Challenges in a unique presentation of congenital dengue with congenital heart disease

Abstract

Vertical transmission of dengue has been documented and is associated with diverse presentations in newborns. Care of such babies requires meticulous support to maintain homeostasis until the baby recovers. We present a neonate diagnosed with congenital dengue, born to a mother diagnosed with dengue on the second day after delivery. Baby was diagnosed by serological tests, underwent appropriate management in neonatal intensive care but was noted to have had coexistent persistent ductus arteriosus and pulmonary hypertension complicating pneumonia and seizures. Management of the baby was complicated by persistent haematological derangements caused by dengue and haemodynamic alterations caused by the heart disease.

Background

Dengue is a tropical disease caused by four serotypes of dengue virus (a fifth serotype has recently been described) belonging to Flaviviridae and presents with varied clinical manifestations complicated by vascular leakage, shock, thrombocytopenia and coagulopathy. Dengue in pregnant women is increasingly reported, presenting with features that mimic more common complications like eclampsia, Haemolysis Elevated Liver enzymes and Low Platelet (HELLP) count syndrome, pulmonary embolism among others.¹ A vertical transmission rate of about 1.6% has been documented in one study.² High index of suspicion is necessary for prompt diagnosis and management of dengue in pregnancy and in neonatal age group. In a case series compilation that described 17 newborns with congenital dengue, only one with comorbidities sustained mortality.³ Though the management of neonatal dengue has unique challenges and has been described, the coexistence of a pneumonia possibly causing pulmonary hypertension (PHT) and congenital heart disease complicating the clinical picture, has not been described so far to the best of our knowledge.

Case presentation

A 24-year-old primigravida woman presented with fever for 1 day with normal blood pressure and no other accompanying features. She was prescribed paracetamol, discharged home and remained afebrile after that. Two days later, she returned with features suggestive of pre-eclampsia with HELLP syndrome and underwent an emergency caesarean section, delivering a healthy female baby at 37+6 weeks of gestation with a birth weight of 2670 g and Apgar scores of 8 and 9 at 1 and 5 min, respectively, after birth. Mother was diagnosed with dengue on the second postoperative day and succumbed to multiorgan dysfunction syndrome a day later. Baby developed fever, seizures and then respiratory distress on day 2 of life prompting admission to the neonatal intensive care unit. She was fed with pasteurised human donor milk from day 5 of life.

Investigations

Chest X-ray showed a bilateral interstitial pattern at admission. There was no radiological worsening in the subsequent chest X-rays performed despite the fluctuating clinical picture.

Although the initial platelet levels were normal, she subsequently developed thrombocytopenia from day 5 of life that persisted until day 16. The lowest platelet count of 15 000/mm³ was evident on day 7. Hyperferritinaemia (S.ferritin level of 1138 ng/mL), hyperbilirubinemia and elevated transaminases (Serum Glutamate Oxaloacetate Transaminase (SGOT): 370 IU/L, Serum Glutamate Pyruvate Transaminase (SGPT): 74 IU/L, Gamma Glutamyl Transpeptidase (GGTP): 294 IU/L) were noted. Blood cultures performed initially and repeated due to worsening clinical status did not reveal any bacterial growth.

An echocardiography (ECHO) was performed soon after admission on day 3 of life owing to a systolic murmur and wide pulse pressure records and that showed a persistent ductus arteriosus (PDA) of size 1.6 mm and evidence of PHT. ECHO performed again due to increasing respiratory distress on day 9 revealed improvement in PHT but also an increase in the size of the PDA to 2.2 mm. ECHO repeated on day 23 following ibuprofen therapy showed that the PDA had increased to a size of 4 mm. Cranial ultrasound scans performed thrice during the hospital stay revealed no abnormalities.

She had elevated titres of NS1 antigen (98.5 U assessed by ELISA methodology) and elevation of IgM levels in paired titres: 1.35 U on day 4 rising to 38.71 U on day 10 of life (lab reference: >11 U considered positive). Real-time PCR for qualitative detection of viral RNA done on day 19 was negative, probably owing to viral clearance or low viral load.

Differential diagnosis

The diagnosis of congenital dengue in this neonate was suspected by history of severe maternal dengue disease and confirmed by serological tests performed. However, the aetiology of pneumonia in this neonate cannot be confirmed in the absence of analysis of nasopharyngeal aspirate or of any other respiratory secretions. Pneumonia could be of bacterial or viral (dengue or others) origin. As this neonate was empirically treated with antibiotics, it is difficult to rule out a bacterial aetiology for the pneumonia. Cerebrospinal fluid (CSF) analysis was not performed due to thrombocytopenia and respiratory distress and so meningitis as a cause of seizures cannot be definitively ruled out. Baby received a week’s course of meropenem and amikacin as well. The probabilities of dengue viral pneumonia causing PHT and dengue encephalitis resulting in seizures could at best only be postulated from a pathophysiological perspective.

Treatment

At admission to the neonatal intensive care unit with fever and seizures, she was started on intravenous phenobarbitone following which seizures were well controlled. She soon developed respiratory distress and so was also started on high-flow nasal cannula oxygen support and intravenous antibiotic (cefoperazone–sulbactum). Intravenous sildenafil was started as her initial ECHO had shown evidence of PHT and that brought about some improvement in distress initially. Owing to thrombocytopenia, concomitant coagulopathy and anaemia, baby received multiple platelet concentrate transfusions, apart from fresh frozen plasma and packed red blood cells.

