A simulation study to compare three self-controlled case series approaches: correction for violation of assumption and evaluation of bias.

PURPOSE: The assumption that the occurrence of outcome event must not alter subsequent exposure probability is critical for preserving the validity of the self-controlled case series (SCCS) method. This assumption is violated in scenarios in which the event constitutes a contraindication for exposure. In this simulation study, we compared the performance of the standard SCCS approach and two alternative approaches when the event-independent exposure assumption was violated. METHODS: Using the 2009 H1N1 and seasonal influenza vaccines and Guillain-Barré syndrome as a model, we simulated a scenario in which an individual may encounter multiple unordered exposures and each exposure may be contraindicated by the occurrence of outcome event. The degree of contraindication was varied at 0%, 50%, and 100%. The first alternative approach used only cases occurring after exposure with follow-up time starting from exposure. The second used a pseudo-likelihood method. RESULTS: When the event-independent exposure assumption was satisfied, the standard SCCS approach produced nearly unbiased relative incidence estimates. When this assumption was partially or completely violated, two alternative SCCS approaches could be used. While the post-exposure cases only approach could handle only one exposure, the pseudo-likelihood approach was able to correct bias for both exposures. CONCLUSIONS: Violation of the event-independent exposure assumption leads to an overestimation of relative incidence which could be corrected by alternative SCCS approaches. In multiple exposure situations, the pseudo-likelihood approach is optimal; the post-exposure cases only approach is limited in handling a second exposure and may introduce additional bias, thus should be used with caution.

Pregnancy modifies the antibody response to trivalent influenza immunization.

We report the immunogenicity of trivalent influenza immunization in 29 pregnant women compared with 22 nonpregnant women. We obtained blood specimens on day 0 prior to 2011-2012 influenza vaccine administration and day 28 after immunization. Hemagglutination inhibition (HAI) geometric mean titers were similar before immunization but were significantly reduced by 40%-50% in pregnant women after immunization for influenza A/California(H1N1) (P = .027) and A/Perth(H3N2) (P = .037). Postimmunization HAI titers were similar between groups for influenza B/Brisbane (P = .390). The geometric mean ratio (fold increase) for influenza A(H1N1) was nonsignificantly reduced in pregnant participants (P = .089). The percentages of participants who seroconverted and achieved seroprotection were similar between groups.

Patterns of Immune Activation in HIV and Non HIV Subjects and Its Relation to Cardiovascular Disease Risk.

Introduction: Insight into inflammation patterns is needed to understand the pathophysiology of HIV and related cardiovascular disease (CVD). We assessed patterns of inflammation related to HIV infection and CVD risk assessed with carotid intima media thickness (CIMT). Methods: A cross-sectional study was performed in Johannesburg, South Africa, including participants with HIV who were virally suppressed on anti-retroviral therapy (ART) as well as HIV-negative participants who were family members or friends to the HIV-positive participants. Information was collected on CVD risk factors and CIMT. Inflammation was measured with the Olink panel 'inflammation', allowing to simultaneously assess 92 inflammation markers. Differences in inflammation patterns between HIV-positive and HIV-negative participants were explored using a principal component analysis (PCA) and ANCOVA. The impact of differentiating immune markers, as identified by ANCOVA, on CIMT was assessed using linear regression while adjusting for classic CVD risk factors. Results: In total, 185 HIV-positive and 104 HIV negative participants, 63% females, median age 40.7 years (IQR 35.4 - 47.7) were included. HIV-positive individuals were older (+6 years, p <0.01) and had a higher CIMT (p <0.01). No clear patterns of inflammation were identified by use of PCA. Following ANCOVA, nine immune markers differed significantly between HIV-positive and HIV-negative participants, including PDL1. PDL1 was independently associated with CIMT, but upon stratification this effect remained for HIV-negative individuals only. Conclusion: HIV positive patients on stable ART and HIV negative controls had similar immune activation patterns. CVD risk in HIV-positive participants was mediated by inflammation markers included in this study.

Quantifying outcome misclassification in multi-database studies: The case study of pertussis in the ADVANCE project.

