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Chapter 54 Infectious Mononucleosis and Other Epstein-Barr Virus–Associated Diseases 753

hepatitis viruses, and toxoplasma. Depending on the presentation, The term secondary HLH generally refers to older children (or
other diseases may be considered such as HIV, rubella, and leukemia adults) who present without a family history or known genetic cause
or lymphoma. for their HLH. EBV is a common trigger for “secondary HLH,”
ranging from inflammation that resolves spontaneously to unrelent-
ing disease requiring HSCT. Differentiating infectious mononucleosis
Treatment from EBV-associated HLH (EBV-HLH) is challenging. Clinical
criteria for HLH should be evaluated in patients with persistently
Supportive therapy should include rest and analgesia in the acute stage high cell-free EBV genome copy numbers in plasma, persistent
of IM. Contact sports should be avoided until the patient has fully symptoms of inflammation, or severe symptoms. Patients who ini-
recovered and the spleen is no longer palpable. The use of corticoste- tially meet clinical criteria for HLH may occasionally improve
roids is not indicated for uncomplicated IM; however, a trial of cor- spontaneously. Patients with less severe presentations may also
ticosteroids is warranted in patients with marked tonsillar inflammation respond to corticosteroids, intravenous immunoglobulins or cyclo-
and hypertrophy resulting in impending airway obstruction. Although sporine. However, in patients with progressive or severe disease, early
acyclovir reduces EBV shedding into oral secretions, treatment of IM initiation (within 4 weeks of onset of symptoms) of etoposide is
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with acyclovir has resulted in no clinical benefit. associated with significant improvement in survival. Because it can
eliminate EBV-infected B cells, rituximab may be a beneficial addi-
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tion to other therapies in patients with progressive EBV-HLH.
OTHER EPSTEIN-BARR VIRUS ASSOCIATED DISEASES Some patients with apparently self-resolving HLH after primary EBV
infection later develop recurrent HLH requiring immunochemo-
Most individuals recover from the acute phase of primary EBV infec- therapy and HSCT. Therefore it remains important to follow patients
tion with no long-term sequelae. However, a minority of patients beyond resolution of initial symptoms. Alemtuzumab has also been
with intrinsic defects in immune function may respond with poten- reported to be effective in patients with recurrent or refractory
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tially lethal uncontrolled pathologic inflammation with fever and disease. Early clinical data also support the use interferon (IFN)-γ
multisystem organ failure, meeting diagnostic criteria for hemo- monoclonal antibodies in patients with refractory HLH.
phagocytic lymphohistiocytosis (HLH). Others may develop chronic
active EBV infections (CAEBV) with persistent fever, arthralgia,
myalgia, and lymphadenopathy, or develop lymphoproliferative and/ X-Linked Lymphoproliferative Diseases
or malignant disorders. In addition to primary immunodeficiencies
that result in failure to control EBV infection, there is an increasing X-Linked Lymphoproliferative Disease 1
group of gene defects associated with complex or acquired immune
dysfunction (ATM, WAS, PIK3CD, PIK3R1, CTPS1, STK4, Mutations or deletions in SH2D1A (Src homology 2 domain protein
GATA2, MCM4, FCGR3A, and CARD11) that predispose not only 1A) results in X-linked lymphoproliferative disease (XLP1; Duncan
to complications of EBV infection but also other viruses, bacteria, disease), an immunodeficiency characterized by fatal IM meeting the
and/or fungi. 9 diagnostic criteria for HLH, agammaglobulinemia, or B-cell lym-
phoma. SH2D1A interacts with SLAM (signaling lymphocyte activa-
tion molecule), which plays a central role in the stimulation of B and
Hemophagocytic Lymphohistiocytosis T cells. SH2D1A controls several distinct key T-cell signaling path-
ways, and mutant SH2D1A does not bind SLAM, suggesting that it
HLH is a syndrome characterized by uncontrolled inflammation (see is a natural SLAM inhibitor. SAP association with SLAM receptors
Chapter 52). Diagnostic criteria defined by the Histiocyte Society is crucial for development of normal NK T cells, formation of normal
reflect the clinical features of pathologic immune activation, includ- GCs, and NK- and T-cell killing of EBV-infected B cells. T cells from
ing persistent fever, splenomegaly, cytopenias, hyperferritinemia, patients with XLP1 are also resistant to apoptosis by radiation-
decreased fibrinogen or increased triglycerides, hemophagocytosis (in induced cell death (RICD). Immune hyperactivation induced by
+
bone marrow, spleen, or lymph nodes), increased soluble IL-2 recep- primary EBV infection may be due to specific defects in NK and
+
tor α, and decreased or absent natural killer (NK) cell function. The CD8 T-cell cytotoxicity rather than from decreased or absent cyto-
diagnosis of HLH can also be established by a pattern of familial toxic proteins. Resistance to apoptosis may exacerbate the inflamma-
inheritance or proven gene defects. It was first characterized as an tory response due to persistence of ineffective activated NK and
inherited disorder in infants in the 1950s, referred to as “familial T cells.
hemophagocytic reticulosis.” Following infection with EBV, XLP1 patients mount a vigorous,
Gene defects resulting in impaired cytotoxic NK- and T-cell func- uncontrolled polyclonal expansion of T and B cells. Infiltrating T
tion have been associated with autosomal recessive inheritance of cells cause extensive tissue destruction of the liver and bone marrow,
HLH, including PRF1 (familial (f)HLH-2), UNC13D (fHLH-3), resulting in death in 50% of XLP1 patients during primary EBV
STX11 (fHLH-4), STXPB2 (fHLH-5), Munc18-2, Rab27a (Griscelli infection. Approximately 30% of patients have acquired hypogam-
syndrome, type 2), LYST (Chédiak-Higashi syndrome), AP3B1 maglobulinemia and 25% of patients develop malignant B-cell
(Hermansky-Pudlak syndrome, type II), ITK, CD27, and MAGT1 lymphomas that are often extranodal, involving the intestinal ileoce-
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(XMEN syndrome). EBV infection may trigger HLH in patients cal region. It is important to realize that some patients with SH2D1A
with any form of familial disease. Gene defects are identified in only mutations may only present with hypogammaglobulinemia mimick-
50% of patients with family history consistent with inherited HLH. ing common variable immunodeficiency, and a diagnosis of XLP1
Therefore, although a diagnosis “primary” or “familial” HLH may be should be considered when more than one male patient with hypo-
proven, it is impossible to exclude. Familial HLH commonly presents gammaglobulinemia is encountered in the same family. Patients with
in young children, but there are reports of new onset of HLH in fulminant immunologic responses to primary EBV infection may be
adults as old as 62 years with mutations in HLH-associated genes. treated with HLH treatment strategies (steroids and etoposide) and/
Patients with familial HLH typically require prompt treatment with or rituximab. However, the only curative therapy for XLP1 is HSCT.
chemotherapy and immune suppression (etoposide/dexamethasone)
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followed by HSCT. Without therapy, survival of patients with active
familial HLH is approximately 2 months. The first international X-Linked Lymphoproliferative Disease 2
treatment protocol for HLH organized by the Histiocyte Society in
1994 reported long-term survival of over 50%. More recently, survival A second X-linked immune deficiency characterized by recurrent
rates of greater than 90% have been reported with reduced intensity HLH (with or without EBV infection) is XLP2, caused by BIRC4
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conditioning regimens. 12 mutations and XIAP deficiency. Unlike patients with XLP1, those