Unusual Indolent Course of a Chronic Active Epstein-Barr Virus-Associated Natural Killer Cell Lymphoproliferative Disorder

Natural killer (NK) cell lymphoproliferative disorders are uncommon and the Epstein-Barr virus (EBV) plays an important aetiological role in their pathogenesis. We report a 20-year-old male with a chronic active EBV infection associated with a NK cell lymphoproliferative disorder which had an unusual indolent course. He presented to the Sultan Qaboos University Hospital in Muscat, Oman, in December 2011 with a history of intermittent fever and coughing. Examinations revealed generalised lymphadenopathy, hepatosplenomegaly, leukocytosis, transaminitis, diffuse bilateral lung infiltrates and bone marrow lymphocyte involvement. A polymerase chain reaction (PCR) test revealed a high EBV viral load in the peripheral blood cells. The patient received a course of piperacillin-tazobactam for Klebsiella pneumoniae, but no active treatment for the lymphoproliferative disorder. However, his lymphocyte count, serum lactate dehydrogenase and liver enzymes dropped spontaneously. In addition, EBV PCR copies fluctuated and then decreased significantly. He remained clinically asymptomatic over the following four years.

While a course of piperacillin/tazobactam was prescribed to treat the bacterial pneumonia, the patient declined any active therapy for his underlying lymphoproliferative disorder.He was closely monitored and a spontaneous gradual drop was observed in his lymphocyte count, serum LDH levels and liver enzymes over the following 12 months.Additionally, EBV PCR copies fluctuated and then decreased significantly [Figure 1].The patient's symptoms resolved over a period of two months and he remained clinically asymptomatic with a gradually decreasing lymphocyte count (4.0 x 10 9 /L) with large granular lymphocyte morphology.His serum LDH levels remained normal and a repeat CT scan showed stable subcentimetre lymphadenopathy in the cervical, pretracheal and hilar areas, along with mild hepatosplenomegaly.The patient remained clinically well over the four years following his initial diagnosis.

Discussion
In general, patients with EBV-associated NK cell lymphoproliferative disease exhibit large granular lymphocytosis, hypersensitivity to mosquito bites, skin rashes, defective NK cell activity and high immunoglobulin E levels. 3,7The diagnostic criteria for this disease entity was first proposed by Okano et al. in the absence of apparent features of a known ulceration/proliferation, coronary artery aneurysms, central nervous system involvement, myocarditis and interstitial pneumonia. 11In addition, these patients respond poorly to chemotherapy and have a high risk of eventual progression to overt leukaemia and lymphomas in the form of extranodal NK/T cell lymphomas of nasal type (ENKLs), aggressive NK cell leukaemia (ANKL) and peripheral T cell leukaemia or lymphomas. 1,11,12Some researchers recommend an early bone marrow transplant while the patient is in good general health, despite the associated transplant-related mortality. 1Further research is required to assess the actual prevalence of EBVassociated T/NK lymphoproliferative disorders and improve patient outcomes.
Poor prognostic features which indicate early intervention include advanced age at onset (over eight underlying disease at the time of diagnosis. 10The patient in the current case displayed morphology similar to patients with the T cell subtype and an immunophenotype of the NK variant.He did not undergo testing for NK cell killing activity; however, he fulfilled the criteria proposed by Okano et al., including persistent infectious mononucleosis-like symptoms, unusual patterns of anti-EBV antibodies, increased EBV genome in affected tissues (including peripheral blood cells) and chronic illness unexplained by other known disease processes. 10e clinical outcome for patients with CAEBV infections is reportedly poor and appears to be worse for CD4 + T cell cases than NK cell cases. 1 CAEBV often results in life-threatening complications such as haemophagocytic syndrome, disseminated intravascular coagulopathy, hepatic failure, digestive tract years old), the presence of thrombocytopaenia (platelet count: <120,000/L) and T cell (rather than NK cell) associated disease. 13The overall outcome of NK cellassociated disease is variable.There are reports of some patients who eventually developed ENKL and ANKL while other cases seem to have indolent courses. 1 Two indolent cases reportedly achieved complete remission with oral acyclovir therapy and weekly intravenous cytarabine administration; however, the role of these agents in achieving complete remission is not clear. 1n the current case, the patient appeared to exhibit an indolent course despite persistent lymphocytosis, generalised lymphadenopathy, initial multi-organ involvement (including lung involvement) and poor prognostic indicators.

Conclusion
EBV-associated T/NK lymphoproliferative disorders are uncommonly seen outside of Japan, Korea and Taiwan and are often aggressive.To the best of the authors' knowledge, the patient in this report represents the first case from the Middle East with an unusual indolent course which resolved spontaneously without therapeutic intervention.

Figure
Figure 1A-C: Graphs showing the significant drop over time in (A) total white cell count, (B) liver enzyme levels and (C) Epstein-Barr viral load in a 20-year-old male with an unusual indolent course of chronic active Epstein-Barr virusassociated natural killer cell lymphoproliferative disorder.The patient declined to undergo any active therapy for the disorder and seemed to exhibit a spontaneous recovery.WBC = white blood cell count; ANC = absolute neutrophil count; Lymphs = lymphocyte count; LDH = lactate dehydrogenase H; AST = aspartate aminotransferase; ALT = alanine transaminase; ALP = alkaline phosphatase.