Tuberculosis 121 (2020) 101917

Contents lists available at ScienceDirect

Tuberculosis
journal homepage: http://www.elsevier.com/locate/tube

Global tuberculosis research and its future prospects

J.A. Garrido-Cardenas a, *, C. de Lamo-Sevilla b, M.T. Cabezas-Ferna
�ndez c,
d e
F. Manzano-Agugliaro , M. Martínez-Lirola
a
Department of Biology and Geology, University of Almeria, 04120, Almeria, Spain
b
Complejo Hospitalario Torrecardenas de Almeria, Almeria, UGC, Spain
c
UGC Biotecnología, Complejo Hospitalario Torrec�ardenas, Servicio Andaluz de Salud, Almería, Spain
d
Department of Engineering, University of Almeria, 04120, Almeria, Spain
e
Complejo Hospitalario Torrecardenas de Almeria, Almeria, Spain

A R T I C L E I N F O A B S T R A C T

Keywords: Tuberculosis is the infectious disease that causes the most deaths each year in the world. Around 25% of the
Tuberculosis population is estimated to be infected with, Mycobacterium tuberculosis, the bacteria that gives rise to the disease,
Mycobacterium and more than one and a half million people die each year from this cause. A rigorous bibliometric analysis has
Bibliometric
been developed around tuberculosis disease, and the most remarkable results are presented in this paper. It is
Drug-resistant
HIV
observed that interest in tuberculosis is growing, and the control of its spread has become one of the main health
priorities in the world, with the United States, the United Kingdom, and India, leading the research in this area.
On the other hand, it has been observed that there are two main health concerns around the tuberculosis: drug-
resistant tuberculosis and co-infection with HIV. Finally, conclusions are offered, playing a frontline role in
science policy decisions and research performance evaluations.

1. Introduction
Tuberculosis (TB) accounts for a significant global burden of disease
and substantial investment in research and development. Although it is
an ancient and curable disease, TB remains the world’s leading cause of
death from an infectious agent, exceeding human immunodeficiency
virus/acquired immune deficiency syndrome (HIV/AIDS) for the first
time [1,2]. More than 1.7 billion people (about 25% of the world pop­
ulation) are estimated to be infected with Mycobacterium tuberculosis [3].
According to the World Health Organization (WHO), in 2017, 10 million
individuals became ill with TB and 1.6 million died, including 0.3
million among people with HIV [3].
One-third of the new cases (about three million) remain unknown to
the health system, and many of them are not receiving proper treatment.
The TB occurs in every part of the world. In 2017, the largest number of
new TB cases occurred in the South-East Asia and Western Pacific re­
gions, with 62% of new cases, followed by the African region, with 25%
of new cases [4].
Poverty, HIV, and drug resistance are major contributors to the
global TB epidemic [5]. Almost of TB cases occur in developing
countries (95%). The global incidence of TB peaked around 2003 and
appears to be declining, with a deceleration of around 2% per year [6].
Ending the TB epidemic by 2030 is among the health targets of the newly
adopted Sustainable Development Goals. WHO has gone one-step
further and set a 2035 target of 95% reduction in deaths and a 90%
decline in TB incidence – similar to current levels in low TB incidence
countries today.
In the last years, important progress has been made for better control
of the disease. While microscopy and culture continue to be crucial for
diagnosis of TB, molecular diagnostic tests provide more timely results
improving quality of care and patient safety [7]. The range of molecular
diagnostic tests to aid in the diagnosis, including the nucleic acid
amplification test and whole-genome sequencing (WGS), has expanded
tremendously [8]. They are becoming more accessible not only for
detection and identification of Mycobacterium tuberculosis complex
(MTC) in clinical specimens, but now extend to the diagnosis of
drug-resistant strains [9].
Although small changes have been made in the treatment of drug-
susceptible TB, the recent emergence of drug-resistant TB has become
a serious concern increases the cost and duration of treatment, while

