A new therapy in Epstein-Barr virus-associated lymphoproliferative disease: a case report and a revision of the literature

Chronic active Epstein-Barr virus infection (CAEBV) is a systemic EBV-positive lymphoproliferative disorder (EBV-LPD), which is marked by persistent infectious mononucleosis-like symptoms. CAEBV may result in life-threatening complications [1‐6] such as malignant lymphomashepatic failure, interstitial pneumonia, coronary artery aneurysms, central nervous system (CNS) involvement, hemophagocytic syndromes and massive hemorrhage from the gastrointestinal tract. However, it is very rare for a patient to have several synchronous symptoms owing to EBV infection. Hematopoietic stem cell transplantation (HSCT) may be the only cure for CAEBV [7].

We report the case of a boy with CAEBV who synchronously developed an intestinal lymphoproliferative lesion, life-threatening gastrointestinal bleeding, multiple vascular lesions, and encephalitis. A new treatment strategy, which involved the combination of thalidomide, propranolol, ganciclovir, and glucocorticoids, successfully cured the symptoms.

The guardian of the patient consented to treatment and also provided written consent for publication of the data in this case report.

At the age of 3 years and 3 months, he visited another hospital because of recurrent fever and diarrhea. Upper gastrointestinal endoscopy and enteroscopy revealed multiple ulcers in the ileum and colon (Fig. 1a). Pathological diagnosis of intestinal tract could not exclude Crohn’s disease. He was then prescribed methylprednisolone, which he continued on for 1 year with amelioration of his symptoms.

At the age of 5 years, he experienced recurrent fever, abdominal pain, and diarrhea, persisting for nearly 1 month. He also had gastrointestinal hemorrhage for 2 weeks. The laboratory results in the local hospital revealed coagulation dysfunction, anemia (the lowest hemoglobin was 62 g/L), low platelet counts (lowest count: 68 × 10^9/L), and raised procalcitonin levels (the highest level: 4.75 ng/ml). The highest serum ferroprotein level was 899 μg/L. Computed tomography (CT) of the abdomen revealed dilatation of blood vessels in the intestinal walls (Fig. 1d) and gastroscopy showed a duodenal ulcer with bleeding. He developed unexpected and sudden life-threatening hemorrhage from the intestinal vasculature, which led to hypovolemic shock. Routine management included treatment for shock, empirical antibiotics, blood transfusion, and hemostatic therapy. However, the hemorrhage was only controlled for 2 days using duodenal artery embolization. He also developed polyuria (3-4 L/d), frequent convulsions and hyponatremia (109 mEq/L). With treatment, his symptoms improved. However, the gastrointestinal hemorrhage and polyuria persisted, and the patient was transferred to our hospital for further management.

He was unconscious on admission, had a Glasgow Coma Scale (GCS) score of 11 and had hepatomegaly and splenomegaly. Laboratory tests demonstrated a white blood count of 6.02 × 10^9/L, hemoglobin level of 112 g/L, platelet count of 75 × 10^9/L, D-dimer level of 3.82 mg/L, prothrombin time of 13.3 s, activated partial thromboplastin time of 36.4 s, and a fibrinogen level of 1.66 g/L. The serum albumin levels were low at 26 g/L, but the liver function was within normal limits. The serum levels of triglyceride and ferroprotein were within normal range at 1.58 mmol/L (normal range: 0.45–1.7 mmol/L) and 227.5 μg/L, respectively (normal range: 20.0–200.0 μg/L). EBV DNA and cytomegalovirus DNA were both detected in the blood; the levels of viral copies were 1.17 × 10^4/mL and 2.62 × 10^3/mL, respectively. Tests for serum EBV antibodies, including immunoglobulin A (Ig A)/ VCA, immunoglobulin G (IgG) /VCA, and IgM/VCA, were negative. The numbers of natural killer cells in the blood were low, accounting for 0.6% of lymphocytes. Initially, the cerebrospinal fluid (CSF) pressure was abnormally raised (245 cm of H₂O). An EBV-DNA level of 1.43 × 10^4 copies/mL was detected in the CSF by polymerase chain reaction (PCR); the CSF also tested positive for Epstein - Barr virus VCA (IgG). Three-dimensional CT angiography of the head and neck demonstrated an aneurysm in the right internal carotid artery (Fig. 1c). The echocardiography was essentially normal, without any coronary artery dilation or aneurysm. We confirmed the diagnosis of EBV-LPD, based on the results in situ hybridization of EBV-encoded miRNA (EBER) (Fig. 1b). Electroencephalo-graphy showed diffuse slowing (Fig. 1e).

