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Nihpp rs3758745v1
Nihpp rs3758745v1
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DOI: https://doi.org/10.21203/rs.3.rs-3758745/v1
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Abstract
Background
Children share 12% of the global 10 million people infected with tuberculosis (TB) each year. Closing case
detection gap in children remains difficult, with 56% of all children and 65% under-five with TB missed
each year. We aimed to assess the patterns of childhood TB diagnosis and underlying determinants in
Ethiopia when different TB diagnostic platforms are applied.
Methods
A multi-site, cross-sectional study was carried out in Ethiopia as part of the larger EXIT-TB study -
evidence-based multiple focused integrated intensified TB screening package. Outpatient children aged
≤ 15 with cough of any duration seeking care at four healthcare facilities in Ethiopia were enrolled
consecutively. Participants underwent sputum Xpert MTB/RIF and/or smear microscopy and
posteroanterior chest X-ray (CXR), and their clinical and sociodemographic data were captured using a
structured questionnaire. Data were analyzed using Stata version 23. Multiple regression model was
computed to determine the factors that influence TB case detection, with a 95% confidence interval (CI)
and p < 0.05 taken as statistically significant.
Results
A total of 438 children were enrolled. Of these, 399 had CXR examination of which 55 (13.8%) were
suggestive of TB, 270 had Xpert MTB/RIF testing of which 32 (11.9%) were positive, and AFB smear
microscopy was done for 51 children of which 2 (3.9%) were positive. Febrile children were more likely to
be diagnosed with pulmonary TB than those without fever [aPR = 1.3, 95% CI (1.1–1.4)], and those with a
TB contact history were more likely to be diagnosed with pulmonary TB than those with no such contacts
[aPR = 1.2, 95% CI (1.1–1.3)]. Children from rural residences were more likely to be diagnosed with TB
than those from urban residences [aPR = 1.3, 95% CI (1.1–1.5)].
Conclusion
The findings showed that clinical diagnosis remains an important method of TB diagnosis in children
and the preferred choice to avert underdiagnosis. A more sensitive TB diagnostic method for children was
symptom screening, followed by CXR and Xpert MTB/RIF assay or smear microscopy. Hence, an
algorithm that combines clinical, CXR, and microbiological confirmatory tests can improve the rate of
pulmonary TB diagnosis in children till more accurate and cost-effective diagnostic tools are accessible.
Fever, weight loss, and TB contact history are highly associated with TB positivity rates in children.
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Introduction
Globally, tuberculosis (TB) remains a major cause of death among infectious diseases, with an estimated
10.6 million people falling ill and 1.3 million dying of TB in 2022 [1]. In the last four decades, the
emergence of drug-resistant TB (DR-TB) strains and complications associated with human
immunodeficiency virus (HIV) co-infection increased the incidence of TB and made TB diagnosis and
treatment more problematic [2, 3]. Children have been considered a priority in the 2035 global End TB
strategy [4]. Globally in 2022, 16% of the HIV-negative and 18% of HIV-positive people who died from TB
were children aged < 15 years [1]. Available data on children suggests limited access to diagnosis and
treatment and a higher risk of developing TB among exposed infants and young children [1, 5, 6].
Worldwide, There is a large gap in case detection among children. This age group is most at risk of severe
forms of TB and delays in diagnosis can lead to death [7].
According to the WHO 2023 progress update, Ethiopia has almost reached the second End TB Strategy
milestone, with rapid reduction of TB mortality rates by 34% [8]. However, the country remains one of 30
high TB burden countries and TB incidence was reported at 119 per 100,000 population in 2021. Despite
the availability of rapid microbiological detection methods such as Xpert MTB/RIF, over a half of children
are treated for TB based on clinical criteria alone [8]. This underestimates the true nature of TB in children
and leaves them vulnerable. In order to correctly diagnose and treat pediatric TB, the performance of the
microbiological confirmatory diagnosis modality of pediatric TB needs to be improved through the use of
more sensitive and specific diagnostic techniques.
Children less than 7 years of age cannot expectorate sputum specimens properly for laboratory
examinations, which calls for more accurate diagnostic techniques and algorithms. TB in children up to
10 years is mostly primary while above 10 years is similar in clinical and radiological presentation to the
patterns seen in adults. WHO has adopted standards for TB that emphasize the importance of clinical,
radiological and epidemiological data consistent with TB and bacteriological confirmation where
possible to diagnose the disease in children. Although chest radiography (CXR) has recently been
promoted and recommended by the WHO as a useful tool for TB screening and triage algorithms, access
to the instrument and timely diagnosis remain limitations [9–12].
