Long-term health outcomes in patients with Prader-Willi Syndrome: a nationwide cohort study in Denmark.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare congenital disease that affects growth, sexual development, cognitive function and behavior. Individuals exhibit food preoccupation and hyperphagia, which may lead to obesity with premature morbidity and mortality. The aim of this work was to evaluate the risk of venous thromboembolisms (VTEs), myocardial infarction, pulmonary hypertension, sleep apnea, depression, anxiety and all-cause mortality among persons with PWS as compared with an age- and sex-matched general-population cohort. METHODS: All persons diagnosed with PWS (n=155) were identified in the Danish Health Registries; an age- and sex-matched comparison group was selected from the general population of Denmark (n=15 500); diseases of interest were identified through the health registry and cause of death register. Follow-up began on date of birth or first medical record availability through to first occurrence of an outcome of interest; follow-up ceased at emigration from Denmark or end of study. Incidence rates (IRs) were calculated and Cox's proportional hazards models were used to understand the relative risk (RR) of disease. RESULTS: The IRs for VTE among patients with PWS was 144 (60-347) per 100 000 person-years. Risks for VTE events and all-cause mortality were 9.4 times (95% confidence interval (CI): 3.7-23.5) and 11.0 times (95% CI: 5.7-21.1) higher, respectively, for patients with PWS versus the general population. Increased risks were also found individually for deep venous thromboses (DVTs) (RR: 9.1; 95% CI: 3.2-25.2), pulmonary embolisms (RR: 11.0; 95% CI: 1.4-86.9), myocardial infarction (RR: 7.2; 95% CI: 1.7-30.2) and anxiety (RR: 2.8; 95% CI: 1.0-7.5). No cases of pulmonary hypertension, sleep apnea or depressive disorders were identified within this PWS cohort. CONCLUSIONS: Multiple cardiovascular and behavioral illnesses are more likely to occur among patients with PWS than within the general population. These increased risks may provide an impetus for enhanced disease prevention, screening, diagnosis and treatment.

Inactivated influenza vaccine (IIV) in children <2 years of age: examination of selected adverse events reported to the Vaccine Adverse Event Reporting System (VAERS) after thimerosal-free or thimerosal-containing vaccine.

Thimerosal as a preservative (in all but trace amounts) was removed from vaccines used in infants starting in the late 1990s, though the preservative-including inactivated influenza vaccine is still available for use in individuals >or=6 months of age. We compared the proportion of injection site reactions, rash, and infections reported to the Vaccine Adverse Event Reporting System (VAERS) after preservative-free (PFV), preservative-including (PIV), and preservative unknown (PUV) vaccines in reports from 7/1/2004 to 1/4/2006. There were 145, 175, and 216 reports after vaccination with PFV, PIV, and PUV, respectively. The most frequently reported coding terms (fever, rash, and urticaria) were seen in similar proportions in the PFV, PIV, and PUV groups. No difference was detected in the proportion of injection site reactions (ISR), rash, or infections in the PIV, PFV, and PUV reports. Keeping in mind the inherent limitations of VAERS, including underreporting and potential reporting biases, we conclude that there were no substantial differences in the proportion of rash, ISR, and infection reports in the PIV, PFV and PUV reports in infants.

Heart failure among younger rheumatoid arthritis and Crohn's patients exposed to TNF-alpha antagonists.

