Epidemiology of tuberculous lymphadenitis in Africa: A systematic review and meta-analysis
Epidemiology of tuberculous lymphadenitis in Africa: A systematic review and meta-analysis
Daniel MekonnenID 0 1
Awoke DerbieID 0 1
Andargachew Abeje 1
Abebe Shumet 1
Endalkachew Nibret 1
Fantahun Biadglegne 0 1
Abaineh Munshae 1
Kidist Bobosha 1
Liya Wassie 1
Stefan Berg 1
Abraham Aseffa 1
0 Department of Medical Microbiology, Immunology and Parasitology, College of Medicine and Health Sciences, Bahir Dar University , Bahir Dar , Ethiopia , 2 Biotechnology Research Institute, Bahir Dar University , Bahir Dar , Ethiopia , 3 The Centre for Innovative Drug Development and Therapeutic Trials for Africa (CDT- Africa), Addis Ababa University , Addis Ababa , Ethiopia , 4 Geospatial Data and Technology Center, Bahir Dar University , Bahir Dar , Ethiopia , 5 Amhara Regional State Health Bureau, Felege Hiwot Referral Hospital , Bahir Dar , Ethiopia , 6 Department of Biology, Bahir Dar University , Bahir Dar , Ethiopia , 7 Armauer Hansen Research Institute , Addis Ababa, Ethiopia, 8 Animal and Plant Health Agency, Weybridge, the United Kingdom
1 Editor: Pere-Joan Cardona, Fundacio ? Institut d'Investigacio ? en Cie?ncies de la Salut Germans Trias i Pujol, Universitat Auto?noma de Barcelona , SPAIN
Tuberculous lymphadenitis is the most frequent form of extra-pulmonary TB (EPTB) and accounts for a considerable proportion of all EPTB cases. We conducted a systematic review of articles that described the epidemiological features of TBLN in Africa. Any article that characterized TBLN cases with respect to demographic, exposure and clinical features were included. Article search was restricted to African countries and those published in English language irrespective of publication year. The articles were retrieved from the electronic database of PubMed, Scopus, Cochrane library and Lens.org. Random effect pooled prevalence with 95% CI was computed based on Dersimonian and Laird method. To stabilize the variance, Freeman-Tukey double arcsine root transformation was done. The data were analyzed using Stata 14. Of the total 833 articles retrieved, twenty-eight articles from 12 African countries fulfilled the
Data Availability Statement: All relevant data are
within the manuscript and its Supporting
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
eligibility criteria. A total of 6746 TBLN cases were identified. The majority of the cases,
4762 (70.6%) were from Ethiopia. Over 77% and 88% of identified TBLN were cervical in
type and na?ve to TB drugs. Among the total number of TBLN cases, 53% were female,
68% were in the age range of 15?44 years, 52% had a history of livestock exposure, 46%
had a history of consuming raw milk/meat and 24% had history of BCG vaccination. The
proportion of TBLN/HIV co-infection was much lower in Ethiopia (21%) than in other African
countries (73%) and the overall African estimate (52%). Fever was recorded in 45%, night
Abbreviations: BCG, Bacillus Calmette?Guerin; CI,
Confidence Interval; EPTB, Extra-pulmonary TB;
ES, Prevalence estimate of study; GRADE, Grading
of Recommendations Assessment, Development
and Evaluation; HIV, Human immune Deficiency
Syndrome; I2, Inconsistency squared; MTBC,
Mycobacterium tuberculosis complex; PP, pooled
Prevalence; PRISMA, preferred reporting items for
systematic reviews and meta- analysis; PTB,
Pulmonary TB; QoE, Quality of Evidence; TB,
tuberculosis; TBLN, Tuberculous lymphadenitis;
WHO, World Health Organization.
sweating in 55%, weight loss in 62% and cough for longer than two weeks in 32% of the
TBLN was more common in females than in males. The high prevalence of TBLN in Ethiopia
did not show directional correlation with HIV. Population based prospective studies are
warranted to better define the risk factors of TBLN in Africa.