Studies done in Ethiopia reported the prevalence, impact, and molecular epidemiology dynamics of
childhood TB [13–20]. However, information is scarce about the potential role and contributions of
implementing alternative clinical, radiological, and microbiological TB diagnostic platforms for childhood
TB case findings. Hence, this study aimed to determine the pattern of TB diagnosis in children in selected
public health facilities in Ethiopia and their determinants as evaluated using different diagnostic
platforms.
Methods
Study design and setting
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The study was a facility-based cross-sectional study using secondary carried out in Ethiopia as part of
the larger EXIT-TB study (Evidence-Based Multiple focus Integrated Intensified TB Screening package).
The current study focused selectively on TB in children in Ethiopia. EXIT-TB is a larger multi-country
intervention study that involved intensified passive TB case finding (screening all patients at the
Outpatient departments who passively report any cough irrespective of duration); integrating TB case
finding activities into reproductive and child health clinics and diabetics clinics; screening for TB
irrespective of symptoms among HIV/AIDS infected individuals with advanced diseases attending Care
and Treatment Centers; and targeted contact tracing for all TB patients with child household members.
Briefly, the EXIT-TB intervention package involved: I) Screening for TB for all individuals who passively
report a cough at OPD and RCH using CXR. Pregnant women with a cough attending RCH were tested
using GeneXpert. Those with abnormal CXR were subject to either GeneXpert or sputum smear
microscopy depending on the availability of GeneXpert machines in the selected facilities. II) Testing for
TB irrespective of symptoms among HIV clinic attendees with advanced diseases and diabetic clinics
using GeneXpert. III) Conducting household contact tracing of children with a household member with TB
and symptoms screening followed by CXR and those with symptoms and/or abnormal CXR further
diagnosed using TB score chart, GeneXpert, or smear microscopy depending on the availability of the
GeneXpert machine.
The settings of the current study were four health facilities that were selected from two national regional
states (Oromia and Harari) and two city administrations (Addis Ababa and Dire Dawa). These facilities
were randomly selected from respective stratified settings by urban and rural. In summary, Chelenko
Primary Hospital was from Oromia National Regional State, Hiwot Fina Specialized University Hospital
from Harari Regional State, Zewditu Memorial Hospital from Addis Ababa, and Melka Jebdu Health
Center from Dire Dawa City Administration. Hiwot Fina Specialized University Hospital and Zewditu
Memorial Hospital were from an urban setting whereas Chelenko Primary Hospital and Melka Jebdu
Health Center were from rural settings. Hence, in the current study, all four study sites were included and
the necessary children-based data was pooled to address the study objectives.
Participants
Study participants were children (age < = 15) with cough of any duration who visited either of the study
facilities. In the collection of the data, healthcare providers linked participants with cough of any duration
to the data collectors, requested consent or parental consent based on the participant’s age per the
Ethiopian and WHO ethics guidelines. Trained data collectors checked and identified eligible participants,
including eligibility for CXR screening procedure and enrollment into the study. Those TB patients who are
on anti-TB treatment before the start of the study and those who are diagnosed in other facilities and
came to the study facilities for anti-TB treatment services were excluded.
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TB clinical symptom screening using the WHO TB symptom screening tool. III) TB diagnostic modality
and algorithm, thus the diagnostic modality used to investigate further or confirm TB, including CXR, AFB
sputum smear microscopy, Xpert MTB/RIF assay, TB liquid or solid culture, and DR-TB susceptibility
testing as applicable.
When patients visit study health facilities, they were screened and recruited immediately as they fulfill the
eligibility criteria. The date of health facility visits, first dates of symptom (cough), and dates of diagnosis
were captured using the study questionnaire. CXR was offered to the participants stratifying by cough
duration of < 2 weeks and ≥ 2 weeks. Sputum specimens were collected and microbiological
confirmatory tests were performed among those with CXR results of TB suggestive for < 2 weeks cough
duration and those with CXR results of all types (normal, TB suggestive, and non‑TB suggestive) for ≥ 2
weeks cough duration.