OBJECTIVES: New onset heart failure (HF) has been associated with the use of TNF-alpha antagonists etanercept and infliximab based upon spontaneous adverse event reports. HF clinical trials of these agents were stopped early due to futility or worsening of existing HF. A potential association between etanercept and infliximab and new onset HF has been studied minimally at a population level. METHODS: Using administrative claims from a large U.S. health care organization, we identified rheumatoid arthritis (RA) and Crohn's disease (CD) patients receiving infliximab or etanercept (exposed), and comparator cohorts of RA and CD patients receiving non-biologic immunosuppressives (unexposed). We studied adults < 50 years to reduce potential confounding related to common age-related comorbidities. Based on abstracted medical records of suspected HF cases, a physician panel adjudicated cases as definite, possible or no HF. RESULTS: Among 4018 RA and CD patients with mean duration follow-up of 18 months, 9 of 33 suspected HF cases (identified using claims data) were adjudicated as definite (n = 5) or possible (n = 4) HF. The relative risk of HF among TNF-alpha antagonist-treated RA and CD patients was 4.3 and 1.2, respectively (P = NS for both). The absolute difference in cumulative incidence of HF among infliximab or etanercept-exposed compared to unexposed patients was 3.4 and 0.3 cases per 1000 persons for RA and CD (P = NS), respectively, yielding a number needed to harm of 294 for RA and 3333 for CD. CONCLUSION: We found only a small number of presumed HF cases (n = 9, or 0.2%) in a large population of relatively young RA and CD patients. Although there was an increased relative risk of incident, HF that was not statistically significant among those exposed to TNF-alpha antagonists compared to those unexposed, larger cohorts are needed to provide more precise risk estimates and permit adjustment for potential confounding.

Comparison of military and civilian reporting rates for smallpox vaccine adverse events.

INTRODUCTION: US smallpox vaccination (SMA) started most recently in December 2002. Military and civilian personnel report adverse events (AEs) to the Vaccine Adverse Event Reporting System (VAERS), a surveillance system that relies on spontaneous reports. Although reported rates of probable myo/pericarditis after SMA in the literature are similar between military personnel and civilian healthcare workers, some civilian AE reporting rates after SMA appeared higher than those in the military. OBJECTIVE: Determine if SMA-associated reporting rates are different in civilians than in the military, considering age, sex, seriousness, and expectedness of the AE, as well as self-reporting. METHODS: Numerators were SMA reports in VAERS from 12/12/02 to 3/1/04. Limitations of VAERS include underreporting and lack of diagnostic confirmation. Denominators were number of military and civilian vaccinees. RESULTS: Reporting rates stratified by age and sex of serious and non-serious AEs were significantly higher in civilian than military personnel ages <55 years (rate ratios 4-27). These rate ratios decreased with increasing age. CONCLUSIONS: Reporting rates in VAERS differed significantly and substantially in civilians compared to military personnel <55 years of age. Differences in stimulated passive surveillance systems, and AE reporting practices, including the 'threshold' for reporting most likely explain these findings. These results suggest that in the case of smallpox vaccine AEs, there may be systematic differences in reporting completeness between the civilian and military sectors, and that passive surveillance data should be interpreted with caution.

Risk of anaphylaxis after vaccination of children and adolescents.

OBJECTIVE: To quantify the risk of anaphylaxis after vaccination of children and adolescents. METHODS: The study population consisted of children and adolescents who were enrolled at 4 health maintenance organizations that participated in the Vaccine Safety Datalink Project. For the period 1991-1997, we identified potential cases by searching for occurrences of International Classification of Diseases, Ninth Revision (ICD-9) code 995.0 (anaphylactic shock), E948.0 through E948.9 (adverse reaction from bacterial vaccines), and E949.0 through E949.9 (adverse reaction from other vaccines and biological substances). At 1 study site, we also included a range of other allergy codes. We restricted to diagnoses on days 0 to 2 after vaccination (ICD-9 995.0) or day 0 (all other ICD-9 codes). We then reviewed the medical record to confirm the diagnosis. RESULTS: We identified 5 cases of potentially vaccine-associated anaphylaxis after administration of 7 644 049 vaccine doses, for a risk of 0.65 cases/million doses (95% confidence interval: 0.21-1.53). None of the episodes resulted in death. Vaccines that were administered before the anaphylactic episodes were generally given in combination and included measles-mumps-rubella, hepatitis B, diphtheria-tetanus, diphtheria-tetanus-pertussis, Haemophilus influenzae type b, and oral polio vaccine. One case of anaphylaxis followed measles-mumps-rubella vaccine alone. At the site at which we reviewed additional allergy codes, we identified 1 case after 653 990 vaccine doses, for a risk of 1.53 cases/million doses (95% confidence interval: 0.04-8.52). CONCLUSIONS: Patients and health care providers can be reassured that vaccine-associated anaphylaxis is a rare event. Nevertheless, providers should be prepared to provide immediate medical treatment should it occur.

Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent.

BACKGROUND: Infliximab is a humanized antibody against tumor necrosis factor alpha (TNF-alpha) that is used in the treatment of Crohn's disease and rheumatoid arthritis. Approximately 147,000 patients throughout the world have received infliximab. Excess TNF-alpha in association with tuberculosis may cause weight loss and night sweats, yet in animal models it has a protective role in the host response to tuberculosis. There is no direct evidence of a protective role of TNF-alpha in patients with tuberculosis. METHODS: We analyzed all reports of tuberculosis after infliximab therapy that had been received as of May 29, 2001, through the MedWatch spontaneous reporting system of the Food and Drug Administration. RESULTS: There were 70 reported cases of tuberculosis after treatment with infliximab, for a median of 12 weeks. In 48 patients, tuberculosis developed after three or fewer infusions. Forty of the patients had extrapulmonary disease (17 had disseminated disease, 11 lymph node disease, 4 peritoneal disease, 2 pleural disease, and 1 each meningeal, enteric, paravertebral, bone, genital, and bladder disease). The diagnosis was confirmed by a biopsy in 33 patients. Of the 70 reports, 64 were from countries with a low incidence of tuberculosis. The reported frequency of tuberculosis in association with infliximab therapy was much higher than the reported frequency of other opportunistic infections associated with this drug. In addition, the rate of reported cases of tuberculosis among patients treated with infliximab was higher than the available background rates. CONCLUSIONS: Active tuberculosis may develop soon after the initiation of treatment with infliximab. Before prescribing the drug, physicians should screen patients for latent tuberculosis infection or disease.

Data mining in the US Vaccine Adverse Event Reporting System (VAERS): early detection of intussusception and other events after rotavirus vaccination.

The Vaccine Adverse Event Reporting System (VAERS) is the US passive surveillance system monitoring vaccine safety. A major limitation of VAERS is the lack of denominator data (number of doses of administered vaccine), an element necessary for calculating reporting rates. Empirical Bayesian data mining, a data analysis method, utilizes the number of events reported for each vaccine and statistically screens the database for higher than expected vaccine-event combinations signaling a potential vaccine-associated event. This is the first study of data mining in VAERS designed to test the utility of this method to detect retrospectively a known side effect of vaccination-intussusception following rotavirus (RV) vaccine. From October 1998 to December 1999, 112 cases of intussusception were reported. The data mining method was able to detect a signal for RV-intussusception in February 1999 when only four cases were reported. These results demonstrate the utility of data mining to detect significant vaccine-associated events at early date. Data mining appears to be an efficient and effective computer-based program that may enhance early detection of adverse events in passive surveillance systems.

Surveillance for poliovirus vaccine adverse events, 1991 to 1998: impact of a sequential vaccination schedule of inactivated poliovirus vaccine followed by oral poliovirus vaccine.

