G Ferreira

Pandemrix™ and narcolepsy: A critical appraisal of the observational studies

A link between Pandemrix™ (AS03-adjuvanted H1N1 pandemic influenza vaccine, GSK Vaccines, Belgium) and narcolepsy was first suspected in 2010 in Sweden and Finland following a number of reports in children and adolescents. Initial scepticism about the reported association faded as additional countries reported similar findings, leading several regulatory authorities to restrict the use of Pandemrix™. The authors acknowledge that currently available data suggest an increased risk of narcolepsy following vaccination with Pandemrix™; however, from an epidemiologists perspective, significant methodological limitations of the studies have not been fully addressed and raise questions about the reported risk estimates. We review the most important biases and confounders that potentially occurred in 12 European studies of the observed association between Pandemrix™ and narcolepsy, and call for further analyses and debate.

Effect of the adjuvanted (AS03) A/H1N1 2009 pandemic influenza vaccine on the risk of rejection in solid organ transplant recipients in England: a self-controlled case series

Objective To assess the risk of solid organ transplant (SOT) rejection after vaccination with the adjuvanted (AS03) A/H1N1 2009 pandemic influenza vaccine Pandemrix. Design Self-controlled case series (SCCS) in the UK Clinical Practice Research Datalink (CPRD) and its linked component of the Hospital Episodes Statistics (HES) inpatient database. Analyses were conducted using the SCCS method for censored, perturbed or curtailed post-event exposure. Participants Of the 184 transplant recipients having experienced at least one SOT rejection (liver, kidney, lung, heart or pancreas) during the study period from 1 October 2009 to 31 October 2010, 91 participants were included in the main analysis, of which 71 had been exposed to Pandemrix. Main outcome measures Occurrence of SOT rejection during risk (30 and 60 days after any Pandemrix dose) and control periods. Covariates in the CPRD included time since transplantation, seasonal influenza vaccination, bacterial and viral infections, previous SOT rejections and malignancies. Results The relative incidence (RI) of rejection of any one of the five transplanted organs, adjusted for time since transplantation, was 1.05 (95% CI 0.52 to 2.14) and 0.80 (95% CI 0.42 to 1.50) within 30 and 60 days after vaccination, respectively. Similar estimates were observed for rejection of a kidney only, the most commonly transplanted organ (RI within 30 days after vaccination: 0.85 (95% CI 0.38 to 1.90)). Across various models and sensitivity analyses, RI estimates remained stable and within a consistent range around 1.0. Conclusions These results suggest a reassuring safety profile for Pandemrix with regard to the risk of rejection in SOT recipients in England and contribute to inform the benefit–risk of AS03-adjuvanted pandemic influenza vaccines in transplanted patients in the event of future pandemics. Trial registration number NCT01715792.

Risk of solid organ transplant rejection following vaccination with seasonal trivalent inactivated influenza vaccines in England: A self-controlled case-series.

BACKGROUND Annual seasonal influenza vaccination is recommended for transplant recipients. No formal pharmacoepidemiology study has been published on the association between solid organ transplant (SOT) rejection and vaccination with seasonal trivalent inactivated influenza vaccines (TIIVs). METHODS The risk of SOT (liver, kidney, lung, heart or pancreas) rejection after TIIV vaccination was assessed using a self-controlled case-series method (NCT01715792). SOT recipients in England with transplant rejection were selected from the Clinical Practice Research Datalink and linked Hospital Episode Statistics inpatient data. The study period (September 2006 to August 2009) encompassed three consecutive influenza seasons. We calculated the relative incidence (RI) of SOT rejection between the 30- and 60-day post-vaccination risk periods and the control periods (any follow-up period excluding risk periods), using a Poisson regression model. RESULTS In seasons 2006/07, 2007/08, 2008/09 and pooled seasons, 132, 136, 168 and 375 subjects, respectively, experienced at least one transplant rejection; approximately half (45%-51%) of these subjects had received a TIIV. For season 2006/07, the RI of rejection of any organ, adjusted for time since transplantation, was 0.74 (95% CI: 0.24-2.28) and 0.58 (95% CI: 0.24-1.38) during the 30-day and 60-day risk periods, respectively. Corresponding RIs for season 2007/08 were 1.21 (95% CI: 0.55-2.64) and 1.31 (95% CI: 0.69-2.48); for season 2008/09, 0.99 (95% CI: 0.43-2.28) and 0.64 (95% CI: 0.31-1.33); and for pooled seasons 1.01 (95% CI: 0.58-1.76) and 0.88 (95% CI: 0.56-1.38). The results of a separate analysis of kidney rejections and analyses that took into account additional potential confounders were consistent with those of the main analyses, with 95% CIs including 1 and upper limits below 3. CONCLUSION This study provides reassuring evidence of the safety profile of TIIVs in SOT recipients, thus supporting current recommendations to vaccinate this risk group annually.

