Rifampicin-resistance pattern of Mycobacterium tuberculosis and associated factors among presumptive tuberculosis patients referred to Debre Markos Referral Hospital, Ethiopia: a cross-sectional study
Received: 5 January 2016
Accepted: 8 December 2016
Published: 3 January 2017
Abstract
Background
Prevailing data on rifampicin-resistant M. tuberculosis is essential for early management of MDR-TB. Therefore, this study was conducted to determine the prevalence of rifampicin-resistant Mycobacterium tuberculosis and associated factors among presumptive TB cases in Debre Markos Referral Hospital, Ethiopia.
Methods
A cross-sectional study was conducted from September 2014 to March 2015. Detection of M. tuberculosis and resistance to rifampicin was performed using Gene Xpert MTB/RIF assay. Data was collected using structured questionnaire by face to face interview. Logistic regression analysis was computed to determine the associated factors of rifampicin-resistant M. tuberculosis.
Results
A total of 505 presumptive TB patients included in the study. The prevalence of M. tuberculosis confirmed cases was 117 (23.2%) (95% CI 19.7–27%). It was higher among males (27.9%) than females (17.9%) (AOR: 2.17; CI 1.35–3.49). Of the 117 M. tuberculosis confirmed cases, 12 (10.3%) (95% CI 6.0–17.1%) were resistant to rifampicin. Rifampicin-resistant M. tuberculosis was noticed in 7 previously treated TB patients (17.1%) and 5 treatment naive patients (6.7%) (AOR: 4.16; CI 1.04–16.63). The prevalence of rifampicin-resistant M. tuberculosis was 6 (9.8%) and 6 (11.3%) in pulmonary and extra-pulmonary infections, respectively. Of the 30, MTB/HIV co-infection, 3 (10%) were rifampicin-resistant M. tuberculosis.
Conclusion
Rifampicin-resistant M. tuberculosis is prevalent in both pulmonary and extra-pulmonary tuberculosis patients. Previous treatment with anti-TB drugs was significantly associated with rifampicin resistance. Therefore, the use of Gene Xpert should be scaled up across the country for rapid detection and management of drug resistant M. tuberculosis.
Keywords
Background
Mycobacterium tuberculosis (M. tuberculosis) remains one of the most significant causes of death from an infectious agent [1]. Tuberculosis (TB) remains a major public health problem, accounting more than 9.4 million incident cases and 1.7 million deaths every year, worldwide [2]. World Health Organization (WHO) estimates that 4.5 million people are co-infected with Human Immunodeficiency Virus (HIV) and TB globally [1, 2].
Ethiopia is one of the 22 high burden countries for TB. TB remains one of the leading causes of mortality [3]. According to the 2014 WHO report, the prevalence and incidence of all forms of TB are 211 and 224/100,000 populations, respectively [4]. TB mortality was estimated to be 32/100,000 populations in 2013. Among estimated all new TB cases, 13% are HIV co-infected [3, 4].
The emergence of drug resistance to M. tuberculosis has become a significant obstacle for TB control [5]. The emergence and spreading of multidrug (MDR) and extensively (XDR) drug-resistant M. tuberculosis complex (MTBC) strains poses significant challenges to TB control [2]. Ethiopia is one of the highest MDR-TB burden countries [3]. In Ethiopia, 2.3% of new TB cases and 17.8% of previously treated TB cases were estimated to have MDR [3]. Studies in Ethiopia reported 4.7–18.3% prevalence of rifampicin-resistant M. tuberculosis [6–10]. Mutations in a ‘hotspot’ region of 81 base pairs (bp) of rpoB gene have been found in about 96% of rifampicin (RMP) resistant M. tuberculosis [6].
Despite low sensitivity in detection of M. tuberculosis, acid-fast staining remains the main diagnostic method in resource-limited settings [11, 12]. Mycobacterial culture is the gold standard and the most sensitive method for TB diagnosis; however, its use in clinical practice is limited due to a slow turnaround time, biosafety requirements, and high cost [11, 12]. In 2011, WHO introduced the wide use of Xpert MTB/RIF assay. It is a fully automated diagnostic molecular test using real-time polymerase chain reaction (PCR) technology to simultaneously detect M. tuberculosis and rifampicin resistance mutations in the rpoB gene [13]. The Xpert assay is highly rapid, sensitive and specific in diagnosis of both pulmonary and extra pulmonary TB [8–14]. Furthermore; it was shown to be cost-effective for TB diagnosis compared to microscopy in low and middle income settings [14].