BACKGROUND: The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private collaboration aiming to develop and test a system for rapid benefit-risk (B/R) monitoring of vaccines using European healthcare databases. Event misclassification can result in biased estimates. Using different algorithms for identifying cases of Bordetella pertussis (BorPer) infection as a test case, we aimed to describe a strategy to quantify event misclassification, when manual chart review is not feasible. METHODS: Four participating databases retrieved data from primary care (PC) setting: BIFAP: (Spain), THIN and RCGP RSC (UK) and PEDIANET (Italy); SIDIAP (Spain) retrieved data from both PC and hospital settings. BorPer algorithms were defined by healthcare setting, data domain (diagnoses, drugs, or laboratory tests) and concept sets (specific or unspecified pertussis). Algorithm- and database-specific BorPer incidence rates (IRs) were estimated in children aged 0-14 years enrolled in 2012 and 2014 and followed up until the end of each calendar year and compared with IRs of confirmed pertussis from the ECDC surveillance system (TESSy). Novel formulas were used to approximate validity indices, based on a small set of assumptions. They were applied to approximately estimate positive predictive value (PPV) and sensitivity in SIDIAP. RESULTS: The number of cases and the estimated BorPer IRs per 100,000 person-years in PC, using data representing 3,173,268 person-years, were 0 (IR = 0.0), 21 (IR = 4.3), 21 (IR = 5.1), 79 (IR = 5.7), and 2 (IR = 2.3) in BIFAP, SIDIAP, THIN, RCGP RSC and PEDIANET respectively. The IRs for combined specific/unspecified pertussis were higher than TESSy, suggesting that some false positives had been included. In SIDIAP the estimated IR was 45.0 when discharge diagnoses were included. The sensitivity and PPV of combined PC specific and unspecific diagnoses for BorPer cases in SIDIAP were approximately 85% and 72%, respectively. CONCLUSION: Retrieving BorPer cases using only specific concepts has low sensitivity in PC databases, while including cases retrieved by unspecified concepts introduces false positives, which were approximately estimated to be 28% in one database. The share of cases that cannot be retrieved from a PC database because they are only seen in hospital was approximately estimated to be 15% in one database. This study demonstrated that quantifying the impact of different event-finding algorithms across databases and benchmarking with disease surveillance data can provide approximate estimates of algorithm validity.

Impact and longevity of measles-associated immune suppression: a matched cohort study using data from the THIN general practice database in the UK.

OBJECTIVE: To test the hypothesis that measles infection increases the incidence of non-measles infectious diseases over a prolonged period of time. DESIGN: A population-based matched cohort study. DATA SOURCES: This study examined children aged 1-15 years in The Health Improvement Network UK general practice medical records database. Participants included 2228 patients diagnosed with measles between 1990 and 2014, which were matched on age, sex, general practitioner practice and calendar year with 19 930 children without measles. All controls had received at least one measles vaccination. Children with a history of immune-compromising conditions or with immune-suppressive treatment were excluded. PRIMARY OUTCOME MEASURES: Incidence rate ratio (IRR) of infections, anti-infective prescriptions and all-cause hospitalisations following measles in predetermined periods using multivariate analysis to adjust for confounding variables. RESULTS: In children with measles, the incidence rate for non-measles infectious disease was significantly increased in each time period assessed up to 5 years postmeasles: 43% in the first month (IRR: 1.43; 95% CI 1.22 to 1.68), 22% from month one to the first year (IRR: 1.22; 95% CI 1.14 to 1.31), 10% from year 1 to 2.5 years (IRR: 1.10; 95% CI 1.02 to 1.19) and 15% (IRR: 1.15; 95% CI 1.06 to 1.25) in years 2.5 to 5 years of follow-up. Children with measles were more than three times as likely to receive an anti-infective prescription in the first month and 15%-24% more likely between the first month and 5 years. The rate of hospitalisation in children with measles was increased only in the month following diagnosis but not thereafter (IRR: 2.83; 95% CI 1.72 to 4.67). CONCLUSION: Following measles, children had increased rates of diagnosed infections, requiring increased prescribing of antimicrobial therapies. This population-based matched cohort study supports the hypothesis that measles has a prolonged impact on host resistance to non-measles infectious diseases.

