Outcomes of empiric treatment for pediatric tuberculosis, Kampala, Uganda, 2010–2015

Abstract

Background
Childhood tuberculosis (TB) diagnoses often lack microbiologic confirmation and require empiric treatment. Barriers to empiric treatment include concern for poor outcomes and adverse effects. We thus determined the outcomes of empiric TB treatment from a retrospective cohort of children at a national referral hospital in Kampala, Uganda from 2010 to 2015.

Methods
Children were diagnosed clinically and followed through treatment. Demographics, clinical data, outcome and any adverse events were extracted from patient charts. A favorable outcome was defined as a child completing treatment with clinical improvement. We performed logistic regression to assess factors associated with loss to follow up and death.

Results
Of 516 children, median age was 36 months (IQR 15–73), 55% (95% CI 51–60%) were male, and HIV prevalence was 6% (95% CI 4–9%). The majority (n = 422, 82, 95% CI 78–85%) had a favorable outcome, with no adverse events that required treatment discontinuation. The most common unfavorable outcomes were loss to follow-up (57/94, 61%) and death (35/94, 37%; overall mortality 7%). In regression analysis, loss to follow up was associated with age 10–14 years (OR 2.38, 95% CI 1.15–4.93, p = 0.02), HIV positivity (OR 3.35, 95% CI 1.41–7.92, p = 0.01), hospitalization (OR 4.14, 95% CI 2.08–8.25, p < 0.001), and living outside of Kampala (OR 2.64, 95% CI 1.47–4.71, p = 0.001). Death was associated with hospitalization (OR 4.57, 95% CI 2.0–10.46, p < 0.001), severe malnutrition (OR 2.98, 95% CI 1.07–8.27, p = 0.04), baseline hepatomegaly (OR 4.11, 95% CI 2.09–8.09, p < 0.001), and living outside of Kampala (OR 2.41, 95% CI 1.17–4.96, p = 0.02).

Conclusions
Empiric treatment of child TB was effective and safe, but treatment success remained below the 90% target. Addressing co-morbidities and improving retention in care may reduce unfavorable outcomes.

Full text

R E S E A R C H A R T I C L E Open Access
Outcomes of empiric treatment for
pediatric tuberculosis, Kampala, Uganda,
2010–2015
Eric Wobudeya
1*†
, Devan Jaganath
2†
, Moorine Penninah Sekadde
3
, Betty Nsangi
4
, Heather Haq
5
and
Adithya Cattamanchi
6,7,8
Abstract
Background: Childhood tuberculosis (TB) diagnoses often lack microbiologic confirmation and require empiric
treatment. Barriers to empiric treatment include concern for poor outcomes and adverse effects. We thus
determined the outcomes of empiric TB treatment from a retrospective cohort of children at a national referral
hospital in Kampala, Uganda from 2010 to 2015.
Methods: Children were diagnosed clinically and followed through treatment. Demographics, clinical data,
outcome and any adverse events were extracted from patient charts. A favorable outcome was defined as a child
completing treatment with clinical improvement. We performed logistic regression to assess factors associated with
loss to follow up and death.
Results: Of 516 children, median age was 36 months (IQR 15–73), 55% (95% CI 51–60%) were male, and HIV
prevalence was 6% (95% CI 4–9%). The majority (n= 422, 82, 95% CI 78–85%) had a favorable outcome, with no
adverse events that required treatment discontinuation. The most common unfavorable outcomes were loss to
follow-up (57/94, 61%) and death (35/94, 37%; overall mortality 7%). In regression analysis, loss to follow up was
associated with age 10–14 years (OR 2.38, 95% CI 1.15–4.93, p= 0.02), HIV positivity (OR 3.35, 95% CI 1.41–7.92,
p= 0.01), hospitalization (OR 4.14, 95% CI 2.08–8.25, p< 0.001), and living outside of Kampala (OR 2.64, 95% CI
1.47–4.71, p= 0.001). Death was associated with hospitalization (OR 4.57, 95% CI 2.0–10.46, p< 0.001), severe
malnutrition (OR 2.98, 95% CI 1.07–8.27, p= 0.04), baseline hepatomegaly (OR 4.11, 95% CI 2.09–8.09, p< 0.001),
and living outside of Kampala (OR 2.41, 95% CI 1.17–4.96, p= 0.02).
Conclusions: Empiric treatment of child TB was effective and safe, but treatment success remained below the 90%
target. Addressing co-morbidities and improving retention in care may reduce unfavorable outcomes.
