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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 2  |  Issue : 3  |  Page : 51-55

Clinical profile and outcome of extrapulmonary tuberculosis in children in Indonesia


Department of Pediatric, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, Indonesia

Date of Web Publication19-Oct-2018

Correspondence Address:
Dr. Rina Triasih
Department of Pediatric, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Jl. Kesehatan No. 1, Yogyakarta 55284
Indonesia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/prcm.prcm_10_18

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  Abstract 


Context: Tuberculosis (TB) is a significant problem among children in Indonesia. While pulmonary TB has been widely reported, information on extrapulmonary TB (EPTB) among children in Indonesia has not been well documented. Aims: The aim of this study is to document demographic and clinical characteristics and outcome of EPTB in children. Settings and Design: A retrospective study was conducted in Dr. Sardjito Hospital, Yogyakarta, Indonesia. Subjects and Methods: Medical records were reviewed for all children aged younger than 18 years diagnosed with EPTB and admitted to this hospital between 2009 and 2015. Results: Fifty-three patients with EPTB were admitted to the hospital during the study period. EPTB was more common in children aged >5 years, with median (interquartile range) age of presentation at 12.5 years (4.1–14.7 years). Major presenting symptoms were fever (72%), cough (55%), and weight loss (38%). Common types of EPTB were meningitis (28%), miliary TB (23%), and osteoarthritis (20%). The diagnosis was confirmed by either acid-fast bacilli smear or GeneXpert MTB/rifampicin (RIF) in 13 patients. Evidence of TB infection was documented in 26 % of children with positive result of tuberculin skin test. Mycobacterium TB was detected by GeneXpert MTB/RIF in 23% of children. The mortality rate was 19% which mostly occured in children with meningitis (60%). Conclusion: EPTB was commonly seen in older children, and tuberculous meningitis was both the most common type and cause of death of EPTB in our setting.

Keywords: Characteristic, child, extrapulmonary tuberculosis, outcome


How to cite this article:
Triasih R, Helmi R, Laksanawati IS. Clinical profile and outcome of extrapulmonary tuberculosis in children in Indonesia. Pediatr Respirol Crit Care Med 2018;2:51-5

How to cite this URL:
Triasih R, Helmi R, Laksanawati IS. Clinical profile and outcome of extrapulmonary tuberculosis in children in Indonesia. Pediatr Respirol Crit Care Med [serial online] 2018 [cited 2018 Nov 17];2:51-5. Available from: http://www.prccm.org/text.asp?2018/2/3/51/243740




  Introduction Top


Indonesia ranks the second among countries with high burden of tuberculosis (TB) in 2016 with incidence of 391/100,000 population.[1] While data on pulmonary TB have been widely reported, information on extrapulmonary TB (EPTB) among children in Indonesia has not been well documented. The impact of EPTB is greatest among young children and immunocompromised individuals who tend to develop more severe extrapulmonary disease, especially meningitis and miliary TB.[2],[3]

The diagnosis of EPTB is confirmed by identification of Mycobacterium tuberculosis in the specimen through Ziehl–Neelsen staining or culture in Loewenstein–Jensen media. This becomes problematic in children because invasive procedure is needed to obtain the specimen. In the absence of microbiology confirmation, clinical, laboratory, radiological, or histopathological evidence can be used to diagnose EPTB. Nevertheless, this is also often difficult, since the early presentation of EPTB is commonly nonspecific, tuberculin skin test mostly negative, and chest X-ray nondiagnostic.[4] This may result in underdiagnosis of EPTB and delayed treatment leading to poorer outcome.[5] Hence, early diagnosis is important. In the limited-resource setting, recognition of demographic and clinical profiles of EPTB in children may help health workers in making clinical decision on the management of EPTB. This study aimed to describe clinical profile and outcomes of children with EPTB admitted to a tertiary hospital in one of the provinces in Indonesia within a 6-year period.


  Subjects and Methods Top


This study was conducted in Dr. Sardjito Hospital, a teaching hospital in Yogyakarta, Indonesia. All children aged younger than 18 years admitted to Dr. Sardjito Hospital, Yogyakarta, between 2009 and 2015 with a final diagnosis of EPTB written in the medical record were included in this study. Diagnosis of EPTB included miliary TB (ICD-10: A19); TB meningitis, brain and spinal cord (A17); osteoarticular TB (A18.0); TB of genitourinary system (A18.1); abdominal TB (A18.3); TB cutis/lymphadenitis (A18.4); TB of heart/pericarditis (A18.8); TB of the larynx, trachea, and bronchus (A15.5); and pleural effusion TB (A15.6). We retrospectively reviewed medical records and extracted data on demography, clinical manifestations, history of TB contact, radiological findings, histopathological finding, tuberculin skin test, and microbiology confirmation. Outcomes of the patients were also recorded.