Effectiveness of pneumococcal vaccines in preventing pneumonia in adults, a systematic review and meta-analyses of observational studies

Introduction S. pneumoniae can cause a wide spectrum of diseases, including invasive pneumococcal disease and pneumonia. Two types of pneumococcal vaccines are indicated for use in adults: 23-valent pneumococcal polysaccharide vaccines (PPV23) and a 13-valent pneumococcal conjugate vaccine (PCV13). Objective To systematically review the literature assessing pneumococcal vaccine effectiveness (VE) against community-acquired pneumonia (CAP) in adults among the general population, the immunocompromised and subjects with underlying risk factors in real-world settings. Methods We searched for peer-reviewed observational studies published between 1980 and 2015 in Pubmed, SciELO or LILACS, with pneumococcal VE estimates against CAP, pneumococcal CAP or nonbacteremic pneumococcal CAP. Meta-analyses and meta-regression for VE against CAP requiring hospitalization in the general population was performed. Results 1159 unique articles were retrieved of which 33 were included. No studies evaluating PCV13 effectiveness were found. Wide ranges in PPV23 effectiveness estimates for any-CAP were observed among adults ≥65 years (-143% to 60%). The meta-analyzed VE estimate for any-CAP requiring hospitalization in the general population was 10.2% (95%CI: -12.6; 33.0). The meta-regression indicates that VE against any-CAP requiring hospitalization is significantly lower in studies with a maximum time since vaccination ≥60 months vs. <60 months and in countries with the pediatric PCV vaccine available on the private market. However, these results should be interpreted cautiously due to the high influence of two studies. The VE estimates for pneumococcal CAP hospitalization ranged from 32% (95%CI: -18; 61) to 51% (95%CI: 16; 71) in the general population. Conclusions Wide ranges in PPV23 effectiveness estimates for any-CAP were observed, likely due to a great diversity of study populations, circulation of S. pneumoniae serotypes, coverage of pediatric pneumococcal vaccination, case definition and time since vaccination. Despite some evidence for short-term protection, effectiveness of PPV23 against CAP was not consistent in the general population, the immunocompromised and subjects with underlying risk factors.

Application of Probabilistic Multiple-Bias Analyses to a Cohort- and a Case-Control Study on the Association between Pandemrix™ and Narcolepsy.

Background An increase in narcolepsy cases was observed in Finland and Sweden towards the end of the 2009 H1N1 influenza pandemic. Preliminary observational studies suggested a temporal link with the pandemic influenza vaccine Pandemrix™, leading to a number of additional studies across Europe. Given the public health urgency, these studies used readily available retrospective data from various sources. The potential for bias in such settings was generally acknowledged. Although generally advocated by key opinion leaders and international health authorities, no systematic quantitative assessment of the potential joint impact of biases was undertaken in any of these studies. Methods We applied bias-level multiple-bias analyses to two of the published narcolepsy studies: a pediatric cohort study from Finland and a case-control study from France. In particular, we developed Monte Carlo simulation models to evaluate a potential cascade of biases, including confounding by age, by indication and by natural H1N1 infection, selection bias, disease- and exposure misclassification. All bias parameters were evidence-based to the extent possible. Results Given the assumptions used for confounding, selection bias and misclassification, the Finnish rate ratio of 13.78 (95% CI: 5.72–28.11) reduced to a median value of 6.06 (2.5th- 97.5th percentile: 2.49–15.1) and the French odds ratio of 5.43 (95% CI: 2.6–10.08) to 1.85 (2.5th—97.5th percentile: 0.85–4.08). Conclusion We illustrate multiple-bias analyses using two studies on the Pandemrix™-narcolepsy association and advocate their use to better understand the robustness of study findings. Based on our multiple-bias models, the observed Pandemrix™-narcolepsy association consistently persists in the Finnish study. For the French study, the results of our multiple-bias models were inconclusive.

