CLINICAL AND LABORATORY OBSERVATIONS
Severe Leukemoid Reaction in a Preterm Infant With
Congenital Cytomegalovirus Infection
Dilek U. Isik, MD,* Ozge Aydemir, MD,* Yusuf Kale, MD,* Husniye Yucel, MD,*
Ahmet Y. Bas, MD,* Nihal Demirel, MD,* Nilufer Arda, MD,w and Sema Apaydn, MDw
Summary: Leukemoid reaction, dened as a total leukocyte count
of >50,000/mm3, is most commonly related to antenatal admin-
istration of steroids, infections, and transient myeloproliferative
disorder of Down syndrome in newborns. Atypical presentations of
viral infections can be a diagnostic challenge in the newborn
period. Cytomegalovirus (CMV) infection causes a multisystem
disease, and symptomatic infants generally present with intra-
uterine growth restriction, hepatosplenomegaly, cholestasis, rash,
thrombocytopenia, and microcephaly. We present a case of a
preterm infant with severe myeloid leukemoid reaction (leukocyte
count >100,000/mm3) at birth who was diagnosed with congenital
CMV infection on the basis of CMV polymerase chain reaction
results after the appearance of cholestasis, blueberry mun rash,
and hepatosplenomegaly.
Key Words: cytomegalovirus, leukemoid reaction, preterm infant,
viral infection
(J Pediatr Hematol Oncol 2014;36:e310e312)
L eukemoid reaction (LR) is dened as a total white blood
cell (WBC) count of >50,000/mm3, with a signicant
increase in early mature neutrophil precursor numbers.
Physiological leukocytosis is seen in the early postnatal
period and normal leukocyte counts range from 9000 to
30,000/mm3 in neonates.1 Because of dierences in leuko-
cyte and absolute neutrophil counts (ANCs) between adults
and infants, some authors dene LR as an ANC of 10 SD
above the mean for the gestational age or of 30,000/mm3
during the rst week of life.2 The most common causes
include antenatal administration of steroids, transient LRs
of Down syndrome, and infections.3
Cytomegalovirus (CMV) is one of the most common
causes of congenital infections in the fetus and neonate,
with an incidence of 0.2% to 2.4% of live births. About
10% of infected newborns will have symptomatic diseases.
Infants with congenital CMV infection may show intrauterine
growth restriction, prematurity, hepatosplenomegaly, jaun-
dice, conjugated hyperbilirubinemia, hepatitis syndrome,
thrombocytopenia, blueberry munlike rash, microcephaly,
seizures, chorioretinitis, hearing loss, and pneumonitis.4,5
Received for publication May 13, 2013; accepted August 21, 2013.
From the *Neonatal Intensive Care Unit, Department of Neonatology,
Etlik Zubeyde Hanm Womens Health Teaching and Research
Hospital; and wDepartment of Pathology, Dr Sami Ulus Maternity
and Childrens Hospital, Ankara, Turkey.
The authors declare no conict of interest.
Reprints: Dilek U. Isik, MD, Neonatal Intensive Care Unit, Depart-
ment of Neonatology, Etlik Zubeyde Hanm Womens Health
Teaching and Research Hospital, Yeni Etlik Caddesi 55, Etlik,
Ankara 06010, Turkey (e-mail: dilekulubas@yahoo.com).
Copyright r 2013 by Lippincott Williams & Wilkins
e310 | www.jpho-online.com
Viral infections occasionally present with unusual symptoms
at birth that may delay diagnosis.
Herein, we report a case of a preterm infant with
congenital CMV infection who presented with myeloid LR
on the rst postnatal day and later developed classic nd-
ings of CMV infection, such as blueberry mun rash,
hepatitis, and hearing impairment.
