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Gastric ulcer as the main complication in hemophagocytic lymphohistiocytosis: A case report

To the Editor, Hemophagocytic lymphohistiocytosis (HLH), presenting with a wide range of non-specific clinical symptoms, is a rare hyperinflammatory syndrome. Primary HLH usually occurs in children who have a genetic defect, while secondary HLH is more commonly seen in adults and is associated with infection, malignancy, rheumatological disease or metabolic disorder. Viral infection is the main trigger for adult HLH, and Epstein-Barr virus (EBV) infection accounts for 43% of all viral cases in a study of 2197 patients. HLH is characterized by uncontrolled immune activation and organ injury; it is always fulminant and frequently fatal. Overall survival from HLH is approximately 55%. Fever and hepatosplenomegaly are the cardinal symptoms of HLH. Laboratory abnormities include cytopenia, hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis, low or a lack of natural killer (NK) cell activity, and high levels of ferritin and soluble CD25 (sCD25). These characteristics are critical diagnostic clues for HLH according to the HLH-2004 diagnostic and therapeutic guidelines. Although HLH may affect multiple organs, gastrointestinal involvement, especially that in the stomach, is rare. Here, we report a case of HLH in an immunocompetent 33-year-old woman, with the main and the earliest manifestation of gastric ulcers. A 33-year-old woman with no history of personal or family disease was admitted to our hospital complaining of gastric ulcer, diarrhea, edema and fever. Three months before her admission, she visited a local hospital due to hematemesis and melena. An esophagogastroduodenoscopy (EGD) was performed and hemorrhagic ulcers were found at the body of the stomach with chronic and nonatrophic inflammation. Laboratory tests showed hemoglobin 90 g/L (reference, 120-165 g/L), hypoalbuminemia (28.7 g/L; reference, 35-50 g/L), and slightly elevated levels of liver enzymes. Hemorrhage was soon stopped after proton pump inhibitors (PPIs) were administrated. Two months later the patient presented diarrhea and progressive edema of the eyelids and lower limbs. Ten days before her admission to our hospital, she started having intermittent fever. During hospitalization, she underwent a repeat EGD which showed multiple ulcers at the body of the stomach that had remained unhealed for 3 months (Figure 1A), with histopathology of chronic non-atrophic gastritis. Laboratory tests showed decreased levels of hemoglobin (90 g/L) and albumin (19.4 g/L), while levels of alkaline phosphatase (546 U/L; reference, 40-110 U/L), γ-glutamyl transpeptidase (141 U/L; reference, <50 U/L), and C-reactive protein (45.58 mg/L; reference <5 mg/L) were elevated. Tumor markers such as CA199 (132 U/mL; reference, <27.00 U/mL), CA125 (178 U/mL; reference, <35 U/mL) and CA50 (123 U/mL; reference, <20 U/mL) were above the upper limit of normal. A rapid urease test for Helicobacter pylori, T-SPOT test for tuberculosis, and blood culture of bacteria were all negative. Her thyroid function and serum gastrin level, as well as rheumatic examination results, were all within normal ranges. Echocardiography revealed moderate-to-massive pericardial effusion. And computed tomography (CT) showed the thickening of the intestinal wall, with enlarged lymph nodes and polyserositis (Figure 1B). The patient presented with massive hematochezia (10001500 mL per day) soon after her admission. Her blood pressure quickly dropped to 80/60 mmHg. Her coagulation function deteriorated, showing prolonged activated partial thromboplastin time to 90.5 seconds (reference, 32-43 s), prothrombin time to 18.3 seconds (reference, 11-14 s), decreased fibrinogen of 0.74 g/L (reference, 2-4 g/L), and increased levels of D-dimer (5.16 mg/L; reference, <0.55 mg/L) and fibrinogen degradation products (40.10 mg/L; reference, <5 mg/L), indicating the occurrence of disseminated intravascular coagulation (DIC). Additionally, the hemoglobin level and platelet count quickly declined to 66 g/L and 40 × 10/L (reference, [100-300] × 10/L), respectively. Blood transfusion, hemostatic therapy and supportive treatment were immediately applied. After consultation with our multidisciplinary team, hematological disorder was considered. Thus, a bone marrow biopsy was performed. The appearance of hemophagocytes on the smears (Figure 1C) indicated a diagnosis of HLH. Further laboratory tests showed increased levels of sCD25 of >7500 U/L (reference, <2400 U/L), ferritin of 1030.40 μg/ L (reference, <150 μg/L) and plasma EBV DNA of 2.53 × 10 copies/ mL (reference, <400 copies/mL). Moreover, strong positive EBVencoded RNA was observed in a gastric biopsy (Figure 1D). According to the diagnostic guidelines, the patient was diagnosed as having HLH with EBV infection. Antiviral therapy with ganciclovir, impact therapy with methylprednisolone and immunoglobulin were administrated immediately. However, the patient's condition deteriorated rapidly and she died of severe hypoxemia and DIC 6 days after admission. EBV infects about 95% of human beings worldwide, although most of them are asymptomatic. However, it is involved in the pathogenesis of lymphoma and HLH. The latter is a rare but life-threatening disease characterized by uncontrolled hyperinflammation and subsequent systemic organ failure. The spleen and liver are the most Received: 11 May 2020 Revised: 23 June 2020 Accepted: 5 August 2020