Respiratory infections in X-linked hyper-IgM syndrome with CD40LG mutation: a case series of seven children in China

Abstract

Background X-linked hyper-immunoglobulin M (XHIGM), a primary immunodeficiency syndrome caused by mutations in the CD40 ligand gene(CD40LG), presents with recurrent respiratory infections in pediatric patients. We aimed to evaluate the spectrum of clinical features and respiratory pathogens in pediatric patients with XHIGM in China. Methods We retrospectively reviewed seven pediatric patients who were diagnosed with XHIGM and received follow-up treatment at the Guangzhou Women and Children’s Medical Center between January 2010 and January 2021. We determined their clinical characteristics, causative pathogens, and prognosis by performing peripheral immunological and genetic tests. Results There were seven boys with age ranging from 4–20 months (median age, 13 months). Four of the seven respiratory infections were caused by Talaromyces marneffei(T. marneffei). Two patients had viral infections caused by cytomegalovirus (CMV) and human adenovirus respectively. One patient had a mixed infection caused by Pneumocystis carinii and CMV. Except for one child who died of respiratory failure, one patient received hematopoietic stem cell transplantation (HSCT) and recovered well, the other five patients survived with regular infusions of intravenous immunoglobulin (IVIg) during the follow-up period. Six patients had reduced antibody levels, especially IgG, IgA, and IgE levels. Increased serum IgM levels were detected in four cases, and three cases presented normal IgM levels at onset. All children were diagnosed with XHIGM with CD40LG variation. Three novel mutations were identified in the present study. Conclusions Our study suggests that respiratory infections usually begin within 2 years old, fungi and viruses are important pathogens causing respiratory infections in children with XHIGM. In endemic areas, T. marneffei is the common pathogen of respiratory tract infection in children with the disease.

Talaromyces marneffei infection and complicate manifestation of respiratory system in HIV-negative children

“…The decreased Th17 differentiation impairs IL-17 function in the defense against extracellular pathogens like fungi, which might explain the patient’s susceptibility to T.marneffei [ 32 , 33 ]. CD40LG mutation can cause X-linked hyper-immunoglobulin M (XHIGM), which has been classified as combined T and B immunodeficiency [ 34 ]. A hemizygous mutation of IL2RG was identified in one patient diagnosed with SCID [ 35 ].…”

A Retrospective Study of Clinical and Immunological Features of a Pediatric Population with Talaromyces marneffei Infection

“…After receiving anti-fungal treatment and IVIg replacement, the patient underwent allogeneic stem cell transplantation, eventually being discharged in good condition [ 28 ]. Another study by Fan et al showed that children with XHIGM were more vulnerable to respiratory infections, including T. marneffei , which in turn would help pediatricians to identify XHIGM [ 29 ]. Hence, in order to avoid life-threatening infection, allogeneic stem cell transplantation should be carried out once the patient is diagnosed with XHIGM.…”

Of Mycelium and Men: Inherent Human Susceptibility to Fungal Diseases

“…While MSMDs were initially recognized for their distinct susceptibility to mycobacteria (particularly non-tuberculous (NTM) and occasionally M. tuberculosis ) and Salmonella (predisposing victims to extra-intestinal salmonellosis) [ 38 , 39 , 150 , 151 , 152 , 153 , 154 ], they were also subsequently found in patients with otherwise unexplained disseminated TDEF infection, including histoplasmosis (IL12RB1 [ 153 , 155 , 156 , 157 ]; IFNGR1 [ 158 ]), coccidioidomycosis (IFNGR1 [ 159 ] and IL12RB1 [ 160 ]), and paracoccidioidomycosis (IL12RB1 [ 161 ]). These findings provided the framework of human immunity to TDEF, which was followed by the identification of other IEI congruent with defective IFN-γ-mediated immunity, including CD40L deficiency [ 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 ] (discussed further in the section on “Pneumocystis”), GATA2 deficiency [ 171 ], and STAT1 GOF [ 168 , 169 , 172 , 173 ].…”