Plasma Metagenomic Sequencing Expedites Diagnosis of Disseminated BCG in an Infant With IKBKB Mutation

Abstract

Background: Infants with inborn errors of immunity (IEI), born in countries where Bacillus-Calmette-Guerin (BCG) vaccination is recommended at birth, are at risk of developing infectious complications following vaccination. A prompt diagnosis of disseminated BCG infection in these infants is essential, as many will require stem cell transplantation (SCT) for the immunologic cure. In patients with IEI, the mortality risk from disseminated mycobacterial infection is high, both before and following SCT. Methods: A 7-month-old Qatari infant with an IEI, homozygous IKBKB gene mutation, was evaluated at our institution for SCT. He had a history of recurrent pneumonias, but pretransplant evaluation revealed negative cultures from bronchoalveolar fluid, blood and urine. At 8 months of age, the infant developed skin nodules of unclear etiology, prompting additional evaluation. Results: Given his profound immunosuppression and receipt of broadspectrum antimicrobials, plasma metagenomic next-generation sequencing (mNGS) was obtained and identified Mycobacterium tuberculosis complex within 72 hours. A skin biopsy was performed, and antimycobacterial therapy was initiated. Mycobacterium bovis-BCG was confirmed from cultures 3 weeks later. Treatment was complicated by elevated serum liver transaminases and aminoglycoside-associated high-frequency hearing loss. The infant completed 14 months of treatment from engraftment. Evaluation for active BCG infection after SCT was negative. Conclusion:In an infant with a unique IEI, plasma mNGS provided the first diagnosis of disseminated BCG infection. We believe that early initiation of antimycobacterial treatment improved the infant's clinical outcome. Plasma mNGS testing should be considered as a noninvasive screen for infectious pathogens in children with IEIs before SCT.

Metagenomic sequencing expedites diagnosis of disseminated BCG in an infant with BRAFV600E mutation

“…The medical management of disseminated BCG disease can be challenging for potential adverse drug events [18]. In our study, the infant developed severe myelosuppression, consistent with toxicity from antimycobacterial agents including rifampicin, isoniazid and linezolid, which prompted further adjustments to the antituberculosis regimens.…”

“…The strengths of mNGS include avoidance of invasive diagnostic procedures, simplification of various infectious diseases evaluations, identification of pathogens otherwise undetected by conventional techniques [16], and contribution to the identification of MTB complex strains as in our study. Recently, some case reports have described the application of plasma mNGS in the early diagnosis of BCG-associated infection [17,18]. Given the long-term history of exposure to broad-spectrum antibiotics in our case, we did not perform plasma mNGS due to a high risk of false-negative results, which was the main limitation of our study.…”