20 articles reviewed, eight studies were undertaken in the Amhara region [15–22], four studies in Addis Ababa [23–26], four in Oromia [27–30], one study in the Southern Nations Nationalities and People Region [31], and the remaining three studies were based on data collected from different regions of the country [32–34]. The data collection period ranges from 1998 [31] to 2020 [26]. The sample size investigated ranged from 90 [18] to 1,198 participants [34]. The majority of the studies were cross-sectional studies, with one retrospective study. Fourteen studies only examined one type of sample, while the remaining six studies reported evaluating various sample types. Regarding diagnostic methods, five studies used smear microscopy and culture methods [26,29,32–34], three studies used smear microscopy, culture, and Xpert MTB/RIF assay [15,25,28], two studies applied smear microscopy [16,31], two studies used the Xpert MTB/RIF assay [20,22], two studies used the culture and Xpert MTB/RIF assay [19,30], one study used the Xpert MTB/RIF and microscopy [21], and the remaining five studies used the culture [17,18,23,24,27] (Table 1).

Table 1. General characteristics of studies describing extrapulmonary tuberculosis in Ethiopia.

First Author [ref.]	Publication Year	Study Design	Study area	Study Setting	Study time	Sample size (N)	Number of cases with bacteriological confirmation (n/N, %)	Type of EPTB	Diagnostic Method	Risk factors for bacteriologically confirmed TB
Yassin et al [31]	2003	cross-sectional	Butajira	Facility-based	1998–2000	147	107 (72.8)	Lymph node	Microscopy	not stated
Iwnetu et al [32]	2009	cross-sectional	Addis Ababa, Bar Dar, Diredawa	Facility-based	2004–2005	150	117 (78)	Lymph node	Microscopy Culture	not stated
Derese et al [33]	2012	Retrospective	Woldia, Butajira, Gonder	Facility-based	2011	134	50 (37.3)	Lymph node	Microscopy Culture	not stated
Biadglegne et al [15]	2013	cross-sectional	Bahirdar, Gondar & Dessie	Facility-based	2012	437	226 (51.7)	Lymph node	Microscopy Culture Xpert MTB/RIF	Retreated, Male, Age < 14, Urban
Zenebe et al [16]	2013	cross-sectional	Gonder	Facility-based	2012	344	34 (9.9)	Lymph node	Microscopy	history of PTB, raw milk, monthly less income, TB contact
Garedew et al [17]	2013	cross-sectional	Debre Birhan	Facility-based	2010–2011	98	36 (36.7)	Lymph node	Culture	not stated
Abdissa et el [27]	2014	cross-sectional	Jimma	Facility-based	2012	200	147 (73.5)	Lymph node	Culture	not stated
Birhanu et al [18]	2014	cross-sectional	Dessie	Facility-based	2012–2013	90	32 (35.6)	Lymph node	Culture	not stated
Berg et al [34]	2015	cross-sectional	Gondar, Woldiya, Ghimbi, Fiche, and Butajira, Jinka and Filtu, AA	Facility-based	2006–2010	1198	456 (38.1)	Lymph node	Microscopy Culture	having regular and direct contact with live animals, low education level
Tadesse et al [28]	2015	cross-sectional	Jimma	Facility-based		143	88 (61.5)	Lymph node	Microscopy Culture Xpert MTB/RIF	not stated
Korma et al [23]	2015	cross-sectional	Addis Ababa	Facility-based	2012 to 2013	200	116 (58)	pleural, peritoneal and synovial fluids	Culture	not stated
Abdissa et al [29]	2015	cross-sectional	Jimma	Facility-based	2013	144	96 (66.7)	Lymph node	Microscopy Culture	not stated
Fanosie et al [19]	2016	cross-sectional	Gonder	Facility-based	2015	141	37 (26.3)	Peritoneal fluid, CSF, Pleural fluid, lymph node	Culture Xpert MTB/RIF	Adult patients, history of contact with known pulmonary TB, HIV positive
Zewdie et al [24]	2016	cross-sectional	Addis Ababa,	Facility-based	2013	206	74 (35.9)	Lymph node	Culture	not stated
Mulu et al [20]	2017	cross-sectional	Debre Markos	Facility-based	2014 to 2015	182	53 (29.1)	Peritoneal, Pus, lymph node, pleural fluid	Xpert MTB/RIF	Retreated, Male, HIV positive, Age 41–50
Metaferia et al [21]	2018	cross-sectional	Dessie	Facility-based	2017	353	31 (8.8)	Peritoneal fluid, CSF, Pleural fluid, lymph node	Microscopy Xpert MTB/RIF	history of PTB, contact with PTB patients
Tadesse et al [30]	2018	cross-sectional	Jimma	Facility-based	2015–2017	572	242 (42.3)	Lymph node, CSF, pleural, peritoneal, and pericardial fluids.	Culture Xpert MTB/RIF	not stated
Fantahun et al [25]	2019	cross-sectional	Addis Ababa	Facility-based	2015–2016	152	75 (49.3)	Lymph node	Microscopy Culture Xpert MTB/RIF	not stated
Tedla et al [22]	2019	cross-sectional	Dessie	Facility-based	2018	337	92 (27.3)	Peritoneal fluid, CSF, Pleural fluid, lymph node synovial fluid	Xpert MTB/RIF	HIV-positive, history of PTB
Assefa et al [26]	2021	cross-sectional	Addis Ababa	Facility-based	2020	211	50 (23.7)	Lymph node	Microscopy Culture	not stated

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HIV-human immunodeficiency virus; MTB/RIF-Mycobacterium tuberculosis/ Rifampicin; PTB-pulmonary tuberculosis; TB-Tuberculosis.

The pooled prevalence of bacteriologically confirmed EPTB

The frequency of EPTB varied widely over the 20 studies. The prevalence ranged from 9% [21] to 78% [32]. The pooled prevalence of bacteriologically confirmed EPTB was 43% (95%CI; 0.34–0.52, I²; 98.45%) according to the random-effects methodology. The highest EPTB prevalence was reported from Addis Ababa, Bar Dar, and Dire Dawa [32], with a rate of 78%, while the lowest was reported from Dessie [21], with a rate of 9% (Fig 2). The pooled proportion of bacteriologically confirmed EPTB studies is represented by a funnel plot (Fig 3). The graph depicted studies with fewer participants and events scattered throughout the pooled horizontal estimate, implying a greater influence due to chance.

