Abstract
Background: Disseminated Bacillus Calmette-Guérin disease (D-BCG) in children with chronic granulomatous disease (CGD) can be fatal, while its clinical characteristics remain unclear because both diseases are extremely rare. The patients with CGD receive BCG vaccination, because BCG vaccination is usually performed within 24 h after delivery in China.Methods: We prospectively followed-up Chinese patients with CGD who developed D-BCG to characterize their clinical and genetic characteristics. The diagnoses were based on the patients' clinical, genetic, and microbiological characteristics.Results: Between September 2009 and September 2016, we identified 23 patients with CGD who developed D-BCG. Their overall 10-year survival rate was 34%. We created a simple dissemination score to evaluate the number of infected organ systems and the survival probabilities after 8 years were 62 and 17% among patients with simple dissemination scores of ≤3 and >3, respectively (p = 0.0424). Survival was not significantly associated with the CGD stimulation index or interferon-γ treatment. Eight patients underwent umbilical cord blood transplantation and 5 of them were successfully treated. The genetic analyses found mutations in CYBB (19 patients), CYBA (1 patient), NCF1 (1 patient), and NCF2 (1 patient). We identified 6 novel highly likely pathogenic mutations, including 4 mutations in CYBB and 2 mutations in NCF1.Conclusions: D-BCG is a deadly complication of CGD. The extent of BCG spreading is strongly associated with clinical outcomes, and hematopoietic stem cell transplantation may be a therapeutic option for this condition.
Highlights
Bacille Calmette-Guerin (BCG), an attenuated strain of Mycobacterium bovis, was originally isolated from a cow with tuberculosis
It is caused by an inherited defect in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex that consists of two membrane-spanning subunits, gp91phox and p22phox, as well as three cytosolic components p47phox, p67phox, and p40phox [10]
Mutations within the X-linked gp91 phox gene (CYBB) cause the X-linked form of chronic granulomatous disease (CGD), while the autosomal recessive forms of CGD are due to mutations in in CYBA, NCF1, NCF2, or NCF4 which encode for p22 phox, p47 phox, p67 phox, and p40 phox, respectively [10]
Summary
Bacille Calmette-Guerin (BCG), an attenuated strain of Mycobacterium bovis, was originally isolated from a cow with tuberculosis. With protective effect against lifethreatening tuberculosis(TB) such as tuberculosis meningitis and disseminated TB in children, BCG vaccination is recommended in countries with a high TB burden [2]. Patients with CGD suffer from a variety of recurrent bacterial and fungal infections [9] It is caused by an inherited defect in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex that consists of two membrane-spanning subunits, gp91phox and p22phox, as well as three cytosolic components p47phox, p67phox, and p40phox [10]. Disseminated Bacillus Calmette-Guérin disease (D-BCG) in children with chronic granulomatous disease (CGD) can be fatal, while its clinical characteristics remain unclear because both diseases are extremely rare. The patients with CGD receive BCG vaccination, because BCG vaccination is usually performed within 24 h after delivery in China
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