Fatal Yellow Fever in a Traveler Returning from Venezuela, 1999

On September 28, 1999, a previously healthy 48-year-old man from California sought care at a local emergency department (ED) and was hospitalized with a 2-day history of fever (102 F [38.9 C]), chills, headache, photophobia, diffuse myalgias, joint pains, nausea, vomiting, constipation, upper abdominal discomfort, and general weakness. On September 26, he had returned from a 10-day trip to Venezuela. On September 29, an infectious disease physician from the ED contacted the Marin County Health Department (MCHD) about the patient's symptoms; MCHD reported his illness to the California Department of Health Services (CDHS) as a suspected case of viral hemorrhagic fever. This report describes the investigation of the case.

On admission to the hospital, physical examination revealed icteric sclerae and tenderness in the upper abdomen. Multiple red papular lesions with excoriations consistent with recent mosquito bites were seen on his lower legs and feet. No hepatosplenomegaly or lymphadenopathy was noted. Laboratory results indicated markedly elevated serum bilirubin (5.9 mg/dL) and liver enzymes (alanine aminotransferase: >5000 U/L; aspartate aminotransferase: >3750 U/L; and alkaline phosphatase: 194 U/L), leukopenia (white cell count: 3.4x10³/mm³ with 82% segmented, 2% bands, and 2% atypical lymphocytes), thrombocytopenia (platelet count: 77,000/mm³), and evidence of acute renal failure (creatinine: 5.9 mg/dL; potassium: 6.4 mmol/L; and bicarbonate: 16 mmol/L).

A preliminary diagnosis of hemorrhagic fever syndrome was made, and the patient was placed on doxycycline and ceftriaxone. Cultures of blood and urine were negative for bacterial pathogens. Blood smears for malaria were negative. On October 1, the patient developed general seizures and upper respiratory obstruction. He was placed on mechanical ventilation and transferred to the intensive care unit. His condition deteriorated rapidly, with severe coagulopathy and cardiac arrhythmias. He died on October 4.

On October 7, an autopsy of the chest and abdomen was performed at the University of California San Francisco Medical Center. Histopathologic examination of the liver showed extensive necrosis, steatosis, and numerous Councilman bodies compatible with fulminant yellow fever (YF) hepatitis. Evidence of disseminated angioinvasive aspergillosis involving the lungs, heart, kidneys, adrenal glands, small and large bowel, stomach, and disseminated intravascular coagulation also was seen. Specimens of the liver were examined at CDC; YF viral antigens were found by immunohistochemistry (IHC) and YF virus-specific nucleic acids by polymerase chain reaction. Other IHC tests were negative for dengue virus, leptospira, New World arenaviruses, spotted fever group rickettsiae, and hantavirus. The patient's serum was tested by CDHS; no antibody to YF virus (17D) was detected by immunofluorescence in serum drawn September 28, but an IgG titer of 1:128 and an IgM titer of >1:80 were detected in serum drawn October 1.

During September 16--25, the patient had traveled with six companions to rainforests in southern Venezuela (Amazonas State). He experienced multiple mosquito bites during his visit despite using DEET-based repellents. Before his trip, the patient had received tetanus toxoid, typhoid vaccine, hepatitis A vaccine, and malaria prophylaxis, but not YF vaccine. The six travel companions were contacted by CDHS about their health and vaccination status; none had become ill during or following the trip. Five had received YF vaccine before travel. The unvaccinated traveler's serum was negative for YF virus antibody tested at CDC by enzyme-linked immunosorbent assay.

Reported by: F Schwartz, MD, Marin County Health Dept, San Rafael; F Drach, MD, ME Guroy, MD, San Rafael; J Olson, MD, J Rabban, MD, H Sanchez, MD, Univ of California San Francisco, San Francisco; MS Ascher, MD, CA Glaser, MD, SB Werner, MD, DJ Vugia, MD, Acting State Epidemiologist, California Dept of Health Svcs. Infectious Disease Pathology Activity, Div of Viral and Rickettsial Diseases; Arbovirus Diseases Br, Div of Vector-Borne Infectious Diseases; Surveillance and Epidemiology Br, Div of Quarantine, National Center for Infectious Diseases; and an EIS Officer, CDC.

