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.