Skip directly to site content Skip directly to page options Skip directly to A-Z link Skip directly to A-Z link Skip directly to A-Z link
Volume 28, Number 3—March 2022
Research

Treatment Outcomes of Childhood Tuberculous Meningitis in a Real-World Retrospective Cohort, Bandung, Indonesia

Heda M. Nataprawira1, Fajri Gafar1Comments to Author , Nelly A. Risan, Diah A. Wulandari, Sri Sudarwati, Ben J. Marais, Jasper Stevens, Jan-Willem C. Alffenaar, and Rovina Ruslami
Author affiliations: Hasan Sadikin Hospital, Bandung, Indonesia (H.M. Nataprawira, N.A. Risan, D.A. Wulandari, S. Sudarwati); Universitas Padjadjaran, Bandung, Indonesia (H.M. Nataprawira, N.A. Risan, D.A. Wulandari, S. Sudarwati, R. Ruslami); University of Groningen, Groningen, the Netherlands (F. Gafar, J. Stevens); Children’s Hospital at Westmead, Sydney, New South Wales, Australia (B.J. Marais); University of Sydney, Sydney (B.J. Marais, J.-W.C. Alffenaar); Westmead Hospital, Sydney (J.-W.C. Alffenaar)

Main Article

Table 5

Multivariate logistic regression model for predictors of postdischarge death, tracked until the end of tuberculous meningitis treatment in children treated for TBM at Hasan Sadikin Hospital, Bandung, Indonesia, 2011–2020*†

Variable Died‡§ Alive‡ Crude OR (95% CI) p value aOR (95% CI) p value
No. cases
 18
 91
Age group, y
<2 3 (16.7) 26 (28.6) 0.65 (0.15–2.86) 0.573 0.13 (0.01–1.12) 0.064
2–4 6 (33.3) 9 (9.9) 3.78 (0.98–14.56) 0.054 1.60 (0.26–9.86) 0.610
5–9 3 (16.7) 22 (24.2) 0.77 (0.17–3.41) 0.734 0.23 (0.03–1.75) 0.156
10–14
 6 (33.3)
 34 (37.4)
 Referent
Referent
Sex
M 10 (55.6) 39 (42.9) 1.67 (0.60–4.61) 0.325 3.43 (0.76–15.45) 0.109
F
 8 (44.4)
 52 (57.1)
 Referent
Referent
TBM stage¶
Stage I or II 7 (38.9) 67 (73.6) Referent Referent
Stage III
 11 (61.1)
 24 (26.4)
 4.39 (1.53–12.6)
 0.006
 2.31 (0.56–9.54)
 0.247
Known BCG vaccination
No 7 (38.9) 15 (16.5) 3.22 (1.08–9.66) 0.037 5.38 (1.07–27.07) 0.041
Yes
 11 (61.1)
 76 (83.5)
 Referent
Hydrocephalus on CT
No 3 (16.7) 66 (72.5) Referent Referent
Yes 13 (72.2) 23 (25.3) 12.43 (3.25–47.59) <0.001 18.97 (2.68–134.38) 0.003
Unknown
 2 (11.1)
 2 (2.2)
 22.00 (2.26–214.23)
 0.008
 17.85 (1.30–245.49)
 0.031
Tuberculoma on CT#
No 12 (66.7) 85 (93.4) Referent Referent
Yes
 4 (22.2)
 4 (4.4)
 7.08 (1.56–32.13)
 0.011
 8.78 (1.10–70.39)
 0.041
Positive TST
No 10 (55.6) 76 (83.5) Referent Referent
Yes 8 (44.4) 15 (16.5) 4.05 (1.37–11.96) 0.011 4.79 (0.96–24.05) 0.057