In countries with high burden of TB, rapid detection, continuous surveillance and regular monitoring of drug resistance TB is essential for disease management and earlier treatment initiation. However, there is limited capacity to perform Xpert assay, even from patients suspected of harboring drug-resistant strains with TB/HIV co-infection in Ethiopia. Moreover, documented data on the prevalence of rifampicin resistant M. tuberculosis using the newly endorsed method Gene Xpert in our country is limited. Therefore, the aim of this study was to determine the prevalence and associated factors of rifampicin-resistant M. tuberculosis among patient’s presumptive for either TB or drug resistant TB (DR TB) in Debre Markos Referral Hospital.
Methods
Study design, area and period
A cross-sectional study was conducted from September 2014 to March 2015 at Debre Markos referral Hospital (DMRH). DMRH has more than 147 beds offering different specialized services. It receives patients from the catchment area and referred from different areas of East Gojjam zone. The hospital has TB/HIV clinic as well as MDR-TB ward used for diagnosis and treatment of MDR-TB patients. The Gene Xpert MTB/RIF assay was conducted at DMRH tuberculosis laboratory.
Sample size
The sample size was determined using single population proportion formula considering 50% expected proportion of rifampicin-resistant M. tuberculosis using Gene Xpert MTB/RIF assay, 95% confidence level and marginal error of 5%. Assuming 10% non-response rate, the sample size was: n = 384 + 10% = 384 + 38 = 422. However, 505 patients provided clinical specimen adequately. Any patients attending in the TB clinic of DMRH presumptive for either TB or DR TB were the study population and they were enrolled consecutively.
Inclusion criteria
Patients presumptive for pulmonary or extra-pulmonary tuberculosis attending in the TB clinic of DMRH and volunteered to participate in the study were included.
Exclusion criteria
Presumptive patients of pulmonary or extra-pulmonary tuberculosis who provided inadequate specimen for the laboratory analysis were excluded from the study.
Variables
Rifampicin-resistant M. tuberculosis was the dependent variable where as demographic factors, HIV infection status, tuberculosis and treatment related conditions were the independent variables.
Laboratory procedures
Each eligible patient who signed written consent provided clinical specimens. From each patients presumptive of pulmonary TB, 4 ml of sputum sample was collected. In the case of presumptive extra-pulmonary TB, four ml of either pus, CSF, lymph node aspirate or peritoneal and pleural fluid samples were collected. Samples were immediately processed for Gene Xpert MTB/RIF assay. Clinical samples were diluted and decontaminated and Xpert MTB/RIF assay (Cepheid) was performed according to manufacturer’s instruction. The Xpert® MTB/RIF purifies and concentrates M. tuberculosis bacilli from clinical samples. Genomic material isolated from the captured bacteria by sonication and subsequently amplifies the genomic DNA by polymerase chain reaction (PCR). Furthermore, the process identifies all the clinically relevant rifampicin resistance inducing mutations in the RNA polymerase beta (rpoB) gene in the M. tuberculosis genome in a real time format using fluorescent probes called molecular beacons.
HIV testing
Testing for HIV was done according to the current national algorithm recommended by the Federal Ministry of Health of Ethiopia. Two rapid HIV tests, HIV (1 + 2) rapid test strip (KHB) and Stat-Pak were run sequentially. Samples were tested first with KHB. Positive samples were confirmed with Stat-Pak. Discordant results were resolved using a third confirmatory testing kit, HIV-1/2 Unigold Recombinant assay. Pre and post-test HIV counseling was provided for all consenting individuals.
Using a structured questionnaire data was collected by both face to face patient interviews and patients’ clinical record review. The main variables included in the study were age, sex, residence, reason for diagnosis, treatment history, and category of presumptive DR TB and site of tuberculosis.
Data analysis
Data were analyzed using Statistical Package for Social Sciences (SPSS® 20, USA). Descriptive statistics were used to describe the study participants in relation to relevant variables. Chi-square and logistic regression analysis were computed to identify the associated factors of M. tuberculosis and rifampicin-resistance.
