Introduction
Recently, tuberculosis has been recognized as a silent epidemic disease in children [
1]. Of the 10 million estimated new TB cases that occurred in 2021, 1.1 million were children [
2]. Moreover, it has been reported that an estimated 33,000 children developed Multi-drug resistant tuberculosis (MDR-TB) each year across the world [
3]. A 2015 modeling study reported that a high burden of childhood DR-TB was observed in the European and Western Pacific World Health Organization (WHO) regions due to the presence of high proportions of Drug Resistant-Tuberculosis (DR-TB) among the general population in those regions [
4].
Based on the previous survey, Ethiopia was under high MDR-TB burden country (2.7% among new and 14% among previously treated TB cases) [
5]. However, with the current 3rd round DR-TB surveys, the country was excluded from the 30 high MDR-TB burden counties[
6].
In Ethiopia, the burden of childhood TB was estimated 24,000 in 2017 [
7]. However, in the first population-based national tuberculosis prevalence survey of Ethiopia, children were not included due to the technical difficulty of screening and diagnosing TB cases in this population [
5,
8]. Interestingly, after the introduction of GeneXpert MTB/RIF assay (Cepheid, Sunnyvale, CA, USA) in the country, studies have been conducted that show the improvement of TB case and rifampicin resistance tuberculosis cases detection from children with TB [
9‐
11]. Even then, diagnosis of childhood TB is still challenging because of having non-specific symptoms and difficulty in detecting paucibacillary TB in children. As a result, the country recently endorsed Xpert MTB/RIF Ultra since it has a better ability to detect paucibacillary TB compared to GeneXpert MTB/RIF assay [
12].
Ethiopia adopted a national childhood TB roadmap in 2015 following the global childhood TB roadmap to improve case detection and management [
13]. So far, Childhood TB treatment success in Ethiopia ranged from 78.0 to 92.6% [
14,
15]. The country’s performance of BCG vaccination coverage increased from year to year (by 47.6% % during the years 2002 to 2019) [
16] although, the efficacy of BCG was low[
17].
In this connection, it is of paramount importance for TB programs to understand the epidemiology of childhood TB as it may give an opportunity for better prevention and control of the disease in this population and consequently in the community at large because childhood TB is a marker of recent transmission [
18]. However, there is a scarcity of studies on the burden of childhood TB, and more so on bacteriologically confirmed childhood PTB and DR-TB, case notification reports at the national level. Therefore, this study was conducted to determine the level of childhood TB case notification and the burden of DR-TB among Ethiopian children registered for bacteriologically confirmed Tuberculosis cases during the third-round drug resistance tuberculosis survey.
Discussion
There is limited literature on the epidemiology and drug resistance pattern of childhood tuberculosis in Ethiopia [
8]. This is the first report on a countrywide bacteriologically confirmed childhood PTB CNRs in the country.
A total of 102 nationally identified bacteriologically confirmed childhood PTB cases were included in this study. Of these 102 bacteriologically confirmed childhood PTB cases, only fewer (6/102; 5.9%) were among children younger than five years of age, which was higher than bacteriologically confirmed childhood PTB cases reported from southern Ethiopia (1.9%) [
28]. But much lower than both clinically identified and bacteriologically confirmed cases reported from scattered locally focused previous studies: 21.8% from Addis Ababa [
15], 30.4% from Tigray region [
29], and 45.5% from southern Ethiopia [
28]. Similar to the previous studies from the aforementioned Ethiopian regions, but in contrast to our finding, studies from other parts of Africa such as Zambia (61%) also showed a higher burden of TB among children younger than five years of age compared to children aged 5–14 years [
30]. This disagreement between our findings and those from the other studies above may be because of the fact that our study included only children with bacteriologically confirmed childhood PTB cases while the other studies considered both bacteriologically confirmed and clinically diagnosed TB cases. This difference also highlights the challenges associated with the reliability of childhood TB diagnosis and decision-making merely based on clinical findings without considering bacteriological confirmation [
31,
32].
Whereas bacteriologically-confirmed childhood pulmonary TB cases were slightly higher among female (52.9%) than male (47.1%) children in this study, with an incidence rate of 5.3 per 100,000 and 4.87 per 100,000 children, respectively, adult TB cases from the same 3rd round DR-TB survey and those reported from most previous studies, contrarily, demonstrated a male TB case predominance [
33]. Similar to our finding, however, previous findings from Addis Ababa (55.4% vs. 44.6%) [
15] and Zimbabwe (53% vs. 47%) [
30] also reported a TB detection rate higher among females than males. The reason why more female than male children are affected could probably be due to female children staying at home taking care of their sick household adults more than their male counterparts. Nevertheless, this needs further investigation to definitely understand the true reasons behind such a lopsided TB detection rate among female children.
In this study, most of the children with confirmed TB were from rural areas (79.4%) which was similar to the finding from a study done in Debre Markos Referral Hospital, Northwest, Ethiopia[
10]. In contrast, many other studies demonstrated that a high TB burden occurs in urban environments due to overcrowding, high HIV prevalence, and occupational transmission [
33,
34]. However, the reports from these other studies, including even the one from the national TB program, took patients’ reporting sites into consideration during their data analyses instead of from patients’ places of residence [
35]. Data on bacteriologically confirmed childhood PTB CNRs by place of residence (as is the case in this study) rather than a place of diagnosis (as the cases in the other studies mentioned above) may correctly identify the source of TB transmission more accurately [
36].
