Risk factors associated with multidrug-resistant tuberculosis (MDR-TB) in a tertiary armed force referral and teaching hospital, Ethiopia

Risk factors associated with multidrug-resistant tuberculosis (MDR-TB) in a tertiary armed force... Background: Ethiopia is one of the world health organization defined higher tuberculosis (TB) burden countries where the disease remains a massive public health threat. This study aimed to identify the prevalence and associated factors of multidrug-resistant tuberculosis (MDR-TB) using all armed force and civilian TB attendants in a tertiary level armed force hospital, where data for MDR-TB are previously unpublished. Methods: Cross-sectional study was conducted from September 2014 to August 2015 in a tertiary level Armed Force Referral and Teaching Hospital (AFRTH), Ethiopia. Armed force members (n = 251) and civilians (n = 130) which has been undergone TB diagnosis at AFRTH were included. All the specimens collected were subjected to microscopic smear observation, culture growth and drug susceptibility testing. Data were analyzed using statistical package for social sciences following binary logistic regression and Chi-square. P-values < 0.05 were considered statistically significant. Results: Among 381 TB patients, 355 (93.2%) new and 26 (6.8%) retreatment cases were identified. Culture and smear positive TB cases were identified in 297 (77.9%) and 252 (66.1%) patients, respectively. The overall prevalence of MDR-TB in AFRTH was found 1.8% (1.3% for armed force members and 0.5% for civilian patients) all of which were previously TB treated cases. The entire treatment success rates were 92.6% achieved highest in the armed force (active and pension) than the civilian patients. The failure and dead cases were also found 2.5 and 4.6%, respectively. Using bivariate analysis, category of attendants and TB contact history were strong predictors of MDR-TB in armed force and civilian patients. Moreover, human immunodeficiency virus (HIV) infection also identified a significant (OR = 14.6; 95% CI = 2.3–92.1; p = 0.004) predicting factor for MDR-TB in armed force members. However, sex, age and body mass index were not associated factor for MDR-TB. Conclusions: In AFRTH, lower prevalence of MDR-TB was identified in armed force and civilian patients that were significantly associated with category of attendants, HIV infection and TB contact history. Considering armed force society as one segment of population significantly helps to plan a better MDR-TB control management, especially for countries classified as TB high burden country. Keywords: Tuberculosis, Armed force, Ethiopia, Drug susceptibility, Risk factors * Correspondence: awokeguadie@gmail.com State Key Laboratory of Pollution Control and Resource Reuse, College of Environmental Science and Engineering, Tongji University, Shanghai, China Department of Biology, College of Natural Sciences, Arba Minch University, P.O. Box 21, Arba Minch, Ethiopia Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This 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. Demile et al. BMC Infectious Diseases (2018) 18:249 Page 2 of 10 Background drug, increasing cost of drug and physician errors) and in- Tuberculosis (TB) is an infectious disease caused by adequate adherence (such as poor compliance, alcoholism, Mycobacterium tuberculosis (M. tuberculosis) complex drug addiction, length of treatment and adverse drug which usually affects the lung [1]. The bacteria are trans- reactions) have been also identified as a drug resistance mitted via close contact with an infected individual who enhancing mechanisms by creating a selective pressure for is actively spreading the bacteria through coughing [2]. a rapid evolution of M. tuberculosis [14–17]. Once inhaled, the infection remains latent for decades in Globally, 3.5% of new and 20.5% of previously treated 90 to 95% healthy adult [1–3]. However, illness of latent TB patients were estimated to have had MDR-TB [1]. TB manifested only when the bacteria become active. Sub-Saharan Africa represents 14% of the global burden There are many factors that contribute the latent TB of new MDR-TB cases [18]. World Health Organization bacteria become active including human immunodefi- in 2016 listed Ethiopia 8th out of 30 high MDR-TB bur- ciency virus (HIV), older age, diabetics, close contact den countries in the world with a prevalence of 2.7% with an active case of TB disease and other immuno- (1.5–4.0) in newly and 14.0% (3.6–25.0) in previously compromising illness conditions [1, 4]. treated TB patients. Like Ethiopia which is listed 3rd, Although TB is an old disease with many efforts to other six countries in Africa including (new/retreatment treat and control, still it remains the main cause of mor- % accordingly) Angola (2.6/18%), DR Congo (2.2/17%), bidity for millions of people each year [1, 3]. According Kenya (1.3/9.4%), Nigeria (4.3/25%), Somalia (8.7/47%) to World Health Organization (WHO) estimates showed and Zimbabwe (4.6/14%) also listed among the 30 high that there were almost 9.6 (5.4 men, 3.2 women and 1.0 MDR-TB burden countries in the world [1]. Although children) million new TB cases globally in 2014, of MDR-TB is a growing concern in Africa where limited which 1.5 million cases were accounted TB deaths [5]. resource exists, it is largely under-reported [18, 19]. In The same WHO report also showed that 86% of TB in- Ethiopia, many of the MDR-TB patients are remain undiag- fection is from South-East Asia and Western Pacific nosed due to the low socioeconomic status of the popula- (58%) and African (28%) regions. The presence of rela- tion, lack of awareness and inaccessibility of health service. tively higher HIV patient in these regions significantly For instance, WHO in 2012 estimated that the number of contributed an increased incidence of TB [6]. Ethiopia is patients in Ethiopia tested for MDR-TB was < 1% of new one of the WHO defined higher TB burden countries and < 4% of retreatment cases [5]. where the disease remains a massive public health threat There are small numbers of MDR-TB studies in differ- and an economic burden. World Health Organization in ent regions of Ethiopia [16, 20–22], however, most of 2016 listed Ethiopia 10th out of the 30 high TB priority these surveys were restricted only to civilian patients countries in the globe [1]. and civilian hospitals. To the best of our knowledge, Based on WHO recommended six-month standard there is no published information about the status of TB course of medication, several countries treat TB disease and MDR-TB concerning armed force as one segment of using four first-line (rifampin, isoniazid, pyrazinamide the population in Ethiopia. This condition significantly and ethambutol) anti-TB drugs [2, 7, 8]. When M. tuber- compromises the MDR-TB control efforts. Therefore, culosis becomes resistant to treatment with at least the this study has been designed to evaluate the prevalence two first-line drugs (i.e, isoniazid and rifampin), the con- and risk factors of MDR-TB using armed force and civil- dition is known as multidrug-resistant tuberculosis ian patients in a tertiary level Armed Force Referral and (MDR-TB) [1, 3, 9]. Previous studies mentioned that M. Teaching Hospital (AFRTH) Addis Ababa, Ethiopia. The tuberculosis develops various drug-resistance mechanisms subjects were from Ministry of Defense members (active by using its special cellular structure and metabolic system military and pension) and civilian clients which have got [9, 10]. For instance, the unique structures like mycolic service from AFRTH. acid (as part of the cell wall) and trans-membrane protein help the M. tuberculosis to restrict entry of drug molecules Methods to the cell, and to pump out antibiotics from the cell, re- Study area spectively [10, 11]. The M. tuberculosis also utilizes differ- The study was conducted at AFRTH which is located in ent enzymatic strategies to alter the structure of drug Addis Ababa, the capital city of Ethiopia. It is the only synthesis target sites (such as ribosomes and deoxyribo- referral and teaching military hospital of the country at nucleic acid) and thereby avoid the action of antibiotics the rank of tertiary level. It is organized under Health [12]. Moreover, there are also reports that mentioned the Main Directorate (HMD), Ministry of Defense. ability of M. tuberculosis directly modify the anti-TB drug Armed Force Referral and Teaching Hospital provides into another form which in turn leads to inactivate the tar- medical services to members of the Ethiopian defense get drug compound action designed for its specific cellular forces. It accepts referral case from all secondary level site [10–13]. Inadequate treatment (due to shortage of (Eastern, Central, North and South-western) command Demile et al. BMC Infectious Diseases (2018) 18:249 Page 3 of 10 referral hospitals located all over the country. In AFRTH, drug-resistance in TB [23]. In this study, all patients there is also a limited ward allocated to give service to ci- who diagnosed TB in AFRTH between September 2014 vilian clients. Although the AFRTH provides service for a to August 2015 and whose information found to be large number of TB patients per year, however, the data complete and qualify the NTLCP guidelines had been included in this study were only collected from those pa- included. The study subjects include direct register pa- tients who had complete information registered according tients at AFRTH (armed force members and civilians) to National Tuberculosis and Leprosy Control Program and those referred from secondary level armed hospitals (NTLCP) guideline of Ethiopia [7] adopted from WHO. (armed force members only) located all over the country. As a result, our study population especially the armed Definition of TB cases and treatment outcome force members appears to be a representative sample of According to the standard definitions