Case Report: BCG-Triggered Hemophagocytic Lymphohistiocytosis in an Infant With X-Linked Recessive Mendelian Susceptibility to Mycobacterial Disease Due to a Variant of Chronic Granulomatous Disease

Abstract

In the United Arab Emirates, BCG (Bacillus Calmette-Guérin) is administered to all newborns. We present here a young infant with an inborn error of immunity (IEI) who developed fatal adverse events to this live-attenuated vaccine. This male infant received BCG (Serum Institute of India Pvt., Ltd., India) on Day 11 of life. On Day 25, he developed fever, followed by cervical lymphadenitis and bilateral otitis media with fluid drainage. On Day 118, he was admitted with severe hemophagocytic lymphohistiocytosis (HLH), and passed away on Day 145. The diagnostic exome sequencing test identified a hemizygous nonsense variant, NM_000397.3(CYBB):c.676C>T, p.Arg226* (rs137854592). Pathogenic variants of CYBB [cytochrome b(-245), beta subunit; Mendelian Inheritance in Man [MIM] accession code, 300481] are known to cause “immunodeficiency 34, mycobacteriosis, X-linked” (IMD34, MIM#300645) and “chronic granulomatous disease, X-linked” (CGDX, MIM#306400). The natural history of his illness is consistent with “X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD).” This entity is responsible for his BCG disease and is a likely trigger of his HLH. This disastrous event underlines the importance of developing worldwide policies that target BCG disease prevention, especially in communities with high prevalence of IEI. Moreover, screening for genetic causes of MSMD in the community could pave the way, at least partially, for scale-up of tuberculosis (TB) prevention.

Novel mutations in CYBB Gene Cause X-linked chronic Granulomatous Disease in Pakistani patients

“…In fact, one of our patients exhibited adverse BCG vaccination reaction and later developed tuberculosis. BCGitis occurred in 23.53% of our patients with tuberculosis, which is almost similar to the other published data [ 27 , 28 ] and lower than Iranian patients (56%) [ 29 ]. It is presumed that such differences could be due to the type of BCG strain, age at the time of vaccination, amount of BCG dosages and type of mutations.…”

Case Report: A Case of Leukocyte Adhesion Deficiency, Type III Presenting With Impaired Platelet Function, Lymphocytosis and Granulocytosis

“…Therefore, LAD3 should be added to the list of "defects in intrinsic and innate immunity" where BCG should be avoided as a precaution, and a prophylactic treatment for BCG disease should be considered (48,49). Moreover, it is prudent to change the time of BCG administration from birth to 1 year of age, when most IEI become more recognizable (50). It is well to reemphasize that a cautious consideration of BCG complications in infants is necessary, especially in regions with a high prevalence of IEI such as UAE.…”