The diagnosis of EPTB was made by a pediatrician. Microbiology confirmation, either acid-fast bacilli (AFB) staining or GeneXpert MTB/rifampicin (RIF), of the specimens (sputum, cerebrospinal fluid, pleural effusion fluid, or tissues) was performed. In case the diagnosis could not be confirmed, the diagnosis was made based on symptoms (prolonged fever, chronic cough, or weight loss), clinical findings, tuberculin skin test, and other investigations related to the site of the diseases. The types of EPTB were divided into six major organ involvements: meninges, miliary, osteoarticular, abdominal, pleural, and lymph node. All other sites of infection were considered as “other EPTB group.” We divided TB meningitis into three stages using the modified criteria of the British Medical Research Council to determine the severity of meningitis TB: Stage I Glasgow Coma Scale (GCS 15 with no focal neurologic signs), Stage II (GCS 11–14 or GCS of 15 with focal neurologic deficit), and Stage III (GCS <11).[6]

Statistical analysis

Data were collected using a questionnaire and were entered into the database using the EpiData Entry version 3.1 (The EpiData Association, Odense, Denmark). Descriptive statistics (frequency for categorical variables and mean or median for continuous variable) were used to describe the data. Statistical analysis was performed using SPSS software (SPSS Statistics for Windows, version 23; SPSS Inc., IBM Corp., Armonk, Chicago, NY, USA). The protocol for this study was approved by the Ethics Committee, Faculty of Medicine, Gadjah Mada University, Yogyakarta, Indonesia.


  Results Top


A total of 53 patients with EPTB were admitted to Dr. Sardjito Hospital during the study period. The number of EPTB admissions each year was presented in [Figure 1], which saw an increase in the last 3 years of the study period. The characteristics of the children were listed in [Table 1]. EPTB was more common in children aged 5 years or more than in younger children, with a median age (interquartile range) of 12.5 years (4.1-14.7). The most common type of EPTB was meningitis (n = 17; 28%), miliary (n = 14; 23%), osteoarticular (n = 12; 20%), and TB adenitis as well as pleural effusion (n = 5 each; 8% each). Other form of EPTB included pericardium (n = 1), suprasellar (n = 1), endobronchial (n = 1), and scrotal TB (n = 1) [Figure 2]. Seven patients had both meningitis and miliary TB. Forty-two patients had AFB smear of specimens, in which 5 showed positive result. Xpert MTB/RIF was performed in 13 patients, of which three was positive and no resistant to RIF was reported. Two patients with pleural TB had positive result of both AFB smear and Xpert MTB/RIF [Table 2]. Major presenting symptoms were fever (72%), cough (55%), and weight loss (38%). The mortality rate was 19%, which mostly occurred in TB meningitis patients (60%).
Figure 1: Number of extrapulmonary tuberculosis cases per year (2009–2015).

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Table 1: Characteristics of children with extrapulmonary tuberculosis (n=53)

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Figure 2: Organ involvement of extrapulmonary tuberculosis.

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Table 2: Positive microbiology confirmation

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Meningitis tuberculosis

Of 17 patients with TB meningitis TB, 7 also had miliary TB. TB Meningitis was more common in children aged 5 years or more, with male-to-female ratio was 1:2.4. None of the diagnosis of TB meningitis TB was confirmed by microbiology. History of contact was found in 35% of patients. Details of clinical signs, symptoms, imaging, and laboratory findings in children with TB meningitis were presented in [Table 3]. Most children belonged to Stage II (52%), followed by Stage III (29%) and Stage I (19%). Of 17 children with TB meningitis, 6 (35%) died. All patients who died belonged to Stage II and III, and two had concomitant miliary TB.
Table 3: Demographic and clinical profile of children with tuberculosis meningitis (n=17)

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Miliary tuberculosis

Of the 14 children with miliary TB, 7 had concurrent meningitis TB. Two cases were confirmed, one by AFB smear and one by GeneXpert MTB/RIF. Miliary TB was more common in children aged 5 years or more (median age of 11.9 years [IQR: 1.9–16.5]), with male-to-female ratio was 1.3:1. History of TB contact was positive in 5 children. Common signs and symptoms were cough (79%), fever (71%), dyspnea (50%), hepatomegaly (50%), and lymphadenopathy (36%). The mortality rate was 29% among miliary TB patient.