Most of the variables were fitted to Chi-square test. Then all variables having a P value of ≤2 in the Chi-square test were further entered into logistic regression model. In the multivariate analysis, backward step wise logistic regression techniques were fitted and confounding were controlled. Variables having P value <0.05 in the multivariate analysis were taken as statistically significant. Adjusted odds ratios with their 95% confidence intervals were calculated. The Hosmer and Lemshow gardens-of-fit test was used to assess whether the necessary assumptions for the application of multiple regressions were fulfilled and P value >0.05 was considered as good fit.
Quality assurance
Both SPC and PCC internal controls used during Gene Xpert MTB/RIF assay. The specimen was excluded from the analysis if it was an invalid sample for Xpert assay or sample error according to Cepheid package insert. All procedures were done using standard operating methods.
Results
Patient characteristics
Prevalence of M. tuberculosis among presumptive TB patients referred to DMRH using Gene Xpert MTB/RIF assay, 2015
Characters | M. tuberculosis | Total N (%) | P value | |
|---|---|---|---|---|
Detected N (%) | Not detected N (%) | |||
Age, years | ||||
≤10 | 9 (23.7) | 29 (76.3) | 38 (7.5) | 0.017 |
11–17 | 7 (29.2) | 17 (70.8) | 24 (4.8) | |
18–30 | 46 (34.3) | 88 (65.7) | 134 (26.7) | |
31–40 | 25 (18.7) | 109 (81.3) | 134 (26.5) | |
41–50 | 15 (15.1) | 82 (84.5) | 97 (19.2) | |
51–60 | 9 (18) | 41 (82) | 50 (9.9) | |
61–95 | 6 (21.4) | 22 (79.6) | 28 (5.5) | |
Sex | ||||
Male | 74 (27.9) | 191 (72.1) | 265 (52.4) | 0.008 |
Female | 43 (17.9) | 197 (82.1) | 240 (47.6) | |
Residence | ||||
Urban | 57 (20.2) | 225 (79.8) | 282 (55.7) | 0.007 |
Rural | 60 (26.9) | 163 (73.1) | 223 (44.3) | |
HIV infection | ||||
Positive | 30 (16.6) | 153 (83.4) | 183 (36) | 0.008 |
Negative | 87 (26.9) | 235 (73.1) | 322 (64) | |
Reason for diagnosis | ||||
Presumptive TB | 48 (15.1) | 269 (84.8) | 317 (62.8) | <0.001 |
Presumptive DR TB | 69 (36.7) | 119 (63.3) | 188 (37.2) | |
Treatment history with anti-TB drugs | ||||
Previously treated | 41 (31.6) | 91 (68.9) | 132 (26.2) | 0.013 |
Previously untreated | 76 (20.4) | 297 (79.6) | 372 (73.8) | |
Presumptive DRTB | ||||
New | 28 (45.2) | 34 (54.8) | 62 (32) | 0.024 |
Relapse | 26 (25.7) | 75 (74.3) | 101 (52.1) | |
Failure | 14 (92.3) | 12 (7.7) | 26 (13.4) | |
Lost to follow-up | 0 | 1 | 1 (0.5) | |
MDR-contact | 1 (25) | 3 (75) | 4 (2.1) | |
Site of presumptive TB | ||||
Pulmonary | 64 (19.8) | 259 (80.2) | 323 (64) | 0.013 |
Extra-pulmonary | 53 (29.1) | 129 (70.9) | 182 (36) | |
Type of specimen | ||||
Respiratory (sputum) | 64 (19.8) | 259 (80.2) | 323 (64) | 0.007 |
Non-respiratory | 53 (29.1) | 129 (70.9) | 182 (36) | |
Type of non-respiratory specimen | ||||
Pus | 46 (35.1) | 85 (64.9) | 131 (26) | |
Peritoneal fluid | 2 (11.8) | 15 (88.2) | 17 (3.4) | |
Lymph node aspirate | 1 (7.1) | 13 (92.9) | 14 (2.8) | |
Pleural fluid | 3 (23.1) | 10 (76.9) | 13 (2.6) | |
Other | 1 (14.3) | 6 (83.7) | 7 (1.2) | |
Total | 117 (23.2) | 388 (76.8%) | 505 (100) | |
Prevalence of tuberculosis
The prevalence of M. tuberculosis confirmed TB was 117 (23.2%) (95% CI 19.7–27%). The proportion of M. tuberculosis was 74 (27.9%) in males and 43 (17.9%) in females. The proportion of M. tuberculosis was 48 (15.1%) and 69 (36.7%) among patients presumptive of TB and DR TB, respectively. From 188 presumptive DRTB cases, M. tuberculosis was noticed in 28 new (45.2%), 26 relapse (25.7%) and 14 treatment failure (53.8%) cases. M. tuberculosis was detected in 64 pulmonary (19.8%) and 53 extra-pulmonary TB cases (29.1%). The rate of MTB/HIV co-infection was 30 (16.6%) (Table 1).
