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Published in final edited form as:

Pneumonia (Nathan). 2016 ; 8: . doi:10.1186/s41479-016-0018-6.

Global Burden of Childhood Tuberculosis

Helen E. Jenkinsa
aDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.

Abstract
In 2015, the World Health Organization (WHO) declared tuberculosis (TB) to be responsible for
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more deaths than any other single infectious disease. The burden of TB among children has
frequently been dismissed as relatively low with resulting deaths contributing very little to global
under-five all-cause mortality, although without rigorous estimates of these statistics, the burden of
childhood TB was, in reality, unknown. Recent work in the area has resulted in a WHO estimate of
1 million new cases of childhood TB in 2014 resulting in 136,000 deaths. Around 3% of these
cases likely have multidrug-resistant TB and at least 40,000 are in HIV-infected children. TB is
now thought to be a major or contributory cause of many deaths in children under five years old,
despite not being recorded as such, and is likely in the top ten causes of global mortality in this age
group. In particular, recent work has shown that TB is an under-lying cause of a substantial
proportion of pneumonia deaths in TB-endemic countries. Childhood TB should be given higher
priority: we need to identify children at greatest risk of TB disease and death and make more use
of tools such as active case-finding and preventive therapy. TB is a preventable and treatable
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disease from which no child should die.

Keywords
Incidence; mortality; estimation; drug resistance

Introduction
In 1963, Edith Lincoln and Edward Sewell wrote in their seminal book, Tuberculosis in
Children: “At the present time the death rate from tuberculosis is markedly reduced in some
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Corresponding author Dr Helen E. Jenkins, Department of Biostatistics, Boston University School of Public Health, Boston, MA,
02118, USA. Telephone number: +1 617 216 7893. [email protected].
Declarations
Ethics approval and consent to participate
Not applicable
Consent for publication
Not applicable
Availability of data and materials
All extracted data and references used are cited within this manuscript
Competing interests
HEJ declares no competing interests
Authors' contributions
HEJ was invited to write this manuscript and was provided with the title by the series editor. HEJ conceived the structure and content
of the manuscript. HEJ wrote the manuscript and was responsible for final approval and submission of the manuscript.
 Jenkins Page 2

areas and it is possible to look forward to the day when tuberculosis will no longer be a
public health problem1.” More than 50 years later, in 2015, the World Health Organization
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(WHO) declared tuberculosis (TB) to be the number one killer among infectious diseases2.

The underlying reasons for this resurgence are complex. They include HIV, the oldest known
sample of which was taken just three years before the publication of ‘Tuberculosis in
Children’, although it was not identified as HIV until many decades later3. Another
contributory factor, drug resistance, was already known about in 1963, although few could
have foretold the devastating impact it would have on TB control. But what has the impact
been on children? What proportion of the estimated 9.6 million new TB cases in 20152
occurred in children? How many were HIV-infected or infected with drug-resistant TB? And
how many died? We simply don’t know many of these basic statistics, largely because the
diagnosis of TB in children still relies heavily on the methods that Edith Lincoln was using
in Bellevue Hospital more than half a century ago1. However, there is a growing
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understanding that many cases of TB disease in children are not reported as such4.

While TB is the number one infectious cause of death among all age groups, pneumonia
bears that title among children under five years old, with an estimated 935,000 deaths in
20135. Mycobacterium tuberculosis, the causative agent of tuberculosis, is also a recognized,
although under-diagnosed, cause of pneumonia, especially in TB endemic areas and among
HIV-infected children6. A recent review found that between 1% and 23% of pneumonia
cases also had TB disease7. The true extent to which tuberculosis is an under-lying cause of
morbidity and mortality attributed to other causes is unknown, largely due to problems with
the diagnosis of TB in children4. However, with increasing attention on childhood TB in
recent years8, there have been considerable steps taken to use mathematical and statistical
tools to help us understand the true burden of childhood TB.
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Here, I summarise our current knowledge about the burden of childhood TB, with specific
reference to incidence and mortality, as well as the impact of HIV and drug resistance on
this vulnerable and often neglected population.