*Data are no. (%) except as indicated. aOR, adjusted odds ratio; BCG, bacillus Calmette-Guérin; CT, computed tomography; GCS, Glasgow Coma Scale; TBM, tuberculous meningitis; TST, tuberculin skin test. †The goodness-of-fit of the model using Hosmer-Lemeshow test was p = 0.877. The performance of the model using the area under the receiver operating characteristic curve was 0.91 (95% CI 0.85–0.97). ‡Including patients who were tracked until death or treatment completion, and excluding patients who were lost to follow-up and with unknown treatment outcomes. §Positive TST and motor disorders were associated with higher odds of postdischarge death in univariate analysis but did not remain significant in multivariate analysis. Signs of raised intracranial pressure with hydrocephalus as well as GCS score with TBM staging had the likelihood of collinearity; therefore, only hydrocephalus and TBM staging were included in the final multivariate model. In our subgroup analysis among children aged <5 y, no additional independent predictors of postdischarge death were observed. ¶Stage I TBM was defined as GCS of 15 with no focal neurologic signs, stage II TBM as GCS of 11–14 or 15 with focal neurologic signs, and stage III TBM as GCS ≤10 (20). Patients with stages I and II TBM were combined in the analysis because there were no patients with TBM stage I died after hospital discharge. #Because of the redundancy with the variable “unknown status of hydrocephalus,” the degree of freedom for the variable “unknown status of tuberculoma” was reduced.

