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. 2023 Dec 22;44(1):17.
doi: 10.1007/s10875-023-01633-1.

Clinical and Immunological Features, Genetic Variants, and Outcomes of Patients with CD40 Deficiency

Aaqib Zaffar Banday  1   2   3 , Rahila Nisar  4 , Pratap Kumar Patra  5 , Anit Kaur  6 , Rohit Sadanand  7 , Chakshu Chaudhry  8   9 , Syed Tariq Ahmed Bukhari  1 , Saquib Zaffar Banday  10 , Dharmagat Bhattarai  11 , Luigi D Notarangelo  12
Affiliations

Clinical and Immunological Features, Genetic Variants, and Outcomes of Patients with CD40 Deficiency

Aaqib Zaffar Banday et al. J Clin Immunol. .

Abstract

Purpose: Inherited deficiencies of CD40 and CD40 ligand (CD40L) reflect the crucial immunological functions of CD40-CD40L interaction/signaling. Although numerous studies have provided a detailed description of CD40L deficiency, reports of CD40 deficiency are scarce. Herein, we describe the characteristics of all reported patients with CD40 deficiency.

Methods: The PubMed, Embase and Web of Science databases were searched for relevant literature published till 7th August 2023. Study deduplication and identification of relevant reports was performed using the online PICO Portal. The data were extracted using a pre-designed data extraction form and the SPSS software was used for analysis.

Results: Systematic literature review revealed 40 unique patients with CD40 deficiency. Respiratory tract and gastrointestinal infections were the predominant clinical manifestations (observed in 93% and 57% patients, respectively). Sclerosing cholangitis has been reported in nearly one-third of patients. Cryptosporidium sp. (29%) and Pneumocystis jirovecii (21%) were the most common microbes identified. Very low to undetectable IgG levels and severely reduced/absent switch memory B cells were observed in all patients tested/reported. Elevated IgM levels were observed in 69% patients. Overall, splice-site and missense variants were the most common (36% and 32%, respectively) molecular defects identified. All patients were managed with immunoglobulin replacement therapy and antimicrobial prophylaxis was utilized in a subset. Hematopoietic stem cell transplantation (HSCT) has been performed in 45% patients (curative outcome observed in 73% of these patients). Overall, a fatal outcome was reported in 21% patients.

Conclusions: We provide a comprehensive description of all important aspects of CD40 deficiency. HSCT is a promising curative treatment option for CD40 deficiency.

Keywords: CD40 antigen; CD40 deficiency; CD40 ligand; HIGM3; TNFRSF5; TNFSF5; hyper-IgM immunodeficiency syndrome.

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Conflict of interest statement

Conflict of Interest or Competing Interests None.

Figures

Fig. 1
Fig. 1
Search methodology employed in our study
Fig. 2
Fig. 2
Cumulative frequency of occurrence of symptoms in patients with CD40 deficiency. The median age at onset of symptoms is 6 months and ~ 90% patients are symptomatic by 2 years of age
Fig. 3
Fig. 3
Frequency of occurrence of various important features of CD40 deficiency
Fig. 4
Fig. 4
Overview of the reported variants in CD40 gene and the corresponding protein aberrancies. TNFR-Cys represent the cysteine-rich tumor necrosis factor receptor domains and TR represents the transmembrane region
Fig. 5
Fig. 5
Overall survival in patients with CD40 deficiency (both transplanted and untransplanted patients included)
Fig. 6
Fig. 6
Comparison of the overall survival in patients treated with and without hematopoietic stem cell transplantation
See this image and copyright information in PMC

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