Tuberculosis (TB) is one of the oldest chronic and complex infectious diseases and is caused
by a group of bacteria belonging to the Mycobacterium tuberculosis complex (MTBC). The
complex includes the human adapted species of M. tuberculosis and M. africanum, and
zoonotic pathogens; M. bovis, M. caprae, M. microti and M. pinnipedii which affect cattle, goats/
sheep, voles and seals/lions, respectively [
]. The current body of evidence suggests that
these mycobacteria might have co-evolved along with early hominids in East Africa since as
far back as 3 million years ago [
The 2017 WHO global TB report on Africa showed high TB mortality (41/100,000),
incidence (254/100,000) and TB/HIV co-infection (34%) rates. Moreover, the treatment success
rate was below the WHO target of 85% [
]. In 2016, as many as 82% and 85% of TB deaths
were reported among HIV-negative and total TB patients, respectively, in Africa and WHO
South East Asia Region [
]. Altogether, Africa is the worst affected region with TB.
On average in the world, pulmonary TB (PTB) accounted for 85% of the clinical forms of
TB whereas extra-pulmonary TB (EPTB) accounted for the remaining 15% [
]. The most
common types of EPTB include TB of the lymphatics (TBLN), pleural, bone, meningeal,
genitourinary and peritoneal TB [
]. However, the prevalence of EPTB and its predominant
forms varies from country to country [
]. For instance, Ethiopia reports an EPTB
proportion of 32%; ranking third in case number globally next to India and Pakistan despite
their much larger total population size  and this level has remained high over the years [
Global TB control efforts have largely ignored EPTB. This is because EPTB is generally
considered non-infectious and as such inconsequential to the global epidemic [
recent data from northwest England have shown that the prevalence of active TB disease
among household contacts of EPTB was high (440 per 100 000 contacts screened), indicating
that EPTB cases might have substantial impact on TB transmission [
]. Moreover, it is
conceivable that the slower annual decline rate of EPTB compared to PTB [
] could retard the
progress towards the END-TB targets set by WHO [
Among the risk factors studied for EPTB, immunological drivers are well known and have
been comprehensively reviewed by O?Garra and colleagues [
]. Reports from USA and South
Africa showed that race, sex and HIV are important risk factors for the development of EPTB
]. Another study from Brazil also described an association of EPTB with HIV and
ethnicity . On the other hand, Mehta et al. (1991) compared TB data between pre and post
HIV era in the USA and concluded that EPTB was not associated with HIV there [
et al. (2015) did not find any association of ethnicity, TB strain type or HIV co-infection with
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TBLN prevalence in Ethiopia [
]. Additionally, the role of other potential factors such as over
], bovine origin [
] or lineage tropism [
] were minimal and unable to explain
the high incidence rate of TBLN in Ethiopia.
Several attempts have been made to investigate differences in infectivity and virulence of
strains isolated from PTB and EPTB patients. Viedma et al. (2005) used an ex vivo competitive
macrophage co-infection assay and a murine aerosol-infection model and reported that strains
isolated from EPTB were more efficient and showed higher infectivity than strains derived
from PTB sites. This report suggests a possible role for bacterial factors in determining the
clinical phenotypes [
]. On the other hand, a study by Gomes et al. (2013) failed to detect any
association between clinical phenotypes of TB and MTBC genotypes. Rather, they found a link
between clinical phenotypes of TB and host factors [
Tuberculosis may be considered as a disease with a continuous and dynamic spectrum [
TBLN as one pole of the spectrum occurring with a relatively strong host resistance, and
disseminated TB as the other pole with relatively weaker host resistance. TB lymphadenitis is
distinct from disseminated TB where lymph nodes could be involved in addition to pulmonary
illness. TBLN is a form of TB with no evidence of pulmonary involvement or TB illness in any
other organ of the body. The same strain types have been isolated from TBLN and PTB cases
in Ethiopia, suggesting that host and/or environmental factors might play a role in the
pathogenesis of TBLN rather than strain tropism [
In general, pooled data on the epidemiology of TBLN in Africa were not available.