BACKGROUND: The elimination of wild-virus-associated poliomyelitis in the Western Hemisphere in 1991 and rapid progress in global polio eradication efforts changed the risk-benefit ratio associated with the exclusive use of oral poliovirus vaccine (OPV) for routine immunization. These changes, plus the November 1987 development of an enhanced-potency inactivated poliovirus vaccine (IPV), which poses no risk of vaccine-associated paralytic poliomyelitis (VAPP), resulted in a change in polio immunization policy in the United States. In September 1996, the Centers for Disease Control and Prevention recommended that IPV replace OPV for the first 2 doses in a sequential poliovirus vaccine schedule. The Vaccine Adverse Event Reporting System (VAERS), a passive surveillance system for adverse events after receipt of any US-licensed vaccine, is used to monitor postlicensure vaccine safety. Postlicensure surveillance of vaccines is important to identify new, rare, or delayed-onset adverse reactions not detected in prelicensure clinical trials or when new vaccine schedules are adopted. Through continual monitoring of adverse events and identification of potential vaccine risks, VAERS can serve as an important resource to ensure continued public acceptance of vaccines. We compared VAERS reports after the receipt of IPV to reports after OPV in infants from 1991 through 1998. Comparisons included reports listing IPV and OPV coadministered with other vaccines. METHODS: Annual reporting rates per 100 000 doses distributed within 3 severity categories (fatal, nonfatal serious, less serious) were examined. Distributions of severity categories by vaccine type, age, and time period (pre- and postrecommendation) were constructed. Safety profiles (distribution of 21 symptom groupings) for IPV and OPV reports were compared. Analysis was restricted to reports for infants 1 to 3 months old and 4 to 6 months old, corresponding generally to first- and second-dose recipients. Any notable increase in a severity or safety category for IPV compared with OPV was followed up by examining the frequency of specific symptoms, reporting source, and date of vaccination. An important limitation of VAERS is that reports do not necessarily represent adverse events caused by vaccines. In many cases, the events are temporal associations only. RESULTS: The annual rates of VAERS reports per 100 000 vaccine doses distributed by severity category, 1991 to 1998, were in general similar for reports after IPV compared with those after OPV. The reporting rates for poliovirus vaccine did not increase materially with the shift to IPV usage. The relative frequencies of symptoms in the fatal and nonfatal serious categories for 1998 vaccine administrations were similar to 1997 reports. Severity profiles for IPV and OPV reports in infants 1 to 3 months old and 4 to 6 months old, corresponding to first- and second-dose recipients, were remarkably similar. The frequency of symptoms listed on IPV reports categorized as fatal or serious was examined by age, vaccine combinations, and time period, and the distribution of symptoms was similar for ages 1 to 3 months and 4 to 6 months. In the postrecommendation period, the 10 most frequent symptoms reported with IPV were also reported with OPV in either similar or lower relative frequency. During the postrecommendation period, safety profiles for infants 4 to 6 months old showed a 2.5% higher proportion in the allergic reaction category for IPV than for OPV, but none of the allergic reaction reports indicated anaphylaxis. In general, the distribution of symptom groupings was not markedly different for IPV compared with OPV. No cases of VAPP were reported after the administration of IPV, whereas 5 VAPP cases were reported after the administration of OPV. CONCLUSIONS: Although VAERS is subject to the limitations of most passive surveillance systems, the large number of reports and national coverage provide a unique database for monitoring vaccine safety. There was a marked increase of IPV reports in VAERS after 1996, consistent with implementation of the Advisory Committee on Immunization Practices recommendation for the sequential IPV/OPV poliovirus vaccination schedule. Given the increased use of IPV, a review of potential adverse events in VAERS compared IPV with OPV reports both before and after the introduction of the sequential vaccination schedule. Vaccine safety surveillance indicated no adverse events patterns of potential concern following the use of IPV in infants after the introduction of the sequential vaccination schedule. Ongoing surveillance is documenting a decrease in VAPP. These findings provide useful information to support the Advisory Committee on Immunization Practices recommendation, made in 1999, to shift to an all-IPV schedule.

Safety data on meningococcal polysaccharide vaccine from the Vaccine Adverse Event Reporting System.

