BLOG: 54-year-old female with Dengue fever

Steven Krawitz, MD, is currently a third year fellow in the 3-year combined gastroenterology and advanced transplant hepatology fellowship at Thomas Jefferson University Hospital. He completed his undergraduate education at Johns Hopkins University in Baltimore. He then completed his medical school and internal medicine training at Thomas Jefferson University in Philadelphia.

Case

A 54 year-old female with past medical history significant for diabetes and hypertension was transferred from an outside hospital to our institution for further care of elevated liver function testing and acute change in mental status. Given a language barrier and the patient’s altered mental status, most of her history was obtained from her family as well as through review of records from the transferring hospital.

Steven Krawitz

Her family reports 3 days of progressive fatigue, lethargy, myalgias, and nausea with vomiting. They report the patient had been in her normal state of health while enjoying a trip to Pakistan until the night after returning home. They endorse subjective fevers and chills. They deny any sick contacts at home but report some family members in Pakistan had a brief mild illness while she was visiting. They deny any significant alcohol or substance abuse, and deny any family history of significant illness. The patient was born in Pakistan, however has been living in the United States since 2010.

On exam the patient is febrile at 100.6 F, pulse is 101, blood pressure is 101/51, and respiratory rate is 28 with oxygen saturation 95% on room air. In general she appeared to be in mild distress. She had scleral icterus. Her oropharyngeal exam was normal without lymphadenopathy. The patient was tachypnic but lungs were clear to auscultation bilaterally. Cardiac exam was unremarkable. Abdominal exam showed mild distention without tenderness to palpation or evidence of fluid wave. Peripheral exam showed marked anasarca. Skin examination was notable for scattered petechiae but no rash.

The patient’s blood count was notable for anemia with a hemoglobin of 8.5 g/dL and thrombocytopenia of 34 B/L with a bandemia and lymphopenia. She had an acute kidney injury with a creatinine of 2.3 mg/dL. Liver function testing on day of admission were as follows: protein 6.5 g/dL, albumin 3.1 g/dL, total bilirubin 6.6 mg/dL, direct bilirubin 5.3 mg/dL, AST 10705 IU/L, ALT 1924 IU/L, and alkaline phosphatase 208 IU/L. INR was elevated at 2.44 sec. Lactate was 28 mmol/L. Hepatitis panel was negative for hepatitis A, B, and C as were autoimmune serologies. Salicylate and acetaminophen levels were undetectable. Blood cultures and parasitic exam were negative. Abdominal ultrasound showed diffuse hepatic change consistent with fatty infiltration with a normal Doppler vascular exam.

Chest X-ray is shown in Figure 1. Patient underwent transjugular liver biopsy with resultant pathology shown in Figures 2 and 3.

Figure 1: Chest X-ray

Figures 2, 3: Liver biopsy pathology

Hepatocyte necrosis (H&E, 40X)

Zone 1 steatosis (H&E, 20X)

The patient’s hospital course was complicated by ventilator dependent respiratory failure, seizures, renal failure requiring dialysis, fulminant liver failure non-responsive to MARS, several ischemic cardiovascular accidents, and pneumonia culminating in severe sepsis which ultimately the patient succumbed to. On day number 7 of her hospital course her testing confirmed acute infection with Dengue fever by PCR and serology for strain 1 or 3.

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Discussion

Dengue is an RNA virus first discovered in 1779 with a genome that encodes ten distinct proteins. The virus belongs to the Flavivirus genus and has four different serotypes. The infectious vector is via mosquito; typically the Aedes aegypti. Worldwide, Dengue fever is the most prevalent mosquito-borne viral illness and is recognized in over 100 different countries with a reported 50 to 100 million cases yearly.

Viremia typically develops 2 to 6 days after exposure and lasts for 3 to 6 days. Viremia is detectable 6 to 18 hours before symptom onset and typically resolves with fever resolution. Antibody response and protective effect is serologic specific with waning immunity to other serotypes. The risk of severe disease is higher in secondary infection than primary which is partly explained by the concept of antibody-dependent enhancement.

Neutralization of virus requires a threshold level of antibodies. Below this threshold cellular uptake of antibody bound virus is paradoxically increased up to 100-fold and can lead to more severe infection. Patients previously exposed to the virus might have a low level of antibodies present at the time of re-infection predisposing them to this phenomenon. Other risk factors for severe disease include: Dengue serotype 2, secondary infections, younger age, better nutritional status, and Caucasian race.

Classic Dengue infection presents as an acute febrile illness with headache, retro-orbital pain, myalgias, and joint pain (which explains the moniker “break bone fever”). The typical course consists of 5-7 days of fever with post-resolution fatigue. Associated symptoms include rash, nausea, vomiting, diarrhea, cough, congestion, and hemorrhage in severe cases.

The World Health Organization criteria defining Dengue Hemorrhagic Fever (DHF) include: increased vascular permeability, marked thrombocytopenia (<100,000), fever lasting two to seven days, and hemorrhagic tendency. Dengue shock syndrome (DSS) consists of the above criteria in addition to systemic shock usually from plasma leakage and carried a 12% mortality.

As in the above case, liver failure and central nervous system dysfunction including seizures can complicate severe DHF, although acute liver failure is uncommon. The mechanism of liver injury is unclear, although the virus can be cultured form hepatocytes which supports the common theory of direct viral damage. There may be a bystander immune injury effect as well. The typical pattern of hepatic injury is hepatocellular and pathology usually shows hepatocellular necrosis and Councilman bodies with little inflammatory infiltrate and steatosis as seen above. Treatment is mostly supportive with aggressive hydration and intensive care when needed as well as avoidance of the disease vector mosquitos.

Acknowledgements: Wei Jiang, MD, Thomas Jefferson University Hospital Pathology Department.

References:

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Parkash O, et al. BMC Gastroenterol. 2010;10:43.

Souza LJ, et al. Braz J Infect Dis. 2004;8:156-163.