Classifying ADRs – does dose matter? Phillips, Elizabeth J.
British journal of clinical pharmacology,
January 2016, Letnik:
81, Številka:
1
Journal Article
HLA‐B35:01 and Green Tea–Induced Liver Injury Hoofnagle, Jay H.; Bonkovsky, Herbert L.; Phillips, Elizabeth J. ...
Hepatology (Baltimore, Md.),
June 2021, Letnik:
73, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Background and Aims
Herbal supplements, and particularly multi‐ingredient products, have become increasingly common causes of acute liver injury. Green tea is a frequent component in implicated ...products, but its role in liver injury is controversial. The aim of this study was to better characterize the clinical features, outcomes, and pathogenesis of green tea‐associated liver injury.
Approach and Results
Among 1,414 patients enrolled in the U.S. Drug‐Induced Liver Injury Network who underwent formal causality assessment, 40 cases (3%) were attributed to green tea, 202 to dietary supplements without green tea, and 1,142 to conventional drugs. The clinical features of green tea cases and representation of human leukocyte antigen (HLA) class I and II alleles in cases and control were analyzed in detail. Patients with green tea–associated liver injury ranged in age from 17 to 69 years (median = 40) and developed symptoms 15‐448 days (median = 72) after starting the implicated agent. The liver injury was typically hepatocellular (95%) with marked serum aminotransferase elevations and only modest increases in alkaline phosphatase. Most patients were jaundiced (83%) and symptomatic (88%). The course was judged as severe in 14 patients (35%), necessitating liver transplantation in 3 (8%), but rarely resulting in chronic injury (3%). In three instances, injury recurred upon re‐exposure to green tea with similar clinical features, but shorter time to onset. HLA typing revealed a high prevalence of HLA‐B*35:01, found in 72% (95% confidence interval CI, 58‐87) of green tea cases, but only 15% (95% CI, 10‐20) caused by other supplements and 12% (95% CI, 10‐14) attributed to drugs, the latter rate being similar to population controls (11%; 95% CI, 10.5‐11.5).
Conclusions
Green tea–related liver injury has distinctive clinical features and close association with HLA‐B*35:01, suggesting that it is idiosyncratic and immune mediated.
Background
Even though 8%‐25% of most populations studied globally are labeled as penicillin allergic, most diagnoses of penicillin allergy are made in childhood and relate to events that are either ...not allergic in nature, are low risk for immediate hypersensitivity, or are a potential true allergy that has waned over time. Penicillin allergy labels directly impact antimicrobial stewardship by leading to use of less effective and broader spectrum antimicrobials and are associated with antimicrobial resistance. They may also delay appropriate antimicrobial therapy and lead to increased risk of specific adverse healthcare outcomes. Operationalizing penicillin allergy de‐labeling into a new arm of antimicrobial stewardship programs (ASPs) has become an increasing global focus.
Methods
We performed an evidence‐based narrative review of the literature of penicillin allergy label carriage, the adverse effects of penicillin allergy labels, and current approaches and barriers to penicillin allergy de‐labeling. Over the period 1928‐2018 in Pubmed and Medline, search terms used included “penicillin allergy” or “penicillin hypersensitivity” alone or in combination with “adverse events,” “testing,” “evaluation,” “effects,” “label,” “de‐labeling,” “prick or epicutaneous,” and “intradermal” skin testing, “oral challenge or provocation,” “cross‐reactivity,” and “antimicrobial stewardship”.
Results
Penicillin allergy labels are highly prevalent, largely inaccurate and their carriage may lead to unnecessary treatment and inferior outcomes with alternative agents as well as adverse public health outcomes such as antibiotic resistance.
Conclusions
Operationalizing penicillin allergy de‐labeling as an aspect of ASP has become an increasing global focus. There is a need for validated approaches that optimally combine the use of history and ingestion challenge with or without proceeding formal skin testing to tackle penicillin allergy efficiently within complex healthcare systems. At the same time, there is great promise for penicillin allergy evaluation and de‐labeling as an individual and public health strategy to reduce adverse healthcare outcomes, improve antimicrobial stewardship, and decrease healthcare costs.
Phenytoin is an antiepileptic drug with a narrow therapeutic index and large interpatient pharmacokinetic variability, partly due to genetic variation in CYP2C9. Furthermore, the variant allele ...HLA‐B*15:02 is associated with an increased risk of Stevens–Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for the use of phenytoin based on CYP2C9 and/or HLA‐B genotypes (updates on cpicpgx.org).
