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SHORT REPORT

Premature newborns with fatal intrauterine herpes simplex


virus-1 infection: rst report of twins and review of the
literature
M. Pichler,
1
A. Stafer,
2
N. Bonometti,
1
H. Messner,
2
J. Deluca,
1
T. Thuile,
1
R. Kluge,
3
M. Schmuth,
4
K. Eisendle
1,
*
1
Department of Dermatology, Venereology and Allergology, Academic Teaching Department of Innsbruck Medical University, Central
Teaching Hospital of Bolzano/Bozen, Bolzano/Bozen, Italy
2
Neonatal Intensive Care Unit, Central Teaching Hospital of Bolzano/Bozen, Bolzano, Italy
3
Department of Pathology, Central Teaching Hospital of Bolzano/Bozen, Bolzano, Italy
4
Department of Dermatology, Innsbruck Medical University, Innsbruck, Austria
*Correspondence: K. Eisendle. E-mail: Klauseisendle@hotmail.com
Abstract
Background Neonates with blistering skin diseases are dermatologic emergencies. The pathologies involved can pose
diagnostic difculties and there exists a variety of potential life-threatening differential diagnoses.
Objective description of the rst case of intrauterine acquired herpes simplex virus (HSV) 1 infection in twins.
Methods We present the case of two premature bicordial biamniotic twins (27th week of gestation) whose intrauterine
growth retardation, fetal anaemia and cardiotocography abnormalities led to a caesarean emergency delivery.
Results Accurate medical history revealed a maternal febrile gingivostomatitis at the 23rd week of gestation, which
was neglected by the treating gynaecologist. Respiratory distress was present at delivery and intubation was necessary
in both children. The whole skin showed extensive erosions and ulcerations and the mucosa of the eyes and genitals
was also involved. Intrauterine Herpes simplex virus (HSV) 1 infection was conrmed by immunohistochemistry of skin
Tzanck smear (HSV 1 positive, HSV 2 negative), real-time polymerase chain reaction of both serum and skin (HSV 1 posi-
tive; HSV 2 negative) and maternal serology positive for HSV 1 IgM and IgG. Siblings were immediately treated with
high-dose endovenous acyclovir. Anaemia thrombocytopenia and hepatorenal values markedly deteriorated and both
developed consequential hepatorenal failure. The third day live supportive measures were terminated after parental
informed consent and both siblings deceased shortly after on their mothers breast.
Discussion Intrauterine HSV infection is rare and accounts only for 5% of neonatal HSV infections. Literature reports
only 64 cases and 90% of those are related to HSV-2. Transplacental viral transmission is highest during the rst
20 weeks of gestation and has been observed in pregnant women with disseminated HSV infection. Mortality and mor-
bidity of intrauterine herpetic infection are extremely high.
Conclusion Despite transplacental HSV transmission remains a rare event, the potential devastating outcome justies
immediate adequate antiviral treatment in a pregnant woman affected by primary HSV infection.
Received: 3 April 2014; Accepted: 12 May 2014
Conicts of Interest
None declared.
Funding sources
None declared.
Introduction
Herpes simplex virus (HSV) type 1 and type 2 are common
human companions; seroprevalence of HSV-1 antibodies in
adults in Germany reaches high levels of more than 80%, and
nearly 15% in the case of HSV-2.
1
In contrast, HSV infection of
the newborn is a severe, devastating and life-threatening disease
and HSV is part of the classical group of teratogenic pathogens
referred to as TORCH (Toxoplasma gondii, others like Trepo-
nema pallidum, rubella virus, cytomegalovirus and herpes
simplex virus).
2
The transmission usually occurs due to skinskin, skin
mucosa or mucosamucosa contact. In the cases of newborns,
HSV can be acquired in utero, intrapartum or postnatal. In
8590% of neonatal HSV infection, the virus is acquired at time
2014 European Academy of Dermatology and Venereology JEADV 2014
DOI: 10.1111/jdv.12583 JEADV
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2014 European Academy of Dermatology and Venereology JEADV 2014
2 Pichler et al.
of delivery.
3
Intrauterine HSV infection is rare and accounts
only for 5% of neonatal HSV infections.
4
Literature reports only
64 cases of intrauterine HSV and 90% of those cases are related
to HSV-2,
5
because primary HSV-2 infection during pregnancy
is more frequent as primary HSV-1 infection and responsible
for 7090% of cases (Table 1). Both primary infection in 50
75% and recurrent maternal genital infection in less than 5%
can result in congenital disease.
