Here, we present the clinical course and treatment of adverse reactions to BCG and TB in 79 Mexican patients with CGD. Adverse reactions to BCG were observed in 72% of the CGD-vaccinated patients during the first three years of life, and TB was diagnosed in 24% of the included patients. According to the World Health Organization (WHO) guidelines, BCG vaccination is routinely administered after birth in Mexico as a preventive strategy against TB, with > 90% coverage (14). It is estimated that high global coverage (> 90%) and universal infant BCG immunization could reduce global childhood TB mortality by 16.5% (15). Adverse reactions to the BCG vaccine in the general population were estimated to be 1:2,500 for localized BCG-itis and 1:100,000 for disseminated BCG-osis disease (16). The risk of disseminated disease increases in immunocompromised hosts. In this study, over half of patients with CGD had disseminated BCG reactions. Therefore, vaccination with BCG (a live attenuated strain of M. bovis) should be avoided in individuals with suspected or confirmed inborn IEI such as CGD (17). There is limited information regarding appropriate treatment of mycobacterial diseases (BCG and TB) in CGD (4, 18, 19). There is no single regimen for the treatment of local, regional, or disseminated side effects of BCG for CGD (4, 20, 21). In this study, the therapeutic regimens used for BCG adverse reactions differed according to the duration and regimen of the drugs used. Therapeutic approaches for BCG-itis include conservative management, antituberculosis therapy, and/or surgical intervention. Relapse in patients with disseminated BCG was observed in 10% of patients with CGD treated for BCG-osis. Therefore, the treatment of mycobacterial infections in CGD must be individualized and involve collaboration between pediatricians, immunologists, and pediatric infectious disease specialists, with close follow-up owing to the risk of relapse. In the patients reported here, disseminated BCG infection was not the cause of death, which correlated with the results of an Indian cohort (9).
Mexico is considered a country with a high burden of TB by the World Health Organization (WHO). In 2023, the TB incidence rate for all ages was 133 per 100,000, with children younger than 14 years accounting for 12% of all cases (22). In the present cohort, 24% of the CGD were diagnosed with TB, similar to other countries where TB is endemic (6, 7, 12). In North America and Europe, TB is diagnosed in 1–2% of patients with CGD (23, 24). The variability in TB frequency in patients with CGD between countries suggests that exposure to the pathogen plays an essential role in mycobacterial diseases in genetically susceptible patients (25). The frequency of BCG side effects and TB was similar in patients with pathogenic variants of the X-linked CYBB gene versus recessive genes, as previously reported by Ishikawa et al. (26). In the patients reported herein, the lungs were the organs most affected by TB; however, other organs were also affected. Therefore, evaluating the pulmonary involvement as well as other organs (including the lymph nodes, bowel, and CNS) is recommended in patients with CGD who have TB infections. For optimal management, microbiological confirmation of M. tuberculosis and M. bovis BCG, and antibiotic susceptibility testing are recommended in addition to clinical diagnosis. In this study, the treatment of TB did not differ from that established for patients without an identified IEI based on the four antimicrobial agents. However, prolonged antimycobacterial therapy should be considered for TB disease and disseminated BCG-osis in patients with CGD owing to the risk of TB relapse (20). We recommend a duration of 24 months for patients with CGD, with close follow-up and monitoring of possible relapses and side effects of medication, individualized by a pediatric infectious disease specialist. Daily treatment is also recommended over intermittent therapy to reduce the risk of relapse and drug resistance (20, 27).
This study was subject to the potential biases of retrospective reviews, including incomplete clinical data and microbiological identification of mycobacterial infections. A longitudinal national database of the clinical characteristics and genetic analysis of CGD would further advance our understanding of the disease and its association with TB and BCG disease.