Keywords: Child, Tuberculosis, Treatment, Outcomes
Background
Timely initiation of treatment is critical for effective
tuberculosis (TB) care and control in children. Of the
estimated 233,000 children that die from TB each year,
96% did not receive treatment [1,2]. For primary care
providers in TB endemic settings, challenges with
confirming a TB diagnosis in children and concern of
adverse effects with empiric treatment (i.e., without
microbiological confirmation) are key barriers to initiat-
ing anti-TB treatment [3,4]. Symptoms are non-specific,
chest x-ray findings variable, and diagnostic testing is
often unavailable or not feasible due to difficulty obtain-
ing sputum [3,5]. Even when diagnostic testing occurs,
sensitivity is decreased due to the paucibacillary nature
of pediatric TB [6]. This contributes to 55% of child TB
cases not being reported to national programs [2] from
high TB burden settings have consistently documented
that health care workers feel uncomfortable about
making a TB diagnosis in a child and that there are often
© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribut ion 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
* Correspondence: ewobudeya@gmail.com
†
Eric Wobudeya and Devan Jaganath contributed equally to this work.
1
Directorate of Pediatrics & Child Health, Mulago National Referral Hospital,
P.O. Box 23491, Kampala, Uganda
Full list of author information is available at the end of the article
Wobudeya et al. BMC Public Health (2019) 19:446
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delays in care [7–9]. For example, a cross-sectional study
of six primary clinics in Kampala found that no children
who met clinical criteria for TB had been started on
anti-TB treatment [10]. While algorithms exist to iden-
tify children with TB based on clinical factors [11–13], a
concern is that without microbiologic confirmation, mis-
diagnosis could result in poor outcomes or adverse
events from anti-TB treatment. A better understanding
of outcomes of children treated empirically for TB based
on a clinical diagnosis would provide more guidance to
providers about the effectiveness and safety. We thus an-
alyzed outcomes of children less than 15 years of age
with clinically diagnosed TB receiving empiric treatment
over a five-year period at a national referral hospital in
Kampala, Uganda, and factors associated with the
unfavorable outcomes of lost to follow up and death.
Methods
Study design and setting
This was a retrospective cohort study of children treated
for clinically diagnosed TB at Mulago National Referral
Hospital Pediatric TB Clinic. The clinic treats children
up to 14 years of age with drug-susceptible TB using
Fixed Dose Combination (FDC) treatment in accordance
with Uganda National TB and Leprosy Programme
(NTLP) guidelines [13]. Children are seen in clinic every
two weeks during the first month of treatment and
monthly thereafter for the standard six-month or
twelve-month treatment depending on the TB disease
type. At each visit, clinical notes are documented using
standardized forms and entered into a secure electronic
database. Adverse events are monitored based on clinical
symptoms and exam, without routine laboratory testing.
Management of any adverse events were completed
according to national guidelines [12]. The Mulago
Hospital Research and Ethics Committee approved the
study protocol and waived the requirement for informed
consent.
Study population
We included all children less than 15 years old treated
empirically for TB between January 2010 and December
2015. Clinical diagnosis was made per NTLP guidelines
[12,13]. We excluded children if they had multi-drug
resistant (MDR) TB, were transferred, or were missing
key variables (age and treatment outcome). As a com-
parison, outcomes on children with confirmed TB were
also collected.
Data collection and definitions
The data was not publically available hence we obtained
Mulago Hospital permission to use the data. We
extracted demographic and clinical data including HIV
status, type of TB, TB treatment outcome, and any
adverse events from the Pediatric TB Clinic electronic
database. We defined severe malnutrition as a weight-
for-age Z score less than −3. We defined a favorable
outcome if the child completed treatment and had
documented clinical improvement, and an unfavorable
outcome if the child died, failed treatment (no clinical
improvement or treatment discontinuation) or was lost
to follow-up prior to completion of treatment.
Statistical analysis
Descriptive statistics were assessed with proportions and
95% confidence intervals (CI) for categorical variables
and median and interquartile range (IQR) for continuous
variables. For bivariate analysis of characteristics associ-
ated with favorable versus unfavorable outcome, we
compared proportions using the chi-squared test. We
stratified unfavorable outcomes into loss to follow up
and death, and conducted logistic regression on char-
acteristics with p-value < 0.05 from the unfavorable
bivariate analysis. HIV status and severe malnutrition
(known to be associated with unfavorable outcome)
[14,15], and sex were also included. Odds Ratios
(OR) were presented with 95% Confidence Intervals
(CI); p-value < 0.05 was considered significant. We
performed analyses using STATA 15 (Stata Corp,
College Station, TX, USA).