of NTLCP guide- all military members at risk for TB that are located all line of Ethiopia [7], the following case and treatment over Ethiopia. outcome definitions were used in the current study. The In AFRTH, the suspected TB patients were first identi- following are case definitions: (i) new case is used if a fied through examining signs and symptoms, chest x-ray patient who never had treatment for TB or has been on and prior history of TB. Although a large number of pa- previous anti-TB treatment for less than 4 wk in the tients had been registered in the AFRTH-TB Clinic, those past, (ii) relapse if a patient declared cured or whose who failed to qualify the preliminary examination have treatment was completed of any form of TB in the past, not been included in the current study. Among 389 cases but who reports back to the health service and is now qualified for preliminary examination, 8 suspected TB found to be microscopic smear positive or culture posi- cases were also excluded due to incomplete information. tive, (iii) treatment failure if a patient who is smear posi- Demographic data such as gender, age, HIV status, the tive at the end of the fifth month or later, after category of attendants and TB contact history were col- commencing and it also includes a patient who was ini- lected from the patient record books. In addition, routine tially sputum smear negative but who becomes smear data were obtained from AFRTH laboratory reports for positive during treatment, (iv) return after default if a sputum smear microscopy, culture growth and drug sus- patient previously recorded as defaulted from treatment ceptibility testing (DST). The clinical samples were proc- and returns to the health facility with smear positive essed using the N-acetyl-L-cysteine NaOH (NALC-NaOH) sputum, and (v) others if a patient who does not fit in method. The processed samples were suspended in any of the above mentioned categories (e.g, smear 1000 mL neutral sterile phosphate buffer and then 100 mL negative pulmonary TB case who returns after default, of resuspended pellet was inoculated onto Lowenstein– extaplumonary TB case returning after default and pre- Jensen (LJ) medium slants. M. tuberculosis was confirmed viously treated TB patients with an unknown outcome in cultures using measurements of growth rate, colony of that previous treatment). morphology, pigmentation and commercial biochemical According to NTLCP guideline [7], the following treat- tests. The biochemical testing (niacin assay, nitrate reduc- ment outcome definitions were also used in the current tion, and catalase tests) was used to identify the isolated study: (i) cured if patients have finished treatment with Mycobacterium once they were categorized into a prelim- negative bacteriology result at the end of treatment, (ii) inary subgroup based on their growth characteristics [24]. treatment completed if the patient finished treatment, All isolates of M. tuberculosis were subjected to DST using but without bacteriology result at the end of treatment, concentration method. Drug susceptibility testing for the (iii) treatment failure if a TB patient remains smear posi- four (rifampin, isoniazid, streptomycin and ethambutol) tive at 5 mo follow-up despite correct intake of medica- first-line anti-TB drug was performed according to WHO tion, (iv) defaulted treatment if the patients who guidelines [23]. Smear for microscopic examination was interrupted their treatment for two consecutive months also stained using the Ziehl–Neelsen method and results or more than 2 mo after registration, (v) died if the pa- were reported as smear positive and negative. tient died from any cause during the course of treat- The AFRTH laboratory was subjected to quality control ment, (vi) transfer out if the patient treatment result is through WHO guideline [23]. Drug susceptibility testing unknown due to transfer to another health facility, and quality control was done using standard strains of M. (vi) treatment success is used defined as the sum of tuberculosis (H37Rv). All data included here were reported cured and completed treatments. by qualified laboratory technicians and physicians. Study design, data collection and laboratory sputum Statistical analysis sample processing The data were analyzed using Epi Info 6, Excel 2010 and A cross-sectional study was conducted following the statistical package for the social sciences (SPSS) version most recent WHO guidelines for surveillance of 20.0 (IBM, NY, USA). A total of 389 patient information’s Demile et al. BMC Infectious Diseases (2018) 18:249 Page 4 of 10 were initially enter into the data system, however, eight samples were identified which has been relatively lower (2.0%) patients whose information were found to be in all patient groups (69.2% for civilian, 64.4% for active incomplete and excluded during data analysis. Either and 65.7% for pension armed force members) than the binary logistic regression or Chi-square (likelihood ratio) corresponding culture growth results. The DST results statistics were used to assess the possible risk factors asso- showed that 7(1.8%) specimens identified as MDR-TB ciated with the dependent variable MDR-TB and the inde- cases and 374 (98.2%) specimens non-MDR-TB cases. pendent variables such as sex, age, body mass index, The number of civilian and armed force members with patient categories, TB contact history and HIV infection. MDR-TB was identified in 2 (0.5%) and 5 (1.3%) pa- Two-sided p-values were considered significant when the tients, respectively in which all patients were previously value was less than 0.05. treated TB case (Table 2). There were no new MDR-TB cases identified, rather all MDR-TB patients have been Results found to be a failure (n = 1) and relapse (n = 6) cases Demography, culture and drug susceptibility tests (Table 2). As shown in Table 1, a total of 389 clinically diagnosed In AFRTH, all smear positive (n = 252) and negative TB patients were enrolled in AFRTH, of which 98% (n = 129) patients were treated with first-line TB drugs. cases were included in this study. Eight (2.0%) cases Except for 97 (25.5%) cases that have been transferred were excluded for MTB culture growth, microscopic out (results unknown), most (74.5%) TB patient out- smear observation and drug sensitivity tests due to comes were known. Most of the TB patients completed incomplete demography data (n = 5) and contamination (56.7%) the treatment, while 12.6, 3.4 and 1.8% were a (n = 3). The new and retreatment TB cases included cure, dead and failure cases, respectively. All the dead were found 355 (93.2%) and 26 (6.8%), respectively. cases (n = 13) were newly diagnosed patients which were Based on the category of patients registered in AFRTH, identified from active armed force members (n = 11) and active armed force, pension and civilians were found 216 civilian patients (n = 2). Interestingly, in the current (56.7%), 35 (9.2) and 130 (34.1%), respectively. study there was no defaulter treatment outcome seen As shown in Table 2, the proportion of men and either in civilian or armed force patients (Table 2). Com- women patients were found 273 (71.7%) and 108 pared with Ethiopian national TB treatment success rate (28.3%), respectively resulting male to female ratio to be (84.0%) [1], the current study treatment success rate 2.5 to 1. The age of the study participants varies from 18 (69.3%) has been found lower due to most of the transfer to 96 years with a median age of 34 years. The mean age out cases (25.5%), which is expected from AFRTH that of the patients was 36.76 ± 13.84 years, of which 288 accepts referred patients from all secondary level (75.6%) patients were in the age range of 18–45 years (Eastern, Central, North and South-western) command (most in the active armed force). referral hospitals located all over the country. Among 381 TB suspected patients, 26 (6.8%) patients Although all (n = 381) TB patients requested to give have TB contact history, particularly attendants from the blood for HIV test, most (n = 355) accepted the offer, armed force was higher (n = 20). Culture growth on LJ particularly all the pension attendants (Table 2). How- media was observed from 297 (77.9%) specimens. The ever, 16 (4.2%) civilian patients and 10 (2.6%) active pension sputum samples almost all (97.1%) found cul- armed force members rejected the offer. Among 114 ture positive. However, in the active armed force and civilians, 206 active and 35 pension TB patients who civilians specimens, the culture positive results were accepted the HIV test, respectively 9, 15 and 10 samples below 80%. Compared with culture positive samples, were identified HIV positive. Among HIV test positive overall 66.1% (n = 252) of microscopic smear TB positive (n = 34) TB patients, 28 (82.4%) patients started taking Table 1 Classification of cases included from new and TB-retreatment cases Classification Total-patients TB-new patients TB-previously treated patients Number % Number % Number % Total TB-patients 389 100 362 100 27 100 TB-patients excluded 8 2.0 7 1.9 1 3.7 TB-patients included 381 98.0 355 98.1 26 96.3 Category of attendants Armed force-Active 216 56.7 203 57.2 13 50.0 Armed force-Pension 35 9.2 26 7.3 9 34.6 Civil 130 34.1 126 35.5 4 15.4 Demile et al. BMC Infectious Diseases (2018) 18:249 Page 5 of 10 Table 2 General demographic and clinical findings of civilian and armed force patients in AFRTH Variables Total cases Civilian Armed force members (n = 381) (n = 130) Active Pension (n = 216) (n = 35) No % No % No % No % Sex Female 108 28.3 63 48.5 42 19.4 4 11.4 Male 273 71.7 67 51.5 174 80.6 31 88.6 Age (year) 18–44 288 75.6 96 73.8 192 88.9 0 0 ≥ 45 93 24.4 34 26.2 24 11.1 35 100 Body mass index (kg/m ) < 18.5 39 10.2 15 11.5 22 10.2 2 5.7 18.5–25 217 57.0 67 51.5 129 59.7 21 60.0 > 25 125 32.8 48 37.0 65 30.1 12 34.3 History of TB contact Yes 26 6.8 6 4.6 15 6.9 5 14.3 No 355 93.2 124 95.4 201 93.1 