Editorial Note:

This report describes the second case of imported fatal YF in a U.S. resident returning from South America since 1996, and the first such cases since 1924. Neither patient had received YF vaccine before travel. In the case described in this report, viral hemorrhagic fever was suspected and reported to the local health department. Histopathology, IHC studies, nucleic acid testing, and serology all demonstrated that the traveler died of YF complicated by angioinvasive aspergillosis. In 1996, a Tennessee resident returned from a 9-day trip to Brazil with fever, headache, and myalgias (1). He died 10 days after onset of symptoms, and YF virus was identified from tissue culture.

YF occurs in at least seven tropical South American countries (Bolivia, Brazil, Colombia, Ecuador, French Guiana, Peru, and Venezuela) and much of sub-Saharan Africa (2). The sylvatic cycle involves nonhuman primates and mosquitoes that breed in tree holes (3). Persons living or working in proximity to such jungle or forest habitats who are bitten by infected mosquitoes can develop "jungle YF." Another cycle exists between humans and Aedes aegypti mosquitoes. Ae. aegypti mosquitoes are present in most urban centers of South and Central America, the Caribbean, and parts of the southern United States; persons in these areas are at risk for urban YF infection. YF has not been reported from India or other parts of Asia despite the presence of Ae. aegypti (4).

World Health Organization (WHO) data suggest that YF transmission is increasing (4,5). After adjustments for underreporting, WHO estimates that approximately 200,000 YF cases occur each year, most in sub-Saharan Africa (4). Concomitant with increased YF transmission, the number of travelers from the United States to South America and Africa has more than doubled since 1988 (6). These travelers may be at risk for YF unless precautions are taken, including receipt of YF vaccine.

YF is one of three diseases (the others are plague and cholera) subject to international quarantine regulations (7). CDC is required to notify WHO of all YF cases in the United States within 24 hours. Accordingly, all suspected and confirmed cases should be reported immediately through local and state health departments to CDC's National Center for Infectious Diseases, Division of Quarantine (DQ), telephone (404) 639-8100; acute and convalescent-phase serum should be collected and sent for viral isolation and diagnosis to CDC's National Center for Infectious Diseases, Division of Vector-borne Infectious Diseases, telephone (970) 221-6400. CDC's DQ also is responsible for certifying YF vaccination centers in the United States. Since September 1, 1977, CDC has delegated to state and territorial health departments the responsibility to designate and supervise nonfederal YF vaccination centers within their jurisdictions. The location of certified U.S. YF vaccination centers is available from local and state health departments. If YF vaccine is medically contraindicated, health-care providers should supply persons with a letter listing reasons for not vaccinating, and persons should carry this with them when traveling. Details of vaccine recommendations and requirements of individual countries are available from the CDC World-Wide Web site, http://www.cdc.gov/travel (2).

CDC recommends YF vaccination for travelers to countries reporting YF (2). Vaccination also is recommended for travel outside urban areas of countries that officially do not report the disease but are in the YF-enzootic zone. Travelers should also take protective measures to reduce contact with mosquitoes; these include wearing clothes that cover most of the body, staying in well-screened areas, using insect repellent (containing DEET at a concentration of <35% are recommended) on exposed skin and clothing, and sleeping under bed nets treated with permethrin or deltamethrin insecticides.

References

1. McFarland JM, Baddour LM, Nelson JE, et al. Imported yellow fever in a United States citizen. Clin Infect Dis 1997;25:1143--7.
2. CDC. Health information for international travel 1999--2000. Atlanta, Georgia: US Department of Health and Human Services, 1999. Available at http://www.cdc.gov/travel.
3. Monath TP. Yellow fever. In: Plotkin SA, Orenstein WA, eds. Vaccines. 3rd ed. Philadelphia, Pennsylvania: WB Saunders, 1999:815--79.
4. Robertson SE, Hull BP, Tomori O, Bele O, LeDuc JW, Esteves K. Yellow fever: a decade of reemergence. JAMA 1996;276:1157--62.
5. World Health Organization. Yellow fever, 1996--1997. Wkly Epidemiol Rec 1998;73:354--9.
6. International Trade Administration. U.S. resident travel to Canada, Mexico and overseas countries historical visitation outbound----1988--1998. Available at: http://www.tinet.ita.doc.gov/research/reports/basic/national. Accessed April 12, 2000.
7. World Health Organization. International health regulations (1969): third annotated edition. Geneva, Switzerland: World Health Organization, 1983:10--2.

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