A strong emphasis was given to keeping the quality of CXR reading and CXRs read by radiologists. For
health centers that lack CXR machines, patients were transported to a nearby public healthcare facility
with a CXR machine and the study covered the cost. Microbiological confirmation was as per the national
TB guideline with either GeneXpert mycobacterium tuberculosis (MTB)/RIF assay or acid‑fast bacilli
(AFB) microscopy.
Statistical Analysis
Data were analyzed using Stata version 23. We assessed the screening algorithms with the yields of
pulmonary TB cases diagnosed. We calculated the pattern of pulmonary TB cases diagnosis among the
presumptive TB cases obtained from children screened for cough of any duration using symptom and/or
chest X-ray screening at study health facilities. We assessed the factor that determined the diagnosis of
TB cases using multiple regression model with 95% confidence interval (CIs) and p < 0.05 was taken as
statistically significant.
Ethical Considerations
This study was approved by the Institutional Review Board of the College of Health Sciences, Addis
Ababa University, and the Institutional Health Research Ethics Review Committee of the College of Health
and Medical Sciences, Haramaya University. Written consent was obtained from each participant or
parents as applicable, and assent was sought from children under the age of 18. All patients received
standard care according to national guidelines and those diagnosed with TB were linked to TB treatment
clinics.
Definition of Terms
Presumptive TB cases
patients with cough of ≥ 2 weeks with any chest X-ray results, cough < 2 weeks with chest X-ray
abnormality suggestive of TB, and cough of any duration for pregnant women, ART, and diabetic patients
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with or without the presence of night sweats, fever, hemoptysis or loss of weight were presumptive TB
cases who were eligible to be evaluated
a participant with lung TB confirmed by Xpert/smear microscopy or clinically diagnosed as per Ethiopian
national TB guidelines.
Bacteriologically-confirmed TB case
a patient from whom at least one sputum was positive for mycobacterium TB either by Xpert/smear
microscopy
participant who did not fulfill the criteria for a bacteriologically confirmed case, but was diagnosed with
TB by an experienced clinician and given a full course of TB treatment.
Results
Characteristics of study participants
Of 438 study participants, two hundred thirty-two 232/438 (53%) were females and two hundred and six
206/438 (46.8%) were males with a mean age of 7.48 years with a range of 13 years. Age was
categorized into three groups; 1–5,5–10 and 10–14 years old (Kefyalew et al,2022). About 155/438
(35.4%) children were less than or equal to 5 years, 178/438 (40.6%) were 5–10 years old and 105/438
(24.0%) were 10–14 years. TB screening was done for 235/438(53.7%) residents of rural and
201/438(45.9%) resident of urban children (Table 1).
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Table 1
Soci-demographic characteristics of participants and pattern
of childhood TB diagnosis among presumptive TB cases in
children at health facilities in Ethiopia
Variables Pulmonary TB,n(%) No TB,n(%) P value
10–14
Female
Urban
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Table 2
Clinical characteristics of study participants and pattern of TB diagnosis
among suspected TB cases in children at public health facilities, Ethiopia
Variables Childhood PTB,n(%) No PTB,n(%) P value
No 29(67.4) 202(51.1)
Yes
No 27(62.8) 214(54.2)
Yes
No 12(27.9) 4(1)
Yes
No 24(55.8) 171(43.3)
Yes .
No 3(7) 12(3)
Yes
No 4(9.3) 2(0.5)
Yes
.>2 weeks
Table 3
Diagnostic algorithm and and pattern of TB diagnosis among suspected TB cases in children at public
health facilities, Ethiopia
Algorithm Childhood No PTB, P
PTB, value
n (%)
n(%)
Cough > 2 weeks followed by CXR screening, then 27(6.2) 204(56.6) <
GeneXpert/AFB smear. 0.0001
9(2.1) 159(40.3)
Cough < 2 weeks followed by CXR screening, then
GeneXpert/smear 7(1.5) 32(8.1)
GeneXpert of was done for 270/438(61.6%) of which 32 were positive with a positivity rate of 11.85
whereas GeneXpert from stool sample was done for 75 children of which 4/75(5.3%) were positive. AFB
smear was done only for 51 children and only 2 samples was positive with a positivity rate 2/51(4%)
(Fig. 1).
The Sensitivity and specificity of chest x-ray, GeneXpert and AFB smear were 17.41% and 70.13%,7.98%
and 86.76% and 1.05% and 98.96% respectively.
