Mycobacterium Tuberculosis Infection Among Child and Adolescent Contacts of Pulmonary Tuberculosis Cases in Brazil: A Multi-Center Prospective Cohort Study

Background: Identification of Mycobacterium tuberculosis infection (TBI) is essential to prevent progression to tuberculosis (TB) in children and adolescents.Methods: Close contacts of pulmonary TB patients enrolled between 2015 and 2019 in a multi-center Brazilian cohort study were followed for up to 24 months and classified according to age group: <5 years, 5-9 years, 10-14 years and 15-18 and >18 years old (the reference group). Clinical evaluation, radiographic examination, interferon gamma release assay (IGRA) testing at baseline and month 6, and additional data were collected. A multivariable stepwise mixed-effects logistic regression was performed to identify factors associated with TBI.Findings: Among 1,795 TB contacts identified, 530 (29.5%) were ≤18 years old. The proportion with a positive IGRA (at baseline or month 6) was 28% (<5 years), 34.5% (5-9 years), 40.7% (10-14 years), and 44.7% (15-18 years old). In addition, at month 6, the highest frequency (10.4%) of IGRA conversion (negative at baseline and positive at month 6) was observed in persons 15-18 years old. Multivariable regression revealed that increased age, male sex, presence of cavitation on chest X-ray, persistent cough, and positive acid-fast bacilli smear of the TB index case, as well as older age among contacts, were independently associated with a positive IGRA result. Furthermore, cavitation on chest X-ray of the TB index case and older age in contacts were also independently associated with IGRA conversion at month 6 in all age groups. Interpretation: The proportion with a positive IGRA increases with age, even among children. It is possible that IGRA-positivity, particularly in older children, is due to exposure other than from this household contact in Brazil. This highlights the importance of distinguishing between prior and recent TBI. The findings also warrant the need to develop better diagnostic tests and follow-up policies for those contacts of individuals with TB.Funding Information: The study was supported by the Intramural Research Program of the Fundação Oswaldo Cruz (B.B.A.), Intramural Research Program of the Fundação José Silveira (B.B.A., M.S.R.), Departamento de Ciência e Tecnologia (DECIT) - Secretaria de Ciência e Tecnologia (SCTIE) – Ministério da Saúde (MS), Brazil [25029.000507/2013-07 to V.C.R.], Fogarty International Center and National Institute of Child Health & Human Development of the National Institutes of Health under [Award Number D43 TW009763 through a research scholarship awarded to M.B.A.], and the National Institutes of Allergy and Infectious Diseases [U01- AI069923 to T.R.S, ABS, MBA, BMFN, MSR, AB, ASRM, JGO, VCR, BD, JRLS, ALK, SC, TRS, BBA, and MCS and U01-AI115940 to B.B.A.]. M.B.A. received a fellowship from the Fundação de Amparo à Pesquisa da Bahia (FAPESB). MAP and B.B.D received a fellowship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Finance code: 001). B.B.A, J.R.L.S, A.K. and V.C.R. are senior investigators whereas A.B.S. is a PhD fellow from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil. J.R.L.S. and A.K are recipients of the Scientist of our State fellowship from Rio de Janeiro Research Council/FAPERJ.Declaration of Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All other authors declare no competing interests.Ethics Approval Statement: All clinical investigations were conducted according to the principles of the Declaration of Helsinki. All regulatory documents were approved by the Research Ethics Committee of all participating sites (CAAE: 25102414.3.2009.5543). Written informed consent was obtained from each participant or their legally responsible guardians, at the time of study enrollment. The anonymity of study subjects was preserved; all research data were de-identified.