Factors associated with social contacts in four communities during the 2007-2008 influenza season.

Mathematical models of influenza pandemics are sensitive to changes in contact rates between individuals. We conducted population-based telephone surveys in four North Carolina counties to determine the number of social interactions between individuals during the 2007-2008 influenza season. Influenza activity was monitored through sentinel medical practices. Among 3845 adults, the number of social contacts varied with age, was lower on weekends than on weekdays, and further decreased during school holiday periods. Adults with influenza-like illnesses had fewer social contacts. Adults' contacts in the community setting increased during periods of peak influenza activity. Among 290 children, potential contacts (i.e. other people in the same location) were lowest among preschool-age children and decreased on weekends and during school holidays. In adjusted analyses, children's potential social contacts did not change during periods of peak influenza activity. These results should be useful for modelling influenza epidemics and pandemics and in planning mitigation and response strategies.

Predictive value of ICD-9-CM codes used in vaccine safety research.

OBJECTIVES: To assess how well selected ICD-9-CM diagnosis codes predict adverse events; to model bias and power loss when vaccine safety analyses rely on unverified codes. METHODS: We extracted chart verification data for ICD-9-CM diagnosis codes from six Vaccine Safety Datalink (VSD) publications and modeled biases and power losses using positive predictive value (PPV) estimates and ranges of code sensitivity. RESULTS: Positive predictive values were high for type 1 diabetes (80%) in children, relative to WHO criteria, and intussusception (81%) in young children, relative to a standard published case definition. PPVs were moderate (65%) for inpatient and emergency department childhood seizures and low (21%) for outpatient childhood seizures, both relative to physician investigator judgment. Codes for incident central nervous system demyelinating disease in adults had high PPV for inpatient codes (80%) and low PPV for outpatient codes (42%) relative to physicians' diagnoses. Modeled biases were modest, but large increases in frequencies of adverse events are required to achieve adequate power if unverified ICD-9-CM codes are used, especially when vaccine associations are weak. CONCLUSIONS: ICD-9-CM codes for type 1 diabetes in children, intussusception in young children, childhood seizures in inpatient and emergency care settings, and inpatient demyelinating disease in adults were sufficiently predictive for vaccine safety analyses to rely on unverified diagnosis codes. Adverse event misclassification should be accounted for in statistical power calculations.

Vaccines and autism: evidence does not support a causal association.

A suggested association between certain childhood vaccines and autism has been one of the most contentious vaccine safety controversies in recent years. Despite compelling scientific evidence against a causal association, many parents and parent advocacy groups continue to suspect that vaccines, particularly measles-mumps-rubella (MMR) vaccine and thimerosal-containing vaccines (TCVs), can cause autism.

Immunity to tetanus is protective against the development of multiple sclerosis.

Following allegations that Hepatitis B vaccination causes or triggers multiple sclerosis (MS), several epidemiological studies have been conducted to evaluate the association between MS and vaccination. In one study conducted in the US, a significant protective effect on the development of MS was observed for tetanus immunization. We reviewed the medical literature and found two additional recent studies, as well as several older studies, which also observed a significant protective effect of tetanus immunization on the development or progression of MS. Furthermore, decreased humoral and cellular immunity to tetanus toxoid has been observed among MS patients. We postulate that naturally acquired or vaccine-induced immunity to tetanus has a protective effect against the development and progression of MS. We also postulate that this link to tetanus is in part responsible for the gender, age, geographic and socio-economic distribution of MS, as well as its pattern among migrants. The biological basis for this protective effect could be an unspecific boost of bystander suppression of auto-immunity as shown for other infections. Our hypothesis can be tested in several ways. The simplest approach would be to compare tetanus exposure and MS occurrence on a population level. Stronger support would come from the re-analysis of previous studies that have information at the individual level on both tetanus exposure, whether induced or natural, and on the development of MS. Laboratory evidence could be sought by testing the effect of tetanus toxoid on experimental allergic encephalomyelitis, the experimental animal model of MS.