Subgroup analysis by diagnostic testing methods

There was no heterogeneity among studies conducted in culture, smear microscopy, and Xpert MTB/RIF assay, according to the subgroup analysis diagnostic test. There is heterogeneity among studies that look at multiple diagnostic tests. For culture, smear microscopy, and Xpert MTB/RIF assay diagnostic methods, the prevalence of pooled effect estimates was 49% (95%CI; 0.41–0.57, I² = 96.43%) (see Fig 4), 22% (95%CI; 0.13–0.30, I² = 98.56%) (see Fig 5), 39% (95%CI; 0.23–0.54, I² = 98.73%) (see Fig 6), respectively.

Risk of bias across studies publication

Visual inspection revealed indications of publication bias for the majority of the culture diagnostic method estimates, with most studies clustered at the funnel’s apex and a few spread to the extreme right and left corners (Fig 7). The funnel plots for Xpert MTB/RIF assay and smear microscopy methods were most studies clustered at the funnel’s bottom and a few spread to the extreme right corners (Figs 8 and 9).

Associated risk factors of bacteriologically confirmed EPTB

The impact of each study on the overall meta-analysis summary estimate was investigated. A history of PTB infection and contact with PTB patients was found to be significant risk factors for EPTB incidence in the majority of investigations [15,16,19–22]. Furthermore, having regular and direct contact with live animals, as well as the consumption of raw milk, were found to be strongly related to the incidence of EPTB [16,34]. Additionally, being HIV-positive [19,20,22], ages <14 [15], age 41–50 [20], being male [15,20], monthly less income [16], urban [15] were all linked to the most common EPTB.

Discussion

This systematic review and meta-analysis estimated the pooled prevalence of bacteriologically confirmed EPTB and the associated risk factors among persons suspected to have non-respiratory tuberculosis in Ethiopia using published studies over the last two decades. This meta-analysis included a total of 5439 EPTB suspects from 20 studies published between 2003 and 2021. The pooled estimated prevalence of samples with any bacteriological evidence in the studies was 43% (95%CI; 0.34–0.52, I²; 98.45%). A history of PTB infection and contact with PTB patients, contact with live animals, raw milk, HIV, male, less income, and urban, contact with EPTB patients were all found to be independently associated with EPTB in this study.

The overall pooled prevalence of bacteriologically confirmed EPTB in this systematic review and meta-analysis data was 43%. This finding is approximately similar to that previously reported from Cameroon [35]. In contrast, when compared to the estimated prevalence of bacteriologically-confirmed EPTB among all cases of TB in Africa, this is a high figure. According to a 2017 WHO report, the prevalence of EPTB in all cases of TB in Africa and the rest of the globe was 16% and 15%, respectively [7]. Furthermore, a systematic review and meta-analysis of the prevalence of bacteriologically-confirmed EPTB among patients living with HIV/AIDS in Sub-Saharan Africa revealed a lower prevalence of bacteriologically-confirmed EPTB than our findings [36]. However, in the current study, the funnel plot revealed that there is publication bias, where among 20 studies included in this study, 10 were above the 95% upper limit and 5 were below the 95% lower limit and only 5 were within the CI. This might be due to the low number of studies conducted so far in Ethiopia and their variations in using laboratory methods. Thus, this may underestimate the pooled bacteriologically confirmed EPTB prevalence among EPTB presumptive cases in Ethiopia.

In this current systematic review and meta-analysis investigation, HIV-1 infected patients were the most significant risk factors for EPTB infection [19,20,22]. Similarly, several studies have examined the association between HIV-1 infection and EPTB infection [6,37]. Furthermore, nearly half of EPTB patients were HIV-1 infected, according to a prior study [38]. This is due to the virus’s immune deficiency condition, which allows the bacteria to spread from the primary infection site, the lung, to other parts of the body. During TB-HIV-1 co-infection, there is a lack of granuloma growth and functional disruption of the local immune response within the granuloma [39].

Our study showed that having a history of TB and a history of contact with known pulmonary TB patients was found to be significant risk factors for EPTB development [16,19–22]. Similarly, it is well known that patients with a history of anti-TB treatment cases have an increased risk of EPTB [37].

In this study, we also discovered that men had a higher prevalence of EPTB involvement than women [15,20], which is consistent with similar findings in the previous study [40]. However, another systematic review and meta-analysis study in Africa found that refers to women with lymphadenitis with a higher rate of EPTB than men [41]. Likewise, women had a higher rate of EPTB infections than men [42]. In addition, another study reported women with a higher rate of EPTB than men [43].

In the end, the current study had its limitations. Firstly, the degree of EPTB prevalence in many parts of the country has yet to be addressed, making it impossible to conclude the true burden of EPTB in Ethiopia. Secondly, the observed publication bias that could be due to the differences in the laboratory methods might underestimate the estimated prevalence. Thirdly, Only three databases were searched. This could lead to publication bias. Finally, there is high heterogeneity among studies that might affect the true estimates. However, the findings are still significant, because the rising rate of EPTB patients in the general population is concerning.

Conclusions

The finding of this study revealed that there is a high bacteriologically confirmed EPTB among persons suspected to have EPTB in Ethiopia. Patients having a history of previous tuberculosis, a poor income, a history of tuberculosis contact with a known PTB case, being HIV-1 positive, and having contact with PTB patients and a history of underlying diseases was with the most reported risk factors for EPTB. Thus, we recommend strengthening laboratory services for the diagnosis of EPTB in Ethiopia.

Supporting information

S1 File. PRISMA checklist.

(DOC)

Click here for additional data file.^{(65.5KB, doc)}

S2 File. Literature search strategy from searched databases.

(DOCX)

Click here for additional data file.^{(333.1KB, docx)}

S3 File. Detailed data of the included studies.

(XLSX)

Click here for additional data file.^{(20KB, xlsx)}

S4 File. Newcastle-Ottawa quality assessment scale for cross-sectional studies.

(DOCX)

Click here for additional data file.^{(23.9KB, docx)}

Acknowledgments

We acknowledge Ethiopian Public Health Institute for the access to article searching. We also acknowledge the authors of the original articles included in this systematic review and meta-analysis study.

Data Availability

All the important information is available within the manuscript and its supplementary files.

Funding Statement

The author(s) received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0276701.r001

Decision Letter 0

Elizabeth S Mayne

10 Mar 2022

PONE-D-22-00257Bacteriologically confirmed extrapulmonary tuberculosis and the associated risk factors among extrapulmonary tuberculosis suspected patients in Ethiopia: A systematic review and meta-analysisPLOS ONE

Dear Dr. Diriba,

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.

