Infectious mononucleosis (IM) is an important clinical entity that is associated with Epstein-Barr virus (EBV) infection (1,2). This clinical manifestation was first described in 1889, but the term IM was coined in 1920, when it was discovered that a number of patients with glandular fever had similar blood films (3). In 1968, the then newly discovered EBV was identified as the cause of IM (4). The currently estimated incidence of IM is at ~500 cases per 100,000 persons annually. IM diagnosis is often established with the classical clinical triad of pharyngitis, fever and lymphadenopathy. Serological testing for the identification of EBV antibodies is required for a definitive diagnosis (1,2). The treatment of patients with IM is mainly supportive. Corticosteroids are considered as the standard treatment for severe complications associated with IM (1,2).

Uric acid (UA) is a purine degradation metabolite. A high serum level of UA is considered harmful. Hyperuricemia is considered to be closely associated with a number of metabolic disorders (5–7). For example, it was previously demonstrated that UA and metabolic syndrome were closely associated, and young women with hyperuricemia were at the highest risk of developing metabolic syndrome (5). Our recent study investigated subclinical thyroid dysfunction and hyperuricemia. It was demonstrated that, in subjects with hyperuricemia, mild hypothyroidism was a risk factor for men, while not for women (6). UA is also an important endogenous antioxidant, as well as a natural scavenger of peroxynitrate. Abnormalities in the serum levels of UA have been observed in several diseases. For example, a low UA level has been detected in stroke (8–10), multiple sclerosis (MS) (11,12), infections of the central nervous system (CNS) (13,14) and leprosy reaction episodes (15). As regards IM, the number of previous related studies is limited and the results are conflicting. A total of three early articles (16–18) with small number of recruited subjects and one previous case report (19) were retrieved. Dylewski et al (16) investigated 35 cases with IM after a case report, and reported that 7 men and 2 women had UA levels above the laboratory's upper limit of normal. Cowdrey (17) reported UA elevation during the first 10 days of the disease course in 21 patients. However, Sugita et al (19) described a case of a 27-month-old boy with persistent EBV infection and CNS manifestations, who had lymphadenopathy and low UA levels.

Therefore, the aim of the present study was to analyze the associations between UA and IM in a comprehensive manner, in order to determine whether low UA is a significant risk factor for IM, and whether there is a sex difference.

The aim of the present study was to investigate whether UA has diagnostic and predictive value for IM, prompted by the fact that a low UA level was found to be associated with pathological conditions such as stroke (8–10), MS (11,12,20) and CNS infections (13,14). Our research group previously investigated UA, but the focus was the association of hyperuricemia with various metabolic disorders (5–7). The fact that low UA levels have important clinical implications has become intriguing; therefore, collaborative efforts were focused on investigating the association between UA and IM. It was demonstrated that UA was significantly lower in patients with IM compared with healthy controls. Low UA level was found to have adequate diagnostic and predictive power for IM. Subjects with low UA levels, indicating low antioxidant reserve, were significantly more likely to develop IM, and these effects were more pronounced in women.

IM commonly affects patients who have had a primary EBV infection during childhood or adolescence. As the overall socioeconomic and sanitary conditions have improved, EBV infection in early childhood has become less common (1), with no obvious annual cycles or seasonal changes in incidence, and no apparent predisposition of either sex (1). IM usually runs a self-limiting course. The majority of IM patients recover without sequelae and return to normal activities ~2 months after the onset. As numerous individuals are EBV-positive, special precautions against transmission are not necessary. However, severe complications (including upper airway obstruction, hemolytic anemia, thrombocytopenia, hepatitis, myocarditis, splenic rupture, neurological and hematological complications) may occur, and fulminant infection is also possible. Clinical experience suggests that corticosteroids are helpful in the management of these complications, although randomized trials evaluating their efficacy are limited (1,2). No specific guidelines are currently available for the treatment of IM, and no serum factor for predicting IM in either sexes has been identified (1,2). The findings of the present study indicate that UA levels may be such a predictor.

