Background
Tuberculosis (TB) is an infectious disease caused by
Mycobacterium tuberculosis (
M. tuberculosis) complex which usually affects the lung [
1]. The bacteria are transmitted via close contact with an infected individual who is actively spreading the bacteria through coughing [
2]. Once inhaled, the infection remains latent for decades in 90 to 95% healthy adult [
1‐
3]. However, illness of latent TB manifested only when the bacteria become active. There are many factors that contribute the latent TB bacteria become active including human immunodeficiency virus (HIV), older age, diabetics, close contact with an active case of TB disease and other immunocompromising illness conditions [
1,
4].
Although TB is an old disease with many efforts to treat and control, still it remains the main cause of morbidity for millions of people each year [
1,
3]. According to World Health Organization (WHO) estimates showed that there were almost 9.6 (5.4 men, 3.2 women and 1.0 children) million new TB cases globally in 2014, of which 1.5 million cases were accounted TB deaths [
5]. The same WHO report also showed that 86% of TB infection is from South-East Asia and Western Pacific (58%) and African (28%) regions. The presence of relatively higher HIV patient in these regions significantly contributed an increased incidence of TB [
6]. Ethiopia is one of the WHO defined higher TB burden countries where the disease remains a massive public health threat and an economic burden. World Health Organization in 2016 listed Ethiopia 10th out of the 30 high TB priority countries in the globe [
1].
Based on WHO recommended six-month standard course of medication, several countries treat TB disease using four first-line (rifampin, isoniazid, pyrazinamide and ethambutol) anti-TB drugs [
2,
7,
8]. When
M. tuberculosis becomes resistant to treatment with at least the two first-line drugs (i.e, isoniazid and rifampin), the condition is known as multidrug-resistant tuberculosis (MDR-TB) [
1,
3,
9]. Previous studies mentioned that
M. tuberculosis develops various drug-resistance mechanisms by using its special cellular structure and metabolic system [
9,
10]. For instance, the unique structures like mycolic acid (as part of the cell wall) and trans-membrane protein help the
M. tuberculosis to restrict entry of drug molecules to the cell, and to pump out antibiotics from the cell, respectively [
10,
11]. The
M. tuberculosis also utilizes different enzymatic strategies to alter the structure of drug synthesis target sites (such as ribosomes and deoxyribonucleic acid) and thereby avoid the action of antibiotics [
12]. Moreover, there are also reports that mentioned the ability of
M. tuberculosis directly modify the anti-TB drug into another form which in turn leads to inactivate the target drug compound action designed for its specific cellular site [
10‐
13]. Inadequate treatment (due to shortage of drug, increasing cost of drug and physician errors) and inadequate adherence (such as poor compliance, alcoholism, drug addiction, length of treatment and adverse drug reactions) have been also identified as a drug resistance enhancing mechanisms by creating a selective pressure for a rapid evolution of
M. tuberculosis [
14‐
17].
Globally, 3.5% of new and 20.5% of previously treated TB patients were estimated to have had MDR-TB [
1]. Sub-Saharan Africa represents 14% of the global burden of new MDR-TB cases [
18]. World Health Organization in 2016 listed Ethiopia 8th out of 30 high MDR-TB burden countries in the world with a prevalence of 2.7% (1.5–4.0) in newly and 14.0% (3.6–25.0) in previously treated TB patients. Like Ethiopia which is listed 3rd, other six countries in Africa including (new/retreatment % accordingly) Angola (2.6/18%), DR Congo (2.2/17%), Kenya (1.3/9.4%), Nigeria (4.3/25%), Somalia (8.7/47%) and Zimbabwe (4.6/14%) also listed among the 30 high MDR-TB burden countries in the world [
1]. Although MDR-TB is a growing concern in Africa where limited resource exists, it is largely under-reported [
18,
19]. In Ethiopia, many of the MDR-TB patients are remain undiagnosed due to the low socioeconomic status of the population, lack of awareness and inaccessibility of health service. For instance, WHO in 2012 estimated that the number of patients in Ethiopia tested for MDR-TB was < 1% of new and < 4% of retreatment cases [
5].
There are small numbers of MDR-TB studies in different regions of Ethiopia [
16,
20‐
22], however, most of these surveys were restricted only to civilian patients and civilian hospitals. To the best of our knowledge, there is no published information about the status of TB and MDR-TB concerning armed force as one segment of the population in Ethiopia. This condition significantly compromises the MDR-TB control efforts. Therefore, this study has been designed to evaluate the prevalence and risk factors of MDR-TB using armed force and civilian patients in a tertiary level Armed Force Referral and Teaching Hospital (AFRTH) Addis Ababa, Ethiopia. The subjects were from Ministry of Defense members (active military and pension) and civilian clients which have got service from AFRTH.