Rifampicin- resistant M. tuberculosis
Prevalence of rifampicin-resistant M. tuberculosis in each variable among the total M. tuberculosis cases using Gene Xpert MTB/RIF assay, DMRH, 2015
Variables | Resistance pattern | P value | |
|---|---|---|---|
Resistance N (%) | Sensitive N (%) | ||
Age, years | |||
≤10 | 2 (22.2) | 7 (77.8) | 0.02 |
11–17 | 1(14.3) | 6 (83.6) | |
18–30 | 3 (6.7) | 43 (93.3) | |
31–40 | 0 | 25 (100) | |
41–50 | 5 (33.3) | 10 (66.7) | |
51–60 | 0 | 9 (100) | |
61–92 | 1 (16.7) | 5 (83.3) | |
Sex | |||
Male | 8 (11.3) | 64 (88.7) | 0.77 |
Female | 4 (8.9) | 41 (91.1) | |
Residence | |||
Urban | 5 (17.9) | 53 (91.2) | 0.76 |
Rural | 7 (11.9) | 52 (88.1) | |
HIV infection | |||
Positive | 5 (17.9) | 24 (82.1) | 0.17 |
Negative | 7 (8) | 81 (92) | |
Reason for diagnosis | |||
Presumptive TB | 3 (5.9) | 49 (94.1) | 0.22 |
Presumptive DR TB | 9 (13.8) | 56 (86.2) | |
Treatment history with anti-TB drugs | |||
Previously treated | 7 (17.1) | 34 (82.9) | 0.11 |
Previously untreated | 5 (6.7) | 71 (93.3) | |
Presumptive DR TB | |||
New | 3 (10.7) | 25 (89.3) | 0.87 |
Relapse | 5 (19.2) | 21 (80.8) | |
Failure | 2 (14.3) | 12 (91.7) | |
MDR-contact | 0 | 1 | |
Site of presumptive TB | |||
Pulmonary | 6 (9.4) | 58 (90.6) | 0.77 |
Extra pulmonary | 6 (11.3) | 47 (88.7) | |
Specimen type | |||
Respiratory (sputum) | 6 (9.5) | 58 (90.6) | 0.67 |
Non-respiratory | 6 (11.3) | 47 (88.7) | |
Type of non-respiratory specimen | |||
Pus | 4 (8.5) | 43 (91.5) | |
Peritoneal fluid | 0 | 2 | |
Lymph node aspirate | 0 | 1 | |
Pleural fluid | 2 | 1 | |
Total | 12 (10.3) | 105 (89.7) | |
Associated factors
Multivariate analysis showing the associated predictors of M. tuberculosis in DMRH, 2015
Variables | Gene expert result | |||
|---|---|---|---|---|
M. tuberculosis | AOR (95% CI) | P value | ||
Detected | Not detected | |||
Residence | ||||
Urban | 57 | 225 | 1.35 (0.86–2.13) | 0.19 |
Rural | 60 | 163 | a | |
Sex | ||||
Male | 74 | 191 | 2.17 (1.35–3.49) | 0.001 |
Female | 43 | 197 | a | |
Age, years | ||||
≤10 | 9 | 29 | 3.2 (1.23–8.21) | 0.02 |
11–17 | 7 | 17 | 3.3 (1.08–10.08) | 0.036 |
18–30 | 46 | 88 | 4.6 (1.63–12.71) | 0.004 |
31–40 | 25 | 109 | 2.76 (0.77–9.91) | 0.12 |
41–50 | 15 | 82 | 1.1 (0.46–2.70) | 0.82 |
51–60 | 9 | 41 | 1.2 (0.36–4.02) | 0.77 |
61–92 | 6 | 22 | a | |
HIV infection | ||||
Positive | 30 | 153 | 1.36 (0.80–2.3) | 0.25 |
Negative | 87 | 235 | a | a |
Reason for examination | ||||
Presumptive TB | 48 | 269 | a | a |
Presumptive DR TB | 69 | 119 | 6.83 (3.55–13.15) | <0.001 |
Treatment history with anti-TB drugs | ||||
Previously treated | 41 | 91 | 2.02 (1.03–3.96) | 0.04 |
Previously untreated | 76 | 297 | a | |
Site of TB infection | ||||
Pulmonary | 64 | 259 | 2.19 (1.36–3.51) | 0.001 |
Extra-pulmonary | 53 | 129 | ||
Multivariate analysis showing the associated predictors of rifampicin resistant M. tuberculosis in DMRH, 2015
Variables | Resistance pattern | AOR (95% CI) | P value | |
|---|---|---|---|---|
Resistance | Sensitive | |||
Age, years | ||||
0–10 | 2 | 7 | 2.3 (0.15–37.67) | 0.55 |
11–17 | 1 | 6 | 1.84 (0.08–44.6) | 0.71 |
18–30 | 3 | 43 | 0.55 (0.04–6.80) | 0.64 |
31–40 | 0 | 25 | ||
41–50 | 5 | 10 | 4.3 (0.34–54.99) | 0.23 |
51–60 | 0 | 9 | ||
61–92 | 1 | 5 | a | |
HIV infection | ||||