Enhancing global vaccine pharmacovigilance: Proof-of-concept study on aseptic meningitis and immune thrombocytopenic purpura following measles-mumps containing vaccination.

New vaccines designed to prevent diseases endemic in low and middle-income countries (LMICs) are now being introduced without prior record of utilization in countries with robust pharmacovigilance systems. To address this deficit, our objective was to demonstrate feasibility of an international hospital-based network for the assessment of potential epidemiological associations between serious and rare adverse events and vaccines in any setting. This was done through a proof-of-concept evaluation of the risk of immune thrombocytopenic purpura (ITP) and aseptic meningitis (AM) following administration of the first dose of measles-mumps-containing vaccines using the self-controlled risk interval method in the primary analysis. The World Health Organization (WHO) selected 26 sentinel sites (49 hospitals) distributed in 16 countries of the six WHO regions. Incidence rate ratios (IRR) of 5.0 (95% CI: 2.5-9.7) for ITP following first dose of measles-containing vaccinations, and of 10.9 (95% CI: 4.2-27.8) for AM following mumps-containing vaccinations were found. The strain-specific analyses showed significantly elevated ITP risk for measles vaccines containing Schwarz (IRR: 20.7; 95% CI: 2.7-157.6), Edmonston-Zagreb (IRR: 11.1; 95% CI: 1.4-90.3), and Enders'Edmonston (IRR: 8.5; 95% CI: 1.9-38.1) strains. A significantly elevated AM risk for vaccines containing the Leningrad-Zagreb mumps strain (IRR: 10.8; 95% CI: 1.3-87.4) was also found. This proof-of-concept study has shown, for the first time, that an international hospital-based network for the investigation of rare vaccine adverse events, using common standardized procedures and with high participation of LMICs, is feasible, can produce reliable results, and has the potential to characterize differences in risk between vaccine strains. The completion of this network by adding large reference hospitals, particularly from tropical countries, and the systematic WHO-led implementation of this approach, should permit the rapid post-marketing evaluation of safety signals for serious and rare adverse events for new and existing vaccines in all settings, including LMICs.

Incidence rates of narcolepsy diagnoses in Taiwan, Canada, and Europe: The use of statistical simulation to evaluate methods for the rapid assessment of potential safety issues on a population level in the SOMNIA study.

BACKGROUND & OBJECTIVES: Vaccine safety signals require investigation, which may be done rapidly at the population level using ecological studies, before embarking on hypothesis-testing studies. Incidence rates were used to assess a signal of narcolepsy following AS03-adjuvanted monovalent pandemic H1N1 (pH1N1) influenza vaccination among children and adolescents in Sweden and Finland in 2010. We explored the utility of ecological data to assess incidence of narcolepsy following exposure to pandemic H1N1 virus or vaccination in 10 sites that used different vaccines, adjuvants, and had varying vaccine coverage. METHODS: We calculated incidence rates of diagnosed narcolepsy for periods defined by influenza virus circulation and vaccination campaign dates, and used Poisson regression to estimate incidence rate ratios (IRRs) comparing the periods during which wild-type virus circulated and after the start of vaccination campaigns vs. the period prior to pH1N1 virus circulation. We used electronic health care data from Sweden, Denmark, the United Kingdom, Canada (3 provinces), Taiwan, Netherlands, and Spain (2 regions) from 2003 to 2013. We investigated interactions between age group and adjuvant in European sites and conducted a simulation study to investigate how vaccine coverage, age, and the interval from onset to diagnosis may impact the ability to detect safety signals. RESULTS: Incidence rates of narcolepsy varied by age, continent, and period. Only in Taiwan and Sweden were significant time-period-by-age-group interactions observed. Associations were found for children in Taiwan (following pH1N1 virus circulation) and Sweden (following vaccination). Simulations showed that the individual-level relative risk of narcolepsy was underestimated using ecological methods comparing post- vs. pre-vaccination periods; this effect was attenuated with higher vaccine coverage and a shorter interval from disease onset to diagnosis. CONCLUSIONS: Ecological methods can be useful for vaccine safety assessment but the results are influenced by diagnostic delay and vaccine coverage. Because ecological methods assess risk at the population level, these methods should be treated as signal-generating methods and drawing conclusions regarding individual-level risk should be avoided.