Recent recommendations by the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices may lead to the increased use of the meningococcal polysaccharide vaccine. The Vaccine Adverse Event Reporting System (VAERS) is useful for the detection of previously unrecognized reactions and for the monitoring of known reactions. Limitations of VAERS include underreporting and the inability to establish a causal relationship between vaccination and adverse events in most cases. From July 1990 through 31 October 1999, 110 adverse events were reported after receipt of meningococcal vaccine alone. Thirteen (12%) were serious, including 6 injection site reactions, 3 allergic reactions, 1 case of Guillain-Barré syndrome, and 3 miscellaneous events. Fever (30%), headache (17%), dizziness (15%), injection site hypersensitivity (13%), urticaria (12%), and paresthesia (10%) were among the most common events reported. Fever and injection site and allergic reactions are most likely causally linked to the vaccine. That there were few reports of serious adverse events, with >6 million doses having been distributed, and no clear signal of a previously unrecognized serious reaction is reassuring with regard to the safety of meningococcal vaccine.

Stevens-Johnson syndrome and toxic epidermal necrolysis after vaccination: reports to the vaccine adverse event reporting system.

We conducted a telephone survey of reports of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) to the Vaccine Adverse Event Reporting System. We identified six cases of SJS or TEN after vaccination without other obvious triggers, suggesting that SJS and TEN might very rarely be caused by vaccination. Confirmation of this hypothesis will likely require controlled studies.

Infant immunization with acellular pertussis vaccines in the United States: assessment of the first two years' data from the Vaccine Adverse Event Reporting System (VAERS).

OBJECTIVE: To evaluate the safety of infant immunization with acellular pertussis vaccines in the United States. BACKGROUND: The US Food and Drug Administration approved the first acellular pertussis vaccine for use in infants in the United States on July 31, 1996. OUTCOME MEASURES: Adverse events in the United States after infant immunization with pertussis-containing vaccines, representing temporal (but not necessarily causal) associations between vaccinations and adverse events. DATA SOURCE: Reports to the Vaccine Adverse Event Reporting System (VAERS), a passive national surveillance system. DESIGN: Reports concerning infant immunization against pertussis between January 1, 1995 (when whole-cell vaccine was in exclusive use) and June 30, 1998 (when acellular vaccine was in predominant use) were analyzed, if the reports were entered into the VAERS database by November 30, 1998. RESULTS: During the study, there were 285 reports involving death, 971 nonfatal serious reports, and 4514 less serious reports after immunization with any pertussis-containing vaccine. For 1995 there were 2071 reports; in 1996 there were 1894 reports; in 1997 there were 1314 reports, and in the first half of 1998 there were 491 reports. Diphtheria-tetanus-pertussis vaccine (DTP) was cited in 1939 reports, diphtheria-tetanus-whole-cell pertussis-Haemophilus influenzae type b vaccine (DTPH) in 2918 reports, and diphtheria-tetanus-acellular pertussis vaccine (DTaP) in 913 reports. The annual number of deaths during the study was 85 in 1995, 82 in 1996, 77 in 1997, and 41 in the first half of 1998. The annual number of reported events categorized as nonfatal serious (defined as events involving initial hospitalization, prolongation of hospitalization, life-threatening illness, or permanent disability) to VAERS for all pertussis-containing vaccines declined: 334 in 1995, 311 in 1996, 233 in 1997, and 93 in the first half of 1998. Similarly, the annual number of less serious reports to VAERS for pertussis-containing vaccines declined: 1652 in 1995, 1501 in 1996, 1004 in 1997, and 357 in the first half of 1998. A comparison of the adverse event profiles (proportional distributions) for DTaP, DTP, and DTPH, as well as an analysis of specific adverse events considered in a 1991 Institute of Medicine report on the safety of diphtheria-tetanus-pertussis vaccine, did not identify any new, clear safety concerns. CONCLUSIONS: These findings reflect the administration of millions of doses of acellular pertussis vaccine and are reassuring with regard to the safety of marketed acellular pertussis vaccines. VAERS data, although subject to the limitations of passive surveillance, support the prelicensure data with regard to the safety of the US-licensed acellular pertussis vaccines that we evaluated.

Hypotonic-hyporesponsive episodes reported to the Vaccine Adverse Event Reporting System (VAERS), 1996-1998.

