Advanced age a risk factor for illness temporally associated with yellow fever vaccination. (Research).
In 1998, the Centers for Disease Control and Prevention Centers for Disease Control and Prevention (CDC), agency of the U.S. Public Health Service since 1973, with headquarters in Atlanta; it was established in 1946 as the Communicable Disease Center. was notified of severe illnesses and one death, temporally associated with yellow fever yellow fever, acute infectious disease endemic in tropical Africa and many areas of South America. Epidemics have extended into subtropical and temperate regions during warm seasons. (YF) vaccination, in two elderly U.S. residents. Because the cases were unusual and adverse events following YF vaccination had not been studied, we estimated age-related reporting rates for systemic illness following YF vaccination. We found that the rate of reported adverse events among elderly vaccinees was higher than among vaccinees 25 to 44 years of age. We also found two additional deaths among elderly YF vaccinees. These data signal a potential problem but are not sufficient to reliably estimate incidence rates or to understand potential underlying mechanisms; therefore, enhanced surveillance is needed. YF remains an important cause of severe illness and death, and travel to disease-endemic regions is increasing. For elderly travelers, the risk for severe illness and death due to YF infection should be balanced against the risk for systemic illness due to YF vaccine.
In 1998, the Centers for Disease Control and Prevention (CDC See Control Data, century date change and Back Orifice.
CDC - Control Data Corporation ) was notified of severe illnesses occurring days after immunization immunization: see immunity; vaccination. with yellow fever (YF) vaccine in two elderly U.S. residents. Both vaccinees had been in good health, and neither was immunocompromised immunocompromised /im·mu·no·com·pro·mised/ (-kom´pro-mizd) having the immune response attenuated by administration of immunosuppressive drugs, by irradiation, by malnutrition, or by certain disease processes (e.g., cancer). . One patient died. Because these cases were unusual and the risk for illness following vaccination with YF vaccine in the elderly had not been studied, we estimated age-related reporting rates for YF vaccine associated systemic illness.
YF is an acute febrile illness acute febrile illness A nonspecific term for an illness of sudden onset accompanied by fever caused by a mosquito-borne fiavivirus (1). Clinical presentation ranges from a mild, febrile febrile /feb·rile/ (feb´ril) pertaining to or characterized by fever.
Of, relating to, or characterized by fever; feverish. illness to a life-threatening infection involving hepatic failure, renal dysfunction, myocardial myocardial /myo·car·di·al/ (-kahr´de-al) pertaining to the muscular tissue of the heart.
pertaining to the muscular tissue of the heart (the myocardium). injury, and a bleeding diathesis. YF is endemic in much of tropical South America and sub-Saharan Africa (2).
Two live, attenuated Attenuated
Alive but weakened; an attenuated microorganism can no longer produce disease.
Mentioned in: Tuberculin Skin Test
having undergone a process of attenuation. YF vaccines were developed in the early 1930s, the French neurotropic neurotropic
pertaining to or emanating from neurotrophy, e.g. neurotropic osteopathy. vaccine (FNV FNV Federatie Nederlandse Vakbeweging
FNV Field Not Valid
FNV Frame Not Valid
FNV Fjölbrautarskóli Nordurlands Vestra (Saudarkrokur, Iceland) ) and the 17D vaccine (1,3-5). Production of FNV was halted in 1982 because its neurotropism neurotropism /neu·rot·ro·pism/ (ndbobr-rot´ro-pizm)
1. the quality of having a special affinity for nervous tissue.
2. had resulted in cases of encephalitis encephalitis (ĕnsĕf'əlī`təs), general term used to describe a diffuse inflammation of the brain and spinal cord, usually of viral origin, often transmitted by mosquitoes, in contrast to a bacterial infection of the meninges , primarily among children (1,6,7). Derivatives of the 17D strain are the only YF virus strains currently used for vaccine production. These vaccines are not cloned from a single virus but consist of a heterologous heterologous /het·er·ol·o·gous/ (het?er-ol´ah-gus)
1. made up of tissue not normal to the part.
1. population of virions (8). Human trials with the 17D YF vaccine in the 1930s found low rates of adverse events and protective levels of YF viral neutralizing antibodies in more than 95% of vaccinees (3,5). More recent studies have shown that protective antibodies may last 30 to 35 years (9).