Results
Cohort characteristics
Of 713 children treated for TB during the study period,
there were 64 with confirmed TB, 1 with MDR TB, 1
with missing age information, 23 who were transferred
out, and 108 with missing treatment outcome (Fig. 1),
for a total of 516 children empirically started on anti-TB
treatment.
Details of patient characteristics by outcome are
shown in Table 1. The median age was 36 months (IQR
15–73), 55% (95% CI 51–60%) were male, and about half
resided outside of Kampala district (46, 95% CI 41–
50%). The majority (65, 95% CI 61–69%) were below
five years old, and HIV prevalence was 6% (31/509,
95% CI 4–9%). The prevalence of severe malnutrition
was 22% (76/349, 95% CI 18–26%). Over two-thirds
(69%, 354/515, 95% CI 65–73%) of diagnoses were
pulmonary TB cases.
Outcomes of empiric treatment
Of the 516 children empirically started on anti-TB
treatment, 422 (82%) children had a favorable treatment
outcome. Of the 94 children with unfavorable outcomes,
61% (57/94) were lost to follow-up, 37% (35/94) died,
and 2% (2/94) failed treatment. The majority of deaths
were in children under five years (22/35, 63%); three
deaths occurred in children infected with HIV. The
Wobudeya et al. BMC Public Health (2019) 19:446 Page 2 of 6
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765 records
extracted
64 confirmed TB cases
1 MDR TB case
1 No age
23 Transferred out
108 No treatment outcomes
516 started on
empiric therapy
94 (18%)
unfavorable
outcome
422 (82%)
favorable
outcome
713 started on
TB therapy
Fig. 1 Participant Flowchart
Table 1 Demographic and clinical characteristics of children empirically treated for TB at Mulago Pediatric TB unit (N= 516)
*
Characteristic Favorable (N= 422) Unfavorable (N= 94) p-value
†
N (%, 95 CI) N (%, 95 CI)
Age group
< 5 years 280 (66, 62–71) 57 (61,50–70) 0.006
5–9 years 104 (25, 21–29) 18 (19, 12–28)
10–14 years 38 (9, 7–12) 19 (20, 13–30)
Male Sex 238 (56, 52–61) 48 (51, 41–61) 0.35
Reside outside of Kampala 174 (41, 37–46) 62 (66, 56–75) < 0.001
Pulmonary TB (n= 515) 291 (69, 65–73) 53 (67, 57–76) 0.69
HIV positive (n= 509) 19 (5, 3–7) 12 (14, 8–23) 0.001
Severe Malnutrition
‡
(n= 349) 60 (20, 16–25) 16 (32, 20–46) 0.06
Hospitalized (n= 480) 33 (8, 6–11) 26 (34, 24–45) < 0.001
Abnormal Chest X-ray (n= 367) 297 (93, 90–96) 46 (94, 82–98) 1.0
BCG vaccinated (n= 301) 239 (92, 88–95) 35 (83, 68–92) 0.06
Baseline Hepatomegaly (n= 383) 28 (8, 6–12) 13 (30, 18–46) < 0.001
TST Positive (n= 246) 161 (75, 69–80) 18 (58, 40–74) 0.05
*N = 516 unles s missing data, with number available indicated in parentheses
†p-value by Chi-squared or Fisher’s exact testing
‡Severe malnutrition defined as weight-for-age Z score less than −3
Wobudeya et al. BMC Public Health (2019) 19:446 Page 3 of 6
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proportion of children on empiric treatment with
favorable outcomes was similar to the children who had
confirmed TB (48 of 54 with outcomes, 89%, versus 82%
on empiric treatment, p= 0.17).
In total, there were eight drug reactions reported at
follow up visits, with complaints that included
paresthesia in the lower limbs, scaling in the plantar
foot, vomiting, pallor and myalgia. However, there were
no adverse events reported that required treatment
discontinuation.