30 85.7 Culture growth on LJ media Positive 297 77.9 93 71.5 170 78.7 34 97.1 Negative 84 22.1 37 28.5 46 21.3 1 2.9 Microscopic smear observation Positive 252 66.1 90 69.2 139 64.4 23 65.7 Negative 129 33.9 40 30.8 77 35.6 12 34.3 Drug susceptibility testing MDR-TB 7 1.8 2 1.5 2 0.9 3 8.6 Non-MDR-TB 374 98.2 128 98.5 214 99.1 32 91.4 TB-patient categories at start New 355 93.2 126 97.0 203 94.0 26 74.2 Relapse 6 1.6 2 1.5 7 3.2 7 20.0 Failure 1 0.3 0 0.0 1 0.5 0 0.0 Return after default 2 0.6 0 0.0 1 0.5 1 2.9 Others 17 4.3 2 1.5 4 1.8 1 2.9 TB-treatment outcome Complete 216 56.7 69 53.1 121 56.0 26 74.3 Cure 48 12.6 5 3.8 41 19.0 2 5.7 Dead 13 3.4 2 1.5 11 5.1 0 0 Failure 7 1.8 1 0.8 1 0.5 5 14.3 Transfer out 97 25.5 53 40.8 42 19.4 2 5.7 HIV result Positive 34 8.9 9 6.9 15 7.0 10 28.6 Negative 321 84.3 105 80.8 191 88.4 25 71.4 Not tested 26 6.8 16 12.3 10 4.6 0 0 Demile et al. BMC Infectious Diseases (2018) 18:249 Page 6 of 10 Table 2 General demographic and clinical findings of civilian and armed force patients in AFRTH (Continued) Variables Total cases Civilian Armed force members (n = 381) (n = 130) Active Pension (n = 216) (n = 35) No % No % No % No % Antiretroviral therapy status ART started 28 7.4 8 6.1 12 5.6 8 22.9 ART not started 6 1.6 1 0.8 3 1.4 2 5.7 HIV negative 321 84.2 105 80.8 191 88.4 25 71.4 HIV not tested 26 6.8 16 12.3 10 4.6 0 0 antiretroviral therapy (ART). However, one civilian, p = 0.546), body mass index (OR = 0.6–3.4; 95% CI = 0.1– three active military and two pension attendants didn’t 57.2; p =0.402–0.581) and HIV infection (OR = 13.0; 95% start the ART drug (Table 2). CI = 0.7–227.8; p = 0.079) were not associated with MDR-TB in civilian patients. Multidrug-resistant tuberculosis risk factors The relationship between individual exposure variables Discussion (category of attendants, gender, age, body mass index, TB remains the major global health problem which TB contact history and HIV status) and the dependent ranked the 9th leading cause of death worldwide [1]. variables (MDR-TB status) were shown in Tables 3 and 4. Currently, the emergency of MDR-TB is also the main In general, the category of attendants was the predicting public health problem in both developing and developed factor (p = 0.029) for MDR-TB in AFRTH patients countries. Globally, the prevalence of MDR-TB case (Table 3). Compared with active armed force members among the newly and previously treated TB patients has (2/216 = 0.9%) and civilian attendants (2/130 = 1.5%), been found 3.5 and 20.5%, respectively [1]. The same pensions have shown significant (p = 0.013) higher WHO report also indicated that 7 African countries are (3/35 = 8.6%) value of MDR-TB positive results. The listed out of 30 high burden MD-RTB countries in the occurrence of lower MDR-TB positive than MDR-TB world with the overall prevalence of 2.7% new and 14.0% negative results was also found a strong predicting factor previously treated cases [1]. (p = 0.007) for the category of attendants. In the current study, the overall prevalence of As shown in Table 4, HIV infection result (OR = 14.6; MDR-TB in armed force and civilian patients were iden- 95% CI = 2.3–92.1; p = 0.004) and TB contact history tified 1.8%, in which all have been found previously TB (OR = 57.5; 95% CI = 6.1–545.1, p = 0.0004) were treated patients. Although published data is deficient to significantly associated with MDR-TB in armed force compare this study with a similar setting (armed force + members. However, sex (OR = 1.0; 95% CI = 1.0–1.1; civilian), there is limited information reported in some p = 0.153), age (OR = 5.1; 95% CI = 0.8–31.2; p =0.079) countries focus on armed force patients (Table 5). Most and body mass index (OR = 1.0–6.9; 95% CI = 0.6–79.8; of the studies found in the literature were civilian pa- p = 0.122–0.983) were not the predicting factor for tients carried out in civilian hospital. The prevalence re- MDR-TB in armed force members. ports were in agreement with our study, particularly In civilian patients, TB contact history has been found studies conducted in Indian (1.2%) and Turkey (2.7%) strong predicting factor for MDR-TB (OR = 0.04, 95% that focus on armed force patients (Table 5). A study on CI = 0.02–0.8; p = 0.031). However, sex (OR = 1.1; 95% USA military population also stated that the incidence CI = 0.1–17.4; p =0.965), age (OR =2.4; 95% CI = 0.14–38.9; of TB disease identified in military population has been Table 3 Association of MDR-TB value in armed force and civilian TB patients in AFRTH Category (p = 0.029) Total MDR-TB OR (95% CI) p-value + – Active-Armed force 216 2 214 Ref Ref Pension-Armed force 35 3 32 10.0 (1.6–62.4) 0.013 Civilian 130 2 128 1.7 (0.2–12.0) 0.610 p-value – 0.007 (χ = 9.86) –– OR Odds ratio, CI Confident interval, Ref Reference for binary logistic value, MDR-TB Multidrug resistant tuberculosis + Positive, − Negative, χ Chi-square Demile et al. BMC Infectious Diseases (2018) 18:249 Page 7 of 10 Table 4 Factors associated with MDR-TB in AFRTH patients (armed force and civilian) Variables Armed force members Civilian MDR-TB OR (95% CI) p-value MDR-TB OR (95% CI) p-value + – + – Sex Female 1 45 1.0 (1.0–1.1) 0.153 1 62 1.1 (0.1–17.4) 0.965 Male 4 201 Ref Ref 1 66 Ref Ref Age (year) 18–44 2 190 Ref Ref 1 90 Ref Ref ≥ 45 3 56 5.1 (0.8–31.2) 0.079 1 38 2.4 (0.14–38.9) 0.546 Body mass index (kg/m ) < 18.5 2 22 6.9 (0.6–79.8) 0.122 1 15 3.4 (0.2–57.2) 0.402 18.5–25 2 148 1.0 (0.9–11.5) 0.983 0 67 0.6 (0.1–4.5) 0.581 > 25 1 76 Ref Ref 1 48 Ref Ref History of TB contact No 1 19 Ref Ref 1 123 Ref Ref Yes 4 227 57.5 (6.1–545.1) 0.0004 1 5 0.04 (0.02–0.8) 0.031 HIV result Negative 2 214 Ref Ref 1 104 Ref Positive 3 22 14.6 (2.3–92.1) 0.004 1 8 13.0 (0.7–227.8) 0.079 OR Odds ratio, CI Confident interval, Ref Reference + Positive, − Negative 16 from civil and 10 from armed force excluded Table 5 Comparing MDR-TB in this study with other previous findings Study area Study population Sample size (Number) MDR-TB prevalence (%) Reference TH in Addis Ababa, Ethiopia Armed force members + civilian 381 1.8 This study Chest hospital in Istanbul, Turkey Armed force members 365 2.7 [32] Northwest, India Armed force members 172 1.2 [27] Tertiary chest hospital, India Armed force members 1120 4.2 [30] AF capital hospital, Korea Armed force members (young) 198 8.1 [8] Eastern, Ethiopia Civilian 357 1.1 [16] Northwest, Ethiopia Civilian 124 5.7 [21] Northeast, China Civilian 205 6.8 [33] Southeast, Nigeria Civilian 180 7.7 [34] Harare, Zimbabwe Civilian 213 12.0 [28] Sinaloa, Mexico Civilian 671 17.9 [35] Four regions, Swaziland Civilian 633 19.3 [29] Four sentinel sites, Georgia Civilian 931 28.1 [36] Kassala, Sudan Civilian 60 30.0 [37] Oromia region, Ethiopia Civilian 265 33.2 [22] Amara region, Ethiopia Civilian 413 36.3 [20] Samara region, Russia Civilian + prisoner 600 45.5 [38] TH Tertiary hospital, AF Armed force, AFRTH Armed force referral and teaching hospital Demile et al. BMC Infectious Diseases (2018) 18:249 Page 8 of 10 found eight times lower (0.4 per 100,000) than the over- variation among active armed force and civilian attendants all USA population (3.0 per 100,000) which supports the suggested that the later went to a tertiary level AFRTH for current study recorded lower MDR-TB infection [2]. seeking better medical service that has been offered for Compared with the current study, relatively higher limited private wing clients most probably in a better eco- MDR-TB prevalence result also reported in Korean nomic status. Previous studies showed that annual income young armed force patients (Table 5). Compared with status has been found a significant risk factor for Ethiopian overall MDR-TB reported data (2.7% in newly MDR-TB prevalence [15, 25]. The statistical significance and 14.0% in previously treated patients), the current difference observed among pension and active military MDR-TB prevalence result observed in AFRH is also members were also most probably due to living environ- found much smaller [1]. ment/lifestyle and age of the patients. For example, health Except Seyoum et al. [16] reported lower (1.1%) education (one time/week) and sanitation (two times/ MDR-TB prevalence, several other studies carried out in week) programs have been designed and implemented in Ethiopia using civilians as a study participant was active military societies that might help to reduce M. reported a higher result of MDR-TB results (Table 5). tuberculosis infection that aggravated due to poor hygiene For instance, using civilian patients the prevalence of and ventilation [15, 25]. Moreover, the early treatment MDR-TB was 36.3% in Amara [20] and 33.2% in Oromia made in active military society without any cost from the Regions [22] of Ethiopia. Compared with other countries patient side might probably contribute to reducing the study on MDR-TB prevalence using civilian society spread of drug-resistant TB in the community [26]. It is (Table 5), the current study also much lower than re- also clear that pension attendant is expected to have a ports from Georgia (28.1%), Eastern Sudan (30.0%), high probability of developing MDR-TB than active Swaziland (19.3%), Zimbabwe (12.0%), Samara in Russia military staff which is related to advancement in age [1]. (45.5%) and Sinaloa in Mexico (17.9%). Although not statistically significant (p = 0.079 and 0.546), The lower MDR-TB prevalence reported in this study advancement in age has been found 5 and 2 times more primarily due to the variations in the selection of patient likely at risk for MDR-TB than younger age in armed force groups studied. In the present study, the subjects were and civilian patients, respectively (Table 4). Moreover, civilian and armed force members. The armed force pension attendants’ loss most of the active military privi- members were non-referred (living in Addis Ababa) and leges (such as health education, sanitation, early treatment referred cases from