Bell's palsy and influenza(H1N1)pdm09 containing vaccines: A self-controlled case series.

BACKGROUND: An association between AS03 adjuvanted pandemic influenza vaccine and the occurrence of Bell's palsy was found in a population based cohort study in Stockholm, Sweden. To evaluate this association in a different population, we conducted a self-controlled case series in a primary health care database, THIN, in the United Kingdom. The aim of this study was to determine whether there was an increased risk of Bell's palsy following vaccination with any influenza vaccine containing A/California/7/2009 (H1N1)-like viral strains. Secondly, we investigated whether risks were different following pandemic influenza A(H1N1)pdm09 vaccines and seasonal influenza vaccines containing the influenza A(H1N1)pdm09 strain. METHODS: The study population comprised all incident Bell's palsy cases between 1 June 2009 and 30 June 2013 identified in THIN. We determined the relative incidence (RI) of Bell's palsy during the 6 weeks following vaccination with either pandemic or seasonal influenza vaccine. All analyses were adjusted for seasonality and confounding variables. RESULTS: We found an incidence rate of Bell's palsy of 38.7 per 100,000 person years. Both acute respiratory infection (ARI) consultations and pregnancy were found to be confounders. When adjusted for seasonality, ARI consultations and pregnancies, the RI during the 42 days after vaccination with an influenza vaccine was 0.85 (95% CI: 0.72-1.01). The RI was similar during the 42 days following seasonal vaccine (0.96, 95%CI: 0.82-1.13) or pandemic vaccine (0.73, 95%CI: 0.47-1.12). CONCLUSION: We found no evidence for an increased incidence of Bell's palsy following seasonal influenza vaccination overall, nor for monovalent pandemic influenza vaccine in 2009.

Administrative data misclassifies and fails to identify nephrotoxin-associated acute kidney injury in hospitalized children.

OBJECTIVES: Nephrotoxin exposure is a common cause of acute kidney injury (AKI) in hospitalized children. AKI detection relies on regular serum creatinine (SCr) screening among exposed patients. We sought to determine how well administrative data identify hospitalized noncritically ill children with nephrotoxic medication-associated AKI in the contexts of incomplete and complete screening. METHODS: We conducted a single-center retrospective cohort study among noncritically ill hospitalized children. We compared administrative data sensitivity to that among a separate cohort for whom adequate screening was defined as daily SCr measurement. For the original cohort, nephrotoxin exposure was defined as exposure to ≥3 nephrotoxins at once or ≥3 days of aminoglycoside therapy. AKI was defined by the change in SCr (pediatric-modified Risk Injury Failure Loss End-Stage Renal Disease [pRIFLE] criteria) or discharge code. Adequate SCr screening was defined as 2 measurements obtained ≤96 hours apart. Administrative data and laboratory values were merged to compare AKI by discharge code and pRIFLE criteria. RESULTS: 747 of 1472 (50.7%) nephrotoxin-exposed patients were adequately screened; 82 (11.0%) had AKI by pRIFLE criteria, 52 (7.0%) by discharge code. Sensitivity of nephrotoxin-associated AKI diagnosis by discharge code compared with pRIFLE criteria was 23.2% (95% confidence interval = 14.0-32.3). In the comparison cohort, 70 (26.8%) patients had AKI by pRIFLE criteria and 26 (10.0%) by discharge code; sensitivity was 21.4% (95% confidence interval = 11.8%-31.0%). CONCLUSIONS: pRIFLE criteria identified more patients than were identified by discharge code. Identifying patients with nephrotoxin-associated AKI by discharge code, even in the presence of complete AKI detection, underrepresents the true incidence of nephrotoxin-associated AKI in hospitalized children.

Comparison of a new transport medium with universal transport medium at a tropical field site.