Moreover, the factors behind the development of TBLN are not well understood and this might
require a combined analysis of data from host (genomics, immunity, co-morbidity),
environment and pathogen genomics and be triangulated using powerful statistical and mathematical
The central thesis of this review was to determine the geo-spatial distribution of TB
lymphadenitis in Africa and to characterize TBLN cases by different demographic (gender, age groups),
exposure (previous TB treatment history, raw meat/ milk exposure, BCG vaccination) and
clinical variables (HIV co-infection, fever, weight loss, night sweat, cough).
This review protocol is registered at the National Institute for Health Research; PROSPERO
international prospective register of systematic reviews with registration number
CRD42018104170 at (https://www.crd.york.ac.uk/PROSPERO/#recordDetails).
Any article that characterized TBLN in African countries with respect to: gender, age, TBLN/
HIV co-infection, lymph node features, exposure status (livestock, raw milk/meat, BCG
vaccination and TB treatment) and cardinal TB symptoms was included. Peer review articles
published in the English language irrespective of publication year were included. Tuberculous
lymphadenitis cases diagnosed on clinical criteria plus cytology and/or bacteriology were
included. Those, TBLN cases diagnosed on clinical criteria alone were excluded. Sample size
was not used as inclusion or exclusion criterion.
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Information sources and search strategy
Articles were retrieved from the electronic data bases of PubMed, Scopus, Cochrane library,
and Lens.org. The search was done using key words and MeSH term. The key words included
tuberculosis lymphadenitis, tuberculous lymphadenitis, lymph node tuberculosis, and Africa.
The full search was done by combining key words and related MeSH terms using Boolean
operators. S1 Table shows the full search strategy.
All of the identified articles were imported to an Endnote library. Initial screenings were done
by title followed by abstract and then full text reading. Articles were assessed independently
for the fulfillment of the inclusion criteria by two authors (AD, AS). Disagreements regarding
the inclusion or exclusion of articles were resolved by discussion.
Data collection process and data items
Data from the selected articles were extracted by two authors (DM, AM) independently using
excel data extraction sheet. Key indicators such as first author, year of publication, study
period, country, number and types of TBLN cases, lymph node features, sex, age and TBLN/
HIV co-infection status were extracted. Moreover, history of exposure to raw milk/meat, BCG
vaccination, contact with chronic cougher, previous TB treatment history were also extracted.
Furthermore, cardinal TB symptoms (fever, night sweat, weight loss, and cough for longer
than two weeks) were extracted. Distribution of patients? place of origin and number of TBLN
cases were mapped using ArcGIS 10.3 (ArcGIS Desktop, ESRI 2011. Redlands, Canada).
Risk of bias in individual studies
To assess risk of bias, two authors of this paper (DM, EN) independently used the seven
itembased ROBINS-I risk of bias assessment tool [
]. Each item scored one point and
discrepancies were resolved by a third independent author (FB). Moreover, to determine the certainty of
evidence generated and strength of recommendations; Grading of Recommendations
Assessment, Development and Evaluation (GRADE) tool was applied [
Summary measures and synthesis of results
The collected data were analyzed using quantitative measures. For random effect
meta-analysis, approximate likelihood approach was followed. Moreover, to make the normal distribution
assumptions more applicable to significance testing and stabilize the variances;
FreemanTukey double arcsine rooted transformation was done [
]. Furthermore, to estimate the
transformed pooled prevalence, Dersimonian and Laird method was used [
together, using the metan command in Stata, study estimate (ES) as prevalence was computed
using Freeman-Tukey double arcsine root transformation with 95% confidence interval. In the
forest plot, the box indicated weight of articles from random effect analysis. The crossed line is
the 95% confidence interval (CI), the solid vertical line is zero to x-axis. The analysis was done
using Stata 14 (Stata Corp. College Station, TX, US). Country/sub-region/ wise sub-group
analysis was done with regard to TBLN types, TBLN features, gender, age and TBLN/HIV
coinfection status. The summary measures were presented as forest plots and table.
