Brazilian Journal of Pulmonology

ISSN (on-line): 1806-3756 | ISSN (printed): 1806-3713


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Current Issue: 2019 - Volume 45 - Number 2 (March/April)


Management and outcomes of severe childhood tuberculosis in the pediatric intensive care setting: can we identify best practices?

Tratamento e desfechos da tuberculose grave em crianças na unidade de terapia intensiva pediátrica: é possível identificar as melhores práticas?


Svetlana Velizarova1; a; Natalia Gabrovska1; b; Albena Spasova1; c; Ben Marais2; 3; d; Elizabeth Page Harausz4; e; Simon Tiberi5; 6; f; Giovanni Battista Migliori7; g; Davide Manissero8; h


1. Medical University, Department of Pulmonary Diseases, Hospital for Lung Disease "St. Sofia" - Children's Clinic, Sofia, Bulgaria.
2. Department of Respiratory Medicine, The Children's Hospital at Westmead, Sydney, Australia.
3. Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, Australia.
4. State University of New York, Upstate Medical University, Syracuse (NY) USA.
5. Barts Health NHS Trust, Royal London Hospital, Division of Infection, London, United Kingdom.
6. Blizard Institute, Barts and the London School of Medicine and Dentistry, Centre for Primary Care and Public Health, London, United Kingdom.
7. Servizio di Epidemiologia Clinica delle Malattie Respiratorie, Istituti Clinici Scientifici Maugeri - IRCCS - Tradate, Italia.
8. University College of London, Institute for Global Health, London, United Kingdom.
a.; b.; c.;
d.; e.; f.;
g.; h.




Tuberculosis continues to be a clinical and public health priority. In 2017, there were an estimated 10.0 million new cases of tuberculosis and 1.3 million deaths from the disease, approximately 1.0 million of the cases and 195,000 of the deaths occurring in children under 15 years of age.(1,2) Tuberculosis is now recognized as one of the top 10 leading causes of death in children under 5 years of age living in areas with a high tuberculosis incidence. Historically, attention has been focused on pulmonary tuberculosis in adults, because it is the most infectious form. Adults with pulmonary tuberculosis transmit the disease through infectious aerosol particles, which are typically produced when a patient with cavitary lung disease coughs. Young children are less likely to have cavitary lung disease and are therefore not considered to pose a major transmission risk.(3-6) It is also more difficult to diagnose tuberculosis in children, and the burden of disease is therefore generally underestimated.

Recently, there has been increased awareness of the global burden of tuberculosis in children, resulting in more attention being given to pediatric tuberculosis from a clinical, public health, and research perspective. (1,2,7-11) Improving the accuracy of the diagnosis of tuberculosis in children is made more difficult by the paucibacillary nature of their disease; the fact that the symptoms and signs they present, as well as the radiological findings, are often nonspecific; and the inability of immunodiagnostic tests (interferon-gamma release assays and tuberculin skin tests) to differentiate between infection with Mycobacterium tuberculosis and active disease. Expanding the evidence available in the scientific literature to support quality diagnostic and treatment guidelines specific to pediatrics is a core issue,(1,2,7-11) as is the need to increase the availability of the child-friendly drug formulations that are now available through the Global Drug Facility of the international Stop TB Partnership.(12)

Despite the extensive morbidity and mortality caused by the severe forms of tuberculosis in children (tuberculous meningitis and miliary tuberculosis), scarce attention has been paid to the optimal management of tuberculosis in children admitted to the ICU. Ongoing research and reviews are attempting to explore and define best practices in adult tuberculosis cases treated in the ICU. (13) The admission of adults with tuberculosis to the ICU is most often due to extensive pulmonary involvement, leading to ARDS, life-threatening hemoptysis, or lung surgery.(14) In immunocompromised adults, neurological deterioration due to tuberculous meningitis might be another reason for ICU admission. Approaches to recognizing and managing such presentations have been discussed in the literature. (15) Overall, the mortality in ICU patients with tuberculous is quite high, usually exceeding 50%.(16)

