ArticlesMortality in children diagnosed with tuberculosis: a systematic review and meta-analysis
Introduction
Increased attention is being paid to the long-neglected global epidemic of childhood tuberculosis, and there is a growing consensus that far more children have tuberculosis than was previously thought, most of whom are undiagnosed and thus untreated.1, 2, 3 Around 1 million children are estimated to develop tuberculosis annually, of whom only 36% are notified.3 The greatest case detection failure occurs in children younger than 5 years, who probably account for around half of all paediatric cases.2 The mortality associated with these more than 500 000 new cases of tuberculosis each year is largely preventable and could contribute more than previously thought to global mortality in children younger than 5 years.4
Given that so many children with tuberculosis are never diagnosed, estimation of childhood tuberculosis mortality presents unique challenges. Cohort studies from the past three decades have included very few children who did not receive tuberculosis treatment. Mortality estimates (including the WHO global estimate of 136 000 annual tuberculosis deaths among children3) often rely on vital registration data,3 but attribution of deaths to undiagnosed tuberculosis posthumously is hampered by autopsy costs and the unreliability of vital records and verbal autopsy.5 Because symptoms in children are generally non-specific, many deaths caused by tuberculosis could be erroneously attributed to more common diseases, such as pneumonia.6 An alternative source of information on children who did not receive tuberculosis treatment is the scientific literature published before the discovery of antituberculosis chemotherapy.
Quantification of the mortality impact of the global failure to diagnose and treat childhood tuberculosis necessitates a better understanding of the mortality risks associated with the disease in relevant age groups, with and without access to appropriate treatment. Therefore, we did a systematic review and meta-analysis to estimate case fatality ratios—ie, the proportion of children with tuberculosis who die—stratified by treatment, age group, and HIV infection.
Section snippets
Search strategy
We first searched for systematic reviews of tuberculosis mortality or outcomes in children with all forms of tuberculosis. We found only systematic reviews of outcomes among children with tuberculous meningitis7 and children with multidrug-resistant tuberculosis (ie, strains of tuberculosis that are resistant to isoniazid and rifampicin).8 In both of these reviews, only cohorts receiving treatment were included. We then searched for studies in which deaths among children with tuberculosis were
Results
Of 1087 unique citations found through the database search, 253 studies were eligible for full-text review, 22 of which were included in our analysis (figure 1). Three of these papers were included only after we received additional information from their authors. We also reviewed 89 papers identified in reference lists of reviewed papers or obtained from authors' personal libraries, and included nine of these papers in our analysis.
The 31 included papers10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20
Discussion
To our knowledge, ours is the first comprehensive analysis of case fatality ratios among children with tuberculosis. We found that children receiving adequate treatment had a low mortality risk. By contrast, before the widespread availability of antituberculosis chemotherapy and the BCG vaccination, children with tuberculosis had far worse outcomes; one in five died overall, and 40% of children younger than 5 years old died. Case fatality ratios in young children (aged 0–4 years) were
References (62)
- et al.
Incidence of multidrug-resistant tuberculosis disease in children: systematic review and global estimates
Lancet
(2014) - et al.
Burden of childhood tuberculosis in 22 high-burden countries: a mathematical modelling study
Lancet Glob Health
(2014) Global burden of childhood tuberculosis
Pneumonia
(2016)- et al.
Importance of tuberculosis control to address child survival
Lancet
(2014) - et al.
Treatment outcomes of childhood tuberculous meningitis: a systematic review and meta-analysis
Lancet Infect Dis
(2014) - et al.
Treatment outcomes for children with multidrug-resistant tuberculosis: a systematic review and meta-analysis
Lancet Infect Dis
(2012) - et al.
BCG vaccination of Indian infants in Saskatchewan
Tubercle
(1949) - et al.
Tuberculosis in young children
Lancet
(1953) - et al.
Screening and preventive therapy for tuberculosis
Clin Chest Med
(2009) - et al.
Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness
Lancet
(2006)
Interrupted BCG vaccination is a major threat to global child health
Lancet Respir Med
Turning off the tap: stopping tuberculosis transmission through active case-finding and prompt effective treatment
Lancet
Controlling the seedbeds of tuberculosis: diagnosis and treatment of tuberculosis infection
Lancet
Diagnostic approaches for paediatric tuberculosis by use of different specimen types, culture methods, and PCR: a prospective case-control study
Lancet Infect Dis
New diagnostics for childhood tuberculosis
Infect Dis Clin North Am
Global Tuberculosis Report 2015
Validity of verbal autopsy procedures for determining cause of death in Tanzania
Trop Med Int Health
Requirements for the clinical evaluation of new anti-tuberculosis agents in children
Int J Tuberc Lung Dis
Tuberculosis in Kenya: follow-up of the second (1974) national sampling survey and a comparison with the follow-up data from the first (1964) national sampling survey. An East African and British Medical Research Council co-operative investigation
Tubercle
Tuberculosis in Tanzania: a follow-up of a national sampling survey of drug resistance and other factors
Tubercle
Multidrug and extensively drug-resistant tuberculosis in Canada 1997–2008: demographic and disease characteristics
PLoS One
Cuba's strategy for childhood tuberculosis control, 1995–2005
MEDICC Rev
Tuberculosis from Mycobacterium bovis in binational communities, United States
Emerg Infect Dis
Epidemiology of smear-negative pulmonary tuberculosis in the United States, 1993–2008
Int J Tuberc Lung Dis
Mortality before or during treatment among tuberculosis patients in North Carolina, 1993–2003
Int J Tuberc Lung Dis
BCG vaccination in tuberculous households
Am Rev Respir Dis
Tuberculosis control among the North American Indians
Am Rev Tuberc
Present trend of case fatality rates in tuberculosis
Am Rev Tuberc
Tuberculosis attack and death rates of household associates; the influence of age, sex, race, and relationship
Am Rev Tuberc
BCG vaccination in Montreal: statistical analysis of the results of research by Dr JA Baudouin on BCG vaccination in Montreal
Am Rev Tuberc
The natural history of tuberculosis in the human body. I. The demonstrable primary pulmonary infiltrate
Am Rev Tuberc
Cited by (175)
Complicated intrathoracic tuberculosis: Role of therapeutic interventional bronchoscopy
2023, Paediatric Respiratory Reviews
- †
These authors contributed equally to this work