By day 9, baby had worsening of respiratory distress. Antibiotics were changed to meropenem and amikacin. When the second ECHO showed an increase in PDA size possibly resulting in persistent respiratory distress and oedema, fluid allowance was restricted, and diuretics commenced. Baby was further treated with three doses of ibuprofen from day 18 but the ductus remained patent and her respiratory distress persisted. Owing to persistence of haemodynamically significant PDA resulting in oxygen dependence, surgical PDA closure was performed, following which she was successfully weaned off oxygen.

Outcome and follow-up

She was followed up in clinic until 1 month after discharge. Her growth, feeding pattern and systemic examination were found to be optimal. She was subsequently transferred to a nearby neonatal facility for further follow-up.

Discussion

Congenital dengue should be considered, when appropriate, in endemic areas. The said mother–baby duo presented during an epidemic outbreak in a southern city in India. Mother at presentation had features suggestive of pre-eclampsia (hypertension and proteinuria) with HELLP syndrome (thrombocytopenia, elevated lactate dehydrogenase and transaminases) and was afebrile except for a mild rise in temperature for 1 day that occurred 2 days before admission. However, despite the intensive care imparted, she deteriorated on postoperative day 2. A diagnosis of dengue was suggested by haematological changes and subsequently confirmed by serological tests.

Illness in a newborn with congenital dengue could possibly be due to antepartum or intrapartum transmission of virus or platelet dysfunction causing fetal injury.⁴ This is the first time the mother sustained dengue in her life as per history, making it unlikely for her to have transferred passive immunity against dengue to the fetus. Failure to transfer protective antibodies from mother to fetus when maternal infection immediately precedes parturition might cause severe neonatal dengue and death. On the other hand, previous subclinical Flavivirus infections in the mother might lead to the development of ‘infection enhancing antibodies’ that play a pivotal role in severe illness in the neonate.⁵ Owing to the absence of IgG antibody in maternal serum along with the presence of IgM, this possibility becomes less likely here.

Hyperferritinemia in adults with dengue has been well described⁶ and has been associated with immune activation and coagulation disturbances. The baby lacked other features of macrophage activation syndrome and so the hyperferritinemia was attributed to the acute phase response elicited by dengue infection. She manifested with seizures on day 2 of life. Seizures have been recognised as one of the well-known presentations of dengue encephalitis in older children and adults but have not been described commonly in neonates. Although CSF analysis was not performed in this neonate due to thrombocytopenia and respiratory distress, seizures in this context could possibly represent dengue encephalitis.

A causative role for dengue virus in neonatal dengue-related cardiomyopathy has been described and attributed to possible direct viral damage to cardiac fibres or to a hypersensitivity response elicited.⁷ However, a combination of complex interplay of congenital dengue, PHT complicating pneumonia and congenital heart disease (PDA) has not been described so far to the best of our knowledge. Their pathophysiology and management are interrelated, necessitating a special discussion. PDA in a newborn warrants fluid restriction and diuretic therapy to manage fluid overload, whereas in case of dengue there might be a need for replenishment of intravascular volume due to vascular leakage. PDA results in an oxygen-dependent state among other consequences in the baby, in which case administration of non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen or indomethacin are necessary. However, a well-known complication of NSAIDs is thrombocytopenia which is one of the predominant haematological abnormalities in dengue as was noted to have persisted in this baby until day 16 of life. A course of ibuprofen given after thrombocytopenia had resolved did not close the PDA and so surgical closure was necessary to enable weaning of oxygen support.

The presence of PHT possibly secondary to the parenchymal disease had probably been preventing the PDA from causing significant haemodynamic effects and pulmonary oedema. With the improvement in pneumonia, systemic inflammatory state and with the effect of sildenafil, as the pulmonary pressures fell, pulmonary oedema worsened resulting in dependence on high-flow oxygen. Administration of ibuprofen for closure of PDA has been associated with development of PHT⁸ and so caution was exercised in this case. This has been attributed to early administration of ibuprofen or due to its acidification, precipitation and microembolism of the lung. However, no worsening of PHT was noted in this baby. Dengue can cause cutaneous, mucosal or organ-related haemorrhage at any site including the brain. PDA has been associated with hypoperfusion followed by reperfusion of brain resulting in intraventricular haemorrhage⁹ (IVH) and so the combination warrants close attention. The baby described was constantly monitored with cranial ultrasound and did not develop IVH.

The concurrence of congenital dengue associated with PDA and PHT along with a complex interplay of their haemodynamic consequences and drugs used in their management, seizures possibly due to dengue encephalitis, hyperferritinaemia as an acute phase response and underlying risk of IVH in this baby make this scenario a unique one. Coexistence of congenital heart diseases like PDA and PHT make management more complicated. Prompt recognition and management focused on maintenance of homeostasis and haemodynamic stability brought about good recovery in this neonate despite the severe disease causing maternal mortality.

Learning points.

• Congenital dengue should be suspected in a neonate born to a mother with features suggestive of dengue in the peripartum period and close monitoring of these neonates is essential.

• Presence of persistent ductus arteriosus and the ensuing fluid overload status complicates the management of dengue in a neonate due to the contradicting needs of the two pathologies.

• Pulmonary hypertension (PHT) secondary to pneumonia might impede the pulmonary blood flow that could have otherwise been excessive due to a coexistent persistent ductus arteriosus (PDA).

• However, when the pneumonia and the PHT resolve, such babies may experience a respiratory worsening secondary to increased pulmonary blood flow, warranting adequate and timely attention to the PDA.