Frederick Varricchio

Understanding vaccine safety information from the Vaccine Adverse Event Reporting System

The Vaccine Adverse Event Reporting System (VAERS) is administered by the Food and Drug Administration and CDC and is a key component of postlicensure vaccine safety surveillance. Its primary function is to detect early warning signals and generate hypotheses about possible new vaccine adverse events or changes in frequency of known ones. VAERS is a passive surveillance system that relies on physicians and others to voluntarily submit reports of illness after vaccination. Manufacturers are required to report all adverse events of which they become aware. There are a number of well-described limitations of such reporting systems. These include, for example, variability in report quality, biased reporting, underreporting and the inability to determine whether a vaccine caused the adverse event in any individual report. Strengths of VAERS are that it is national in scope and timely. The information in VAERS reports is not necessarily complete nor is it verified systematically. Reports are classified as serious or nonserious based on regulatory criteria. Reports are coded by VAERS in a uniform way with a limited number of terms using a terminology called COSTART. Coding is useful for search purposes but is necessarily imprecise. VAERS is useful in detecting adverse events related to vaccines and most recently was used for enhanced reporting of adverse events in the national smallpox immunization campaign. VAERS data have always been publicly available. However, it is essential for users of VAERS data to be fully aware of the strengths and weaknesses of the system. VAERS data contain strong biases. Incidence rates and relative risks of specific adverse events cannot be calculated. Statistical significance tests and confidence intervals should be used with great caution and not routinely. Signals detected in VAERS should be subjected to further clinical and descriptive epidemiologic analysis. Confirmation in a controlled study is usually required. An understanding of the systems defined objectives and inherent drawbacks is vital to the effective use of VAERS data in vaccine safety investigations.

A local reaction at or near injection site: Case definition and guidelines for collection, analysis, and presentation of immunization safety data

The need for developing a case definition and guidelines for a local reaction at or near the injection site, methods for the development of the case definition and guidelines as an adverse event following immunization as well as the rationale for selected decisions about the case definition for a local reaction at or near the injection site are explained in the Preamble section. The case definition is structured in 2 levels of diagnostic certainty: level 1 includes any description of morphological or physiological change at or near the injection site that is described or identified by a healthcare provider. Level 2 is any description of morphological or physiological change at or near injection site that is described by any other person. In Guidelines section, the working group recommends to enable meaningful and standardized data collection, analysis, and presentation of information about a local reaction at or near the injection site. However, implementation of all guidelines might not be possible in all settings. The availability of information may vary depending upon resources, geographic region, and whether the source of information is a prospectively designed clinical trial, a post-marketing surveillance or epidemiologic study, or an individual report of a local reaction at injection site.

Identification of interleukin-13 receptor α2 chain overexpression in situ in high-grade diffusely infiltrative pediatric brainstem glioma

Human malignant glioma cell lines and adult brain tumors overexpress high levels of interleukin-13 receptor alpha2 chain (IL-13Ralpha2). Because the IL-13Ralpha2 chain is an important target for cancer therapy and prognosis for patients with brainstem glioma (BSG) remains dismal, we investigated the expression of this receptor in specimens of diffusely infiltrative pediatric BSG relative to normal brain tissue. Twenty-eight BSG specimens and 15 normal brain specimens were investigated for IL-13Ralpha2 protein expression by immunohistochemical analysis (IHC) using two different antibodies in two different laboratories. Highly sensitive Q-dot-based IHC and in situ hybridization (ISH) assays were also developed to identify IL-13Ralpha2 protein and RNA in these specimens. The results were evaluated independently in two laboratories in a blinded fashion. By Q-dot IHC or a standard IHC assay, 17 of 28 (61%) tumor specimens showed modest to strong staining for IL-13Ralpha2, while 15 normal brain tissue samples showed weak expression for IL-13Ralpha2 protein. Significant interrater agreement between the two laboratories was seen in the assessment of IL-13Ralpha2 intensity. High-level IL-13Ralpha2 RNA expression was detected in tumor samples by Q-dot ISH, but only weak RNA expression was observed in normal brain. Significant agreement between ISH and IHC assays was observed (simple kappa [kappa] estimate=0.358, weighted kappa=0.89, p=0.001). IL-13Ralpha2 protein and mRNA are expressed to significantly higher levels in BSG than in normal brain tissue. Both IHC and ISH represent robust methods to detect expression of the IL-13Ralpha2 receptor in BSG that could represent an important new drug target for treatment of this disease.

