Spectrum of Hepatic Manifestation in Neonatal Dengue: A Case Report

Abstract

Dengue is endemic in India, placing all pregnant women at risk, with the highest likelihood of vertical transmission in the third trimester. Perinatal dengue remains poorly understood, particularly its hepatic manifestations and management in preterm neonates. We report a preterm male neonate (30 + 6 weeks, 1.94 kg) born to a dengue-infected mother, presenting with fever on day 4. Vertically transmitted dengue was confirmed by positive IgM and NS1 antigen. The infant developed severe hepatitis (SGOT 2160 U/l, SGPT 358 U/l), refractory thrombocytopenia (nadir 21 000/cumm) and hyperferritinaemia (>100 000 ng/ml). The baby was successfully managed with intravenous N-acetylcysteine for dengue-associated hepatitis and methylprednisolone for refractory thrombocytopenia, resulting in dramatic clinical improvement. Subsequently, he developed prolonged cholestasis, and by day 36, ultrasound showed hepatic dystrophic calcifications as post-infective sequelae, highlighting the need for vigilance and prolonged follow-up.

Case Report

A 33-year-old pregnant woman of parity index G3P1L1A1, at 30 + 6 weeks of gestational age was referred to our hospital from outside with complaints of preterm onset of labour pains and previous LSCS scar tenderness. On admission she was afebrile and haemodynamically stable. An emergency LSCS was performed and she delivered a live male baby with an Apgar score 7 at 1 minute and 8 at 5 minutes, respectively, with a birth weight of 1.94 kg.

Mother had temperature spikes since first postpartum day and was evaluated further. Her complete blood count showed reducing platelet count with lowest being 60 000/cumm with normal total cell count and haemoglobin level. Dengue IgM was found to be positive. Her platelet count began to rise after 5 days and no platelet transfusion was required. Post-partum period was uneventful without any complications.

The baby was shifted to neonatal ICU in view of respiratory distress. The baby was managed with CPAP, surfactant, IV fluids and other supportive measures. Respiratory distress settled by 24 hours of life and was gradually weaned to room air. Feeds were initiated.

Clinical Course

On day 4, the baby developed low grade fever spikes and had flushed peripheries. Antibiotics were initiated prophylactically for neonatal sepsis. Haemoglobin on day 4 was 15.7 g/dl with total leucocyte count of 8200 cells/cumm and platelet count of 23 000/cumm. He was investigated for dengue infection and confirmed vertical transmission of dengue as Dengue IgM and Dengue NS1 ELISA tests were positive.

Cranial ultrasound showed bilateral grade II germinal matrix haemorrhage and ultrasound abdomen showed gall bladder wall oedema. Echocardiography showed right ventricular dysfunction. Platelet counts were in reducing trend with a nadir of 21 000/cumm and the baby received multiple platelet transfusions.

Serum ferritin done on day 8 of life was more than 1 lakh ng/ml. Baby also developed progressive anaemia with a nadir of 9.6 g/dl on second week of life. In view of bicytopenia with hyperferritinaemia, haemophagocytic lymphohistiocytosis was suspected initially, however serum triglycerides were normal and peripheral smear did not show any evidence of haemophagocytosis.

Liver enzymes showed worsening transaminitis with SGOT rising to 2160 U/l and SGPT to 358 U/l. In view of highly elevated inflammatory markers, intravenous immunoglobulin was given. Baby also received intravenous N-Acetylcysteine at a loading dose of 150 mg/kg over 15 minutes followed by maintenance dose of 12.5 mg/kg/hour for 4 hours and 6.25 mg/kg/hour for 72 hours.

Baby improved clinically with reducing serum ferritin and liver enzymes. Platelet count improved transiently but began to fall again. Repeat septic screen was negative. In view of refractory thrombocytopenia with negative septic screen, intravenous methylprednisolone was given for 3 days at a dose of 2 mg/kg/day. Platelet count dramatically improved to 1.44 lakhs/cumm.

During the course of stay, baby had increasing cholestasis with a direct fraction more than 50%. After ruling out other causes of cholestasis, baby was managed conservatively with choleretics and multivitamin supplementation. He was discharged well on day 20 of life.