* Corresponding author. Department of Biology and Geology, University of Almeria, Cra Sacramento s/n 04120, Almeria, Spain.
E-mail addresses: jcardena@ual.es (J.A. Garrido-Cardenas), cristina.lamo.sspa@juntadeandalucia.es (C. de Lamo-Sevilla), mt.cabezas.sspa@juntadeandalucia.es
(M.T. Cabezas-Fern�andez), fmanzano@ual.es (F. Manzano-Agugliaro), miguelj.martinez.lirola.sspa@juntadeandalucia.es (M. Martínez-Lirola).

https://doi.org/10.1016/j.tube.2020.101917
Received 23 October 2019; Received in revised form 2 February 2020; Accepted 20 February 2020
Available online 23 February 2020
1472-9792/© 2020 Elsevier Ltd. All rights reserved.
J.A. Garrido-Cardenas et al.
decreasing the efficacy. Data on increased effectiveness with new and
repurposed tuberculosis drugs (delamanid, bedaquiline, pretomanid,
clofazimine, carbapenems, and linezolid) have led WHO to recommend
all-oral therapy for drug-resistant tuberculosis [10]. Studies have shown
that new shorter regimens for latent tuberculosis treatment containing
rifampicin or rifapentine are as effective as longer, isoniazid-based
regimens [11,12]. By the other hand, there is a promising TB vaccine
candidate to prevent the progression of infection to the disease. How­
ever, new tools alone are not sufficient [13].
The main purpose of this paper is to bring-out a bibliometric analysis
of the most current advances published in scientific journals about the
human TB. This systematic mapping study, despite the possible limita­
tions of this type of indicator, plays a first-line role in scientific policy
decisions and in evaluations of research performance. To address this
bibliometric analysis, different items have been studied and analyzed in
depth. These are: the progression of scientific production; the distribu­
tion of publications by countries and institutions; the main authors; and
the most relevant keywords of these publications.
2. Materials and methods
The use of databases is a common practice in the development of any
scientific research process, as they are a resource that offers many pos­
sibilities when carrying out specific searches on a particular subject. The
most important scientific databases are: PubMed, Scopus, Web of Sci­
ence and Google Scholar. They all deal with a wide range of scientific
fields, but today only Web of Science and Scopus can download large-
scale bibliographic information from scientific journals. For this
reason, one of these two databases is used when carrying out a biblio­
metric analysis on a specific scientific issue. In this study, the Scopus
database has been selected to perform a bibliometric analysis of global
tuberculosis research, as it is the database with the largest number of
indexed journals and conference proceedings. Recent studies have
shown that, comparing the titles indexed by Elsevier Scopus database
with that of the Web of Science (WoS), the former includes 84% of the
WoS titles, while only 54% of the publications included in Scopus are
indexed in WoS [14]. For this reason, Scopus, with more than 35,000
titles belonging to more than 10,000 publishers, is usually the database
most used in the bibliometric analysis, and works can be found in sci­
entific disciplines such as teaching or parasitology [15,16].
To carry out the present analysis, a search was performed on the
Scopus database, using the search criteria [TITLE-ABS-KEY (myco­
bacteri* and tuberculosis)], and obtaining 95718 publications from
1925 to 2018. Note that variations in search criteria can lead to signif­
icantly different results. Similarly, continuous automodifications of the
database to adjust publications to their exact publication date may also
result in data that is not exactly the same as that obtained in this anal­
ysis. In any case, this susceptibility of the Scopus database does not
Fig. 1. Methodology developed in the analyses.
2
Tuberculosis 121 (2020) 101917
invalidate it. For the analysis of the keywords, a manual curing of the
results obtained was carried out, grouping terms with the same mean­
ings and discarding terms such as article, which does not contribute
anything to the analysis. The aspects analyzed are: progression of sci­
entific output; publication distribution by countries and institutions;
main authors; and keywords (Fig. 1).
3. Results
3.1. Progression of scientific output
Analysis of the data, looking for publications on tuberculosis,
returned a result of 95718. The first record is from the year 1925, and
during the first twenty years, less than forty articles were published. The
last of the years studied was 2018, as it is the last year for which the
Scopus database presents its complete records. Fig. 2 shows the pro­
gression in the number of tuberculosis publications between 1925 and
2018. It can be observed that there is a continuous annual growth, which
is particularly notable from 1990 onwards. That is to say, two linear
trends have been described, and they have been represented with
dashed lines in Fig. 2. The first of them includes from 1925 to 1990, and
the second from 1990 to 208. Both trends present very different char­
acteristics in terms of their slopes and regression coefficients. The first
trend has a slope of 11, while the second trend has a slope of more than
150, demonstrating the enormous interest that tuberculosis has gener­
ated in the international scientific community in the last 30 years, with
more than 80% of the works published in this period. In this sense, it is
remarkable the fact that, since 2011, more than 4000 articles have been
published every year.
Overall, growth is positive in virtually every year, with very few
relative highs and lows. But an important relative maximum is presented
in 1974, in which 702 publications were published, a value that was not
surpassed until 1990. The explanation for this fact can be found in the
ninth report by WHO’s Expert Committee on Tuberculosis, one of the
most influential and controversial in the fight against tuberculosis. It
decided to take measures such as abandoning indiscriminate tubercu­
losis case-finding by mobile mass radiography to focus exclusively on
the bacteriological fight against the disease [17]. The aim of the report
was to establish the basic principles for prioritizing risk groups and
choosing a screening approach, but its interpretation generated a great
deal of international controversy.
3.2. Publication distribution by countries and institutions
159 countries - out of 194 recognized by the UN - present authors
who have published at least one article, or have collaborated in its
publication, on tuberculosis. All of them are represented in the world­
map of Fig. 3, in which the intensity of the color represents the largest
J.A. Garrido-Cardenas et al. Tuberculosis 121 (2020) 101917