Unfavorable outcomes were more likely among
children aged 10–14 years, HIV positive, not residing in
Kampala, with baseline hepatomegaly, and
hospitalization (Table 1). When stratified by loss to
follow up and death (Table 2), loss to follow up was
associated with age 10–14 years (OR 2.38, 95% CI 1.15–
4.93, p= 0.02), HIV infection (OR 3.35, 95% CI 1.41–
7.92, p= 0.01), hospitalization (OR 4.14, 95% CI 2.08–
8.25, p< 0.001), and residing outside of Kampala (OR
2.64, 95% CI 1.47–4.71, p= 0.001). Death was associ-
ated with being hospitalized (OR 4.57, 95% CI 2.0–
10.46, p< 0.001), severe malnutrition (OR 2.98, 95% CI
1.07–8.27, p= 0.04), hepatomegaly at baseline (OR 4.11,
95% CI 2.09–8.09, p < 0.001), and residing outside of
Kampala (OR 2.41, 95% CI 1.17–4.96, p=0.02).
Discussion
In this study, we describe empiric treatment outcomes
of children clinically diagnosed with TB at a referral cen-
ter in Kampala, Uganda from 2010 to 2015. The majority
of children (82%) had a favorable outcome with clinical
improvement. However, this is below the World Health
Organization (WHO) target of 90% treatment success
[16]. There were no adverse events that required discon-
tinuation of treatment. Loss to follow-up was the most
common unfavorable outcome and was associated with
older age (10–14 years), HIV infection, hospitalization,
and living outside of Kampala. Death was the next cause
of unfavorable outcome, and was associated with
hospitalization, severe malnutrition, baseline hepatomeg-
aly, and living outside of Kampala. Thus, empiric
treatment was found to be safe and effective for most chil-
dren, but greater efforts are needed to improve outcomes.
While the proportion with favorable outcome was
below the global target, it corresponds with child TB
outcomes in similar settings [16]. Retrospective studies
in Nigeria, South Africa and Ethiopia found child TB
(confirmed and clinically diagnosed) success rates of
77.4% [17], 78% [18], and 85.5% [19,20], respectively.
We also found a similar favorable proportion among the
confirmed child TB cases. Our data support that empiric
treatment of TB in children without microbiologic
confirmation does not lead to worse outcomes.
Loss to follow-up was the most common reason for an
unfavorable outcome. HIV co-infection has been associ-
ated with loss to follow up in youth [21,22], and may be
related to the additional pill burden, stigma and fear of
discrimination. Hospitalization and not living in
Kampala also were associated with loss to follow up;
improved efforts are needed to ensure follow up after a
child is discharged from the hospital, and to address
barriers to obtaining care if the child does not live near
the clinic. For example, Defeat TB is an initiative in
Uganda to improve TB treatment success through health
system strengthening to improve coordination of care
and decentralize TB diagnosis and management [23].
Children age 10–14 years were more than twice as
likely to be lost to follow up as children under 5 years.
Compared to younger children, adolescents with TB face
unique challenges to their care, including greater peer
pressure, stigma, behavioral issues, substance abuse and
prevalence of co-morbidities including HIV [2]. A retro-
spective analysis in South Africa found that 15% of ado-
lescents with HIV aged 15–19 years discontinued TB
Table 2 Factors associated with loss to follow up or death in children empirically treated at Mulago Pediatric TB unit, 2010–2015
Loss to Follow Up Death
OR (95% CI) p-value OR (95% CI) p-value
Age Group
< 5 yrs REF –REF –
5–9 yrs 0.88 (0.43–1.80) 0.73 0.87 (0.36–2.09) 0.76
10–14 yrs 2.38 (1.15–4.93) 0.02 1.68 (0.65–4.36) 0.28
Male sex 0.75 (0.43–1.31) 0.31 0.84 (0.42–1.67) 0.62
HIV positive 3.35 (1.41–7.92) 0.01 1.60 (0.46–5.57) 0.46
Hospitalization 4.14 (2.08–8.25) < 0.001 4.57 (2.0–10.46) < 0.001
resides outside of Kampala 2.64 (1.47–4.71) 0.001 2.41 (1.17–4.96) 0.02
Severe Malnutrition 1.46 (0.65–3.3) 0.36 2.98 (1.07–8.27) 0.04
Baseline Hepatomegaly 1.36 (0.83–2.22) 0.22 4.11 (2.09–8.09) < 0.001
CI Confidence Interval, OR odds ratio, HIV Human Immunodeficiency Virus
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treatment [24]. A study in Botswana found that adolescents
were twice as likely to be lost to follow-up compared to
adult [21]. These results emphasize that adolescent-friendly
TB programs are needed to address their unique issues and
continue to engage adolescents in care.
Mortality was the second most common unfavorable
outcome. Our overall mortality was high at 7%, similar
to the study in Nigeria that found a child TB mortality
of 6% [17]. Consistent with past studies [17–19], our
analyses found that factors related to more severe dis-
ease were associated with death, namely hospitalization,
severe malnutrition and hepatomegaly. Living outside of
Kampala district was also associated with death, and
may reflect socioeconomic factors or delays in diagnosis
and management.