BACKGROUND: A hypotonic-hyporesponsive episode (HHE) is the sudden onset of hypotonia, hyporesponsiveness, and pallor or cyanosis that occurs within 48 hours after childhood immunizations. This syndrome has been primarily associated with pertussis-containing vaccines administered to children <2 years of age, and has been estimated to occur once every 1750 diphtheria-tetanus-pertussis (DTwP) vaccinations. Previous studies of HHE were limited by small numbers of cases and, sometimes, by limited details of the event. OBJECTIVES: To characterize a large number of HHE cases reported to the Vaccine Adverse Event Reporting System (VAERS), to assist clinicians in identifying HHE, and to assist researchers in investigating the risk factors, cause, and pathogenesis of this syndrome. METHODS: More than 40,000 VAERS reports received between 1996 and 1998 were screened for HHE by a computer algorithm and reviewed, and a telephone follow-up questionnaire was administered to the witness of HHE. RESULTS: There were 215 HHE cases, all nonfatal. The median age of onset of HHE was 4.0 months (range: 1.1-107 months). Over half of the reports (53%) concerned females. The median birth weight was 3. 36 kg (range: 1.27-4.96 kg); 4.7% had a birth weight <2500 g. The median interval between vaccination and HHE was 210 minutes (range: 1 minute-2 days). Among children with HHE who were <24 months of age, the episode occurred within 5 minutes in only 8.5%, compared with 66.7% of children with HHE >24 months of age. There were no relevant findings regarding family medical history or the mothers' gestational history. Nearly all of the children (98.6%) returned to their prevaccination state according to the telephone questionnaire; median time to return was 6 hours (range: 1 minute- 4 months). The 3 children reported as not returning to their prevaccination state all had VAERS reports submitted after they developed conditions (autism, complex partial epilepsy, and developmental delays with infantile spasms) that are not known to be causally associated with immunization. The vast majority of children (93%) with HHE received a pertussis-containing vaccine, either diphtheria-tetanus-acellular pertussis (DTaP, 28%), DTwP (11%), or diphtheria-tetanus-pertussis-Haemophilus influenzae type b (DTwP-HIB, 61%). During the HHE episode, 90.1% of the children had pallor and 49% had cyanosis. Because of the HHE event, 6.8% of children had had all vaccines withheld as of the date of the interview. Of the remainder, 66.5% of children have had 1 or more subsequent vaccinations or vaccine components withheld, and 26.7% have not had any subsequent vaccinations withheld. Only 1 child was reported to have had a repeat episode of HHE, occurring after hepatitis B vaccination. From 1996 to 1998, the number of HHE reports decreased from 99 to 38, when the predominant pertussis vaccine administered to infants changed from whole-cell to acellular. CONCLUSION: This study represents the largest published case series of children with HHE and supports the generally benign, self-limited, nonrecurrent nature of this syndrome. Although HHE has been less frequently reported to VAERS after increased use of DTaP, HHE does occur after the administration of DTaP and other nonpertussis-containing vaccines. Although most parents and pediatricians withheld the pertussis component of subsequent vaccinations, many did not, with no reported adverse events occurring in the children after the subsequent immunizations. Restricting the definition of HHE to a more narrow age range (eg, <2 years of age) is also proposed because most of the older children probably experienced vasovagal syncope rather than HHE within 5 minutes of immunization.

Postlicensure safety surveillance for varicella vaccine.

