Extensive haemorrhagic necrosis of liver is an unpredictable fatal complication in dengue infection: a postmortem study

BMC Infectious Diseases Extensive haemorrhagic necrosis of liver is an unpredictable fatal complication in dengue infection: a postmortem study SAM Kularatne 2 IVB Imbulpitiya 1 RA Abeysekera 1 RN Waduge 0 RPVJ Rajapakse 4 KGAD Weerakoon 3 0 Department of Pathology, Faculty of Medicine, University of Peradeniya , Peradeniya , Sri Lanka 1 Medical Unit, Teaching hospital , Peradeniya , Sri Lanka 2 Department of Medicine, Faculty of Medicine, University of Peradeniya , Peradeniya , Sri Lanka 3 Department of Parasitology, Faculty of Medicine and Allied Sciences, Rajarata University of Sri Lanka , Saliyapura , Sri Lanka 4 Department of Veterinary Pathobiology, Faculty of Veternary Medicine and Animal Science, University of Peradeniya , Peradeniya , Sri Lanka Background: Dengue infection carries a potential risk of death despite stringent management of plasma leak and haemorrhage. It appears that the extent of liver dysfunction determines the outcome. Methods: We present a postmortem study of five patients, died of dengue shock syndrome who had markedly elevated liver enzymes and irreparable circulatory failure. Results: All were females with a median age of 46 years (range 20-50 years). All had positive NS1 and IgM. Clinically, one patient developed severe degree of hepatic encephalopathy whilst three patients developed uncontrollable bleeding manifestations. Dengue virus was detected in three liver specimens by reverse transcription PCR. Histology of the liver revealed massive necrosis with haemorrhages in these patients with evidence of micro and macrovesicular steatosis with significant periportal inflammatory infiltrate. No significant ischaemic changes or necrosis was observed in the other organs. Conclusions: Severe haemorrhagic necrosis of the liver was the cause of death in these patients probably due to direct viral infection. Predilection for severe liver disease remains unknown. Therefore, it is prudent to think beyond plasma leak as the main pathology of dengue infection and attempts should be made to develop other treatment modalities to prevent and manage unforeseen fatal complications of dengue infection. Dengue fever; Liver cell necrosis; Acute liver failure; Autopsy study - Background Dengue fever is an arboviral infection transmitted by mosquitoes of the genus Aedes, which is widely distributed in tropical and subtropical regions of the globe affecting up to 100 million people per year with 2.5 billion people at risk [1]. In Sri Lanka, dengue fever epidemics have been occurring with increased magnitudes but the worst epidemic was reported in 2009 with 35008 cases and 346 deaths of which 6638 cases and 51 deaths reported in the Central Province of Sri Lanka [2]. Dengue infection is caused by a single stranded RNA virus in the family Flaviviridae, which consists of 4 serotypes (DEN 14). Infection with any of the dengue virus serotypes may be asymptomatic in the majority of cases, but in symptomatic cases the severity could vary from * Correspondence: 2Medical Unit, Teaching hospital, Peradeniya, Sri Lanka Full list of author information is available at the end of the article dengue fever (DF) to dengue haemorrhagic fever (DHF) including dengue shock syndrome (DSS) [1]. The virus can infect many organs including liver, described from 1950s [3,4]. Over the years the pathophysiology of dengue virus infection had been extensively studied [5]. Studies suggest that three main systems play an important role in the pathogenesis of DHF/DSS: the immune system, the liver and endothelial cell linings of blood vessels [6]. Increased permeability of microvasculature and plasma leak is supposed to be the main dysfunction that leads to DHF and DSS [6]. With this understanding many management guidelines have been developed totally based on fluid resuscitation, resulting in reduced mortality [7]. Despite these efforts and stringent management, there is still a small proportion of patients die due to severe form of dengue infection all over the world. Severe liver involvement is one of the risk factors identified in patients who die of dengue infection. In general, mild to moderate liver involvement with elevated liver enzymes is common in dengue infection [8] but, acute liver failure and hepatic encephalopathy are rare [9]. Many pathogenic mechanisms have been put forth to explain the liver involvement, but none has been fully conclusive. Therefore, further studies are needed to understand the exact mechanisms of liver damage. The Teaching Hospital Peradeniya (THP) in the hilly Central Province of Sri Lanka maintains a prospective registry of all adult dengue admissions to the hospital since year 2000. The patients are managed according to the guidelines of WHO and the National Guideline of Sri Lanka [7]. The attempts have been made to keep the deaths to the minimum by using stringent fluid management. Yet five patients succumbed to dengue haemorrhagic fever and shock in spite of fluid resuscitation, intensive care and adequate supportive therapy. They all had extensive liver involvement. This necropsy based study aims to describe the extent of liver damage in dengue infection with its impact on the outcome and to think beyond fluid management as the sole treatment. Methods Confirmation of the diagnosis All patients with fever admitted to the Professorial Medical Unit of THP were clinically assessed to identify dengue cases. The confirmation of the diagnosis was made using NS1 antigen in the first few days of fever and using serology later (dengue specific IgM and IgG ELISA). The clinical and laboratory data were recorded in a formatted data sheet and the regular daily assessments were recorded during the hospital stay. Depending on the severity of the infection, frequent monitoring of vital parameters were done and stringent fluid management was carried out. Autopsies were done in all deceased patients. All five cases included in this study presented during the period of year 2011 2013 and they qualified for the diagnosis of dengue infection as they had either positive NS1 antigen or positive serology or they had positive Reverse Transcription Polymerase Chain Reaction (RT-PCR) for dengue in tissues obtained at autopsy. Informed written consent for the autopsy study was taken from the next of kin and complete pathological postmortem was carried out in four cases whereas in one case, only core biopsies of liver, heart and kidneys were taken. This autopsy study is a part of dengue fever studies we are conducting, for which the ethical clearance has been obtained from the Ethics Committee, Faculty of Medicine, University of Peradeniya, Sri Lanka. Written consent for postmortem was obtained from next of kin of all deceased patients. Histopathological study The autopsies were done by a pathologist with advanced experience in autopsy studies with the participation of a member from the medical team. Sections from all organs were sent to Department of Pathology, Facul (...truncated)