Diagnostic Algorithm
On cough duration and diagnostic tests to confirm TB cases, three different algorithms were used. The
first algorithm was cough of more than or equal to 2 weeks followed by chest X-ray screening with any
results followed by Xpert /AFB smear microscopy and with this algorithm, we found 63% PTB cases. The
second algorithm was the cough of less than 2 weeks followed by chest X-ray screening with TB-
suggestive results followed with GeneXpert /smear microscopy and with this algorithm we found 21%
PTB cases. The third algorithm was cough of any duration followed by Xpert/smear microscopy and with
this algorithm 16% of TB is diagnosed (Fig. 3).
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with PTB as age group < 5 years. Children from rural residence are (APR = 1.3,95% CI:1.1–1.5) times more
likely diagnosed than that of urban residence.
Among clinical characteristics, children with a sign and symptoms of of fever were (APR = 1.3 95%
CI:1.1–1.4)times more likely to be diagnosed with TB than children with no fever. Additionally, Children
with history of contact with TB case in house hold were were (APR = 1.2,95% CI 1.1–1.3)times more
diagnosed with PTB than those who had no history of of contact with TB Case (Table 4).
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Table 4
Factor that determine Pattern of Tuberculosis diagnosis in children at health
facilities, Ethiopia
Variables CPR APR Frequency(%)
Age 1 1 10(23)
10–14
Gender 1 1 11(25.6)
Female
Rural 1 1 14(32.6)
Urban
No 1 1 3(7)
Not sure
Yes 1 1 19(44.2)
No
No
Yes 1 1 16(37.2)
No
No
Page 12/20
CPR, Crude prevalence ratio; APR, Adjusted prevalence ratio;TB, Tuberculosis.
Discussions
This study examined patterns of TB diagnosis among children in Ethiopia's public health facilities. The
diagnostic pattern was evaluated using three groups of variables; Sociodemographic characteristics of
study participants, screening for clinical symptoms, diagnostic modality, and diagnostic algorithm..
Among the socio-demographic characteristics examined, tuberculosis is more frequently diagnosed in
young children between the ages of 5 and 10 than in children under 5 and over 10 years of age. This can
be explained by the fact that children start school at this age, which increases their exposure to different
environments, which increases the risk of infection at this age. The disease, which is also more likely to
occur in rural than urban areas, can be explained by poor access to medical care, low vaccination rates
and socio-cultural problems, as well as living conditions in rural areas that contribute to the spread of
tuberculosis [21, 22].
Clinical signs of suspected TB in children included fever, and were more likely to be diagnosed with PTB
than children without fever, and children with a contact history were more likely to be diagnosed with PTB
have a higher likelihood of being diagnosed with PTB than those with no contact history. While contact
history is less useful in countries with high TB endemic rates [23, 24] an important consideration is that
children contract TB in the household in which they live. can be easily traced, unlike adults with many. For
example, one study shows that it is not difficult to diagnose multidrug-resistant tuberculosis (MDR-TB) in
children, since exposure to adults with MDR-TB is essential to establish this presumptive diagnosis [6].
This result supports the findings of another studies that clinical diagnosis is essential in the management
of childhood tuberculosis [7, 25], which is why improving the competence of frontline health workers in
the priority in most countries as clinical diagnosis of childhood tuberculosis commonly used in clinical
practice [26–29].
Based on the duration of the cough, three different algorithms were used to detect cases of tuberculosis
in children. The first algorithm is a cough for ≥ 2 weeks, followed by a chest x-ray with all findings,
followed by GeneXpert/AFB swab microscopy, and with this algorithm, tuberculosis is diagnosed 63% of
the time, which is less than the survey rate in all age groups in the same area, 81.2% of PTB cases [30].
The discrepancy could be due to the difference in population.The second algorithm is a cough < 2 weeks
followed by a chest x-ray with findings suggestive of tuberculosis, followed by a GeneXpert/microscopic
swab. Using this algorithm, we found 21% of tuberculosis cases, which is more than the study of all age
groups in the same areas, accounting for 14.2% of PTB cases [30], this inequality is due to population
defference.
The third algorithm was any-duration cough followed by GeneXpert/AFB swab microscopy, and with this
algorithm we found 16%, more than one study in the same area across all ages, as 4.5% of PTB cases.