CONTEXT: Since its licensure in 1995, the extensive use of varicella vaccine and close surveillance of the associated anecdotal reports of suspected adverse effects provide the opportunity to detect potential risks not observed before licensure because of the relatively small sample size and other limitations of clinical trials. OBJECTIVES: To detect potential hazards, including rare events, associated with varicella vaccine, and to assess case reports for clinical and epidemiological implications. DESIGN AND SETTING: Postlicensure case-series study of suspected vaccine adverse events reported to the US Vaccine Adverse Event Reporting System (VAERS) from March 17, 1995, through July 25, 1998. MAIN OUTCOME MEASURES: Numbers of reported adverse events, proportions, and reporting rates (reports per 100,000 doses distributed). RESULTS: VAERS received 6574 case reports of adverse events in recipients of varicella vaccine, a rate of 67.5 reports per 100,000 doses sold. Approximately 4% of reports described serious adverse events, including 14 deaths. The most frequently reported adverse events were rashes, possible vaccine failures, and injection site reactions. Misinterpretation of varicella serology after vaccination appeared to account for 17% of reports of possible vaccine failures. Among 251 patients with herpes zoster, 14 had the vaccine strain of varicella zoster virus (VZV), while 12 had the wild-type virus. None of 30 anaphylaxis cases was fatal. An immunodeficient patient with pneumonia had the vaccine strain of VZV in a lung biopsy. Pregnant women occasionally received varicella vaccine through confusion with varicella zoster immunoglobulin. Although the role of varicella vaccine remained unproven in most serious adverse event reports, there were a few positive rechallenge reports and consistency of many cases with syndromes recognized as complications of natural varicella. CONCLUSION: Most of the reported adverse events associated with varicella vaccine are minor, and serious risks appear to be rare. We could not confirm a vaccine etiology for most of the reported serious events; several will require further study to clarify whether varicella vaccine plays a role. Education is needed to ensure appropriate use of varicella serologic assays and to eliminate confusion between varicella vaccine and varicella zoster immunoglobulin. JAMA. 2000;284:1271-1279

Report of a US public health service workshop on hypotonic-hyporesponsive episode (HHE) after pertussis immunization.

Hypotonic-hyporesponsive episode (HHE) is a term used to describe a somewhat heterogenous group of clinical disorders that have been reported primarily in association with whole-cell pertussis vaccination. A 1991 review by the Institute of Medicine determined that the evidence available was indeed consistent with a causal relation between whole-cell pertussis-diphtheria-tetanus immunization and HHE, but that the evidence was insufficient to indicate a causal relationship between HHE and the subsequent development of permanent neurologic damage. More recent data from clinical trials conducted in Europe suggest that HHE also occurs after vaccination with acellular pertussis vaccines. The US Food and Drug Administration, in collaboration with the US Public Health Service, sponsored a workshop on HHE in Rockville, Maryland, on June 19, 1997. The primary goals of the workshop were to develop a case definition of HHE and to evaluate the general design and feasibility of possible studies of HHE using the federal Vaccine Adverse Event Reporting System (VAERS), a national passive surveillance system. The goals of such studies would be to understand better the acute HHE event and to evaluate the possibility of long-term sequelae. Case Definition. There has been no generally accepted definition of HHE, and a standard definition would be useful for vaccine safety work and would potentially facilitate interstudy comparisons of the growing number of licensed vaccines containing acellular pertussis components. The workshop defined HHE as an event of sudden onset occurring within 48 hours of immunization, with duration of the episode ranging from 1 minute to 48 hours, in children younger than 10 years of age. All of the following must be present: 1) limpness or hypotonia, 2) reduced responsiveness or hyporesponsiveness, and 3) pallor or cyanosis or failure to observe or to recall skin coloration. HHE is not considered to have occurred if there is a known cause for these signs (eg, postictal), if urticaria is present during the event, if normal skin coloration is observed throughout the episode, or if the child is simply sleeping. This inclusive (sensitive) case definition will allow investigators, through the technique of stratification according to certain characteristics (eg, time from vaccination to onset of HHE), to attempt to hone the definition and make it more specific. Refinement of the definition of HHE has been hindered by the lack of information on its pathophysiology and by the lack of pathognomonic signs, symptoms, and diagnostic tests. Another hindrance is that by the time the child presents for medical evaluation, the signs of HHE often have normalized. Moreover, different mechanisms may be involved in different individuals whose events meet this workshop's HHE definition. Further Study of HHE. Probably the most important question about HHE is whether it has any permanent sequelae. The workshop assessed the possible contribution VAERS-based studies could make to answering this question and found substantial methodologic problems; however, ongoing studies in Sweden and The Netherlands have the potential to provide useful information on this question. The most useful contribution of VAERS data would be in a descriptive study of HHE, with a possible case-control study of factors that may affect the risk of HHE after vaccination, rather than a study of possible permanent sequelae. The workshop participants felt that a detailed descriptive study of approximately 100 HHE events reported during a 1- to 2-year period could provide a more in-depth description of HHE cases in greater numbers than has been published previously, but the study would not address the issue of long-term sequelae of HHE. Better descriptive data may lead to new hypotheses concerning risk factors, etiology, and pathophysiology of HHE that might be evaluated further by studying subsequent cases and controls from VAERS or from other sources, depending on the hypoth