Why is it important to understand the burden of childhood TB?

Firstly, we must consider what we mean by the word “burden”. Burden is a non-specific
term measuring the impact of a health problem in terms of financial cost, mortality,
morbidity or other indicators and here we will focus primarily on morbidity and mortality
due to varying forms of TB. The reasons behind the need to understand disease burdens are
broadly similar across diseases: without robust estimates of the true burden of disease, we
cannot identify gaps in identification of cases, estimate the resources required to reduce this
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burden, begin to plan the types of interventions that might be effective or measure the impact
of these interventions. The specific reasons for understanding the burden of childhood TB
have been covered previously9 but include the need to raise advocacy for childhood TB,
which has been traditionally much neglected10; a need for increased research into improved
diagnostics and treatment regimens specifically for children; demonstration of the
importance of TB in the context of overall childhood morbidity and mortality; and because
childhood TB is a surveillance indicator for recent transmission within a community11.

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The END TB Strategy has the specific aims of reducing global TB incidence and mortality
by 90% and 95% respectively by the year 203512. However, without good estimates of
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incidence and mortality, it will be impossible to know if these targets have been met.
Children make up 26% of the global population and 43% in low-income countries13.
Therefore, to monitor our progress towards the END TB goals, we need robust estimates of
incidence and mortality in children.

Incidence of childhood TB disease

In 2011, the WHO produced their first estimate of global childhood (< 15 years) TB annual
incidence of 490,00014, assuming equal case detection rates in children and adults. Earlier
estimates had included 663,99015 (1990), 884,01916 (2000) and 1,039,00015 (2000). In
2014, three new pediatric TB incidence estimates were put forward. Jenkins et al. published
an estimate of approximately 1 million17 (Table 1). This was produced by scaling up age-
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disaggregated smear positive notifications reported to the WHO, in such a way as to account
for the substantial difference that exists between adults and children in terms of the
proportion of all TB cases expected to be smear positive18,19. In the second method, Dodd et
al. used a mathematical model that estimated the incidence of TB infection in children using
WHO TB prevalence data and demographic information20. Their model then estimated
childhood TB disease incidence by incorporating the age-dependent risk of progression from
infection to disease, accounting for HIV infection and BCG vaccination. They estimated that
there were 651,000 incidence cases of childhood TB in the 22 high-burden countries
(HBCs)20 in 2010. This was later updated to produce a global estimate of around 850,00021
in 2014 (Table 1). A third independent group, the Institute of Health Metrics and Evaluation
(IHME), estimated that there were 150,000 incident pediatric TB cases in 201322 (among
HIV-negative cases only). Notably, this was lower than the number of cases notified by
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countries to the WHO.

Following a meeting of the WHO Global Task Force on TB Impact Measurement in 201523,
it was recommended that the WHO combine the methods of Jenkins et al.17 and Dodd et
al.20 to produce their pediatric TB incidence estimates23. The method of Murray et al. was
excluded due to lack of information about the uncertainty of the estimate24. The new WHO
combined estimate was 1 million incident child TB cases in 20142 (Table 1).

Given that only 359,000 pediatric TB cases were notified to the WHO in 2014, this implies
that two-thirds of all children that developed active TB disease in 2014 were not notified.
The assumption is that these children were not diagnosed and therefore, did not receive
treatment. The morbidity and mortality implications of so many children not receiving
treatment are profound and very worrying. Estimation of how many of these “invisible”
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children exist has been an essential part of raising advocacy for these children and
demonstrating the need for improved diagnostics25 and methods to find these children (e.g.
active case-finding26). TB is both preventable and treatable but we need to identify these
children in the first place.