There are established theories as to why normal level of UA is important. Humans cannot efficiently catabolize UA to a more soluble compound (allantoin), due to lack of urate oxidase function. This hepatic enzyme is inactivated during early primate evolution due to two independent nonsense mutations (21). As a result, humans naturally have higher levels of UA compared with most non-primates. This genetic modification actually confers an evolutionary advantage. Under conditions of increased oxidative stress, UA may be oxidized into allantoin and other metabolites via non-enzymatic oxidation and through exposure to pro-oxidant molecules (22). UA is the most abundant natural antioxidant in humans and it accounts for two-thirds of the antioxidant capacity of the plasma (23). However, too high a level of UA is also detrimental, as it exerts a pro-oxidant effect. In the clinical setting, higher levels of UA have been associated with gout (24,25), and associations between hyperuricemia and an increased risk of various metabolic disorders have also been described (5,6). In fact, a U-shaped association between extremely low or high UA levels and worse outcome has been described in stroke (10,26). However, it appears that, under conditions of increased oxidative stress, as occurs in acute ischemic stroke, the balance between anti- and pro-oxidant properties shifts to promote neuroprotection (27–30).

In ischemic stroke, highly reactive oxidant molecules are the major force driving the ischemic cascade (31). The brain develops enzymatic and non-enzymatic endogenous antioxidant defenses. UA, being a non-enzymatic molecule, is a powerful antioxidant at physiological concentrations. It was observed that a gradual depletion of UA occurred during the acute phase of stroke (32). Moreover, decreases in UA after stroke onset have been correlated with increased severity and poor long-term outcome (33). Based on promising pre-clinical evidence (32,34), more clinical trials of exogenous administration of UA for stroke are currently performed (8). The mechanisms underlying the role of UA in MS have also been extensively investigated. It has been observed that MS and gout are mutually exclusive (35). It is now generally accepted that the lower serum UA level in MS patients may be due to the intrinsically reduced antioxidant capacity, as well as the increased consumption of UA in MS (11,12). The mechanisms of CNS injury during infection are complex. It has been indicated that oxidative stress and antioxidant imbalance play a central role in the pathophysiology of meningitis (36–38). Recently, Liu et al (13) reported that the serum levels of UA in patients with various types of CNS infections were significantly lower compared with those in normal subjects. However, after effective therapy, the UA levels increased significantly compared with prior to treatment, and were almost restored to normal in some patients.

The design of the present study framework focused on EBV infection causing IM. In fact, it is known that increased oxidative stress plays a fundamental role in the pathogenesis of several types of infections, causing extensive cellular and tissue damage. Previous studies have demonstrated that this mechanism exists in various pathogens, including influenza virus (39), hepatitis virus (40), respiratory viruses (41), human immunodeficiency virus (42), Staphylococcus aureus (43), Helicobacter pylori (44), spirochetal bacteria (45) and mycoplasma (46), among others. It would be reasonable to deduce that infection due to EBV may also cause oxidative stress, leading to obvious depletion of antioxidants, such as UA. In addition, three early clinical studies demonstrated a transitory UA increase during acute onset of IM, which was explained by the increase in de novo purine biosynthesis necessary to accommodate the stepped-up nucleic acid production in IM (16–18). In fact, IM patients visiting our hospital (a tertiary hospital in Tianjin Municipality with a population of ~20 million) were often cases with more severe complications, with an IM disease duration of >10-14 days. In such patients, oxidative stress and depletion of the antioxidants may well overwhelm the de novo purine biosynthesis of UA. Therefore, this may be considered as the mechanism underlying the findings of the present study.

However, the reason for the obvious female predisposition to IM under conditions of low UA levels remains unclear. It is a common phenomenon that men have a significantly higher level of serum UA compared with women, and the rate of increase in UA levels is also significantly higher in men (5). The present study also confirmed this finding (Table III). A higher level of UA may promote a stronger antioxidant protection in men. Thus, women may be more vulnerable to oxidative stress-related UA depletion, which was also demonstrated by our findings. As a result, a decreased UA level may be more predictive of IM in women (Fig. 1, Table V).

There were certain limitations to the present study. First, the cross-sectional nature of the investigation meant that no causality could be determined from the results. A prospective study should be planned in the future. Second, a limited number of IM patients and controls were included. More participants should be recruited in order to limit the case number-related inherent drawback. Third, due to study budget limitations, measurements such as reactive oxygen species and activities of antioxidants were not performed, which should be included in future investigations. Finally, administration of UA as an adjuvant therapy should be investigated in the future to validate the findings of the present study.

To the best of our knowledge, this is the first study to demonstrate the inverse association between UA and IM, suggesting a progressive decrease of antioxidant reserve in IM. Moreover, low UA level is predictive for IM, particularly in women.