With the spread of the new SARS-CoV-2 variants, many countries have begun COVID-19 vaccine booster programs with the mix-and-match strategy. However, research on the adverse events (AE) of booster ...doses is still scarce. The aim of our study was to analyze the reported incidence rate (IR), and factors associated with AE, including short-term serious adverse events (SAE) and short-term non-serious adverse events (NSAE), among different vaccine products through the hospital-based Vaccine Adverse Event Reporting System (VAERS). A total of 7432 records were collected during the three-month study period. While more than half of the responses (52.2%) reported the presence of AE after receiving a booster dose, only a few AE were considered SAE (2.4%). AE were significantly higher among women and people of younger age, and the brand of vaccines is the strongest factor associated with post-booster dose AE. The incidence of AE in mRNA1273 is higher than in BNT162b2 and MVC-COV1901 (IRR mRNA1273 vs. BNT162b2: 1.22, 95% CI: 1.11–1.34; BNT162b2 vs. MVC-COV1901: 2.77, 95% CI: 2.27–3.39). The IR of different groups were calculated to support the decision making of the booster vaccine. Although AE were not uncommon for booster vaccines, almost all AE were not serious and predictable using estimated IR. This result can be used to optimize booster vaccine decision making.
Background
Immune‐related adverse events (irAEs) have emerged as a serious clinical issue in the use of immune checkpoint inhibitors (ICIs). Risk factors for irAEs remain controversial. Therefore, we ...studied sex differences in irAEs in patients treated with anti‐programmed cell death protein 1 (PD‐1) therapy.
Materials and Methods
All patients with metastatic melanoma and non‐small cell lung cancer (NSCLC) treated with anti‐PD‐1 therapy at Mayo Clinic Rochester and Florida from 2015 to 2018 were reviewed. Kaplan‐Meier method and log‐rank test was used for time‐to‐event analysis.
Results
In 245 patients with metastatic melanoma, premenopausal women were more likely to experience irAEs (all grades) compared with postmenopausal women and men (67% vs. 60% vs. 46%), primarily because of an increase in endocrinopathies (33% vs. 12% vs. 10%, respectively). In patients with NSCLC (231 patients), women (all ages) were also more likely to develop irAEs of all grades (48% vs. 31%). Women with NSCLC were more likely to develop pneumonitis (11% vs. 4%) and endocrinopathies (14% vs. 5%). No differences in grade ≥3 toxicities were seen across sexes in both cohorts, but women were more likely to receive systemic steroids for the treatment of irAEs compared with men. Better progression‐free‐survival was observed in women with NSCLC and irAEs (10 months vs. 3.3 months) compared with women without irAEs.
Conclusion
Women with metastatic melanoma and NSCLC are more likely to experience irAEs compared with men. We also observed differences between sexes in the frequency of certain irAEs. Larger studies are needed to investigate the mechanisms underlying these associations.
Implications for Practice
The results of this study suggest that women may be at a higher risk for immune‐related adverse events (irAEs) compared with men when treated with anti‐programmed cell death protein 1 therapy. In addition, women were more likely to develop certain irAEs, including endocrinopathies and pneumonitis. Close follow‐up of women undergoing treatment with immune checkpoint inhibitors will allow clinicians to diagnose these treatment‐related complications early, potentially reducing their associated morbidity and mortality. In addition, a possible association between irAEs and response to therapy was observed.