Risk of bias across studies
Statistical heterogeneity estimate among the articles estimate was assessed using Cochrane Q,
I2 statistic and P-value. The I2 value of <25%, 25?50% and 50% was taken as low, moderate
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and high degree of heterogeneity, respectively [
]. To deal with heterogeneity, sub-group and
sensitivity analyses were performed; possible publication bias was assessed using funnel plot
A total of 831 articles were retrieved from the four electronic databases and imported to an
Endnote library. Two additional articles were identified through hand searching in the
Ethiopian Journal of Health Development and African Journals Online. After removing duplicates
(97 articles), 736 articles were screened. Of these, 632 articles did not fulfill the inclusion
criteria and they were removed. A further 55 articles were excluded for the same reason after
reading the abstract. Twenty-eight articles were included in the quantitative analysis. Over all, full
screening was done based on the preferred reporting items for systematic reviews and
metaanalysis (PRISMA) flow diagram (Fig 1).
A total of 6746 TBLN cases from 12 African countries were reviewed. Majority of the cases,
4762 (70.6%) were from Ethiopia; Djibouti reported only eight confirmed TBLN cases. The
geographic distribution of TBLN cases is summarized in Fig 2A and 2B. The spatial data used
for the maps were taken from Map library which is a public domain that can be accessed at
Of the total of 28 articles reviewed, 14 articles were from Ethiopia [
16, 26, 37?48
articles each from Zambia [
], South Africa [
] and Nigeria [
]. One article each
were identified from Burkina Faso [
], Uganda [
], Djibouti [
], Mozambique [
], Tunisia [
], Tanzania [
], and Malawi [
]. Data collection period of articles was
between 1970 and 2015 (46 years) while the publication years range was between 1975 and
2018 (44 years) (Table 1).
Most articles contained complete and clear data about sex, age, TBLN/HIV co-infection
status and types of TBLN (Table 1). However, some articles lacked complete information about
livestock exposure, history of consumption of raw milk/meat/ and history of BCG vaccination.
Different articles categorized age differently. Thus, best educated guess was applied to assign
data to the respective age ranges. Groups with unknown HIV status were removed in the
meta- analysis. Meta-analysis was done when at least two articles had the variables of interest.
Risk of bias within studies
The risk of bias for each individual article was measured as no risk of bias, probably yes, yes
and no information. Probably yes, yes and no information scored zero and no risk of bias got a
score of one. The total score therefore ranged from zero to seven, with higher scores indicating
higher quality of outcome. Of the total 28 articles reviewed; 17, 10 and one article showed an
overall low, moderate and critical risk of bias, respectively (Table 2). Further, S2 Table shows
that patient classification, measurement of outcome and reporting bias were the identified
source of bias in the included articles. Overall, the included articles were judged as good
Results of individual studies
In this review, TBLN was disaggregated against 15 variables. The result of individual studies
and its summary measure is presented using forest plot (Figs 3?7).
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Fig 1. PRISMA flow diagram of literature selection, Africa, 2018.
Cervical TBLN is the most prevalent form and ranged from 47% [
] to 98% [
subgroup analysis showed that cervical LN type was lower in Ethiopia (69%) compared with
articles from northern and eastern African countries (89%) and southern and western sub-regions
(85%) (Fig 3A). On the other hand, Bem (1997) reported low prevalence of matted type
], while other studies reported higher than 50% prevalence of the matted types
16, 38, 41, 51, 61
] (Fig 3B).
Three sub-group analyses were done on proportion of females among TBLN subjects;
Ethiopia in one group, southern and western African articles in the second group and that of
northern and other eastern African countries in a third group. Pooled prevalence of female
gender among north and eastern African studies, excluding Ethiopia, reported the lowest
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Fig 2. Geographic distribution and number of TBLN cases in Africa and Ethiopia, Africa, 1970?2015.
prevalence (42%) followed by southern and western African countries (47%). In Ethiopia it
was 54%. Individual article estimates of female proportion ranged from 38% to 75%. The
pooled African female proportion was 53% (95%CI: 51?55%) showing more females with
TBLN than males (Fig 4A). When sensitivity analysis was performed, Muluye et al [
an influence on Ethiopian and African overall estimates. After removing the Muluye et al
article, the female proportion turned out to be 52% in Ethiopia and 50% for overall Africa. We
noted that Muluye et al [
] analyzed a large number of TBLN cases (Table 1) and the study
quality was rated as good (Table 2). Part A of S1 Fig depicts the sensitivity analyses of articles
included in gender wise meta- analysis.
