Splenomegaly

We present the clinical case of a 20-year-old male soldier who appeared in general good physical condition. He suffered from infectious mononucleosis caused by Epstein-Bart virus that had recurred 2 years after the first serologically documented episode. The detected splenomegaly persisted in the healthy young man, who otherwise showed no apparent immune deficiency. To our knowledge, this is an extremely rare condition.

Introduction

College and military populations experience the greatest morbidity from infectious mononucleosis, although cases occur in other groups as well. Epstein-Barr virus (EBV) persists in human B-lymphocytes. Immune restraints of the virus are usually effective enough to prevent symptomatic disease after infection. Still, infectious mononucleosis, i.e., a self-limited lymphoproliferative disease, is common in adolescents and young adults. Reactivation appears almost exclusively in organ transplant recipients during their immunosuppressive therapy or in persons exhibiting other causes for impaired immune function(s).2 This case of the young male soldier with recurrent infectious mononucleosis and persistent enlarged spleen could increase our understanding of latent EBV infection in immunocompetent patients.

Case Report

In August 1995, our patient suffered from tonsillitis lingualis accompanied by flu-like symptoms and fever up to 40degC. Epipharyngeal adenoids appeared inflamed and enlarged. Because of recurrent tonsillitis, tonsillectomy had been performed 3 years earlier. The patient's physical examination indicated an enlarged liver. Sonography of the abdominal organs revealed hepatosplenomegaly. Laboratory examinations showed a marked leukocytosis (17.0 g/L) comprising increased numbers of so-called "atypically enlarged" lymphocytes (14%). Transaminases were greatly increased (aspartate aminotransferase, 190 units/L; glutamate pyruvate transaminase, 250 units/L; y-glutamyl transpeptidase, 180 units/L) in the patient's serum, and this was accompanied by a moderately increased total bilirubin (4.0 mg/dL). Serological testing (immune fluorescent test) revealed antibodies directed to EBV of the immunoglobulin (Ig)M isotype (viral capsid antigen). Based on these findings, the diagnosis of acute infectious mononucleosis with concomitant hepatitis caused by EBV was made. Supportive medication and antibiotic therapy with cephalosporins to address any bacterial superinfection were initiated, with good clinical response. Follow-up examinations indicated normalization of blood cell counts, liver transaminases, and bilirubin; however, the spleen was still enlarged 2 months after the initial event (Table I).

Two years later, the patient was again hospitalized due to influenza-like symptoms. He complained of sore throat, malaise, and nausea; his body temperature was moderately increased to 38degC. After symptomatic therapy, the patient recovered rapidly but still presented an enlarged spleen. Blood cell counts were normal, as were serum levels of liver-specific enzymes during this incident.

Repeated serologic tests to detect IgM and IgG antibodies directed to EBV were performed using enzyme immunoassays (Enzygnost, Behring Diagnostics, Marburg, Germany). This assay was 100% specific and 92% sensitive for antibodies directed to EBV antigens, as detailed by the manufacturer. Thus, in January 1997, serum IgM and IgG antibodies against EBV were observed. Four months later (April 1997), serum IgM to EBV were undetectable, whereas serum levels of IgG to EBV were found increased from 600 IU/mL in February 1997 to 1,100 IU/mL in April 1997. As a final test, in July 1999, 500 IU/mL was measured. For confirmation, serological testing was complemented using Unilisa2 (BIOMED, Oberschleissheim, Germany), an enzyme immunoassay specific for EBV capsid antigens. Serum IgM and IgG directed to EBV-viral capsid antigen were detected in January and February 1997 (IgM cutoff index, 20.4 in January 1997 and 4.2 in February 1997). Hence, a recurrence or reactivation of the previously diagnosed EBV infection was assumed.

Serum antibodies directed to cytomegalovirus, to hepatitis viruses A, B, and C, to Toxoplasma gondii and to human immunodeficiency virus-I and -2 were not detectable at any time. This not only suggested the absence of heterophilic serum antibodies to EBV that otherwise could have cross-reacted with the EBV-specific antigens present in the enzyme immunoassays but also excluded other important causes for the patient's condition. An increase attributable to a polyclonal stimulation with the appearance of unrelated IgM antibodies seemed to be unlikely but could not be ruled out completely.

In February and April 1997, testing of blood for EBV-related DNA by polymerase chain reaction' was performed. EBV-specific DNA was not detectable, because the clinical symptoms had already ceased at the time of examination. Therefore, persistent viremia was not proven in this patient. Humoral immunological parameters, including immunoglobulin fractions, serum electrophoresis, and serum complement factors, were repeatedly observed to be within normal ranges. Immunophenotyping of peripheral blood lymphocytes by flow cytometry showed slightly decreased counts of CD4(+) cells (0.53 g/L in January 1997 and 0.57 g/L in April 1997) and CD3^sup 3^cells (0.84 g/L in January 1997 and 0.69 g/L in July 1999).