CASE
A 1080 g male neonate was born at 26 weeks of gestation by
cesarean section. His mother had preterm rupture of the mem-
branes over a 10-hour duration with no fever or leukocytosis and a
normal C-reactive protein level. Steroid treatment was not
administered antenatally. The Apgar scores at 1 and 5 minutes were
6 and 7, respectively. The patient was intubated and mechanically
ventilated and received surfactant for respiratory distress syn-
drome. Other than the ndings of prematurity and respiratory
distress, the results of a physical examination were normal. A blood
cell count revealed marked leukocytosis (109,000/mm3), a normal
hemoglobin level (15.4 g/dL), and a normal platelet count (228,000/
mm3). A peripheral blood smear (PBS) showed 5% myelocytes, 5%
metamyelocytes, 25% band forms, 35% neutrophils, 20% lym-
phocytes, and 10% monocytes, with no atypical cells or blasts. The
WBC count increased to 120,000/mm3 at the 48th hour of life.
Penicillin G and gentamicin were initiated for suspected neonatal
sepsis. The initial C-reactive protein level was normal and cultures
for bacterial and fungal infections were negative. The patient was
weaned on nasal continuous airway pressure on day 5 and sup-
plemental oxygen on day 10. The WBC count decreased to 15,000/
mm3 on the 15th day of life, but a shift to the left was still present in
a PBS. Conjugated hyperbilirubinemia, with a serum total bilirubin
level of 5.6 mg/dL and a direct bilirubin level of 1.5 mg/dL, was
detected. Titers for toxoplasmosis, rubella, CMV, herpes simplex
virus-type 1 and 2, and syphilis (TORCH), parvovirus B19, and
Epstein-Barr virus were measured. The CMV IgG titer was pos-
itive, whereas the CMV IgM titer was negative. We ordered CMV
polymerase chain reaction (PCR) for suspected CMV infection on
the 16th day. The patient did not receive any blood products before
this time. Furthermore, appropriate neonatal cholestasis workup
was undertaken to exclude biliary atresia, neonatal hemochroma-
tosis, a-1 antitrypsin deciency, and various metabolic and infec-
tious diseases. Ursodeoxycholic acid was started. On day 17, 0.5- to
1-cm purple nonblanching palpable nodules resembling a blueberry
mun rash appeared on the patients face, upper back, shoulders,
and extremities (Fig. 1). On physical examination, the infant had
hepatomegaly (3 cm below the right costal margin) and splenome-
galy (2 to 3 cm below the left costal margin). His WBC count was
38,000/mm3, and mature neutrophil precursors were detected in a
PBS. A skin biopsy was consistent with extramedullary hema-
topoiesis (Fig. 1). Bone marrow aspiration showed increased
mature myeloid cell precursor numbers and decreased mega-
karyocyte numbers, with no evidence of leukemia or inltrating
diseases. The results of karyotype analysis were normal. CMV
DNA was detected by PCR in blood and urine samples (1842 and
13,800 copies per mL, respectively). The mothers breast milk was
negative for CMV PCR. An ophthalmologic examination and
J Pediatr Hematol Oncol  Volume 36, Number 5, July 2014
J Pediatr Hematol Oncol  Volume 36, Number 5, July 2014
FIGURE 1. Blueberry muffin rash and extramedullary hematopoiesis in skin biopsy.
cranial ultrasonography were normal. Brainstem auditory-evoked
potential analysis revealed a bilateral delay in central conduction.
The patients general conditioned worsened. Repeated cultures
for bacterial and fungal infections were negative. The patient required
red blood cell and platelet transfusions for anemia and severe
thrombocytopenia. As his levels of liver transaminases increased and
the direct hyperbilirubinemia worsened, intravenous ganciclovir
(12 mg/kg/d) was initiated on the 25th day of life. Despite antiviral
therapy and supportive measures, the patients status worsened and
he died of fulminant hepatic failure on the 33rd day of life. Histologic
assessment of the liver tissue in a postmortem percutaneous liver
biopsy sample revealed mainly mixed lymphocytic/granulocytic
inammatory inltration and brosis related to CMV hepatitis.
Typical CMV inclusions were not found in the biopsy specimen.
