Pathophysiologic Correlations in a Rhesus Monkey Model of Yellow Fever

With Special Observations on the Acute Necrosis of B Cell Areas of Lymphoid Tissues

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  • Vector-Borne Diseases Division, Bureau of Laboratories, Center for Disease Control (CDC), Public Health Service, (PHS), U.S. Department of Health and Human Services, Pathology Division, Bureau of Laboratories, CDC, PHS, U.S. Department of Health, Education, and Welfare, Post Office Box 2087, Fort Collins, Colorado 80522

Rhesus monkeys inoculated with yellow fever (YF) (DakH 1279) virus had a predictable course. Death occurred 108–135 hours after infection and was preceded by a 14- to 25-hour period during which clinical signs and physiological changes were present. Viremia was first detected 48 hours after inoculation and peaked at 96 hours. Abnormal liver function (elevated serum bilirubin and transaminases and retention of bromsulfalein) was not detected until approximately 24 hours before, nor hypoglycemia until 8 hours or less before death. Chemical hepatic dysfunction and histopathologic alterations developed precipitously; needle liver biopsies up to 23 hours before death revealed only Kupffer cell changes without hepatocellular degeneration, whereas at necropsy there was coagulative necrosis of the entire liver. Renal function was also not impaired until the terminal 24-hour period, during which urine output diminished, proteinuria, and cylindruria appeared, and serum creatinine rose. A marked fall in 24-hour urinary Na+ excretion was a feature of the early oliguric phase, and needle biopsies of the kidney were normal. At autopsy, there was necrosis of the tubular epithelium and accumulation of cell debris and proteinaceous material in the tubular lumina. These findings suggest that the acute tubular necrosis may be the end result of prerenal hemodynamic alterations and azotemia, and thus be preventable. Acid-base and electrolyte disturbances were late findings. Between 2 and 9 hours before death, arterial pCO2 fell; there followed a modest decline in pH, and systolic and pulse pressures gradually decreased. In the final 1–2 hours, pCO2 rose acutely and severe acidemia, hyperkalemia, and shock developed. These pathophysiologic changes suggest the need to investigate therapeutic countermeasures. No definitive evidence for disseminated intravascular coagulation was obtained in our experiments. An interesting finding was the marked acute necrosis of B cell areas of lymphoid tissues, and further studies are indicated to define possible immunosuppressive effects of YF viral lymphoid injury. The lymphoid necrosis may be diagnostically helpful; examination of spleen and nodes has been overlooked in the histopathologic diagnosis of human YF. Speculations on the possible role of bacterial endotoxemia in the pathogenesis of fatal YF are discussed.

Author Notes

Present address: Division of Nephrology, Department of Internal Medicine, University of Texas Health Science Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235.