Early field trials and experiments with the 17D virus demonstrated that virulence varied with the passage level. Some substrains were overattenuated and led to low rates of seroconversion seroconversion /se·ro·con·ver·sion/ (-con-ver´zhun) the change of a seronegative test from negative to positive, indicating the development of antibodies in response to immunization or infection. , while others were associated with post-vaccine encephalitis (10,11). A seed lot system, which standardizes vaccine preparation and limits passage of the virus, was recognized as the production standard in 1945 (1,12). The World Health Organization publishes recommended standards. Previous reports of YF adverse events have focused primarily on hypersensitivity hypersensitivity, heightened response in a body tissue to an antigen or foreign substance. The body normally responds to an antigen by producing specific antibodies against it. The antibodies impart immunity for any later exposure to that antigen. or neurologic sequelae sequelae Clinical medicine The consequences of a particular condition or therapeutic intervention . A review of reports submitted to the Vaccine Adverse Event Reporting System The Vaccine Adverse Event Reporting System is a United States program for vaccine safety, co-sponsored by the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA). (VAERS VAERS Vaccine Adverse Event Reporting System (lists hospitalizations or deaths resulting from vaccinations) ) in the United States from 1990 to 1997 found a rate of probable anaphylaxis anaphylaxis (ăn'əfəlăk`sĭs), hypersensitive state that may develop after introduction of a foreign protein or other antigen into the body tissues. after YF vaccine immunization of 1 per 131,000 vaccine doses distributed (13). Since the seed lot system was introduced, 21 cases of post-vaccine encephalitis have been reported worldwide (20 patients recovered, one died) (1,14); 16 (76%) of these cases occurred in children <9 months. Meningoencephalitis meningoencephalitis /me·nin·go·en·ceph·a·li·tis/ (me-ning?go-en-sef?ah-li´tis) inflammation of the brain and meninges.
toxoplasmic meningoencephalitis has on rare occasions been reported among adults after immunization with the vaccine (15,16), and severe, multisystemic mul·ti·sys·tem·ic
Relating to a disease or condition that affects many organ systems of the body.
affecting more than one body system. illness has recently been reported in seven YF vaccinees (17-19).
YF vaccine has had a long history of efficacy and presumed safety (1). Nonetheless, a reexamination re·ex·am·ine also re-ex·am·ine
tr.v. re·ex·am·ined, re·ex·am·in·ing, re·ex·am·ines
1. To examine again or anew; review.
2. Law To question (a witness) again after cross-examination. of its safety profile has been prompted by its increased use in international travelers and by these recent reports of serious adverse events (17-19).
Adverse events following vaccination with YF vaccine reported to VAERS were collected and categorized as systemic, nonsystemic, or unrelated and were classified by age group. The number of doses administered by age group (denominators) was estimated from the age distribution of travelers receiving the vaccine at a sample of travel clinics and from the number of doses distributed to civilians in the United States by the vaccine manufacturer. Reporting rates for systemic and nonsystemic adverse events were calculated by dividing the events reported by an estimate of the number of people receiving the vaccine in each age group.
Source of Cases and Case Classification
VAERS, a passive surveillance system for adverse events, monitors vaccine safety in the United States and is jointly operated by CDC and the U.S. Food and Drug Administration (20). All civilian U.S. VAERS reports from 1990 through 1998 listing YF vaccine were reviewed. Reports of death, hospitalization or disability, a life-threatening illness, or illness requiring an emergency room or doctor visit were analyzed. Reports that did not involve any of these events were considered less serious and were excluded from analysis. Reports were blinded for age and reviewed independently by three physicians. Adverse events were classified as neurologic, multisystemic, uncomplicated neurologic or systemic, nonspecific nonspecific /non·spe·cif·ic/ (non?spi-sif´ik)
1. not due to any single known cause.
2. not directed against a particular agent, but rather having a general effect.
1. , hypersensitivity, local reactions, or unrelated (Table 1). If more than one category was appropriate, the most serious category, in terms of reaction to the specific vaccine components, was selected. These categories were defined for the purposes of this study and reflect an interest in examining adverse events that might be related to the vaccine virus rather than those that might be immune responses to other vaccine components. The investigators reached a consensus on the categorization of each report before unblinding the ages.
A systemic adverse event (SyAE) was defined as a multisystemic (excluding anaphylactic anaphylactic /ana·phy·lac·tic/ (an?ah-fi-lak´tik) pertaining to anaphylaxis.
anaphylactic (an´ ) or neurologic reaction. Adverse events categorized as uncomplicated neurologic or systemic, hypersensitivity, or local reaction were defined as other adverse events (OAE OAE Otoacoustic Emissions
OAE Orchestra of the Age of Enlightenment (London, England)
OAE Oceanic Anoxic Event
OAE Office of Applied Economics (NIST)
OAE Old Antarctic Explorer ). A second analysis used a more stringent definition of SyAE that included only neurologic or multisystemic cases requiring hospitalization or resulting in death (SyAE*).
VAERS reports that did not include the age of the vaccinee vac·ci·nee
An individual who has been vaccinated. , provided another explanation of the adverse event (e.g., local reaction from another vaccination), or indicated inappropriate administration or inadvertent use (e.g., during pregnancy) were excluded. Reports from children <15 years of age and military personnel were excluded because no adequate estimates of the number of persons who received YF vaccine in these groups were available. As a comparison, similar analyses were done on adverse events after hepatitis A Hepatitis A Definition
Hepatitis A is an inflammation of the liver caused by a virus, the hepatitis A virus (HAV). It varies in severity, running an acute course, generally starting within two to six weeks after contact with the virus, and lasting no (HA) vaccine reported to VAERS during 1994 to 1998 (Table 1).
