W. Katherine Yih

The Increasing Incidence of Pertussis in Massachusetts Adolescents and Adults, 1989–1998

From 1989 to 1998, the incidence of pertussis increased in Massachusetts adolescents and adults, reaching 71 and 5 per 100,000, respectively, by 1998, whereas the incidence in children remained stable. By 1998, 92% of cases occurred in adolescents and adults. Nationally, in contrast, adolescents and adults had incidences of only 5 and 0.8 per 100,000, respectively, and accounted for 47% of cases. The availability of a specific serologic test and active surveillance by public health personnel in Massachusetts are at least partial explanations. The rise in incidence may be real, however, because, as diagnostic efforts increased, the percentage of patients with a positive serologic test result also increased. Cases identified in adolescents and adults were quite severe: 83% and 87%, respectively, experienced paroxysmal cough, 45% and 41% experienced vomiting, and 41% and 52% experienced a cough lasting >4 weeks. Administration of acellular pertussis vaccine in these age groups could prevent this substantial morbidity.

The incidence of varicella and herpes zoster in Massachusetts as measured by the Behavioral Risk Factor Surveillance System (BRFSS) during a period of increasing varicella vaccine coverage, 1998–2003

BackgroundThe authors sought to monitor the impact of widespread varicella vaccination on the epidemiology of varicella and herpes zoster. While varicella incidence would be expected to decrease, mathematical models predict an initial increase in herpes zoster incidence if re-exposure to varicella protects against reactivation of the varicella zoster virus.MethodsIn 1998–2003, as varicella vaccine uptake increased, incidence of varicella and herpes zoster in Massachusetts was monitored using the random-digit-dial Behavioral Risk Factor Surveillance System.ResultsBetween 1998 and 2003, varicella incidence declined from 16.5/1,000 to 3.5/1,000 (79%) overall with ≥66% decreases for all age groups except adults (27% decrease). Age-standardized estimates of overall herpes zoster occurrence increased from 2.77/1,000 to 5.25/1,000 (90%) in the period 1999–2003, and the trend in both crude and adjusted rates was highly significant (p < 0.001). Annual age-specific rates were somewhat unstable, but all increased, and the trend was significant for the 25–44 year and 65+ year age groups.ConclusionAs varicella vaccine coverage in children increased, the incidence of varicella decreased and the occurrence of herpes zoster increased. If the observed increase in herpes zoster incidence is real, widespread vaccination of children is only one of several possible explanations. Further studies are needed to understand secular trends in herpes zoster before and after use of varicella vaccine in the United States and other countries.

Intussusception Risk after Rotavirus Vaccination in U.S. Infants

BACKGROUND International postlicensure studies have identified an increased risk of intussusception after vaccination with the second-generation rotavirus vaccines RotaTeq (RV5, a pentavalent vaccine) and Rotarix (RV1, a monovalent vaccine). We studied this association among infants in the United States. METHODS The study included data from infants 5.0 to 36.9 weeks of age who were enrolled in three U.S. health plans that participate in the Mini-Sentinel program sponsored by the Food and Drug Administration. Potential cases of intussusception and vaccine exposures from 2004 through mid-2011 were identified through procedural and diagnostic codes. Medical records were reviewed to confirm the occurrence of intussusception and the status with respect to rotavirus vaccination. The primary analysis used a self-controlled risk-interval design that included only vaccinated children. The secondary analysis used a cohort design that included exposed and unexposed person-time. RESULTS The analyses included 507,874 first doses and 1,277,556 total doses of RV5 and 53,638 first doses and 103,098 total doses of RV1. The statistical power for the analysis of RV1 was lower than that for the analysis of RV5. The number of excess cases of intussusception per 100,000 recipients of the first dose of RV5 was significantly elevated, both in the primary analysis (attributable risk, 1.1 [95% confidence interval, 0.3 to 2.7] for the 7-day risk window and 1.5 [95% CI, 0.2 to 3.2] for the 21-day risk window) and in the secondary analysis (attributable risk, 1.2 [95% CI, 0.2 to 3.2] for the 21-day risk window). No significant increase in risk was seen after dose 2 or 3. The results with respect to the primary analysis of RV1 were not significant, but the secondary analysis showed a significant risk after dose 2. CONCLUSIONS RV5 was associated with approximately 1.5 (95% CI, 0.2 to 3.2) excess cases of intussusception per 100,000 recipients of the first dose. The secondary analysis of RV1 suggested a potential risk, although the study of RV1 was underpowered. These risks must be considered in light of the demonstrated benefits of rotavirus vaccination. (Funded by the Food and Drug Administration.).

Real-time surveillance to assess risk of intussusception and other adverse events after pentavalent, bovine-derived rotavirus vaccine.