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.

Immunization site pain: Case definition and guidelines for collection, analysis, and presentation of immunization safety data

mmunization site pain: Case definition and guidelines for collection, analysis, nd presentation of immunization safety data ane F. Gidudua,∗, Gary A. Walcob, Anna Taddioc, William T. Zempskyd, Scott A. Halperine, ngela Calugara, Neville A. Gibbs f, Renald Hennigg, Milivoj Jovancevich, Eva Netterlid i, erri O’Connor j, James M. Oleskek, Frederick Varricchio l,1, Theodore F. Tsaim, Harry Seifertn, nne E. Schuindn, The Brighton Immunization Site Pain Working Group2

Pediatric deaths reported after vaccination: the utility of information obtained from parents

BACKGROUND The federally administered Vaccine Adverse Event Reporting System (VAERS) is a passive reporting system that receives domestic and foreign reports of adverse events that occur following immunization. This investigation explored whether routinely interviewing parents for follow-up of VAERS pediatric deaths would provide additional information important to vaccine safety. METHODS The study was designed to follow up 100 consecutive pediatric deaths reported to VAERS by interviewing a parent and a healthcare provider (HCP) for each case. Several strategies contributed to successful follow-up. A standardized questionnaire was utilized to interview HCPs and parents. Overall and specific group frequencies (HCPs and parents) were calculated for each variable. McNemars statistical tests of exact inference were calculated to assess whether there were statistically significant differences between HCP and parent knowledge by case for various variables. RESULTS The median age of the cases was 4 months. Approximately half of the deaths were attributed to sudden infant death syndrome. In many instances, the information was equivalent in quality. For certain variables, such as knowledge of the childs position when found in distress, more parents than HCPs indicated that they knew the answer. CONCLUSIONS Conducting parental and HCP follow-up for pediatric deaths reported to VAERS was resource intensive. In some instances, parents were more likely than HCPs to provide information regarding some important variables about the nature of the death. None of the additional information obtained from parents, however, provided a signal or confirmation of a causal link between the vaccine and death.

Thrombocytopenia after vaccination: case reports to the US Vaccine Adverse Event Reporting System, 1990-2008.

We reviewed thrombocytopenia (TP) reports to the US Vaccine Adverse Event Reporting System (VAERS). We examined TP patterns for differences in single versus multiple immunization reports, presence of a live viral vaccine, seriousness, age, and interval to symptom onset. We found 1510 reports of possible TP and after exclusions evaluated 1440 for possible causes. Most (1078; 75%) met the regulatory definition of a serious adverse event. TP was reported after inactivated and live viral vaccines. Platelet counts <10×10(9)/L were reported. Identified vaccines could be prioritized for hypothesis-testing studies.

Detection of human herpesvirus 6 sequences in lymphoma tissues by immunohistochemistry and polymerase chain reactions.

We have analyzed one Hodgkins and six non-Hodgkins lymphomas for the presence of human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) DNA by polymerase chain reaction (PCR) and antigens by immunohistochemistry. A large cell B-cell lymphoma and a T-cell lymphoma were positive for HHV-6 antigens by immunohistochemistry. Using PCR primers from the HHV-6 ZVH14 transforming DNA segment, all seven tumors were positive. EBV DNA was not detected by PCR using sequences from EBV internal repeat-3 region as primers. The data suggest an etiologic involvement of HHV-6 in some human lymphomas. Although all seven of the lymphoma tissues examined contained HHV-6 DNA, expression of HHV-6 antigens was observed in only two cases, suggesting that expression of proteins was not required for transformation.

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.

Neonatal death: Case definition & guidelines for data collection, analysis, and presentation of immunization safety data

More than 40% of all deaths in children under 5 years of age occur during the neonatal period: the first month of life. Immunization of pregnant women has proven beneficial to both mother and infant by decreasing morbidity and mortality. With an increasing number of immunization trials being conducted in pregnant women, as well as roll-out of recommended vaccines to pregnant women, there is a need to clarify details of a neonatal death. This manuscript defines levels of certainty of a neonatal death, related to the viability of the neonate, who confirmed the death, and the timing of the death during the neonatal period and in relation to immunization of the mother.