Dengue fever, or break bone fever, is a systemic viral infection, and it is a mosquito-borne disease and an important cause of tropical fever. It manifests in three forms as dengue haemorrhagic fever, dengue shock syndrome which is characterized by severe plasma leakage leading to shock or respiratory distress and dengue with severe organ involvement of liver, heart and kidney defined as expanded dengue syndrome.1,2 These unusual presentations of dengue with organ involvement are usually associated with co-infection, co-morbidities, or complications of prolonged shock. The global burden of dengue is a growing challenge to public health officials and policymakers 2–4. Expanded dengue syndrome is uncommon; however, the increasing geographical reach of dengue and greater adult involvement causing increasingly atypical presentation of dengue fever. 4. Atypical hepatic manifestations include milder forms like acalculous cholecystitis and hepatitis or in severe cases, fulminant hepatic failure. The pathophysiology of hepatitis in severe dengue5,6, is poorly understood. The hepatocytes and Kupffer cells in the liver are prime targets for dengue infection. It could be related to the direct cytopathic effect from the dengue virus causing apoptotic changes, and another postulated mechanism is immune-mediated hepatocyte injury, which causes a dysregulated host immune response via antibody-dependent enhancement and cytokine storm. It results in T cell-mediated destruction of infected hepatocytes. This enhanced immune reaction is believed to be responsible for severe dengue disease. In severe dengue shock syndrome, hepatic hypoperfusion Hepatic hypoperfusion from shock-related microcirculatory dysfunction causes further hepatic injury. Dengue-related acute liver failure has been well described in the paediatric population and less common in adults1,7. The rationale for this study is to address the dramatic and sustained increase in the global burden of dengue, which has led to a rise in atypical and severe clinical presentations, such as expanded dengue syndrome. This is supported by recent data from the World Health Organization (WHO), which reported a historic high of over 14.6 million dengue cases in 2024, surpassing all previous annual records globally.8 The current study details the presentation of a dengue infection with severe hepatitis.

Study Design and Ethical Approval This was a structured, cross-sectional, retrospective medical record review of patients. The study was approved by the Institutional Review Board and was exempted from the requirement for written informed consent due to its retrospective nature and minimal risk to the subjects. Study Setting and Population The study was conducted at a tertiary care academic medical center. All patients admitted with febrile illness between June and August 2024 were included if they met the following criteria: thrombocytopenia, a positive NS1 dengue test, and a positive dengue IgM test. Study Protocol and Data Collection A computerized search of electronic medical records was performed to identify all inpatients during the study period. Patients diagnosed with dengue were included for analysis. Dengue was defined by the presence of clinical symptoms, thrombocytopenia, and organ involvement, supported by laboratory evidence of viral products (NS1 protein) or host immune response (dengue-specific IgM and IgG). Severe dengue hepatitis cases were specifically identified as those with liver enzyme levels (SGOT/SGPT) greater than 1000 IU/L. The following data points were collected for analysis: Demographics: Age, sex, social class, and locality. Clinical Data: Travel history, duration of fever onset, symptoms upon hospital presentation, and disease course. Outcomes: Outcome details were recorded. The primary outcome was 28-day mortality, and secondary outcomes were the length of ICU and hospital stays. Statistical Analysis Descriptive statistics were used to summarize the data. Continuous variables were reported as mean (standard deviation), while binary data were reported as numbers (percentages).

During the study period, 808 patients were admitted with febrile illness, thrombocytopenia, and positive NS1-protein tests; they were from the rural area of Bellary - Koppal - Gadag- Dharwad belt with fever, thrombocytopenia, and deranged liver function tests (LFTs). Among them, 269 tested positive for dengue-specific IgM (Immunoglobulin M). Out of the 112 patients with elevated liver enzymes, 10 were diagnosed with severe hepatitis characterized by SGOT/SGPT levels exceeding 1000 IU/L, and among these, 4 patients had maximum levels greater than 35000 IU/L. Those 10 patients with severe dengue hepatitis were included for analysis. Coagulopathy was present in all ten patients, as evident by raised INR more than 1.5 up to 3.66 (mean INR 2.38), and multi-organ failure, including acute kidney injury (75%) and respiratory failure (60%), was more common. Clinical presentations were vomiting (n=4), abdominal pain (n=4), loose stools (n=2), breathlessness (n=5), bleeding manifestation (n=3), and shock (n=8). Laboratory findings were summarized in Table 1. Management was mainly supportive care, including early judicious fluid resuscitations, monitoring for bleeding complications, and supportive management of organ failure. All patients received an N-acetylcysteine infusion of 100 mg/kg over 24 hours until their liver function was normalized. Blood and blood products were used to optimize coagulation with abnormal bleeding and in cases of large-volume resuscitation with ongoing capillary leak (refractory shock). Other supportive care includes invasive mechanical ventilation (n=6) and renal replacement therapy (n=3). Case 7 with severe ARDS (Acute Respiratory Distress Syndrome) was managed with ECMO (Extracorporeal Membrane Oxygenation), a rarely observed intervention in severe dengue. He was 37 years old with a severe capillary leak leading to ARDS, could not ventilate, was connected to VV-ECMO, and recovered. Case 10: A 27-year-old female is co-infected with Hepatitis B (HBsAG negative and HBcAB positive state) with severe hepatic encephalopathy. Despite aggressive supportive measures, her GCS (Glasgow Coma Scale) remained poor with a high ammonia level. For three consecutive days, the medical team carried out low-volume plasma exchange using frozen plasma with a 1:1 blood volume exchange ratio, followed by sustained low-efficiency dialysis for 10 hours, as her hemodynamics improved and continued for the next 3 days. Subsequently these procedures were deferred in view of her clinical improvement. Outcomes in 6 out of 10 patients were improved, and they were discharged to home with normalized liver function and platelet counts. The survivors had higher platelet counts and lower hepatic enzymes compared to non-survivors. This is shown in Figure 1.

