Background
Tuberculosis (TB) is a bacterial disease that remains one of the leading causes of mortality worldwide, with an estimated 10 million cases and 1.2 million deaths in 2018 [
1]. In 2015, the World Health Organization (WHO) initiated the End TB Strategy, which aims for a 90% reduction in TB incidence and a 95% reduction in TB mortality by the year 2035 [
2]. Currently, the global TB incidence is falling at an average rate of about 2% per year, which is not fast enough to meet the milestones set by the End TB Strategy [
1]. In 2018, the first-ever United Nations General Assembly high-level meeting on TB endorsed an ambitious and powerful political declaration to accelerate progress toward End TB targets. Notably, the political declaration intensified research and innovation as one of the key strategies to accelerate progress [
3]. WHO has developed a ten-year global action framework for TB research to foster high-quality TB research at both national and global levels [
4].
One of the targets in the End TB Strategy is 90% preventive treatment coverage, which relates to the detection and treatment of latent TB infection (LTBI) cases prior to their progression to active TB disease [
1]. LTBI is defined as a state of persistent immune response to
Mycobacterium tuberculosis without clinically manifested evidence of active TB. WHO estimates that 23% of the world’s population (1.7 billion people) have LTBI, and a small proportion of these (5–10% of the 1.7 billion people with LTBI) are expected to progress to develop TB disease during their lifetimes [
1]. Intensifying efforts to detect and treat LTBI could help reduce the reservoir of potential TB cases and thus contribute to the reduction and eventual elimination of TB incidence.
Global efforts to intensify TB prevention, control, and research activities have resulted in a large number of scientific publications about TB. An increase in research activities has been reported for TB in general [
5,
6] and multidrug-resistant TB [
7]. These reports used a tool called bibliometric analysis that allows tracking and assessment of research productivity and growth over a period of time. As similar comprehensive assessments have not been done for LTBI research, it is unclear whether the global trend in scientific publications for LTBI has also been increasing. WHO recently published an updated and consolidated guideline for LTBI programmatic management and has also identified research priorities for LTBI [
8]. We are interested in whether publication trends specifically for LTBI are on par with WHO’s recommendations, and also whether the research gaps prioritized by WHO are being addressed across countries. This study therefore aimed to investigate the research trends in LTBI at the global level and to analyze gaps in research emphasis in selected countries.
Discussion
We conducted a bibliometric analysis on LTBI-related articles, analyzing publication trends (both globally and among the top 13 countries) of LTBI-related articles relative to all scientific and all TB-related publications from 1995 to 2018. Globally, we found that the average proportions of LTBI-related publications against both all scientific and all TB-related publications were similar in all three research areas (laboratory, clinical, and public health), ranging between 41 and 49%. LTBI-related publications in all three areas significantly increased over time. This could be partly due to the challenges of LTBI case detection and ascertainment [
23]. People with LTBI tend to be asymptomatic, with high rates of infection occurring among specific risk groups, particularly household contacts of TB cases [
8]. Contact investigation at the community or population level is thus necessary to identify candidates for LTBI testing and treatment [
8]. Identifying and initiating treatment among groups of people at high risk of developing TB disease is one of the priorities for TB elimination [
3].
All the top 13 countries that we have identified as being involved in most LTBI-related research have also contributed funding to TB research and development (R&D), either as an individual country or as part of an association, such as the European Union or BRICS (Brazil, Russia, India, China, and South Africa) [
24]. Our findings are also in line with a previous bibliometric analysis of overall TB research that found the same countries to be also the top publishing countries for overall TB research [
5]. In 2017, the largest funder for TB R&D was the United States, followed by the European Union and the United Kingdom [
24]. The list of top funders also includes four BRICS countries (i.e., South Africa, China, India, and Brazil). BRICS accounted for 53% of the global funding for TB and 47% of the world’s notified TB cases in 2018 [
1]. South Africa, China, India, and Brazil are also part of the top 30 high TB burden countries (i.e., those with TB incidence of > 100 per 100,000 population) as defined by WHO [
25].
Even though BRICS countries are in the top 13 countries for LTBI-related research, further analysis found that they in fact placed more emphasis on TB research than specifically on LTBI research. In particular, South Africa, India, and Brazil had significantly higher RRs for TB-related publications relative to all scientific publications. One possible explanation lies in the TB burden of each country: All three countries have high TB incidence rates (520, 199, and 45 per 100,000 population in South Africa, India, and Brazil, respectively in 2018) and are among the top 30 high TB burden countries [
25]. All three countries also have a high burden of HIV, and the presence of this infection is known to be a predisposing and precipitating factor for the development of TB [
23]. TB is a major occupational disease among mineworkers in South Africa, whose TB incidence rates are 3 to 7 times higher than that of the country’s general population [
26]. Recognizing the importance of TB, these countries have invested significantly in TB R&D. India has publicly recognized the financial implications of the TB burden in the country, and its government has pledged to fund TB research activities [
27]. South Africa invests more than 0.1% of the country’s gross domestic product to TB R&D (called the 0.1% fair share target) [
24]. This could explain why we found high RRs of both TB- and LTBI-related research, relative to all scientific publications, in South Africa.