Osteoarticular tuberculosis

Twelve patients were diagnoses as osteoarticular TB, and one of them was confirmed by AFB smear. The majority of the patients aged 5 years or more. The most common site was thoracic vertebra (66.7%). Besides fever and weight loss, back pain and weakness of the extremities were other common sign and symptoms in these patients [Table 4].
Table 4: Demographic and clinical profile of children with osteoarticular tuberculosis (n=12)

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  Discussion Top


Young children and people in immunocompromised condition are at higher risk of developing EPTB. Previous studies reported higher EPTB rates in children under 5 years of age.[2],[7] Our study shows different finding, in which 70% of the children with EPTB aged 5 years or more with a median age of 12.5 years. This was in line with a study conducted in Turkey.[8] Higher coverage of Bacillus Calmette–Guérin (BCG) vaccination in Indonesia may explain this, in which BCG vaccine has been shown to be effective in protecting children from severe form of EPTB.[9],[10] The mortality rate of EPTB in our study was 19%, which mostly occurred in children with TB meningitis. Six of 17 (35.3%) children with meningitis TB died, of which all were at Stage II and III at admission.

The most common form of EPTB in this study was TB meningitis, followed by miliary TB, osteoarticular TB, pleural TB, and lymphadenitis TB. Similar findings were reported from previous study in India: 46% cases TB meningitis, 21% cases miliary TB, 10% abdominal TB, 7% lymphadenitis TB, and 4% osteoarticular TB,[11] whereas other studies reported that lymphadenitis TB was the most common EPTB, accounted for 35%–47%.[2],[11],[12]

Diagnosis of EPTB is often difficult, since the clinical symptoms can be vague, tuberculin skin test was mostly negative, and specimen is often difficult to obtain, in particular in limited-resource facilities.[4] The majority of children in this study presented with general symptoms of TB, i.e., fever, cough, and weight loss. Specific symptoms related to the site of organ involvement were documented, but not all of the children presented with specific symptoms. Evidence of TB infection which is identified by positive result of tuberculin skin test or close contact to an infectious case of TB may help to support the diagnosis of EPTB. However, only one-third of children with EPTB showed a positive result of tuberculin skin test and close contact.[7],[11] The source of infection was disclosed in higher proportion (42%) of children in our study.

Bacteriological confirmation in the specimen is the gold standard of EPTB, while prompt management is needed in EPTB for better outcome, in particular in severe forms of TB such as meningitis or miliary TB. Only nine percent of the children in our study had positive AFB, and none of the cultures was positive. GeneXpert MTB/RIF has been shown to have better sensitivity and specificity for the initial test for EPTB and may help in making decision on treatment initiation.[13] Almost one-quarter of patients had M. tuberculosis detected through Xpert MTB/RIF, and none was resistant to RIF.

Miliary TB is diagnosed mainly based on calssical miliary pattern on the chest X-ray.[14] The most common symptoms in children are cough, fever, and dyspnea, while hepatomegaly and peripheral lymphadenopathy were more common in adults.[15] In our study, 7 of 14 (50%) patients had TB meningitis concurrent with miliary TB. This was higher than that reported previously reported of 25%.[16] Central nervous system involvement was reported as an independent predictor for mortality in miliary TB.[16]

Osteoarticular TB was found in 20% EPTB, with thoracic vertebrae being the most common site affected. Baghaiae et al. reported similar finding that osteoarticular TB was found in 21% EPTB, especially in thoracic vertebrae.[11] From the imaging, we found that osteolytic lesion was a common finding, followed by compressed vertebrae and kyphosis. Around half of the children had infiltration of inflammatory cells from the biopsy, whereas necrosis caseosa and tubercle were only found in 25% and 8.3%, respectively.

