BMC Geriatr. 2022 Jun 17;22(1):505. doi: 10.1186/s12877-022-03118-z.

ABSTRACT

BACKGROUND: The effectiveness of interventions to improve medication safety in older inpatients is unclear, given a paucity of properly designed intervention studies applying clinically relevant endpoints such as hospital-acquired preventable Adverse Drug Events (pADEs) and unrecognized Adverse Drug Events (uADEs). Therefore, we conducted a quality improvement study and used hospital-acquired pADEs and uADEs as main outcomes to assess the effect of an intervention aimed to improve medication safety in older inpatients.

METHOD: The study followed an interrupted time series design and consisted of three equally spaced sampling points during baseline and during intervention measurements. Each sampling point included between 80 to 90 patients. A total of 500 inpatients ≥65 years and admitted to internal medicine wards of three Dutch hospitals were included. An expert team retrospectively identified and assessed ADEs via a structured patient chart review. The findings from baseline measurement and meetings with the internal medicine and hospital pharmacy staff were used to design the intervention. The intervention consisted of a structured medication review by hospital pharmacists, followed by face-to-face feedback to prescribers, on average 3 days per week.

RESULTS: The rate of hospital-acquired pADEs per 100 hospitalizations was reduced by 50.6% (difference 16.8, 95% confidence interval (CI): 9.0 to 24.6, P < 0.001), serious hospital-acquired pADEs by 62.7% (difference 12.8, 95% CI: 6.4 to 19.2, P < 0.001), and uADEs by 51.8% (difference 11.2, 95% CI: 4.4 to 18.0, P < 0.001). Additional analyses confirmed the robustness of the intervention effect, but residual bias cannot be excluded.

CONCLUSIONS: The intervention significantly decreased the overall and serious hospital-acquired pADE occurrence in older inpatients, and significantly improved overall ADE recognition by prescribers.

TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number Register, trial registration number: ISRCTN64974377 , registration date (date assigned): 07/02/2011.

PMID:35715742 | DOI:10.1186/s12877-022-03118-z

Methods Mol Biol. 2022;2496:259-282. doi: 10.1007/978-1-0716-2305-3_14.

ABSTRACT

Drug-drug interactions (DDIs) and adverse drug reactions (ADR) are experienced by many patients, especially by elderly population due to their multiple comorbidities and polypharmacy. Databases such as PubMed contain hundreds of abstracts with DDI and ADR information. PubMed is being updated every day with thousands of abstracts. Therefore, manually retrieving the data and extracting the relevant information is tedious task. Hence, automated text mining approaches are required to retrieve DDI and ADR information from PubMed. Recently we developed a hybrid approach for predicting DDI and ADR information from PubMed. There are many other existing approaches for retrieving DDI and ADR information from PubMed. However, none of the approaches are meant for retrieving DDI and ADR specific to patient population, gender, pharmacokinetics, and pharmacodynamics. Here, we present a text mining protocol which is based on our recent work for retrieving DDI and ADR information specific to patient population, gender, pharmacokinetics, and pharmacodynamics from PubMed.

PMID:35713869 | DOI:10.1007/978-1-0716-2305-3_14

Methods Mol Biol. 2022;2496:237-258. doi: 10.1007/978-1-0716-2305-3_13.

ABSTRACT

Drug-drug interactions (DDIs) and adverse drug reactions (ADRs) occur during the pharmacotherapy of multiple comorbidities and in susceptible individuals. DDIs and ADRs limit the therapeutic outcomes in pharmacotherapy. DDIs and ADRs have significant impact on patients' life and health care cost. Hence, knowledge of DDI and ADRs is required for providing better clinical outcomes to patients. Various approaches are developed by the scientific community to document and report the occurrences of DDIs and ADRs through scientific publications. Due to the enormously increasing number of publications and the requirement of updated information on DDIs and ADRs, manual retrieval of data is time consuming and laborious. Various automated techniques are developed to get information on DDIs and ADRs. One such technique is text mining of DDIs and ADRs from published biomedical literature in PubMed. Here, we present a recently developed text mining protocol for predicting DDIs and ADRs from PubMed abstracts.

