CORRESPONDENCE

Antiquity of Epstein-Barr Virus, Sjögren's Syndrome, and Hodgkin's Disease—Historical Concordance and Discordance

Eric Lewin Altshuler

Correspondence to: Eric Lewin Altschuler, M.D., Ph.D., Brain and Perception Laboratory, University of California, San Diego, 9500 Gilman Dr., 0109, La Jolla, CA 92093-0109 (e-mail: elaltsch{at}sdcc3.ucsd.edu).

As Koch noted, correlation does not prove causation. Thus, historical concordance cannot definitively rule in a certain factor as the cause of a disease; however, it can rule out a factor. I apply this notion in examining the relationships of the antiquities of Hodgkin's disease (1832), Sjögren's syndrome (1888), and Epstein-Barr virus (EBV) (1885).

In January 1832, Thomas Hodgkin read a paper to the Medical-Chirugical Society of London. He reported the clinical history and gross pathology of six cases. On examination with more strict modern criteria in 1926, Fox found that cases 2 and 4 of Hodgkin were indeed cases of Hodgkin's disease (1).

EBV is thought to play an important role in a number of cancers: B-cell non-Hodgkin's lymphomas in acquired immunodeficiency syndrome patients and post-transplant immunosuppressed patients, nasopharyngeal carcinoma, and some T-cell non-Hodgkin's lymphomas. Serologic studies have suggested a role for EBV in Hodgkin's disease. However, the role of EBV in the pathogenesis of Hodgkin's disease, if any, is still not completely established. Also, the disease may well be a heterogeneous disease, with EBV playing a role in only some subtypes (2).

In January 1888, Johann Milculicz reported on a patient with bilateral swelling of the lacrimal, parotid, and submandibular glands. The swelling recurred following partial resection. Milculicz performed a complete excision. In 1933, H. Sjögren noted a confluence in patients of a dry eye, dry mouth, arthritis syndrome. In 1954, Morgan and Castleman gave the definitive clinicopathologic correlation to the Milculicz-Sjögren syndrome (3). Aside from local and systemic symptoms, patients with Sjögren's syndrome have an increased incidence of lymphoma. EBV-associated antigens and DNA have been found in salivary gland biopsy specimens from patients with Sjögren's syndrome. However, the role of EBV in this syndrome is still not well established (4).

I note here that the antiquity of EBV in Europe can be traced through infectious mononucleosis, the vast majority cases of which are now known to be caused by EBV. (In Africa the antiquity can be traced using Burkitt's lymphoma.) The first report of infectious mononucleosis was in 1885 (5).

The apparently late appearance of EBV in Europe, especially if it had been present in Africa for thousands of years (6), is surprising. In contrast, all of the pediatric exanthems had been observed by Robert Willan by 1809.

Perhaps infectious mononucleosis was observed, but modern writers have failed to find the previous descriptions. However, when I checked five American and British pediatric textbooks from the first half of the 19th century, I could find no mention of a disease resembling infectious mononucleosis. Alternatively, differences in society between the early 1800s and today may have somehow profoundly reduced the incidence of the disease. But, in that less densely populated and more rural era, we might expect a higher incidence of infectious mononucleosis because primary EBV infection tends to be milder when contracted at an earlier age as is common in locations of high population density. However, it cannot be ruled out that the EBV virus could have mutated in recent times, so that while it caused Hodgkin's disease in Europe in 1832 and Burkitt's lymphoma in Africa, only later did it start causing infectious mononucleosis in Europe and the Americas.

The antiquity of EBV can be further probed by the additional searching of historical records for cases of infectious mononucleosis and by examining well-preserved historical specimens by use of the polymerase chain reaction, immunologic, or other methods to look for evidence of EBV infection.

Even though the dates for both EBV and Sjögren's syndrome must be considered only the latest date of their arrival in Europe, the current appearance of a concordance in their antiquities is intriguing. The cardinal features of this syndrome are symptoms, not a sign or laboratory finding. So, if Sjögren's syndrome existed earlier, we might have expected it to have been reported. The current striking concordance in their antiquities may stimulate further research into an EBV-Sjögren's syndrome link. If such a link is established, I note that the drug mycophenolate mofetil, an inhibitor of inosine monophosphate dehydrogenase, might be useful in the treatment of Sjögren's syndrome, both due to its immunosuppresant properties and possible antiviral activity (7).

The historical discordance in the antiquities of EBV and Hodgkin's disease is disquieting. I hope it promotes more research into the antiquity of EBV and into laboratory investigations into a possible EBV-Hodgkin's disease link.

REFERENCES

1 Fox H. Remarks on microscopical preparations made from some of the original tissue described by Thomas Hodgkin, 1832. Ann Med History 1926;8:370-4.

2 Liebowitz D. Pathogenesis of Epstein-Barr virus. In: McCance DJ, editor. Human tumor viruses. Washington (DC): Am Soc Microbiology; 1998. p. 173-99.

3 Talal N. Sjogren's syndrome: historical overview and clinical spectrum of disease. Rheum Dis Clin North Am 1992;18:507-15.[Medline]

4 Fox RI. Sjogren's syndrome. Curr Opin Rheumatol 1995;7:409-16.[Medline]

5 Evans AS. The history of infectious mononucleosis. Am J Med Sci 1974;267:189-95.[Medline]

6 Burkitt DP. Classics in oncology. A sarcoma involving the jaws in African children. CA Cancer J Clin 1972;22:345-55.[Medline]

7 Alfieri C, Allison AC, Kieff E. Effect of mycophenolic acid on Epstein-Barr virus infection of human B lymphocytes. Antimicrob Agents Chemother 1994;38:126-9.[Abstract]



             
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