Discussion
The pathogenesis of GS remained still a mystery, which was defined as
the significant reduction or absence of peripheral B cells and impaired
T-cell mediated immunity in adults[1, 2]. GS patients were
characterized by thymoma and hypogammaglobulinemia. Their initial
symptoms tended to occur due to recurrent infection or secondary to
thymoma itself, and hypogammaglobulinemia was not corrected following
thymectomy[21-23].Moreover, GS patients might also suffer from
autoimmune complications, such as pure red cell aplasia, hypothyroidism,
arthritis, myasthenia gravis, systemic lupus erythematosus, Sjögren’s
syndrome[2, 22]. In this case, the female patient presented with
chronic diarrhea, hypogammaglobulinemia, absence of B lymphocytes, and
thymoma, and the symptoms were not improved after the tumor removal.
Therefore, the GS was clinically diagnosed based on her history and
blood tests. However, the diagnosis was not confirmed during her initial
manifestation nine years ago, indicating the lacked awareness of GS
among clinicians.
Diarrhea was the patient’s initial manifestation. It was reported that
chronic diarrhea was present in almost up to 50% of GS patients, which
was mainly caused by opportunistic infections, such as Salmonella
spp. , Campylobacter. jejuni , Clostridium difficile , and
CMV, but in some cases the pathogen was not identified[3-5, 24]. A
study on GS in China found that 36% of patients suffered from diarrhea,
and it was postulated that this might be related to malabsorption.
Moreover, it also revealed that CMV was the most common pathogen among
viral infections[25]. Kelesidis, T. et al systematically summarized
the characteristics of 152 patients with GS, and discovered that
diarrhea was present in 31.8 % of patients, and 35.7% of them were
caused by infection, while the pathogenesis of most cases had not been
identified. Meanwhile, this study also found that CMV was the most
common opportunistic pathogen reported, and the main cause of diarrhea
in five cases[24]. Except for infections, the pathogenesis of
diarrhea might also be related to immune factors, since some patients
could relieve symptom through thymectomy and human immunoglobulin
replacement treatment or steroids, as well as villous atrophy of
intestines which led to malabsorption[5, 26-28]. It was supposed
that intestinal malabsorption and inflammation seemed to cause diarrhea,
hypoalbuminemia, and electrolyte imbalance, resulting in fatigue, weight
loss, and numbness of hands and feet of this patient.
CMV was a common human viral infection, which could cause various system
or organ infections in GS patients[4, 6-14]. There might be a high
prevalence of undiscovered CMV
gastroenteritis in chronic diarrhea of unknown origin[12]. CMV could
infect the whole alimentary tract,of which the most common is the colon,
and gastric involvement iscommonest in the upper gastrointestinal
tract[29, 30]. Yeh, P. J. et al retrospectively investigated 53
cases diagnosed with CMV gastritis in both immunocompromised and
immunocompetent patients and concluded that gastric ulcer (88.9%) was
the most common endoscopic feature and the gastric antrum was the most
commonly affected location[29]. You, D. M. et al reviewed the
endoscopic manifestations of gastrointestinal CMV diseases, including
ulcers, fragile, hyperemic, or erythematous mucosa, edema, and
subepithelial hemorrhage[30]. A recent study also reported that the
commonest endoscopic feature of CMV disease was ulcers, followed by
polypoid lesions and inflammation[31]. The endoscopic manifestations
of patients diagnosed with GS and CMV infection with gastrointestinal
tract involvement were also non-specific, mainly charactered by
intestinal mocosal ulcers, inflammation and edema of the intestinal
mucosa, which might be easily confused with inflammatory bowel disease,
and even some cases showed normal manifestations. Therefore, the
clinical confirmation depended on biopsy results and further
immunohistochemical method[7, 20]. In addition, some patients
suffered from both CMV gastroenteritis and ulcerative colitis, and they
responded well to steroids and/or immunosuppressive treatment,
indicating that autoimmune factors might also play a significant role in
the inflammation of gastrointestinal mucous membrane[5, 15]. In the
present case, the patient presented with mucosal inflammation and
polypoid lesion under gastrointestinal endoscopy.
Ganciclovir was considered as the first-line therapy for CMV disease.
The recommended dose for ganciclovir was 5 mg/kg intravenously twice
daily (the dose shouled be adjusted according to the glomerular
filtration rate, and the infusion time should last for over one
hour).The course of treatment was at least 2-3weeks, or even 3-6 weeks.
However, in immunocompromised individuals, the potential adverse effects
of ganciclovir were common, including headaches, elevated transaminases,
fever, rash, and myelosuppression. On this basis, Foscarnet, 90 mg/kg
twice daily, could be considered as the initial therapy or in patients
with ganciclovir nonresponse or intolerance. In addition, combined
therapy might be effective after failure of monotherapy[30]. Pierce,
B. et al showed that Foscarnet was effective in the treatment of most
ganciclovir-resistant CMV documented in the literature, and the
incidence of nephrotoxicity in patients with solid organ transplantation
was lower[32]. Wang, C. H. suggested in his report that the
treatment of disseminated CMV infection in GS could be similar to that
of solid organ transplant recipients due to severe immunosuppression
condition[33]. The patient, Tavakol, M. reported, diagnosed with
unilateral CMV retinitis with GS switched to oral valganciclovir
maintenance after 6 months of intravenous ganciclovir treatment, and
subsequent follow-up examination of the involved retina showed partial
response[3].
There was insufficient evidence or
consensus on standard treatment strategies for CMV gastroenteritis with
GS, and reference to other systems for the prevention and treatment of
CMV infection might be reasonable. According to the literature review,
ganciclovir could be used as the first line of initial treatment for GS
and CMV gastroenteritis, and Foscarnet or combined with both could be
used for ganciclovir resistance or symptom recurrence, and cidofovir
could be used for those who were not responsive or intolerant to
Foscarnet, which was currently the accepted treatment option. Although
our patient was not tested for resistance, there was no significant
clinical improvement after 2 weeks of ganciclovir and human
immunoglobulin replacement therapy. Considering that ganciclovir might
be resistant or the course of treatment might be inadequate, foscarnet
sodium was adjusted for antiviral treatment with a dose according to the
drug instruction. After 3 weeks of foscarnet treatment, serum CMV DNA
level decreased and the symptom of diarrhea improved almost completely.
Despite active treatment, four
patients still deteriorated and died, and the main cause of death was
refractory severe infection and complications according to the
literature review. Therefore, it was significant for GS patients to
prevent the infection. Because the immunodeficiency persisted after
thymectomy, patients with GS should receive regular lifelong
human immunoglobulin replacement
therapy(IGRT), every three months or once a month, so as to maintain IgG
levels of above 500 mg/dL in case of low IgG, and furthermore, if a
patient had recurrent infection regardless of IgG levels, IGRT could
reduce the incidence of further severe infections[4, 23, 33]. Wang,
C. H. reported that the GS patient who was recurrently admitted to the
hospital for pneumonia was administered with human immunoglobulin to
maintain serum IgG levels of at least 500 mg/dL, while monitoring for
signs of infection, and further infections had been prevented in the
1-year follow-up[33]. Most reports had come to similar conclusions.
Therefore, it was necessary for our patient to undertake periodic human
immunoglobulin replacement treatment and monitor immunity status in
order to prevent and timely identify opportunistic infection.