Fig. 2. Trend in the number of publications from 1925 to 2018.

number of publications. On the other hand, Fig. 4 represents the 14
countries with more than 2000 publications, representing among them
more than 60% of all publications on tuberculosis. Note that a publi­
cation may be signed by authors from more than one country. The
country at the top of the ranking shown in Fig. 4 is the USA. It presents
more than 22,000 publications, while in second and third place are the
United Kingdom and India, respectively, with almost 9000 publications
each. Next, 11 countries are found, with 2000–5000 publications. Of
these countries, 6 are European -France, Germany, Italy, Spain,
Netherlands, and Switzerland-; 2 are Asian -Japan and China-; 2 are
American -Canada and Brazil-; and 1 is African -South Africa-.
To standardize the results of scientific production, Table 1 has been
elaborated. It puts into perspective the number of publications in each
country in relation to its population and wealth. The data referring to the
population of each country are based on the 2018 statistics obtained
from the website http://www.worldometers.info/world-population/p
opulation-by-country/. The data referring to the wealth of each coun­
try are taken from the IMF, and expressed in GDP per capita. It can be
observed that Switzerland, Netherlands, and UK stand out, with more
than 100 publications per million inhabitants. These three are among
the six countries with the highest per capita incomes, while India and
China, two of the three poorest countries among the 14 with the highest
scientific output, are the ones that publish the fewest articles per million
inhabitants.
According to the institutions, 140 have published at least 200 arti­
cles. Of these, the 12 most prominent are shown in Fig. 5. These are the
ones that have published at least 800 articles. Of these 12 institutions, 4
are from the USA –Centres for Disease Control and Prevention, National
Institutes of Health, Colorado State University, and Harvard Medical
School –; 3 are from UK –Imperial College of London, London School of
Hygiene & Tropical Medicine, and UCL University College of London–; 3
are from France –Institut national de la sant�e et de la recherche
m�edicale, Inserm; Centre National de la Recherche Scientifique, CNRS;
and Institut Pasteur–; and 2 are from South Africa –University of Cape
Town and Universiteit Stellenbosch–.