Main Article

References
  1. World Health Organization. Global tuberculosis report 2020. 2020 [cited 2021 Dec 28]. https://www.who.int/publications/i/item/9789240013131
  2. Chiang  SS, Khan  FA, Milstein  MB, Tolman  AW, Benedetti  A, Starke  JR, et al. Treatment outcomes of childhood tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis. 2014;14:947–57. DOIPubMedGoogle Scholar
  3. Marais  BJ, Gie  RP, Schaaf  HS, Hesseling  AC, Obihara  CC, Starke  JJ, et al. The natural history of childhood intrathoracic tuberculosis—a critical review of the pre-chemotherapy literature. Int J Tuberc Lung Dis. 2004;8:392–402.PubMedGoogle Scholar
  4. García-Basteiro  AL, Schaaf  HS, Diel  R, Migliori  GB. Adolescents and young adults: a neglected population group for tuberculosis surveillance. Eur Respir J. 2018;51:1800176. DOIPubMedGoogle Scholar
  5. Marais  BJ, Amanullah  F, Gupta  A, Becerra  MC, Snow  K, Ngadaya  E, et al. Tuberculosis in children, adolescents, and women. Lancet Respir Med. 2020;8:335–7. DOIPubMedGoogle Scholar
  6. World Health Organization. Roadmap towards ending TB in children and adolescents, second edition [cited 2021 Dec 28]. https://apps.who.int/iris/bitstream/handle/10665/274374/9789241514668-eng.pdf
  7. Wilkinson  RJ, Rohlwink  U, Misra  UK, van Crevel  R, Mai  NTH, Dooley  KE, et al.; Tuberculous Meningitis International Research Consortium. Tuberculous meningitis. Nat Rev Neurol. 2017;13:581–98. DOIPubMedGoogle Scholar
  8. van Toorn  R, Solomons  R. Update on the diagnosis and management of tuberculous meningitis in children. Semin Pediatr Neurol. 2014;21:12–8. DOIPubMedGoogle Scholar
  9. Hill  J, Marais  B. Improved treatment for children with tuberculous meningitis: acting on what we know. Arch Dis Child. 2022;107:68–9. DOIPubMedGoogle Scholar
  10. Huynh  J, Thwaites  G, Marais  BJ, Schaaf  HS. Tuberculosis treatment in children: The changing landscape. Paediatr Respir Rev. 2020;36:33–43.PubMedGoogle Scholar
  11. van Well  GTJ, Paes  BF, Terwee  CB, Springer  P, Roord  JJ, Donald  PR, et al. Twenty years of pediatric tuberculous meningitis: a retrospective cohort study in the western cape of South Africa. Pediatrics. 2009;123:e1–8. DOIPubMedGoogle Scholar
  12. van Toorn  R, Schaaf  HS, Laubscher  JA, van Elsland  SL, Donald  PR, Schoeman  JF. Short intensified treatment in children with drug-susceptible tuberculous meningitis. Pediatr Infect Dis J. 2014;33:248–52. DOIPubMedGoogle Scholar
  13. Yaramiş  A, Gurkan  F, Elevli  M, Söker  M, Haspolat  K, Kirbaş  G, et al. Central nervous system tuberculosis in children: a review of 214 cases. Pediatrics. 1998;102:E49. DOIPubMedGoogle Scholar
  14. Nataprawira  HM, Ruslianti  V, Solek  P, Hawani  D, Milanti  M, Anggraeni  R, et al. Outcome of tuberculous meningitis in children: the first comprehensive retrospective cohort study in Indonesia. Int J Tuberc Lung Dis. 2016;20:909–14. DOIPubMedGoogle Scholar
  15. Faried  A, Ramdan  A, Arifin  MZ, Nataprawira  HM. Characteristics and surgical outcomes of tuberculous meningitis and of tuberculous spondylitis in pediatric patients at Dr. Hasan Sadikin Hospital, Bandung: a single center experience. Interdiscip Neurosurg Adv Tech Case Manag. 2018;11:37–40.
  16. Faried  A, Putra  SPS, Suradji  EW, Trianto , Akbar  RR, Nugraheni  NK, et al. Characteristics and outcomes of pediatric tuberculous meningitis patients with complicated by hydrocephalus with or without tuberculoma at Regional Public Hospital Teluk Bintuni, West Papua, Indonesia. Interdiscip Neurosurg. 2020;19:100609. DOIGoogle Scholar
  17. Rahajoe  NN, Nawas  A, Setyanto  DB, Kaswandani  N, Triasih  R, Indawati  W, et al. Buku petunjuk teknis manajemen dan tatalaksana TB anak [National guideline on the management of tuberculosis in children]. Ministry of Health of the Republic of Indonesia. Jakarta (Indonesia): Ministry of Health of the Republic of Indonesia; 2016.
  18. Marais  S, Thwaites  G, Schoeman  JF, Török  ME, Misra  UK, Prasad  K, et al. Tuberculous meningitis: a uniform case definition for use in clinical research. Lancet Infect Dis. 2010;10:803–12. DOIPubMedGoogle Scholar
