Paediatrica Indonesiana

p-ISSN 0030-9311; e-ISSN 2338-476X; Vol.57, No.2(2017). p. 63-6; doi: http://dx.doi.org/10.14238/pi57.2.2017.63-6

Original Article

Risk factors for miliary tuberculosis in children

Clarissa Cita Magdalena1, Budi Utomo2, Retno Asih Setyoningrum3

M
Abstract iliary tuberculosis (TB) is caused by
Background Miliary tuberculosis (TB) is a fatal form of hematogenous and lymphatogenous
tuberculosis with severe clinical symptoms and complications. dissemination of Mycobacterium tuber­
The mortality rate from this disease remains high, therefore, it culosis bacteria in the body, infecting
is important to identify the risk factors for miliary TB for early
detection and treatment.
multiple organs. It accounts for 3–7% of all TB
Objective To identify risk factors for miliary tuberculosis in cases.1 Although there have been few reports on the
children. prevalence of miliary TB in Indonesian children, the
Methods A case-control study of children aged 0-14 years with Indonesian Ministry of Health reported 1,168 cases of
miliary TB was conducted in Dr. Soetomo Hospital from 2010 to pediatric pulmonary acid-fast bacilli (AFB) positive TB
2015. Data were taken from medical records. Case subjects were
in 2014.2 The mortality rate from miliary TB is usually
children with miliary TB, and control subjects were children
with pulmonary TB. Patients with incomplete medical records around 25%, but may reach 100% if left untreated.3
were excluded. Case subjects were identified from the total Complications from the disease include respi­
patient population; control subjects were included by purposive ratory distress syndrome, renal failure, pericarditis,
sampling, with case:control ratio of 1:1. Potential risk factors were shock, disseminated intravascular coagulation, and
age, nutritional status, BCG immunization status, and history of
contact with TB patients. Statistical analyses were done with
acute respiratory failure.3,4 Miliary TB in children
Chi-square and logistic regression tests. P values < 0.05 were has been closely linked to the pathogenesis of TB
considered to be statistically significant. meningitis (TBM), the most fatal form of TB. The
Results A total of 72 children were analyzed, with 36 case and 36 proportion of children with miliary TB who suffer
control subjects. Nutritional status had a significant associatation TBM is larger than that of adults with miliary TB.4,5
with miliary TB in children (OR 3.182; 95%CI 1.206 to 8.398;
P=0.018) in both bivariate and multivariate analyses. The
Some proposed risk factors for developing miliary
probability of a child with moderate or severe undernutrition TB in children have been younger age, malnutrition,
developing miliary TB was 76.09%. Other factors were not lack of BCG immunization, and history of contact
significantly associated with miliary TB. with tuberculosis patients.4,6-8 Since pediatric TB and
Conclusion Nutritional status is significantly associated with the severe complications of miliary TB are a health
miliary TB in children, and moderate or severe undernutrition
increases the risk for developing miliary TB. [Paediatr In-
dones. 2017;57:63-6. doi: http://dx.doi.org/10.14238/
pi57.2.2017.63-6 ].
From the Medical Student1, Department of Public Health and Preventive
Medicine2, and Department of Child Health3, Airlangga University
Keywords: miliary tuberculosis; children; risk Medical School/Dr. Soetomo Hospital Surabaya, East Java, Indonesia.
factors
Reprint requests to: Clarissa Cita Magdalena, Airlangga University
Medical School Surabaya, Jl. Mayjen Prof. Dr. Moestopo 47, Surabaya,
East Java, Indonesia. Tel. +62-31-5020251; E-mail: citamagdalena@
gmail.com