Discussion
TB remains the major global health problem which ranked the 9th leading cause of death worldwide [
1]. Currently, the emergency of MDR-TB is also the main public health problem in both developing and developed countries. Globally, the prevalence of MDR-TB case among the newly and previously treated TB patients has been found 3.5 and 20.5%, respectively [
1]. The same WHO report also indicated that 7 African countries are listed out of 30 high burden MD-RTB countries in the world with the overall prevalence of 2.7% new and 14.0% previously treated cases [
1].
In the current study, the overall prevalence of MDR-TB in armed force and civilian patients were identified 1.8%, in which all have been found previously TB treated patients. Although published data is deficient to compare this study with a similar setting (armed force + civilian), there is limited information reported in some countries focus on armed force patients (Table
5). Most of the studies found in the literature were civilian patients carried out in civilian hospital. The prevalence reports were in agreement with our study, particularly studies conducted in Indian (1.2%) and Turkey (2.7%) that focus on armed force patients (Table
5). A study on USA military population also stated that the incidence of TB disease identified in military population has been found eight times lower (0.4 per 100,000) than the overall USA population (3.0 per 100,000) which supports the current study recorded lower MDR-TB infection [
2]. Compared with the current study, relatively higher MDR-TB prevalence result also reported in Korean young armed force patients (Table
5). Compared with Ethiopian overall MDR-TB reported data (2.7% in newly and 14.0% in previously treated patients), the current MDR-TB prevalence result observed in AFRH is also found much smaller [
1].
Table 5
Comparing MDR-TB in this study with other previous findings
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 | |
Northwest, India | Armed force members | 172 | 1.2 | |
Tertiary chest hospital, India | Armed force members | 1120 | 4.2 | |
AF capital hospital, Korea | Armed force members (young) | 198 | 8.1 | |
Eastern, Ethiopia | Civilian | 357 | 1.1 | |
Northwest, Ethiopia | Civilian | 124 | 5.7 | |
Northeast, China | Civilian | 205 | 6.8 | |
Southeast, Nigeria | Civilian | 180 | 7.7 | |
Harare, Zimbabwe | Civilian | 213 | 12.0 | |
Sinaloa, Mexico | Civilian | 671 | 17.9 | |
Four regions, Swaziland | Civilian | 633 | 19.3 | |
Four sentinel sites, Georgia | Civilian | 931 | 28.1 | |
Kassala, Sudan | Civilian | 60 | 30.0 | |
Oromia region, Ethiopia | Civilian | 265 | 33.2 | |
Amara region, Ethiopia | Civilian | 413 | 36.3 | |
Samara region, Russia | Civilian + prisoner | 600 | 45.5 | |
Except Seyoum et al. [
16] reported lower (1.1%) MDR-TB prevalence, several other studies carried out in Ethiopia using civilians as a study participant was reported a higher result of MDR-TB results (Table
5). For instance, using civilian patients the prevalence of MDR-TB was 36.3% in Amara [
20] and 33.2% in Oromia Regions [
22] of Ethiopia. Compared with other countries study on MDR-TB prevalence using civilian society (Table
5), the current study also much lower than reports from Georgia (28.1%), Eastern Sudan (30.0%), Swaziland (19.3%), Zimbabwe (12.0%), Samara in Russia (45.5%) and Sinaloa in Mexico (17.9%).
The lower MDR-TB prevalence reported in this study primarily due to the variations in the selection of patient groups studied. In the present study, the subjects were civilian and armed force members. The armed force members were non-referred (living in Addis Ababa) and referred cases from various secondary command referral hospitals which are located in the different geographical location of the country. This makes the current study unique from surveys carried out by other workers mostly covering a particular geographical region using civilian subjects. The variation might also due to sample size, time of the study, access to health care facilities, and effectiveness of TB control programs. Compared to a remote area of Ethiopian health centers which deal with civilian population, there is an effective functioning of TB control program in military societies. The regular supplies of anti-tuberculosis drugs, well-organized patient diagnosis, treatment follow-up and good patient adherence are effectively implemented in armed forces which presumably contribute to the lower prevalence of MDR-TB in the current study. Indeed, this has been well reflected in the patient categories which include the civilian, pension and active armed members (Table
3).
With analysis of binary logistic regression model, the category of attendants showed a statistically significant difference with MDR-TB, particularly pension attendants were ten times more likely at risk for MDR-TB (OR = 10.0; 95% CI = 1.6–62.40;
p = 0.013) than active armed force members. However, the active military attendants and civilian patients didn’t show statistically significant (
p = 0.610) difference for MDR-TB positive result. Although it needs further investigation, the insignificant variation among active armed force and civilian attendants suggested that the later went to a tertiary level AFRTH for seeking better medical service that has been offered for limited private wing clients most probably in a better economic status. Previous studies showed that annual income status has been found a significant risk factor for MDR-TB prevalence [
15,
25]. The statistical significance difference observed among pension and active military members were also most probably due to living environment/lifestyle and age of the patients. For example, health education (one time/week) and sanitation (two times/week) programs have been designed and implemented in active military societies that might help to reduce
M. tuberculosis infection that aggravated due to poor hygiene and ventilation [
15,
25]
. Moreover, the early treatment made in active military society without any cost from the patient side might probably contribute to reducing the spread of drug-resistant TB in the community [
26]. It is also clear that pension attendant is expected to have a high probability of developing MDR-TB than active military staff which is related to advancement in age [
1]. Although not statistically significant (
p = 0.079 and 0.546), advancement in age has been found 5 and 2 times more likely at risk for MDR-TB than younger age in armed force and civilian patients, respectively (Table
4). Moreover, pension attendants’ loss most of the active military privileges (such as health education, sanitation, early treatment and follow-up) which might enhance the probability of pension attendants contracted with TB bacteria that resist drug [
11,
15,
25].
