In June 2001, seven cases of yellow fever
vaccine-associated viscerotropic disease (YEL-AVD)
(previously called multiple organ system failure) in
recipients of 17D-derived yellow fever vaccine (YEL)
were reported to the Advisory Committee on Immunization
Practices (ACIP).[1-3] ACIP reviewed the
cases, recommended enhanced surveillance for adverse
events, and updated the ACIP statement on YEL.
This report summarizes the preliminary surveillance
findings, including two new suspected cases of YEL-AVD
and four suspected cases of YEL-associated neurotropic
disease (YEL-AND) (previously called postvaccinal
encephalitis). Although YEL remains essential for
travelers to areas in which yellow fever (YF) is endemic
(Figure), these findings underscore the need for
continued enhanced surveillance and timely clinical
assessment of YEL-associated disease.
The Vaccine Adverse Event Reporting System (VAERS) receives reports of
adverse events following licensed vaccine administration
in the United States. Enhanced
surveillance for YEL adverse events was initiated in
June 2001 and includes soliciting reports from
health-care providers at certified YF-vaccination
clinics and reviewing all VAERS case reports of febrile
illness associated temporally with YEL (i.e., illness
onset </=30 days following receipt of YEL). During June
20, 2001-August 31, 2002, a total of 117 reports of
adverse events following YEL administration were
reported compared with 104 reports during a comparable
period in 2000-2001. Of the 117 reports, six cases of
persons with severe adverse events consistent with YEL-AND
or YEL-AVD were reported. All six patients were
vaccinated in the United States with 17D-derived YEL,
required hospitalization, and recovered without sequelae.
The first case was reported initially as nonserious in
May 2001 but was reclassified after the enhanced
surveillance system was in place.
Case 1. On April 27, 2001, a man aged 25 years
received YEL and influenza and poliovirus vaccines in
preparation for travel to North Africa, Israel, Turkey,
and Ecuador. One day after vaccination, he had
lymphadenopathy, headache, and malaise; 2 days later, he
reported nausea, diarrhea, diaphoresis, and fever. Nine
days after vaccination, he was hospitalized with a
fulminant illness characterized by fever of 101.6° F
(38.7° C) and acute hepatic and renal failure (Table).
The next day, he had hypotension and respiratory failure
requiring resuscitation, vasopressors, dialysis, and
mechanical ventilation. No bacterial pathogens were
identified from urine, blood, or stool specimens. A
toxicology screen was negative. After 24 days of
hospitalization, he recovered and was discharged. No
acute-phase serum or tissue samples for viral isolation
or polymerase chain reaction (PCR) were obtained.
Convalescent-phase serum samples collected 351 days
after vaccination demonstrated a YF-neutralizing
antibody titer of 1:640.
Case 2. On March 28, 2002, a man aged 70 years
received YEL in preparation for travel to Venezuela. He
had fever, dyspnea, myalgia, and malaise 5 days after
vaccination; 3 days later, he was hospitalized because
of fever, thrombocytopenia, and elevated hepatocellular
enzymes, bilirubin, and creatinine (Table).
He subsequently became hypotensive and was intubated for
respiratory failure. Hyponatremia developed and dialysis
was required for renal failure. Blood and urine cultures
were negative for bacteria, fungi, and viruses. Serum
collected on hospital days 21, 25, and 33 and pleural
fluid collected on day 26 were negative by real-time,
quantitative PCR (TaqMan®) with consensus
flavivirus primers and viral culture. Serum collected on
hospital day 26 had a neutralizing antibody titer of
1:1,280. After a 41-day hospitalization, he recovered
and was discharged.
Case 3. On September 17, 2001, a man aged 36
years received YEL in preparation for travel to Brazil.
He had diaphoresis, fever of 102.2° F (39.0° C), rigors,
and headache 13 days after vaccination; 16 days after
vaccination, he lost consciousness and was hospitalized
with severe headache and fever of 106.0° F (41.1° C) (Table).
