History of Thymic Dysfunction and Yellow Fever Vaccination

Conference Coverage by Mary Louise Scully, MD

Synopsis: New information provides updated guidance on assessing the risk of yellow fever vaccine-associated viscerotropic disease (YEL-AVD). Health care providers should carefully weigh the risks and benefits of the vaccine in elderly travelers or any patient, regardless of age, who has a history of thymus disorder or dysfunction, including myasthenia gravis, thymoma, thymectomy, or DiGeorge syndrome.

Source: Barwick Eidex R. Thymus Disease as a Potential Risk Factor for Yellow Fever Vaccine-Associated Viscerotropic Disease. ASTMH Annual Meeting. Miami, FL: Nov 8, 2004; Barwick Eidex R. The Yellow Fever Vaccine Safety Working Group. History of Thymoma and Yellow Fever Vaccination (letter). Lancet. 2004;364:936.

At the 53rd meeting of the American Society of Tropical Medicine and Hygiene in Miami, FL, November 7-11, 2004, Rachel Barwick Eidex of the CDC presented the latest update on the history of thymic dysfunction and risks of yellow fever vaccination. This information was also published in a Lancet September 2004 letter. Yellow fever vaccine-associated viscerotropic (YEL-AVD) and neurotropic disease (YEL-AND) are the newer terms for post-vaccination multiple organ system failure and post-vaccinal encephalitis, respectively. YEL-AVD is a disease that both clinically and histologically, resembles naturally acquired yellow fever. It occurs in primary vaccinees 2-5 days after receiving 17D yellow fever vaccine. Patients develop fever, myalgias, arthalgias, lymphopenia, elevated liver enzymes, sometimes progressing to liver failure, thrombocytopenia, and DIC. Viral dissemination to organs such as liver, lung, spleen, lymph nodes, brain, and muscle has been documented in several cases. As of July 2004, 23 cases of YEL-AVD have been reported worldwide, of which 14 (61%) have been fatal. Advancing age appears to be associated with a higher risk of YEL-AVD, with individuals over 60 years being at greatest risk. In the United States, the reported incidence of YEL-AVD is about 3 cases per million civilian doses of yellow fever vaccine given. A similar incidence of YEL-AVD (2.5 per million doses distributed since 1996) was reported in a UK study.1

Attempts to identify risk factors associated with YEL-AVD are quite challenging because of its low incidence. Of the 23 vaccinees reported to have YEL-AVD, 4 (17%) were found to have a history of thymus disease, suggesting thymic dysfunction as a possible independent risk factor for development of YEL-AVD. The first case was a 67-year-old female from the United States with a malignant thymoma and thymectomy 2 years before vaccination, who subsequently developed fatal YEL-AVD. A second patient, also from the United States, was a 70-year-old man with a history of myasthenia gravis and thymectomy for thymoma 20 years before vaccination who developed YEL-AVD and survived. A third patient from Switzerland had a thymectomy due to thymoma 8 years prior to vaccination and also developed YEL-AVD, but survived. The final patient was a 44-year-old man with a history of thymectomy for benign thymoma 2 years before yellow fever vaccination in Columbia. He developed YEL-AVD with fulminant hepatic failure and died.

The thymus, derived from the Greek word meaning mind, life-force, or soul, is important in the processing and maturation of T-lymphocytes and regulating the integrity of T-cell and B-cell function. At birth, the thymus weighs 12 to 15 grams. It reaches its maximum weight of 40 grams at puberty, then involutes and persists in an atrophic state into old age. These normal changes of the thymus with aging may in part explain the higher risk of YEL-AVD observed in the elderly. The incidence of thymoma is rare (0.15 cases per 100,000 person years), but increases with age older than 40 years up through the age of 80 years.2 Thymic tumors are also associated with various autoimmune disorders, reduced numbers of circulating B lymphocytes, and hypogammaglobulinemia. It was also shown in an animal model that use of antithymocyte serum to induce immune suppression would potentiate lethal yellow fever 17-D infection.3

Yellow fever vaccination for travelers to endemic areas for yellow fever is is an essential role of travel medicine providers. It is estimated that 9 million travelers visit yellow fever endemic countries each year. The risk of illness and death due to yellow fever in an unvaccinated traveler for a 2 week trip to Africa are estimated to be 1:2000 and 1:10,000, respectively.4 The risk of yellow fever will vary with the season of travel, length of exposure, the specific recreational or professional activities of the traveler, and the rate of yellow fever virus transmission at the time. The risk increases dramatically during epidemic periods. However, reporting of human yellow fever cases from endemic areas is often delayed and underestimated, adding to the challenge of assessing risk. The risk of yellow fever in a traveler to South America is less than that for a traveler to Africa, but cases do occur. Three of the 4 travelers from Europe and the United States who became ill with yellow fever during 1996-1999 had traveled to South America.5,6 Proper use of the yellow fever vaccine remains the most effective means to decrease the risk of disease in travelers and residents of endemic countries.

In summary, new data point to thymic dysfunction as an independent risk factor for YEL-AVD. Health care providers should now specifically ask patients about a history of thymus disorder or dysfunction, irrespective of the patient’s age. This should include any history of thymoma, thymectomy, myasthenia gravis, or DiGeorge syndrome (congenitalabsence of thymus and parathyroids). In these patients, yellow fever vaccine should be waived and, if travel to yellow fever endemic areas cannot be avoided, patients should be advised to use other protective measures such as insect repellents containing DEET and permethrin products to avoid mosquito bites. The CDC has updated the Vaccine Information Statement (VIS) for yellow fever vaccine to include a caution about vaccinating persons with a history of thymic disease and is available at www.cdc.gov/nip/publications/VIS/#yf. Physicians in the United States are urged to continue to report any possible adverse events to yellow fever vaccine to the United States Vaccine Adverse Event Reporting System (www.vaers.org) or by telephone, 1-800-822-7967.

References

1. Kitchener S. Viscerotropic and Neurotropic Disease Following Vaccination With the 17D Yellow Fever Vaccine, ARILVAX. Vaccine. 2004;22:2103-2105.

2. Kelleher P, et al. What is Good’s Syndrome: Immunologic Abnormalities in Patients With Thymoma. J Clin Path. 2003;56:12-16.

3. Hirsch MS, et al. Effects of Antithymocyte Serum on 17-D Yellow Fever Infection in Adult Mice. Nature. 1967;216:179-180.

4. Monath T, et al. Prevention of Yellow Fever in Persons Traveling to the Tropics. Clin Infect Dis. 2002;34: 1369-1378.

5. World Health Organization. Yellow Fever 1998-1999. Wkly Epidem Rec. 2000;75:322-327.

6. World Health Organization. Yellow Fever 1996-1997. Part 1. Wkly Epidem Rec. 1998;73:354-359.