Most of TBLN patients were in the age range of 15?44 years. Articles reported as low as
], 39% [
] and as high as 98% [
] prevalence of age range of 15?44 years among
TBLN cases (Fig 4B). The sensitivity analysis in Part B of S1 Fig shows the influence of Berg
et al. [
] and Muluye et al. [
] studies. Before removing these two studies, the pooled
prevalence of age range of 15?44 years was 67%, 70% and 68% in Ethiopia, in other Africa countries
and also in the overall African pooled estimate, respectively. However, when these two
influential articles [
] were removed, the pooled prevalence turned out to be 72%, 70% and 72%
in Ethiopia, in other African countries and in overall Africa, respectively.
The prevalence of HIV among TBLN cases showed a clear difference between Ethiopia and
other African countries. The majority of cases in Africa other than Ethiopia showed higher
prevalence of HIV among TBLN cases (Fig 5). The sensitivity analysis for TBLN/HIV
co-infection showed minimal influence by a single study. Part C of S1 Fig depicts the sensitivity
The majority of TBLN cases were new which ranged from 67% [
] to 94% [
individual and pooled prevalence of various exposure status are summarized in Fig 6. Moreover,
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CS: Cross-sectional, H: Hospital, CCS: Comparative Cross-Sectional, HA: Hospital admitted patients, C: Community based study, P: Prospective study, HC: Health
Center, HF: Health Facility, R: Retrospective/Registry review, ND: No data found, #LNTB pts: Number of Tuberculous lymphadenitis patients, M: Male, F: Female, Po:
Positive, N: Negative, U: Unknown
Fig 7 shows that the prevalence of the cardinal TB symptoms lies between 32% and 62%)
among TBLN cases.
Synthesis of results
Seventy seven percent of TBLN cases included in this review were cervical lymph node (Fig
3A). Closer inspection of Fig 3B and Table 3 shows that matted and mobile type TBLN were
more frequent than discrete and firm types, respectively. Moreover, TBLN was more frequent
in female (53%) than in male patients (Fig 4A) and also more frequent in the age range of 15?
44 years (68%) than in other age ranges (Fig 4B). The most surprising difference was the HIV
prevalence among TBLN patients in Ethiopia, which differed significantly from the average in
other African countries; 21% versus 73% (Fig 5).
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The prevalence of exposure variables such as history of anti-TB drugs, history of contact
with TB patients, BCG vaccination history, history of drinking raw milk and eating raw meat
was generally lower than 50% and did not show any trend (Table 3 and Fig 6). Likewise,
prevalence of cardinal TB symptoms among TBLN cases also varied. For example, the prevalence of
weight loss and night sweating was 62% and 55%, respectively (Table 3 and Fig 7).
Risk of bias across studies. Except for female gender, the meta-analysis results were very
heterogeneous and therefore, a random effect meta-analysis was done. The random effect
analysis was also heterogeneous. To sort out the cause, publication bias was assessed. The funnel
plot figures in S2 Fig shows the presence of possible publication bias. This bias might be due to
missing of grey literatures across the continent and exclusion of non-English language articles.
The other causes of heterogeneity might be due to differences in the recruitment criteria of
TBLN cases and measurement of outcome variables. Sensitivity analysis was done for gender,
age and TBLN/HIV co-infection for which over ten articles had been included. While
omission of a single study at a time had minimal influence on the pooled prevalence of TBLN/HIV
co-infection, it showed an influence on pooled prevalence of age groups [
] and gender
. We noted that, the two influential articles have good methodological and outcome
quality. Thus, it is less likely to influence the result away from the true pooled estimate. The
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Fig 3. Pooled prevalence of TBLN types and features, Africa, 1970?2015.
Fig 5. Proportion of TBLN/HIV co-infection among TBLN cases, Africa 1970?2015.