Limited data are available in rural Honduran settings describing the etiology of respiratory infections, partially due to limited specimen transport. A new molecular transport media (MTM) preserves released nucleic acid at ambient temperature for later detection. Prospective surveillance was conducted in a Honduran clinic to identify 233 children less than 5 years of age presenting with respiratory symptoms. We obtained 2 nasopharyngeal samples and stored 1 in PrimeStore® MTM at room temperature and 1 in universal transport media (UTM) at -80 °C. The specimens were then transported to Cincinnati Children's Hospital and tested for 16 respiratory viruses using a multiplex PCR panel. The 2 specimen collection systems were similar for detecting the 4 most common viruses: influenza (Kappa = 0.7676, P < 0.0001), human metapneumovirus (Kappa = 0.8770, P < 0.0001), respiratory syncytial virus (Kappa = 0.6849, P < 0.0001), and parainfluenza (Kappa = 0.8796, P < 0.0001). These results suggest that clinical specimens transported via PrimeStore® MTM and UTM yield similar viral multiplex PCR results.

IgA and neutralizing antibodies to influenza a virus in human milk: a randomized trial of antenatal influenza immunization.

BACKGROUND: Antenatal immunization of mothers with influenza vaccine increases serum antibodies and reduces the rates of influenza illness in mothers and their infants. We report the effect of antenatal immunization on the levels of specific anti-influenza IgA levels in human breast milk. (ClinicalTrials.gov identifier NCT00142389; http://clinicaltrials.gov/ct2/show/NCT00142389). METHODS AND FINDINGS: The Mother's Gift study was a prospective, blinded, randomized controlled trial that assigned 340 pregnant Bangladeshi mothers to receive either trivalent inactivated influenza vaccine, or 23-valent pneumococcal polysaccharide vaccine during the third trimester. We evaluated breast milk at birth, 6 weeks, 6 months, and 12 months, and serum at 10 weeks and 12 months. Milk and serum specimens from 57 subjects were assayed for specific IgA antibody to influenza A/New Caledonia (H1N1) using an enzyme-linked immunosorbent assay (ELISA) and a virus neutralization assay, and for total IgA using ELISA. Influenza-specific IgA levels in breast milk were significantly higher in influenza vaccinees than in pneumococcal controls for at least 6 months postpartum (p = 0.04). Geometric mean concentrations ranged from 8.0 to 91.1 ELISA units/ml in vaccinees, versus 2.3 to 13.7 ELISA units/mL in controls. Virus neutralization titers in milk were 1.2 to 3 fold greater in vaccinees, and correlated with influenza-specific IgA levels (r = 0.86). Greater exclusivity of breastfeeding in the first 6 months of life significantly decreased the expected number of respiratory illness with fever episodes in infants of influenza-vaccinated mothers (p = 0.0042) but not in infants of pneumococcal-vaccinated mothers (p = 0.4154). CONCLUSIONS: The sustained high levels of actively produced anti-influenza IgA in breast milk and the decreased infant episodes of respiratory illness with fever suggest that breastfeeding may provide local mucosal protection for the infant for at least 6 months. Studies are needed to determine the cellular and immunologic mechanisms of breast milk-mediated protection after antepartum immunization. TRIAL REGISTRATION: ClinicalTrials.gov NCT00142389.

International collaboration to assess the risk of Guillain Barré Syndrome following Influenza A (H1N1) 2009 monovalent vaccines.

BACKGROUND: The global spread of the 2009 novel pandemic influenza A (H1N1) virus led to the accelerated production and distribution of monovalent 2009 Influenza A (H1N1) vaccines (pH1N1). This pandemic provided the opportunity to evaluate the risk of Guillain-Barré syndrome (GBS), which has been an influenza vaccine safety concern since the swine flu pandemic of 1976, using a common protocol among high and middle-income countries. The primary objective of this project was to demonstrate the feasibility and utility of global collaboration in the assessment of vaccine safety, including countries both with and without an established infrastructure for vaccine active safety surveillance. A second objective, included a priori, was to assess the risk of GBS following pH1N1 vaccination. METHODS: The primary analysis used the self-controlled case series (SCCS) design to estimate the relative incidence (RI) of GBS in the 42 days following vaccination with pH1N1 vaccine in a pooled analysis across databases and in analysis using a meta-analytic approach. RESULTS: We found a relative incidence of GBS of 2.42 (95% CI 1.58-3.72) in the 42 days following exposure to pH1N1 vaccine in analysis of pooled data and 2.09 (95% CI 1.28-3.42) using the meta-analytic approach. CONCLUSIONS: This study demonstrates that international collaboration to evaluate serious outcomes using a common protocol is feasible. The significance and consistency of our findings support a conclusion of an association between 2009 H1N1 vaccination and GBS. Given the rarity of the event the relative incidence found does not provide evidence in contradiction to international recommendations for the continued use of influenza vaccines.