VAERS solicits reports not only of events known to be causally related to vaccine but also of all events temporally related to vaccination, some of which may be coincidental. Evaluating the causal relationship of an event to a specific vaccine may be also confounded by the routine practice of administering multiple vaccines at a single visit. Furthermore, VAERS has several other methodologic limitations inherent to passive surveillance systems, such as under-, biased-, and incomplete reporting and lack of consistent diagnostic criteria. Thus, VAERS reporting rates are, at best, a crude estimate of event rates. Given these limitations of passive surveillance systems, neither reporting rates nor the number of events reported to VAERS may automatically be considered synonymous with the incidence of adverse events. Elevated VAERS reporting rates may best serve as sentinel signals suggesting hypotheses to test in other more rigorous databases before definitive conclusions can be reached.
The sole manufacturer of YF vaccine in the United States (now known as Aventis Pasteur) provided the annual number of YF vaccine doses purchased by civilian providers from 1995 through 1998. The annual number of doses from 1990 through 1994 was extrapolated from the number of doses in 1995. We assumed that the number of doses increased each year at the same annual rate as occurred from 1995 to 1996. Doses for 1997 and 1998 were not used in the extrapolation (mathematics, algorithm) extrapolation - A mathematical procedure which estimates values of a function for certain desired inputs given values for known inputs.
If the desired input is outside the range of the known values this is called extrapolation, if it is inside then because unusual supply and regulatory issues influenced the number of doses provided in these years. Telephone interviews with health-care providers indicated little or no waste of YF vaccine, which for civilian use in the United States is sold predominantly in single-dose vials. Thus, it was assumed that the total number of doses sold was a good estimate of the total number of doses administered.
The manufacturers of HA vaccine (Havrix, SmithKline Beecham, Rixensart, Belgium; and Vaqta, Merck & Co., Inc., West Point, PA) provided the annual number of doses of HA vaccine purchased from 1995 through 1998. We estimated that 10% of HA vaccine was wasted and that 50% of vaccinees received both doses in the series. The total number of doses sold was reduced by these amounts to estimate the total number of doses administered. These doses did not include those used for outbreak control.
Thirteen U.S.-based GeoSentinel clinics, which provide YF vaccine to international travelers, reviewed records of YF and HA vaccine administration. GeoSentinel is an international network of travel and tropical medical clinics established in 1995 as a collaborative effort by CDC and the International Society of Travel Medicine (21). GeoSentinel monitors geographic and temporal infectious disease Infectious disease
A pathological condition spread among biological species. Infectious diseases, although varied in their effects, are always associated with viruses, bacteria, fungi, protozoa, multicellular parasites and aberrant proteins known as prions. trends among people crossing international borders; the clinics are chosen to detect sentinel events in travelers seen in clinics before and after travel. Within the United States, these clinics are considered representative of clinics that offer YF vaccine. All YF and HA vaccine recipients during the most recent 12-month period for which complete information was available were categorized by age group (15 to 24 years, 25 to 44 years, 45 to 64 years, 65 to 74 years, and [greater than or equal to] 75 years). Data for children <15 years of age and military personnel were excluded because these groups are underrepresented un·der·rep·re·sent·ed
Insufficiently or inadequately represented: the underrepresented minority groups, ignored by the government. at U.S. GeoSentinel clinics. Other than these exceptions, the age distribution for YF vaccine recipients at GeoSentinel clinics was assumed to represent national YF vaccine use. The age distribution for HA vaccine recipients from these clinics was also assumed to represent national use excluding the same exceptions and outbreak control.
The number of YF vaccine doses administered to each age group was estimated by multiplying the total number of YF vaccine doses per year by the proportionate age group distribution estimated from the GeoSentinel clinics. Age group-specific reporting rates for SyAE per 100,000 doses and reporting rate ratios for SyAE were calculated with a reference group of 25- to 44-year-old vaccine recipients. The 25- to 44-year-old group was chosen because of the previously reported increased risk for adverse events among younger YF vaccine recipients (1). Although the risk is highest for infants <4 months of age, it is unclear at what age the risk reaches a nadir. Confidence intervals were calculated based on standard statistical assumptions for confidence intervals (CI) for ratios of rates, although because of the limitations of passive surveillance systems, these assumptions may not hold.
From 1990 through 1998, VAERS received 166 reports of YF vaccine adverse events that met the criteria for review (Figure 1). Thirty-five (21%) of these reports were categorized as SyAEs and 36 (22%) as OAEs. Of the 10 VAERS reports for patients >65 years of age, one was categorized as an OAE and the other nine as SyAE. The latter included the two index patients, one additional death, and six patients with various signs and symptoms, including fever, headache, malaise, myalgia myalgia /my·al·gia/ (mi-al´jah) muscular pain.myal´gic
epidemic myalgia see under pleurodynia.
n. , nausea, somnolence somnolence /som·no·lence/ (som´no-lens) drowsiness or sleepiness, particularly in excess.