Ethiopia is a high-burden country for HIV-TB co-infection [
37]. We found that 4% of childhood tuberculosis cases in our study occurred among children with HIV co-infection, a value higher than that reported from a previous study in southern Ethiopia (2.3%) [
28] but much lower than reported from Addis Ababa (28.2%) and other African countries (E.g., Togo (14.9%) [
38]. The low rate of HIV-TB co-infection in our study may be related to the high number of cases occurring in rural areas (79.4%), where HIV prevalence is lower than that in urban areas of Ethiopia [
39].
In the present study, almost all childhood TB cases (98%) were from newly diagnosed patients, which is similar to a previous report from south Ethiopia (98.2%) but slightly higher than the report from Addis Ababa (92%) [
15]. This high childhood TB prevalence from newly diagnosed patients most likely indicates the presence of an ongoing transmission of tuberculosis within the community [
40] since children are at higher risk of developing the disease within a short period of infection [
41]. In this connection, it has already been established that the majority of children, especially those < 5 years of age and those with HIV co-infection, develop tuberculosis disease within the first two years of infection [
40]. This underscores the importance of understanding the epidemiology of TB among Ethiopian children all over the country in order to identify TB hot spots and devise appropriate and better TB prevention, case identification, and control strategies. Another closely related and significantly relevant issue is the fact that children are usually infected with tuberculosis from close contact with actively coughing persons. The source case may be from household contacts, schools, or healthcare facilities [
42]. The finding in the present study, in which slightly over half of the cases (51%) had known TB contacts, is also in line with this notion.
The nationwide incidence of bacteriologically confirmed childhood PTB in this study was 5.1 per 100,000 children. Interestingly, remarkable variations between regions to regions and regions ot the national childhood TB incidences were observed. The lowest bacteriologically confirmed childhood tuberculosis cases (2.45/100,000) incidence was observed from the Tigray region while the highest was from Gambella (11.57/100,000). Of course, differences in the incidence pattern among various regions within a country are not unique to our study; for example, region-to-region variation was reported from Taiwan (that ranged from 1.93 to 100,000 at the center region to 16.02 per 100,000 in the south region) [
43]. Such region-to-region differences may be due to differences in the practice of TB prevention and control besides the actual differences in the burden of TB [
44].
In this nationwide DR-TB survey, we found a 6.5% childhood TB drug resistance among the participant children. This rate is much lower than the one reported previously from China (28%) [
45] but higher than the one reported from Zimbabwe (3%) [
30]. Usually, drug-resistant tuberculosis in children originates from the transmission of DR-TB from adult patients in the community (predominantly household exposure) harboring high levels of DR [
46]. This notion is supported by our finding that the children with DR-TB identified in this study had no previous history of TB treatment, demonstrating the presence of high adult-to-children DR-TB transmission in the community. On the other hand, the burden of childhood MDR TB cases was 1.3% in our result, which was lower than the rate reported from the drug resistance survey in South Africa (2.3%) [
46] and China (4.6% ) [
45]. The reason why childhood MDR-TB was higher in the two countries than the one observed in our study may be that the burden of MDR-TB in these countries is expected to be high as both of them are known to belong to high MDR-TB burden countries in contrast to Ethiopia, which has been currently removed by WHO, from the list of the 30 MDR-TB high burden countries [
6].
In the present study, 80% (4 of the 5 cases) of DR-TB cases were observed among children in the age group 10–14 years, while none was detected among the under-five children, which is in agreement with the report indicated in a 2021 review [
47]. This might reflect the possibility of under-detection among under-5 children probably due to difficulty to obtain appropriate sputum specimens from this population, which makes it one of the important ongoing challenges in the understanding of DR-TB in children.
Another interesting observation from our study is that childhood drug-resistant TB was higher among urban residents (3/5, 60%) compared to rural ones (2/5, 40%), in spite of the fact that TB incidence was higher among the rural than the urban resident children. But this was not the case in China, where high drug-resistant TB was observed more in rural (66.1%) than urban (33.9%) settings [
45]. In Ethiopia, a previous study observed that some MDR-TB patients including adults diagnosed at rural health facilities could be referred to urban hospitals for better management, which may cause delays to patient diagnosis and treatment and consequently increase the risk of MDR-TB transmission [
48]. Alternatively, it could be that TB treatment is more available in urban settings where there is a higher chance of developing drug resistance due to interment usage of drugs when patients fail to adhere to the appropriate treatment dose or duration (as is often the case or if the treatment outcome is unfavorable[
49,
50]. Thus, children who have regular and prolonged contact with such adult patients could acquire drug-resistant TB from them; hence, more resistance rate among urban than rural children in this report [
50].
Strengths and Limitations of the study
Although the exclusion of presumably TB cases diagnosed based on clinical findings alone in this study may further muddle our understanding of childhood TB epidemiology in Ethiopia, our study, nevertheless, helps to peer through the level of bacteriologically confirmed childhood PTB cases and TB-drug sensitivity profile among this age group, which indirectly reflects DR-TB in the community. Both of these have not been previously addressed adequately. However, we were also challenged to find bacteriologically confirmed childhood PTB case notifications from previous studies to compare our study with since most childhood TB studies included both bacteriologically and clinically diagnosed TB cases.
An important limitation of this study, however, is that phenotypic DST was not performed for all of the 102 identified TB cases because of the difficulty encountered in resuscitating a significant number of the archived isolates (11 formerly culture-positive TB cases, and the remaining nine identified TB cases which were GeneXepertMTB/RIF positive but culture negative).
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