3
We report the case of two siblings with intrauterine HSV-1
infection after primary dismissed HSV-1 infection of the mother
presenting as painful febrile gingivostomatitis. Both siblings pre-
sented without vesicles but with widespread erosions of the skin
and mucous membranes and were referred for the suspicion of
congenital blistering disease. Differential diagnosis of skin ulcer-
ations in the newborn includes congenital epidermolysis bullosa:
Mendelian Disorders Of Cornication (Ichthyoses), Pemphigus
vulgaris, Staphylococcal scalded skin syndrome, toxic epidermal
necrolysis, Herpes simplex and Varicella virus infections, aplasia
cutis, Incontinentia pigmenti and neonatal lupus erythema-
todes.
3
Case 1
At 27 weeks of gestation two siblings were born to a 32-year-old
pregnant woman (2nd gravida) by urgent caesarean delivery
after CTG abnormalities and signs of fetal anaemia. Prenatal his-
tory, laboratory ndings and prenatal ultrasound were unre-
markable until the 23rd week of gestation, when the mother
developed herpetic gingivostomatitis with multiple oral ulcer-
ations associated with eating and drinking difculties, myalgias,
asthenia and fever over 5 days. The symptoms healed without
specic treatment. Retrospective inquiry revealed that she had
never suffered from herpes labialis, and that her 2-year-old rst
son recovered from febrile gingivostomatitis in that period. The
treating gynaecologist dismissed the symptoms and no specic
treatment was introduced. Parents were not genetically related
and prenatal testing was negative for Syphilis, Hepatitis C, HIV,
Parvovirus B19 and Cytomegalovirus.
The rst female sibling had a birthweight of 750 g. Laboratory
ndings showed an important leucocytosis of 54.50 9 10
3
/lL
(10.0026.00 9 10
3
/lL) with 38% granulocytes, 38% lympho-
cytes and 23% monocytes, without eosinophilia or basophilic
granulocytes. There were also signs of hepatitis with normal
gamma-glutamyl transferase (GGT) 68 and high levels of glu-
tamic pyruvic transaminase (GPT) 776 U/L (<60 U/L) and glu-
tamic oxaloacetic transaminase (GOT) 4143 U/L (<95 U/L).
Also, direct bilirubin 9.9 mg/dL (<0.3 mg/dL), total bilirubin
15.4 mg/dL (<13 mg/dL) and the ammoniaemia 297.2 lg/dL
(27.2102.0 lg/dL) were increased. The laboratory ndings also
showed elevated levels of serum creatinine of 1.35 mg/dL (0.24
0.85 mg/dL) and an increased C-reactive protein (CRP) of
2.74 mg/dL (<0.50 mg/dL).
The skin showed widespread conuent erosions and ulcer-
ations that involved nearly the whole skin with important
involvement of the ear, ocular and genital mucosal membranes.
Case 2
The male sibling weighed 800 g at delivery. The laboratory
ndings showed a milder leucocytosis with 24.80 9 10
3
/lL
leucocytes (10.0026.00 9 10
3
/lL), 53% neutrophils, 26% lym-
phocytes, 16% monocytes, 3% basophiles and no eosinophils.
He showed higher levels of liver enzymes as his sister with GPT
652 U/L (<60 U/L), GOT 3889 (<95 U/L) and GGT 75 (<175 U/
L), direct bilirubin 9.2 mg/dL (<0.3 mg/dL), total bilirubin
14.4 mg/dL (<13 mg/dL) and ammoniaemia 361.1 lg/dL (27.2
102 lg/dL). The serum creatinine was 1.25 mg/dL (0.24
0.85 mg/dL) and the CRP was 1.81 mg/dL (< 0.50 mg/dL).
Immediately after delivery he had to be intubated because of
severe respiratory distress. The skin presented similar extensive
erosions and ulcerations involving nearly of the whole body with
ocular and genital mucosal involvement, only palms and plants
were untouched. The oral mucosa, however, was free of erosions
in both siblings.
Neither sibling showed vesicles at time of delivery or at fol-
low-up (see Figs 1,2). The immediate neonatal course was simi-
lar in both babies and complicated by respiratory distress,
intubation and multiorgan affection. Neurosonography showed
signs of cerebral involvement with involvement of basal gangli-
ons.
At birth skin and mucosal swabs for HSV PCR and immuno-
histochemistry were performed in both siblings. The infants
received prophylactic systemic antibiotic therapy because of the
skin barrier disruption due to extensive ulcerations and immedi-
ate high-dose antiviral therapy with acyclovir (60 mg/Kg/day).
Figure 1 Male sibling: diffuse extensive vegetating ulcerations of
the skin. Note the ocular and genital involvement.