PMID:35713868 | DOI:10.1007/978-1-0716-2305-3_13

J Dtsch Dermatol Ges. 2022 Jun;20(6):747-748. doi: 10.1111/ddg.14827.

NO ABSTRACT

PMID:35711044 | DOI:10.1111/ddg.14827

Arch Osteoporos. 2022 Jun 17;17(1):84. doi: 10.1007/s11657-022-01129-2.

ABSTRACT

Denosumab is a newly approved treatment for osteoporosis in China. However, the clinical safety and advantages of denosumab have not been much established. The current study evaluates the real-world safety of denosumab versus zoledronic acid in treating cancer-free adults aged 50 years or older with osteoporosis to provide clinical settings guidelines.

PURPOSE: A head-to-head comparison of the safety profiles between denosumab (60 mg subcutaneously every 6 months) and zoledronic acid (5 mg, intravenously yearly) was performed in cancer-free adults aged 50 years or older with osteoporosis.

METHODS: MEDLINE, EMBASE, and Cochrane Library databases were searched for cohort studies comparing the safety of denosumab and zoledronic acid in cancer-free adults aged 50 years or older with osteoporosis till December 2021. The outcomes included the risk of fracture and other severe adverse events. Based on the Cochrane Handbook for Systematic Reviews of Interventions 5.0.2, we identified the eligible studies.

RESULTS: Three cohort studies having 38,845 cancer-free adults aged 50 years or older were included in the study. The results showed that denosumab was not superior to zoledronic acid in reducing fracture risk [RR (95% CI): 1.05 (0.90, 1.23), P = 0.52]. However, denosumab had a low risk of composite cardiovascular disease [RR (95% CI): 0.82 (0.70, 0.96), P = 0.01]. There were no significant differences between the hazards of serious infection, and total adverse events (P > 0.05).

CONCLUSION: The present meta-analysis demonstrated that for cancer-free adults aged 50 years or older with osteoporosis, denosumab was as safe as zoledronic acid for the risk of drug-induced fractures. However, denosumab had a lower incidence of composite cardiovascular disease, and may be a better option for the population with cardiovascular disease. Nonetheless, due to limitations like a short-term follow-up, gender, and incomplete types of adverse effects, more randomized controlled trials (RCTs) are required to further verify this conclusion.

PMID:35715524 | DOI:10.1007/s11657-022-01129-2

Reg Anesth Pain Med. 2022 Jun 17:rapm-2022-103830. doi: 10.1136/rapm-2022-103830. Online ahead of print.

ABSTRACT

The medical field has been experiencing numerous drug shortages in recent years. The most recent shortage to impact the field of interventional pain medicine is that of iodinated contrast medium. Pain physicians must adapt to these changes while maintaining quality of care. This position statement offers guidance on adapting to the shortage.

PMID:35715014 | DOI:10.1136/rapm-2022-103830

Acta Neurol Scand. 2022 Jun 16. doi: 10.1111/ane.13659. Online ahead of print.

ABSTRACT

OBJECTIVES: Cenobamate is an antiseizure medication (ASM) approved in Europe as adjunctive therapy for adults with inadequately controlled focal seizures. This post hoc analysis reports onset of efficacy and characterizes time to onset, duration, and severity of the most common treatment-emergent adverse events (TEAEs) during cenobamate titration.

MATERIALS & METHODS: Adult patients with uncontrolled focal seizures taking 1 to 3 concomitant ASMs were randomized to receive adjunctive cenobamate or placebo (double-blind studies C013 and C017) or cenobamate (open-label study C021). Outcome assessments included efficacy (median percentage change in seizure frequency and onset [studies C013 and C017]) and safety (onset, duration, and severity of TEAEs [all studies]).