Both reviewers felt that the paper had merit. Both did however identify concerns with the methodology. Specifically, there was a concern that the denominator of the study (all PTB cases) was not realistic and undefined and 1 reviewer felt strongly that the review question needed to be tightened. There were also concerns with the construction of the forest plots which reviewer 1 felt should be ordered from low to high. Both reviewers highlighted a number of small stylistic errors which should also be corrected.

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Additional Editor Comments:

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #1: Partly

Reviewer #2: Partly

**********

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

Reviewer #1: No

Reviewer #2: N/A

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: No

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: Line

22 lack of a strong…

24 insert full stop

27 spread across

29 insert full stop

31 “majority”: what is the percentage?

31 substitute “articles” for “research”

32 variations

33 “medium/high risk”: the funnel plot in fig 3 for the 20 papers shows 10 papers above the 95% upper limit and 5

below the 95% lower limit and only 5 within the CI. More discussion is required for your assessment. Is this justified

by the standard error of the effect size on the y-axis?

34 Delete “having”. PTB must be in full here, that is, “pulmonary tuberculosis”

35 Delete “being”

41 Keywords:… “Pulmonary Tuberculosis” for Tuberculosis…

49 Use “EPTB”; this has already been defined

54 EPTB

55 15%

61 Delete “and”

62 Delete extra space after “resource- “

64 turnaround times

70 “had started” for “have been started”

72 (11) for [11]

76 et seq. Remove end full stops in numbering, for example, 2. and 2.1. should be 2 and 2.1

86 Delete “the”

88 Delete “language”

93 “using a Microsoft Excel worksheet” should be “Microsoft Excel® 2016” (or whatever version was used)

96 “resolved inconsistencies that arose”

99-102 The WHO definition of a positive test result was applied. This states that a positive diagnostic test result using

smear microscopy, culture, Xpert MTM/RIF or nucleic acid amplification test is a bacteriological confirmation of an

EPTB infection.

104 Delete “included”

105-107 Persistent disagreements indicate a lack of clarity in applying the Newcastle-Ottawa scale. Should the scale be

modified and would different interpretations be applied by researchers on similar studies. The nature of the

disagreements and outcomes of using alternative interpretations should be discussed especially in light of the

small sample of 20 papers

112 STATA® 14.2 StataCorp LLC, Texas, USA

113 a 95% confidence interval. Random-effects

114 The ‘metaprop’ command in STATA was used.

115-116 A forest plot shows distributional information not prevalence

119-127 This requires the editing out of excess detail in light of the PRISMA diagram. The PRISMA diagram is important

and sets out clearly the process in reducing the 938 articles to 20 used in this study

123 The 36 non-Ethiopian papers should either be included as controls in the forest plots or in separate forest plots. These

could indicate possible biases, inconsistencies or differences in interpretation of data in Ethiopian papers (for example

see disagreements in 105-107 above). This applies to funnel plots as well

135 Delete “was”

142 Delete “another”

Page 8 Some hyphens missing in “cross-sectional”. Associated factors column requires some editing (spaces and spacing

of commas)

148 The frequency of EPFB varied widely over the 20 studies. The prevalence ranged from 9% (21) to 78% (32). See also

general comment below on superscript of paper reference.

150 random-effects

157 using a random-effects model

157 “Effect size” should appear in full in the x-axis label

158 “twenty studies”, delete used.

158-159 Standard error of effect size should appear in full on the y-axis

160 The subgroups of the 20 studies should be shown in the PRISMA diagram to ensure completeness and intelligibility

170 Pooled proportion of culture-positive EPTB using random-effects model

172 Same style as 170

174 Same style as 170

184 Funnel plot of subgroup of 15 of the 20 selected studies

184 Standard error of effect size and effect size should appear in the axis labels

186 Same style as 184

188 Same style as 184

192 A history of PTB infection

200 Delete “of”

196 HIV should be HIV-1

204 A history of PTB infection ("history" implies previous history)

210 … similar to that…

214 “systemic” should be “systematic”

217 HIV-1

218 …risk factors associated with EPTB infection…

219 HIV-1

220 … EPTB patients were HIV-1 infected,…

223 TB-HIV-1 co-infection

227 … with a history of… (“history” implies previous history)

235 Firstly,

237 Secondly,

238 Statistical power and its reduction has not been discussed in the paper. What is the estimate of the reduction and has

this invalidated the paper? (Does statistical power here refer to I^2, p-value or items outside the 95% pseudo-

confidence gradients in the funnel plots?

238 “poor quality of several studies” – I am not sure this has been sufficiently discussed (if at all)

244 HIV-1

General: number references to papers should preferably be shown as superscripts to avoid with number in the paper. For example, line 49, …region (8%) (3) should be …region (8%)3 (3 as superscript)

References: Journal references should be italicised. Latinisms like et.al. should be italicised

Figure 1: PRISMA diagram should show the subgroups budding off the “Final analysis” box. Reference to this in the main body of the paper will simplify some of the wording in the main body

Figure 2: Forest plot should be sorted by ES and show ranking from lowest to highest ES. Metaferia et. al. would be at the bottom and Iwnetu et.al. at the top

Figure 3: Axis-labels to be described in full

Figure 4: Sort the publications as in figure 2

Figure 5: Sort the publications as in figure 2

Figure 6: Sort the publications as in figure 2

Figures 7, 8 and 9 – same as in figure 3

Reviewer #2: This is a well written article, and findings will be helpful to Ethiopian health care workers, and others working in a LMIC/African context.

However, I have a difficulty with the foundational methodology (meta-analysis) of the study.

o It is not stated what the research questions for the descriptive studies of EPTB which were included in the meta-analysis were.

o Studies which were included could have identified EPTB as a subset of all PTB, or they may have described EPTB alone, from persons with clinical criteria matching only those in whom EPTB is suspected.

o Without specifying which approach the authors of this meta-analysis wanted de novo, the selection criteria results in a wide range of approaches to EPTB diagnosis being selected, which will lead to enormous heterogeneity, and lack of meaningful comparison.

Before conducting a meta-analysis, it is critical to given to formulate the review question clearly. I think the review question ‘to investigate the prevalence of EPTB in Ethiopia’ is too broad. It will be helpful to say ‘Investigate the prevalence of EPTB amongst persons with non-pulmonary TB’. The results are then clearly applicable to persons in whom PTB has been excluded.