A repeated duodenal artery embolization and symptomatic therapy could not control the hemorrhage. He subsequently received treatment with ganciclovir, glucocorticoid, thalidomide at a dose of 2 mg/kg/d in 3 divided doses, and propranolol at an initial dose of 1.5–2 mg/kg/d. Hemorrhage was controlled in 5 days; his symptoms improved and urine output was normalized. The GCS score was 14. Then, the fever did not recur and the CSF pressure was also normalized. The level of EBV DNA of CSF was 2.5 × 10^2 copies /mL (normal value: ≤500).

He had a spontaneous remission of seizures on day 19 of admission. He was discharged from hospital on day 24 of admission. After discharge, he was diagnosed with epilepsy owing to recurring seizures, which required the successive use of levetiracetam and oxcarbazepine to control. A follow-up CT at 3 months after admission showed regression of the aneurysm in the right internal carotid artery and the vascular lesion in the duodenum. The drug therapy schedule and levels of EBV DNA are shown in Fig. 1f.

A literature search revealed only 3 reports of cases with 2 or more rare EBV-associated clinical manifestations. Mashima et al. [8] reported the case of a 55-year-old woman with aplastic anemia who was diagnosed with EBV-LPD and EBV encephalitis. Another report, by Noda et al. (2011), described the case of an immunocompetent 65-year-old man who presented with complaints of general malaise and severe disturbance of consciousness. He was initially suspected to have EBV encephalitis based on the findings on MRI of the brain, elevated EBV antibody titers, and the presence of EBV DNA in the CSF. Finally, he was diagnosed with an EBV-associated B-cell LPD with CNS involvement, and found to have EBER by in situ hybridization positivity in the brain tissue on autopsy. In the third report, Raman et al. (2014) described a patient with newly diagnosed HIV infection, who also developed cerebral vasculitis and encephalitis due to EBV.

A review of the literature is presented, with a summary of 8 cases of CAEBV-associated enteritis and EBV-LPD in non-immunocompromised individuals (Table 1).

The clinical manifestations of CAEBV vary according to the site of involvement, such as multiple vascular lesions, intestinal lesions, central nervous system complications and so on. A standard and effective treatment protocol for systemic EBV-LPD is lacking. HSCT is the only cure.

We report a rare case of CAEBV with intestinal, vascular, and neurological involvement. He presented a sudden life-threatening gastrointestinal hemorrhage because of enteritis and the dilatation of intestinal vasculature. It has been reported in the literature [15] that most of these conditions required surgical resection of the bowel, and if surgery was not possible, most died of massive bleeding. For our case, titanium clips and somatostatin were employed to control the hemorrhage, but it soon recurred. Interestingly, the hemorrhage was controlled within 5 days after treatment with ganciclovir, thalidomide, and propranolol. The intestinal vasculature was caused by EBV, not caused by a congenital vascular malformation, because EBER-lymphocytes were positive in the intestinal tract. A follow-up CT scan showed regression of all aneurysm. Thalidomide and propranolol are apparently effective in treating enteritis and vascular lesions secondary to EBV infection.

Both propranolol and thalidomide were known as angiogenesis inhibitor. Propranolol is the preferred treatment for accidentally diagnosed infantile hemangiomas [16, 17]. Thalidomide has proven efficacy in myeloma [18]. However, neither of these drugs have previously been used for vascular lesions associated with EBV infection.

Jones et al. [19] reported that thalidomide and pomalidomide may reactivate EBV-positive resting memory B cells, thereby enhancing the EBV lytic cycle and host immune suppression. However, thalidomide is less effective than pomalidomide in enhancing the EBV lytic cycle [19]. And patients with CAEBV may have deficiencies of EBV-specific cellular immunity, and nearly all resting memory B cells are activated. Therefore, only a few of these cells may be reactivated by thalidomide with minimal impact on the condition of these patients. Our case showed that thalidomide was safe for treating CAEBV.

Yager et al. [20] found that oral valganciclovir could inhibit EBV replication. In our patient, long-term oral ganciclovir therapy could inhibit EBV replication in the gastrointestinal tract; corticosteroids offered symptomatic relief. The improvement in the intestinal lesions in our patient confirmed this effect.

With the combination treatment, our patient’s clinical symptoms disappeared despite the persistence of EBV DNA load in peripheral blood. This proved the efficacy of this combination therapy. Our goal of treatment was not the achievement of complete remission, but long-term symptom control, regardless of the presence of the EBV genome.

We think this report and discussion may improve the understanding and management of CAEBV. This therapy may represent a safe and feasible alternative for severe CAEBV and associated LPD patients, which warrants further research.