Primary
Epstein Barr virus (EBV) infection can cause
leucoplakia and variety of neoplasms such as EBV
lymphoproliferative syndromes, nasopharyngeal
carcinoma, Burkitt’s lymphoma, Hodgkin’s
lymphoma and a subset of EBV positive gastric
carcinomas especially in immunocompromised
patients [1,2]. In immunocompromised hosts, it
may infect liver cells, neural cells and
hematological cells other than lymphocytes
leading to cytopenias [3]. It has been found
that in HIV infected patients, highly active
antiretroviral therapy (HAART) does not lead to
decrease in EBV viremia even when HIV viral load
becomes undetectable or CD4
count increases [4]. We
report an HIV infected girl on HAART with
undetectable viral load and normal CD4 counts
who developed infectious mononucleosis with
peripheral cytopenia and
persistent fever that responded to valacyclovir.
Case Report
An 8 years old HIV infected
girl presented with fever for 1 month, cough and
ear discharge for 15 days. She had been treated
for pulmonary tuberculosis 2 years back. She had
been on antiretroviral therapy (ART) since past
1 year consisting of Zidovudine (AZT),
Lamivudine (3TC) and Efavirenz (EFV). She was
febrile, had insignificant axillary and cervical
lymphadenopathy, splenomegaly and oral thrush.
Other systems were normal. Investigations showed
anemia and leucopenia (Table I).
Peripheral smear did not show any atypical
lymphocytes. Her Chest X-Ray showed
haziness in right lower zone. Blood culture,
peripheral smear for malaria, optiMAL test,
Widal test, urine, stool, sputum examinations
were normal. Ear swab grew diphtheroids. Fundus
examination was also normal. Her Weil Felix
test, RA factor, ANA and anti-dsDNA were
negative. Serial hemograms showed a trend of
gradual pancytopenia (Table I).
USG Abdomen showed hepatosplenomegaly. Bone
marrow examination showed hypocellular marrow
with early fibrosis. Her CD4 count was 406/mm3
(27.6%) with CD4:CD8 ratio of 1.63, and HIV
viral load was undetectable. Her EBV viral
capsid antigen (VCA) IgM was negative (0.61
Index) and Parvovirus IgM was also negative.
Renal and liver function tests were normal. She
was treated with IV antibiotics and fluconazole
for 14 days to which pneumonia and oral thrush
responded. However, she continued to be febrile
and subsequently, on Day 40 of her fever,
developed large cervical and axillary
lymphadenopathy. Chest X-ray did not show
any mediastinal widening. A lymph node biopsy
was done which was suggestive of necrotizing
lymphadenopathy. In view of persistent fever,
pancytopenia and lymphadenopathy, she was
suspected to have infectious mononucleosis and
her repeat CMV IgM was done, which was negative.
Her EBV viral capsid antigen IgM after 15 days
was positive (1.12 Index). She was then treated
with valacyclovir (10 mg/kg/dose TDS) for 12
days till anti-EBV VCA-IgM became negative. EBV
nuclear antigen and EBV PCR were not done. She
responded to the above treatment and fever
subsided within 5 days of therapy and hemogram
normalized within a week. On follow up, her
hemogram continued to be normal, and she is
asymptomatic and on regular ART.
TABLE I Serial Hemogram of The Print
Hemogram |
Day 7 |
Day 15 |
Day 30 |
Day 35 |
Hemoglobin (g/dL) |
7.7 |
9.8 |
6.4 |
5.8 |
WBC (cells/cumm) |
3,400 |
2,600 |
2,100 |
1,300 |
Polymorphs (%) |
40 |
66 |
|
|
Lymphocytes (%) |
56 |
42 |
|
|
Platelets (cells/cumm) |
2,46,000 |
2,73,000 |
1,83,000 |
59,000 |
Discussion
An antiviral drug that could
reduce the severity of acute infectious
mononucleosis and potentially lower the risk for
serious sequelae would be highly desirable [5].
Several antiviral drugs
inhibit replication of EBV in cell culture by
targeting viral DNA polymerase including acidic
nucleoside analogues caciclovir, ganciclovir,
penciclovir as well as their prodrug-
valacyclovir, valganciclovir and famciclovir,
acyclic nucleotide analogues (cidofovir and
adefovir) and pyrophosphate analogues (foscarnet)
[1]. Despite their potency in vitro, these drugs
have limited use in vivo for treatment of acute
primary EBV infection as well as EBV associated
malignancies due to toxicity and non-specific
antiviral activities. The reason for antiviral
failure may be that most of the symptoms and
signs of acute EBV are not directly due to viral
cytopathology in infected tissues, but to
immunopathic responses to EBV-infected cells,
particularly EBV-infected B-lymphocytes and also
the levels of acyclovir achieved in the
oropharynx, particularly after oral
administration of the drug are inadequate as
compared to titres that are produced by
acyclovir given intravenously [1]. Valacyclovir
is the l-valyl ester of acyclovir. This
modification increases acyclovir bioavailability
by 3- to 5-fold compared with oral acyclovir
[6]. Pharmacokinetic data suggests that dose of
valacyclovir regimen of about 30 mg/kg/day gives
similar AUC as that with acyclovir given 250
mg/m 2
intravenously [7]. Due to its improved
absorption with higher serum concentrations,
this drug is preferable to acyclovir for the
treatment of EBV infections [8]. Common adverse
drug reactions associated with valacyclovir
therapy are the same as for acyclovir, its
active metabolite, and include: nausea,
vomiting, diarrhea and headache [9].
The association of HIV and
Epstein-Barr virus infection has been reported
in children with lymphocytic interstitial
pneumonia and lymphomas [9]. Peripheral
cytopenia with persistent fever has rarely been
reported in HIV infected children as was seen in
our patient. A study from Minnesota has found
valacyclovir to be effective in treating
infectious mononucleosis where the drug lowered
or eliminated EBV in research subjects who took
it for two weeks [10]. Similarly in our patient,
cytopenias and fever responded to valacyclovir
following which EBV VCA IgM also became negative
signaling latency of EBV in the child.
Studies of corticosteroids in
infectious mononucleosis show amelioration of
acute symptoms; however, the risks of
prednisolone are only justified in severe
disease, for example where there is incipient
airway obstruction, where steroids may reduce
the need for surgical intervention to protect
the airway.
There have been no reports of
response of EBV infection to valacyclovir in HIV
infected children. Though we had a good response
to valacyclovir in our patient, detailed studies
are required to determine efficacy of
valacyclovir to treat complicated infectious
mononucleosis in HIV infected children.
References
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Accessed on February 09, 2007.
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