Baby presented with anaemia and pale bloody stools on day 36 of life and was evaluated further. TORCH screen was negative. Ultrasound abdomen showed multiple foci of dystrophic calcifications, probably post-infective sequelae. Cow milk protein allergy was suspected and baby was treated with blood transfusion and initiated on hypoallergenic formula. Baby tolerated well and was discharged. Baby was being followed up on outpatient basis and cholestasis was gradually resolving.

Discussion

Dengue is a viral infection transmitted to humans through the bite of infected female Aedes aegypti mosquito. The virus responsible is DENV with 4 serotypes. As per recent WHO survey, about 100 to 400 million infections occur each year worldwide. ¹ A systematic review conducted by Pouliot et al indicates higher incidence of maternal complications like miscarriage, caesarean deliveries, pre-eclampsia and postpartum haemorrhage. Dengue during pregnancy is also associated with several neonatal complications such as perinatal death, low birth weight and preterm delivery. ²

Vertical Transmission and Clinical Presentation

Congenital dengue should be kept in differential diagnosis if a neonate presents with fever, rash or thrombocytopenia in dengue season especially in endemic areas.^3,4 The incubation period in humans is 3 to 10 days and its half-life in neonate is 40 days. Average time between maternal fever and neonatal symptoms ranged from 5 to 13 days, with a median of 7 days. ⁵

Vertical transmission of dengue, although rare, has been reported in the last trimester. This is mainly due to inadequate transfer of protective maternal antibodies from mother to her foetus. ⁶ Intrauterine transmission of dengue infection is greatest when a pregnant woman delivers at or near the peak of viraemia, due to transmission of virus from mother to her unprotected neonate.^5,7 A Pregnant female can transmit the infection to foetus if she develops fever from 10 days before delivery to 10 hours after delivery. Mode of delivery does not affect transmission.

Common symptoms in neonate include fever, thrombocytopenia, elevated liver enzymes, hepatic dysfunction and rarely dengue shock syndrome with severe bleeding requiring multiple blood product transfusions. The most common symptom is fever, and the most common sign is flushing. The onset of fever in neonates varies from days 1 to 11 after birth and the signs and symptoms usually last for 1 to 5 days.^3,8

Dengue fever in children consists of 3 stages: febrile phase lasting 2 to 7 days, critical phase lasting 1 to 2 days and convalescent phase lasting 2 to 4 days. These phases may be indistinguishable in neonates. The main complication is increased vascular permeability, which reduces with increasing age. Hence children with lower birth weights are at higher risk of severe dengue (Figure 1).

Figure 1.

Trends of labouratory parameters. (A) Haemoglobin trend showing progressive decline. (B) Platelet count trend demonstrating fluctuation with nadir of 21 000/cumm, followed by dramatic improvement after methylprednisolone therapy. (C, D) Liver enzyme trends showing marked elevation with SGOT reaching 2160 U/l and SGPT 358 U/l, demonstrating severe hepatocellular injury, followed by improvement after N-Acetylcysteine therapy.

Thrombocytopenia and Its Management

The mechanism of thrombocytopenia is complex and involves activation of platelets, procoagulants, anticoagulants, complement factors, cytokines and endothelial cells. It might also be due to bone marrow suppression or peripheral destruction of platelets induced by platelet antibodies. Platelet count usually does not correlate well with clinical bleeding. ⁹

Use of Methylprednisolone: A single dose of methylprednisolone has been shown to prevent progression of dengue, higher rise in platelet counts, earlier resolution of severity, reduced hospital stay and lesser need for platelet transfusion. ¹⁰ In our case, intravenous methylprednisolone at 2 mg/kg/day for 3 days resulted in dramatic improvement of platelet count from refractory thrombocytopenia to 1.44 lakhs/cumm, demonstrating its efficacy in neonatal dengue with severe thrombocytopenia.