Prior assessments of child TB outcomes have included
both confirmed and clinically diagnosed TB. Confirmed
cases may reflect children with higher bacterial load or
occur in settings where there is greater access to diag-
nostics. By focusing only on children empirically treated
for TB based on a clinical diagnosis, we sought to
provide outcome data that was more generalizable to the
majority of health care workers in low-resource settings.
There were also some potential limitations to our
study. As a retrospective cohort, we cannot comment on
the accuracy of the clinical diagnoses, although docu-
mented symptoms and signs were consistent with na-
tional guidelines. The study was conducted at a referral
hospital, and may lower generalizability to primary care
clinics. Mortality from alternative diagnoses were
possible, and the exact causes of death were unknown.
Adherence was not consistently documented. There was
no available data on contacts with multi-drug resistant
(MDR) TB to address empiric MDR treatment. The
sample had a low proportion with HIV infection and
limits the assessment of outcomes of empiric TB treat-
ment in HIV-TB co-infected children. In particular,
HIV-related mortality was low, and may be an underesti-
mate as we did not include children with confirmed TB,
who were transferred out or who had missing outcomes.
The low number of unfavorable outcomes did not pro-
vide the power for a multivariable stratified regression
analysis. Data was also not available on any follow-up la-
boratory testing to determine sub-clinical adverse events
such as elevated liver transaminases on treatment.
Conclusions
Our results highlight that initiation of empiric TB care
in children is overall safe and effective if health care
workers use appropriate clinical guidelines. However,
they also suggest that diagnosis and initiation of treat-
ment are only the beginning of the care cascade; health
facility strengthening and age-appropriate care is critical
to ensure favorable outcomes and retention in care.
Abbreviations
aOR: Adjusted odds ratio; BCG: Bacillus Calmette–Guérin; CI: Confidence
interval; FDC: Fixed Dose Combination; HIV: Human Immunodeficiency Virus;
IQR: Interquartile Range; MDR: Multi-drug resistant; OR: Odds ratio;
TB: Tuberculosis; TST: Tuberculin Skin Test; WHO: World Health Organization
Acknowledgements
We thank the families, staff, and administration at the Mulago National
Referral Hospital for their efforts in diagnosing and managing these
children with TB.
Funding
DJ is a Fellow in the Pediatric Scientist Development Program. This project
was supported by grants from the Eunice Kennedy Shriver National Institute
of Child Health and Human Development (K12 HD000850) and the National
Heart, Lung, and Blood Institute (R01 HL139717). The funders had no role in
the design, collection, analysis, interpretation, or writing of the study.
Availability of data and materials
The datasets used and/or analyzed during the current study are available
from the corresponding author on reasonable request.
Authors’contributions
DJ, EW and AC conceptualized the study and analysis. EW, MPS, BN and HH
provided oversight and collection of the data. EW and DJ conducted the
analysis. DJ and EW drafted the manuscript, and all authors provided
revisions. All authors have read and approved the manuscript.
Ethics approval and consent to participate
The Mulago Hospital Research and Ethics Committee approved the study
protocol and waived the requirement for informed consent. We conduct
chart reviews and did not get into contact with human subjects.
Consent for publication
Not applicable.
Competing interests
EW is an associate editor of the BMC Public Health journal. All the authors
declare that they have no competing interests.
Publisher’sNote
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1
Directorate of Pediatrics & Child Health, Mulago National Referral Hospital,
P.O. Box 23491, Kampala, Uganda.
2
Division of Pediatric Infectious Diseases,
University of California, 550 16th St. 4th floor, San Francisco, CA 94158, USA.
3
National TB and Leprosy Program (NTLP), Plot 6, Lourdel Road, Nakasero, P.
O. Box 7272, Kampala, Uganda.
4
USAID RHITES-EC, University Research Co.
LLC, Plot 40, Ntinda II Road, PO Box 28745, Kampala, Uganda.
5
Department
of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
6
Division of
Pulmonary and Critical Care Medicine, University of California, 1001 Potrero
Ave, SFGH 5, San Francisco, CA 94110, USA.
7
Center for Vulnerable
Populations, Department of Medicine, University of California, San Francisco,
USA.
8
Curry International Tuberculosis Center, University of California, San
Francisco, USA.
Received: 7 February 2019 Accepted: 15 April 2019
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