In this study, history of contact with TB patient has been found the predicting factor of MDR-TB for both armed force members (
p = 0.0004) and civilian (
p = 0.031) patients. When all cases (
n = 381) merged together and analyzed, pension (OR = 3.4; 95% CI = 1.0–12.1) and civilian attendant (OR = 1.5; 95% CI = 0.6–4.1) have a much higher risk of TB infected person contact than the active military staff which presumably suggested that the TB control is better managed in active military society through regular education about communicable and non-communicable diseases, and sanitation programs. Of course,
M. tuberculosis is transmitted via close contact with an infected individual who is actively spreading the bacteria through coughing [
1,
2]. Once inhaled, the infection is established with or without a visible primary lung lesion; lymphatic and hematogenous spread usually follows within 3 weeks of infection [
2]. This study is in agreement with the study in USA military that mentioned higher TB risk among service members who may be exposed to infected persons, such as personnel involved in humanitarian assistance and health care operations serving local, high-risk populations [
2].
Among 381 TB suspected patients, the new and retreatment TB cases that showed growth on the media were found 71.1 and 6.8%, respectively. However, 11.8% of culture positive samples did not found smear positive. The growth of
M. tuberculosis on LJ media in cases of smear negative for acid-fast bacilli is a known phenomenon as 10
5 bacilli per mL of sputum are required for the organism to be seen on light microscope but culture may show growth [
27].
In the current study, the number of HIV positive and negative patients were identified 34 (9.6%) and 321 (90.4%) for all patients tested, respectively. Compared with other studies [
28,
29] in Swaziland (22.6% = 102/451) and Zimbabwe (74.0% = 157/211), HIV positive patients are relatively lower in this study (25/241 in armed force members and 9/114 in civilian patients). However, the HIV positive results were found a significant predicting factor for MDR-TB (OR = 14.6; 95% CI = 2.3–92.1;
p = 0.004) in armed force members. Particularly, the infection is magnificent in pension attendants (10 out of 25) (Table
3), suggested that during the study period the pension staff with HIV might frequently register at AFRTH for medical service which is provided free as a staff member. Moreover, pension staffs are at the older age in which much of the physiological activities are downgraded and contributed to the co-infection of HIV-TB under immunocompromised conditions [
28,
29]. Statistical analysis also showed that there was a positive significant correlation between MDR-TB and HIV co-infection (
r = 0.229;
p < 0.01).
In the current study, the status of 284 (74.5%) patients was identified while 97 (25.5%) patients transferred out and status unknown. Among the status identified patients, the treatment success rate was found 93.0%, highest in active armed force followed by pension and civilian patients (Table
2). The higher rate of treatment success in armed force patients most probably indicates that there is a good efficacy of the standard treatment regimen in armed force society. The adequate follow-up, early identification and management of adverse drug reactions had been mentioned the key to favorable treatment outcome success [
26,
30]. Drug sensitive pulmonary TB is generally treated with four active drugs isoniazid, rifampin, pyrazinamide and ethambutol [
17]. These drugs are continued for the first 2 months of therapy and are subsequently followed by at least 4 mo of two drugs (most commonly with isoniazid and rifampin). There was no default cases observed in the current study. However, 7.0% treatment failure rate was attributed due to death and failure cases. Similar to this study, 9.0% failure rate (dead and failure) was recorded in Germany [
31]. However, higher treatment failure rate was observed in other studies in civilian hospitals [
20,
26,
29], suggesting that TB drug administration in AFRTH is implemented efficiently.
Our retrospective study has limitations. Since reports were not designed for study purposes, some demographic MDR-TB predicting factors such as annual income, size of living space, family history, history of prison and others were lacking. The clinical treatment outcome of referred outpatients to secondary level command hospitals was not identified. Follow-up time was recorded to the completion of treatment at AFRTH. Although this time frame is sufficient for documenting surveillance-based treatment outcomes, it may not be sufficient to assess long-term clinical outcomes. It was also difficult to distinguish the referred patient where they came (which military command hospital) that might help to identify which geographical location contributed more to MDR-TB case and plan better management. Despite these limitations, the current study provides information about the MDR-TB prevalence and associated factors in AFRTH where data has not been previously published. Moreover, comparative studies among armed force members (active and pension) and civilian patients also unique to this study to provide information about MDR-TB.