Between these two episodes of illness, the patient continuously presented in good physical condition. The spleen, however, remained enlarged (Table I). Additional factors that could have led to splenomegaly, such as abnormal hemoglobin, spherocytosis, or portal vein obstruction, and infiltrative disease of the spleen had been excluded by laboratory methods, the morphologic presentation of abdominal organs by ultrasonography, and the prolonged period of observation. Further monitoring of the patient did not reveal any health problems, and his general practitioner reported the absence of clinical problems at follow-up examinations.

Discussion

Acute infectious mononucleosis, common in adolescents and young adults, is a self-limiting infectious lymphoproliferative disease. College and military populations experience the highest morbidity from acute EBV infection. Although primary EBV infection may be clinically apparent in only about 10% of military cases, infectious mononucleosis ranked fourth as the cause of days lost for illness in military personnel.4,5 Recent data suggest that service members who suffer from chronic fatigue syndrome frequently have acute or chronic EBV infections The host response determines whether an EBV infection develops symptoms or not. The vast majority of clinically apparent disease resolves spontaneously during a 2- to 3-week period. Prolonged splenomegaly after acute disease is a well-known complication. Reactivation of EBV replication, and thus recurrence of the disease, appears almost exclusively in immunologically impaired persons. Most serial mononucleosis-like episodes are caused by sequential infections with various pathogens.2

This young patient, who was in excellent physical condition, developed splenomegaly concomitant with his first episode of illness. Then, his spleen decreased in size during a period of 3 months, but it increased again during the second incident. Because the clinical and laboratory findings of acute manifestation were present in both incidents, this case does not fit the typical chronic mononucleosis syndrome but rather indicates a reactivation of his EBV infection. The etiologic role of EBV was evaluated by different tests, although persistent viremia could not be demonstrated.

The role of EBV in the development of lymphoma is under investigation, and especially chronic persistent infection with EBV has been associated with lymphoma development. 7,8

This fact suggests close monitoring of our patient or other persons in similar conditions. Furthermore, splenomegaly in active military personnel can be a risk factor, e.g., in parachute jumping. Because many EBV infections are subclinical and reactivation and presumably polyclonal stimulation by other infectious diseases after an episode of acute mononucleosis may lead to (temporarily) enlarged spleen, we suggest keeping this possible complication in mind when treating an adolescent military population.

References

1. Schooley RT, Dolin RP Epstein-Barr virus (infectious mononucleosis). In Principles and Practice of Infectious Diseases, Ed 3, pp 1172-84. Edited by Mandell R, Douglas G, Bennett JE. New York, Churchill Livingston, 1990.

2. Straus SE: Epstein-Barr virus infections: biology, pathogenesis, and management. Ann Intern Med 1993; 118: 45-58.

3. Lucas KG, Burton RL, Zimmermann SE, et al: Semiquantitative Epstein-Barr virus (EBV) polymerase chain reaction for the determination of patients at risk for EBV-induced lymphoproliferative disease after stem cell transplantation. Blood 1998:91: 3654-61.

4. Evans AS: Infectious mononucleosis in the armed forces. Milit Med 1970; 135: 300-4.

5. Lehane DE: A seroepidemiologic study of infectious mononucleosis: the development of EB virus antibody in a military population. JAMA 1970; 212: 2240-2.

6. Carver LA, Connallon PF, Flanigan SJ, Crossley-Miller MK: Epstein-Barr virus infection in Desert Storm reservists. Milit Med 1994; 159: 580-2.

7. Niedobitek G, Kremmer E, Herbst H, et al: Immunohistochemical detection of the Epstein-Barr virus-encoded latent membrane protein 2A in Hodgkin's disease and infectious mononucleosis. Blood 1997; 90: 1664-72.

8. Kanegane H, Bhatia K, Gutierrez M, et al: A syndrome of peripheral blood T-cell infection with Epstein-Barr virus (EBV) followed by EBV-positive T-cell lymphoma. Blood 1998; 91: 2085-91.

Guarantor: Jorg Berg, MD Contributors: Robert Pichler, MD PhD*; Jorg Berg, MD^; Angelika Hengstschlager, MD^^; Wilma Maschek, MD*; Johannes Wiesinger, CLT(sec); Hans Schon, CLT(sec)

*Institute of Nuclear Medicine and Endocrinology, ^lnstitute for Laboratory Medicine, and ^^Department of Internal Medicine I, General Hospital Linz, Linz, Austria.

(sec)Austrian Army Medical Corps, Hoersching, Austria.

This manuscript was received for review in June 2000. The revised manuscript was accepted for publication in December 2000.

Copyright Association of Military Surgeons of the United States Aug 2001
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