Quality assessments of HMO diagnosis databases used to monitor childhood vaccine safety.

OBJECTIVE: To assess the quality of automated diagnoses extracted from medical care databases by the Vaccine Safety Datalink (VSD) study. METHODS: Two methods are used to assess quality of VSD diagnosis data. The first method compares common automated and abstracted diagnostic categories ("outcomes") in 1-2% simple random samples of study populations. The second method estimates positive predictive values of automated diagnosis codes used to identify potential cases of rare conditions (e.g., acute ataxia) for inclusion in nested case-control medical record abstraction studies. RESULTS: There was good agreement (64-68%) between automated and abstracted outcomes in the 1-2% simple random samples at 3 of the 4 VSD sites and poor agreement (44%) at 1 site. Overall at 3 sites, 56% of children with automated cerebella ataxia codes (ICD-9 = 334) and 22% with "lack of coordination" codes (ICD-9 = 781.3) met objective clinical criteria for acute ataxia. CONCLUSIONS: The misclassification error rates for automated screening outcomes substantially reduce the power of screening analyses and limit usefulness of screening analyses to moderate to strong vaccine-outcome associations. Medical record verification of outcomes is needed for definitive assessments.

Medically recorded allergies and the risk of childhood acute lymphoblastic leukaemia.

Data on five allergic conditions were abstracted from the medical records of 180 cases of childhood acute lymphoblastic leukaemia (ALL) and 718 matched controls. Odds Ratios (OR) and 95% Confidence Intervals (CI) were estimated for composite variables and for individual allergies using conditional logistic regression modelling. Allergies were divided into late and early diagnoses (those made within the year before the matched case's ALL diagnosis and those made earlier, respectively). Among the early diagnoses, atopy or hives was significantly associated with ALL (OR=2.20; 95% CI: 1.16-4.16). Significant associations were found for late diagnoses of atopy or hives (OR=3.78; 95% CI: 1.00-14.29) and of asthma (OR=3.10; 95% CI: 1.39-6.95). None of the other allergic conditions were associated with ALL. These results are contrary to those of prior studies of childhood ALL and allergy.

Allogeneic bone marrow transplantation (BMT) for adults with acute lymphoblastic leukemia (ALL): predictive role of minimal residual disease monitoring on relapse.

We developed a PCR-based method to monitor clonogenic IgH VDJ rearrangement as a possible predictor of relapse in patients with acute B-ALL after allogeneic bone marrow transplantation (BMT). We studied 23 patients at diagnosis, before and after BMT. At the time of BMT, 13 patients were in first complete remission, eight in second complete remission and two in relapse. Four patients were PCR negative before BMT and remained PCR negative also after BMT (-/- pattern). They are still in remission after a median follow-up of 41 months. Nineteen patients were MRD-positive before BMT: three were PCR negative at first determination after BMT (+/- pattern) and maintain remission. Sixteen patients were PCR-positive at first determination after BMT (+/+ pattern): five became PCR negative (+/+/- pattern) (four with chronic graft-versus-host disease (GVHD) and two after donor lymphocyte infusions (DLI)). Nine patients remained PCR-positive (+/+/+ pattern) (four remain in remission, and six relapsed); two patients died before transplant. In conclusion, PCR negative patients before BMT remained negative post-BMT; many pre-BMT positive patients had initial MRD positivity after BMT: 37% of them achieved a molecular remission with cGVHD or DLI.

Childhood vaccinations, vaccination timing, and risk of type 1 diabetes mellitus.