various secondary command referral and follow-up) which might enhance the probability of hospitals which are located in the different geographical pension attendants contracted with TB bacteria that resist location of the country. This makes the current study drug [11, 15, 25]. unique from surveys carried out by other workers mostly In this study, history of contact with TB patient has been covering a particular geographical region using civilian found the predicting factor of MDR-TB for both armed subjects. The variation might also due to sample size, force members (p = 0.0004) and civilian (p =0.031) pa- time of the study, access to health care facilities, and ef- tients. When all cases (n = 381) merged together and fectiveness of TB control programs. Compared to a re- analyzed, pension (OR = 3.4; 95% CI = 1.0–12.1) and mote area of Ethiopian health centers which deal with civilian attendant (OR = 1.5; 95% CI = 0.6–4.1) have a civilian population, there is an effective functioning of much higher risk of TB infected person contact than the TB control program in military societies. The regular active military staff which presumably suggested that the supplies of anti-tuberculosis drugs, well-organized pa- TB control is better managed in active military society tient diagnosis, treatment follow-up and good patient through regular education about communicable and adherence are effectively implemented in armed forces non-communicable diseases, and sanitation programs. Of which presumably contribute to the lower prevalence of course, M. tuberculosis is transmitted via close contact MDR-TB in the current study. Indeed, this has been well with an infected individual who is actively spreading the reflected in the patient categories which include the ci- bacteria through coughing [1, 2]. Once inhaled, the vilian, pension and active armed members (Table 3). infection is established with or without a visible primary With analysis of binary logistic regression model, the lung lesion; lymphatic and hematogenous spread usually category of attendants showed a statistically significant dif- follows within 3 weeks of infection [2]. This study is in ference with MDR-TB, particularly pension attendants agreement with the study in USA military that mentioned were ten times more likely at risk for MDR-TB (OR = 10.0; higher TB risk among service members who may be 95% CI = 1.6–62.40; p = 0.013) than active armed force exposed to infected persons, such as personnel involved in members. However, the active military attendants and humanitarian assistance and health care operations serv- civilian patients didn’t show statistically significant ing local, high-risk populations [2]. (p = 0.610) difference for MDR-TB positive result. Al- Among 381 TB suspected patients, the new and though it needs further investigation, the insignificant retreatment TB cases that showed growth on the media Demile et al. BMC Infectious Diseases (2018) 18:249 Page 9 of 10 were found 71.1 and 6.8%, respectively. However, 11.8% MDR-TB predicting factors such as annual income, size of of culture positive samples did not found smear positive. living space, family history, history of prison and others The growth of M. tuberculosis on LJ media in cases of were lacking. The clinical treatment outcome of referred smear negative for acid-fast bacilli is a known outpatients to secondary level command hospitals was not phenomenon as 10 bacilli per mL of sputum are re- identified. Follow-up time was recorded to the completion quired for the organism to be seen on light microscope of treatment at AFRTH. Although this time frame is suffi- but culture may show growth [27]. cient for documenting surveillance-based treatment out- In the current study, the number of HIV positive and comes, it may not be sufficient to assess long-term clinical negative patients were identified 34 (9.6%) and 321 (90.4%) outcomes. It was also difficult to distinguish the referred for all patients tested, respectively. Compared with other patient where they came (which military command hos- studies [28, 29] in Swaziland (22.6% = 102/451) and pital) that might help to identify which geographical loca- Zimbabwe (74.0% = 157/211), HIV positive patients are tion contributed more to MDR-TB case and plan better relatively lower in this study (25/241 in armed force mem- management. Despite these limitations, the current study bers and 9/114 in civilian patients). However, the HIV provides information about the MDR-TB prevalence and positive results were found a significant predicting factor associated factors in AFRTH where data has not been pre- for MDR-TB (OR = 14.6; 95% CI = 2.3–92.1; p = 0.004) in viously published. Moreover, comparative studies among armed force members. Particularly, the infection is armed force members (active and pension) and civilian magnificent in pension attendants (10 out of 25) (Table 3), patients also unique to this study to provide information suggested that during the study period the pension staff about MDR-TB. with HIV might frequently register at AFRTH for medical service which is provided free as a staff member. Moreover, Conclusions pension staffs are at the older age in which much of the MDR-TB is a major public health problem and mainly physiological activities are downgraded and contributed to affects economically productive age group of the popula- the co-infection of HIV-TB under immunocompromised tion. Compared with many civilian hospitals, the preva- conditions [28, 29]. Statistical analysis also showed that lence of MDR-TB in AFRTH was found low. This shows there was a positive significant correlation between that TB control management is well implemented in MDR-TB and HIV co-infection (r = 0.229; p < 0.01). armed society. In general, this study might be scale-up In the current study, the status of 284 (74.5%) patients and applicable all over in Ethiopia and elsewhere in the was identified while 97 (25.5%) patients transferred out world, where information is scant (armed force society) to and status unknown. Among the status identified pa- improve the availability and quality of MDR-TB service. tients, the treatment success rate was found 93.0%, high- Abbreviations est in active armed force followed by pension and AF: Armed force; AFRTH: Armed force referral and teaching hospital; civilian patients (Table 2). The higher rate of treatment ART: Antiretroviral therapy; CI: Confidence interval; DST: Drug susceptibility testing; HIV: Human immunodeficiency virus; HMD: Health main directorate; success in armed force patients most probably indicates LJ: Lowenstein Jensen; MDR-TB: Multidrug-resistant tuberculosis; OR: Odds that there is a good efficacy of the standard treatment ratio; Ref: Reference; SPSS: Statistical package for the social sciences; regimen in armed force society. The adequate follow-up, TB: Tuberculosis; TH: Tertiary hospital; WHO: World Health Organization early identification and management of adverse drug Acknowledgments reactions had been mentioned the key to favorable The authors would like to thank Armed Force Health Main Directorate giving treatment outcome success [26, 30]. Drug sensitive permission to carry out this research. We would also like to extend our appreciation to Armed Force Referral and Teaching Hospital staff members pulmonary TB is generally treated with four active drugs for their cooperation. isoniazid, rifampin, pyrazinamide and ethambutol [17]. These drugs are continued for the first 2 months of ther- Availability of data and materials All data analyzed during this study are included in this published article. Raw apy and are subsequently followed by at least 4 mo of data is also available from the corresponding author and will be shared two drugs (most commonly with isoniazid and rifampin). upon reasonable request. There was no default cases observed in the current Authors’ contributions study. However, 7.0% treatment failure rate was attributed BD participated in the design of this study, collect data and draft the due to death and failure cases. Similar to this study, 9.0% manuscript. AZ, HS, and SX participated in revising the manuscript. AG failure rate (dead and failure) was recorded in Germany participated in the design of this study, wrote the manuscript, interpreting the results and discussion. All authors have read and approved the final manuscript. [31]. However, higher treatment failure rate was observed in other studies in civilian hospitals [20, 26, 29], Ethics approval and consent to participate suggesting that TB drug administration in AFRTH is The current investigation followed the tenets of the Declaration of Helsinki and ethical clearance was obtained from Health Main Directorate in Armed implemented efficiently. Force Referral and Teaching Hospital. Before the investigation was Our retrospective study has limitations. Since reports performed, written informed consent was obtained from all study were not designed for study purposes, some demographic participants about their information to be used for research purpose. Demile et al. BMC Infectious Diseases (2018) 18:249 Page 10 of 10 Competing interests 18. Migliori GB, Dheda K, Centis R, Mwaba P, Bates M, O ’ Grady J, Hoelscher M, The authors declare that they have no competing interests. Zumla A. Review of multidrug resistant and extensively drug resistant TB: global perspectives with a focus on sub-Saharan Africa. Tropical Med Int Health. 2010;15:1052–66. 19. Ben AY, Nemser B, Singh A, Sankin A, Schluger N. Under reported threat of Publisher’sNote multidrug-resistant tuberculosis in Africa. Emerg Infect Dis. 2008;14:1345–52. Springer Nature remains neutral with regard to jurisdictional claims in 20. 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Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis 2014. Version March 2010; available at http://apps.who.int/iris/bitstream/10665/ 75146/1/9789241548441_eng.pdf. Accessed 20 May 2018. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Infectious Diseases Springer Journals