GRADE pro system of grading the quality of evidence showed low quality of evidence. This is
due to the methodological quality of the articles included in the review.
Tuberculous lymphadenitis (scrofula) has been recognized for thousands of years and remains
one of the most common forms of EPTB [
]. Cervical TBLN is the most frequent form
followed by axillary and inguinal TBLN. In the middle ages in Europe, it was believed that a
touch from royalty could heal this disease [
]. Unlike PTB which is more common in males
], our review identified a relatively higher percentage of females (53%) than males among
TBLN cases (low quality of evidence) (Table 3 and Fig 4A). The link between being female and
TBLN is not well known. However, reports have shown that differences in tumor necrosis
factor, interleukin-10, CD4+ lymphocyte counts, endocrine, socioeconomic and cultural factors
] might influence the development of TBLN. A review of 31 articles from Afghanistan,
Pakistan, India and Bangladesh agrees with our report [
]. Katsnelson (2017) discussed
pregnancy, diabetes, vitamin D deficiency and low protein consumption as potential factors
associated with TBLN.
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Fig 6. Prevalence of key exposure variables among TBLN cases, Africa, 1970?2015.
The pooled prevalence for the age group of 15?44 years was higher than for other age
groups among TBLN cases (low quality of evidence). TBLN was previously considered a
disease of childhood [
]. Recent reports also showed that high TBLN cases occur in the age
range of 20 to 40 years [
]. A critical review by Biadglegn et al. (2013) showed that EPTB
(with TBLN being the most common presentation) was more common among young adults
Sub-group analysis of TBLN/HIV co-infection by country/sub-region/ showed that the
pooled prevalence of HIV among TBLN in African countries other than Ethiopia was 73%
whereas it was 21% in Ethiopia (low quality of evidence). This indicates that Ethiopia?s high
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Fig 7. Prevalence of cardinal TB symptoms among TBLN cases, Africa, 1970?2015.
TBLN rate is probably unique in its epidemiology and seems to lack directional correlation
with HIV. Multiple studies showed that HIV infection was significantly associated more with
allopatric than sympatric host-pathogen relationships [
]. Absence of directional
correlation between TBLN and HIV in Ethiopia might be a consequence of co-evolution. Moreover,
evidence shows that EPTB is associated with HIV when it is the disseminated form rather than
when it is exclusively localized [
]. The TBLN cases reviewed here are exclusively TBLN cases
having no apparent pulmonary involvement. When considering Africa, the epidemiology of
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HIV: Human immune deficiency syndrome; TBLN: Tuberculous Lymphadenitis; BCG: Bacille of Calmitte and Guerin; PP: pooled prevalence, CI: Confidence interval;
QoE: Quality of Evidence
HIV among TBLN cases appears to be in line with other parts of the world in which HIV is the
main driver of EPTB, including TBLN [
The majority (88%) of TBLN cases were newly identified cases showing no association
between TBLN and TB treatment history. The history of eating raw meat/drinking raw milk
among TBLN cases in Africa was 46% (low quality of evidence). In the past, it has been
reported that 10?20% of all TBLN in Europe was caused by M. bovis, which was acquired from
drinking unpasteurized milk [
]. However, recent studies from countries with similar settings
(endemic bovine TB in cattle and no pasteurization) [
] have not shown such high prevalence
of zoonotic TB. For instance, molecular analysis of 173 isolates from pastoral communities
who had contact with livestock revealed as many as 160 M.tuberculosis and three M. bovis.
Similarly, molecular analysis of 39 isolates from their camels, cattle and goats showed 24 M.
bovis and 1 M. tuberculosis [
]. These data confirmed the low incidence of M. bovis as a cause
for human TB. On the contrary, a systematic review of global epidemiology of TB due to M.
bovis showed a higher rate (2.8%) among humans in Africa [
]. Such high prevalence of TB
due to M. bovis is possibly because Mu?ller et al. (2013) included articles reporting M. bovis
using biochemical methods as diagnostic tool. It is known that biochemical method lacks
specificity for identification of M. bovis. Taken together M. bovis was rarely detected in human TB
] but should not be ruled out as a zoonotic disease.