RESULTS: Onset of efficacy was observed by Weeks 1 to 4 of titration in studies C013 and C017 which used a faster titration schedule than study CO21. In study C013, the median percentage seizure frequency reduction was 36.7% in patients receiving cenobamate versus 16.3% in those taking placebo (p = .002); in study C017, significant differences in seizure frequency emerged in Week 1 and continued throughout titration between all cenobamate groups and placebo (p < .001). The most commonly reported TEAEs were somnolence, dizziness, fatigue, and headache, with first onset of each reported as early as Week 1; however, the majority resolved.

CONCLUSIONS: Reductions in seizure frequency occurred during titration with initial efficacy observed prior to reaching the target dose. These reductions were regarded as clinically meaningful because they may indicate early efficacy at lower doses than previously expected and had a considerable impact on patient quality of life. Long-term treatment with adjunctive cenobamate was generally safe and well-tolerated.

PMID:35711112 | DOI:10.1111/ane.13659

S D Med. 2022 Apr;75(4):162-165.

ABSTRACT

Immune checkpoint inhibitors (ICIs) have recently gained recognition as valuable treatment options for a variety of cancers. Pembrolizumab is a monoclonal antibody that acts as an inhibitor of programmed cell death receptor-1 (PD-1). This helps release host T-cells from regulatory inhibition by tumor neoantigens, therefore mediating antitumor effects. Pembrolizumab has been approved for a variety of cancers including melanoma, head and neck squamous cell carcinoma, non-small cell lung cancer, and urothelial cell carcinoma. It has also recently gained attention for possible use in hepatocellular carcinoma and triple negative breast cancer. Although efficacious, ICIs manifest a unique set of immune-related adverse effects (irAEs) including acute kidney injury (AKI) and acute liver injury (ALI) of which the mechanism is poorly understood. While these irAEs have been described previously in literature individually, there is a paucity of literature describing their simultaneous occurence. With the growing incorporation of ICIs in oncological regimens, it is important to characterize the presentation of irAEs to facilitate earlier recognition and intervention to avoid further complications. We present a case of a 60-year-old male who presented with concurrent AKI and ALI secondary to pembrolizumab therapy for advanced metastatic melanoma. To the authors' knowledge, this is the first reported incident in literature of AKI and ALI occurring simultaneously secondary to ICI immunotherapy with pembrolizumab, although each have been reported and characterized individually.

PMID:35709347

Drug Ther Bull. 2022 Jun 16:dtb-2022-000030. doi: 10.1136/dtb.2022.000030. Online ahead of print.

ABSTRACT

Commentary on: Sheppard JP, Burt J, Lown M, et al Effect of antihypertensive medication reduction vs usual care on short-term blood pressure control in patients with hypertension aged 80 years and older: The OPTIMISE randomized clinical trial. JAMA 2020;323:2039-51.

PMID:35710539 | DOI:10.1136/dtb.2022.000030

Drug Ther Bull. 2022 Jun 15:dtb-2022-000033. doi: 10.1136/dtb.2022.000033. Online ahead of print.

ABSTRACT

Overview of: Undela K, Goldsmith L, Kew KM, et al Macrolides for chronic asthma. Cochrane Database Syst Rev 2021;11:10.1002/14651857.CD002997.pub5.

PMID:35705323 | DOI:10.1136/dtb.2022.000033

J Immunother Cancer. 2022 Jun;10(6):e004670. doi: 10.1136/jitc-2022-004670.

ABSTRACT

BACKGROUND: Immune checkpoint inhibitors (ICIs) have improved survival and are increasingly used for non-small cell lung cancer. However, use may be limited by immune-related adverse events such as checkpoint-inhibitor pneumonitis (CIP). Literature estimates for CIP incidence are inconsistent. Real-world adherence to guidelines, clinical course, and healthcare utilization in the treatment of CIP has not been described in large cohorts.