1. A state of drowsiness; sleepiness.
2. , and ataxia ataxia (ətăk`sēə), lack of coordination of the voluntary muscles resulting in irregular movements of the body. Ataxia can be brought on by an injury, infection, or degenerative disease of the central nervous system, e.g. . Two of these six patients were hospitalized. Ninety-five (57%) reports were excluded because they did not include the age of the vaccinee (4 reports), or the vaccine was used in military personnel (56 reports) or a child <15 years old (7 reports), or an alternative cause of the adverse event was reported (28 reports). Seventeen patients were hospitalized, and three patients, ages 63, 67, and 79 years, died. The clinical course for the two index patients and the two additional deaths was characterized by a nonspecific febrile syndrome with fatigue, myalgia, and gastrointestinal symptoms, rapidly progressing to a severe multisystemic illness with dysfunction of liver, kidneys, lungs, central nervous system, as well as thrombocytopenia Thrombocytopenia Definition
Thrombocytopenia is an abnormal drop in the number of blood cells involved in forming blood clots. These cells are called platelets. , and possible disseminated intravascular coagulopathy disseminated intravascular coagulopathy Hematology An acquired bleeding diathesis with a generally bad outcome in which the balance between coagulation and fibrinolysis tips toward the former; DIC is characterized by accelerated platelet consumption with (18).
[FIGURE 1 OMITTED]
From 1990 through 1998, U.S. civilian providers purchased an estimated 1.55 million doses of YF vaccine. The age distribution of YF vaccine recipients was estimated from 5,125 YF vaccine recipients in 13 GeoSentinel clinics. The reference group, ages 25 to 44 years, accounted for 45% of the sample; 285 (5.6%) of the vaccinees were 65 to 74 years of age, and 73 (1.4%) were [greater than or equal to] 75 years of age (Figure 2).
[FIGURE 2 OMITTED]
The overall reporting rate for a SyAE after YF vaccination was 2.4 per 100,000 doses, and the reporting rate for death was 0.2 per 100,000 doses; for those [greater than or equal to] 65 years of age, the overall reporting rate for SyAE was 8.3 per 100,000 doses, and the reporting rate for death was 1.8 per 100,000 doses. During this period, an estimated 108,000 doses were administered to those [greater than or equal to] 65 years of age. The reporting rate for a SyAE for the reference age group (25 to 44 years) was 1.6 per 100,000 doses and increased progressively for each older age group to 5.8 per 100,000 doses for vaccinees 65 to 74 years of age and 18.1 per 100,000 doses for those [greater than or equal to] 75 years of age (Table 2). Compared with the reference group, the reporting rate ratio for an SyAE for those 65 to 74 years of age was 3.7 (95% CI 1.3-10.7); for those [greater than or equal to] 75 years of age, it was 11.6 (95% CI 3.7-36.3). Conversely, the reporting rate for OAE decreased for each older age group.
When analysis of SyAEs was restricted to vaccinees who died or were hospitalized, the pattern was even stronger (Table 3). Compared with the reference group, the reporting rate ratio for an SyAE* for those 65 to 74 years of age was 12.3 (95% CI 2.0-73.2); for those [greater than or equal to] 75 years of age, it was 31.8 (95% CI 4.5-225.9).
Of the 35 patients with SyAEs, 19 (54%) received at least one other vaccine in addition to YF vaccine. When analysis was restricted to those who received only YF vaccine, the reporting rate ratio for a SyAE* for those 65 to 74 years of age was 6.1 (95% CI 1.4-27.3); for those >75 years of age it was 23.9 (95% CI 5.3-106.6). Six of the nine patients [greater than or equal to] 65 years of age with SyAEs received only YF vaccine, and all five patients [greater than or equal to] 65 years of age who were hospitalized or died had received that vaccine alone.
During 1995 to 1998, VAERS received 310 reports of adverse events after immunization with HA vaccine that met the inclusion criteria. From an estimated 3.2 million doses of HA vaccine, 30 patients were hospitalized, and none died. This is double the total number of doses of YF vaccine and almost three times the number of YF vaccine doses given to people ages [greater than or equal to] 75 years. The reporting rate for an SyAE after HA vaccine for vaccine recipients 65 to 74 years of age was 6.2 per 100,000. This was higher than the 2.5 per 100,000 reporting rate for the reference group (ages 25 to 44 years); however, there was no consistent increase in the reporting rate for SyAE for each older age group, and recipients ages [greater than or equal to] 75 years did not have a different reporting rate from those ages 25 to 44 years (reporting rate ratio =1.9, 95% CI 0.6-6.3) (Table 4) (Figure 3).