As the current aim stands, it implies that that the aim is to identify the burden of TB amongst all TB cases in Ethiopia. This begs the question of a denominator. Assessing the prevalence of EPTB requires that one knows the total burden of TB. How is it possible to assess the prevalence by identifying only studies that described EPTB? These studies would have identified persons who were suspected of EPTB as the starting point. Equally, an ascertainment of risk factors can only be done by comparison with non-EPTB groups.

Without narrowing the research question, it is not meaningful to present or interpret Forest plots.

Other minor comments

A small consideration re methodology, search strategy – are there articles published by Ethiopians in literature that would not be listed in pubmed, Science Direct or on google scholar?

Line 49 Extrapulmonary Tuberculosis – ‘tuberculosis’ should be lower case.

Line 64 Turnaround Time – T should be lower case,

Line 70 Anti-TB medicine – rather ‘anti-tuberculosis therapy’

Line 108 The NewCastle Ottowa quality assessment scale is a checklist for cohort and case control studies. What motivated the use of this scale, over and above the PRISMA guidelines which are sufficient for meta-analyses and systematic reviews.

**********

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2022 Nov 23;17(11):e0276701. doi: 10.1371/journal.pone.0276701.r002

Author response to Decision Letter 0

5 Apr 2022

Ref: PONE-D-22-00257

Bacteriologically confirmed extrapulmonary tuberculosis and the associated risk factors among extrapulmonary tuberculosis suspected patients in Ethiopia: A systematic review and meta-analysis

Dear Editor,

Thank you for your informative comments and thoughtful comments on our manuscript. We have addressed your and the reviewers' comments one by one. We also appreciate the reviewers for their critical observation and informative comments which radically improved our manuscript quality. We have provided point-by-point responses to the reviewers' comments below. Also, we would like to inform you that we have used a hyperlink to indicate where we made changes in the previous version of the manuscript based on the reviewers’ comments.

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

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Response: Thank you for the comment. The manuscript was prepared according to PLOS ONE's style requirements.

Response: Thank you for the valuable comment. In the revised manuscript we included a sentence about ethical consideration “Since this study is based on previously published articles ethical approval is not applicable”.

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:

a) 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.

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

d) 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.

Response: Thank you. This work did not receive any funding for this study and we have already stated it in the first submission before the reference section “The author(s) received no specific funding for this work”

Response: Thank you. All the important information is available within the manuscript and its supplementary files.

5. Please ensure that you refer to Figure 5 in your text as, if accepted, production will need this reference to link the reader to the figure.

Response: Thank you for your critical observation and comment; we revised as per the suggestion.

Additional Editor Comments:

Response: Thank you for your suggestions and constructive comments. We have addressed your comments across the manuscript methodology. All the forest plots are arranged from low to high. Also, all technical errors have been corrected.

Review Comments to the Author

Reviewer #1

22 lack of a strong…

Response: Thank you, we revised it accordingly.

24 insert full stop

Response: Thank you, we corrected it as per the suggestion.

27 spread across

Response: Thank you for your suggestion. We have corrected it.

29 insert full stop

Response: Thank you for your suggestion. We inserted a full stop in the revised manuscript.

31 “majority”: what is the percentage?

Response: Thank you for the question. At this stage, we revised the result section of the abstract.

31 substitute “articles” for “research”

Response: Thank you for your suggestion. We revised it accordingly.

32 variations

Response: Thank you. We have corrected it.

33 “medium/high risk”: the funnel plot in fig 3 for the 20 papers shows 10 papers above the 95% upper limit and 5 below the 95% lower limit and only 5 within the CI. More discussion is required for your assessment. Is this justified by the standard error of the effect size on the y-axis?

Response: Thank you for the valuable comment. Now we included a detailed paragraph in the discussion section that described it.

34 Delete “having”. PTB must be in full here, that is, “pulmonary tuberculosis”

Response: Thank you for the valuable comment. Now, defined it in full first and then we used the abbreviation.

35 Delete “being”

Response: Thank you. We have deleted the comment

41 Keywords:… “Pulmonary Tuberculosis” for Tuberculosis…

Response: Thank you for the suggestion. We revised it.

49 Use “EPTB”; this has already been defined

Response: Thank you. In the current version, we used EPTB.

54 EPTB

Response: Thank you for your suggestion. We have corrected it.

55 15%

Response: Thank you for your comment. We have added the % according to the comment

61 Delete “and”

Response: Thank you for your suggestion. We have deleted it.

62 Delete extra space after “resource- “

Response: Thank you. We have deleted the extra space.

64 turnaround times

Response: Thank you for your suggestion. We corrected it accordingly.

70 “had started” for “have been started”

Response: Thank you for your suggestion. We revised it as per the given suggestion.

72 (11) for [11]

Response: Thank you for the suggestion. We revised the format for the whole referencing style based on the Plos One journal requirements.

76 et seq. Remove end full stops in numbering, for example, 2. and 2.1. should be 2 and 2.1

Response: Thank you for your suggestion. In the revised version, we have removed the numbers in the entire manuscript according to the Journal’s criteria.

86 Delete “the”

Response: Thank you for your suggestion. We deleted it.

88 Delete “language”

Response: Thank you for your suggestion. We deleted it.

93 “using a Microsoft Excel worksheet” should be “Microsoft Excel® 2016” (or whatever version was used)

Response: Thank you for your suggestion. We have revised it accordingly.

96 “resolved inconsistencies that arose”

Response: Thank you for your suggestion. We revised it as per the suggestion

99-102 The WHO definition of a positive test result was applied. This states that a positive diagnostic test result using smear microscopy, culture, Xpert MTM/RIF or nucleic acid amplification test is a bacteriological confirmation of an EPTB infection.

Response: Thank you for the valuable comment and suggestion. We have revised it as per the given suggestion.

104 Delete “included”

Response: Thank you, we have deleted it.

105-107 Persistent disagreements indicate a lack of clarity in applying the Newcastle-Ottawa scale. Should the scale be modified and would different interpretations be applied by researchers on similar studies. The nature of the disagreements and outcomes of using alternative interpretations should be discussed especially in light of the small sample of 20 papers

Response: Thank you; we have addressed this according to the comment

112 STATA® 14.2 StataCorp LLC, Texas, USA

Response: Thank you, we revised it accordingly.

113 a 95% confidence interval. Random-effects

Response: We have changed according to the comment

114 The ‘metaprop’ command in STATA was used.

Response: Thank you, we revised it accordingly.

