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.