Heredity and prostate cancer: a study of World War II veteran twins.

BACKGROUND: Increased risk of prostate cancer among men with a family history of the disease has been observed in several epidemiological studies, and family studies have identified hereditary prostate cancer characterized by early onset and autosomal dominant inheritance. METHODS: In this study, we examine prostate cancer heritability among twins in the NAS-NRC Twin Registry, with cases ascertained from a number of sources: recent telephone interviews, Medicare and Department of Veterans Affairs hospitalizations, previous mail questionnaires, and death certificates. A total of 1,009 prostate cancer cases were identified among the cohort of 31,848 veteran twins born in the years 1917-1927. RESULTS: Probandwise concordance for prostate cancer was substantially higher among monozygous twin pairs, 27.1%, than among dizygous twin pairs, 7.1% (P < 0.001). CONCLUSIONS: These data suggest that genetic influences account for approximately 57%, and environmental influences for 43%, of the variability in twin liability for prostate cancer.

Descriptive epidemiology of adverse events after immunization: reports to the Vaccine Adverse Event Reporting System (VAERS), 1991-1994.

OBJECTIVE: To provide an overview of the data, function, and performance of the Vaccine Adverse Event Reporting System. DESIGN: Descriptive and correlational analyses. SETTING: United States, 1991 through 1994. SUBJECTS: Reports to the Vaccine Adverse Event Reporting System, a passive national surveillance system, that represents temporal (but not necessarily causal) relationships between vaccinations and adverse events. MAIN OUTCOME MEASURES: Demographic variables, birth weight, vaccine type, severity of adverse event after immunization. RESULTS: A total of 38,787 adverse events was reported during the study period without a clearly increasing or decreasing trend in the annual number of total reports or deaths. Of the deaths with known age, 72.4% were reported in the first year of life, and 63.7% of these were male. The peak age for death reports was 1 to 3 months, with a gradual decline through age 9 months, after which death was relatively rare. Adverse events with onset of symptoms the day of vaccination accounted for 45.5% of total reports; 20.4% had onset of symptoms the following day. Onset within 2 weeks after vaccination was noted for 92.5% of all reports. Simultaneous administration of multiple vaccines was noted in 75.7% of reports for immunizations at ages younger than 20 years. In contrast, among those 20 years or older, only 6.0% of reports named multiple vaccines. Wide geographic variations were noted in adverse event reporting rates for children younger than 2 years, and the states with the lowest reporting rates of less serious events included the most populous states. CONCLUSIONS: The peak age of deaths at ages 1 to 3 months could be expected on the basis of prior studies showing that sudden infant death syndrome deaths peak at that age, that most deaths in the Vaccine Adverse Event Reporting System are attributed to sudden infant death syndrome, and that sudden infant death syndrome has not been associated with vaccination. The large number of reports and national coverage of the Vaccine Adverse Events Reporting System make it useful for monitoring the safety of vaccine lots and for accumulating case series to detect or better understand adverse events that may occur too rarely to be assessed in clinical trials or in the larger studies that are sometimes carried out by manufacturers after vaccine licensure (phase IV studies).