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TITLE PAGE
Latent tuberculosis infection (LTBI) in children less than 12 years of age in a tertiary care
centre, Lahore, Pakistan
‫ باكستان‬، ‫ الهور‬، ‫ سنة من العمر في مركز الرعاية الثالثية‬12 ‫ ) في األطفال أقل من‬LTBI ( ‫عدوى السل الكامنة‬
Muhammad Faheem Afzal (FCPS, Paediatrics) Muhammad Ashraf Sultan (MRCPCH), Anum
Masood (MBBS), Asif Hanif (PhD, Biostatistics)
‫ آصف حنيف‬، ‫ أنعم مسعود‬، ‫ محمد أشرف سلطان‬، ‫محمد فهيم أفضل‬
Disclaimer
The authors declare that there is no conflict of interests. The study was funded by research grant,
King Edward Medical University, Lahore.
Short Running Title
Latent tuberculosis infection (LTBI) in children
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Department of Paediatrics, King Edward Medical University/Mayo Hospital, Nila Gumbad,
Lahore, Pakistan.
. ‫ باكستان‬، ‫ الهور‬، Gumbad ‫ نيال‬، ‫ مستشفى الملك إدوارد الطبية مايو‬/ ‫ جامعة‬، ‫قسم طب األطفال‬
Corresponding Author:
Muhammad Faheem Afzal, Assistant Professor, Paediatrics, King Edward Medical
University/Mayo Hospital, Lahore, Pakistan.
Email: [email protected]
Telephone & Fax: 00924237356987
. ‫ باكستان‬، ‫ الهور‬، ‫ مستشفى مايو كلينيك‬/ ‫ جامعة الملك إدوارد الطبية‬، ‫ طب األطفال‬، ‫ أستاذ مساعد‬، ‫محمد فهيم أفضل‬
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ABSTRACT
Objective: To determine the prevalence of LTBI in children by using QuantiFERON-TB Gold
in-tube test (QFT-GIT) in children less than 12 years of age in a tertiary care centre,Lahore,
Pakistan.
Methods: This cross sectional study was conducted in the Department of Paediatrics, King
Edward Medical University, Lahore, Pakistan, from July 2014 to June 2015.By non-probability
convenient sampling, 250 children having contact with confirmed(sputum positive adult case of
pulmonary TB)or suspected tuberculosis case(adult having fever & unremitting cough for 3
weeks)were included in the study. Presence or absence of BCG vaccination scar was
documented. Diagnosed cases of TB were excluded. All children were subjected to QFT-GIT for
evidence of LTBI. Each child was treated according to the individual merit(prophylaxis was
offered to positive cases). Data was analyzed by SPSS 20.0.
Results: Total of 250 children under 12 years were enrolled. Mean age was 6.48 ± 2.97 years.
Among 250, 136 (54.4%) were male & 114 (45.6%) were female. Out of 250, 75 (30.8) of
children were found to be suffering from LTBI as evident by positive QFTGIT. Although QFTGIT was found negative in children with positive BCG scar, but the difference in any age group
or gender was not statistically significant.
Conclusion: The prevalence of latent tuberculosis infection in children less than 12 years of age
is 30%.It is need of time to screen each child for LTBI who has close contact with adult case of
TB in developing countries like Pakistan.