摘要
背景。免疫相关不良事件 (irAE)在需要使用免疫检查点抑制剂 (ICI)时是一种严重的临床问题。有关 irAE 风险因素的讨论仍存在争议。因此，我们研究了采用抗程序性细胞死亡蛋白1 (PD‐1) 治疗患者的 irAE 性别差异。
材料和方法。本文回顾了 2015 年至 2018 年罗彻斯特与佛罗里达州梅奥诊所所有接受抗‐PD‐1 治疗的转移性黑色素瘤与非小细胞肺癌 (NSCLC) 患者的临床资料。采用 Kaplan‐Meier 法和时序检验法进行时间事件分析。
结果。245 例转移性黑色素瘤患者中，绝经前女性比绝经后女性和男性 (67% vs. 60% vs. 46%) 出现 irAE(所有等级)的可能性更高，主要原因为内分泌疾病的增加(分别为 33% vs. 12% vs. 10%)。NSCLC 患者中(231 例)，女性(所有年龄段)发生各种等级 irAE 的可能性更高 (48% vs. 31%)。NSCLC 女性患者出现肺炎 (11% vs. 4%) 和内分泌疾病 (14% vs. 5%) 的可能性更高。两组患者的 ≥3 级毒副反应未显示出性别上的差异，但女性因 irAE 而接受全身类固醇治疗的可能性较男性更高。NSCLC 并 irAE 女性患者的无进展生存期(10 个月 vs. 3.3 个月)优于无 irAE 的女性患者。
结论。转移性黑色素瘤和NSCLC的女性患者发生 irAE 的概率高于男性。结果还发现，某些 irAE 的频率在不同性别之间存在差异。需要更大规模的研究调查这些关联背后的机制。
实践意义:本项研究结果表明，与接受抗程序性细胞死亡蛋白 1 治疗的男性相比，女性发生免疫相关不良事件 (irAE) 的风险更高。此外，女性更容易出现内分泌疾病和肺炎等某些特定irAE。对接受免疫检查点抑制剂治疗的女性患者进行密切随访，有助于临床医生尽早诊断此类与治疗相关的并发症，从而降低相关病损率和死亡率。此外，结果显示，irAE 与治疗反应之间可能具有一定的关联。
This article reports on differences between men and women as related to immune‐related adverse events incidence and the potential link with response to therapy in patients with metastatic melanoma and non‐small cell lung cancer treated with anti‐PD1 agents.
Objective
Guillain–Barré syndrome (GBS) induced by immune checkpoint inhibitors (ICIs) has been occasionally reported in randomized clinical trials (RCTs), but the post-marketing data are quite ...limited. This study aimed to comprehensively examine GBS events secondary to ICI treatments in the real-world patients based on the Food and Drug Administration Adverse Event Reporting System (FAERS).
Methods
Reports from January 2004 to March 2020 were extracted from the FAERS. GBS cases related to ICIs were identified to characterize their clinical features. The disproportionality and Bayesian analysis were performed for the detection of GBS signals associated with ICIs.
Results
In total, 149 GBS reports with ICIs as suspect drugs were screened out. These events were found to be more prevalent in adults ≥ 45 years (63.09%) and males (63.09%). The onsets of GBS were variable with a median time of 38 (range 0–628) days after ICI initiation. The outcomes tended to be severe with 61.74% hospitalization and 22.82% death. GBS events were most commonly reported in ipilimumab plus nivolumab treatment (24.83%), and this combination therapy also yielded stronger signal for GBS than other therapies based on the highest reporting odds ratio (ROR = 12.43, two-sided 95% CI = 8.62, 17.93), proportional reporting ratio (PRR = 12.39,
χ
2
= 300.90), information component (IC = 3.62, IC025 = 2.51) and empirical Bayes geometric mean (EBGM = 12.28, EBGM05 = 9.04).
Conclusion
As complements to the safety data from RCTs, the current pharmacovigilance research helps establish a more detailed overview of ICI-related GBS, which facilitates the understanding of this rare adverse drug effect.
Immune checkpoint inhibitors (ICIs) are approved for a wide range of malignancies. They work by priming the immune system response to cancer and have changed the landscape of available cancer ...treatments. As anticipated, modulation of the regulatory controls in the immune system with ICIs results in diverse immune‐related adverse events, targeting any organ or gland. These toxicities are rarely fatal and generally regress after treatment discontinuation and/or prescription of corticosteroids. Recently, several cases of ICI‐related cardiotoxicity have been reported with complications ranging from cardiogenic shock to sudden death. The true incidence of ICI‐associated myocarditis is likely underestimated, due to a combination of factors including the lack of specificity in the clinical presentation, the potential of overlap with other cardiovascular and general medical illnesses, the challenges in the diagnosis, and a general lack of awareness of this condition. Currently, there are no clear guidelines for surveillance, diagnosis, or management of this entity. There are multiple unresolved issues including, but not limited to, identifying those at risk of this uncommon toxicity, elucidating the pathophysiology, determining if and what type of surveillance is appropriate, optimal work‐up of suspected patients, and methods for resolution of myocarditis. Here we describe a clinical vignette and discuss the salient features and management strategies of ICI‐associated myocarditis.