We drew upon our experience at the National Pediatric Reference Department for Respiratory Infections, in Sofia, Bulgaria, to identify research feasibility and gaps in the treatment of severe pediatric tuberculosis. Between 2015 and 2018, five children with tuberculous meningitis were admitted to the hospital, with a mean age of 1.2 years (range, 0-3 years) and a mean body weight of 9.6 kg (range, 6-13 kg). Two had non-HIV immunosuppression and no other major comorbidities. On the basis of cultures (of cerebrospinal fluid, in 3 cases, and gastric aspirate, in 2), all five children had a confirmed diagnosis of infection with drug-susceptible strains of M. tuberculosis; one patient was also smear positive on Ziehl-Neelsen staining. All of the children had non-cavitary pulmonary involvement on chest X-ray, bilateral disease suggestive of miliary tuberculosis being seen in two. None of the children had respiratory distress severe enough to require ventilatory support, and none developed any signs of sepsis. Routine treatment with isoniazid, rifampin, ethambutol, and pyrazinamide was initiated an average of 4.4 days after presentation (range, 1-16 days). The mean time to culture conversion, based on monthly cultures, was 43.2 days (range, 40-46 days). In all five children, a clinical cure was achieved after 10-12 months of treatment with an all-oral regimen. Although the evidence from those five clinical cases is limited, it provides an encouraging picture in terms of the potential outcomes of severe childhood tuberculosis treated in the ICU. Nevertheless, the cases described represent a small number of children with a limited range of tuberculosis disease manifestations. In addition, none of those children received a treatment regimen that was optimized to penetrate the central nervous system. Therefore, there is a need for a more comprehensive review of all pediatric patients with tuberculosis who are admitted to the ICU. Although children with miliary tuberculosis have disseminated disease, they often do not appear critically ill, no cases of children presenting with classic sepsis or septic shock having been documented. However, more information is needed in order to accurately describe the full range of manifestations of severe tuberculosis in children. Similarly, there have been only a few reports of ARDS in children with acute pneumonia-like symptoms secondary to tuberculosis, which can be easily confused with acute bacterial coinfection.(17) More insight is necessary in order to describe the epidemiology, presentation, and management of such cases in pediatric ICUs.(18)

Experience from adult cases demonstrates the complexity of the pharmacokinetics and pharmacodynamics of antituberculosis drugs in critically ill patients. Absorption of oral antituberculosis drugs may be reduced by 70% due to gastroparesis, intestinal paralysis, pharmacological prophylaxis against gastric ulcers, and altered gut microbiota. Suboptimal drug levels, in blood and affected tissues, can be attributed to several factors, including impaired circulation efficiency, with fluid accumulation, and glomerular hyperfiltration, with increased renal clearance.(19,20) Although this experience seems to be transferable to pediatric cases, no specific documented evidence is available for such cases. There are other concerns unique to children, including variable drug distribution and metabolism among different age groups.(21) The need to ensure adequate blood and tissue levels of the available oral and intravenous tuberculosis drug formulations, as well as to provide optimal supportive care, are key factors in managing such complex cases of tuberculosis. There are still few pharmacokinetic data for very young or critically ill children treated with first- or second-line tuberculosis drugs, and much more remains to be done.

The paucity of evidence on childhood tuberculosis in the context of ICU care of critically ill patients calls for a collective effort to determine the magnitude of this unmet medical need, as well as for the development of best practice guidelines. Although we have described a few cases of tuberculous meningitis requiring ICU care, there is a need for a more comprehensive overview of the full spectrum of the disease and its clinical presentations, as well as the best management approaches, in children who require ICU admission for severe tuberculosis. That can be achieved only in collaborative multicenter observational studies using standard data collection tools and a shared data platform.


This article is an output of the WHO Collaborating Centre for Tuberculosis and Lung Diseases, Tradate, ITA-80, 2017-2020-GBM/RC/LDA and of the GTN Paediatric TB Committee (Chair: Ben Marais).