)QFT - GIT ( ‫ الذهب في أنبوب اختبار‬QuantiFERON -TB ‫ في األطفال باستخدام‬LTBI ‫ لتحديد مدى انتشار‬: ‫الهدف‬
. ‫ باكستان‬، ‫ الهور‬، ‫ سنة من العمر في مركز الرعاية الثالثية‬12 ‫في األطفال أقل من‬
‫ من يوليو‬، ‫ باكستان‬، ‫ الهور‬، ‫ جامعة الملك إدوارد الطبية‬، ‫ أجريت هذه الدراسة المقطعية في قسم طب األطفال‬: ‫الطرق‬
‫ طفال وجود اتصال مع وأكد ( البلغم حالة إيجابية من‬250 ، ‫ غير االحتمالية أخذ العينات مريحة‬By.2015 ‫ إلى يونيو‬2014
‫ وقد تم‬.‫ أسابيع) في الدراسة‬3 ‫الرئة الكبار أدرجت السل ) أو يشتبه حاالت السل (الكبار جود الحمى و السعال المتواصل لمدة‬
‫ تم إخضاع جميع‬. ‫ تم استبعاد الحاالت التي تم تشخيصها من مرض السل‬.‫ ندبة التطعيم‬BCG ‫توثيق وجود أو عدم وجود‬
‫ كان يعامل كل طفل وفقا ل الجدارة الفردية ( تم تقديم العالج الوقائي ل حاالت‬. LTBI ‫ عن أدلة على‬QFT - GIT ‫األطفال ل‬
. SPSS 20.0 ‫ تم تحليل البيانات‬. ) ‫إيجابية‬
54.4 ( 136 ‫ و‬250 ‫ بين‬. ‫ سنة‬2.97 ± 6.48 ‫ وكان متوسط أعمارهم‬. ‫ عاما‬12 ‫ طفل دون سن‬250 ‫ تم تسجيل عدد‬:‫النتائج‬
‫ كما‬LTBI ‫ ) من األطفال وجدت أن الذين يعانون من‬30.8 ( 75 ، 250 ‫ من‬. ‫ ) من اإلناث‬٪ 45.6 ( 114 ‫ ) من الذكور و‬٪
‫ سلبيا في األطفال الذين يعانون من ندبة‬QFT - GIT ‫ على الرغم من أن وجدت‬. ‫ إيجابية‬QFTGIT ‫هو واضح من قبل‬
.‫ ولكن الفرق في أي فئة عمرية أو جنس ال يعتد به إحصائيا‬، ‫ إيجابية‬BCG
‫ بل هو بحاجة إلى الوقت لفحص‬. ٪ 30 ‫ سنة من العمر هو‬12 ‫ إن انتشار عدوى السل الكامنة في األطفال أقل من‬:‫والخالصة‬
‫ الذي لديه اتصال وثيق مع حالة البالغين من السل في البلدان النامية مثل باكستان‬LTBI ‫كل طفل ل‬
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INTRODUCTION
Tuberculosis (TB) is a leading cause of morbidity and mortality in all age groups especially in
developing countries.1 World Health Organization (WHO) has estimated that 13.7 million of the
world’s population has active TB and about 1 million (11%) of them are children <15 years of
age. This figure varies from 3% to 25% in different countries. Pakistan ranks 6th in Eastern
Mediterranean region of WHO and 44% overall prevalence of TB in the country.2 There are 4%
registered cases of TB in children, 2.5% are at risk of getting infection, out of which only 5%10% of infected children will progress to primary progressive disease while 80‑90% will get
latent tuberculosis infection (LTBI) in Pakistan.3
Close contacts with patients with sputum smear-positive and culture-confirmed Mycobacterium
tuberculosis have been shown to be at a higher risk for developing LTBI, which can be followed
by overt TB disease. An effective way to disrupt the transmission of infection and to improve
disease control is tracing the contacts of TB patients, as well as diagnosing and performing
interventions against LTBIs.4 The tuberculosis skin test (TST), has been widely used to
determine LTBI, however, false positives may occur in patients who have received the Bacillus
Calmette-Guérin (BCG) vaccine.5, 6 In order to address the challenges posed by the TST, the
QuantiFERON®-TB Gold in-tube test (QFT-GIT) has been introduced as new diagnostic tests
for LTBI. QFT-GIT uses whole blood specimens to assess the presence of LTBI. Studies have
shown that the QFT-GIT assay has a comparable sensitivity to the TST, as well as superior
specificity, negative predictive value, and positive predictive value.7, 8, 9
Individuals with LTBI represent a reservoir of infection, many of whom will progress to
tuberculosis (TB) disease. A central pillar of TB control program should be reducing this
reservoir through targeted testing and treatment, so that the United Nations Millennium Goals
(MDGs) of eliminating the disease may be achieved.3 Based upon this review, the screening of
children younger than 12 years of age, having close contact with source, is important to identify
the LTBI at this age group so that they should be treated timely to avoid the progression to active
disease. Early detection of the LTBI cases will decline mortality and also the overall burden of
the disease. Therefore, this study was planned to determine the prevalence of LTBI by QFT-GIT
in children less than 12 years of age in a tertiary care centre, Lahore, Punjab, Pakistan.
