Rebecca Chandler

Vasculitis as an adverse event following immunization - Systematic literature review.

BACKGROUND Several types of vasculitis have been observed and reported in temporal association with the administration of various vaccines. A systematic review of current evidence is lacking. OBJECTIVE This systematic literature review aimed to assess available evidence and current reporting practice of vasculitides as adverse events following immunization (AEFI). METHODS We reviewed the literature from 1st January 1994 to 30th June 2014. This review comprises randomized controlled trials, observational studies, case series, case reports, reviews and comments regardless of vaccine and target population. RESULTS The initial search resulted in the identification of 6656 articles. Of these, 157 articles were assessed for eligibility and 75 studies were considered for analysis, including 6 retrospective/observational studies, 2 randomized controlled trials, 7 reviews, 11 case series, 46 case reports and 3 comments. Most of the larger, higher quality studies found no causal association between vaccination and subsequent development of vasculitis, including several studies on Kawasaki disease and Henoch-Schönlein purpura (IgA vasculitis). Smaller case series reported a few cases of vasculitis following BCG and vaccines against influenza and hepatitis. Only 24% of the articles reported using a case definition of vasculitis. CONCLUSIONS Existing literature does not allow establishing a causative link between vaccination and vasculitides. Further investigations were strengthened by the use of standardized case definitions and methods for data collection, analysis and presentation to improve data comparability and interpretation of vasculitis cases following immunization.

Safety Concerns Reported by Patients Identified in a Collaborative Signal Detection Workshop using VigiBase: Results and Reflections from Lareb and Uppsala Monitoring Centre

IntroductionPatient reporting in pharmacovigilance is important and contributes to signal detection. However, descriptions of methodologies for using patient reports in signal detection are scarce, and published experiences of how patient reports are used in pharmacovigilance are limited to a few individual countries.ObjectiveOur objective was to explore the contribution of patient reports to global signal detection in VigiBase.MethodsData were retrieved from VigiBase in September 2016. Drug–event-combination series were restricted to those with >50% patient reports, defined as reporter type “Consumer/non-health professional” per E2B reporting standard. vigiRank was applied to patient reports to prioritize combinations for assessment. Product information for healthcare professionals (HCPs) as well as patient information leaflets (PILs) were used as reference for information on adverse drug reactions (ADRs). Staff from the Uppsala Monitoring Centre and the Netherlands Pharmacovigilance Centre Lareb categorized the combinations. Potential signals proceeded to a more in-depth clinical review to determine whether the safety concern should be communicated as a “signal.”ResultsOf the 212 combinations assessed, 20 (9%) resulted in eight signals communicated within the World Health Organization (WHO) programme for international drug monitoring. Review of PILs revealed insufficient ADR descriptions for patients and examples of poor consistency with product information for HCPs. Patient narratives provided details regarding the experience and impact of ADRs and evidence that patients make causality and personal risk assessments.ConclusionsSafety concerns described in patient reports can be identified in a global database including previously unknown ADRs as well as new aspects of known ADRs. Patient reports provide unique information valuable in signal assessment and should be included in signal detection. Novel approaches to highlighting patient reports in statistical signal detection can further improve the contribution of patient reports to pharmacovigilance.

Kawasaki disease and immunisation: Standardised case definition & guidelines for data collection, analysis

http://dx.doi.org/10.1016/j.vaccine.2016.09.025 0264-410X/ 2016 Published by Elsevier Ltd. Abbreviations: ADR, adverse drug reaction; AHA, American Heart Association; ALT, alanine transaminase; AST, aspartate transaminase; BCG, Bacillus Calmette (vaccine); CAAs, coronary artery aneurysms; CMRA, cardiac magnetic resonance angiography; CRP, C-reactive protein; DTP, diphtheria, tetanus, pertussis diphtheriatetanus, acellular pertussis; EBV, Epstein Barr Virus; ESR, erythrocyte sedimentation rate; GGT, gamma glutamyl transferase; HHV, human herpes vi Haemophilus influenza type b; HPF, high powered field; HSP, heat shock protein; IVIG, intravenous gamma globulin; JMoH, Japanese Ministry of Health; KD, Kawasaki LAD, left anterior descending; LV, left ventricular; MRI, magnetic resonance imaging; MSCT, multi, slice computed tomography; PAN, polyarteritis nodosa; PCV, pneum conjugate vaccine; PCR, polymerase chain reaction; RCA, right coronary artery; RMSF, Rocky Mountain Spotted Fever; RTPE,, recurrent toxin, mediated perineal er sJIA, systemic juvenile idiopathic arthritis; SPECT, single photon emission computed tomography; TSS, toxic shock syndrome; TST, tuberculin skin test; WBC, wh cells. ⇑ Corresponding author at: The Brighton Collaboration Foundation, c/o Universitäts-Kinderspital beider Basel, Spitalstrasse 33, 4056 Basel, Switzerland. E-mail address: contact@brightoncollaboration.org (J. Bonhoeffer). 1 Brighton Collaboration homepage: http://www.brightoncollaboration.org.