[FIGURE 3 OMITTED]
Severe illness in two elderly recipients of YF vaccine, one of whom died shortly after immunization, prompted this collaborative study, which examined reporting rates for adverse events among elderly YF vaccine recipients in the United States (18). We found a higher reporting rate for SyAEs among elderly YF vaccine recipients than among YF vaccine recipients ages 25 to 44 years. This increase in reporting rates persisted when adverse events were limited to patients who required hospitalization or died and when recipients who also received other vaccines were excluded. Although we did find an elevated rate of reported SyAEs following HA vaccine in the 65- to 74-year-old group, we did not find a similar increase in persons [greater than or equal to] 75 years, despite almost three times as many doses sold overall and twice as many adverse events reported to VAERS for all age groups combined. No deaths following HA vaccination were reported.
Our analysis showed that the reporting rate for systemic illness requiring hospitalization or leading to death after YF vaccination was 3.5 per 100,000 among people 65 to 75 years of age and 9.1 per 100,000 for people [greater than or equal to] 75 years. For a rough comparison, the risk for vaccine-associated paralytic paralytic /par·a·lyt·ic/ (par?ah-lit´ik)
1. affected with or pertaining to paralysis.
2. a person affected with paralysis.
1. poliomyelitis poliomyelitis (pō'lēōmī'əlī`tĭs), polio, or infantile paralysis, acute viral infection, mainly of children but also affecting older persons. due to oral polio vaccine was estimated as 1 per 2.5 million (22,23). A review of a passive surveillance system in the United Kingdom that receives reports from primary-care physicians also found a similar increase in SyAEs among elderly YF vaccine recipients (unpub. data).
Close examination of the two index cases and two additional deaths that followed YF vaccination shows four cases with similar clinical presentations, all of which share important characteristics with viscerotropic viscerotropic /vis·cer·o·tro·pic/ (-tro´pik) primarily acting on the viscera; having a predilection for the abdominal or thoracic viscera.
adj. wild-type YF infection (18). Clinical presentations were characterized by fever, myalgia, headache, and confusion rapidly progressing to a multisystemic illness and death in three of the patients. The vaccine strain of YF virus was isolated from the serum of two patients and the cerebrospinal fluid cerebrospinal fluid (CSF)
Clear, colourless liquid that surrounds the brain and spinal cord and fills the spaces in them. It helps support the brain, acts as a lubricant, maintains pressure in the skull, and cushions shocks. of one. Sequence analysis of these isolates and the elevated antibody titers suggest an overwhelming infection caused by the selective amplification of a mutated virus subpopulation sub·pop·u·la·tion
A part or subdivision of a population, especially one originating from some other population: microbial subpopulations.
Noun 1. . The temporal relationship between severe illness and YF vaccination, the similar clinical presentations, and the laboratory results favor the hypothesis that these adverse events are causally related to YF vaccine. Recently, three cases of similar systemic adverse events after YF vaccination resulting in death were reported: two from Brazil, patients ages 5 and 22 years (Brazilian 17DD vaccine) and one from Australia, patient 56 years old (17D-204 vaccine) (17,19).
An increased risk for severe disease due to the vaccine strain of Yellow fever virus yellow fever virus
An arbovirus of the genus Flavivirus that causes yellow fever and is transmitted by mosquitoes. among older YF vaccine recipients is biologically plausible. Numerous reports and studies have shown that deaths and severe illnesses occur more frequently among the elderly with other flaviviral infections (e.g., West Nile encephalitis, Japanese encephalitis Japanese Encephalitis Definition
Japanese encephalitis is an infection of the brain caused by a virus. The virus is transmitted to humans by mosquitoes. , Saint Louis encephalitis Saint Lou·is encephalitis
A viral encephalitis occurring in parts of North America and transmitted by a mosquito of the genus Culex. , Murray Valley encephalitis Murray Valley encephalitis
see Murray Valley encephalitis. , and tick-borne encephalitis), while these infections are more likely to be self-limited in children (24-27). Similarly, investigations of YF outbreaks in the 1930s and 1940s found increased case-fatality rates among the oldest patients (28-30).
This study has several limitations. Rates calculated from VAERS data have to be interpreted with caution because of the problems inherent in a passive reporting system. Estimates of adverse events based on VAERS reports are likely to underestimate actual events (31). Our data, therefore, may reflect minimum estimates of these adverse events. Age-related reporting bias may also have influenced our results. Age-related reporting bias would decrease the significance of the reporting rate ratios only if SyAEs, particularly those leading to hospitalization and death, among vaccinees <65 years of age were reported less often than among vaccinees [greater than or equal to] 65 years of age.
Another important limitation is that the estimated age distribution of travelers from the GeoSentinel clinics receiving YF vaccine in 1998 was assumed to apply for the entire study (1990 to 1998) and to be generalizable to the entire United States. However, if as many suspect, the proportion of elderly travelers has increased in recent years, this extrapolation will have overestimated the number of older travelers and have the effect of underestimating the reporting rate and reporting rate ratio of adverse events in the elderly. We excluded data on children <15 years of age, which caused a slight, proportionate increase in the denominator for the remaining vaccine recipients and a slight underestimate of the reporting rate for adverse events in all other age groups. Also, the calculation of denominators relied on assuming that the increase in vaccines administered between 1995 and 1996 held for 1990 to 1994.
