Glandular Fever

Lymphocytosis is a common indication for a film. The main concern is whether there may be a lymphoproliferative disorder but in most cases the cause will be a viral infection. Epstein Barr virus (EBV) infection cause glandular fever / infectious mononucleosis. Theses clinical conditions are thought to rarely be associated with other viruses but primarily with acute primary EBV infection. The majority of adults are EBV positive, and the majority of acute EBV infections occur in children or young adults.

EBV gives a characteristic film apperance which can be concerning if you're not familiar with it. The lymphocytes are extremely large with copious cyroplasm and they can be seen on the film scalloping around nerby red cells. These cells are T cells, and are CD57 negative CD8 positive cells. This can be seen on immunophenotyping as a reversed CD4/8 ratio. Normally there are more CD4 positive than CD8 positive T cells in the peripheral blood (the ratio is normally about 2:1). An inverted CD4/8 ratio can signify a number of viral infections such as HIV or CMV but more commonly with EBV.

These reactive cells are typically large with pleomorphic nuclei and cytoplasm. Some can have immature looking features (such as a high NC ratio, open chromatin or even nucleoli) but their presence in large numbers, pleomorphic appearance and scalloping suggest a reactive origin. Some of these lymphocytes may be termed Atypical Lymphocytes.

These are the infected B lymphocytes which more closely resemble blasts but are unlikely to represent leukaemia in the context. There are also lymphoplasmacytoid B lymphocytes which have  deep blue cytoplasm and are also reactive.

It is noteworthy in a patient with suspected EBV infections that the platelet count is normal. This is important because viral infections in younger adults can be associated with ITP, and being able to identify a clear viral illness is reassuring in a patient with profound thrombocytopenia.

There are also reactive changes in the other white cells - both monocytes and neutrophils are reactive. The red cells will sometimes show rouleaux as the infected B cells increase production of IgM and we see non-specific agglutination. 

Chronic EBV infections are associated with lymphoproliferative disorders such as Burkitts lymphoma. The process underlying this is due to activation of a small subset of latently infected B lymphocytes by the latently expressed membrane proteins 1 and 2a (LMP1, LMP2a). These cell surface proteins constituately activate some cellular pathways and can potentiate the effect of a c-myc translocation. The translocation remains essential for development of LPD - infection with EBV alone is not sufficient. Remember that most of the abnormal cells we see in the perpheral blood are the reactive T cells, not the infected B cells. This leads to some physicians being inapprorpiately concerned about lymphoma associated with an EBV infection. The lymphadenopathy associated with EBV infection can be very pronounced and last many months so it is a frequent referral to a haematology clinic. A serious pathology here is vanishingly rare - the LPD (if there ever will be one) comes years or decades after the acute infection. 

The appropriate testing for EBV is with a Paul-Bunnell or a Monospot test (see the lab teaching sessions for more info), and followup for such patients is with a repeat FBC/film in 4 to 6 weeks. We can normally leave this to the primary care team.