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Pediatric Infectious Disease xxx (2016) xxxxxx

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Pediatric Infectious Disease


journal homepage: www.elsevier.com/locate/pid

Congenital Dengue Infection: Are we missing the Diagnosis? Case report with review of literature

Congenital dengue infection: Are we missing the diagnosis?


Ramani Ranjan a,*, Kishore Kumar b,c, Nandini Nagar d
a
Consultant Neonatologist and Pediatrician Adiyta Birla Hospital, Veraval, Gujarat, India
b
Consultant Neonatologist & Paediatrician Chairman - Cloudnine Hospitals, India
c
Adjunct Professor of Neonatology & Paediatrics, Notre Dame University, Australia
d
Consultant Neontalogist and Paediatrician Cloudnine Hospital, Bangalore

A R T I C L E I N F O A B S T R A C T

Article history: Neonatal dengue is now being increasingly reported for changing epidemiology and improved rapid
Received 2 May 2016 detection methods. Vertical transmission with dengue virus is concordant with rules of nanomedicine
Accepted 13 July 2016 and may present differently in newborns from what we normally see in older children. It may have
Available online xxx
prolonged symptomatology and protracted thrombocytopenia. There are no specic guidelines for
neonatal dengue management. There is dearth of standard literature about neonatal dengue per se and
Keywords: most recommendations are based on experiences with older children and adults. The unique pathogen
Neonatal dengue
host interaction complicates dengue vaccine development and creates provocative questions in vaccine
Vertical transmission
development. We present a case report of neonatal dengue with review of literature. A day 8 old
newborn with maternally acquired dengue was admitted in our NICU and had an eventful course. This
congenital dengue infection case gives us good learning experiences in a not so well understood entity.
2016 Published by Elsevier B.V. on behalf of Indian Academy of Pediatrics, Infectious Disease Chapter.

1. Introduction pregnancy has not been shown to cause any congenital abnormal-
ities however transmission from mother to fetus can cause
Dengue is the most important tropical mosquito-borne infec- perinatal mortality and morbidity.4 In one study recent dengue
tious disease caused by an arbovirus, the dengue virus. After being infection was demonstrated in 2.5% of parturients, with a vertical
bitten by a vector mosquito, human beings will obtain the dengue transmission rate of 1.6%.5
virus, which can result in infection. The dengue virus is a single- DHF in the newborn may begin as a severe, non-specic illness
stranded RNA virus in the genus Flavivirus and family Flaviviridae. and symptoms may not be present immediately after birth.
This virus is approximately 4060 nm. There are four distinct Because symptoms in the newborn may be non-specic, a high
serotypes of dengue virus that can cause disease. A high fever, degree of suspicion is needed.6 We present a case report of
accompanied by hemo-concentration and thrombocytopenia, is newborn with congenital dengue which presented to us on day 8 of
the hallmark of severe dengue disease.1,2 life with maternal positive dengue report.
Concern regarding women who are pregnant becoming infected
with dengue has been heightened in recent years due to an 2. Case report
increase in adolescent and adult infections3 Women of child-
bearing age are now increasingly at risk of acquiring dengue A term male baby born to 29 year old Primi mother (out born)
infection while pregnant and may be more likely to develop severe by normal vaginal delivery with birth weight 3.05 kg was admitted
disease as second infections occur later in life. DHF during in our NICU on day 8 of life with history of fever for 1 day after
being referred by a local pediatrician. Antenatal history was
unremarkable. Apgars were normal at birth but baby developed
Abbreviations: CRP, C reactive protein; CPAP, continuous positive airway pressure; tachypnea at 2 hour of birth and was treated at transient
I.V., intravenous; LFT, liver function test; RFT, renal function test; DSS, dengue shock tachypnea of newborn. Baby was discharged to home on 3rd
syndrome; DHF, dengue hemorrhagic fever; ADE, antibody dependant enhance- post-natal day with mother. Mother was readmitted in same
ment; NS1, non-structural antigen 1; RT-PCR, reverse transcriptase polymerase hospital on 4th post-natal day with high grade fever and was
chain reaction.
diagnosed to have dengue fever by positive IgM Elisa test. She had
* Corresponding author at: Consultant Neonatologist and Pediatrician Adiyta
Birla Hospital, Veraval, Gujarat, India. severe thrombocytopenia (lowest platelet being 16,000/cmm) and
E-mail address: dr.r.ranjan@gmail.com (R. Ranjan). recovered without any hemorrhagic manifestations.

http://dx.doi.org/10.1016/j.pid.2016.07.003
2212-8328/ 2016 Published by Elsevier B.V. on behalf of Indian Academy of Pediatrics, Infectious Disease Chapter.

