Case 1B -
Acute Infectious Mononucleosis with a Reactive Florid CD8 Lymphocytosis
Cynthia M. Magro
Weill Medical College of Cornell University
New York, New York
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Case 1B: Acute Infectious Mononucleosis with a Reactive Florid CD8 Lymphocytosis
Epstein Barr virus infection is gamma herpes virus that is ubiquitous in our environment with most
children having sustained exposure and active lytic infection with this virus. Nevertheless most people
infected with the virus are asymptomatic. This virus is a fascinating and complex one associated with
significant morbidity and mortality in humans based on its implicated role in many inflammatory and
neoplastic diseases such as multiple sclerosis, Guillain Barre syndrome, chronic fatigue syndrome, and
certain lymphomas including Hodgkins lymphoma, natural killer cell lymphoma, Burkitt lymphoma, CD30
positive large cell B cell lymphoma and plasmablasatic lymphoma. The role of EBV in these aforesaid
lymphomas is typically in the context of latent as opposed to lytic infection whereby proteins produced
by various EBV genes are incorporated into the host cell altering the genetic makeup of the cell
including the induction of proliferation and oncogenic transformation of B cells. During latent
infection EBV is capable of expressing selective viral antigens: EBV determined nuclear antigens (EBNAS)
consisting of EBNA-1,2, 3C, and leader protein LP and three latent membrane proteins (LMP 1,2,3). In
addition to these proteins, EBV encoded small nuclear RNAS (EBER) are always present during latent
infection. Latent infection essentially defines a form of reactivation since there is active synthesis
of protein. It should be emphasized however that the EBV DNA may simply be incorporated in the cell
without any evidence of active protein synthesis (i.e persistent infection without reactivation ). While
most patients with the acute form of lytic infection are asymptomatic, a subset of patients will be
symptomatic. The range of symptoms encompass those which could be mild and analogous to a common cold to
symptoms which are more severe and compatible with acute infectious mononucleosis. However certain
genetically predisposed patients can develop very severe immunologic responses to Epstein Barr virus
with an exuberant effective or ineffective T cell host response to EBV infected lymphoid cells. A
further subset of these patients will not be able to eradicate the lytic and or latent productive phase
of infection; infected B and T cells undergo excessive clonal expansion. Perhaps this concept is best
exemplified by patients with so called X linked lymphoproliferative disease. The basis of this lethal
syndrome includes an excessive response to the virus by reactive T cells. However the response is
ineffectual in the eradication of the virus. This leads to unchecked proliferation of the virus in B
cells resulting in B cell immortalization and ultimately the development of B cell lymphoma. In addition
proliferation in NK and T cells could eventuate in aggressive NK/ T cell lymphomas and or produce enough
infected NK and NK like T cells that elaborate cytokines that activate the histiocyte system, defining
hemophagocytic syndrome despite the absence of overt lymphoma. The genetic defect that rests behind X
linked lymphoproliferative disease has now been elucidated. X linked lymphoproliferative syndrome or
Purtilo syndrome is a rare inherited immunodeficiency that are among those associated with severe and
potentially lethal generalized hemophagocytic syndrome/hemophagocytic lymphistiocytosis. These patients
have an extremely high susceptibility to infection with EBV triggering what is in essence a severe
infectious mononucleosis like picture however unlike self limited acute infectious mononucleosis the
eradication of lytic infection does not occur. Sixty percent of patients have hemophagocytic
lymphohistiocytosis. In brief these patients experience an excessive polyclonal proliferation of T cells
and NK cells as well there are infected EBV B cells which continue to proliferate and many activated
macrophages infiltrate various organs and at least in the marrow can eventuate in cytopenias. One of the
hallmarks is dysgammaglobulinemia . XLP is divided into subtypes depending on the genetic defect
implicated. XLP-1 is caused by mutations in the gene SH2DiA1A or SAP (signaling lymphocyte activation
molecule) whereas mutations in the gene XIAP (X linked apoptosis inhibitor protein )underlie XLP -2.
The loci of these two genes are located at nearby positions on chromosome xq25 suggesting a possible
functional link between the genes . Lymphomas have been described only in XLP-1. The defect in the gene
SH2D1A results in impaired 2B4 and NTB-A function in cytotoxic T and NK cells impairing their ability to
kill EBV infected B cells.
Case 1b - Slide 1
There are other severe reactions to EBV reflecting a similar hybrid pattern of striking reactive T
cell infiltration in concert with progressive clonally restricted EBV + T cell and or NK cell
proliferation . The best known is one of mosquito bite hypersensitivity. In this condition the children
typically of Japanese and Mexican origin develop a large ulcerative plaque at the site of a mosquito
bite. The patients will have concomitant systemic symptoms including fever, lymphadenopathy,
hepatomegaly and at times cytopenia, the latter likely a sequelae of hemophagocytosis, a common theme in
severe EBV infection. Essentially there are two limbs to its pathogenesis. The first is an actual type
IV CD4 dominant immune response to mosquito salivary gland extracts. The response to the mosquito is
extremely exuberant. Why these patients develop this dysregulated immune response to the saliva is
unclear but presumably reflects an underlying endogenous immune dysregulatory effect, a point which will
be alluded to presently. The second reflects a subclinical presumably latent infection of a few NK and T
cells which are then induced into a state of reactivation and possibly even lytic infection with the
production of EBV associated proteins(i.e. latent infection) or the synthesis of complete virions(lytic
infection). In addition the mosquito extract antigen responding specific T cells may result in a
cytokine milieu that leads to the release of free virions into the circulation, providing an additional
venue for further infection. Hence it is the consensus that the robust CD4 positive cytokine milieu in
some way results in this reactivation. The end result is an excessive clonal proliferation of EBV
infected NK and T cells which could undergo further oncogenic evolution into overt aggressive EBV
positive NK/T cell lymphoma. This is an interesting and widely accepted theory however a question that
remains to be answered is why any exuberant CD 4 immune response to antigen does not result in this
reactivation of EBV in latently infected T or NK cells. An unidentified genetic defect similar to that
seen in X linked lymphoproliferative disease could be operational in these patients.
A deleterious excessive T cell response to a few EBV infected cells is observed in lymphomatoid
granulomatosis. In this syndrome the inherent endogenous immune dysregulatory state in these patients
results in an ineffectual excessive CD4 as opposed to CD8 immune response to a few EBV infected B cells.
The CD4 cells exhibit angioentric accentuation resulting in an obliterative lymphomatoid vasculitis.
This can lead to considerable tissue destruction and interfere with function by virtue of the extent of
reactive CD4 T cell accumulation. The B cells will also continue to proliferate and eventually some of
these patients develop an EBV positive large cell B cell lymphoma.
In this case the patient developed the appropriate CD8 immunologic response to Epstein Barr virus
however it was unusually excessive hence defining an immunologic response resembling that observed in X
linked lymphoproliferative syndrome. The virus was confined to B cells and did not affect T cells. The
patient's symptoms resolved and the blood values returned to normal. Hence the CD8 response was
apparently successful in eradicating the infection. This patient therefore differed from the clinical
settings that I have outlined above whereby in such cases an excessive T cell response is not successful
in eradicating virus and or the milieu promotes viral replication in infected T or B cells. The main
abnormality was the robust nature of the response which lead to her constitutional symptoms and the
peripheral blood abnormalities. As a point of reiteration the excessive nature of the immune reaction
could potentially signify some component of immune dysregulation. Long term follow up will be needed to
determine if this patient develops EBV associated T cell or B cell lymphoproliferative disease if in fact
the excessive immune response may signify some defect in clearing virus.
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