Fig. 3. World map with main countries and their number of scientific publications on tuberculosis. The brown color indicates a greater number of publications, the
orange/yellow color indicates the smaller, and white when it does not exist. (For interpretation of the references to color in this figure legend, the reader is referred to
the Web version of this article.)

3
J.A. Garrido-Cardenas et al. Tuberculosis 121 (2020) 101917

3.3. Main authors

The analysis of the most outstanding authors in the bibliometric

studies offers information of these at individual level as well as at the
level of the relations established with the rest of authors, from the
analysis of communities. In Fig. 6, the 14 authors with more than 200
publications on tuberculosis are shown. Among them there are 5 authors
from USA, 2 authors from France and another 2 author from
Netherlands, with Dick van Soolingen, from the National Institute of
Public Health and the Environment, in Bilthoven, leading the ranking. In
addition, there is 1 author from Japan, Guadeloupe, the United
Kingdom, India, and Germany. The author Nalin Rastogi deserves a
special mention in this analysis. He has divided his research activity
between the Institut Pasteur in Paris and the Institut Pasteur in
Guadeloupe, a small archipelago of less than 400,000 inhabitants,
belonging to the Caribbean Antilles, forming an overseas region of
France. For this reason, this author has more articles than the entire
region of Guadeloupe.
SciVal is a tool for identifying and analysing new and emerging
Fig. 4. Top 14 countries in scientific output on tuberculosis. research trends based on an author’s publications in recent years. By
analysing the SciVal Topics of an author in the last 5 years, it can be
known in which areas of work he has the greatest strength. Thus, seeing
Table 1
this aspect in the main authors who research and publish about tuber­
Leading countries in terms of scientific publications and the relationship with
culosis, it is detected that authors such as D. Van Soolingen and N.
their population and wealth.
Rastogi are working with variable-number repeats of mycobacterial
Country No. Population (mill. No. pub/ GDP per interspersed repetitive units (MIRU-VNTR), while others such as W.R.
publications of inhabitants) mill. inhab. capita (€)
Jacobs are working on gene expression analysis of Mycobacterium
United 22.646 331,003 68,416 53.233 smegmatis, and G.S. Besra is focused on the study of Galactosylceramides
States
as lipid antigens.
UK 8.881 67,886 130,822 36.410
India 8.742 1380,004 6,335 1.741 By analyzing these 14 authors and studying the institutions in which
Japan 4.880 126,476 38,584 33.271 they research, it is found that only one of them -Ian M. Orme- works in
France 4.813 65,274 73,735 34.980 one of the 12 institutions in Fig. 5 -Colorado State University-. The rest
China 4.576 1439,324 3,179 8.263 of the authors work at different institutions, not the most prominent in
Germany 4.184 83,784 49,940 40.340
South Africa 3.312 59,309 55,843 5.386
the ranking established previously. For example, Dick van Soolingen
Italy 3.086 60,462 51,040 29.220 researches at the National Institute of Public Health and the Environ­
Spain 3.069 46,755 65,640 25.730 ment, or William Robert Jacobs researches at the Albert Einstein College
Netherlands 2.357 17,135 137,555 44.920 of Medicine of Yeshiva University. This shows that in the most presti­
Canada 2.317 37,742 61,390 39.306
gious centres there are numerous and important teams. In other words,
Brazil 2.295 212,559 10,797 7.562
Switzerland 2.149 8,655 248,296 70.200 these institutions do not owe their prestige to the presence of a single
important researcher. The good result is the result of a great centre
policy and depends, to a large extent, on international collaborations
with groups from other institutions and countries.