115-116 A forest plot shows distributional information not prevalence

Response: Thank you, it is revised accordingly.

119-127 This requires the editing out of excess detail in light of the PRISMA diagram. The PRISMA diagram is important and sets out clearly the process in reducing the 938 articles to 20 used in this study 123 The 36 non-Ethiopian papers should either be included as controls in the forest plots or in separate forest plots. These could indicate possible biases, inconsistencies or differences in interpretation of data in Ethiopian papers (for example see disagreements in 105-107 above). This applies to funnel plots as well

Response: Thank you, we revised it as per the suggestion.

135 Delete “was”

Response: We have deleted it.

142 Delete “another”

Response: We have deleted it.

Page 8 Some hyphens missing in “cross-sectional”. Associated factors column requires some editing (spaces and spacing of commas)

Response: Thank you, we revised it accordingly.

148 The frequency of EPFB varied widely over the 20 studies. The prevalence ranged from 9% (21) to 78% (32). See also general comment below on superscript of paper reference.

Response: Thank you for the comment. The numbers in the bracket are the references, now we revised the referencing based on the journal’s criteria or using [ ].

150 random-effects

Response: We have changed according to the comment

157 using a random-effects model

Response: We have corrected accordingly.

157 “Effect size” should appear in full in the x-axis label

Response: Thank you. We have addressed the comment

158 “twenty studies”, delete used.

Response: We have deleted it.

158-159 Standard error of effect size should appear in full on the y-axis

Response: Thank you for the suggestion, we corrected it accordingly.

160 The subgroups of the 20 studies should be shown in the PRISMA diagram to ensure completeness and intelligibility

Response: Thank you for the suggestion. We sub-grouped the included studies based on the laboratory method used, and we described it in the flow diagram and early in the result section.

170 Pooled proportion of culture-positive EPTB using random-effects model

Response: Thank you, we revised it as per the suggestion.

172 Same style as 170

Response: We have changed according to the comment

174 Same style as 170

Response: We have changed according to the comment

184 Funnel plot of subgroup of 15 of the 20 selected studies

Response: We have changed according to the comment

184 Standard error of effect size and effect size should appear in the axis labels

Response: Thank you for the valuable comment; we revised accordingly per the suggestion. and effect size according to the comment

186 Same style as 184

Response: Thank you, we revised it accordingly.

188 Same style as 184

Response: Thank you, we revised it accordingly.

192 A history of PTB infection

Response: Thank you, we corrected it.

200 Delete “of”

Response: Thank you we have deleted it.

196 HIV should be HIV-1

Response: Thank you for the suggestion, we revised it accordingly.

204 A history of PTB infection ("history" implies previous history)

Response: We have corrected per the suggestion.

210 … similar to that…

Response: We revised it.

214 “systemic” should be “systematic”

Response: Thank you, now it is corrected.

217 HIV-1

Response: Thank you for the suggestion, we revised it accordingly.

218 …risk factors associated with EPTB infection…

Response: Thank you, we revised it as per the suggestion.

219 HIV-1

Response: Thank you, now it is revised accordingly.

220 … EPTB patients were HIV-1 infected,…

Response: Thank you. We revised as per the suggestion.

223 TB-HIV-1 co-infection

Response: Thank you. We revised it accordingly.

227 … with a history of… (“history” implies previous history)

Response: We have revised it accordingly.

235 Firstly,

Response: Thank you, we revised it.

237 Secondly,

Response: Thank you, we revised it.

238 Statistical power and its reduction has not been discussed in the paper. What is the estimate of the reduction and has this invalidated the paper? (Does statistical power here refer to I^2, p-value or items outside the 95% pseudo-confidence gradients in the funnel plots? 238 “poor quality of several studies” – I am not sure this has been sufficiently discussed (if at all)

Response: Thank you for the valuable comment. Now, we revised the limitation of the study as follows “In the end, the current study had its limitations. Firstly, the degree of EPTB prevalence in many parts of the country has yet to be addressed, making it impossible to conclude the true burden of EPTB in Ethiopia. Secondly, the observed publication bias that could be due to the differences in the laboratory methods might underestimate the estimated prevalence. Thirdly, there is high heterogeneity among studies that might affect the true estimates. However, the findings are still significant, because the rising rate of EPTB patients in the general population is concerning”

244 HIV-1

Response: We revised it accordingly.

Response: Thank you for the valuable comment and suggestion. Now we revised all the references according to the PloS One guideline, Such that we used the square brackets “[ ]”.

References: Journal references should be italicised. Latinisms like et.al. should be italicized

Response: Thank you, we revised as per the suggestion.

Figure 1: PRISMA diagram should show the subgroups budding off the “Final analysis” box. Reference to this in the main body of the paper will simplify some of the wording in the main body

Response: Thank you for the suggestion, as we have stated in the previous response we revised the flow diagram according to the PRISMA guideline.

Figure 2: Forest plot should be sorted by ES and show ranking from lowest to highest ES. Metaferia et. al. would be at the bottom and Iwnetu et.al. at the top

Response: Thank you for the comment, we revised it accordingly.

Figure 3: Axis-labels to be described in full

Response: We have described in full according to the comment

Figure 4: Sort the publications as in figure 2

Response: Thank you, we revised it accordingly.

Figure 5: Sort the publications as in figure 2

Response: Thank you, we revised it accordingly.

Figure 6: Sort the publications as in figure 2

Response: Thank you, we revised it accordingly.

Figures 7, 8 and 9 – same as in figure 3

Response: Thank you, we revised it accordingly.

Reviewer #2:

This is a well written article, and findings will be helpful to Ethiopian health care workers, and others working in a LMIC/African context.

However, I have a difficulty with the foundational methodology (meta-analysis) of the study.

o It is not stated what the research questions for the descriptive studies of EPTB which were included in the meta-analysis were.

Without narrowing the research question, it is not meaningful to present or interpret Forest plots.

Response: Thank you for the pertinent comments and valuable suggestions. This study is designed to investigate/estimate/ the prevalence of bacteriologically confirmed EPTB among individuals who are presumptive to have EPTB. Thus, the denominator is the number of EPTB or non-respiratory TB presumptive individuals, while the numerator is the number of bacteriologically confirmed EPTB presumptive individuals. Now we described in detail the research questions and the objectives in the revised manuscript. We revised the abstract section, the objectives at the end of the introduction section, and the first paragraph in the discussion section.

Other minor comments

A small consideration re methodology, search strategy – are there articles published by Ethiopians in literature that would not be listed in pubmed, Science Direct or on google scholar?