1. World Health Organization. Global Tuberculosis report 2018. Geneva: World Health Organization; 2018.
2. Carvalho ACC, Cardoso CAA, Martire TM, Migliori GB, Sant'Anna CC. Epidemiological aspects, clinical manifestations, and prevention of pediatric tuberculosis from the perspective of the End TB Strategy. J Bras Pneumol. 2018;44(2):134-144.
3. Lönnroth K, Migliori GB, Abubakar I, D'Ambrosio L, de Vries G, Diel R, et al. Towards tuberculosis elimination: an action framework for low-incidence countries. Eur Respir J. 2015;45(4):928-52.
4. Getahun H, Matteelli A, Abubakar I, Aziz MA, Baddeley A, Barreira D, et al. Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries .Eur Respir J. 2015;46(6):1563-76
5. Duarte R, Silva DR, Rendon A, Alves TG, Rabahi MF, Centis R, et al. Eliminating tuberculosis in Latin America: making it the point. J Bras Pneumol. 2018;44(2):73-76.
6. Silva DR, Mello FCQ, Kritski A, Dalcolmo M, Zumla A, Migliori GB. Tuberculosis series. J Bras Pneumol. 2018;44(2):71-72.
7. Sandgren A, Cuevas LE, Dara M, Gie RP, Grzemska M, Hawkridge A, et al. Childhood tuberculosis: progress requires an advocacy strategy now. Eur Respir J. 2012;40(2):294-7.
8. World Health Organization. Best practices in child and adolescent tuberculosis. Geneva: World Health Organization; 2018.
9. Harausz EP, Garcia-Prats AJ, Seddon JA, Schaaf HS, Hesseling AC, Achar J, et al. New and Repurposed Drugs for Pediatric Multidrug-Resistant Tuberculosis. Practice-based Recommendations. Am J Respir Crit Care Med. 2017;195(10):1300-1310.
10. Marais BJ, Tadolini M, Zignol M, Migliori GB. Paediatric tuberculosis in Europe: lessons from Denmark and inclusive strategies to consider. Eur Respir J. 2014;43(3):678-84.
11. Graham SM, Grzemska M, Gie RP. The background and rationale for a new fixed-dose combination for first-line treatment of tuberculosis in children. Int J Tuberc Lung Dis. 2015;19 Suppl 1:3-8.
12. Brigden G, Furin J, van Gulik C, Marais B. Getting it right for children: improving tuberculosis treatment access and new treatment options. Expert Rev Anti Infect Ther. 2015;13(4):451-61.
13. Hagan G, Nathani N. Clinical review: tuberculosis on the intensive care unit. Crit Care. 2013;17(5):240.
14. Borisov SE, D'Ambrosio L, Centis R, Tiberi S, Dheda K, Alffenaar JW, et al. Outcomes of patients with drug-resistant-tuberculosis treated with bedaquiline-containing regimens and undergoing adjunctive surgery. J Infect. 2019;78(1):35-39.
15. Otu A, Hashmi M, Mukhtar AM, Kwizera A, Tiberi S, Bacrae B, et al. The critically ill patient with tuberculosis in intensive care: Clinical presentations, management and infection control. J Crit Care. 2018;45:184-196.
16. Ferreira MD, Neves CPD, Souza AB, Beraldi-Magalhães F, Migliori GB, Kritski AL, et al. Predictors of mortality among intensive care unit patients coinfected with tuberculosis and HIV. J Bras Pneumol. 2018;44(2):118-124.
17. Oliwa J, Karumbi J, Marais BJ, Madhi SA, Graham S. Tuberculosis as a cause or comorbidity of childhood pneumonia in tuberculosis-endemic countries: a systematic review. Lancet Resp Med. 2015;3(3):235-43.
18. Chisti MJ, Parvin I, Ashraf H, Saha H, Matin FB, Pietroni MA. Interstitial lung disease and profound hypoxaemia in a severely-malnourished child with very severe pneumonia and potential lymph-node tuberculosis: an uncommon but serious co-morbidity. J Health Popul Nutr. 2013;31(1):133-7.
19. Koegelenberg CF, Nortje A, Lalla U, Enslin A, Irusen EM, Rosenkranz B, et al. The pharmacokinetics of enteral antituberculosis drugs in patients requiring intensive care. S Afr Med J. 2013;103(6):394-8.
20. Mer M, Lipman. Antibiotic administration in the critically ill - in need of intensive care! S Afr Med J. 2015;105(5):357-9.
21. Nachman S, Ahmed A, Amanullah F, Becerra MC, Botgros R, Brigden G, et al. Towards earlier inclusion of Children in tuberculosis drugs trials: a consensus statement. Lan-cet Infect Dis. 2015;15(6):711-20.



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