The current study highlights critical insights into the clinical course and management of severe dengue hepatitis in North Karnataka, India. The observed mortality was 40%, similar to the meta-analysis reporting 47% in dengue-associated ALF9. In a retrospective analysis of 199 dengue hepatitis patients by Prajapati et al., dengue hepatitis incidence was 11.9%, and the independent predictor for mortality was the presence of shock at presentation10. Other prognostic markers include coagulopathy (raised INR) associated organ failure (AKI) and hypoalbuminemia. Teerasarntipan et al 9,10 established the Model for End-Stage Liver Disease (MELD) score and INR as a predictor for death in dengue-induced acute liver failure. Infections with a more virulent strain and higher viral load lead to greater hepatic injury, mediated by cytopathic effects, activation of inflammatory cells, and possibly circulatory dysfunction. Liver enzymes rise on the third day of illness, reach a maximum on the 7th day, and are usually normalized around 21 days11. The benefit of N‐acetylcysteine (NAC) treatment in dengue hepatitis has been established in many case series and case studies11 12, by understanding the pathogenesis of dengue hepatitis and NAC, it is suggested to have a hepatoprotective effect; NAC may have helped to recover hepatic dysfunctions, but its clinical efficacy remains under investigation11. In a large series of dengue-infected patients (n=1664), the observed incidence of dengue hepatitis was 11.9% (n=199) with 17% mortality10. A meta-analysis in 2024, encompassing 26,839 dengue-infected patients revealed a pooled incidence of Acute liver failure of 2.0% 13. Patients with severe ARDS in dengue are rare as an early presentation; it may be due to increased vascular permeability and plasma leakage into the lung, which leads to severe ARDS14. Which confirms delayed presentation to hospital considering rural area; in those scenarios, as a recue measures Veno venous ECMO can be considered to bridge recovery. Due to the limitation of specialized service in rural areas, ECMO in dengue was rarely reported. High-volume therapeutic plasma exchange (TPE) in acute liver failure (ALF) has been well established in recent randomized controlled trials with increasing transplant-free survival. The proposed hypothesis related to high-volume plasma exchange in ALF is to remove inflammatory mediators, cytokines, and toxins and replace coagulation factors15. TPE has been attempted successfully16 in dengue hepatitis-associated hyperferritinemia-associated multiple organ failure13 and ALF with hyperammonemia16. The mean days to shock onset in dengue patients were 5 days (4-5 days) and a high vasoactive inotropic score of more than 30 was an important clinical predictor of outcome17. Early detection of dengue Shock is a pivotal for efficient management. Future research should focus on optimizing early diagnostic tools at the community level and therapeutic strategies like early hemodynamic stabilization, NAC infusion therapy, and easy access to ECMO therapy and Plasma exchange therapy to improve outcomes in resource-limited settings. The findings from this study lay the groundwork for several important avenues of future research. The immediate priority is the prospective validation of this marker in a large, diverse, multi-center cohort. This validation study should include patients from a variety of clinical settings, including both urban and rural hospitals, to ensure generalizability. Limitations Owing to the small sample size of 10 patients it was difficult to ascertain a correlation between laboratory parameters between survivors and non-survivors. Therefore, going ahead a larger sample size would be required to establish co-relationship between these parameters. Another limitation is the retrospective design. The study cohort was drawn from two tertiary care referral hospitals, which may introduce a referral bias; these patients may represent a more severe spectrum of the disease. Consequently, our findings may not be fully generalizable to patients managed in primary or secondary care settings or in different geographical regions

Severe dengue hepatitis is a life-threatening complication of dengue fever with high mortality. This study aims to highlight the increasing incidence of dengue presenting as severe hepatitis in northern Karnataka, India, with seasonal spikes. Further, it highlights the clinical challenges and urgent need for advanced intensive care units with trained ICU staff in rural parts of India to manage severe dengue-related complications effectively. Dengue with severe organ failure and ARDS can be safely considered for ECMO. Plasma exchange can be used as a successful treatment strategy with careful selection of patients. Where organ transplant concerns may exist, a plasma exchange trial can serve as a transitional step towards liver recovery. These findings highlight the need for early intervention and robust referral systems in endemic regions; larger studies are required to optimize management protocols in resource-limited settings.

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