Paediatr Indones, Vol. 57, No. 2, March 2017 • 63

 Clarissa Cita Magdalena et al: Risk factors for miliary tuberculosis in children

problem in Indonesia, we aimed to identify risk factors records. We performed bivariate Chi-square and
for miliary TB in children, in order to facilitate early multivariate logistic regression analyses using SPSS
prevention and intervention. version 20 software. Results with P values <0.05 were
considered to be statistically significant, with 95%
confidence intervals.
Methods
We conducted a hospital-based, case-control, Results
retrospective study using secondary data from medical
records of pediatric patients admitted to the Division Out of 1,184 TB patients admitted during the
of Respirology, Department of Child Health, Airlangga study period, 46 had miliary TB. Ten patients were
University Medical School, Dr. Soetomo Hospital, excluded, leaving 36 subjects in the case group.
Surabaya from 2010 to 2015. This study was approved Thirty-six pulmonary TB patients were included as
by the Medical Ethics Committee of Dr. Soetomo the control group. The characteristics of the subjects
Hospital, Surabaya, East Java, Indonesia. are presented in Table 1.
Subjects were divided into case and control
groups. Children under 14 years of age and diagnosed Table 1. Characteristics of subjects
with miliary TB were selected as case subjects.
Characteristics N=72
Children under 14 years of age and diagnosed with
pulmonary TB using Indonesian Pediatric Tuberculosis Age, n(%)
< 2 years 25 (34.7)
Scoring System1 with a diagnostic score ≥6 were ≥ 2 years 47 (65.3)
selected as control subjects. The scoring system was Nutritional status, n(%)
used only for the control subjects. Children with Moderate or severe undernutrition 40 (55.6)
incomplete medical records were excluded. Cases Normal 32 (44.4)
BCG immunization status, n(%)
were taken from the total population of those with
No 12 (16.7)
miliary TB, while controls were included by purposive Yes 60 (83.3)
sampling, with a case: control ratio of 1:1. History of contact with TB patients, n(%)
Potential risk factors analyzed were age, nutritional Yes 53 (73.6)
No 19 (26.4)
status, BCG immunization status, and history of contact
with TB patients. Age was categorized as ≤2 years or
>2 years. Nutritional status was determined using the Bivariate analysis of the possible risk factors
weight/height WHO curves for subjects under 5 years showed that only nutritional status was significantly
or the CDC curves for those over 5 years,1 according associated with miliary TB in children (OR 3.182;
to subject’s sex. All data were taken from the medical 95%CI 1.206 to 8.398; P=0.018). Age, BCG

Table 2. Bivariate analysis of miliary tuberculosis risk factors in children

Case Control
Variables OR 95%CI P value
(n=36) (n=36)
Age, n
16 9
< 2 years 2.400 0.882 to 6.528 0.083
20 27
≥ 2 years
Nutritional status, n
Moderate or severe undernutrition 25 15 3.182 1.206 to 8.398 0.018
Normal 11 21
BCG immunization status, n
No 9 3 3.667 0.902 to 14.901 0.058
Yes 27 33
History of contact with TB patients, n
Yes 25 28 0.649 0.225 to 1.871 0.422
No 11 8

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 Clarissa Cita Magdalena et al: Risk factors for miliary tuberculosis in children

immunization status, and history of contact with from active TB disease and TB infection.
associated with miliary TB in children (OR 3.182; We found no statistically significant associations
95%CI 1.206 to 8.398; P=0.018). Age, BCG between age, BCG immunization status, or history of
immunization status, and history of contact with TB contact with TB patients and the incidence of miliary
patients were not significantly associated with miliary TB in children. However, we suggest that younger
TB (Table 2). age and negative BCG immunization status may also
Multivariate analysis revealed similar results, increase the risk of miliary TB, as reported by previous
with nutritional status as the only significant risk factor studies.6,7
of miliary TB in children (Table 3). The probability The difference between our findings and those
of a child with moderate or severe undernutrition of previous studies may be due to several reasons.
developing miliary TB was found to be 76.09%. First, age in our study may have been affected by the
Table 3. Multivariate analysis of miliary risk factors in children
Variables Coefficient (B) OR 95%CI P value
Age 0.702 2.017 0.653 to 6.235 0.223
Nutritional status 1.165 3.204 1.166 to 8.805 0.024
BCG immunization status 0.891 2.437 0.527 to 11.263 0.254

Discussion higher prevalence of older pediatric TB patients. A

previous study noted that even though an age under
We identified moderate/severe malnutrition as a 2 years was a risk factor of miliary TB, most children
significant risk factor for miliary TB in children. with TB infection in endemic areas were older than 2
Similarly, a study in India found that malnutrition was years, so there was a higher chance of more children
a risk factor for miliary tuberculosis.4 Also, another over 2 years suffering from miliary TB.6 Another
study in India found a significant association between study in England and Wales also found more miliary
nutritional status and the incidence of pulmonary TB in older children, which indicated the possible
tuberculosis infections.9 A previous study in Peru also reactivation of latent disease.14 Thus, we suggest
found a significant association between malnutrition that miliary TB should be suspected in children of
and mortality in children with TB.10 Furthermore, a any age. Second, BCG immunization coverage was
systematic review of studies in developed countries high in our study. According to a systematic review by
like the United States, Hong Kong, Finland, and Trunz et al., the estimated efficacy of BCG prevention
Norway, found a consistent relationship between the of miliary TB reached 77%, but in Asian countries,
incidence of TB and the body mass index (BMI) of there might be an overestimation of the number, due
the patients, with a 14% increased risk of TB for a to the inclusion of studies of countries with higher
decrease of one BMI unit.11 immunization coverage than Asian countries but with
The relationship between nutritional status lower risk of infection, while Asian countries have
in children and miliary tuberculosis incidence may higher rate of infection and reinfection despite the
be explained by Jaganath et al. who suggested that high immunization coverage.15 Moreover, Fine found
nutrient deprivation may have a detrimental effect on that the protective effect of BCG was influenced by
Th1 cells, which act as an important component in geographic location, as the protective effect declined
cell-mediated immune system defense against miliary in regions closer to the equator.16 BCG immunization
TB.12 A previous study reported that cell-mediated itself should continue to be administered as regulated,
immunity is a key factor in host defense mechanisms but we suggest continuing future study for a better
against the progression of TB infection to active vaccine. Third, the majority of our subjects reported
TB disease.13 Therefore, the compromised cellular a positive history of contact with TB patients, in
immune system in children with undernutrition contrast to previous studies with more subjects
possibly increases the risk of developing miliary TB who had no history of contact with TB patients.8,17