Etiology and seasonality of viral respiratory infections in rural Honduran children.

BACKGROUND: Limited data are available in Honduras that describe the etiology and seasonality of respiratory infections, especially in rural outpatient settings. Better data may lead to improved therapeutic and preventive strategies. The goal of our study was to determine the viral etiology and seasonality of acute respiratory infections in a rural Honduran population of children. METHODS: Prospective clinic surveillance was conducted to identify children < 5 years of age presenting with respiratory symptoms of < 5 days duration. We obtained data on age, sex, medical history, breastfeeding history, symptoms, risk factors, household setting, temperature, respiratory rate and chest examination findings. To assess the association between specific viruses and weather, regional meteorological data were collected. Nasopharyngeal samples were tested for 16 respiratory viruses using a multiplex polymerase chain reaction panel. RESULTS: From February 2010 through June 2011, 345 children < 5 years of age were enrolled; 17%, 23%, 30% and 31% were <6, 6-11, 12-23 and 24-60 months old, respectively. Including all clinics in the region, 44.5% of patients < 5 years of age with documented respiratory diagnoses were enrolled. At least 1 virus was identified in 75.4% children, of which 7.5% were coinfections; 13.3% were positive for parainfluenza, 11.9% for influenza, 8.1% for human metapneumovirus and 7.5% for respiratory syncytial virus. Rainfall correlated with parainfluenza (P < 0.0001), influenza (P < 0.0001), human metapneumovirus (P = 0.0182) and respiratory syncytial virus (P < 0.0001). CONCLUSIONS: These results suggest that the spectrum of viruses in ill, rural, Honduran children is similar to that in North and Central America, although the seasonality is typical of some tropical regions.

Antibody persistence in mothers one year after pneumococcal immunization in pregnancy.

BACKGROUND: Pneumococcal infections are a significant cause of morbidity and mortality, and young infants are particularly vulnerable to infection. Maternal immunization can protect infants, but there are limited data on the duration of pneumococcal vaccine antibody in pregnant women. We report on maternal antibody concentrations one year after immunization with 23-valent pneumococcal polysaccharide (23vPPS) vaccine. METHOD: The Mother's Gift study randomly assigned 340 pregnant Bangladeshi mothers between ages 18 and 36 to receive either inactivated influenza vaccine (Fluarix(®)) or the 23vPPS vaccine (Pneumovax(®)) during the third trimester. Sera were collected before immunization, at delivery, and at one year post-delivery. We determined anti-capsular IgG antibody to 9 pneumococcal serotypes by a multiplex Luminex ELISA. We report antibody geometric mean concentrations (GMCs) for 9 serotypes, 12 month/delivery geometric mean ratios (GMRs) and proportions seroprotected (>0.35 mcg/mL) in 23vPPS vaccine recipients and controls at delivery and at 12 months. RESULTS: Among pneumococcal vaccinees, GMCs remained stable, with an overall 12 month/delivery GMR of 0.83 (95% CI, 0.75-0.92). In the control group, GMCs increased with a mean ratio of 1.98 (95% CI, 1.81-2.17; P<0.0001). GMCs in these vaccinees did not decline significantly in the 12 months after antenatal immunization. CONCLUSION: GMCs in these adult vaccinees and controls did not decline significantly in the 12 months after antenatal immunization. Interestingly, mothers who did not receive 23vPPS in pregnancy show a substantial increase of GMC for most serotypes in the first year after immunization. Further studies are needed to determine the need for repeat doses of 23vPPS vaccine in subsequent pregnancies more than a year later.