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2002 Case #10

Epidemiology: Born in Lima but working for the past 5 years as a logging supervisor in remote jungle near Pucallpa on the shores of the Ucayali River (joins the Maranon to form the Amazon river). Takes no malaria prophylaxis and has not received any vaccines since early childhood.

Physical Examination: (on admission to Cayetano Hospital) Temperature 38.8°C. HR 110. Respiratory rate 24. BP 110/70. Agitated, unresponsive to verbal commands. Icteric. Spontaneous bleeding of oral mucosa, and at venepuncture and IV sites. Multiple large ecchymotic areas on all limbs, the trunk and the face (see digital images for representative areas). No lymphadenopathy. Liver felt 3 cm below right costal margin. Marked flap of hands. No focal neurologic signs.

Labs/X-ray: Hematocrit 30. WBC 8,700 with 62 PMN, 4 bands, 28 lymphs. Platelets 110,000. Urine gross hematuria, 3+ proteinuria. BUN 81 mg/dl, Creatinine 1.2. Bilirubin 11.6 (9.2 direct) mg/dl, AST 2890, ALT 2676, Alk P 476. INR 2.6.

Blood cultures negative. Malaria thick film negative X 3. Brucella serology negative. Widal negative. Hepatitis B IgM core negative.

Over the next 3 days the patient developed increasing hepatic encephalopathy, coma, DIC with increasing spontaneous bleeding. On CXR bilateral pulmonary infiltrates compatible with ARDS developed. Repeat lab values on Day 3 showed BUN 120, Creatinine 6.5, AST 100, ALT 200. The patient expired on Day 4.

2002 Case #10
Diagnosis and Discussion

The hallmarks of the full Yellow Fever syndrome include the pathognomonic triad of hemorrhagic fever with jaundice and renal disease. Other viral hemorrhagic fevers may present with either jaundice or with renal disease, but the combination should always suggest yellow fever if there has been appropriate exposure according to the epidemiologic history.

• Dengue hemorrhagic fever is co-endemic in many areas but the pathophysiology is related to increased capillary leakage and illness is usually accompanied by a history of rash at some point in the illness. Hepatitis occurs only occasionally and is mild. Renal involvement does not occur with dengue and the finding of significant proteinuria on a urine dipstick should always suggest yellow fever over dengue even early in the course of the clinical evolution.
• Rift valley fever, like yellow fever, is highly hepatotropic and may be accompanied by renal dysfunction. However, severe cases with hemorrhagic manifestions are <1% of all cases. Rift Valley fever predominates in livestock raising areas of Africa, which don't overlap much with the forested and forest fringe areas where yellow fever occurs.
• Fulminant hepatitis B infection is often a diagnostic consideration in these cases, though proteinuria and renal disease are not usually as severe or common during the earlier stages of disease. Appropriate hepatitis B markers can usually be quickly obtained in settings where they are available.
• Severe icteric leptospirosis (Weil's disease) may be clinically similar to yellow fever although hemorrhagic manifestations are not usually as severe. However, hepato-necrosis is not a hallmark of leptospirosis - there may be dramatic hyperbilirubinemia but hepatic transaminases are no more than 5 times normal levels.

More than 80% of yellow fever infections are symptomatic and the incubation period is usually 3-6 days. After an acute febrile illness with headache and myalgia without rash, that likely represents the peak viremia, there may be a period of remission. Fever may then resume with back pain, nausea, vomiting, mental status changes progressing to the severe clinical syndrome already described above. Black vomitus (hematemesis) is commonly described. In fatal cases death usually occurs 7-10 days into the illness.

Pathologically, yellow fever causes hepatocellular and Kuppfer cell infection. There is mid-zonal hepatocellular necrosis with a minimal inflammatory response. So-called Councilman bodies and microvesicular fatty change is seen. The marked decrease of hepatic transaminases in our patient from 100 times normal to near normal just before death likely represented near total destruction of functioning hepatocytes.

As with other flaviviruses there is no specific treatment for Yellow fever, making prevention by use of 17D yellow fever vaccine (essentially 100% effective) imperative. While most individuals in endemic areas (Amazon basin and sub-saharan Africa) have poor access to vaccines there is dramatic under-use of vaccine by travelers and expatriates. At least 8 unvaccinated short-term travelers to endemic areas have died of Yellow Fever since 1995. Data indicates that the number of unvaccinated travelers visiting risk areas is substantial.