Risk factors associated with multidrug-resistant tuberculosis (MDR-TB) in a tertiary armed force referral and teaching hospital, Ethiopia

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Abstract

Background: Ethiopia is one of the world health organization defined higher tuberculosis (TB) burden countries where the disease remains a massive public health threat. This study aimed to identify the prevalence and associated factors of multidrug-resistant tuberculosis (MDR-TB) using all armed force and civilian TB attendants in a tertiary level armed force hospital, where data for MDR-TB are previously unpublished. Methods: Cross-sectional study was conducted from September 2014 to August 2015 in a tertiary level Armed Force Referral and Teaching Hospital (AFRTH), Ethiopia. Armed force members (n = 251) and civilians (n = 130) which has been undergone TB diagnosis at AFRTH were included. All the specimens collected were subjected to microscopic smear observation, culture growth and drug susceptibility testing. Data were analyzed using statistical package for social sciences following binary logistic regression and Chi-square. P-values < 0.05 were considered statistically significant. Results: Among 381 TB patients, 355 (93.2%) new and 26 (6.8%) retreatment cases were identified. Culture and smear positive TB cases were identified in 297 (77.9%) and 252 (66.1%) patients, respectively. The overall prevalence of MDR-TB in AFRTH was found 1.8% (1.3% for armed force members and 0.5% for civilian patients) all of which were previously TB treated cases. The entire treatment success rates were 92.6% achieved highest in the armed force (active and pension) than the civilian patients. The failure and dead cases were also found 2.5 and 4.6%, respectively. Using bivariate analysis, category of attendants and TB contact history were strong predictors of MDR-TB in armed force and civilian patients. Moreover, human immunodeficiency virus (HIV) infection also identified a significant (OR = 14.6; 95% CI = 2.3–92.1; p = 0.004) predicting factor for MDR-TB in armed force members. However, sex, age and body mass index were not associated factor for MDR-TB. Conclusions: In AFRTH, lower prevalence of MDR-TB was identified in armed force and civilian patients that were significantly associated with category of attendants, HIV infection and TB contact history. Considering armed force society as one segment of population significantly helps to plan a better MDR-TB control management, especially for countries classified as TB high burden country. Keywords: Tuberculosis, Armed force, Ethiopia, Drug susceptibility, Risk factors * Correspondence: awokeguadie@gmail.com State Key Laboratory of Pollution Control and Resource Reuse, College of Environmental Science and Engineering, Tongji University, Shanghai, China Department of Biology, College of Natural Sciences, Arba Minch University, P.O. Box 21, Arba Minch, Ethiopia Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This 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. Demile et al. BMC Infectious Diseases (2018) 18:249 Page 2 of 10 Background drug, increasing cost of drug and physician errors) and in- Tuberculosis (TB) is an infectious disease caused by adequate adherence (such as poor compliance, alcoholism, Mycobacterium tuberculosis (M. tuberculosis) complex drug addiction, length of treatment and adverse drug which usually affects the lung [1]. The bacteria are trans- reactions) have been also identified as a drug resistance mitted via close contact with an infected individual who enhancing mechanisms by creating a selective pressure for is actively spreading the bacteria through coughing [2]. a rapid evolution of M. tuberculosis [14–17]. Once inhaled, the infection remains latent for decades in Globally, 3.5% of new and 20.5% of previously treated 90 to 95% healthy adult [1–3]. However, illness of latent TB patients were estimated to have had MDR-TB [1]. TB manifested only when the bacteria become active. Sub-Saharan Africa represents 14% of the global burden There are many factors that contribute the latent TB of new MDR-TB cases [18]. World Health Organization bacteria become active including human immunodefi- in 2016 listed Ethiopia 8th out of 30 high MDR-TB bur- ciency virus (HIV), older age, diabetics, close contact den countries in the world with a prevalence of 2.7% with an active case of TB disease and other immuno- (1.5–4.0) in newly and 14.0% (3.6–25.0) in previously compromising illness conditions [1, 4]. treated TB patients. Like Ethiopia which is listed 3rd, Although TB is an old disease with many efforts to other six countries in Africa including (new/retreatment treat and control, still it remains the main cause of mor- % accordingly) Angola (2.6/18%), DR Congo (2.2/17%), bidity for millions of people each year [1, 3]. According Kenya (1.3/9.4%), Nigeria (4.3/25%), Somalia (8.7/47%) to World Health Organization (WHO) estimates showed and Zimbabwe (4.6/14%) also listed among the 30 high that there were almost 9.6 (5.4 men, 3.2 women and 1.0 MDR-TB burden countries in the world [1]. Although children) million new TB cases globally in 2014, of MDR-TB is a growing concern in Africa where limited which 1.5 million cases were accounted TB deaths [5]. resource exists, it is largely under-reported [18, 19]. In The same WHO report also showed that 86% of TB in- Ethiopia, many of the MDR-TB patients are remain undiag- fection is from South-East Asia and Western Pacific nosed due to the low socioeconomic status of the popula- (58%) and African (28%) regions. The presence of rela- tion, lack of awareness and inaccessibility of health service. tively higher HIV patient in these regions significantly For instance, WHO in 2012 estimated that the number of contributed an increased incidence of TB [6]. Ethiopia is patients in Ethiopia tested for MDR-TB was < 1% of new one of the WHO defined higher TB burden countries and < 4% of retreatment cases [5]. where the disease remains a massive public health threat There are small numbers of MDR-TB studies in differ- and an economic burden. World Health Organization in ent regions of Ethiopia [16, 20–22], however, most of 2016 listed Ethiopia 10th out of the 30 high TB priority these surveys were restricted only to civilian patients countries in the globe [1]. and civilian hospitals. To the best of our knowledge, Based on WHO recommended six-month standard there is no published information about the status of TB course of medication, several countries treat TB disease and MDR-TB concerning armed force as one segment of using four first-line (rifampin, isoniazid, pyrazinamide the population in Ethiopia. This condition significantly and ethambutol) anti-TB drugs [2, 7, 8]. When M. tuber- compromises the MDR-TB control efforts. Therefore, culosis becomes resistant to treatment with at least the this study has been designed to evaluate the prevalence two first-line drugs (i.e, isoniazid and rifampin), the con- and risk factors of MDR-TB using armed force and civil- dition is known as multidrug-resistant tuberculosis ian patients in a tertiary level Armed Force Referral and (MDR-TB) [1, 3, 9]. Previous studies mentioned that M. Teaching Hospital (AFRTH) Addis Ababa, Ethiopia. The tuberculosis develops various drug-resistance mechanisms subjects were from Ministry of Defense members (active by using its special cellular structure and metabolic system military and pension) and civilian clients which have got [9, 10]. For instance, the unique structures like mycolic service from AFRTH. acid (as part of the cell wall) and trans-membrane protein help the M. tuberculosis to restrict entry of drug molecules Methods to the cell, and to pump out antibiotics from the cell, re- Study area spectively [10, 11]. The M. tuberculosis also utilizes differ- The study was conducted at AFRTH which is located in ent enzymatic strategies to alter the structure of drug Addis Ababa, the capital city of Ethiopia. It is the only synthesis target sites (such as ribosomes and deoxyribo- referral and teaching military hospital of the country at nucleic acid) and thereby avoid the action of antibiotics the rank of tertiary level. It is organized under Health [12]. Moreover, there are also reports that mentioned the Main Directorate (HMD), Ministry of Defense. ability of M. tuberculosis directly modify the anti-TB drug Armed Force Referral and Teaching Hospital provides into another form which in turn leads to inactivate the tar- medical services to members of the Ethiopian defense get drug compound action designed for its specific cellular forces. It accepts referral case from all secondary level site [10–13]. Inadequate treatment (due to shortage of (Eastern, Central, North and South-western) command Demile et al. BMC Infectious Diseases (2018) 18:249 Page 3 of 10 referral hospitals located all over the country. In AFRTH, drug-resistance in TB [23]. In this study, all patients there is also a limited ward allocated to give service to ci- who diagnosed TB in AFRTH between September 2014 vilian clients. Although the AFRTH provides service for a to August 2015 and whose information found to be large number of TB patients per year, however, the data complete and qualify the NTLCP guidelines had been included in this study were only collected from those pa- included. The study subjects include direct register pa- tients who had complete information registered according tients at AFRTH (armed force members and civilians) to National Tuberculosis and Leprosy Control Program and those referred from secondary level armed hospitals (NTLCP) guideline of Ethiopia [7] adopted from WHO. (armed force members only) located all over the country. As a result, our study population especially the armed Definition of TB cases and treatment outcome force members appears to be a representative