TB meningitis is usually diagnosed based on a combination of clinical symptoms, cerebrospinal fluid analysis, and imaging of cerebrospinal system.[17] It typically presents a subacute insidious course with a nonspecific clinical presentation in early stages.[18] The major presenting symptom of TB meningitis in our study was fever, which occurred in all children with meningitis TB. Specific symptoms related to central nervous system disturbance were decreased consciousness (13/17), vomiting (8/17), headache (7/17), and seizure (6/17). Gosai et al. reported that fever was the most common symptom in TB meningitis (97%), followed by decreased consciousness and seizure.[7]

Cerebrospinal fluid shows a moderately increased white cell count with lymphocyte predominance, increased protein, and low level of glucose. Hydrocephalus was the most common finding in CT scan.[7],[19] Communicating hydrocephalus is usually secondary to the obstruction of cerebrospinal fluid flow in basal cisterns.[20] In some cases, obstructive hydrocephalus can be found due to tuberculoma or abscess.[18]

TB meningitis is a severe form of EPTB with high mortality rate. Younger age, delayed administration of anti-TB drugs, and late stage at presentation increase the risk of mortality. Delayed treatment due to misdiagnosis results in progression to late stage of the disease, leading to high mortality rates.[19] The majority of children in our study presented in late stage, leading to high mortality rate (6/17). All of these children were at Stage II or III at admission.

We acknowledged that not all of the patients in our study underwent microbiological investigations, and hence, only a small proportion of the patients were microbiologically confirmed. There are also potential problems related to the retrospective nature of the study.


  Conclusion Top


EPTB in Indonesia was more common in school-age children than preschool children. TB meningitis was the most common EPTB with the highest mortality rate in our setting.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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World Health Organization. Global Tuberculosis Report 2017. Geneva: World Health Organization; 2017.  Back to cited text no. 1
    
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Whitehorn J, Ayles H, Godfrey-Faussett P. Extra-pulmonary and smear-negative forms of tuberculosis are associated with treatment delay and hospitalisation. Int J Tuberc Lung Dis 2010;14:741-4.  Back to cited text no. 5
    
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STREPTOMYCIN treatment of tuberculous meningitis. Lancet 1948;1:582-96.  Back to cited text no. 6
    
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Gosai D, Gosai J, Shukla O. Study of clinical profile of childhood extra pulmonary tuberculosis. Int J Res Med Sci 2014;2:501-5.  Back to cited text no. 7
    
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Trunz BB, Fine P, Dye C. Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: A meta-analysis and assessment of cost-effectiveness. Lancet 2006;367:1173-80.  Back to cited text no. 9
    
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Bonifachich E, Chort M, Astigarraga A, Diaz N, Brunet B, Pezzotto SM, et al. Protective effect of bacillus calmette-guerin (BCG) vaccination in children with extra-pulmonary tuberculosis, but not the pulmonary disease. A case-control study in Rosario, Argentina. Vaccine 2006;24:2894-9.  Back to cited text no. 10
    
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Baghaie N, Khalilzade S, Boloursaz MR, Khodayari AA, Velayati AA. Extra pulmonary tuberculosis in children: Two years study. Acta Med Iran 2010;48:239-43.  Back to cited text no. 11
    
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Hatwal D, Chaudhari S, Joshi A, Rathaur V. Patterns of extrapulmonary tuberculosis in children: A hospital based study. Indian J Community Health 2013;25:22-7.  Back to cited text no. 12
    
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Yuan M, Lyu Y, Chen ST, Cai C, Li Y, Zhang ZG, et al. Evaluation of xpert MTB/RIF for the diagnosis of extrapulmonary tuberculosis in China. Biomed Environ Sci 2016;29:599-602.  Back to cited text no. 13
    
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Sharma SK, Mohan A, Sharma A. Challenges in the diagnosis & treatment of miliary tuberculosis. Indian J Med Res 2012;135:703-30.  Back to cited text no. 14
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Hussey G, Chisholm T, Kibel M. Miliary tuberculosis in children: A review of 94 cases. Pediatr Infect Dis J 1991;10:832-6.  Back to cited text no. 15
    
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Tanrikulu C, Gurkan F, Dagli C, Gozu A, Saner A. A comparative review of pediatric and adult patients with miliary tuberculosis. Eur J Gen Med 2007;4:6.  Back to cited text no. 16
    
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Solomons RS, Visser DH, Marais BJ, Schoeman JF, van Furth AM. Diagnostic accuracy of a uniform research case definition for TBM in children: A prospective study. Int J Tuberc Lung Dis 2016;20:903-8.  Back to cited text no. 17
    
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Sanei Taheri M, Karimi MA, Haghighatkhah H, Pourghorban R, Samadian M, Delavar Kasmaei H, et al. Central nervous system tuberculosis: An imaging-focused review of a reemerging disease. Radiol Res Pract 2015;2015:202806.  Back to cited text no. 18
    
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