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MATERIAL AND METHODS
This cross sectional study was conducted in the Department of Paediatrics, King Edward
Medical University, Lahore, Pakistan, from July 2014 to June 2015. The study was approved by
Institutional Review Board (IRB) of the university. By non-probability convenient sampling, 250
children (using 20% prevalence of childhood TB in Pakistan, 95% confidence interval & 5%
margin of error), having contact with confirmed (sputum positive adult case of pulmonary TB) or
suspected tuberculosis case (adult having fever & unremitting cough for 3 weeks) were included
in the study. Presence or absence of BCG vaccination scar was documented. Diagnosed cases of
TB were excluded. All children were subjected to QFT-GIT for evidence of LTBI. A 3cc nonheparanized sample was into 3 tubes by aseptic measures. The sample was sent to Paeditric
Immunology Laboratory, which was centrifuged and analyzed within 12 hours of collection. A
value of 0.35 IU/ml above the nil control was considered as positive. Each child was treated
according to the individual merit (prophylaxis was offered to positive cases). Information was
recorded on structured questionnaire. Data was analyzed by SPSS 20.0 and was presented as
frequency tables. Chi square test was applied to see the association between vaccination status
and LTBI.
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RESULTS
Total of 250 children 1-12 years of age were enrolled. The mean age was 6.48 ± 2.97 years.
Among 250, 136 (54.4%) were male & 114 (45.6%) were female. Out of 250, 75 (30.8) of
children were found to be suffering from LTBI as evident by positive QFT-GIT, among which
male and female were 14% and 16% respectively . (Table I)
When data was analyzed for association of BCG scar and QFT-GIT positivity, it was found that
46 (18.4%) of BCG vaccinated children were having LTBI. However, the difference in any age
group or gender was not statistically significant. (Table II)
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DISCUSSION
Tuberculosis control program in Pakistan is generally facing low case detection rates. LTBI
constitute hidden pools, feeding the new cases. Present study had reported the 30% prevalence of
LTBI among study population, among which male and female were 14% and 16% respectively.
Unfortunately, we did not find any local data of LTBI in children to compare our results.
However, international data is there. Mancuso et al10 from United States reported the estimated
prevalence of LTBI as 4.8%. This difference might be due to the fact that surveillance of
infectious diseases is much better in developed countries and screening programs are better in
force there to identify the cases. Saiman et al11 reported LTBI in 19% of internationally adopted
children in United states. These children are not natives of United States so the overall
prevalence was relatively high.
Kizza et al12 from South Africa reported overall prevalence of LTBI as 49% and authors
observed the increase in overall LTBI prevalence with age. Authors also observed the higher
prevalence of LTBI in males as compared to females. However, there was no sex-specific
statistical difference in LTBI was found. In present study, the prevalence observed was 30%,
higher in females, but statistically, there was no difference found. The comparable results might
be due to the fact that South Africa is also endemic for TB and population there might have
direct exposure with active TB cases leading to more cases of LTBI.
BCG is given immediately after birth in Pakistan and vaccination coverage is reported to be high
(>75%). Despite the former vaccination with BCG, it has been suggested that a positive QFTGIT in a child who has close contact with an adult with infectious TB most likely represents
LTBI and treatment of this latent infection should be considered, especially if the child is
younger than 5 years. This finding is of importance in light of the increasing rates of TB in
Pakistan, where children who are vaccinated with BCG are exposed to adults with active TB.2 In
present study, when data was analyzed for association of BCG scar and QFT-GIT positivity, it
was found that it was found that 46 (18.4%) of BCG vaccinated children were having LTBI. This
necessitates the importance of tracing of even vaccinated children who are in contact with the
active cases.
The authors believe that this is amongst the first study from Pakistan targeting the LTBI in
children by QFT-GIT. However, the major limitation is that it is single centered, hospital based
study which might not reflect the true prevalence from the community. Due to financial
limitations, sample size was also small. More community based studies are needed on larger
scale to determine the prevalence of LTBI in Pakistani children so that TB control program may
be recommended to take initiatives to diagnose and treat LTBI in contacts.