Of particular concern are children under the age of five years. These children are less likely
to be diagnosed with TB, given that they have the disease, but more likely to suffer serious

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sequelae such as TB meningitis27. So far, Dodd et al. are the only group to specifically
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estimate TB incidence in children under five, although WHO under-five estimates may be
published in their annual TB report later in 2015. Dodd et al. estimated that 51.4% of all
pediatric cases of TB disease in 2014 occurred in children aged under five years of age21
(Table 2). Applying this to the WHO pediatric TB incidence estimate would indicate that
514,000 children under five developed TB disease in 2014, which is nearly four and half
times the number notified to the WHO for that year28.

Drug-resistant TB disease
Drug-resistant TB is under-diagnosed among all age groups due to the resources and costs
required for diagnosis and limited access to testing facilities in many parts of the world29.
Difficulties with obtaining bacteriologically positive sputum from children with TB only
serve to amplify these issues30. It is believed that the majority of cases of pediatric drug-
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resistant TB are undiagnosed as such and therefore inappropriately treated11, if they receive
any treatment at all. With so much under-diagnosis of pediatric drug-resistant TB, how do
we know how many children globally develop active TB disease annually due to a drug-
resistant strain?

Until 2014, no estimate of the global burden of multidrug-resistant (strains resistant to the
drugs isoniazid and rifampicin, the backbone of TB therapy) TB (MDR-TB) existed. A
systematic review of the literature published before 12 January 2012 identified 97 reports
that included 8,382 children with drug-susceptibility results for isoniazid and rifampicin17.
Of these, 348 children tested positive for MDR-TB. In 2012, authors from the WHO
reported results from an analysis of their full database of the Global Project on Anti-
tuberculosis Drug Resistance Surveillance31 on MDR-TB reporting between 1994 and 2011.
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They found that of 6,070 children tested for MDR-TB, 456 were positive. A 2012 review of
the literature published before 31 October 2011 on treatment outcomes among children with
MDR-TB identified 315 children with MDR-TB32. These three studies taken together
indicate that, even assuming no overlapping of study populations, just 1,119 children with
MDR-TB have been documented in the published literature.

In 2014, the first global estimate of the annual incidence of pediatric MDR-TB was
published17. This work reviewed the literature for studies that included both children and
adults tested for MDR-TB in the same setting and quantified the relationship between the
percentage of new (treatment-naïve) adult TB cases with MDR-TB and the percentage
observed in children. The authors then used WHO national estimates of the percentage of
new TB cases with MDR-TB by country to estimate the percentage of childhood TB cases
that had MDR-TB for every country worldwide. They then multiplied these percentages by
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their aforementioned pediatric TB estimates to obtain the global estimated number of

pediatric MDR-TB cases in 2010 of 32,00017 (Table 1), i.e. 3.2% of total childhood TB
incidence.

Although outcomes for children with MDR-TB who receive appropriate treatment can be
excellent32,33, the vast majority of these 32,000 annual new cases are never correctly
diagnosed with MDR-TB, much less receive appropriate treatment. It is sobering to think

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that the 1,119 children ever reported in the literature represent just 3.5% of the total incident
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cases that occur in one year.

The burden of other forms of drug-resistant TB also requires quantification. Isoniazid

preventive therapy (IPT) is one of our most effective, but under-used, tools against pediatric
TB34. However, its effectiveness could be under-mined by isoniazid-resistant (INH-R) latent
TB infection (LTBI). A recent review by Yuen et al. estimated that 12.1% of children with
TB globally had INH-R TB disease (including mono-resistance and combined with other
forms of resistance), representing 121,000 cases of disease35 (Table 1). This percentage was
highest in the former Soviet Union countries. Assuming that the percentage of TB cases with
isoniazid resistance in children with active disease is reflected in those with LTBI, isoniazid
preventive therapy will be ineffective in 12.1% of children with TB. It therefore crucial to
understand which children might be at highest risk of INHR-TB so that other preventive
methods can be used, such a regimen containing rifapentine or rifampicin36.
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Finally, Dodd et al. recently published an extension of their mathematical model to estimate
the number of children with several different forms of drug-resistant TB21. Noting that their
estimates worked from a lower baseline of overall TB incidence than those of Jenkins et al.,
they estimated that 24,800 had MDR-TB (i.e. 2.9% of all TB incidence) (Table 1) and
58,300 had mono-INH-R TB (i.e. 6.9% of all TB incidence). For comparison with the results
from Yuen et al., the total INH-R TB resistance estimate from Dodd et al. was 84,000 cases
constituting approximately 9.9% of all pediatric TB cases21. In addition, they estimated that
1,160 children had extensively drug-resistant TB (TB that is MDR-TB plus resistance to a
fluoroquinolone and an injectable drug).