OBJECTIVES: To evaluate suggested associations between childhood vaccinations, particularly against hepatitis B and Haemophilus influenzae type b, and risk of developing type 1 diabetes; and to determine whether timing of vaccination influences risk. METHODS: We conducted a case-control study within 4 health maintenance organizations (HMOs) that participate in the Vaccine Safety Datalink project of the Centers for Disease Control and Prevention. Study eligibility was restricted to children who met the following criteria: 1) born during 1988 through 1997; 2) HMO member since birth; 3) continuously enrolled for first 6 months of life; and 4) at least 12 months of HMO membership before diabetes incidence date (or index date for controls) unless incidence date was before 12 months of age. All 4 HMOs maintain registries of their members who have diabetes, and we used the registries to identify potential cases of diabetes. We conducted chart reviews to verify that potential cases met the World Health Organization epidemiologic case definition for type 1 diabetes mellitus (ie, a physician's diagnosis of diabetes plus treatment with daily insulin injections). We defined the incidence date of diabetes as the first date that the child received a diagnosis of diabetes. We attempted to match 3 controls to each case. Controls had the same eligibility criteria as cases and were matched to individual cases on HMO, sex, date of birth (within 7 days), and length of health plan enrollment (up to the incidence or index date). The index date for controls was defined as the incidence date of the case to which the control was matched. Chart abstraction was performed by trained chart abstractors using standardized forms. In addition to complete vaccination histories, the chart abstraction forms for both cases and controls included information on sociodemographic characteristics, selected medical conditions, history of breastfeeding, and family medical history. We used conditional logistic regression to estimate the odds ratio (OR) of diabetes associated with vaccination, with vaccine exposure defined as before the diabetes incidence date (or index date for controls). RESULTS: Two hundred fifty-two confirmed cases of diabetes and 768 matched controls met the study eligibility criteria. The OR (95% confidence interval) for the association with type 1 diabetes was 0.28 (0.07-1.06) for whole cell pertussis vaccine (predominantly in combination as diphtheria, tetanus toxoids and pertussis vaccine), 1.36 (0.70-2.63) for measles-mumps-rubella, 1.14 (0.51-2.57) for Haemophilus influenzae type b, 0.81 (0.52-1.27) for hepatitis B vaccine, 1.16 (0.72-1.89) for varicella vaccine, and 0.92 (0.53-1.57) for acellular pertussis-containing vaccines. Compared with children who had not received hepatitis B vaccine, the OR of diabetes was 0.51 (0.23-1.15) for children vaccinated at birth and 0.86 (0.54-1.35) for those first vaccinated against hepatitis B at 2 months of age or later. Race and ethnicity and family history of diabetes were independently associated with risk of type 1 diabetes, but adjustment for these factors did not materially alter the ORs for any of the vaccines. CONCLUSIONS: In this large, population-based, case-control study, we did not find an increased risk of type 1 diabetes associated with any of the routinely recommended childhood vaccines. Our study adds to previous research by providing data on newer vaccines, including hepatitis B, acellular pertussis, and varicella vaccines. For the older vaccines, our results are generally in agreement with previous studies in not finding any increased risks. Ours is the first epidemiologic study to evaluate the possibility that timing of vaccination is related to risk of clinical diabetes in children. Our results on hepatitis B vaccine do not support the hypothesis; risk of type 1 diabetes was not different between infants vaccinated at birth and those who received their first vaccination later in life. The results of our study and the preponderance of epidemiologic evidence do not support an association between any of the recommended childhood vaccines and an increased risk of type 1 diabetes. Suggestions that diabetes risk in humans may be altered by changes in the timing of vaccinations also are unfounded.

Safety of neonatal hepatitis B vaccine administration.