2014 European Academy of Dermatology and Venereology JEADV 2014
Fatal intrauterine HSV-1 infection 3
PCR of the skin swab, available 1 day after delivery, was nega-
tive for HSV-2 but positive for HSV-1. The HSV-1 infection was
also conrmed by positive immunohistochemistry (see Fig. 3).
In addition, the serology of the mother showed IgM and IgG
antibodies positive for HSV-1 and negative for HSV-2, conrm-
ing an intrauterine HSV-1 transmission of the virus. Unfortu-
nately, both infants developed increasingly multiorgan failure
and on the third day live supportive measures were terminated
after parental informed consent and both siblings deceased
shortly after on their mothers breast.
Discussion
Primary HSV infection in pregnancy is uncommon and can lead
to a transplacental virus transmission and fetal infection and as a
consequence to abortion, stillbirth or congenital malforma-
tions.
6
The number of women who acquired HSV infection dur-
ing pregnancy has been calculated as 0.52%.
7
Pregnant women
with primary mucous membrane infection during the third tri-
mester have an increased risk for dissemination,
8
but the highest
risk of intrauterine HSV transmission has been observed in preg-
nant woman with a disseminated HSV infection during the rst
20 weeks of gestation. In the described case transmission
occurred later in pregnancy, this could be possibly related to the
risk in pregnancy with twins or due to infection with HSV-1.
Neonatal herpes simplex virus infection has three different
presentations: disseminated disease (25%), central nervous
system disease (30%) and disease limited to the skin, eyes or
mouth.
9
Cutaneous lesions are the most common clinical mani-
festation (95%) with presentation at birth or within the rst
12 h of life, most common with vesiculobullous lesions,
especially in the case of intrauterine transmission. Of the
patients described in the literature with cutaneous ndings, 44%
had other manifestations than vesicles or bullae.
5
HSV infection may be identied directly by the detection of
the virus or one of its components or indirectly by specic
serum antibodies. The gold standard is the virus isolation by cell
culture from vesicular content or in absence of vesicles from the
bottom of erosions or mucosa with a high sensitivity of more
than 90% and a specicity of up to 100%.
10
Another less specic method is the cytologic detection of
giant cells of skin and mucosal lesion scratchings with the
Tzanck test,
11
or better immunouorescence or immunohisto-
chemical detection of infected cells from smears or biopsies and
the virus antigen detection by EIA or ELISA.
10
The method for
HSV diagnosis with the highest specicity and sensitivity
(~100%, 9798%) is the virus detection by PCR from skin
lesions, vesicular content or mucosa,
11
as we performed in our
cases from the skin swab of erosions.
There are few denitions of intrauterine HSV infection in
the literature, but not a uniform one. Evidence of infection in
the rst 48 h of life, exclusion of other illnesses and biological
or histological conrmation of HSV infection are the most
common denitions.
12
Cutaneous presentations of congenital
HSV infections are variable and diagnosis of HSV infection in
an infant requires a high index of suspicion, also because fre-
quently the medical history is not straight forward, as in this
case where the mother reported the oral ulcerations only after
specic questioning for oral or genital ulcerations. It is impor-
tant to include intrauterine acquired herpes simplex infection
in the differential diagnosis of neonatal erosions, even in the
absence of vesicles. To our knowledge, congenital HSV-1 infec-
tion with extensive skin lesions has been reported only twice in
the literature.
13,14
This is the rst report of intrauterine HSV
infection in siblings.
In absence of therapy neonates with a disseminated HSV
infection have a high mortality of about 80%. Therefore, antivi-
Figure 3 Immunohistochemistry of Tzanck smear: HSV-1 positive
(right), HSV-2 negative (left).
Figure 2 Female sibling: diffuse ulcerations of the skin with
mucosal involvement of the eyes, ears and genital area.
2014 European Academy of Dermatology and Venereology JEADV 2014
4 Pichler et al.
ral therapy has to be administered immediately even in suspected
cases of HSV infection. Therapy consists in administration of
high-dose intravenous Acyclovir (60 mg/Kg/day) for 14 days in
cases with no CNS involvement and for 21 days when the CNS
is involved or in the case of disseminated infection. Despite
this the outcome remains poor, particularly for babies with
disseminated multiorgan infections or manifestations of CNS
disease.
15
The tragic outcome of the described case also underlines the
emergency of primary herpes simplex infections in pregnancy.
Despite transplacental HSV transmission remains a rare event,
the potential devastating outcome justies immediate adequate
antiviral treatment preferably with intravenous acyclovir.
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