A 75-year-old white male resident of Indiana received yellow fever 17D vaccination on November 29, 1973, in anticipation of a trip to South America. Six days later he developed flu-like symptoms, with fever, chills, myalgia, nausea, vomiting, mild sore throat, and abdominal pain. He was seen by a physician who noted a temperature of 100°F and prescribed penicillin and an analgesic. The next day, the patient became confused and did not take food or fluids. He was admitted the following day (8 days after vaccination) to Parkview Memorial Hospital, Ft. Wayne, IN. Past history was remarkable for an admission to the hospital 6 weeks earlier with lassitude, pallor, peripheral edema, anemia (hemoglobin 6.6 gm/dL), low serum iron, folate, and B12, diagnosed as pernicious anemia. During that admission he had been noted to have mild hepatosplenomegaly, and a slightly elevated bilirubin of 1.4 mg/dL. On the day of the current admission, the patient was found to be moderately obese, lethargic, acutely ill, and complaining of abdominal pain. The temperature was 98.6°F, pulse 120, and blood pressure 84/48. The face appeared swollen, mucus membranes were dry, the abdomen protuberant and generally tender, with liver and spleen palpable on deep inspiration. Serum urea nitrogen (BUN) was 140 mg/dL, glucose 116 mg/dL, total bilirubin 4.4 mg/dL, albumin 2.6 g/dL; alkaline phosphatase, calcium, and phosphorus normal.
On the day after admission, he was admitted to the intensive care unit because of hypotension and deteriorating mental status. The blood pressure was 60/40, temperature 102°F, urine output minimal, and sensorium obtunded. The BUN was 190 mg/dL, creatinine 7.8 mg/dL, bilirubin 5.5 mg/dL (4.2 direct), SGPT 102 U/L, alkaline phosphatase 93 U/L, hematocrit 46.7%, platelets 46,000, white blood cell (WBC) count 13,800/mm3 with 66% polymorphonuclear cells, 3% bands, 31% lymphocytes. Urinalysis showed 12–15 WBC, 50–60 red blood cells, 3–4 renal epithelial cells, 2 + albumin. The patient was thought to be in acute renal failure, dehydrated, and to have significant hepatic dysfunction. His condition deteriorated, with progression from delirium to coma. His temperature, BUN, creatinine, and WBC remained elevated. Bilirubin increased to 11.2 mg/dL (9.4 direct). He developed a consumption coagulopathy with thrombocytopenia (40,000/mm3), prolonged prothrombin time (15.4 seconds, 11.4 seconds control) and partial thromoboplastin (66.0 seconds, 31.9 control), and positive fibrin split products, but did not develop overt bleeding. He was treated with corticosteroids, mannitol, heparin, furosamide, and vasopressors. The electrocardiogram (EKG) showed low voltage and peaked T waves in V1–V6. Chest x-ray showed fluid in the right pleural space and congestion. The patient died 3 days after admission (11 days after vaccination). On autopsy, gross anatomical findings included diffuse, focal necrosis of the liver, atrophic gastritis of the stomach, lipid depletion of the adrenal glands, and congestion of both lower lobes of the lung.
A number of experts evaluated the liver histopathology, including Drs. Kamal G. Ishak (Armed Forces Institute of Pathology), Ruth Kirschstein (NIH/FDA), Wilbur G. Downs (Yale Arbovirus Research Unit), Augusto Gast Galvis, head of the yellow fever viscerotomy service, Bogota Colombia, Frederick A. Murphy (Colorado State University), and myself. The findings included focal single cell necrosis, scattered acidophilic degeneration, marked areas of hepatocellular unrest, marked Kupffer cell hypertrophy, cholestasis, and fatty degeneration. The distribution of lesions was not mid-zonal, and for that reason the changes were not considered caused by yellow fever. A fluorescent stain of the frozen liver was negative for yellow fever antigen and fixed liver tissue was examined by electron microscopy and found negative.
The patient, a 31-year-old African-American female Maryland resident, was admitted to George Washington University Hospital, Washington, DC in June, 1978, 5 days after having received yellow fever 17D (Merrill National Lot 1873GK) and smallpox vaccinations in anticipation of travel. Three days after vaccination, she had sudden onset of fever to 103°F, myalgia, headache, chills, constipation, nausea, and vomiting, and also had swelling, pain, and stiffness at the site of her yellow fever (but not the smallpox) vaccination. On admission to the hospital, she was acutely ill, with temperature of 105°F, blood pressure 110/60, pulse 84, and respirations 20. Her physical exam was unremarkable. The WBC was 8,400 cells/mm3 with a striking left shift (91% polymorphonuclear cells, 5% bands, 2% lymphocytes, 2% monocytes) raising the suspicion of a bacterial infection. She was anemic (hematocrit 28.4%). Electrolytes were normal, BUN was slightly elevated but creatinine was normal (0.9 mg/dL). There was 1–2 + protein in urine, mildly elevated amylase, and the aspartate aminotransferase (SGOT) was elevated (107 U/L). Her anemia was believed caused by a long history of metrorrhagia.
Over the next 7 days in the hospital, the patient continued to run a high fever and required a hypothermia blanket to maintain her temperature between 100 and 102°F. She was treated with intravenous hydration and antiemetics. She experienced shaking chills, severe headache, abdominal pain, nausea, and muscle aches, and at times was obtunded. Her liver became palpable and was tender. She was unable to eat until the sixth hospital day. Her liver enzymes rose to a peak SGOT of approximately 800 U/L, SGPT 542 U/L, and LDH 775 U/L. Coagulation tests were normal. She did not become jaundiced, and her maximum total bilirubin was 1.6 mg/dL. Liver scan showed inhomogeneous uptake but was considered “probably normal”; spleen scan and abdominal ultrasound were unremarkable; blood cultures, febrile agglutinins, and mono spot test were negative. Blood obtained 6 days after onset was cultured for virus at the National Institiutes of Health (NIH) and found negative. A liver biopsy was performed on the fifth hospital day (10 days after vaccination), and was abnormal, showing significant diffuse microvesicular steatosis, liver cell drop-out, Kupffer cell prominence, scattered Councilman bodies, increased intracellular bile staining, without inflammation or midzonal distribution. The liver was sent to Walter Reed Army Institute for Research and immunofluorescent staining performed with yellow fever antibody; results were negative. The patient improved during the second week after admission, liver enzymes normalized and symptoms dissipated. She was discharged 14 days after admission, with a diagnosis of “Viremia non-defined following yellow fever immunization, with hepatocellular inflammation, prolonged high fever.”
During the course of her hospitalization, consultations were held with hospital specialists (gastroenterology, infectious disease) and with outside experts including Drs. Karl Kappus (CDC), Paul Albrecht (NIH/FDA), and William Bancroft (WRAIR). The consultants all noted that “…the illness was consistent with yellow fever…,” but that “…there was no previous known vaccine-induced case of yellow fever.…” The microvesicular steatosis in liver biopsy was thought to be unusual and a feature favoring a diagnosis of yellow fever. Two years later, in 1980, Dr. Kappus referred the records on this patient to the present author, who responded that “The case … is fascinating, and I find it hard to believe (it is) unrelated to the 17D yellow fever vaccination. …Failure to isolate yellow fever virus so late in the course means little. To my knowledge, no one has investigated yellow fever vaccinees with febrile ‘reactions’ to see whether the fever reflects hepatic dysfunction and some residual viscerotropism of the vaccine. This woman might simply be far off on the severe end of the spectrum of febrile reactions with chemical hepatic dysfunction induced by yellow fever vaccine…”