Background: A pentavalent, bovine-derived rotavirus vaccine (RotaTeq, Merck) was licensed in 2006 for use in infants. A previously licensed rotavirus vaccine was withdrawn due to elevated risk of intussusception. We prospectively evaluated the risk of intussusception and other pre-specified adverse events among RotaTeq recipients in the Vaccine Safety Datalink. Methods: The exposed population included children from age 4 to 48 weeks who received RotaTeq between May 2006 and May 2008. Adverse events over the subsequent 30 days were ascertained from inpatient, outpatient, and emergency department files; cases of intussusception were validated by medical record review. An adaptation of sequential probability ratio testing was employed to compare the cumulative number of observed and expected adverse events on a weekly basis, and a “signal” was generated if the log-likelihood ratio reached a predetermined threshold. This allowed near real-time monitoring to detect selected adverse events. The expected number of cases of intussusception was determined from historical rates in the VSD population. Results: There were 207,621 doses of RotaTeq administered to the study population; 42% were first doses. Five children had computerized diagnosis codes for intussusception, and 6.75 cases were expected based on historical rates (relative risk = 0.74). No elevation in risk was identified for intussusception or any other adverse event. Two of five children with suspected intussusception based on diagnosis codes met the case criteria after medical record review. Conclusions: This study illustrates the feasibility of rapid vaccine safety assessment and provides additional evidence that RotaTeq is not associated with an increased risk of intussusception.

Association between Guillain-Barré syndrome and influenza A (H1N1) 2009 monovalent inactivated vaccines in the USA: a meta-analysis

BACKGROUND The influenza A (H1N1) 2009 monovalent vaccination programme was the largest mass vaccination initiative in recent US history. Commensurate with the size and scope of the vaccination programme, a project to monitor vaccine adverse events was undertaken, the most comprehensive safety surveillance agenda in the USA to date. The adverse event monitoring project identified an increased risk of Guillain-Barré syndrome after vaccination; however, some individual variability in results was noted. Guillain-Barré syndrome is a rare but serious health disorder in which a persons own immune system damages their nerve cells, causing muscle weakness, sometimes paralysis, and infrequently death. We did a meta-analysis of data from the adverse event monitoring project to ascertain whether influenza A (H1N1) 2009 monovalent inactivated vaccines used in the USA increased the risk of Guillain-Barré syndrome. METHODS Data were obtained from six adverse event monitoring systems. About 23 million vaccinated people were included in the analysis. The primary analysis entailed calculation of incidence rate ratios and attributable risks of excess cases of Guillain-Barré syndrome per million vaccinations. We used a self-controlled risk-interval design. FINDINGS Influenza A (H1N1) 2009 monovalent inactivated vaccines were associated with a small increased risk of Guillain-Barré syndrome (incidence rate ratio 2·35, 95% CI 1·42-4·01, p=0·0003). This finding translated to about 1·6 excess cases of Guillain-Barré syndrome per million people vaccinated. INTERPRETATION The modest risk of Guillain-Barré syndrome attributed to vaccination is consistent with previous estimates of the disorder after seasonal influenza vaccination. A risk of this small magnitude would be difficult to capture during routine seasonal influenza vaccine programmes, which have extensive, but comparatively less, safety monitoring. In view of the morbidity and mortality caused by 2009 H1N1 influenza and the effectiveness of the vaccine, clinicians, policy makers, and those eligible for vaccination should be assured that the benefits of inactivated pandemic vaccines greatly outweigh the risks. FUNDING US Federal Government.

Active Surveillance for Adverse Events: The Experience of the Vaccine Safety Datalink Project

OBJECTIVE: To describe the Vaccine Safety Datalink (VSD) projects experience with population-based, active surveillance for vaccine safety and draw lessons that may be useful for similar efforts. PATIENTS AND METHODS: The VSD comprises a population of 9.2 million people annually in 8 geographically diverse US health care organizations. Data on vaccinations and diagnoses are updated and extracted weekly. The safety of 5 vaccines was monitored, each with 5 to 7 prespecified outcomes. With sequential analytic methods, the number of cases of each outcome was compared with the number of cases observed in a comparison group or the number expected on the basis of background rates. If the test statistic exceeded a threshold, it was a signal of a possible vaccine-safety problem. Signals were investigated by using temporal scan statistics and analyses such as logistic regression. RESULTS: Ten signals appeared over 3 years of surveillance: 1 signal was reported to external stakeholders and ultimately led to a change in national vaccination policy, and 9 signals were found to be spurious after rigorous internal investigation. Causes of spurious signals included imprecision in estimated background rates, changes in true incidence or coding over time, other confounding, inappropriate comparison groups, miscoding of outcomes in electronic medical records, and chance. In the absence of signals, estimates of adverse-event rates, relative risks, and attributable risks from up-to-date VSD data have provided rapid assessment of vaccine safety to policy-makers when concerns about a specific vaccine have arisen elsewhere. CONCLUSIONS: Care with data quality, outcome definitions, comparison groups, and length of surveillance are required to enable detection of true safety problems while minimizing false signals. Some causes of false signals in the VSD system were preventable and have been corrected, whereas others will be unavoidable in any active surveillance system. Temporal scan statistics, analyses to control for confounding, and chart review are indispensable tools in signal investigation. The VSDs experience may inform new systems for active safety surveillance.