The prevalence of BCG vaccination history among TBLN cases in this review was 24%.
However, the number of articles was a few (only 4 articles). Thus, the quality of the evidence is
low; pending further investigation between BCG vaccination and TBLN. There are few reports
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about the effects of BCG on the incidence of TBLN except a report on its adverse effects
among infants [
The prevalence of the cardinal TB symptoms among TBLN cases in Africa ranged from
32% with history of cough for longer than two weeks to 62% with record of weight loss.
Overall, the prevalence of one or more systemic symptoms was 49%. Based on this report history of
cough was less prevalent than weight loss. Unlike this study, a study from India showed that
fever was the most prevalent symptom in TBLN [
]. Moreover, the prevalence of one or more
systemic symptoms was 56.6% which is slightly higher than 49% in this report [
report from Turkey showed the prevalence of cough to be 26?33% which is in line with this
report. However, night sweating of 29?36% which was reported by a study from Turkey [
was lower than the present report (55%).
Due to methodological exclusion of articles published in languages other than English and
missing of grey literatures; publication bias is likely high. Although we included a large
number of articles in the review, each article however contained only few variables. Thus,
prevalence estimate was based on a small sample size which might make our pooled estimate
imprecise. In addition, most of the included articles were chart reviews and retrospective in
nature likely introducing clinical and methodological heterogeneity. These collectively reduce
the quality of the generated evidence.
This review is the first comprehensive meta-analysis that estimated pooled prevalence for key
demographic, exposure, and clinical variables that could characterize TBLN. Of the total 28
articles included in the review, 19 were from the Horn of Africa with most of these from
Ethiopia (14 studies) suggesting more clustering of TBLN in Eastern Africa than in other sub
regions. Within Ethiopia, TBLN was also relatively more clustered in agrarian than in pastoral
Most TBLN (77%) were cervical in type, matted (67%) and mobile (64%) in their feature.
The majority (68%) were in the age-range of 15?44 years. Unlike PTB which is more prevalent
among males; TBLN is slightly higher among females (53%) and this requires further
investigation. The TBLN/HIV co-infection rate was 52% in overall Africa, 21% in Ethiopia and 73%
in the rest of Africa excluding Ethiopia which indicates the unique feature of TBLN
epidemiology in Ethiopia. Eighty-eight percent of TBLN cases had no prior TB treatment history, 52%
had livestock exposure and 24% had BCG vaccination scar. The prevalence of cardinal
systemic symptoms among TBLN cases were 45%, 55%, 62% and 32% for fever, night sweating,
weight loss, and history of cough for longer than two weeks, respectively.
To identify the most informative risk factors for TBLN, a meta-analysis and/or a
prospective double population-based study is highly desirable. In addition, the host and pathogen
genomic dimension and their evolutionary relationship should be investigated.
S1 Table. Literature search strategy.
S2 Table. Full Robbins-I risk of bias assessment result.
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S1 Fig. Sensitivity analysis of gender, age and TBLN/HIV co-infection.
S2 Fig. Funnel plots showing publication bias.
S1 File. Completed PRISMA check list of the review.
Conceptualization: Abraham Aseffa.
Data curation: Awoke Derbie, Abebe Shumet, Endalkachew Nibret, Fantahun Biadglegne,
Formal analysis: Daniel Mekonnen, Andargachew Abeje, Fantahun Biadglegne, Abaineh
Investigation: Abraham Aseffa.
Software: Andargachew Abeje. Supervision: Abraham Aseffa. Methodology: Daniel Mekonnen, Awoke Derbie, Abebe Shumet, Endalkachew Nibret, Fantahun Biadglegne, Abaineh Munshae, Liya Wassie.
Validation: Fantahun Biadglegne, Stefan Berg, Abraham Aseffa.
Writing ? original draft: Daniel Mekonnen, Kidist Bobosha, Liya Wassie.
Writing ? review & editing: Daniel Mekonnen, Awoke Derbie, Abebe Shumet, Endalkachew
Nibret, Fantahun Biadglegne, Abaineh Munshae, Kidist Bobosha, Liya Wassie, Stefan Berg,
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