  19. World Health Organization. Guidance for national tuberculosis programmes on the management of tuberculosis in children (2nd edition). World Health Organization; 2014 [cited 2022 Feb 5]. https://www.who.int/publications/i/item/9789241548748
  20. Thwaites  GE, Nguyen  DB, Nguyen  HD, Hoang  TQ, Do  TTO, Nguyen  TCT, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med. 2004;351:1741–51. DOIPubMedGoogle Scholar
  21. Donald  PR. The chemotherapy of tuberculous meningitis in children and adults. Tuberculosis (Edinb). 2010;90:375–92. DOIPubMedGoogle Scholar
  22. Gafar  F, Van’t Boveneind-Vrubleuskaya  N, Akkerman  OW, Wilffert  B, Alffenaar  JC. Nationwide analysis of treatment outcomes in children and adolescents routinely treated for tuberculosis in the Netherlands. Eur Respir J. 2019;54:1901402. DOIPubMedGoogle Scholar
  23. Kalita  J, Prasad  S, Misra  UK. Predictors of paradoxical tuberculoma in tuberculous meningitis. Int J Tuberc Lung Dis. 2014;18:486–91. DOIPubMedGoogle Scholar
  24. Chidambaram  V, Tun  NL, Majella  MG, Ruelas Castillo  J, Ayeh  SK, Kumar  A, et al. Male sex is associated with worse microbiological and clinical outcomes following tuberculosis treatment: a retrospective cohort study, a systematic review of the literature, and meta-analysis. Clin Infect Dis. 2021;73:1580–8. DOIPubMedGoogle Scholar
  25. Basu Roy  R, Bakeera-Kitaka  S, Chabala  C, Gibb  DM, Huynh  J, Mujuru  H, et al. Defeating paediatric tuberculous meningitis: applying the WHO “defeating meningitis by 2030: global roadmap.”. Microorganisms. 2021;9:857. DOIPubMedGoogle Scholar
  26. Maree  F, Hesseling  AC, Schaaf  HS, Marais  BJ, Beyers  N, van Helden  P, et al. Absence of an association between Mycobacterium tuberculosis genotype and clinical features in children with tuberculous meningitis. Pediatr Infect Dis J. 2007;26:13–8. DOIPubMedGoogle Scholar
  27. Rohlwink  UK, Donald  K, Gavine  B, Padayachy  L, Wilmshurst  JM, Fieggen  GA, et al. Clinical characteristics and neurodevelopmental outcomes of children with tuberculous meningitis and hydrocephalus. Dev Med Child Neurol. 2016;58:461–8. DOIPubMedGoogle Scholar
  28. Basu Roy  R, Thee  S, Blázquez-Gamero  D, Falcón-Neyra  L, Neth  O, Noguera-Julian  A, et al.; ptbnet TB Meningitis Study Group. Performance of immune-based and microbiological tests in children with tuberculosis meningitis in Europe: a multicentre Paediatric Tuberculosis Network European Trials Group (ptbnet) study. Eur Respir J. 2020;56:1902004. DOIPubMedGoogle Scholar
  29. Abubakar  I, Pimpin  L, Ariti  C, Beynon  R, Mangtani  P, Sterne  JA, et al. Systematic review and meta-analysis of the current evidence on the duration of protection by bacillus Calmette-Guérin vaccination against tuberculosis. [v–vi.] [v–vi.]. Health Technol Assess. 2013;17:1–372, v–vi. DOIPubMedGoogle Scholar
  30. Gafar  F, Ochi  T, Van’t Boveneind-Vrubleuskaya  N, Akkerman  OW, Erkens  C, van den Hof  S, et al. Towards elimination of childhood and adolescent tuberculosis in the Netherlands: an epidemiological time-series analysis of national surveillance data. Eur Respir J. 2020;56:2001086. DOIPubMedGoogle Scholar
  31. 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. DOIPubMedGoogle Scholar
  32. Cernuschi  T, Malvolti  S, Nickels  E, Friede  M. Bacillus Calmette-Guérin (BCG) vaccine: A global assessment of demand and supply balance. Vaccine. 2018;36:498–506. DOIPubMedGoogle Scholar
  33. du Preez  K, Seddon  JA, Schaaf  HS, Hesseling  AC, Starke  JR, Osman  M, et al. Global shortages of BCG vaccine and tuberculous meningitis in children. Lancet Glob Health. 2019;7:e28–9. DOIPubMedGoogle Scholar
  34. World Health Organization. Immunization Indonesia 2021 country profile. 2021 [cited 2021 Dec 28]. https://www.who.int/immunization/monitoring_surveillance/data/idn.pdf
  35. Martinez  L, Cords  O, Horsburgh  CR, Andrews  JR, Acuna-Villaorduna  C, Ahuja  SD, et al.; Pediatric TB Contact Studies Consortium. The risk of tuberculosis in children after close exposure: a systematic review and individual-participant meta-analysis. Lancet. 2020;395:973–84. DOIPubMedGoogle Scholar