OBJECTIVE: To determine whether hepatitis B vaccination of newborns increases the incidence of fever and/or suspected sepsis. METHODS: A prospective clinical study was undertaken at the Kaiser Permanente San Francisco Medical Center involving normal full term newborns born between November 1, 1991, and April 30, 1994. During this time 3302 infants were vaccinated within 21 days of birth with hepatitis B vaccine, and 2353 were not. Clinical and demographic data were collected from Kaiser Permanente's existing clinical information systems, and laboratory data for blood and cerebrospinal fluid (CSF) cultures were obtained from the comprehensive automated regional laboratory reporting system. RESULTS: There were no significant differences between vaccinated and unvaccinated newborns in the proportion of infants who received care for fever (0.8% vaccinated and 1.1% unvaccinated, P = 0.28), allergic reactions, seizures or other neurologic events in the first 21 days of life. Vaccinated newborns were significantly less likely to undergo microbiologic evaluation for possible sepsis. Among vaccinated newborns 4.0% had blood cultures and 1.6% had CSF cultures. Among infants who were not vaccinated 8.3% had blood cultures and 1.6% had CSF cultures (P <0.001 for both tests). CONCLUSION: This study found no evidence that newborn hepatitis B vaccination is associated with an increase in the number of febrile episodes, sepsis evaluations or allergic or neurologic events. In addition our data did not support any increase in medical procedures attributed to receipt of hepatitis B vaccine.

Autism and measles-mumps-rubella vaccination: controversy laid to rest?

It has been suggested that vaccination, particularly with measles-mumps-rubella (MMR) vaccine, may be related to the development of autism. The main evidence for a possible association is that the prevalence of autism has been increasing at the same time that infant vaccination coverage has increased, and that in some cases there is an apparent temporal association in which autistic characteristics are first noted shortly after vaccination. Although the prevalence of autism and similar disorders appears to have increased recently, it is not clear if this is an actual increase or the result of increased recognition and changes in diagnostic criteria. The apparent onset of autism in close proximity to vaccination may be a coincidental temporal association. The clinical evidence in support of an association derives from a series of 12 patients with inflammatory bowel conditions and regressive developmental disorders, mostly autism. The possibility that measles vaccine may cause autism through a persistent bowel infection has generated much interest, since it provides a possible biological mechanism. Epidemiological studies, however, have not found an association between MMR vaccination and autism. The epidemiological findings are consistent with current understanding of the pathogenesis of autism, which has a strong genetic component and in which the neurological defects probably occur early in embryonic development. It seems unlikely that a vaccination that is given after birth could cause autism. A minority of cases of autism may have onset after 1 year of age (regressive autism), but the single epidemiological study that included such cases did not find an association with MMR vaccination. Currently, the weight of the available epidemiological and related evidence does not support a causal association between MMR vaccine, or any other vaccine or vaccine constituent, and autism.

Ability to trace migrant farmworkers ten years after initial identification in a Northern State (Wisconsin).

BACKGROUND: Migrant farmworkers have rarely been included in epidemiologic studies. To assess the feasibility of following farmworkers over extended periods, a critical feature of many study designs, we attempted to trace a sample of Mexican-American farmworkers identified in a clinic in Wisconsin. METHODS: We randomly chose 100 farmworkers from a migrant health center registration list for 1984-85. In 1995, we searched recent clinic records, made telephone calls, and visited migrant camps to find these farmworkers in Wisconsin during the growing season. We also attempted to find 46 farmworkers at their homes in southwest Texas over a two-week period in 1996 using the address listed in the clinic records, local phone books, and conversations with next-door neighbors. RESULTS: Although 25 farmworkers had reregistered at the clinic in recent years, we found only 6 of them in Wisconsin in 1995. In southwest Texas, we either located or ascertained information about the vital status of 25 of the 46 farmworkers (54%). CONCLUSIONS: Tracing efforts must include extensive contacts in farmworkers' home states and must incorporate a variety of information sources. Tracing farmworkers in epidemiologic studies appears to be feasible but requires more intensive methods over longer periods of time than those used in this study.

The risk of seizures after receipt of whole-cell pertussis or measles, mumps, and rubella vaccine.