An assessment of the safety of adolescent and adult tetanus―diphtheria―acellular pertussis (Tdap) vaccine, using active surveillance for adverse events in the Vaccine Safety Datalink

Using a new sequential analytic method, the safety of tetanus-diphtheria-acellular pertussis (Tdap) vaccine was monitored weekly among subjects aged 10-64 years during 2005-2008. Encephalopathy-encephalitis-meningitis, paralytic syndromes, seizures, cranial nerve disorders, and Guillain-Barré syndrome were selected as outcomes based on previous reports and biologic plausibility. The risk following Tdap was not significantly higher than the risk after Td. Statistical power was sufficient to detect a relative risk of 4-5 for Guillain-Barré syndrome and 1.5-2 for the other outcomes. This study provides reassurance that Tdap is similar in safety to Td regarding the outcomes studied and supports the viability of sequential analysis for post-licensure vaccine safety monitoring.

Evidence for Transmission of Pertussis in Schools, Massachusetts, 1996: Epidemiologic Data Supported by Pulsed-Field Gel Electrophoresis Studies

In 1996, 18 of 20 pertussis outbreaks reported in Massachusetts occurred in schools. Pertussis surveillance data were reviewed and a retrospective cohort study was conducted in a high school that experienced an outbreak. Bordetella pertussis isolates from 9 school cases and from 58 cases statewide were examined by use of pulsed-field gel electrophoresis (PFGE). Statewide incidence rates were highest among children aged <1 year, 10-14 years, and 15-19 years (106, 117, and 104 cases per 100,000, respectively). Among 34 confirmed and 20 probable cases at the school, 61% had cough onset within 8 weeks of school opening. Five different PFGE types were identified among the 58 B. pertussis isolates from throughout the state. All 9 isolates from the affected high school were the same PFGE type. School-aged children may play an important role in pertussis epidemics. Consideration should be given to use of acellular pertussis vaccines among school-aged children.

Surveillance for Adverse Events Following Receipt of Pandemic 2009 H1N1 Vaccine in the Post-Licensure Rapid Immunization Safety Monitoring (PRISM) System, 2009–2010

The Post-Licensure Rapid Immunization Safety Monitoring (PRISM) system is a cohort-based active surveillance network initiated by the US Department of Health and Human Services to supplement preexisting and other vaccine safety monitoring systems in tracking the safety of monovalent pandemic 2009 H1N1 influenza vaccine in the United States during 2009-2010. PRISM investigators conducted retrospective analysis to determine whether 2009 H1N1 vaccination was associated with increased risk of any of 14 prespecified outcomes. Five health insurance and associated companies with 38 million members and 9 state/city immunization registries contributed records on more than 2.6 million doses of 2009 H1N1 vaccine. Data on outcomes came from insurance claims. Complementary designs (self-controlled risk interval, case-centered, and current-vs.-historical comparison) were used to optimize control for confounding and statistical power. The self-controlled risk interval analysis of chart-confirmed Guillain-Barré syndrome found an elevated but not statistically significant incidence rate ratio following receipt of inactivated 2009 H1N1 vaccine (incidence rate ratio = 2.50, 95% confidence interval: 0.42, 15.0) and no cases following live attenuated 2009 H1N1 vaccine. The study did not control for infection prior to Guillain-Barré syndrome, which may have been a confounder. The risks of other health outcomes of interest were generally not significantly elevated after 2009 H1N1 vaccination.

Accuracy of Data on Influenza Vaccination Status at Four Vaccine Safety Datalink Sites

BACKGROUND Studies of influenza vaccination using electronic medical records rely on accurate classification of vaccination status. Vaccinations not entered into electronic records would be unavailable for study. PURPOSE This study evaluated the sensitivity and negative predictive value (NPV) of electronic records for influenza vaccination and factors associated with failure to capture vaccinations. METHODS In four diverse medical care organizations in the Vaccine Safety Datalink, those aged 50-79 years with no influenza vaccination record during the 2007-2008 season were surveyed by telephone, and electronic records were analyzed in 2008. The sensitivity and NPV of electronic records were estimated, using survey responses as the gold standard. Logistic regression models determined associations between 1-NPV and demographic factors, risk of influenza complications, and healthcare utilization levels. RESULTS Data were obtained for 933 survey participants and 1,085,916 medical care organization members. Sites varied significantly in the sensitivity (51%, 68%, 79%, 89%) and NPV (46%, 62%, 66%, 87%) of electronic records. In multivariate analysis, the rate of failure to capture vaccinations was significantly higher for those aged 65-79 years than for those aged 50-64 years at three sites. Of vaccinations not captured by electronic records, 58% were reportedly administered in nontraditional settings, usually workplaces; the rest were given within the sites. CONCLUSIONS Influenza vaccination studies relying on electronic records may misclassify substantial proportions of vaccinated individuals as unvaccinated, producing biased estimates of vaccine effectiveness. Sites with limited sensitivity to capture vaccinations administered within their organization should seek possible remedies. More complete capture of vaccinations administered to older patients and in nontraditional settings would further reduce misclassification.