Positive | 5 | 24 | 3.2 (0.69–14.96) | 0.14 |
Negative | 7 | 81 | a | |
Reason for examination | ||||
Presumptive TB | 3 | 49 | a | |
Presumptive DR TB | 9 | 56 | 0.41 (10.04–4.21) | 0.45 |
Treatment history with anti-TB drugs | ||||
Previously treated | 7 | 34 | 4.16 (1.04–16.63) | 0.04 |
Previously untreated | 5 | 71 | a | |
Discussion
In the present study, the prevalence of M. tuberculosis infection was similar with reports of South Africa (26%) [15], Northern Nigeria (23%) [16] and India (27.6%) [17]. However, it was lower compared to reports in Nigeria (31.4%) [18] and Pakistan (37%) [19]. The lower proportion rate of confirmed M. tuberculosis in the present study compared to other studies is due to the fact that we included presumptive cases to identify M. tuberculosis while other studies included identified cases of M. tuberculosis to check gene Xpert technique. In contrast, it is higher than studies conducted in other parts of Ethiopia [20–22] and India [23]. The discrepancy might be due to difference in methods of detection of M. tuberculosis, community and geographical area.
In this study, the detection rate of M. tuberculosis was significantly higher in males than females. Likewise, reports from WHO [24], Ethiopia [7] and Northeast China [25] supports this finding. The reason for this might be due to social and health seeking behavior difference and higher exposure of males to outer environment, smoking and alcoholism [24]. The highest proportion of Gene Xpert positive M. tuberculosis cases were seen in the age group of 18–30 years. This is consistent with previous reports in Ethiopia [20–22, 26]. This might be due to more exposure to the outer environment, high work load and wide range of mobility of young people to acquire the TB bacilli as young people have.
In the present study, the proportion of M. tuberculosis was significantly higher in presumptive DRTB compared to presumptive TB patients (P < 0.001). This might be due to treatment failure and acquiring of resistant bacilli from drug resistant TB contacts. Moreover, significantly higher proportion of M. tuberculosis was found among patients treated with anti-TB drugs compared to treatment naïve patients in the present study. This finding was comparable to a study conducted in Zimbabwe [27].
Rifampicin-resistant M. tuberculosis is a serious health problem in the study population. The prevalence of rifampicin-resistant M. tuberculosis in this study was in keeping with previous studies in Nigeria [28], North India [29], Iran [30] and Northeast China [25]. However, it was higher than studies observed in Ethiopia [8, 9, 31, 32], Kenya [33], Nigeria [34], Uganda [35] and South of Iraq [36]. In contrast, the proportion of rifampicin-resistant M. tuberculosis was lower than reports in other parts of Ethiopia [7, 36] and Chile [37]. The variation could be due to difference in risk for HIV acquisition, exposure to anti-TB drugs and national TB control program. The relative higher proportion of rifampicin-resistant M. tuberculosis in our study could be due to the use of rifampicin to treat other conditions. Moreover, rifampicin has several adverse effects which could result in patient non-adherence and hence may lead to the selection of resistant strains.