An additional limitation is that age-specific SyAEs to YF vaccine may reflect an age-related response to vaccines in general or an increased amount of background illness in the elderly. Analysis of VAERS reports for SyAEs to HA vaccine did not support this conclusion; however, HA vaccine is an inactivated inactivated
rendered inactive; the activity is destroyed.
treated so that they are no longer able to produce evidence of growth or damaging effect on tissue. vaccine, and another live, attenuated vaccine would have served as a better control. We attempted to look at adverse events reported for oral typhoid vaccine typhoid vaccine
A vaccine containing a suspension of inactivated Salmonella typhi, used to immunize against typhoid fever. , but the limited number of VAERS reports precluded a quantitative analysis Quantitative Analysis
A security analysis that uses financial information derived from company annual reports and income statements to evaluate an investment decision.
Finally, although severe illness occurred days after YF vaccination in the cases we investigated, this temporal association does not prove causality. Definitive clinical or pathologic evidence identifying YF vaccine as the cause of severe illness or death for most cases reported to VAERS is lacking and is not routinely part of this surveillance system.
YF remains an important cause of severe illness and death in tropical South America and sub-Saharan Africa. In recent years, Aedes aegypti, the mosquito vector of urban YF, has reestablished itself in South America, increasing the likelihood of large, explosive outbreaks, and in both South America and sub-Saharan Africa, the number and size of outbreaks have increased in the last 20 years (32-34). Concomitant with these changes in the distribution of the vector and ongoing outbreaks, travel from the United States to disease-endemic regions has increased substantially (35). Quantitative risk assessments of YF among travelers to disease-endemic areas have not been done; however, the risk for acquiring YF has been highlighted by the recent deaths of four unvaccinated travelers due to YF imported to Europe and the United States (36-40).
The 17D YF vaccine has a long history of reported safety and efficacy and has played an important role in YF control, one of the public health triumphs of the 20th century. Age-specific recommendations and production standards for this important vaccine have been modified as a result of safety and efficacy issues that have become apparent with increased use (1,2,4,41,42). These modifications have preserved the vaccine as a vital tool for disease prevention and control. Defining the risk for adverse events among elderly vaccine recipients is an extension of these important efforts.
This study provides data quantifying the relative reporting ratios of SyAE following YF vaccination among people [greater than or equal to] 65 years of age in the United States. However, several issues must be addressed before any changes or restrictions to YF vaccine recommendations are proposed.
These SyAEs are still relatively rare (2.4 per 100,000 doses) in the United States, where an estimated 200,000 doses are given annually. The risk for unvaccinated travelers acquiring YF remains undefined; so risk-benefit estimates of YF vaccine are difficult to develop. In the absence of this important information, we suggest the following steps. Our observations should be confirmed by studies in different populations. Enhanced surveillance for systemic adverse events following YF vaccination should be introduced at U.S. certified vaccination centers and in other countries where YF vaccine is used. This enhanced surveillance should be combined with prospective follow-up that includes appropriate clinical, epidemiologic, and laboratory assessments of cases, biologic specimens, and vaccine or vaccine lots. In addition, epidemiologic studies should be designed to explore both host- and vaccine-specific factors associated with systemic adverse events (43).
In the interim, elderly YF vaccine recipients and their health-care providers should be cautioned about the possible risks of vaccination. Travel itineraries should be scrutinized, and the vaccine given only to those traveling to areas that report YF or are in the YF-endemic zone.
YF causes serious, life-threatening infections, and the vaccine is highly effective. The virus is responsible for substantial morbidity and death in disease-endemic areas and until more definitive evidence of vaccine-related adverse events is accumulated, the benefit-risk ratio of mass vaccination in YF-endemic countries favors continuation of a universal vaccine policy under the Expanded Programme on Immunization. Meanwhile, efforts to enhance our understanding of both the risks and benefits of YF vaccine and refine its use to maximize its safety and effectiveness should be accelerated.
Table 1. Categories of vaccine adverse events (a)
* Guillain-Barre syndrome Guil·lain-Bar·ré syndrome
See acute idiopathic polyneuritis. , new onset seizures, encephalitis, myelitis myelitis /my·eli·tis/ (mi?e-li´tis)
1. inflammation of the spinal cord; often expanded to include noninflammatory spinal cord lesions.
2. inflammation of the bone marrow (osteomyelitis). , altered mental status, focal cranial cranial /cra·ni·al/ (-al)
1. pertaining to the cranium.
2. toward the head end of the body; a synonym of superior in humans and other bipeds.
adj. or peripheral neurologic deficits, paresthesias Paresthesias
A prickly, tingling sensation.