Key Points
The incidence of immune checkpoint inhibitor (ICI)‐associated myocarditis is unclear and has been reported to range from 0.06% to 1% of patients prescribed an ICI.
Myocarditis may be difficult to diagnose.
The risk factors for ICI‐associated myocarditis are not well understood but may include underlying autoimmune disease and diabetes mellitus.
The prevalence of myocarditis has been reported to be higher with combination immune therapies.
Myocarditis with ICI's typically occurs early, with an elevated troponin, may present with an normal left ventricular ejection fraction and may have a fulminant course.
The optimal management of myocarditis associated with ICI's is unclear but most cases are treated with high-dose steroids.
Recently, several cases of immune checkpoint inhibitor‐related cardiotoxicity have been reported, with complications ranging from cardiogenic shock to sudden death. Clear guidelines for surveillance, diagnosis, and management of one such adverse event, myocarditis, are not currently available. This article describes a clinical vignette and discusses the salient features and management strategies for immune checkpoint inhibitor‐associated myocarditis.
Introduction
Procedural sedation and analgesia (PSA) is the standard of care for many procedures in the pediatric emergency department (PED). Although generally performed by skilled PED physicians, ...in Israeli PEDs, during nighttime hours, it is mainly performed by pediatric residents. The safety of PSA by residents is considered comparable yet has not been evaluated regarding nighttime performance.
Methods
A retrospective study review of PSA performed in the PED at night (1:00
a
.
m
.–7:00
a
.
m
.). To evaluate these events, we compared each case of nighttime PSA to 2 daytime PSA cases from 2017 to 2019. Adverse events were evaluated using the Quebec criteria.
Results
The study included 451 sedations performed on 438 children from January 2017 to January 2019.
Adverse events
(AEs) occurred in 29 (6.4%) of the sedations.
Serious AEs
were uncommon. This included mostly bag-valve-mask ventilation used in 13 (2.9%) of the cases. Of these, 12 were daytime sedations. There was a clear association between abscess drainage during daytime hours and AEs.
Conclusions
Sedations performed during nighttime hours by pediatric residents seem safe and effective. This should strengthen the empowerment of residents to perform sedations when necessary even at late hours of the night. Recognizing cases at higher risk may avoid possible AEs.
Immune checkpoint inhibitors (ICIs) are widely used in oncology for their favourable antitumor efficacy. ICI therapy is associated with a unique toxicity profile known as immune‐related adverse ...events (irAEs). One such irAE is ICI‐related diabetes mellitus (DM), which is relatively uncommon but can become extremely severe, leading to irreversible impairment of β‐cells, and even lead to death if not promptly recognised and properly managed. The precise mechanisms of ICI‐related DM are not well understood. In this review, we summarise the clinical characteristics, pathophysiology, and management of this adverse effect caused by ICI therapy. Deeper investigation of ICI‐related DM may contribute to elucidate the molecular mechanisms of classical type 1 DM.