  36. Bang  ND, Caws  M, Truc  TT, Duong  TN, Dung  NH, Ha  DTM, et al. Clinical presentations, diagnosis, mortality and prognostic markers of tuberculous meningitis in Vietnamese children: a prospective descriptive study. BMC Infect Dis. 2016;16:573. DOIPubMedGoogle Scholar
  37. Thee  S, Basu Roy  R, Blázquez-Gamero  D, Falcón-Neyra  L, Neth  O, Noguera-Julian  A, et al.; ptbnet TB Meningitis Study Group. Treatment and outcome in children with tuberculous meningitis - a multi-centre Paediatric Tuberculosis Network European Trials Group study. Clin Infect Dis. 2021;ciab982; Epub ahead of print. DOIPubMedGoogle Scholar
  38. Boyles  TH, Lynen  L, Seddon  JA; Tuberculous Meningitis International Research Consortium. Decision-making in the diagnosis of tuberculous meningitis. Wellcome Open Res. 2020;5:11. DOIPubMedGoogle Scholar
  39. Cresswell  FV, Te Brake  L, Atherton  R, Ruslami  R, Dooley  KE, Aarnoutse  R, et al. Intensified antibiotic treatment of tuberculosis meningitis. Expert Rev Clin Pharmacol. 2019;12:267–88. DOIPubMedGoogle Scholar
  40. Donald  PR, Schoeman  JF, Van Zyl  LE, De Villiers  JN, Pretorius  M, Springer  P. Intensive short course chemotherapy in the management of tuberculous meningitis. Int J Tuberc Lung Dis. 1998;2:704–11.PubMedGoogle Scholar
  41. World Health Organization. Rapid communication on updated guidance on the management of tuberculosis in children and adolescents [cited 2021 Dec 28]. https://www.who.int/publications/i/item/9789240033450
  42. Ruslami  R, Gafar  F, Yunivita  V, Parwati  I, Ganiem  AR, Aarnoutse  RE, et al. Pharmacokinetics and safety/tolerability of isoniazid, rifampicin and pyrazinamide in children and adolescents treated for tuberculous meningitis. Arch Dis Child. 2022;107:70–7. DOIPubMedGoogle Scholar
  43. Panjasawatwong  N, Wattanakul  T, Hoglund  RM, Bang  ND, Pouplin  T, Nosoongnoen  W, et al. Population pharmacokinetic properties of antituberculosis drugs in Vietnamese children with tuberculous meningitis. Antimicrob Agents Chemother. 2020;65:e00487–20. DOIPubMedGoogle Scholar
  44. van Toorn  R, Zaharie  S-D, Seddon  JA, van der Kuip  M, Marceline van Furth  A, Schoeman  JF, et al. The use of thalidomide to treat children with tuberculosis meningitis: A review. Tuberculosis (Edinb). 2021;130:102125. DOIPubMedGoogle Scholar
  45. Abo  YN, Curtis  N, Osowicki  J, Haeusler  G, Purcell  R, Kadambari  S, et al. Infliximab for paradoxical reactions in pediatric central nervous system tuberculosis. J Pediatric Infect Dis Soc. 2021 Oct 5;piab094.
  46. Gafar  F, Marais  BJ, Nataprawira  HM, Alffenaar  JC. Optimizing antimicrobial and host-directed therapies to improve clinical outcomes of childhood tuberculous meningitis. Clin Infect Dis. 2021;ciab1036; Epub ahead of print. DOIPubMedGoogle Scholar
  47. Schoeman  JF, Van Zyl  LE, Laubscher  JA, Donald  PR. Effect of corticosteroids on intracranial pressure, computed tomographic findings, and clinical outcome in young children with tuberculous meningitis. Pediatrics. 1997;99:226–31. DOIPubMedGoogle Scholar
  48. Rohlwink  UK, Figaji  A, Wilkinson  KA, Horswell  S, Sesay  AK, Deffur  A, et al. Tuberculous meningitis in children is characterized by compartmentalized immune responses and neural excitotoxicity. Nat Commun. 2019;10:3767. DOIPubMedGoogle Scholar
  49. Rohlwink  UK, Mauff  K, Wilkinson  KA, Enslin  N, Wegoye  E, Wilkinson  RJ, et al. Biomarkers of cerebral injury and inflammation in pediatric tuberculous meningitis. Clin Infect Dis. 2017;65:1298–307. DOIPubMedGoogle Scholar
  50. Marais  BJ, Heemskerk  AD, Marais  SS, van Crevel  R, Rohlwink  U, Caws  M, et al.; Tuberculous Meningitis International Research Consortium. Standardized methods for enhanced quality and comparability of tuberculous meningitis studies. Clin Infect Dis. 2017;64:501–9.PubMedGoogle Scholar

Main Article

1These first authors contributed equally to this article.

Page created: February 08, 2022
Page updated: February 21, 2022
Page reviewed: February 21, 2022
The conclusions, findings, and opinions expressed by authors contributing to this journal do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors' affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above.
file_external