In the present study, the proportion of rifampicin-resistant M. tuberculosis was significantly higher among previously treated patients compared to treatment naive patients which might be due to failure from previous treatment and contact with drug resistant TB patients [26, 38–43]. However, the level of rifampicin resistance among previously untreated cases (6.7%) in the analysis close to the reported prevalence of rifampicin- resistant MTB (10.4%). This finding is a significant relevance in the current global and regional efforts to accurately and timely diagnose MDR-TB with the scale up of molecular technology like Gene Xpert MTB/RIF, providing quick results of rifampicin resistance as a proxy to MDR-TB.
In this study, high prevalence of rifampicin-resistant M. tuberculosis was detected among HIV positive cases which are in accordance with a study done in other part of Ethiopia [26] and Cambodia [44]. However, in the present study, there was a lack of association between HIV infection and development of active tuberculosis as well as rifampicin resistance. This was consistent with the results of earlier studies in Ethiopia [39], Tanzania [42], Calabar Nigeria [35] and Brazil [45].
In the present study, the proportion of extra-pulmonary tuberculosis was significantly higher compared to pulmonary tuberculosis; in addition the proportion of rifampicin-resistant M. tuberculosis was higher in non-respiratory specimens compared to sputum. This conforms to a study in Cambodia [44]. This demonstrates that rifampicin-resistant extra-pulmonary M. tuberculosis infection is a major health problem in resource-limited settings.
The major strength of this study was detection of M. tuberculosis and rifampicin resistance using the newly endorsed method Gene Xpert MTB/RIF assay from sputum and non-respiratory specimens. However, the major limitation of this study was determination of the sample size using single population formula which may overwhelm some of the associated factors. This study could not do the level of resistance to other anti-TB drugs and the finding of Gene Xpert was not compared to acid fast bacilli microscopy. Thus the finding of this study should be interpreted with these limitations.
Conclusions
Rifampicin-resistant M. tuberculosis is prevalent both in pulmonary and extra-pulmonary tuberculosis cases in the study area. Previous treatment with anti-TB drugs was significantly associated with rifampicin resistance. The strong association of rifampicin resistance with previous treatment suggests that improved monitoring of treatment to limit the emergence of drug resistant M. tuberculosis. Hence, the use of Gene Xpert should be scaled up across the country for rapid diagnosis, management and expanded surveillance of drug-resistant M. tuberculosis.
Declarations
Authors’ contributions
WM conceived and designed the study, involved in Gene Xpert MTB/RIF assay, interpret the result, performed the statistical analysis and wrote the manuscript, HA and DA performed the gene Xpert MTB/RIF assay, and revised the manuscript, BA, MY and TH, critically revised the manuscript. All authors read and approved the final manuscript.
Acknowledgements
We would like to acknowledge DMRH for giving permission to conduct the study. We would like also to thank Mr. Belachew Mulu, Medical Laboratory technician at DMRH for his contribution in assisting the data collection process.
Competing interests
The authors declare that they have no competing interests.
Availability of data and materials
The finding of this study is generated from the data collected and analyzed based on the stated methods and materials. All the data are already found in the manuscript and there are no supplementary files. The original data supporting this finding will be available at any time upon request.
Consent for publication
Consent to publish is not applicable for this manuscript because there is no individual data details like images or videos.
Ethics approval and consent to participate
Ethical approval was secured from the research ethics committee of DMRH. We followed all chains of command to get support letter from legally authorized representatives for data collection. Written consent was obtained from each study participants. Moreover, all parents of participants under 18 gave written consent to participate in this study. The results from laboratory analysis were communicated to the responsible physician for early initiation of anti- TB treatment. Confidentiality of the result was also maintained anonymously and not communicated for other purposes.
Funding
Funding is not applicable for this study because the research project was not funded by any organization.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Authors’ Affiliations
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