Response: Thank you very much for your informative comments. The majority of the articles published from Ethiopia are open access, because Ethiopia is among the low-income countries which waived article processing charges. Thus, all open access articles can be accessed through Google Scholar research. In addition, Since we cannot freely access other databases in Ethiopia we could not search them. To address this comment we have added a sentence that indicates as our search is not comprehensive in limitation.

Line 49 Extrapulmonary Tuberculosis – ‘tuberculosis’ should be lower case.

Response: Thank you for the comment, we revised it accordingly.

Line 64 Turnaround Time – T should be lower case,

Response: Thank you, we revised it as per the suggestion.

Line 70 Anti-TB medicine – rather ‘anti-tuberculosis therapy’

Response: Thank you, we revised it accordingly.

Response: Thank you for the valuable question. This systematic review and meta-analysis were conducted following the PRISMA guidelines. We used the Newcastle-Ottawa quality assessment checklist to assess the quality of individuals studies based on the questions available in the checklist as the Joanna Briggs critical appraisal tool. Since all studies included in the current study are cross-sectional studies we have used the Newcastle-Ottawa quality assessment scale adapted for cross-sectional studies.

Yours, Sincerely

Getu Diriba

Attachment

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PLoS One. doi: 10.1371/journal.pone.0276701.r003

Decision Letter 1

Elizabeth S Mayne

23 May 2022

PONE-D-22-00257R1Bacteriologically confirmed extrapulmonary tuberculosis and the associated risk factors among extrapulmonary tuberculosis suspected patients in Ethiopia: A systematic review and meta-analysisPLOS ONE

Dear Dr. Diriba,

==============================

Although both readers felt that the manuscript was substantially improved, there were still significant issues with the statistical analysis as highlighted by Reviewer 1. This, given that the rationale for the study was also unclear and the fact that there are concerns regarding incorrect usage of p values, this manuscript still requires extensive editing.

==============================

Please submit your revised manuscript by Jul 07 2022 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,

Elizabeth S. Mayne, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

[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: (No Response)

Reviewer #2: (No Response)

**********

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

Reviewer #1: Partly

Reviewer #2: Partly

**********

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

Reviewer #1: No

Reviewer #2: I Don't Know

**********

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

Reviewer #1: No

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: No

**********

6. Review Comments to the Author

Reviewer #1: 1 Reviewer 1 comments in the first review have been addressed and the original document has been extensively revised or rewritten. As a result, the revised document is more readable. The revised document has however highlighted additional significant matters and some minor issues. In view of the novelty and importance of the study, it is well worthwhile to resolve these matters and issues.

2 Lines refer to the revised document.

3 Lines 29, 33, 36, 37,117,163,164,180,181,182, and 212. The I^2 test for heterogeneity has values of 98.45%, 98.56%, 98.73% and 96.43%. In terms of Cochran’s Q statistic I^2=((Q-df)/Q*100% (see Cochrane Handbook, 2011), heterogeneity greater than 75% means that studies in the forest plot are not sufficiently comparable and that a meta-analysis may be invalid. A possible remedy is to ignore heterogeneity and adopt a fixed effects model.

4 Lines 170, 183, 184, 185 and Figures 4, 5, and 6. In terms of point 3 (for a I^2 statistic > 75%) a fixed effects model is usually applied unless a suitable analytical justification is given for the application of a random effects model (see Cochrane Handbook, 2011).

5 Lines 116 and 117, a rule of thumb for heterogeneity of I^2 of 50% is moderate and I^2 ≥ 75% is high – see point 3 above. The unqualified statement in line 117 of I^2 ≥ 50% would seem to imply that high heterogeneity is desirable.

6 Lines 180 to 182. P-values of <0.01 are given. P-values as given are incorrectly associated with I^2 tests, which are applied as broad-based categories (see Cochrane Handbook, 2011). P-values are associated with the alternative chi-square test in which a p-value of <0.01 is indicative of a chi-square value in excess of the table value, which indicates high heterogeneity in values and like a high I^2 value (75%), requires further analysis to justify the use of a forest plot (see above).

7 Repetition of statistics in 5 places - see lines in point 3 above. This suggests that the document requires editing.

8 Inconsistency in presentation of statistics. The repetitions of statistics in point 7 are inconsistent. Lines 180 to 182, 164 and 212 give p-values, which are not given in the other lines in point 3 above.

9 The forest plots in Figures 4, 5 and 6 in support of the data in point 3 above have I^2 values >75% which, with p-values <0.01 (presumably relating to a chi-square test), which indicates high heterogeneity. The plots do not indicate if a random effects model or a fixed effects model have been applied. An analysis justifying the relevance of forest plots is required in light of high heterogeneity.

10 Lines 35 to 37 which refer to smear microscopy, Xpert MTB/RIF, culture as separate categories with statistics for each, does not agree with line 106 which adds nucleic acid amplification as an additional test.

11 Lines 35 to 37, tests do not agree with the categories in lines 136 to 138, which combine categories. For example, in line 136, three studies combined culture, Xpert MTB/RIF and smear microscopy. The same combination of categories in lines 152 to 157 is at odds with the separate categories in lines 35 to 37. Proposed categories do not agree with tested categories and evaluated categories.

12 Lines 32, 34, 163, 174, 180-182, 211, 216 do not explain how pooled estimates were computed. Is this a weighted average by subject or by study? How are the 95% confidence intervals computed, are they also weighted by subject or by study?

13 Line 202 risk factors are live animals, raw milk, HIV, male, less income, urban. Line 215 adds contact with EPTB patients and line 258 adds underlying disease as a risk factor. Line 75 risk of misdiagnosis of tuberculosis is also a risk factor as is line 66 – resource limited settings. Line 243 refers to women with lymphadenitis with a higher rate of EPTB than men and Line 245 as women with a higher rate of EPTB than men contrary to line 202 which regards maleness as being an outright risk.

14 Lines 256 to 259, in the conclusion, leaves out male, live animals, raw milk, lymphadenitis, and misdiagnosis as risk factors without justification. Consistency in the set of risk factors, from proposal to testing and conclusion should be maintained. Adding or dropping risk factors has not been explained or justified.

Minor points

15 ‘Previous history’ in lines 37, 41, 212, 237, 239, 256, 258 should be ‘history’.

16 /EPTB/ in lines 25 and 80 should be omitted.