Examination of cerebrospinal fluid (CSF) revealed 406
white blood cells per mm3 (WBC/mm3)
(predominantly lymphocytes) and elevated protein. Blood,
urine, and CSF cultures were negative for bacteria,
fungi, and viruses. YF-specific IgM-capture ELISA
(MAC-ELISA) of CSF was strongly positive (Table).
CSF viral testing by TaqMan® and viral
culture was negative. Additional MAC-ELISA results were
negative for Eastern equine encephalitis, St. Louis
encephalitis, West Nile encephalitis, and La Crosse
encephalitis viruses. After a 5-day hospitalization, he
recovered and was discharged.
Case 4. On October 4, 2001, a man aged 71
years received YEL and typhoid and hepatitis A vaccines
in preparation for travel to Guatemala. He had fever and
malaise 6 days later; 13 days after vaccination, he
became confused, had expressive aphasia, and was
hospitalized with fever of 101.1° F (38.4° C). He had
leukocytosis but normal hepatocellular enzymes. CSF had
137 WBC/mm3 and elevated protein. CSF
YF-specific IgM testing by MAC-ELISA was positive (Table);
viral testing by TaqMan® and viral culture
was negative. CSF was negative for herpes viruses,
flaviviruses, and enteroviruses. After a 7-day
hospitalization, he recovered and was discharged.
Case 5. On February 7, 2002, a man aged 41
years received YEL and hepatitis A vaccine in
preparation for travel to Venezuela. Six days after
vaccination, he had low-grade fever, headache, and
myalgia, which worsened over several days; 16 days after
vaccination, he was hospitalized with fever of 104.0° F
(40.0° C), headache, and rigors. CSF had 63 WBC/mm3
(predominantly mononuclear) and elevated protein.
Hepatocellular enzymes were normal (Table).
Bacterial and fungal cultures of blood and CSF and CSF
cryptococcal antigen were negative. CSF enteroviral
testing and Leptospira serology were negative.
CSF YF-specific IgM testing by MAC-ELISA was strongly
viral testing by TaqMan® and viral culture
was negative. After 5 days, he recovered and was
Case 6. On May 17, 2002, a boy aged 16 years
received YEL in preparation for travel to South America;
23 days after vaccination, he had left-arm numbness,
inability to speak, loss of right-side fine motor
control, expressive aphasia, and severe dysarthria.
Magnetic resonance imaging showed diffuse, bilateral,
white-matter disease; CSF examination was normal.
MAC-ELISA YF-specific IgM tests on CSF collected 26 days
after vaccination were strongly positive (Table);
CSF tests by TaqMan® with consensus
flavivirus primers and viral cell culture were negative.
Tests for Rocky Mountain spotted fever, herpes simplex,
multiple sclerosis, lupus, autoimmune diseases, and
metabolic enzyme deficiencies were negative.
Reverse-transcriptase PCR with primers for Colorado tick
fever was negative; serum collected 4 months after
illness onset did not contain neutralizing antibodies
for that virus. No bacteria or fungi were cultured from
CSF. The patient was afebrile throughout his illness and
was discharged after a 3-day hospitalization.
Reported by:S Levy, MD, Saint Agnes Medical
Center, Fresno, California. K Mullane, DO, Loyola Univ
Medical Center, Maywood, Illinois. M Miller, MD, Albany
Medical College; S Siva, MD, Albany Medical Center
Hospital, Albany, New York. D Barnes, MD, Southview
Medical Group, Birmingham, Alabama. P Dhaliwal, MD,
Brandon Regional Hospital, Brandon, Florida. SC Tiwari,
MD, St. Dominic-Jackson Memorial Hospital, Jackson,
Mississippi. KG Julian, MD, Hershey Medical Center,
Hershey, Pennsylvania. Epidemiology and Surveillance
Div, National Immunization Program; Div of Vector-Borne
Infectious Diseases; Div of Global Migration and
Quarantine, National Center for Infectious Diseases; EIS