4 | Discussion
XHIGM is a primary combined immunodeficiency syndrome that results from mutations in the CD40LG gene, which encodes for the CD40L protein.2 This retrospective analysis of seven pediatric patients aimed to collect data on the clinical presentation, treatment, and causative respiratory pathogens of patients with XHIGM and use this information to gain further understanding of the rare pathogens of respiratory infections in pediatric patients with XHIGM.
XHIGM results in combined immune deficiency with a defect in Ig isotype switching and enhanced susceptibility to opportunistic infections. According to the European and US cohorts, the most common pathogen causing opportunistic infections is P. carinii, while others include Bartonella , Cryptosporidium parvum ,Histoplasma , Mycobacterium avium , Salmonella dublin , Herpes family viruses, etc.3, 11, 12 In this study, only P2 had P. carinii infection, as previously reported, while four patients (P1, P5, P6, and P7) were found to have T. marneffei infection in the lungs. In other words, pediatricians should look out for T. marneffei infection in children with XHIGM, especially in high-prevalence areas. It should be noted that viral infections have also been linked to the development of respiratory infections in these children, such as interstitial pneumonia caused by P. carinii , CMV, and HAdV infections.3, 13 In our study, three patients presented with interstitial pneumonia with extensive ground-glass opacity on HRCT, presumably due to P. carinii and other viral infections. Of these, a unique case of HAdV infection (P3) progressively worsened and the patient eventually died of respiratory failure. Therefore, interstitial lung disease caused by HAdV infection should be checked in pediatric patients with XHIGM as it is potentially lethal.
XHIGM with CD40LG mutations has been classified as combined T and B immunodeficiency, and the overall prognosis of these patients is poor, with an overall survival rate of 28.2% at the age of 40 years in one study and an average of 20% survival rate by the age of 25 years in another study with liver disease as a significant predictor of overall survival.11, 14-16 Earlier management with IVIg replacement therapy and antibiotic prophylaxis could improve the quality of life of patients by reducing the incidence of life-threatening infections.3 In this study, the confirmed cases were regularly administered IVIg replacement therapy, and no serious infections occurred in them during the follow-up years. Hematopoietic stem cell transplantation (HSCT) is a potential curative therapy for XHIGM; however, the outcomes of HSCT are not clearly obvious and end-organ damage reduces the possibility of successful HSCT, which is associated with a higher mortality rate among these patients.3, 17 Six of seven patients survived without HSCT in our study. Further clinical follow-up and large sample sizes are needed to determine whether Ig replacement therapy is more beneficial to patients with XHIGM than HSCT.
XHIGM is a PID caused by mutations in the CD40LG gene.CD40LG is located on the X chromosome, which encodes CD40L (CD154), a member of the tumor necrosis factor family made-up of three functional domains: intracellular, transmembrane and extracellular domains.18 Since CD40L is necessary for T lymphocytes to induce B lymphocytes to undergo class switching from IgM to IgG, IgA, and IgE, patients with XHIGM syndrome have reduced levels of IgG, IgA, and IgE, and normal or elevated levels of IgM. 8, 14In this study, our patients had typical immune parameters of XHIGM at onset, which indicated the possibility of XHIGM and the necessity for genetic testing. As expected, mutations in CD40LG were found in all seven pediatrics patients. Two patients were diagnosed with XHIGM due to microdeletions of the CD40LG gene (P5 and P6). Interestingly, three cases of novel hemizygote mutations have not been reported in gnomAD so far (P1, P2, and P3), where other variants at the same position are found. Based on the clinical manifestations and pedigree analysis of the patients according to the American College of Medical Genetics variation classification guidelines, the three mutations can be taken as evidence for pathogenicity.