TB incidence among HIV-infected children

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Despite the known importance of HIV co-infection in TB infected and diseased

individuals37, there are no estimates of the global burden of TB specifically in HIV-infected
children. Dodd et al. estimated that 5.0% (IQR: 2.4%, 10.1%) of TB incidence in the 22
HBCs occurs in HIV-infected children20. This translates to 32,500 HIV-infected children
developing active TB disease in the HBCs in 2010. A back-of-the-envelope calculation
would suggest that globally in 2014, between 40,000 and 50,000 HIV-infected children
developed TB disease.

We currently have two effective ways to prevent TB disease in TB-infected children:

isoniazid prophylaxis38 and anti-retroviral treatment (Dodd et al. in preparation). Many of
these 40,000 – 50,000 annual cases could be prevented with more rigorous deployment of
these preventive measures.
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Childhood mortality due to TB

Globally, an estimated 6.3 million children under five years old died in 20135 from all
causes. But how many of these children are dying from TB? The first WHO estimates of TB
mortality among children, released in 2015, found that 136,000 children under fifteen years
old died in 2014 from TB2 (Table 1). This estimate was based on data from vital registration
systems and mortality surveys from 129 countries; an imputation method was used for the

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remaining countries without such data (largely from Africa). Vital registration death data
have several limitations. For example, a cause might not be attributed39 or if it is, it might be
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incorrect, especially if only one cause of death is allowed40, despite multiple contributory
causes. For example, studies have shown that TB may come close to bacterial pneumonia as
a respiratory cause of death in children41,42. In addition, in many countries there are few
resources to carry out autopsies, and some deaths may not even be registered at all43. These
limitations are likely to be amplified in high TB burden countries with few resources to carry
out detailed autopsies. The IHME group also produced childhood TB mortality estimates of
60,000 TB-related deaths among HIV-negative children in 201422.

An alternative method of estimating the number of children dying with TB is to multiply

case fatality ratios (CFR; which could be defined in this context as the percentage of
children that die within a year of a TB diagnosis) by the estimated incidence of pediatric TB.
A recent systematic review and meta analysis has quantified CFRs among children with
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TB44. In particular, the authors searched the pre-chemotherapy literature to understand CFRs
in children that do not receive TB treatment. The authors estimated that 21.9% (95% CI:
18.1%, 26.4%) of children from the pre-chemotherapy era studies died from TB, within a
year of TB diagnosis. The case fatality ratio among children aged under 5 years old was
substantially worse at 43.6% (95% CI: 36.8%, 50.6%)44. Children receiving treatment faired
considerably better with less than 1% dying.

That nearly half of all children under five that do not receive treatment will die should be a
call to action. Mortality due to TB is likely a far more substantial problem than currently
thought and we urgently need to find and treat these children to prevent unnecessary deaths.
If we assume that all of the estimated children under-five with incident TB that were not
notified to the WHO in 2014, did not receive treatment, our case fatality ratios would
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suggest that 173,000 of these children died. This is already substantially higher than the
current childhood estimate of 136,000 and does not include children aged between 5 and 14
years old or account for any potential increased risk associated with HIV-infection.

Tuberculosis was not mentioned in a recent paper classifying the causes of global under-five
mortality5. Assuming that 50% of the 136,000 deaths from TB as per the WHO estimate,
occur in children under five years, TB should have been classed as the ninth highest cause of
death worldwide in children aged 1-59 months, above pertussis (Table in Liu et al.5). Our
back-of-the-envelope estimate of 173,000 children would place TB at number six, ahead of
meningitis, AIDS and measles.