BACKGROUND: The administration of the diphtheria and tetanus toxoids and whole-cell pertussis (DTP) vaccine and measles, mumps, and rubella (MMR) vaccine has been associated with adverse neurologic events, including seizures. We studied the relation between these vaccinations and the risk of a first seizure, subsequent seizures, and neurodevelopmental disability in children. METHODS: This cohort study was conducted at four large health maintenance organizations and included reviews of the medical records of children with seizures. We calculated the relative risks of febrile and nonfebrile seizures among 679,942 children after 340,386 vaccinations with DTP vaccine, 137,457 vaccinations with MMR vaccine, or no recent vaccination. Children who had febrile seizures after vaccination were followed to identify the risk of subsequent seizures and other neurologic disabilities. RESULTS: Receipt of DTP vaccine was associated with an increased risk of febrile seizures only on the day of vaccination (adjusted relative risk, 5.70; 95 percent confidence interval, 1.98 to 16.42). Receipt of MMR vaccine was associated with an increased risk of febrile seizures 8 to 14 days after vaccination (relative risk, 2.83; 95 percent confidence interval, 1.44 to 5.55). Neither vaccination was associated with an increased risk of nonfebrile seizures. Analyses of automated data alone gave results similar to the analyses of the data from medical-record reviews. The number of febrile seizures attributable to the administration of DTP and MMR vaccines was estimated to be 6 to 9 and 25 to 34 per 100,000 children, respectively. As compared with other children with febrile seizures that were not associated with vaccination, the children who had febrile seizures after vaccination were not found to be at higher risk for subsequent seizures or neurodevelopmental disabilities. CONCLUSIONS: There are significantly elevated risks of febrile seizures on the day of receipt of DTP vaccine and 8 to 14 days after the receipt of MMR vaccine, but these risks do not appear to be associated with any long-term, adverse consequences.

Safety and immunogenicity of varying dosages of trivalent inactivated influenza vaccine administered by needle-free jet injectors.

To evaluate the perceived pain, other adverse events, and immunogenicity of influenza virus vaccine administered by needle-free jet injector (JI) compared with that of vaccine administered by needle and syringe (N&S), we randomly assigned 304 healthy young adults to receive one of three dosages (0.5, 0.3, or 0.2 ml) of the 1998-1999 season vaccine administered by either of two JI devices or by N&S. In multivariate analysis, female gender and JI administration were associated with higher levels of pain reported at the time of vaccination as well as with the occurrence of local injection site reactions following vaccination. Immune response did not vary significantly by dosage but administration by one JI device was associated with higher post-vaccination H1N1 antibody titers.

Population-based study of rotavirus vaccination and intussusception.

BACKGROUND: During the first year that the rhesus rotavirus tetravalent vaccine (RRV-TV) was licensed, the Vaccine Adverse Event Reporting System received several reports of intussusception after vaccination. To evaluate the risk of intussusception, we conducted a retrospective cohort study in ten managed care organizations. METHODS: Cases of intussusception were identified by searching electronic databases for diagnoses of intussusception (ICD-9 Code 560.0) in infants 1 to 11 months of age and confirmed by medical chart review. Vaccination and enrollment data were obtained from administrative databases. Incidence rate ratios (RR) of intussusception were computed by dividing incidence rates in prespecified risk intervals after vaccination by the background rate of intussusception and adjusted for age by Poisson regression. Cox proportional hazard regression was used to evaluate risk by vaccine dose. RESULTS: Of 463,277 children 56,253 had been vaccinated with a total of 91 371 doses of RRV-TV. The incidence rate of intussusception was 25/100,000 person years among unexposed infants and 340/100,000 person years 3 to 7 days postvaccination. In the interval 3 to 7 days after vaccination, the age-adjusted RR was 16.0 (95% confidence interval, 5.5 to 46.7) for all doses combined and 30.4 (95% confidence interval, 8.8 to 104.9) after the first dose. RRs for the 8- to 14- and 15- to 21-day risk intervals were >1.0, but the confidence intervals substantially overlapped 1.0. The attributable risk was one case of intussusception per 11 073 children vaccinated. CONCLUSIONS: RRV-TV is associated with an increased risk of intussusception. The risk is greatest 3 to 7 days after the first vaccination dose.

