For personal use. Only reproduce with permission from The Lancet Publishing Group. Summary Background In 1998, the US Centers for Disease Control and Prevention was notified of three patients who developed severe illnesses days after yellow fever vaccination. A similar case occurred in 1996. All four patients were more than 63 years old. Methods Vaccine strains of yellow fever virus, isolated from the plasma of two patients and the cerebrospinal fluid of one, were characterised by genomic sequencing. Clinical samples were subjected to neutralisation assays, and an immunohistochemical analysis was done on one sample of liver obtained at biopsy. Findings The clinical presentations were characterised by fever, myalgia, headache, and confusion, followed by severe multisystemic illnesses. Three patients died. Vaccine- related variants of yellow fever virus were found in plasma and cerebrospinal fluid of one vaccinee. The convalescent serum samples of two vaccinees showed antibody responses of at least 1:10 240. Immunohistochemical assay of liver tissue showed yellow fever antigen in the Kuppfer cells of the liver sample. Interpretation The clinical features, their temporal association with vaccination, recovery of vaccine-related virus, antibody responses, and immunohistochemical assay collectively suggest a possible causal relation between the illnesses and yellow fever vaccination. Yellow fever remains an important cause of illness and death in South America and Africa; hence, vaccination should be maintained until the frequency of these events is quantified. Lancet 2001; 358: 98–104 See Commentary page 84 Introduction Yellow fever is an acute febrile illness caused by a mosquito-borne flavivirus transmitted in much of tropical South America and sub-Saharan Africa. Case-fatality rates have ranged from 20 to 50%, with a higher risk among older age-groups in some outbreaks. 1–5 The disease can be prevented by a live, attenuated vaccine, prepared from the 17D strain of yellow fever virus, that induces seroconversion in more than 95% of recipients and provides immunity for 30 years or longer. 6,7 Yellow fever vaccine has been incorporated into routine vaccination programmes in South America, but in Africa, coverage rates are low and the vaccine is distributed mainly on an emergency basis to control outbreaks. The vaccine is also used to protect international travellers who visit yellow fever endemic and epidemic zones, and military personnel in several countries including the USA. The recommendation for universal vaccination of travellers to yellow-fever-endemic zones (except for infants younger than 9 months) was drawn up on the basis of presumptive risk of yellow fever infection and the vaccine’s record of safety. 8 In 1998, the US Centers for Disease Control and Prevention received three reports of severe illness in elderly residents of the USA with onset days after immunisation with yellow fever vaccine; two of the patients died. An additional case of severe illness and death after yellow fever vaccination was reported to the US Vaccine Adverse Events Reporting System in 1996. We describe these four cases in this paper. Patients and methods Patients The first case was a 76-year-old man who presented to hospital in April, 1998, with a 3-day history of fever, myalgias, headache, and fatigue. He had received yellow fever vaccine (YF-vax, Connaught, Swiftwater, PA, USA) and oral typhoid vaccine (Vivotif Berna, Swiss Serum and Vaccine Institute, Berne, Switzerland) 7 and 28 days before admission, respectively. He was preparing for a trip to Nepal and Thailand—neither of which is in a yellow-fever-endemic zone. The patient had a history of mild renal insufficiency, degenerative joint disease, and Crohn’s disease in remission since 1945. He was otherwise healthy and exercised daily. On presentation, his temperature was 38·1ºC, and physical examination was unremarkable. Chest roentgenogram showed a slightly increased heart size with no infiltrates or effusions. An abdominal computed tomography scan revealed small bilateral pulmonary effusions, and a normal liver, spleen, pancreas, and kidneys. Table 1 shows the laboratory results. On the second hospital day, 9 days after vaccination, his blood pressure dropped to 60/40 mm Hg, he became anxious, and complained of shortness of breath. An arterial blood gas on room air showed a pH of 7·26, carbon dioxide partial pressure of 27 mm Hg, and oxygen partial pressure of 62 mm Hg. Results of repeat chest roentgenogram and electrocardiogram were unchanged. ARTICLES 98 THE LANCET • Vol 358 • July 14, 2001 Fever and multisystem organ failure associated with 17D-204 yellow fever vaccination: a report of four cases Michael Martin, Theodore F Tsai, Bruce Cropp, Gwong-Jen J Chang, Derek A Holmes, Jennifer Tseng, Wun-Ju Shieh, Sherif R Zaki, Ibrahim Al-Sanouri, Anthony F Cutrona, Glenn Ray, Leisa H Weld, Martin S Cetron Divisions of Global Migration and Quarantine (M Martin MD, L H Weld PhD, M S Cetron MD), Vector-Borne Infectious Diseases (T F Tsai MPH, B Cropp MSc, G-J Chang PhD, D A Holmes BSc, J Tseng), and Infectious Disease Pathology (W-J Shieh MPH, S R Zaki PhD), National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA; Division of Infectious Diseases, Emory School of Medicine, Atlanta (M Martin); Department of Internal Medicine, Western Reserve Care System, Youngstown, OH (I Al-Sanouri MD, A F Cutrona MD); and Family Medical Center, Western Reserve Care System, Youngstown, OH (G Ray MD) Correspondence to: Dr Martin S Cetron, Division of Global Migration and Quarantine, National Center for Infectious Diseases, Centers for Disease Control and Prevention, MS-E03, 1600 Clifton Road, Atlanta, GA 30333, USA (e-mail: MCetron@cdc.gov)