This difference shows that GeneXpert provides more results in children with an indicative CXR score and
is important in this age group. Chest X-ray was performed in 399/438 (91%), making it the most
Page 13/20
commonly used screening modality in this study. All chest radiographs were frontal (AP). Approximately
55/399 (13.78%) had evidence of tuberculosis on chest X-ray. Diagnosis was based on a cough screening
algorithm followed by chest X-ray. Also, the algorithms required fewer modifications to be sentence
specific. Thus, if a facility has an X-ray machine and a radiologist, this can be incorporated into the
routine standard of care. As recommended by the World Health Organization, CXR screening is a good
healthcare choice because it reduces costs and logistical challenges compared tocommunity-active case
searches. Of 270/438 (61.6%),GeneXpert MTB/Ref gastric lavages were performed, of which 32 were
positive, with a percentage positive of 11.8th %. Only 51 children had an AFB smear, of which 2 were
positive with a positivity rate of 2/51 (3.9%).The use of cough screening algorithms followed by a chest
x-ray followed by a GeneXpert sputum test resulted in 21% more cases of PTB than a chest x-ray alone
(clinical) 13.78%. This result supports the recommendation to use GeneXpert as the first diagnostic test
at the point-of-care [31, 32] over conventional tests due to its rapidity and sensitivity to diagnostic tests.
resistant to TB. The use of cough screening was helpful in the COVID-19 time as TB services were
compromised [33–35].
In this study, fever, weight loss, and TB contact history are highly associated with TB positivity rates in
children. Differences in TB detection rates between countries such as Ethiopia may be influenced by the
prevalence of the HIV epidemic, overcrowding, differences in the sensitivity of laboratory diagnostic
techniques, and variability in the effectiveness of preventive measures [36–40]. In current times where
technologies are rapidly evolving to advance TB care and management [], such advanced technologies
are are urgently needed to improve childhood TB case ditection. (Atehortúa et al., 2015; Hajizadeh et al.,
2021).
Conclusion
Microbiological pulmonary TB detection in children is low compared to clinical and x ray detection
despite advancement in modern rapid test, such as GeneXpert making clinical the most sensitive
diagnostic method in children. Fever ,weight loss and TB contact history is the most important clinical
features that must be emphasized during clinical screening of TB in children. Socio-demographic history
is important in our setting during clinical diagnosis of TB in children and must be given attention. Use the
algorithm of combined clinical and confirmatory tests can improve rate of PTB diagnosis in children. We
recommend use of symptom screening followed by CXR and the confirm by GeneXpert where the tests
are available to improve microbiological diagnosis of childhood tuberculosis using more sensitive and
specific diagnostic technique. In clinically high-risk children use of Chest x ray only is a good choice at
health facilities that reduces the logistic challenges of bacteriological confirmation and possible under
diagnosis. AFB smear is less important in children compared with GeneXpert to confirm TB case in
children and not recommended especially for younger children less than 5 years.
Declarations
Funding
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This work was funded by the European and Developing Countries Clinical Trials Partnership (EDCTP2)
program supported by the European Union under grant number CSA2016S-1608. TM recived support
from the Fogarty International Center and National Institute of Allergy and Infectious Diseases of the US
National Institutes of Health under grant number D43TW009127. The content is solely the responsibility
of the authors and does not necessarily represent the official views of the EDCTP or the US National
Institutes of Health.
This study was approved by the Institutional Review Board of the College of Health Sciences, Addis
Ababa University, and the Institutional Health Research Ethics Review Committee of the College of Health
and Medical Sciences, Haramaya University, Ethiopia. Written informed consents were obtained from all
study participants and their legal guardians.
The datasets used and/or analyzed during the current study will be available from the corresponding
author on reasonable request.
Acknowledgment
The authors are grateful to the Center for Innovative Drug Development and Therapeutic Trials for Africa
(CDT-Africa), College of Health Sciences, Addis Ababa University, Ethiopia for providing technical support
and managing the grant. The authors thank Haramaya University for supporting the execution of the
project.
Authors contributions
Conceptualization: KU, TM, HM. Methodology, KU, HM, TM, YW, GY, LO, KTR, TA, HB, EN, DT, TH. Analysis:
KU, HM, TM, YW. First draft of the manuscript: KU. Critical review of the manuscript: TM, HM, YW. All
authors have reviewd the manuscript and have approved the final version for publication.
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Figures
Figure 1
Diagnostic tests done to diagnose TB in children among presumptive TB case in children at health
Facilities, Ethiopia
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Figure 2
Diagnostic algorithm used to diagnose TB in children among presumptive TB case in children at health
Facilities ,Ethiopia
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