Aim: The safety concern of statins is still a major issue for Asians. The aim of this study is to compare the risk of statin-associated adverse events among potent statins. Methods: We included ...patients from the Taiwan National Health Insurance Research Database who had been treated with atorvastatin, rosuvastatin, or pitavastatin and were without diabetes at baseline. They were classified into three groups: usual-dose statin (atorvastatin 10 mg/d or rosuvastatin 5–10 mg/d), high-dose statin (atorvastatin 20–40 mg/d and rosuvastatin 20 mg/d), and pitavastatin (2–4 mg/d). The primary endpoint is a composite of safety events, including hepatitis, myopathy, and new-onset diabetes mellitus (NODM). We matched age, sex, and year of recruitment among the three groups (n=50,935 in each group) and then used the multivariate Cox proportional hazards model to evaluate the relation between the safety endpoint and different statin groups. Results: After a mean follow-up of 3.08±0.83 years, the safety events occurred in 9.84% in the pitavastatin group, 10.88% in the usual-dose statin group, and 10.49% in high-dose statin group. The multivariate Cox proportional hazards model indicated that usual-dose statin and high-dose statin were associated with a higher risk of the composite safety events compared with pitavastatin (adjusted hazard ratio aHR: 1.12, 95% confidence interval CI: 1.08–1.17 for usual-dose statin and aHR: 1.06, 95% CI: 1.02–1.10 for high-dose statin). The risks of hepatitis requiring hospitalization and NODM were especially lower in pitavastatin group. Conclusions: Compared with atorvastatin and rosuvastatin, pitavastatin might be associated with a lower risk of safety events in Asians.
The development of treatment-related adverse events (trAE) correlates favorably with clinical outcomes in multiple studies of patients receiving immune checkpoint inhibitors (ICI); however, this ...relationship is undefined in patients with hepatocellular carcinoma (HCC).
We derived a cohort of 406 patients with unresectable/advanced HCC receiving ICI therapy as part of international clinical trials submitted to the US Food and Drug Administration (FDA) in support of marketing applications. We tested whether the development of clinically significant trAE (i.e. graded ≥2, trAE2) predicted improved overall survival (OS), progression-free survival (PFS), and objective response rates (ORR) following ICI. We established an international consortium of 10 tertiary-care referral centres located in Europe (n = 67), United States (US, n = 248) and Asia (n = 42) to validate this association.
In the FDA dataset of 406 patients, 325 (80%) with Barcelona Clinic Liver Cancer (BCLC) stage C HCC mostly treated with ICI monotherapy (n = 258, 64%), trAE2 were reported in 228 patients (56.1%). Development of trAE2 was associated with longer OS (16.7 versus 11.2 months) and PFS (5.5 versus 2.2 months) and persisted as an independent predictor of outcome after adjusting for viral aetiology, gender, Child-Pugh class, BCLC stage, AFP levels, ECOG-PS, ICI regimen (mono/combination therapy) and receipt of corticosteroid therapy. In a multi-institutional cohort of 357 patients with similar characteristics mostly treated with ICI monotherapy (n = 304, 85%), the development of trAE2 was associated with longer OS (23.3 versus 12.1 months) and PFS (9.6 versus 3.9 months). TrAE2 were confirmed predictors of improved OS (HR 0.43; 95% CI:0.25–0.75) and PFS (HR 0.48; 95% CI: 0.31–0.75), with multivariable analyses confirming their association with outcome independent of clinicopathologic features of interest. Additional time-varying multivariable analyses also indicated that trAEs were associated with a decreased risk of progression (HR 0.56, 95% CI: 0.46–0.67) in the FDA dataset and death (HR 0.55; 95% CI: 0.32–0.95) in the multi-institutional dataset.
Development of trAE2 correlates with improved outcomes in patients with HCC receiving ICI in clinical trials and in routine practice. Prospective studies aimed at understanding the underlying immunologic foundations of such relationships are warranted to identify predictive biomarkers of toxicity and response.
•Treatment-related adverse events (trAEs) may affect immunotherapy outcomes in HCC.•We correlated trAEs with response and survival in independent datasets.•trAEs predict for better response and survival in trials and clinical practice.
Objective
We aimed to elucidate the clinical features of pituitary immune‐related adverse events (irAEs) induced by PD‐1 inhibitors in a Chinese cohort and the previous literatures.
Patients and ...Design and Measurements
We retrospectively analysed the clinical manifestations, laboratory examination findings, imaging features and treatments of 14 patients with pituitary irAEs caused by PD‐1 inhibitors in our cohort. In addition, we searched PubMed for all English articles on pituitary irAEs induced by PD‐1 inhibitors published from 1950 to 2023. A total of 47 articles were included, and the clinical characteristics of 94 patients with pituitary irAEs induced by PD‐1 inhibitors in these literatures were compared to the characteristics of our cohort.