Safety Concerns with HPV Vaccines Continue to Linger: Are Current Vaccine Pharmacovigilance Practices Sufficient?

The current paradigm of vaccine pharmacovigilance includes three stages: signal detection, development of a causality hypothesis, and testing of the causality hypothesis [1]. Signal detection in the postmarketing setting largely relies on spontaneous reports of adverse events (AEs) following immunization (AEFI) and literature case reports. The development of a causality hypothesis involves an assessment of the relevant case series using standardized case definitions [2], individual-level causality criteria [3], and ‘observed versus expected’ calculations [4]. Testing of the causality hypothesis follows, using large epidemiology studies that rely on diagnostic coding or insurance claims data for measuring outcomes of interest. Such studies allow regulatory and public health agencies to make an estimation of risk at the population level from which conclusions on causality are drawn. Over the last several years, there has been focus on a number of safety signals for the human papillomavirus (HPV) vaccines, including complex regional pain syndrome (CRPS), postural orthostatic tachycardia syndrome (POTS), and chronic fatigue syndrome (CFS). These signals have been a challenge for public health authorities because routine vaccine pharmacovigilance practice is not sufficient to understand suspected harms that are poorly defined and whose pathophysiology are not completely understood. Furthermore, estimations of risk at the population level fail to acknowledge that vaccines may cause harm in subgroups with individual-level risk factors for AEFI. Novel approaches to vaccine pharmacovigilance are required to more fully understand this safety concern for HPV vaccines. In this issue of Drug Safety, Ozawa et al. describe a case series of girls from Japan who experienced multiple symptoms suspected to be caused by the HPV vaccine. They report on diagnostic findings underlying these symptoms and they take a unique approach to the analysis of temporality in their causality assessment [5].

Comment on “Safety of Human Papillomavirus Vaccines: An Updated Review”

We read with interest the article Safety of Human Papillomavirus Vaccines: An Updated Review by Phillips et al. [1] published recently in Drug Safety. We would like to take this opportunity to challenge the apparent devotion of the authors to an increasingly outdated hierarchy of evidence, particularly in the face of a shifting paradigm within the field of vaccinology. Within vaccinology, there is a growing appreciation of a variability in immunological responses, with subsequent implications on both the benefit and the harm individuals may experience from vaccines. Research has identified the presence of inter-individual variation in vaccine responses based upon differences in innate immunity, microbiomes, and immunogenetics [2]. Several publications have already identified a number of individual-level factors associated with an increased risk of adverse events following immunization (AEFI), such as sex, age, past infection status, and genetics. There is evidence of both an increased production of immune responses (cellular and humoral) and the development of more frequent and more severe adverse reactions in females than in males [3, 4]. Older individuals have been found to produce different immune signatures to influenza vaccination, which result in decreased vaccine effectiveness [5, 6]. An increased risk of severe dengue fever after vaccination with the first marketed dengue vaccine, Dengvaxia , has been ascribed to the absence of previous exposure to the dengue virus [7]. Examples of genetic variant-based risks are multiple: narcolepsy after Pandemrix vaccination [8]; febrile convulsions after the measles, mumps, and rubella vaccine [9]; cutaneous reactions after smallpox vaccine [10]; and osteitis after Bacille Calmette-Guerin (BCG) vaccine [11]. While the magnitude of many of these risks is large enough to be estimated by observational studies, others may be rare enough to escape epidemiological detection. For example, despite multiple observational studies concluding no elevated risk of Guillain–Barré Syndrome (GBS) with tetanus toxoid-containing vaccines [12–14], there exists a famous case report of a 42-year-old man who developed a self-limited episode of GBS after each of three vaccinations with tetanus toxoid over a 13-year period [15]. With progress in vaccinology over the last 40 years, it is likely that cases such as these may now be understood and that explanations such as ‘‘unusual susceptibility to Guillain–Barré Syndrome’’ [14] may be further elaborated. The current construction of hierarchy of evidence lies at the core of evidence-based medicine, the limitations of which are increasingly recognized [16]. The randomized controlled trials upon which licensure is based and the observational epidemiological studies by which post-marketing signals are investigated provide only populationbased estimations of risk. No epidemiological study can answer the question ‘‘Did this vaccine cause this event in this patient?’’ A recent review in the journal Vaccine describes a new era of ‘‘predictive vaccinology’’ [17]. In This comment refers to the article available at https://doi.org/10.1007/ s40264-017-0625-z. Reply to this comment refers to the article available at https://doi.org/10.1007/s40264-018-0655-1.