17 Line 45 capitalise f in factors.

18 Line 99 space between 2010 and worksheet.

19 Line 120 …software (STATA) so that line 122 refers to ‘STATA’.

Reviewer #2: The authors have clarified the aim of the study, and it is now possible to make comments on the rest of the paper. Please see detailed comments in word document which are summarised here.

Firstly, the rationale for the study could be made clearer.

Secondly, in table 1, it is not clear what 'associated factors' refer to. I think the authors mean 'risk factors', but it is not clear if the factors listed are 'risk factors for EPTB (as opposed to PTB) or 'risk factors for bacteriologically-confirmed TB (vs non-bacteriologically confirmed TB). Following on from this, in the discussion, the authors have made incorrect comparisons with international iterature, and have focused the discussion on prevalence of EPTB amongst all TB cases. Therefore the discussion does not have bearing on the aim of the paper (to discuss % of EPTB that is bacteriologically confirmed, as opposed to the % which is not bacteriologically confirmed). The authors point out that diagnostic tests in Ethiopia are limited, and that understanding the % of EPTB that is bacteriologically confirmed will guide policy. It's not clear in what direction this policy should go. This could be (should be?) brought up in the discussion.

Thirdly, correction of grammatical/syntax errors will make aspects of the paper easier to understand.

Fourthly, all legends to figures and tables should refer to the context of the figure/table in the paper.

Fifthly, once the above are corrected, a statistical reviewer should assess the validity of the tests that have been conducted and how they have been interpreted.

**********

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: Yes: Anthony Leland Hamilton Mayne

Reviewer #2: No

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PLoS One. 2022 Nov 23;17(11):e0276701. doi: 10.1371/journal.pone.0276701.r004

Author response to Decision Letter 1

7 Jun 2022

Ref: PONE-D-22-00257R1

Bacteriologically confirmed extrapulmonary tuberculosis and the associated risk factors among extrapulmonary tuberculosis suspected patients in Ethiopia: A systematic review and meta-analysis

Dear Editor,

Thank you very much for your informative comments on our manuscript entitled “Bacteriologically confirmed extrapulmonary tuberculosis and the associated risk factors among extrapulmonary tuberculosis suspected patients in Ethiopia: A systematic review and meta-analysis”. We have addressed your comments one by one. We also appreciate you for allowing us to revise our manuscript and correct errors in the previous version. We thank the reviewers for their informative comments, and our point-by-point responses to the reviewers’ comments are given below. Also, we would like to inform you that we have used track changes to indicate where we made changes in response to the reviewers’ comments. Review Comments to the Author

Reviewer #1:

1 Reviewer 1 comments in the first review have been addressed and the original document has been extensively revised or rewritten. As a result, the revised document is more readable. The revised document has however highlighted additional significant matters and some minor issues. In view of the novelty and importance of the study, it is well worthwhile to resolve these matters and issues.

2 Lines refer to the revised document.

Response: Thank you very much for your unreserved constructive comments. These sections of comments (1-6) have been updated to follow a fixed-effects model, as requested.

7 Repetition of statistics in 5 places - see lines in point 3 above. This suggests that the document requires editing.

Response: Thank you for the valuable comment. We have addressed it.

Response: Thank you for the valuable comment. We have corrected it.

Response: Thank you for the valuable comment. We have used the fixed-effect model and put the type of the model of analysis.

10 Lines 35 to 37 which refer to smear microscopy, Xpert MTB/RIF, culture as separate categories with statistics for each, does not agree with line 106 which adds

nucleic acid amplification as an additional test.

Response: Thank you for your suggestion. We are removed additional words.

Response: Thank you for your comments. Our findings are reported on lines 35–37 and the characteristics of the research included in the review are described on lines 152–157. We have omitted the repeated lines 136–138.

Response: Thank you for your critical observations and comments; the pooled estimate was weighted by study.

Response: Thank you for your critical observation and comment; we revised as per the suggestion.

Response: Thank you for your critical observation and comment; we have put the most reported risk factors in the conclusion.

15 ‘Previous history’ in lines 37, 41, 212, 237, 239, 256, 258 should be ‘history’.

Response: Thank you for the suggestion. We revised it.

16 /EPTB/ in lines 25 and 80 should be omitted.

Response: Thank you for your suggestion. We have deleted it.

17 Line 45 capitalise f in factors.

Response: Thank you for your suggestion. We have corrected it.

18 Line 99 space between 2010 and worksheet.

Response: Thank you for your suggestion. We have corrected it.

19 Line 120 …software (STATA) so that line 122 refers to ‘STATA’.

Response: Thank you for your suggestion. We corrected it accordingly.

Firstly, the rationale for the study could be made clearer.

Response: Thank you for your suggestion. We have revised the rational of the study.

Response: Thank you for your suggestion. We have revised it accordingly.

Thirdly, correction of grammatical/syntax errors will make aspects of the paper easier to understand.

Response: Thank you for your suggestion. In the revised manuscript we have addressed the grammatical problems.

Fourthly, all legends to figures and tables should refer to the context of the figure/table in the paper.

Response: Thank you for your suggestion. We have corrected all the legends accordingly.

Fifthly, once the above are corrected, a statistical reviewer should assess the validity of the tests that have been conducted and how they have been interpreted.

Response: Thank you for your suggestion. Every statistical analysis is correct.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(21KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0276701.r005

Decision Letter 2

Elizabeth S Mayne

9 Sep 2022

PONE-D-22-00257R2Bacteriologically confirmed extrapulmonary tuberculosis and the associated risk factors among extrapulmonary tuberculosis suspected patients in Ethiopia: A systematic review and meta-analysisPLOS ONE

Dear Dr. Diriba,

The reviewers were generally satisfied that the majority of their comments were addressed but there are some minor issues that still need correction. A comprehensive list is included.

Please submit your revised manuscript by Oct 24 2022 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,

Elizabeth S. Mayne, M.D.