3.4. Keyword analysis

In Fig. 7 the 8 drugs present among the 160 analyzed keywords are
shown. Each of them is present in, at least, 2300 articles. These are,
ranked in descending order: Rifampicin, isoniazid, ethambutol, pyr­
azinamide, streptomycine, kanamycin, amikacin, and cyprofloxacin.
These are generally drugs used as first-line agents in drug-resistant
tuberculosis. In the year 2012 a peak is observed that reaches a
maximum for most of the drugs. This peak coincides with the update of
the Guidelines for the programmatic management of drug resistant
tuberculosis, edited by the WHO. This update was intended to serve as a
tool for public health professionals working in response to the 62nd
World Health Assembly resolution on the prevention and control of
multidrug-resistant tuberculosis and extensively drug-resistant
tuberculosis.
The peak in 2012 also coincides with the date on which bedaquiline,
by Johnson and Johnson’s, was approved by the Food and Drug
Administration (FDA). This was transcendental since it was the first anti-
Fig. 5. Top 12 institutions by number of scientific publications on tuberculosis.
tuberculosis drug approved by the FDA in 40 years, which meant a
change in the restructuring of the following WHO anti-tuberculosis
clinical guidelines, in 2016.
Other keywords that have been studied are those related to AIDS
(Acquired Immune Deficiency Syndrome). These appear in 7725

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J.A. Garrido-Cardenas et al. Tuberculosis 121 (2020) 101917

Fig. 6. Top 14 authors by number of scientific publications on tuberculosis.

Fig. 7. Representation of the number of publications related to the drugs used in the fight againt tuberculosis.

articles, since 1989. This is approximately 10% of all publications. In

Fig. 8, the progression in the number of AIDS and tuberculosis publi­
cations between 1989 and 2018 is shown.
AIDS is one of today’s major pandemics, and it can be observed that
the publications relating it with tuberculosis overlap in time with the
emergence of multi-resistant tuberculosis. This may be due to the
growing number of people immunocompromised by HIV infection who
increase their sensitivity to tuberculosis infection, with their immune
system having a diminished ability to fight.

4. Conclusions

The bibliometric analysis on tuberculosis has allowed us to define the

current scenario in which global research on this subject is being carried
out. First, we have seen that interest in tuberculosis is growing, and the
control of its spread has become one of the main health priorities in the
Fig. 8. Representation of the number of publications related to AIDS and world.
tuberculosis.

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J.A. Garrido-Cardenas et al.
On the other hand, it has been seen that the main countries pub­
lishing studies related to tuberculosis are the United States, the United
Kingdom, and India. They are publishing more than 40% of all TB-
related articles. The analysis of the main institutions and the main au­
thors publishing on tuberculosis allowed us to establish a map in which,
in addition to the previous countries, France and Holland had to be
included, with some of the most important research groups on tuber­
culosis at world level.
The analysis of the keywords has allowed us to detect two of the main
health concerns around the disease: drug-resistant tuberculosis and co-
infection with HIV. Concern about the spread of drug-resistant tuber­
culosis is a priority, and that is that, every year, more than 100,000
deaths occur from this cause, with patients infected with strains resistant
to isoniazid and rifampicin, and that are virtually incurable with stan­
dard first-line treatment. Thus, controlling the spread of multidrug-
resistant tuberculosis is one of the most urgent and difficult challenges
facing global tuberculosis control. However, new molecular methods are
enabling earlier and more reliable diagnosis, increasing the chances of
adequate and successful treatment [18].
A paradigmatic case is HIV-infected people, as they are more
vulnerable to possible drug-resistant tuberculosis infection. In many
cases, HIV patients are not diagnosed with tuberculosis because they die
while waiting for laboratory confirmation [19]. For this reason, rapid
diagnostic tests are being carried out in settings with high prevalence of
HIV-associated tuberculosis. Once again, early and correct identification
makes possible an adequate treatment that results in a reduction in the
mortality of these coinfected patients.
It is important to note that although the media impact of HIV is not as
high as it was two or three decades ago, HIV infections remain of great
interest to scientists - at least to those working with TB. TB is one of the
leading causes of death among people with HIV. For this reason, treat­
ment is important even in asymptomatic patients with latent TB,
although taking certain anti-HIV drugs and TB drugs at the same time
may increase the risk of drug interactions and side effects.
Funding
Any funding did not support this work.
Declaration of competing interest
None.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.tube.2020.101917.
Tuberculosis 121 (2020) 101917
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