sample of According to the standard definitions of NTLCP guide- all military members at risk for TB that are located all line of Ethiopia [7], the following case and treatment over Ethiopia. outcome definitions were used in the current study. The In AFRTH, the suspected TB patients were first identi- following are case definitions: (i) new case is used if a fied through examining signs and symptoms, chest x-ray patient who never had treatment for TB or has been on and prior history of TB. Although a large number of pa- previous anti-TB treatment for less than 4 wk in the tients had been registered in the AFRTH-TB Clinic, those past, (ii) relapse if a patient declared cured or whose who failed to qualify the preliminary examination have treatment was completed of any form of TB in the past, not been included in the current study. Among 389 cases but who reports back to the health service and is now qualified for preliminary examination, 8 suspected TB found to be microscopic smear positive or culture posi- cases were also excluded due to incomplete information. tive, (iii) treatment failure if a patient who is smear posi- Demographic data such as gender, age, HIV status, the tive at the end of the fifth month or later, after category of attendants and TB contact history were col- commencing and it also includes a patient who was ini- lected from the patient record books. In addition, routine tially sputum smear negative but who becomes smear data were obtained from AFRTH laboratory reports for positive during treatment, (iv) return after default if a sputum smear microscopy, culture growth and drug sus- patient previously recorded as defaulted from treatment ceptibility testing (DST). The clinical samples were proc- and returns to the health facility with smear positive essed using the N-acetyl-L-cysteine NaOH (NALC-NaOH) sputum, and (v) others if a patient who does not fit in method. The processed samples were suspended in any of the above mentioned categories (e.g, smear 1000 mL neutral sterile phosphate buffer and then 100 mL negative pulmonary TB case who returns after default, of resuspended pellet was inoculated onto Lowenstein– extaplumonary TB case returning after default and pre- Jensen (LJ) medium slants. M. tuberculosis was confirmed viously treated TB patients with an unknown outcome in cultures using measurements of growth rate, colony of that previous treatment). morphology, pigmentation and commercial biochemical According to NTLCP guideline [7], the following treat- tests. The biochemical testing (niacin assay, nitrate reduc- ment outcome definitions were also used in the current tion, and catalase tests) was used to identify the isolated study: (i) cured if patients have finished treatment with Mycobacterium once they were categorized into a prelim- negative bacteriology result at the end of treatment, (ii) inary subgroup based on their growth characteristics [24]. treatment completed if the patient finished treatment, All isolates of M. tuberculosis were subjected to DST using but without bacteriology result at the end of treatment, concentration method. Drug susceptibility testing for the (iii) treatment failure if a TB patient remains smear posi- four (rifampin, isoniazid, streptomycin and ethambutol) tive at 5 mo follow-up despite correct intake of medica- first-line anti-TB drug was performed according to WHO tion, (iv) defaulted treatment if the patients who guidelines [23]. Smear for microscopic examination was interrupted their treatment for two consecutive months also stained using the Ziehl–Neelsen method and results or more than 2 mo after registration, (v) died if the pa- were reported as smear positive and negative. tient died from any cause during the course of treat- The AFRTH laboratory was subjected to quality control ment, (vi) transfer out if the patient treatment result is through WHO guideline [23]. Drug susceptibility testing unknown due to transfer to another health facility, and quality control was done using standard strains of M. (vi) treatment success is used defined as the sum of tuberculosis (H37Rv). All data included here were reported cured and completed treatments. by qualified laboratory technicians and physicians. Study design, data collection and laboratory sputum Statistical analysis sample processing The data were analyzed using Epi Info 6, Excel 2010 and A cross-sectional study was conducted following the statistical package for the social sciences (SPSS) version most recent WHO guidelines for surveillance of 20.0 (IBM, NY, USA). A total of 389 patient information’s Demile et al. BMC Infectious Diseases (2018) 18:249 Page 4 of 10 were initially enter into the data system, however, eight samples were identified which has been relatively lower (2.0%) patients whose information were found to be in all patient groups (69.2% for civilian, 64.4% for active incomplete and excluded during data analysis. Either and 65.7% for pension armed force members) than the binary logistic regression or Chi-square (likelihood ratio) corresponding culture growth results. The DST results statistics were used to assess the possible risk factors asso- showed that 7(1.8%) specimens identified as MDR-TB ciated with the dependent variable MDR-TB and the inde- cases and 374 (98.2%) specimens non-MDR-TB cases. pendent variables such as sex, age, body mass index, The number of civilian and armed force members with patient categories, TB contact history and HIV infection. MDR-TB was identified in 2 (0.5%) and 5 (1.3%) pa- Two-sided p-values were considered significant when the tients, respectively in which all patients were previously value was less than 0.05. treated TB case (Table 2). There were no new MDR-TB cases identified, rather all MDR-TB patients have been Results found to be a failure (n = 1) and relapse (n = 6) cases Demography, culture and drug susceptibility tests (Table 2). As shown in Table 1, a total of 389 clinically diagnosed In AFRTH, all smear positive (n = 252) and negative TB patients were enrolled in AFRTH, of which 98% (n = 129) patients were treated with first-line TB drugs. cases were included in this study. Eight (2.0%) cases Except for 97 (25.5%) cases that have been transferred were excluded for MTB culture growth, microscopic out (results unknown), most (74.5%) TB patient out- smear observation and drug sensitivity tests due to comes were known. Most of the TB patients completed incomplete demography data (n = 5) and contamination (56.7%) the treatment, while 12.6, 3.4 and 1.8% were a (n = 3). The new and retreatment TB cases included cure, dead and failure cases, respectively. All the dead were found 355 (93.2%) and 26 (6.8%), respectively. cases (n = 13) were newly diagnosed patients which were Based on the category of patients registered in AFRTH, identified from active armed force members (n = 11) and active armed force, pension and civilians were found 216 civilian patients (n = 2). Interestingly, in the current (56.7%), 35 (9.2) and 130 (34.1%), respectively. study there was no defaulter treatment outcome seen As shown in Table 2, the proportion of men and either in civilian or armed force patients (Table 2). Com- women patients were found 273 (71.7%) and 108 pared with Ethiopian national TB treatment success rate (28.3%), respectively resulting male to female ratio to be (84.0%) [1], the current study treatment success rate 2.5 to 1. The age of the study participants varies from 18 (69.3%) has been found lower due to most of the transfer to 96 years with a median age of 34 years. The mean age out cases (25.5%), which is expected from AFRTH that of the patients was 36.76 ± 13.84 years, of which 288 accepts referred patients from all secondary level (75.6%) patients were in the age range of 18–45 years (Eastern, Central, North and South-western) command (most in the active armed force). referral hospitals located all over the country. Among 381 TB suspected patients, 26 (6.8%) patients Although all (n = 381) TB patients requested to give have TB contact history, particularly attendants from the blood for HIV test, most (n = 355) accepted the offer, armed force was higher (n = 20). Culture growth on LJ particularly all the pension attendants (Table 2). How- media was observed from 297 (77.9%) specimens. The ever, 16 (4.2%) civilian patients and 10 (2.6%) active pension sputum samples almost all (97.1%) found cul- armed force members rejected the offer. Among 114 ture positive. However, in the active armed force and civilians, 206 active and 35 pension TB patients who civilians specimens, the culture positive results were accepted the HIV test, respectively 9, 15 and 10 samples below 80%. Compared with culture positive samples, were identified HIV positive. Among HIV test positive overall 66.1% (n = 252) of microscopic smear TB positive (n = 34) TB patients, 28 (82.4%) patients started taking Table 1 Classification of cases included from new and TB-retreatment cases Classification Total-patients TB-new patients TB-previously treated patients Number % Number % Number % Total TB-patients 389 100 362 100 27 100 TB-patients excluded 8 2.0 7 1.9 1 3.7 TB-patients included 381 98.0 355 98.1 26 96.3 Category of attendants Armed force-Active 216 56.7 203 57.2 13 50.0 Armed force-Pension 35 9.2 26 7.3 9 34.6 Civil 130 34.1 126 35.5 4 15.4 Demile et al. BMC Infectious Diseases (2018) 18:249 Page 5 of 10 Table 2 General demographic and clinical findings of civilian and armed force patients in AFRTH Variables Total cases Civilian Armed force members (n = 381) (n = 130) Active Pension (n = 216) (n = 35) No % No % No % No % Sex Female 108 28.3 63 48.5 42 19.4 4 11.4 Male 273 71.7 67 51.5 174 80.6 31 88.6 Age (year) 18–44 288 75.6 96 73.8 192 88.9 0 0 ≥ 45 93 24.4 34 26.2 24 11.1 35 100 Body mass index (kg/m ) < 18.5 39 10.2 15 11.5 22 10.2 2 5.7 18.5–25 217 57.0 67 51.5 129 59.7 21 60.0 > 25 125 32.8 48 37.0 65 30.1 12 34.3 History of TB contact Yes 26 