Estimating the Burden of Medically Attended Norovirus Gastroenteritis: Modeling Linked Primary Care and Hospitalization Datasets

This study demonstrates that routinely collected primary care and hospitalization datasets such as the UK Clinical Practice Research Datalink are useful resources to estimate and monitor the burden of medically attended norovirus-attributable gastroenteritis in a population over time.

Incidence and prevalence of hepatitis B in patients with diabetes mellitus in the UK: A population-based cohort study using the UK Clinical Practice Research Datalink

We assessed the incidence and prevalence of hepatitis B (Hep B) in patients with or without diabetes mellitus (DM) using the UK Clinical Practice Research Datalink (CPRD). This was a retrospective, observational study of diabetic and nondiabetic cohorts aged 0‐80 years using CPRD (NCT02324218). Incidence rates (IR) for each cohort were calculated. Crude and adjusted (Poisson regression) IR ratios (IRR) were estimated with 95% confidence intervals (CI) to compare the cohorts. Hep B prevalence stratified by age, and hospitalization related to Hep B was also calculated. Of 7 712 043 subjects identified, 4 839 770 were included (DM: 160 760; non‐DM: 4 679 010). Mean ages were 54.4 and 32.0 years, and 57.20% and 50.14% were male in the diabetic and nondiabetic cohorts, respectively. Hep B was identified in 29 diabetic and 845 nondiabetic subjects; IR was 4.03 per 100 000 person‐years and 2.88 per 100 000 person‐years, respectively. The adjusted IRR was 1.00 (95% CI: 0.70‐1.50) between diabetic and nondiabetic cohorts. Hep B prevalence was higher in the diabetic cohort (0.01%‐0.26%) than in the nondiabetic cohort (0.00%‐0.03%) across the different age groups. Hep B‐associated hospitalization IR was higher in the diabetic cohort (4.98‐10.91) than the nondiabetic cohort (0.26‐2.44). The Hep B IR, hospitalization and prevalence were higher in males in both cohorts. In conclusion, the risk of incident Hep B diagnosis in the diabetic cohort was not different from that in the nondiabetic cohort. However, prevalence of Hep B and Hep B‐associated hospitalization rate was higher in the diabetic than in the nondiabetic cohort.

Identifying rare diseases using electronic medical records: The example of allergic bronchopulmonary aspergillosis

The purpose of the study is to evaluate whether primary care electronic medical records (EMRs) from patients with severe asthma can be used to identify allergic bronchopulmonary aspergillosis (ABPA) cases.

Burden of herpes zoster in 16 selected immunocompromised populations in England: a cohort study in the Clinical Practice Research Datalink 2000–2012

Objectives Herpes zoster (HZ) is caused by reactivation of varicella-zoster virus which remains latent in individuals after a varicella infection. It is expected that HZ will be more frequent in immunocompromised (IC) individuals than in immunocompetent (IC-free). This study assessed the incidence rate (IR) of HZ in individuals with a wide set of IC conditions and in IC-free individuals. Setting A retrospective cohort study was conducted in England using data (January 2000 to March 2012) from the Clinical Practice Research Datalink with linkage to the Hospital Episodes Statistics. Participants A cohort of 621 588 individuals with 16 selected IC conditions and a gender/age-matched cohort of IC-free individuals were identified. The IC conditions included haematopoietic stem cell transplant (HSCT), solid organ transplant, malignancies, autoimmune diseases and users of immunosuppressive medications. Outcomes IR of HZ per 1000 person-years (PY) was estimated. Proportions of postherpetic neuralgia (PHN) and other HZ complications within 90 days of HZ onset were also estimated among patients with HZ. Risk factors for PHN in IC individuals with HZ were assessed by a multivariate regression model. Results The overall IR of HZ in the IC cohort was 7.8/1000 PY (95% CI 7.7 to 7.9), increasing with age from 3.5/1000 PY (3.4–3.7) in individuals aged 18–49 years to 12.6/1000 PY (12.2–13.0) in individuals aged ≥80 years. This IR in the IC-free cohort was 6.2/1000 PY (6.1–6.3). The overall IR of HZ varied across IC conditions, ranging from 5.3 (5.1–5.5) in psoriasis to 41.7/1000 PY (35.7–48.4) in HSCT. The proportions of PHN and other HZ complications were 10.7% (10.2–11.1) and 2.9% (2.7–3.2) in the IC cohort, but 9.1% (8.7–9.5) and 2.3% (2.1–2.6) in the IC-free cohort, respectively. Conclusion IC population contributes to the public health burden of HZ in England. Vaccination might be the most preferable HZ preventive measure for the IC population.