Reversing Splenomegalies in Epstein Barr Virus Infected Children: Mechanisms of Toxicity in Viral Diseases Dana F. Flavin, M.D., M.S., B.S. Abstract The rapid reversal of splenomegaly in Epstein Barr Virus (EBV) infected children and young adults was seen in over 50 patients treated with a combination therapy that reduced reactive oxygen species, increased interferon gamma and decreased free nitric oxide in lymphocytes. The patients showed dramatic improvement within 24 hours with successful remission of the disease and complete reversal of splenomegalies. Abbreviations:EBV = Epstein Barr Virus; eNOS= endothelial nitric oxide synthase; iNOS=inducible nitric oxide synthase; NO = Nitric oxide; ROS = reactive oxygen species; XO = Xanthine oxidase Introduction Viral infections with Epstein Barr Virus (EBV) are often seen in young adults commonly peaking during puberty. It is often initially misdiagnosed as a flu, later as Chronic Fatigue Syndrome or even depression.. Mononucleosis is often responsible for general fatigue and malaise. Though less common in young children, the disease may often run more virulent, particularly in males, causing hepato and splenomegaly with mortality resulting from a rupture of the spleen causing rapid internal bleeding. Two to three weeks after the onset of fever and malaise symptoms, pharyngitis and often posterior cervical lymph node enlargement or generalized lymphadenopathy set in . Liver function tests are also abnormal in more than 90% of the cases at this stage of the disease. (1) The Causes of Toxicity in EBV The basic cause of toxicity in EBV is from the generation of Reactive Oxygen Species (ROS). They are a product from the combination of the oxygen radicals from xanthine oxidase (2) (XO), a flavin enzyme, and nitric oxide from the enzyme inducible Nitric Oxide Synthase (iNOS) (3, 4) . It is known that XO is elevated in the blood of patients with EBV (and Hepatitis B) 200 times above normal levels. (5) XO is stored in the liver and intestines and is released following any inflammatory challenge. It binds onto the glycosaminoglycans onthe surface of cells virally infected. The greater the acidity at the surface of the cell, the more receptors exposed. When the adenosine triphosphate (ATP) is broken down intracellularly in virally infected cells, the adenine products hypoxanthine and xanthine act as substrates to XO and generate superoxide radicals. In the presence of free iron, these radicals combine with the gas nitric oxide from iNOS (iNO) to form the toxic product peroxynitrite which then rapidly further convert to a series of further toxic substances. (6) Increased testosterone in males increases XO levels which most likely accounts for the increase viral toxicity in boys. iNO alone however does not appear to be toxic to virally infected cells without oxygen radicals present, in fact, it can be inhibitory to EBV (7) and other viruses. (8, 9, 10, 11) iNO, however, does not have the opportunity to block viral replication when XO is present, instead it combines with the oxygen radicals to generate products toxic to the membrane of the virally infected cells. (12)