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.

Suleiman Al-Hammadi,Amal M Yahya,Amar Shibli,Ghazala B Balhaj,Ranjit Vijayan,Abdul-Kader Souid,Abdulla Al-Amri,Mohamed I Tawil

doi:10.3389/fped.2021.687538

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.

Highlights

Bacillus Calmette-Guérin, a live vaccine derived from attenuated Mycobacterium bovis cultures, is administered to all newborns in the United Arab Emirates (UAE) since 2005 [1]
This practice has resulted in serious adverse events in our tribal communities, especially in children with unrevealed inborn error of immunity (IEI) [2, 3]
Mendelian susceptibility to mycobacterial diseases” (MSMD) embraces inherited entities that result from both “virulent” and “faintly virulent” mycobacteria, including BCG vaccines [5, 6]

Summary

INTRODUCTION

Bacillus Calmette-Guérin, a live vaccine derived from attenuated Mycobacterium bovis cultures, is administered to all newborns in the United Arab Emirates (UAE) since 2005 [1]. This young infant has the hemizygous pathogenic variant CYBB:p.Arg226∗ (rs137854592) and has received the BCG vaccine Thereafter, he developed BCG disease (fever with lymphadenitis) and progressed to severe HLH (systemic inflammation with massive hepatosplenomegaly due to lymphocyte proliferation). Hemoglobin, g/l Platelet count, 109/l Neutrophil count, 109/l Lymphocyte count, 109/l C-reactive protein, mg/l Erythrocyte sedimentation rat, mm/h Ferritin, μg/l Triglyceride, mmol/l Alanine transaminase, U/l Soluble interleukin-2 receptor, pg/ml Hepatosplenomegaly Cytomegalovirus, Epstein–Barr virus, HIV Bone marrow biopsy and spinal tap Neck ultrasound Computerized tomography chest and abdomen Staphylococcus haemolyticus Intravenous dexamethasone Multiorgan failure/disseminated intravascular coagulation. Future studies are needed to determine whether the carrier state of CYBB:p.Arg226∗ could have contributed to the development of SLE in his mother This case report provides further justification for developing and implementing safe rules for BCG vaccination locally and internationally.

CONCLUSIONS

ETHICS STATEMENT

United Arab Emirates