DISCUSSION
The incidence of LR in the neonatal intensive care unit
varies from 1.3% to 15%, with LR being more common in
preterm neonates.3 However, severe LR with WBC counts
of >100,000/mm3 is very rare in neonates and in most cases
is due to congenital leukemia or transient myeloprolifer-
ative disorder of Down syndrome. Infections very rarely
cause WBC counts of >100,000/mm3.6 In our case, LR with
a WBC of 120,000/mm3 and a marked left shift in a PBS
was observed. Congenital leukemia was ruled out by bone
marrow aspiration and the results of karyotype analysis
were normal. Antenatal steroid treatment was not given
and investigations of bacterial, fungal, and TORCH infec-
tions other than CMV were negative. LR associated with
congenital CMV infection in the newborn period was pre-
viously reported only once, in a term infant who presented
initially with a low birth weight, jaundice, petechiae, and
hepatosplenomegaly, and who later developed LR.7 To the
best of our knowledge, this is the rst report of a newborn
with congenital CMV infection who presented initially with
LR with other disease manifestations being absent.
Another interesting nding in the present case was the
predominance of myeloid precursors and absence of atypical
lymphocytes, despite the presence of a viral infection. Gen-
erally, a lymphocytic LR is seen in viral infections,8 and thus
initial investigations did not include viruses in our patient.
Findings of congenital viral infections soon arose and an
extensive workup, including CMV PCR, was ordered. LR
with predominance of neutrophils, as in our case, was reported
in a 40-day-old infant with congenital CMV infection who
presented with intestinal obstruction due to CMV enteritis,
intrauterine growth restriction, and periventricular cerebral
calcication.9 Myeloid leukocytosis in CMV infection can be
explained by 3 mechanisms. Almost all cell types can be
invaded by CMV, including the epithelial cells, endothelial
cells, broblasts, monocytes, and macrophages. When acti-
vated or injured, these cells respond by secreting several
r 2013 Lippincott Williams & Wilkins
Leukemoid Reaction in Congenital CMV Infection
cytokines and chemokines that act systemically and cause
leukocytosis. Viral genes encode cytokine-like molecules that
recruit inammatory cells to the sites of virus replication.
Finally, recent studies showed that CMV engages Toll-like
receptors, resulting in the induction of proinammatory
cytokines and a chemokine cascade, and therefore the virus
itself can recruit cells such as monocytes and neutrophils to the
infection sites.4 The uctuating WBC counts and persistent
shift to the left in PBS in our patient may indicate continuous
but variable release of WBCs from the bone marrow, which
may be attributed to uctuating cytokine levels.
The gold standard for diagnosis of congenital CMV
infection in newborns is the isolation of the virus in body
uids within the rst 3 weeks of life. Detection of viral DNA
by PCR is rapidly replacing viral culture as a rapid, sensitive,
and ecient method of diagnosing CMV infection.10 Both
false-positive and false-negative test results may occur with
CMV IgM assays, and serologic assays are not enough to
exclude CMV infection in neonates.11 In the present case,
positive CMV PCR results for blood and urine, together with
characteristic clinical ndings such as cholestasis, hep-
atosplenomegaly, blueberry mun rash, and bilateral sen-
sorineural hearing loss were considered diagnostic for CMV
infection and a viral culture was not ordered.
In congenital CMV infection, mortality rates of up to
10% to 30% have been reported. Most deaths occur in the
neonatal period and are usually related to multiorgan diseases
with severe hepatic dysfunction, bleeding, disseminated intra-
vascular coagulation, and secondary bacterial infections.4
Antiviral therapy for congenital CMV infection appears to be
useful in ameliorating the severity of central nervous system
disease and focal organ diseases, including hepatitis and
pneumonitis.10 In the present case, ganciclovir was started only
after hepatic involvement had progressed to overt hepatic
failure. This may be the reason for the treatment failure.
Diagnosis in viral infections with atypical presentations may be
dicult in neonates. LR is an uncommon nding in congenital
CMV infection. The absence of other clinical manifestations of
CMV infection delayed diagnosis and treatment in our patient.
Viruses should be considered in the etiology of LR in new-
borns, even in the absence of other suggestive ndings.
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