Epidemiology of autoimmune reactions induced by vaccination.

In order for vaccinations to 'work', the immune system must be stimulated. The concern that immunizations may lead to the development of autoimmune disease (AID) has been questioned. Since AID occur in the absence of immunizations, it is unlikely that immunizations are a major cause of AID. Epidemiological studies are needed, however, to assess whether immunizations may increase the risk in some susceptible individuals. This paper discusses the evidence for and against vaccination as a risk factor for AID. Evidence for immunizations leading to AID come from several sources including animal studies, single and multiple case reports, and ecologic association. However more rigorous investigation has failed to confirm most of the allegations. Unfortunately the question remains difficult to address because for most AIDs, there is limited knowledge of the etiology, background incidence and other risk factors for their development. This information is necessary, in the absence of experimental evidence derived from controlled studies, for any sort of adequate causality assessment using the limited data that are available. Several illustrative examples are discussed to highlight what is known and what remains to be explored, and the type of epidemiological evidence that would be required to better address the issues. Examples include the possible association of immunization and multiple sclerosis (and other demyelinating diseases), type 1 diabetes mellitus, Guillain-Barre Syndrome, idiopathic thrombocytopenic purpura, and rheumatoid arthritis.

Challenges and controversies in immunization safety.

No vaccine is perfectly safe or effective. As diseases such as diphtheria and polio fade, vaccine safety concerns, especially alleged links between vaccinations and several chronic illnesses, have become increasingly prominent in the media and to the public. This article reviews the current scientific evidence on several recent vaccine safety controversies. It also provides information on how various safety research is conducted, some of the concurrent challenges, and finally, some guidance on communicating with patients on vaccine risks.

Measles-mumps-rubella and other measles-containing vaccines do not increase the risk for inflammatory bowel disease: a case-control study from the Vaccine Safety Datalink project.

CONTEXT: A link between measles virus-containing vaccines and inflammatory bowel disease (IBD) has been suggested by recent studies. OBJECTIVE: To address whether receipt or timing of measles-containing vaccine (MCV) increases risk for IBD. DESIGN: A case-control study. SETTING: Four large health maintenance organizations (HMOs) that are part of the Centers for Disease Control and Prevention's Vaccine Safety Datalink project. PATIENTS OR OTHER PARTICIPANTS: A total of 155 persons with codes from International Classification of Diseases, Ninth Revision specific for IBD, born between 1958 and 1989 and enrolled from birth to the onset of disease, were identified. Up to 5 controls were matched by sex, HMO, and birth year. INTERVENTION: None. MAIN OUTCOME MEASURES: Risk for IBD, Crohn's disease, and ulcerative colitis. RESULTS: Past vaccination was not associated with an increased risk for Crohn's disease (odds ratio [OR] for measles-mumps-rubella vaccine [MMR], 0.4; 95% confidence interval [CI], 0.08-2.0), ulcerative colitis (OR, 0.8; 95% CI, 0.18-3.56), or IBD (OR, 0.59; 95% CI, 0.21-1.68). Risk for IBD was not increased among children vaccinated who were younger than 12 months (OR for MMR, 0.61; 95% CI, 0.15-2.45) or aged 12 to 18 months (OR, 0.86; 95% CI, 0.28-2.59) relative to unvaccinated children. Children vaccinated with MMR who were older than 18 months were at significantly decreased risk for IBD (OR, 0.16; 95% CI, 0.04-0.68). Neither past vaccination nor age at vaccination with other MCV was associated with increased risk for Crohn's disease, ulcerative colitis, or IBD. Risk for Crohn's disease, ulcerative colitis, or IBD was not elevated in the time immediately following vaccination with either vaccine. CONCLUSIONS: Vaccination with MMR or other MCV, or the timing of vaccination early in life, did not increase the risk for IBD.