Paediatr Indones, Vol. 57, No. 2, March 2017 • 65

 Clarissa Cita Magdalena et al: Risk factors for miliary tuberculosis in children

Therefore, contact tracing is an important task, but Kampmann B. Paediatric tuberculosis. Lancet Infect Dis.
the precise relationship between contact and miliary 2008;8:498-510.
TB needs further study. 8. Gomes VF, Andersen A, Wejse C, Oliveira I, Vieira FJ,
A limitation of this study was the use of second- Joaquim LC, et al. Impact of tuberculosis exposure at home on
ary data which could create a bias in the information mortality in children under 5 years of age in Guinea-Bissau.
we received. We propose future studies with better Thorax. 2011;66:163-7.
methodologies, preferably with a prospective design. 9. Singh M, Mynak ML, Kumar L, Mathew JL, Jindal SK.
In conclusion, moderate/severe malnutrition Prevalence and risk factors for transmission of infection
is a significant risk factor for miliary TB in children. among children in household contact with adults having
Further study is needed to elucidate the pathogenic pulmonary tuberculosis. Arch Dis Child. 2005;90:624-8.
mechanism between undernutrition and miliary TB. 10. Drobac PC, Shin SS, Huamani P, Atwood S, Furin J, Franke
MF, et al. Risk factors for in-hospital mortality among children
with tuberculosis: the 25-year experience in Peru. Pediatrics.
Conflict of interest 2012;130:e373-9.
11. Lönnroth K, Williams BG, Cegielski P, Dye C. A consistent
None declared. log-linear relationship between tuberculosis incidence and
body mass index. Int J Epidemiol. 2010;39:149-155.
12. Jaganath D, Mupere E. Childhood tuberculosis and
References malnutrition. J Infect Dis. 2012;206:1809-15.
13. Cegielski JP, McMurray DN. The relationship between
1. Kementrian Kesehatan RI. Petunjuk teknis manajemen malnutrition and tuberculosis: evidence from studies in
TB anak. Jakarta: Kementrian Kesehatan Indonesia; 2013. humans and experimental animals. Int J Tuberc Lung Dis.
p.13,18, 85-96. 2004;8:286–98.
2. Kementrian Kesehatan RI. Profil kesehatan Indonesia 2014. 14. Kruijshaar M, Abubakar I. Increase in extrapulmonary
Jakarta: Kementrian Kesehatan Indonesia; 2015. p.110. tuberculosis in England and Wales 1999-2006. Thorax. 2009;
3. Hagan G, Nathani N. Clinical review: tuberculosis on the 64:1090-5.
intensive care unit. Crit Care. 2013;17:240. 15. Trunz BB, Fine P, Dye C. Effect of BCG vaccination on
4. Sharma SK, Mohan A, Sharma A. Challenges in the diagnosis childhood tuberculous meningitis and miliary tuberculosis
& treatment of miliary tuberculosis. Indian J Med Res. worldwide: a meta-analysis and assessment of cost-
2012;135:703-30. effectiveness. Lancet. 2006;367:1173-80.
5. Donald PR, Schaaf HS, Schoeman JF. Tuberculous meningitis 16. Fine PE. Variation in protection by BCG: implications of and
and miliary tuberculosis: the Rich focus revisited. J Infect. for heterologous immunity. Lancet. 1995;346:1339–45.
2005;50:193-5. 17. Rakhmawati W, Fatimah S, Nurhidayah I. Hubungan status
6. Marais BJ, Gie RP, Schaaf HS, Hesseling AC, Obihara CC, gizi, imunisasi & riwayat kontak dengan kejadian tuberkulosis
Starke JJ, et al. The natural history of childhood intra-thoracic pada anak di wilayah kerja puskesmas Ciawi kabupaten
tuberculosis: a critical review of literature from the pre- Tasikmalaya [final research report]. Bandung: Universitas
chemotherapy era. Int J Tuberc Lung Dis. 2004;8:392–402. Padjajaran; 2008. [cited 2016 November 25]. Available from:
7. Newton SM, Brent AJ, Anderson S, Whittaker E, http://repository.unpad.ac.id/4895/.

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