Guide to active vaccine safety surveillance: Report of CIOMS working group on vaccine safety – executive summary

In 2013, the Council for International Organizations of Medical Sciences (CIOMS) created a Working Group on Vaccine Safety (WG) to address unmet needs in the area of vaccine pharmacovigilance. Generating reliable data about specific vaccine safety concerns is becoming a priority due to recent progress in the development and deployment of new vaccines of global importance, as well as novel vaccines targeting diseases specifically endemic to many resource-limited countries (RLCs), e.g. malaria, dengue. The WG created a Guide to Active Vaccine Safety Surveillance (AVSS) to assist national regulatory authorities and national immunization program officers in RLCs in determining the best course of action with regards to non-routine pharmacovigilance activities, when confronted with a launch of a new vaccine or a vaccine that is new to their country. Here we summarize the results of the WG, further detailed in the Guide, which for the first time provides a structured approach to identifying and analyzing specific vaccines safety knowledge gaps, while considering all available sources of information, in order to determine whether AVSS is an appropriate solution. If AVSS is confirmed as being the appropriate tool, the Guide provides additional essential information on AVSS, a detailed overview of common types of AVSS and practical implementation considerations. It also provides a framework for a well-constructed and informative AVSS when needed, thus aiming to ensure the best possible safety of immunization in this new landscape.

Kawasaki disease and immunisation: A systematic review.

BACKGROUND Kawasaki disease is a complex and potentially serious condition. It has been observed in temporal relation to immunisation. METHODS We conducted a systematic literature review using various reference sources to review the available evidence published in the literature. RESULTS We identified twenty seven publications reporting a temporal association between immunisation and Kawasaki disease. We present a systematic review of data drawn from randomised controlled trials, observational studies, case series and reports, and reviews. Overall there was a lack of standardised case definitions, making data interpretation and comparability challenging. CONCLUSIONS Although a temporal relationship between immunisation and Kawasaki disease is suggested, evidence for an increased risk or a causal association is lacking. Implementation of a standardised Kawasaki disease case definition would increase confidence in the findings and add value to future studies of pre- or post-licensure vaccine safety studies.

Correction to: Safety Concerns with HPV Vaccines Continue to Linger: Are Current Vaccine Pharmacovigilance Practices Sufficient?

The following disclaimer was missing from the article.

Serious Neurological Adverse Events after Ivermectin—Do They Occur beyond the Indication of Onchocerciasis?

Abstract. Serious neurological adverse events have been reported from large scale community-based ivermectin treatment campaigns against Onchocerciasis volvulus in Africa. The mechanism of these events has been debated in the literature, largely focusing on the role of concomitant infection with Loa loa versus the presence of mdr-1 gene variants in humans allowing ivermectin penetration into the central nervous system. A case series of serious neurological adverse events occurring with the use of ivermectin outside of the onchocerciasis indication has been identified in VigiBase, an international database of suspected adverse drug reactions. Forty-eight cases have been reported from multiple countries in which ivermectin has been prescribed for multiple indications; clinical review excluded 20 cases with more probable explanations or other exclusion criteria. Within the remaining 28 cases, there is supportive evidence for a causative role of ivermectin including presence of the drug in brain tissue in one case and recurrence of symptoms on repeated exposure in three cases. This series suggests that serious neurological adverse events observed with the use of ivermectin in the treatment of onchocerciasis may not be entirely explained by concomitant high burden loiasis infections. By comparison with the extensive post marketing experience with ivermectin in the successful treatment of parasitic infections, the number of reported cases suggests that such events are likely rare. However, elucidation of individual-level risk factors could contribute to therapeutic decisions that can minimize harms. Further investigation into the potential for drug–drug interactions and explorations of polymorphisms in the mdr-1 gene are recommended.