Results
Among the 14 patients in our cohort with pituitary irAEs induced by PD‐1 inhibitors, 12 patients (85.71%, 12/14) exhibited isolated ACTH deficiency (IAD), 100.0% (14/14) of the central adrenocortical insufficiency, and 2 patients showed more than one hypothalamic‐pituitary axis injury (14.29%, 2/14). Pituitary magnetic resonance imaging in all the 14 patients showed no pituitary enlargement. In previous studies we reviewed, 82.98% of the total (78/94) presented with pituitary irAEs as IAD, 100.0% (94/94) of the central adrenocortical insufficiency, and 78.33% of the patients showed no abnormality of the pituitary gland (47/60). The pituitary irAEs caused by PD‐1 inhibitors did not involve typical manifestations of hypophysitis, such as pituitary enlargement, headache, visual field defects, and multiple pituitary function impairments in our cohort and the previous literatures.
Conclusion
In our study, pituitary immune‐related adverse reactions induced by PD‐1 inhibitors mainly manifested isolated ACTH deficiency rather than hypophysitis.
Background
The programmed death 1 (PD‐1) checkpoint inhibitors (CKIs) can lead to immune‐related adverse events (irAEs). We sought to evaluate whether the development of irAEs correlates with ...treatment response in non‐melanoma malignancies.
Materials and Methods
We conducted a retrospective study of patients who received anti‐PD‐1 CKI monotherapy at Fox Chase Cancer Center. Endpoints included overall response rate (ORR), time to next therapy or death (TTNTD), and overall survival (OS). Fisher's exact tests and logistic regression models were used to determine the association between irAE incidence and ORR, and Kaplan‐Meier curves with log‐rank tests and Cox regression models were used for the comparison of TTNTD and OS.
Results
Between November 2011 and November 2016, 160 patients were treated with >1 dose of an anti‐PD‐1 CKI. Seventy‐three (46%) were treated on a clinical trial. Immune‐related adverse events were noted in 64 patients (40%), with steroids required in 36 (23%). Of the 142 patients evaluable for clinical response, 28 patients (20%) achieved a partial response at first scan. An association between irAEs and ORR was seen in clinical trial patients (p = .007), but not in non‐trial patients (p = .13). When controlling for clinical trial participation and cancer type using multivariate analysis, low‐grade irAEs had higher ORR (p = .017) and longer TTNTD (p = .008). No association between irAE incidence and OS was seen (p = .827). Immune‐related adverse events that required steroid treatment were marginally associated with increased TTNTD (p = .05, hazard ratio 0.62) but were not associated with OS (p = .13).
Conclusion
We demonstrate several positive associations between the development of irAEs and clinical outcomes in non‐melanoma patients treated with PD‐1 CKIs, for which further validation is required.
Implications for Practice
This study evaluated whether the development of immune‐related adverse events in non‐melanoma patients treated with programmed cell death 1 checkpoint inhibitors correlates with improved clinical outcomes. The results indicate that for a subset of patients, in particular those with low‐grade immune‐related adverse events, immune‐related adverse events predicted for an improved response rate and longer time to next therapy or death.
Immune checkpoint inhibitors are a novel class of immunotherapeutic agents being used in clinical practice for many advanced malignancies. Checkpoint blockade targeting the programmed cell death 1 receptor or its primary ligand with pembrolizumab, nivolumab, or atezolizumab has received U.S. Food and Drug Administration approval for the treatment ofmetastatic melanoma, non‐small cell lung cancer, renal cell carcinoma, Hodgkin's lymphoma, head and neck squamous cell carcinoma, and urothelial carcinoma. Considering that checkpoint blockade treatments now extend to tumor types beyond melanoma, a study was conducted to evaluate whether the development of immune‐related adverse events correlates with treatment response in other cancer subtypes.
PDF