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CONCLUSION
The prevalence of latent tuberculosis infection in children less than 12 years of age is 30%. It is
need of time to screen each child for LTBI who has close contact with adult case of TB in
developing countries like Pakistan.
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REFERENCES
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among health care workers in Malaysia. BMC Infect Dis 2011;11:19.
2-Zafar M. Prevalence of latent tuberculosis and associated risk factors in children under 5
years of age in Karachi, Pakistan. J Assoc Chest Physicians 2014;2:16-24.
3-National guidelines for diagnosis and management in children, National TB control
programme, Ministry of Health And Government of Pakistan in Collaboration With Pakistan
Pediatric Association, 1st ed. 2006.
4-Ayubi E, Doosti-Irani A, Mostafavi E. Do the tuberculin skin test and the QuantiFERONTB Gold in-tube test agree in detecting latent tuberculosis among high-risk contacts? A
systematic review and meta-analysis. Epidemiology and Health 2015;37:e2015043.
5-Lee YM, Park KH, Kim SM, Park SJ, Lee SO, Choi SH, et al. Risk factors for falsenegative results of T-SPOT.TB and tuberculin skin test in extrapulmonary tuberculosis.
Infection 2013;41:1089-95.
6-Asl HM, Alborzi A, Pourabbas B, Kalani M. QuantiFERON-TB Gold and Tuberculin Skin
Test for the Diagnosis of Latent Tuberculosis Infection in Children. Iran J Med Sci 2015; 40:
411-17.
7-Diel R, Goletti D, Ferrara G, Bothamley G, Cirillo D, Kampmann B, et al. Interferon-γ
release assays for the diagnosis of latent Mycobacterium tuberculosis infection: a systematic
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8-Pai M, Denkinger CM, Kik SV, Rangaka MX, Zwerling A, Oxlade O, Metcalfe JZ,
Cattamanchi A, Dowdy DW, Dheda K, Banaei N. Gamma Interferon Release Assays for
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QuantiFERON-TB Gold In-Tube test and Tuberculin Skin Test for diagnosis of latent
tuberculosis infection in BCG vaccinated health care workers. Med Sci Monit 2014; 20:
521-9.
10-Mancuso JD, Diffenderfer JM, Ghassemieh BJ, Horne DJ, Kao T.The Prevalence of latent
tuberculosis infection in the United States. Am J Respir Crit Care Med 2016;DOI:
10.1164/rccm.201508-1683OC.
11-Saiman L, Aronson J, Zhou J, Gomez-Duarte C, Gabriel PS, Alonso M. Prevalence of
infectious diseases among internationally adopted children. PEDIATRICS 2001;108: 608-12.
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of latent tuberculosis infection and associated risk factors in an urban African setting. BMC
Infectious Diseases 2015;15:165-72.
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Table I: Distribution of cases by gender (n=250)
Gender
QFT-GIT
Total n(%)
Positive n(%) Negative n(%)
35 (14)
101 (40.4)
136 (54.4)
Male
74 (29.6)
114 (45.6)
Female 40 (16)
75 (30)
175 (70)
250 (100)
Total
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Table II: BCG Scar & QFT-GIT (n=250)
Gender Age
BCG
QFT-GIT
Group
Scar
Positive n(%) Negative n(%)
1-5 years
Present 8 (3.2)
24 (9.6)
Male
Absent
9 (3.6)
8 (3.2)
>5-12
Present 13 (5.2)
57 (22.8)
years
Absent
5 (2)
12 (4.8)
Present 17 (6.8)
26 (10.4)
Female 1-5 years
Absent
10 (4)
3 (1.2)
>5-12
Present 8 (3.2)
38 (15.2)
years
Absent
5 (2)
7 (2.8)
75 (30)
175 (70)
Total
Total
n(%)
32 (12.8)
17 (6.8)
70 (28)
17 (6.8)
43 (17.2)
13 (5.2)
46 (18.4)
12 (4.8)
250 (100)
p value
0.05
0.249
0.019
0.084