The reality is that TB is causing disease in many more young children than we realize,
resulting in undiagnosed, untreated TB and too many preventable deaths. TB is being mis-
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diagnosed as other diseases and is also an under-lying, undiagnosed cause of deaths that are
attributed to other more easily diagnosed diseases, including pneumonia4. As Graham et al.4
pointed out, if just 10% of the 935,000 currently attributed to pneumonia5 were in fact due to
TB, this would add a further 93,500 deaths to the WHO estimate of 136,000, increasing it by
69%. Full recognition of the contribution that TB is making to under-five mortality is a first
and essential step in reducing that contribution.

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Meningitis
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The main cause of serious morbidity and mortality in children with TB is TB meningitis27.
The successes of the roll-out of pneumococcal vaccines in recent years45,46 have resulted in
TB meningitis becoming one of the most prevalent forms of bacterial meningitis47,48. There
are currently no estimates of the number of children that develop TB meningitis worldwide
or that die from the disease, largely due to difficulties with diagnosis49. However, a recent
study found that 19.3% (95% CI: 14.0%, 26.1%) of children with TB meningitis will die and
that among the survivors 53.9% (95% CI: 42.6%, 64.9%) will experience neurological
sequelae50. Given the high mortality and morbidity associated with this form of TB, we
urgently need to understand how many children develop and die from this disease and where
they are most prevalent. This is a major gap in our knowledge regarding the global burden of
childhood TB.
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Latent TB infection
One important way of preventing future morbidity and mortality due to TB is through active
case-finding to identify probable cases of latent tuberculosis infection (LTBI) in children and
target those children with preventive therapy26. However, we need robust estimates of how
many children are likely to have LTBI and where these children are located so that we can
maximize the effectiveness of our active case-finding. Dodd et al. estimated that 67 million
children under fifteen years old were infected with TB in 201421 (Table 1). The majority of
these were located in the SouthEast Asia region (27 million) and the African region (20.9
million)21. In addition, Dodd et al. estimated the number of children latently infected with
various forms of drug-resistant TB21 (Tables 1 and 2). These estimates by Dodd et al. were
generated assuming a constant annual rate of infection (ARI) and extrapolating backwards
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over 15 years. Houben and Dodd have recently produced an estimate of annual LTBI
prevalence in children of 97 million51. In their method, the historical ARI was allowed to
vary, based on changes in WHO estimates of TB disease prevalence and direct ARI
estimates from tuberculin skin test surveys.

These are important statistics to know but it is unrealistic to think that all of these children
can and should be given preventive therapy. Yuen et al. recently published estimates of how
many children might be targeted for preventive therapy52. The authors estimated how many
children live in a household with at least one adult diagnosed pulmonary TB case and
therefore, have been at risk of transmission and should be offered preventive therapy. The
authors also estimated how many of these child contacts were likely to already have TB
disease at the time that they are investigated. The result was an estimated 7.48 million
children living with an adult diagnosed pulmonary TB case, of which, 2.41 million were
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under five years old. Of these 7.48 million, the authors estimated that approximately 660,000
would have TB disease upon investigation, with 239,000 aged under five years. National or
sub-national targets such as these allow a National Tuberculosis Program to plan resources
and interventions to identify and treat children at risk of or already experiencing TB disease.

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Concluding statement
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Focus on and development of methods to estimate the global burden of childhood TB have
advanced enormously in recent years; childhood TB is starting to get the recognition that it
unfortunately deserves, although much more could be done. Approximately 1 million
children develop TB disease each year and at least 14% die, probably considerably more.
We are beginning to drill down and understand the burden among children infected with
HIV, as well as the risk of drug-resistant forms of TB in children. The majority of these
children are never diagnosed with or treated for their TB disease and TB is likely a far more
important cause of under-five mortality than is currently believed. Now that we are
beginning to appreciate the scale of the problem, we need a more accurate understanding of
precisely which children are at greatest risk of morbidity and mortality so that they can be
targeted with preventive treatment. No child should die from TB in the 21st century.
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Acknowledgements
HEJ would like to thank Dr. Courtney Yuen, Dr. Pete Dodd, Dr. Rein Houben and Dr. James Seddon for helpful
comments on an earlier version of this manuscript.