6.8 6 4.6 15 6.9 5 14.3 No 355 93.2 124 95.4 201 93.1 30 85.7 Culture growth on LJ media Positive 297 77.9 93 71.5 170 78.7 34 97.1 Negative 84 22.1 37 28.5 46 21.3 1 2.9 Microscopic smear observation Positive 252 66.1 90 69.2 139 64.4 23 65.7 Negative 129 33.9 40 30.8 77 35.6 12 34.3 Drug susceptibility testing MDR-TB 7 1.8 2 1.5 2 0.9 3 8.6 Non-MDR-TB 374 98.2 128 98.5 214 99.1 32 91.4 TB-patient categories at start New 355 93.2 126 97.0 203 94.0 26 74.2 Relapse 6 1.6 2 1.5 7 3.2 7 20.0 Failure 1 0.3 0 0.0 1 0.5 0 0.0 Return after default 2 0.6 0 0.0 1 0.5 1 2.9 Others 17 4.3 2 1.5 4 1.8 1 2.9 TB-treatment outcome Complete 216 56.7 69 53.1 121 56.0 26 74.3 Cure 48 12.6 5 3.8 41 19.0 2 5.7 Dead 13 3.4 2 1.5 11 5.1 0 0 Failure 7 1.8 1 0.8 1 0.5 5 14.3 Transfer out 97 25.5 53 40.8 42 19.4 2 5.7 HIV result Positive 34 8.9 9 6.9 15 7.0 10 28.6 Negative 321 84.3 105 80.8 191 88.4 25 71.4 Not tested 26 6.8 16 12.3 10 4.6 0 0 Demile et al. BMC Infectious Diseases (2018) 18:249 Page 6 of 10 Table 2 General demographic and clinical findings of civilian and armed force patients in AFRTH (Continued) Variables Total cases Civilian Armed force members (n = 381) (n = 130) Active Pension (n = 216) (n = 35) No % No % No % No % Antiretroviral therapy status ART started 28 7.4 8 6.1 12 5.6 8 22.9 ART not started 6 1.6 1 0.8 3 1.4 2 5.7 HIV negative 321 84.2 105 80.8 191 88.4 25 71.4 HIV not tested 26 6.8 16 12.3 10 4.6 0 0 antiretroviral therapy (ART). However, one civilian, p = 0.546), body mass index (OR = 0.6–3.4; 95% CI = 0.1– three active military and two pension attendants didn’t 57.2; p =0.402–0.581) and HIV infection (OR = 13.0; 95% start the ART drug (Table 2). CI = 0.7–227.8; p = 0.079) were not associated with MDR-TB in civilian patients. Multidrug-resistant tuberculosis risk factors The relationship between individual exposure variables Discussion (category of attendants, gender, age, body mass index, TB remains the major global health problem which TB contact history and HIV status) and the dependent ranked the 9th leading cause of death worldwide [1]. variables (MDR-TB status) were shown in Tables 3 and 4. Currently, the emergency of MDR-TB is also the main In general, the category of attendants was the predicting public health problem in both developing and developed factor (p = 0.029) for MDR-TB in AFRTH patients countries. Globally, the prevalence of MDR-TB case (Table 3). Compared with active armed force members among the newly and previously treated TB patients has (2/216 = 0.9%) and civilian attendants (2/130 = 1.5%), been found 3.5 and 20.5%, respectively [1]. The same pensions have shown significant (p = 0.013) higher WHO report also indicated that 7 African countries are (3/35 = 8.6%) value of MDR-TB positive results. The listed out of 30 high burden MD-RTB countries in the occurrence of lower MDR-TB positive than MDR-TB world with the overall prevalence of 2.7% new and 14.0% negative results was also found a strong predicting factor previously treated cases [1]. (p = 0.007) for the category of attendants. In the current study, the overall prevalence of As shown in Table 4, HIV infection result (OR = 14.6; MDR-TB in armed force and civilian patients were iden- 95% CI = 2.3–92.1; p = 0.004) and TB contact history tified 1.8%, in which all have been found previously TB (OR = 57.5; 95% CI = 6.1–545.1, p = 0.0004) were treated patients. Although published data is deficient to significantly associated with MDR-TB in armed force compare this study with a similar setting (armed force + members. However, sex (OR = 1.0; 95% CI = 1.0–1.1; civilian), there is limited information reported in some p = 0.153), age (OR = 5.1; 95% CI = 0.8–31.2; p =0.079) countries focus on armed force patients (Table 5). Most and body mass index (OR = 1.0–6.9; 95% CI = 0.6–79.8; of the studies found in the literature were civilian pa- p = 0.122–0.983) were not the predicting factor for tients carried out in civilian hospital. The prevalence re- MDR-TB in armed force members. ports were in agreement with our study, particularly In civilian patients, TB contact history has been found studies conducted in Indian (1.2%) and Turkey (2.7%) strong predicting factor for MDR-TB (OR = 0.04, 95% that focus on armed force patients (Table 5). A study on CI = 0.02–0.8; p = 0.031). However, sex (OR = 1.1; 95% USA military population also stated that the incidence CI = 0.1–17.4; p =0.965), age (OR =2.4; 95% CI = 0.14–38.9; of TB disease identified in military population has been Table 3 Association of MDR-TB value in armed force and civilian TB patients in AFRTH Category (p = 0.029) Total MDR-TB OR (95% CI) p-value + – Active-Armed force 216 2 214 Ref Ref Pension-Armed force 35 3 32 10.0 (1.6–62.4) 0.013 Civilian 130 2 128 1.7 (0.2–12.0) 0.610 p-value – 0.007 (χ = 9.86) –– OR Odds ratio, CI Confident interval, Ref Reference for binary logistic value, MDR-TB Multidrug resistant tuberculosis + Positive, − Negative, χ Chi-square Demile et al. BMC Infectious Diseases (2018) 18:249 Page 7 of 10 Table 4 Factors associated with MDR-TB in AFRTH patients (armed force and civilian) Variables Armed force members Civilian MDR-TB OR (95% CI) p-value MDR-TB OR (95% CI) p-value + – + – Sex Female 1 45 1.0 (1.0–1.1) 0.153 1 62 1.1 (0.1–17.4) 0.965 Male 4 201 Ref Ref 1 66 Ref Ref Age (year) 18–44 2 190 Ref Ref 1 90 Ref Ref ≥ 45 3 56 5.1 (0.8–31.2) 0.079 1 38 2.4 (0.14–38.9) 0.546 Body mass index (kg/m ) < 18.5 2 22 6.9 (0.6–79.8) 0.122 1 15 3.4 (0.2–57.2) 0.402 18.5–25 2 148 1.0 (0.9–11.5) 0.983 0 67 0.6 (0.1–4.5) 0.581 > 25 1 76 Ref Ref 1 48 Ref Ref History of TB contact No 1 19 Ref Ref 1 123 Ref Ref Yes 4 227 57.5 (6.1–545.1) 0.0004 1 5 0.04 (0.02–0.8) 0.031 HIV result Negative 2 214 Ref Ref 1 104 Ref Positive 3 22 14.6 (2.3–92.1) 0.004 1 8 13.0 (0.7–227.8) 0.079 OR Odds ratio, CI Confident interval, Ref Reference + Positive, − Negative 16 from civil and 10 from armed force excluded Table 5 Comparing MDR-TB in this study with other previous findings Study area Study population Sample size (Number) MDR-TB prevalence (%) Reference TH in Addis Ababa, Ethiopia Armed force members + civilian 381 1.8 This study Chest hospital in Istanbul, Turkey Armed force members 365 2.7 [32] Northwest, India Armed force members 172 1.2 [27] Tertiary chest hospital, India Armed force members 1120 4.2 [30] AF capital hospital, Korea Armed force members (young) 198 8.1 [8] Eastern, Ethiopia Civilian 357 1.1 [16] Northwest, Ethiopia Civilian 124 5.7 [21] Northeast, China Civilian 205 6.8 [33] Southeast, Nigeria Civilian 180 7.7 [34] Harare, Zimbabwe Civilian 213 12.0 [28] Sinaloa, Mexico Civilian 671 17.9 [35] Four regions, Swaziland Civilian 633 19.3 [29] Four sentinel sites, Georgia Civilian 931 28.1 [36] Kassala, Sudan Civilian 60 30.0 [37] Oromia region, Ethiopia Civilian 265 33.2 [22] Amara region, Ethiopia Civilian 413 36.3 [20] Samara region, Russia Civilian + prisoner 600 45.5 [38] TH Tertiary hospital, AF Armed force, AFRTH Armed force referral and teaching hospital Demile et al. BMC Infectious Diseases (2018) 18:249 Page 8 of 10 found eight times lower (0.4 per 100,000) than the over- variation among active armed force and civilian attendants all USA population (3.0 per 100,000) which supports the suggested that the later went to a tertiary level AFRTH for current study recorded lower MDR-TB infection [2]. seeking better medical service that has been offered for Compared with the current study, relatively higher limited private wing clients most probably in a better eco- MDR-TB prevalence result also reported in Korean nomic status. Previous studies showed that annual income young armed force patients (Table 5). Compared with status has been found a significant risk factor for Ethiopian overall MDR-TB reported data (2.7% in newly MDR-TB prevalence [15, 25]. The statistical significance and 14.0% in previously treated patients), the current difference observed among pension and active military MDR-TB prevalence result observed in AFRH is also members were also most probably due to living environ- found much smaller [1]. ment/lifestyle and age of the patients. For example, health Except Seyoum et al. [16] reported lower (1.1%) education (one time/week) and sanitation (two times/ MDR-TB prevalence, several other studies carried out in week) programs have been designed and implemented in Ethiopia using civilians as a study participant was active military societies that might help to reduce M. reported a higher result of MDR-TB results (Table 5). tuberculosis infection that aggravated due to poor hygiene For instance, using civilian patients the prevalence of and ventilation [15, 25]. Moreover, the early treatment MDR-TB was 36.3% in Amara [20] and 33.2% in Oromia made in active military society without any cost from the Regions [22] of Ethiopia. Compared with other countries patient side might probably contribute to reducing the study on MDR-TB prevalence using civilian society spread of drug-resistant TB in the community [26]. It is (Table 5), the current study also much lower than re- also clear that pension attendant is expected to have a ports from Georgia (28.1%), Eastern Sudan (30.0%), high probability of developing MDR-TB than active Swaziland (19.3%), Zimbabwe (12.0%), Samara in Russia military staff which is related to advancement in age [1]. (45.5%) and Sinaloa in Mexico (17.9%). Although not statistically significant (p = 0.079 and 0.546), The lower MDR-TB prevalence reported in this study advancement in age has been found 5 and 2 times more primarily due to the variations in the selection of patient likely at risk for MDR-TB than younger age in armed force groups studied. In the present study, the subjects were and civilian patients, respectively (Table 4). Moreover, civilian and armed force members. The armed force pension attendants’ loss most of the active military privi- members were non-referred (living in Addis Ababa) and leges (such as health