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: (No Response)

**********

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

Reviewer #1: Partly

**********

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

Reviewer #1: Yes

**********

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: 1 Please insert spaces or remove spaces as indicated in the red or blue underlines on the document

2 line 117 "the presence of publication bias..." is a repetition of the previous sentence

3 line 124 remove STATA 14... details, this has already been defined in line 121

4 line 171 bacteriologically

5 line 121 remove (STATA)

6 line 100 facility-based

7 line 215 meta-analysis

8 line 169 Figure 2: pooled not pooed

9 Table 1 last column is 12 point type, the preceding columns are point 8

10 The document needs a final edit for typos and set-out

**********

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: Yes: Anthony L. H. Mayne

**********

PLoS One. 2022 Nov 23;17(11):e0276701. doi: 10.1371/journal.pone.0276701.r006

Author response to Decision Letter 2

10 Sep 2022

Ref: PONE-D-22-00257R2

Bacteriologically confirmed extrapulmonary tuberculosis and the associated risk factors among extrapulmonary tuberculosis suspected patients in Ethiopia: A systematic review and meta-analysis

Dear Editor,

Regarding our manuscript, "Bacteriologically confirmed extrapulmonary tuberculosis and the associated risk factors among extrapulmonary tuberculosis suspected patients in Ethiopia: A systematic review and meta-analysis" we appreciate your insightful comments. Each of your comments has been addressed one by one. We also appreciate your letting us modify our manuscript and make corrections in the first draft. We appreciate the reviewers' informative comments and suggestions. His comments have improved the manuscript effectively. Also, we would like to inform you that we have used hyperlink to indicate where we made changes in the previous version of the manuscript based on the reviewers’ comments.

Reviewer #1

1 Please insert spaces or remove spaces as indicated in the red or blue underlines on the document

Response: Thank you for the valuable comment. We have addressed it.

2 line 117 "the presence of publication bias..." is a repetition of the previous sentence

Response: Thank you for the valuable comment. We have removed the repetition sntence.

3 line 124 remove STATA 14... details, this has already been defined in line 121

Response: Thank you for your critical observation and comment; we have addressed.

4 line 171 bacteriologically

Response: Thank you for your suggestion. We have corrected it.

5 line 121 remove (STATA)

Response: Thank you for your suggestion. We have remove it.

6 line 100 facility-based

Response: Thank you for your suggestion. We have corrected it.

7 line 215 meta-analysis

Response: Thank you for your suggestion. We have corrected it.

8 line 169 Figure 2: pooled not pooed

Response: Thank you for your suggestion. We have corrected the word.

9 Table 1 last column is 12 point type, the preceding columns are point 8

Response: Thank you for the valuable comment. We have addressed in the revised manuscript.

10 The document needs a final edit for typos and set-out

Response: Thank you for the valuable comment. We have addressed in the revised manuscript.

Kind regards,

Getu Diriba

Ethiopian Public Health Institute

Phone: +251913828019. Fax: +2510112780431

P.O.Box 1242, Addis Ababa, Ethiopia

E-mail: getud2020@gmail.com

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PLoS One. doi: 10.1371/journal.pone.0276701.r007

Decision Letter 3

Elizabeth S Mayne

12 Oct 2022

Bacteriologically confirmed extrapulmonary tuberculosis and the associated risk factors among extrapulmonary tuberculosis suspected patients in Ethiopia: A systematic review and meta-analysis

PONE-D-22-00257R3

Dear Dr. Diriba,

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,

Elizabeth S. Mayne, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: (No Response)

**********

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: Yes

**********

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: Yes

**********

6. Review Comments to the Author

Reviewer #1: ***please edit spacing and ensure consistent font size is used in tables

Already submitted (review no 2)

**********

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: Yes: Anthony Leland Hamilton Mayne

**********

PLoS One. doi: 10.1371/journal.pone.0276701.r008

Acceptance letter

Elizabeth S Mayne

10 Nov 2022

PONE-D-22-00257R3

Bacteriologically confirmed extrapulmonary tuberculosis and the associated risk factors among extrapulmonary tuberculosis suspected patients in Ethiopia: A systematic review and meta-analysis

Dear Dr. Diriba:

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. Elizabeth S. Mayne

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 File. PRISMA checklist.

(DOC)

Click here for additional data file.^{(65.5KB, doc)}

S2 File. Literature search strategy from searched databases.

(DOCX)

Click here for additional data file.^{(333.1KB, docx)}

S3 File. Detailed data of the included studies.

(XLSX)

Click here for additional data file.^{(20KB, xlsx)}

S4 File. Newcastle-Ottawa quality assessment scale for cross-sectional studies.

(DOCX)

Click here for additional data file.^{(23.9KB, docx)}

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Data Availability Statement

All the important information is available within the manuscript and its supplementary files.

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Bacteriologically confirmed extrapulmonary tuberculosis and the associated risk factors among extrapulmonary tuberculosis suspected patients in Ethiopia: A systematic review and meta-analysis

Getu Diriba

Ayinalem Alemu

Kirubel Eshetu

Bazezew Yenew

Dinka Fikadu Gamtesa

Habteyes Hailu Tola

Roles

Abstract

Background

Methods

Results

Conclusion

Introduction

Materials and methods

Search strategy

Eligibility criteria

Data extraction

Operational definition

Risk of bias assessment and study quality

Statistical analysis

Ethical consideration and consent

Result

Study selection

Fig 1. A PRISMA flow diagram depicting the screening and selection process to identify literature describing extra-pulmonary TB cases in Ethiopia.

Characteristics of the studies included in the review

Table 1. General characteristics of studies describing extrapulmonary tuberculosis in Ethiopia.

The pooled prevalence of bacteriologically confirmed EPTB

Fig 2. The pooled proportion of bacteriologically-confirmed EPTB cases amongst all studies identified for review.

Fig 3. Funnel plot for the pooled proportion of bacteriologically-confirmed EPTB cases amongst all studies identified for review.

Subgroup analysis by diagnostic testing methods

Fig 4. Pooled proportion of culture-positive EPTB using a fixed-effects model.

Fig 5. Pooled proportion of smear-positive EPTB using a fixed-effects model.

Fig 6. Pooled proportion of Xpert MTB/RIF assay positive EPTB using a fixed-effects model.

Risk of bias across studies publication

Fig 7. Funnel plot of a subgroup of 15 of the 20 selected studies for culture-positive EPTB.

Fig 8. Funnel plot of a subgroup of 11 of the 20 selected studies for smear-positive EPTB.

Fig 9. Funnel plot of a subgroup of 8 of the 20 selected studies for Xpert MTB/RIF assay positive EPTB.

Associated risk factors of bacteriologically confirmed EPTB

Discussion

Conclusions

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Elizabeth S Mayne

Roles

Author response to Decision Letter 0

Decision Letter 1

Elizabeth S Mayne

Roles

Author response to Decision Letter 1

Decision Letter 2

Elizabeth S Mayne

Roles

Author response to Decision Letter 2

Decision Letter 3

Elizabeth S Mayne

Roles

Acceptance letter

Elizabeth S Mayne

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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