Please cite this article in press as: Ranjan R, et al. Congenital dengue infection: Are we missing the diagnosis? Pediatr Infect Dis. (2016),
http://dx.doi.org/10.1016/j.pid.2016.07.003
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2 R. Ranjan et al. / Pediatric Infectious Disease xxx (2016) xxxxxx

The baby on admission to NICU had moderate fever (100.2 8F) The longer the time interval between the onset of maternal
and other normal vitals. Liver was 2.5 cm palpable under RCM fever and delivery the sooner is the appearance of fever in the
and spleen tip just palpable. Lab tests revealed NS1 antigen infant which is consistent with the incubation period of dengue
positive and negative IgM/IgG Elisa. Platelet count was 1.1 lacs/ infection of 57 days. The incubation period for dengue
cmm and CRP mildly positive (CRP-7 mg/L; normal range 0 infection in infants or the duration between fever in mothers
6 mg/L) on admission. Baby was started on rst line I.V and infants, was shorter in mothers with secondary infection.
antibiotics after drawing blood C/S and put full feeds with plan Severe dengue occurs only when the clinical picture in the
to repeat PCV and Platelet next day. Baby became afebrile next mother happens near term or the birth itself, and no time to
day and clinical examination was other unremarkable except for maternal production of protective antibodies. In our case the
hepatosplenomegaly. Over next few days platelet count fell fever in baby appeared on 8th post-natal day while mother had
(minimum being 10,000/cmm on 11th day of life) and multiple symptoms starting 5th post-natal day so it is quite probable that
platelet transfusions were given during this period (total mother was infected quite close to the delivery day although
9 transfusion during hospital stay). In view of baby not infective period ranges 14 days before to 14 days after delivery.
completing feeds completely I.V. uid was started on D3 of Theoretically horizontal transmission in our case report baby
admission and platelets/PCV checked at regular intervals. On D4 cannot be ruled out but considering the care in hospital it looks
of admission (11th post-natal day) baby developed respiratory improbable.
distress and was started on bubble CPAP. Bedside USG revealed Dengue serotypes may play a role in the severity of disease.
mild ascites and pleural effusion B/L and there was RDS type of Symptoms seemed to be more severe with secondary dengue type
picture on chest X-ray. The baby was kept nil per oral and uids 2 infection.
were hiked. Considering mild rise in CRP value the antibiotics The mode of delivery did not change the course of disease or
were further upgraded too and blood C/S was repeated. The child reduce the rate of bleeding in infants.9
improved next day and CPAP was removed and over next 4 days The dengue virus, an RNA virus, has a small molecular size
remained clinically stable. On D8 of admission the baby had (about 4060 nm) and is concordant with the basic rule of vertical
features of shock and was managed with uid boluses and transmission in nanomedicine. Immunopathogenesis is proposed
ionotropes. There was reappearance of fever (maximum recorded to be the main possible pathogenesis leading to congenital dengue
100.6 8F). USG showed increased third space loss and chest X-ray infection. In the neonate with congenital dengue infection, the
was suggestive of right collapse consolidation. Dengue serology passed dengue virus from the mother might stimulate the antibody
was sent and IgM dengue came positive. Baby started to have response and further induce thrombocytopenia via possible
hemorrhagic manifestations, coagulation prole was abnormal autoimmune mechanisms.
(APTT 90, INR 1.73) and CRP shot up to 110 mg/L. Along with Three mechanisms of dengue-related illness in the fetus can be
platelet, FFP transfusion was given and considering downhill postulated6:
course baby was put on mechanical ventilator. LFT on day
13 post-natal life showed elevated liver enzymes (SGOT 356/ 1. Maternal infection during pregnancy may result in hematoge-
SGPT 565) and both blood culture reports were sterile. Echo was nous spread of the virus to the placenta and subsequent passage
done twice to see myocardial function and was reported normal to the fetus.
on both occasions. USG brain on day 16 of life showed diffuse 2. Maternal viremia during labor could result in viral transmission
brain edema. Inspite of using 3 ionotropes in moderate to high and infection of the fetus or the newborn because of blood
dosage (dopamine, dobutamine and noradrenaline) the mean BP exchange during the delivery process.
was persistently below 40 mmHg. Inspite of all efforts baby sadly 3. Severe maternal illness during pregnancy or labor could alter
expired on day 16 of life. placental function and injure the fetus in the absence of actual
fetal infection.
3. Discussion/review of literature
Fever is the most common Clinical feature in congenital
DHF/DSS is uncommon in children below 1 year who are dengue infection. The age at presentation ranges from 16 h to
usually exposed to infection by dengue virus for the rst time. 11 days after birth and lasts 26 days with body temperatures
However infection-enhancing antibodies acquired by the between 38.0 and 38.8 8C.6 Biphasic fever was seen our case
mother from previous Flavivirus infections are passively trans- (fever reappeared on D 15 of life) and it has been reported once
mitted to the baby and this results in serious manifestations in the in newborns10 but it is not a common feature. Fever in longer in
newborn.7 children experiencing primary infections rather than secondary
Maternal age was the only risk factor associated with dengue infection. Newborn infants often do not mount a febrile
infection as older mothers (>20 years) were signicantly more response to an infection, and consequently cases of perinatal
likely to be sero-positive than younger women. Cord antibody dengue virus transmission may be missed if the mother is not
titers varied with maternal age and antibody titer were signi- identied as having dengue.11 Similarly late appearance of fever
cantly higher in babies born to younger mothers (<20 years) and may mimic late onset neonatal sepsis and confound the clinical
were signicantly correlated with maternal titer. Low birth weight picture. It is not uncommon to have raised CRP values as the
babies had Lower transfer ratios for antibody compared to heavier disease advances as was seen in our case and reported in
babies.8 In our case mothers age was 29 years and possibly it was a literature12,13 Strong suspicion in an endemic zone is needed to
secondary infection considering the severity in mother and the diagnose congenital dengue infection. Non-specic signs such as
baby. poor sucking, irritability, diarrhea, and pallor may be present.
Although many arboviruses are known to cause fetal death, Acrocyanosis or cyanosis of the perioral and periorbital area may
premature birth and teratogenic changes in humans and animals, be present for long duration. Hepatosplenomegaly with elevated
the few reports of fetal malformation or wastage from dengue enzymes (AST or ALT >1000) may herald onset of shock
infection are poorly documented6 and the evidence is contradic- syndrome and should be interpreted as disease advancement
tory. In case of early pregnancy, there is no evidence for vertical and severe dengue.14 Maculo papular Rash may be present on
transmission2 although there are reports of prematurity and low day 1 starting on face and spreading to involve the trunks and
birth weight.5 limbs later.