Hepatic Dysfunction and N-Acetylcysteine

Liver dysfunction in dengue infection may be due to direct viral effect on liver cells, dysregulated immune response, ischaemic hepatic injury due to circulatory collapse or a combination of these.^11,12 Elevated aminotransferases are common markers of hepatic involvement in dengue. ¹² Ferritin may serve as a biomarker of severe dengue. The presence of hyperferritinaemia with haemophagocytic lymphohistiocytosis is potentially a fatal condition.

Use of N-Acetylcysteine (NAC): Intravenous administration of NAC in the early stages of dengue-associated liver failure is safe and beneficial. ¹³ In our case, we administered intravenous NAC at a loading dose of 150 mg/kg over 15 minutes followed by maintenance dose of 12.5 mg/kg/hour for 4 hours and 6.25 mg/kg/hour for 72 hours. The baby showed clinical improvement with reducing serum ferritin and liver enzymes following NAC therapy, supporting its role in management of dengue-associated hepatitis in neonates.

Prolonged Cholestasis

Very few cases of prolonged neonatal cholestasis have been reported as a complication of dengue infection. ¹⁴ The development of cholestatic jaundice without fulminant hepatitis occurs due to ongoing inflammatory process of dengue infection, which can reduce the diameter of the biliary canaliculus lumen, causing obstruction. This case highlights that cholestasis may be an under-recognized clinical manifestation of dengue fever.

Dystrophic Calcification

Very few adult cases of massive dystrophic calcification following dengue have been reported and it is extremely rare in neonates. ¹⁵ Dystrophic calcification represents calcium deposition in previously damaged or necrotic tissue. In our case, ultrasound findings at day 36 demonstrated multiple foci of hyperechoic lesions with posterior acoustic shadowing throughout the liver parenchyma, consistent with dystrophic calcification as post-infective sequelae of severe dengue hepatitis.

The presence of hepatic calcifications in association with documented severe transaminitis, hyperferritinaemia and prolonged cholestasis represents the complete spectrum of hepatic manifestations in neonatal dengue. The calcifications likely represent the end-stage sequela of severe hepatocellular injury sustained during the acute phase of dengue infection (Figure 2).

Figure 2.

Hepatic ultrasound images at day 36 of life demonstrating dystrophic calcification. (Left panel) Longitudinal view showing multiple hyperechoic foci with characteristic posterior acoustic shadowing in the liver parenchyma, indicative of calcific deposits as post-infective sequelae of dengue hepatitis. (Right panel) Transverse view demonstrating the extent and distribution of dystrophic calcification throughout the hepatic tissue.

Diagnosis

Diagnosis can be confirmed by direct dengue virus isolation, nucleic acid detection, NS1 antigen detection or with indirect tests by checking antibodies. Sensitivity depends on timing and duration of illness. Nucleic acid assay and virus isolation are highly specific but costly and are usually done for early detection in the first week. Immunoglobulin M can be detected as early as 4 days of illness. Diagnosis is confirmed by IgM seroconversion between paired acute and convalescent phase obtained 10 to 14 days after the acute phase. A 4-fold or greater rise in antibody titre is diagnostic of recent dengue infection.

Management Principles

Though there is no specific treatment, early detection and vigorous management helps in reducing morbidity and mortality. Early recognition of immune dysregulation and appropriate management will significantly reduce neonatal morbidity and mortality. Adequate hydration, judicious inotropes, appropriate supportive care and vigilant monitoring lead to uneventful recovery.

Our case demonstrates the use of N-acetylcysteine for dengue-associated hepatitis and methylprednisolone for refractory thrombocytopenia in a preterm neonate.

Conclusion

This case highlights the complete spectrum of hepatic manifestations in neonatal dengue, including severe transaminitis, hyperferritinaemia, prolonged cholestasis and dystrophic calcification as a late sequela. The successful management with N-acetylcysteine for hepatitis and methylprednisolone for refractory thrombocytopenia in a preterm neonate represents novel therapeutic approaches that may benefit future cases. Clinicians should maintain high index of suspicion for vertical dengue transmission in endemic areas and be prepared to manage the multisystem complications, particularly severe hepatic involvement. Long-term follow-up is essential to monitor for late sequelae such as dystrophic calcification.