Also, we found that South Africa and India had significantly low RRs for LTBI-related research publications relative to all TB-related publications. In addition to being high TB burden countries as mentioned earlier, both countries are also among the top TB/HIV (incidence rate of 306 and 6.8 per 100,000 population, for South Africa and India respectively) and multidrug-resistant TB (incidence rate of 19 and 9.6 per 100,000 population, for South Africa and India respectively) burden countries [
1]. Hence, this finding could be due to them prioritizing TB disease and not LTBI. Yet one reason for the slow progress against TB is the presence of a huge and persistent reservoir of LTBI. Despite the fact that most high and low TB burden countries already have a national policy addressing LTBI management in specific risk groups, most TB control programs in low- and middle-income countries have focused almost exclusively on detection and treatment of active TB cases [
3]. Taken together, our findings suggest that high TB burden countries tend to prioritize TB-related research, which is unsurprising given the challenges of TB treatment and control in such countries. These countries also need to tackle issues of high HIV incidence, which is a precipitating factor in developing TB disease.
When using all TB-related publications as the denominator for RR analysis, we observed that Canada, Italy, and Spain had significantly higher RRs of LTBI-related publications for the three research areas combined. All three countries have been identified as low TB burden countries (i.e., those with TB incidence of < 10 per 100,000 population) based on recent surveillance reports [
28,
29]. As proposed in WHO’s framework towards TB elimination for low-incidence countries [
30], preventing the progression of LTBI to TB disease (through detection and early treatment of LTBI cases) will play a crucial role in eliminating TB in these countries. This could explain these countries’ emphasis on LTBI research. In particular, Italy has highlighted the prioritization of LTBI testing and treatment in high-risk groups as one of its eight main interventions to eliminate TB [
31].
From the same analysis, we observed high RRs of LTBI compared to TB publications for South Korea in the public health area. South Korea is the only Organisation for Economic Co-operation and Development country with high TB incidence, and since 2013 it has been implementing a five-year TB control plan that emphasizes extensive contact investigation and LTBI management [
32]. This could explain the increase in public health publications on LTBI in South Korea.
Although we observed an overall increasing trend of LTBI-related publications for the public health area, comparing the Rate 2 results across the three research areas in each of the top 13 countries tells us another story. That is, only three countries (China, India, and South Korea) have highest rates (4.9, 3.8, and 11.2% per year, respectively) for public health-related research among the three research areas analyzed. As mentioned earlier, community studies are important to determine the burden of LTBI to allow the implementation of locally tailored interventions. Taken together, our findings suggest that more studies focusing on LTBI are needed, particularly on public health-related research, not only in low TB burden countries but also in high TB burden countries with rapidly expanding economies. Indeed, determining the burden of LTBI in various geographical setting and identifying population groups at-risk of progression to TB disease are the two research public health-related priorities highlighted by WHO [
3]. Modeling studies have shown that implementing a combination of interventions (i.e., to prevent TB infections in addition to detecting and treating TB patients) results in major reductions in TB burden [
33,
34] and thus helps to reach the targets set by the End TB Strategy.
This study has several limitations. First are the methodology limitations mentioned in a previous bibliometric analysis [
13], including potential misclassifications when assigning articles into research areas or countries as well as underappreciation of countries that have only recently begun TB research and with few accumulated publications. We could reduce misclassification bias by assigning each article to multiple subject categories and multiple countries, but bear the side effect that the sum of the number of articles in the three research areas and multiple countries would exceed the sum of the three-areas-combined and the all-countries-combined [
13]. We have limited information for countries just begun TB research in recent years. Similarly, countries published research findings in non-English journals or new journals without impact factors were not captured in our analysis. We suggest a separate analysis after a certain period of follow-up to consider these potential changes in the future. Next, for this study we classified articles into three broad research areas instead of the six specific research priorities identified by WHO’s international roadmap for TB research [
15]. Our classification is not fully representative of each priority in the roadmap, but is still in line: the laboratory sciences area covers the priorities of fundamental research and vaccines, the clinical research area covers diagnosis and treatment, and the public health area covers epidemiology and operation and public health research. Hence, the broadly categorized trends observed in our study could still reflect the research trends proposed by WHO. Using fewer categories, meanwhile, increased the number of LTBI papers in each area and allowed us to perform statistical analyses. Finally, we extracted data on the 13 countries that had the most publications regarding LTBI. However, TB burden generally affects developing countries, where resources for research could be scarce, and this might limit the generalizability of our interpretation to these countries.
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