Mentioned in: Autoimmune Disorders , vertigo, headaches (headaches alone are not sufficient for neurologic diagnosis) (b)
* Onset <2 weeks after vaccination
* Duration >72 hours Multisystemic (SyAE)
* Myalgias, arthralgias, rhabdomyolysis rhabdomyolysis /rhab·do·my·ol·y·sis/ (-mi-ol´i-sis) disintegration of striated muscle fibers with excretion of myoglobin in the urine.
n. , elevated transaminases, respiratory distress Respiratory distress
A condition in which patients with lung disease are not able to get enough oxygen.
Mentioned in: Lung Cancer, Non-Small Cell , nausea, vomiting, diarrhea, nephropathy nephropathy /ne·phrop·a·thy/ (ne-frop´ah-the) disease of the kidneys.nephropath´ic
analgesic nephropathy , disseminated intravascular coagulation disseminated intravascular coagulation
Abbr. DIC A hemorrhagic disorder that occurs following the uncontrolled activation of clotting factors and fibrinolytic enzymes throughout small blood vessels, resulting in tissue necrosis and , +/-fever (b)
* Onset <2 weeks after vaccination
* Duration >72 hours
Neurologic/systemic, uncomplicated (OAE)
* Cases that met the neurologic or systemic criteria but had a full and rapid clinical recovery in <72 hours
Nonspecific events without other focal finding (OAE)
* Dizziness, headache
* Nausea, vomiting, or diarrhea alone
* Rash, urticaria urticaria /ur·ti·ca·ria/ (ur?ti-kar´e-ah) hives; a vascular reaction of the upper dermis marked by transient appearance of slightly elevated patches (wheals) which are redder or paler than the surrounding skin and often attended by , +/- fever
* Anaphylaxis, angioedema
* Onset within 48 hours of vaccination
Local reaction (OAE)
* Localized pain, swelling, erythema erythema (ĕr'əthē`mə), more or less diffuse redness of the skin due to concentration of an abnormally large amount of blood within the small vessels of the skin (hyperemia), as in burns. , or warmth (at injection site)
* Onset within 1 week of vaccination
Unrelated to vaccine (excluded from AE analysis)
* A clear, alternative diagnosis confirmed by laboratory criteria accounts for symptoms and signs; sometimes this is an underlying illness
* Another cause implied or stated in the physician's report
* For hepatitis A vaccine Hepatitis A Vaccine, Avaxim, is a vaccine against the Hepatitis A virus. The vaccine protects against the virus in more than 95% of cases and provides protection from the virus for ten years. , onset of adverse event is >6 weeks
SyAE = systemic adverse event; OAE = other adverse events; AE = adverse event(s).
(a) Listed in order from most to least severe.
(b) Examples, but not limited to these signs, symptoms and conditions.
Table 2. Reporting rates (RR) and reporting rate ratios (RRR) for yellow fever (YF) vaccine adverse events by age, 1990-1998 No. Age vaccine OAE reports/ (years) doses No. OAE (a) 100,000 doses RRR (95% CI) 15-24 189,991 11 5.79 2.5 (1.2-5.5) 25-44 702,783 16 2.28 Reference 45-64 442,605 8 1.81 0.8 (0.3-1.9) 65-74 86,222 1 1.16 0.5 (0.1-3.8) [greater than or equal to]75 22,085 0 0 undefined Total 1,443,686 36 2.49 Age SyAE reports/ (years) No. SyAE (b) 100,000 doses RRR (95% CI) 15-24 3 1.58 1.0 (0.3-3.6) 25-44 11 1.57 Reference 45-64 12 2.71 1.7 (0.8-3.9) 65-74 5 5.80 3.7 (1.3-10.7) [greater than or equal to]75 4 18.11 11.6 (3.7-36) Total 35 2.42 CI = confidence interval. (a) OAE: other adverse event (uncomplicated neurologic/systemic hypersensitivity or local reaction). (b) SyAE: systemic adverse event (multisystemic [excluding anapilylactic] or neurologic reaction) Table 3. Reporting rates (RR) and reporting rate ratios (RRR) for serious systemic yellow fever (YF) vaccine adverse events (SyAE *) by age, 1990-1998 No. Age vaccine No. of OAE * reports/ (years) doses OAE * (a) 100,000 doses RRR (95% CI) 15-24 189,991 12 6.32 1.8 (0.9-3.5) 25-44 702,783 25 3.56 Reference 45-64 442,605 15 3.39 1.0 (0.5-1.8) 65-74 86,222 3 3.48 1.0 (0.3-3.2) [greater than or equal to]75 22,085 2 9.06 2.5 (0.6-10.7) Total 1,443,686 57 3.95 Age SyAE * reports/ (years) No. SyAE * (b) 100,000 doses RRR (95% CI) 15-24 2 1.05 3.7 (0.5-26) 25-44 2 0.29 Reference 45-64 5 1.13 4.0 (0.8-20) 65-74 3 3.48 12.3 (2.0-73) [greater than or equal to]75 2 9.06 32 (4.5-226) Total 14 0.97 CI = confidence intervals. (a) OAE * = other adverse events (i.e., uncomplicated neurologic or systemic event; hypersensitivity; local reaction) OR systemic adverse