The global supply of COVID-19 vaccines remains limited. An understanding of the immune response that is predictive of protection could facilitate rapid licensure of new vaccines. Data from a ...randomized efficacy trial of the ChAdOx1 nCoV-19 (AZD1222) vaccine in the United Kingdom was analyzed to determine the antibody levels associated with protection against SARS-CoV-2. Binding and neutralizing antibodies at 28 days after the second dose were measured in infected and noninfected vaccine recipients. Higher levels of all immune markers were correlated with a reduced risk of symptomatic infection. A vaccine efficacy of 80% against symptomatic infection with majority Alpha (B.1.1.7) variant of SARS-CoV-2 was achieved with 264 (95% CI: 108, 806) binding antibody units (BAU)/ml: and 506 (95% CI: 135, not computed (beyond data range) (NC)) BAU/ml for anti-spike and anti-RBD antibodies, and 26 (95% CI: NC, NC) international unit (IU)/ml and 247 (95% CI: 101, NC) normalized neutralization titers (NF
) for pseudovirus and live-virus neutralization, respectively. Immune markers were not correlated with asymptomatic infections at the 5% significance level. These data can be used to bridge to new populations using validated assays, and allow extrapolation of efficacy estimates to new COVID-19 vaccines.
Imputation of human leukocyte antigen (HLA) alleles from SNP-level data is attractive due to importance of HLA alleles in human disease, widespread availability of genome-wide association study ...(GWAS) data, and expertise required for HLA sequencing. However, comprehensive evaluations of HLA imputations programs are limited. We compared HLA imputation results of HIBAG, SNP2HLA, and HLA*IMP:02 to sequenced HLA alleles in 3,265 samples from BioVU, a de-identified electronic health record database coupled to a DNA biorepository. We performed four-digit HLA sequencing for HLA-A, -B, -C, -DRB1, -DPB1, and -DQB1 using long-read 454 FLX sequencing. All samples were genotyped using both the Illumina HumanExome BeadChip platform and a GWAS platform. Call rates and concordance rates were compared by platform, frequency of allele, and race/ethnicity. Overall concordance rates were similar between programs in European Americans (EA) (0.975 SNP2HLA; 0.939 HLA*IMP:02; 0.976 HIBAG). SNP2HLA provided a significant advantage in terms of call rate and the number of alleles imputed. Concordance rates were lower overall for African Americans (AAs). These observations were consistent when accuracy was compared across HLA loci. All imputation programs performed similarly for low frequency HLA alleles. Higher concordance rates were observed when HLA alleles were imputed from GWAS platforms versus the HumanExome BeadChip, suggesting that high genomic coverage is preferred as input for HLA allelic imputation. These findings provide guidance on the best use of HLA imputation methods and elucidate their limitations.
Drug allergy: A 2022 practice parameter update Khan, David A.; Banerji, Aleena; Blumenthal, Kimberly G. ...
Journal of allergy and clinical immunology,
December 2022, 2022-12-00, 20221201, Letnik:
150, Številka:
6
Journal Article
Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy
. The pathogenesis ...of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1
Ctla4
mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration
. Here, using single-cell RNA and T cell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1
Ctla4
mice, we identify clonal effector CD8
T cells as the dominant cell population. Treatment with anti-CD8-depleting, but not anti-CD4-depleting, antibodies improved the survival of Pdcd1
Ctla4
mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients, which required CD8
T cells. The cardiac-specific protein α-myosin, which is absent from the thymus
, was identified as the cognate antigen source for three major histocompatibility complex class I-restricted TCRs derived from mice with fulminant myocarditis. Peripheral blood T cells from three patients with ICI-MC were expanded by α-myosin peptides. Moreover, these α-myosin-expanded T cells shared TCR clonotypes with diseased heart and skeletal muscle, which indicates that α-myosin may be a clinically important autoantigen in ICI-MC. These studies underscore the crucial role for cytotoxic CD8
T cells, identify a candidate autoantigen in ICI-MC and yield new insights into the pathogenesis of ICI toxicity.
After over a billion of vaccinations with messenger RNA-lipid nanoparticle (mRNA-LNP) based SARS-CoV-2 vaccines, anaphylaxis and other manifestations of hypersensitivity can be considered as very ...rare adverse events. Although current recommendations include avoiding a second dose in those with first-dose anaphylaxis, the underlying mechanisms are unknown; therefore, the risk of a future reaction cannot be predicted. Given how important new mRNA constructs will be to address the emergence of new viral variants and viruses, there is an urgent need for clinical approaches that would allow a safe repeated immunization of high-risk individuals and for reliable predictive tools of adverse reactions to mRNA vaccines. In many aspects, anaphylaxis symptoms experienced by the affected vaccine recipients resemble those of infusion reactions to nanomedicines. Here we share lessons learned over a decade of nanomedicine research and discuss the current knowledge about several factors that individually or collectively contribute to infusion reactions to nanomedicines. We aim to use this knowledge to inform the SARS-CoV-2 lipid-nanoparticle-based mRNA vaccine field.
PDF