Funding HEJ was funded by US National Institutes of Health US NIH K01AI102944. The content of the article is
solely the responsibility of the authors and does not necessarily represent the views of the National Institute of
Allergy and Infectious Disease or the Office of the Director, NIH. The funder had no role in study design, decision
to publish, or writing of the manuscript.

List of abbreviations
ARI Annual Risk of Infection

BCG Baccile Calmette-Guerin Vaccination

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IHME Institute of Health Metrics and Evaluation

INH-R TB Isoniazid Resistant Tuberculosis

IPT Isoniazid Preventive Therapy

LTBI Latent Tuberculosis Infection

MDR-TB Multidrug-Resistant Tuberculosis

TB Tuberculosis

WHO World Health Organization

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Table 1

Annual estimates of the childhood tuberculosis (TB) burden among children aged 0-14 years
Jenkins

Measure TB disease Fraction of all pediatric TB cases Latent TB infection

999,792 (95% CI: 937,877 - 1,055,414)a

TB 847,000 (IQR: 558,000 – 1,280,000)b 67 million (IQR: 52.3 million - 85.7 million)b
N/A
incidence
1,000,000 (UI: 900,000 – 1,100,000)c

150,000d

INH-R TB 120,872 (95% CI: 96,628 - 149,059)c 12.1% (95% CI: 9.8% - 14.8%)c

84,000b+ 9.9%b 6.8 millionb

MDR-TB 31,948 (95% CI: 25,594 – 38,663)a 3.2%a

24,800 (IQR: 16,100 - 37,400)b 2.9% (IQR: 2.7% - 3.1%)b 2.0 million (IQR: 1.6 million – 2.6 million)b

Mortality 136,000 (range: 115,000 – 157,000)c 13.6%c N/A

60,000d

a
Jenkins et al. 201417;
b
Dodd et al. 201621;
c
WHO 20152;
d
Murray et al. 2014 (Note: there are no uncertainty ranges around these estimates);
e
Yuen et al. 201535

Pneumonia (Nathan). Author manuscript; available in PMC 2016 December 19.

+
Note that Dodd et al. 2016 produced an estimate of INH-R TB mono-resistance of 58,300 (IQR: 38,300 – 87,000) cases. The figure presented of 84,000 represents all forms of INH-R (i.e. mono-resistance
plus MDR-TB) but because this was not formally estimated in Dodd et al. 2016, there is no IQR around this result.

INH-R – Isoniazid resistant; MDR – Multidrug-resistant; CI - Confidence Interval; IQR - Interquartile range; UI - Uncertainty Interval
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Table 2

Annual estimated burden of childhood tuberculosis (TB) among children aged 0-4 years*
Jenkins

Measure Estimate (Inter-quartile range) Fraction of all pediatric TB (0-14 yrs of

age)
TB incidence 435,000 (278,000 – 651,000) 51.4%

Isoniazid- 42,200+ 50.2%

resistant TB

Multidrug- 12,700 (8,020 – 19,000) 51.2%

resistant TB

*
All estimates are from Dodd et al. 201621
+
Note that Dodd et al. 2016 produced an estimate of INH-R TB mono-resistance of 58,300 (IQR: 38,300 – 87,000) cases. The figure presented of 84,000 represents all forms of INH-R (i.e. mono-resistance
plus MDR-TB) but because this was not formally estimated in Dodd et al. 2016, there is no IQR around this result.

Pneumonia (Nathan). Author manuscript; available in PMC 2016 December 19.

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