education, sanitation, early treatment referred cases from various secondary command referral and follow-up) which might enhance the probability of hospitals which are located in the different geographical pension attendants contracted with TB bacteria that resist location of the country. This makes the current study drug [11, 15, 25]. unique from surveys carried out by other workers mostly In this study, history of contact with TB patient has been covering a particular geographical region using civilian found the predicting factor of MDR-TB for both armed subjects. The variation might also due to sample size, force members (p = 0.0004) and civilian (p =0.031) pa- time of the study, access to health care facilities, and ef- tients. When all cases (n = 381) merged together and fectiveness of TB control programs. Compared to a re- analyzed, pension (OR = 3.4; 95% CI = 1.0–12.1) and mote area of Ethiopian health centers which deal with civilian attendant (OR = 1.5; 95% CI = 0.6–4.1) have a civilian population, there is an effective functioning of much higher risk of TB infected person contact than the TB control program in military societies. The regular active military staff which presumably suggested that the supplies of anti-tuberculosis drugs, well-organized pa- TB control is better managed in active military society tient diagnosis, treatment follow-up and good patient through regular education about communicable and adherence are effectively implemented in armed forces non-communicable diseases, and sanitation programs. Of which presumably contribute to the lower prevalence of course, M. tuberculosis is transmitted via close contact MDR-TB in the current study. Indeed, this has been well with an infected individual who is actively spreading the reflected in the patient categories which include the ci- bacteria through coughing [1, 2]. Once inhaled, the vilian, pension and active armed members (Table 3). infection is established with or without a visible primary With analysis of binary logistic regression model, the lung lesion; lymphatic and hematogenous spread usually category of attendants showed a statistically significant dif- follows within 3 weeks of infection [2]. This study is in ference with MDR-TB, particularly pension attendants agreement with the study in USA military that mentioned were ten times more likely at risk for MDR-TB (OR = 10.0; higher TB risk among service members who may be 95% CI = 1.6–62.40; p = 0.013) than active armed force exposed to infected persons, such as personnel involved in members. However, the active military attendants and humanitarian assistance and health care operations serv- civilian patients didn’t show statistically significant ing local, high-risk populations [2]. (p = 0.610) difference for MDR-TB positive result. Al- Among 381 TB suspected patients, the new and though it needs further investigation, the insignificant retreatment TB cases that showed growth on the media Demile et al. BMC Infectious Diseases (2018) 18:249 Page 9 of 10 were found 71.1 and 6.8%, respectively. However, 11.8% MDR-TB predicting factors such as annual income, size of of culture positive samples did not found smear positive. living space, family history, history of prison and others The growth of M. tuberculosis on LJ media in cases of were lacking. The clinical treatment outcome of referred smear negative for acid-fast bacilli is a known outpatients to secondary level command hospitals was not phenomenon as 10 bacilli per mL of sputum are re- identified. Follow-up time was recorded to the completion quired for the organism to be seen on light microscope of treatment at AFRTH. Although this time frame is suffi- but culture may show growth [27]. cient for documenting surveillance-based treatment out- In the current study, the number of HIV positive and comes, it may not be sufficient to assess long-term clinical negative patients were identified 34 (9.6%) and 321 (90.4%) outcomes. It was also difficult to distinguish the referred for all patients tested, respectively. Compared with other patient where they came (which military command hos- studies [28, 29] in Swaziland (22.6% = 102/451) and pital) that might help to identify which geographical loca- Zimbabwe (74.0% = 157/211), HIV positive patients are tion contributed more to MDR-TB case and plan better relatively lower in this study (25/241 in armed force mem- management. Despite these limitations, the current study bers and 9/114 in civilian patients). However, the HIV provides information about the MDR-TB prevalence and positive results were found a significant predicting factor associated factors in AFRTH where data has not been pre- for MDR-TB (OR = 14.6; 95% CI = 2.3–92.1; p = 0.004) in viously published. Moreover, comparative studies among armed force members. Particularly, the infection is armed force members (active and pension) and civilian magnificent in pension attendants (10 out of 25) (Table 3), patients also unique to this study to provide information suggested that during the study period the pension staff about MDR-TB. with HIV might frequently register at AFRTH for medical service which is provided free as a staff member. Moreover, Conclusions pension staffs are at the older age in which much of the MDR-TB is a major public health problem and mainly physiological activities are downgraded and contributed to affects economically productive age group of the popula- the co-infection of HIV-TB under immunocompromised tion. Compared with many civilian hospitals, the preva- conditions [28, 29]. Statistical analysis also showed that lence of MDR-TB in AFRTH was found low. This shows there was a positive significant correlation between that TB control management is well implemented in MDR-TB and HIV co-infection (r = 0.229; p < 0.01). armed society. In general, this study might be scale-up In the current study, the status of 284 (74.5%) patients and applicable all over in Ethiopia and elsewhere in the was identified while 97 (25.5%) patients transferred out world, where information is scant (armed force society) to and status unknown. Among the status identified pa- improve the availability and quality of MDR-TB service. tients, the treatment success rate was found 93.0%, high- Abbreviations est in active armed force followed by pension and AF: Armed force; AFRTH: Armed force referral and teaching hospital; civilian patients (Table 2). The higher rate of treatment ART: Antiretroviral therapy; CI: Confidence interval; DST: Drug susceptibility testing; HIV: Human immunodeficiency virus; HMD: Health main directorate; success in armed force patients most probably indicates LJ: Lowenstein Jensen; MDR-TB: Multidrug-resistant tuberculosis; OR: Odds that there is a good efficacy of the standard treatment ratio; Ref: Reference; SPSS: Statistical package for the social sciences; regimen in armed force society. The adequate follow-up, TB: Tuberculosis; TH: Tertiary hospital; WHO: World Health Organization early identification and management of adverse drug Acknowledgments reactions had been mentioned the key to favorable The authors would like to thank Armed Force Health Main Directorate giving treatment outcome success [26, 30]. Drug sensitive permission to carry out this research. We would also like to extend our appreciation to Armed Force Referral and Teaching Hospital staff members pulmonary TB is generally treated with four active drugs for their cooperation. isoniazid, rifampin, pyrazinamide and ethambutol [17]. These drugs are continued for the first 2 months of ther- Availability of data and materials All data analyzed during this study are included in this published article. Raw apy and are subsequently followed by at least 4 mo of data is also available from the corresponding author and will be shared two drugs (most commonly with isoniazid and rifampin). upon reasonable request. There was no default cases observed in the current Authors’ contributions study. However, 7.0% treatment failure rate was attributed BD participated in the design of this study, collect data and draft the due to death and failure cases. Similar to this study, 9.0% manuscript. AZ, HS, and SX participated in revising the manuscript. AG failure rate (dead and failure) was recorded in Germany participated in the design of this study, wrote the manuscript, interpreting the results and discussion. All authors have read and approved the final manuscript. [31]. However, higher treatment failure rate was observed in other studies in civilian hospitals [20, 26, 29], Ethics approval and consent to participate suggesting that TB drug administration in AFRTH is The current investigation followed the tenets of the Declaration of Helsinki and ethical clearance was obtained from Health Main Directorate in Armed implemented efficiently. Force Referral and Teaching Hospital. Before the investigation was Our retrospective study has limitations. Since reports performed, written informed consent was obtained from all study were not designed for study purposes, some demographic participants about their information to be used for research purpose. Demile et al. BMC Infectious Diseases (2018) 18:249 Page 10 of 10 Competing interests 18. Migliori GB, Dheda K, Centis R, Mwaba P, Bates M, O ’ Grady J, Hoelscher M, The authors declare that they have no competing interests. Zumla A. Review of multidrug resistant and extensively drug resistant TB: global perspectives with a focus on sub-Saharan Africa. Tropical Med Int Health. 2010;15:1052–66. 19. Ben AY, Nemser B, Singh A, Sankin A, Schluger N. Under reported threat of Publisher’sNote multidrug-resistant tuberculosis in Africa. Emerg Infect Dis. 2008;14:1345–52. Springer Nature remains neutral with regard to jurisdictional claims in 20. 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Journal

BMC Infectious DiseasesSpringer Journals

Published: May 31, 2018

References

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