Delayed BCG Vaccination, Disseminated BCG Disease (BCGosis) at Six Months of Age, and the Diagnostic Limitations of Tuberculin Skin Testing in Infants: A Systematic Review and Immunopathological Analysis

Background: The Bacillus Calmette-Guérin (BCG) vaccine — the only licensed anti-tuberculosis vaccine — is administered at birth in over 150 countries. In many settings, however, BCG vaccination is deferred beyond the neonatal period, with a significant cohort receiving vaccination at approximately six months of age. An emerging clinical paradox has been identified: infants who receive delayed BCG vaccination at six months may subsequently develop devastating disseminated BCG disease (BCGosis), raising two unresolved questions of critical clinical importance. First, whether pre-existing subclinical Mycobacterium tuberculosis latent infection (LTBI) acquired during the unprotected window period acts as an immunological cofactor precipitating dissemination of the live attenuated BCG strain upon vaccination. Second, whether the tuberculin skin test (TST/PPD) — the most widely available diagnostic tool — provides sufficient sensitivity and specificity at six months of age to serve as a pre-vaccination safety screen.Methods: A systematic review was conducted following PRISMA-2020 guidelines across PubMed/MEDLINE, Embase, the Cochrane Library, and the WHO Global Tuberculosis Database (1990–2025). Search terms included "BCGosis," "disseminated BCG disease," "delayed BCG vaccination," "latent TB infants," "SCID BCG complications," "TST limitations infants," and "IGRA infants under two years." Studies reporting BCGosis following delayed BCG vaccination, pre-vaccination LTBI in infants, and TST/IGRA performance in the first year of life were included.Results: The pooled evidence from 32 high-quality studies across 17 countries confirms that BCGosis occurs almost exclusively in infants with undiagnosed inborn errors of immunity (IEI), especially severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), and Mendelian susceptibility to mycobacterial disease (MSMD). BCG-related complications represented the first clinical manifestation of underlying IEI in 75% of affected infants. A landmark Saudi Arabian cohort study (n=178 SCID patients, 2015–2023) demonstrated that delaying BCG from birth to six months significantly reduced BCG-related complications from 46.1% to 2.6% (p<0.001), illustrating the benefit of pre-vaccination immunological screening rather than blanket deferral. The TST showed false-negative rates of up to 40% in culture-confirmed tuberculosis among children under two years, attributable to T-cell immaturity, the immunological window period, and maternal immune modulation. IGRA assays demonstrated higher specificity but indeterminate rates of 17% in infants under twelve months, particularly in immunocompromised patients (27%), limiting their standalone utility. The mechanistic hypothesis of BCG vaccination precipitating expansion of pre-existing M. tuberculosis latent infection through cross-reactive T-cell activation and immune reconstitution inflammatory syndrome (IRIS)-like pathology is supported by immunological evidence but requires prospective validation.Conclusions: Delayed BCG vaccination at six months of age in infants with undetected IEI or unscreened latent TB infection constitutes a high-risk clinical scenario. The TST alone is an insufficient pre-vaccination safety screen at this age. Newborn screening for SCID using T-cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC), supplemented by comprehensive family history assessment, is essential before administering BCG to any infant beyond the neonatal period. International vaccination policy must distinguish between the protective benefit of BCG deferral for immunodeficient infants and the unacceptable risk of a six-month unprotected window in high-TB-burden populations.