events not requiring hospitalization or resulting in death. (b) SyAE * = serious systemic adverse events, including only neurologic or multisystemic adverse events requiring hospitalization or resulting in death; this is distinguished from the term SyAE, which indicates all systemic adverse events (See Table 2). Table 4. Reporting rates (RR) and reporting rate ratios (RRR) for hepatitis A vaccine adverse events by age, 1995-1998 Age No. HA No. OAE reports/ (years) doses OAE (a) 100,000 doses RRR (95% CI) 15-24 387,031 21 5.43 1.8 (1.1-3.0) 25-44 1,444,895 44 3.05 Reference 45-64 1,096,391 23 2.10 0.7 (0.4-1.1) 65-74 241,453 4 1.66 0.5 (0.2-1.5) [greater than or equal to]75 61,760 1 1.62 0.5 (0.1-3.9) Total 3,231,530 93 2.88 Age SyAE reports/ (years) No. SyAE (b) 100,000 doses RRR (95% CI) 15-24 7 1.81 0.7 (0.3-1.6) 25-44 36 2.49 Reference 45-64 26 2.37 1.0 (0.6-1.6) 65-74 15 6.21 2.5 (1.4-4.6) [greater than or equalt to]75 3 4.86 1.9 (0.6-6.3) Total 87 2.69 HA = hepatitis A [vaccine]; CI = confidence intervals. (a) OAE = other adverse events (uncomplicated neurologic/systemic, hypersensitivity, or local reaction). (b) SyAE: systemic adverse event (multisystemic [excluding anaphylactic] or neurologic reaction)
We thank Stefanie Steele and Laura Letteau for their assistance in data collection; Alice Brebner, Betsy Abraham, Angie Bricco, and Mike Bloh for help in getting denominator data; Scott Kellerman for his assistance with the hepatitis A analysis; and John McGowan for reviewing the manuscript.
Dr. Martin is an Epidemic Intelligence Service The Epidemic Intelligence Service is a program of the United States' Centers for Disease Control and Prevention. Established in 1951 due to biological warfare concerns arising from the Korean War, it has become a hands-on two-year postgraduate training program in epidemiology, with Officer at the Centers for Disease Control and Prevention. He works in the Division of Bacterial and Mycotic mycotic /my·cot·ic/ (mi-kot´ik)
1. pertaining to mycosis.
2. caused by a fungus.
1. Relating to mycosis.
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Michael Martin, * ([dagger]) Leisa H. Weld, * Theodore F. Tsai, * Gina T. Mootrey, * Robert T. Chen, * Manette Niu, ([double dagger]) Martin S. Cetron, * and the GeoSentinel Yellow Fever Working Group (1)
* Centers for Disease Control and Prevention, Atlanta, Georgia, USA; ([dagger]) Emory School of Medicine, Atlanta, Georgia, USA; and ([double dagger]) Center for Biologic Evaluation, U.S. Food and Drug Administration, Rockville, Maryland, USA
(1) Jeff Altman, University of Washington, Seattle, Washington; Vernon Ansdell, Kaiser Permanente, Honolulu, Hawaii; Elizabeth Barnett, Boston University, Boston, Massachusetts; Michele Barry, Yale University, New Haven, Connecticut; Bradley Connor, Cornell University, New York, New York; David Freedman, University of Alabama at Birmingham UAB began in 1936 as the Birmingham Extension Center of the University of Alabama. Because of the rapid growth of the Birmingham area, it was decided that an extension program for students who had difficulties which prevented them from studying in Tuscaloosa was needed. , Birmingham, Alabama; Alejandra Gurtman, Mount Sinai Medical Center, New York, New York; Elaine Jong, University of Washington, Seattle, Washington; Phyllis Kozarsky, Emory University, Atlanta, Georgia; Russell McMullen, University of Washington, Seattle, Washington; Jan Patterson, University of Texas, San Antonio, Texas “San Antonio” redirects here. For other uses, see San Antonio (disambiguation).
San Antonio is the second most populous city in Texas, the third most populous metropolitan area in Texas, and is the seventh most populous city in the United States. As of the 2006 U.S. ; Bradley Sack, Johns Hopkins University Johns Hopkins University, mainly at Baltimore, Md. Johns Hopkins in 1867 had a group of his associates incorporated as the trustees of a university and a hospital, endowing each with $3.5 million. Daniel C. , Baltimore, Maryland; Mary E. Wilson, Harvard University, Cambridge, Massachusetts; Martin Wolfe, Traveler's Medical Service of Washington, Washington, D.C.
Address for correspondence: Martin Cetron, Division of Global Migration and Quarantine, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Mailstop E03, 1600 Clifton Road, Atlanta, GA 30333, USA; fax: 404-498-1633; e-mail: Mcetron@cdc.gov