Please cite this article in press as: Ranjan R, et al. Congenital dengue infection: Are we missing the diagnosis? Pediatr Infect Dis. (2016),
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R. Ranjan et al. / Pediatric Infectious Disease xxx (2016) xxxxxx 3

It has been established that DHF is caused by a Cytokine 4. Conclusion


Tsunami but despite extensive studies for over four decades, its
genesis is still not fully understood. The mechanisms that have Neonatal dengue infection is reported more often now for
been considered to cause DHF include antibody-dependent changing epidemiology of dengue virus and improved rapid
enhancement (ADE), T cell response, and a shift from Th-1 to diagnostic techniques nevertheless high index of suspicion with
Th-2 response.15 DSS/DHF in newborn presents as hypotonia, appropriate maternal history is cornerstone to its diagnosis.
mottled skin, tachypnea and bradycardia. Third space losses Presentation in newborn may be quite subtle and non-specic and
(Pleural effusion/ascites) are usually seen on post-natal day 45 also there is variation from pediatric dengue in terms of extended
but may be prolonged. In our reported case B/L pleural effusion and symptoms and thrombocytopenia therefore giving a false
moderate ascites was rst seen on day 12 of life and gradually impression of septicemia. We found biphasic fever as an
increased during the last phase of illness. Circulatory insufciency/ important nding and in our case it coincided with acute
hypotension may develop in short span of time. In neonatal cases deterioration in babys condition so reappearance of fever should
of DHF, muco-cutaneous or subcutaneous bleeding is the most be regarded as disease advancement. Persisting thrombocytope-
common hemorrhagic manifestation.6 nia inspite of platelet transfusion is a poor prognostic marker as is
Unusual presentations of congenital dengue infection such as increasing evidence of third space loss. We maintain that newborn
prolonged neonatal cholestasis and myocarditis have been with dengue should be managed in hospital set up for at least
reported.16,17 2 weeks from diagnosis or rst symptom lest baby deteriorates at
Laboratory investigations include serial CBCs, Liver function home after getting discharged even in otherwise apparently
tests, blood chemistries, urine analysis (Urinalysis is needed to normal looking newborn.
assess the presence of gross or microscopic hematuria) and
coagulation prole (prothrombin time and partial thromboplastin Authors contribution
time). Coagulation abnormalities can be present in DHF but are not
common in dengue fever. Ancillary tests, e.g. chest X-ray and USG RR: Planned the review and prepared the initial draft of the
scan are required to look for third space losses. In various case manuscript. KK: Conceived the idea and provided the resource
reports thrombocytopenia is universal marker of dengue infection literature. NN: Diagnosed the case and helped in preparing
and may be severe and protracted even up to 2 months. A manuscript.
continuous, marked decline in platelet level and increase in All authors approved the nal manuscript for publication.
hematocrit to >20% of the base value could be the rst sign of the
development of DHF.6 In our case the thrombocytopenia persisted Funding
till last inspite of regular platelet transfusions (minimum platelet
recorded was 10,000/cmm on D5 of admission). None.
Laboratory investigations include virus isolation and RNA
detection which are considered conrmatory evidence of dengue Conicts of interest
infection. Serological diagnosis depends on the presence of
antidengue IgM antibody or a rise in IgG antibody titer in paired The authors have none to declare.
(acute and convalescent phase) sera. Currently, the most widely
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Please cite this article in press as: Ranjan R, et al. Congenital dengue infection: Are we missing the diagnosis? Pediatr Infect Dis. (2016),
http://dx.doi.org/10.1016/j.pid.2016.07.003