METHODS: A combined claims and electronic health record database (TriNetX) was used to identify 13,113 patients with lung cancer treated with programmed cell death receptor/ligand 1 (PD-1/PD-L1) inhibitors, and a propensity score-matched control cohort treated with chemotherapy or targeted therapies. The attributable risk of CIP was calculated in the first 12 months after therapy by comparing the incidence of diagnosis codes for pneumonitis/pneumonia between cohorts. Cases of CIP, identified by the most specific code for drug-induced respiratory conditions, were further analyzed for medication usage, rates of diagnostic bronchoscopy, ICI discontinuation rates, and usage of hospital services compared with patients receiving PD-1/PD-L1 inhibitors who did not develop CIP.

RESULTS: The attributable risk of pneumonitis to PD-1/PD-L1 inhibitors was 2.49% (95% CI, 1.50% to 3.47%). Median time to onset in the CIP subcohort was 3.9 months (IQR, 2.1-7.3 months). Steroid and antibiotic use increased dramatically after a pneumonitis diagnosis, and 70.2% of patients permanently discontinued ICI therapy. Compared with controls, patients with CIP had more than a threefold increased risk of needing critical care (relative risk 3.59, 95% CI, 2.31 to 5.57) and an increased risk of mortality (HR 2.34, 95% CI, 1.47 to 3.71).

CONCLUSIONS: In a large claims-based analysis, PD-1/PD-L1 inhibitors increase the risk of pneumonitis in patients with lung cancer by 2.49%. Cases of CIP are associated with high healthcare utilization, discontinuation of ICIs, and mortality.

PMID:35705313 | DOI:10.1136/jitc-2022-004670

Am J Psychiatry. 2022 Jun 15:appiajp21090964. doi: 10.1176/appi.ajp.21090964. Online ahead of print.

ABSTRACT

OBJECTIVE: Extensive exposure to prescription-type opioids has resulted in major harm worldwide, calling for better-adapted approaches to opioid agonist therapy. The authors aimed to determine whether flexible take-home buprenorphine/naloxone is as effective as supervised methadone in reducing opioid use in prescription-type opioid consumers with opioid use disorder.

METHODS: This seven-site, pan-Canadian, 24-week, pragmatic, open-label, noninferiority, two-arm parallel randomized controlled trial involved treatment-seeking adults with prescription-type opioid use disorder. Participants were randomized in a 1:1 ratio to treatment with sublingual buprenorphine/naloxone (target dosage, 8 mg/2 mg to 24 mg/6 mg per day; flexible take-home dosing) or oral methadone (≈60-120 mg/day; closely supervised). The primary outcome was the proportion of opioid-free urine drug screens over 24 weeks (noninferiority margin, 15%). All randomized participants were analyzed, excluding one who died shortly after randomization, for the primary analysis (modified intention-to-treat analysis).

RESULTS: Of 272 participants recruited (mean age, 39 years [SD=11]; 34.2% female), 138 were randomized to buprenorphine/naloxone and 134 to methadone. The mean proportion of opioid-free urine drug screens was 24.0% (SD=34.4) in the buprenorphine/naloxone group and 18.5% (SD=30.5) in the methadone group, with a 5.6% adjusted mean difference (95% CI=-0.3, +∞). Participants in the buprenorphine/naloxone group had 0.47 times the odds (95% CI=0.24, 0.90) of being retained in the assigned treatment compared with those in the methadone group. Overall, 24 drug-related adverse events were reported (12 in the buprenorphine/naloxone group [N=8/138; 5.7%] and 12 in the methadone group [N=12/134; 9.0%]) and mostly included withdrawal, hypogonadism, and overdose.

CONCLUSIONS: The buprenorphine/naloxone flexible model of care was safe and noninferior to methadone in reducing opioid use among people with prescription-type opioid use disorder. This flexibility could help expand access to opioid agonist therapy and reduce harms in the context of the opioid overdose crisis.

PMID:35702828 | DOI:10.1176/appi.ajp.21090964

Circ Cardiovasc Qual Outcomes. 2022 Jun 14:101161CIRCOUTCOMES122008914. doi: 10.1161/CIRCOUTCOMES.122.008914. Online ahead of print.

NO ABSTRACT

PMID:35698975 | DOI:10.1161/CIRCOUTCOMES.122.008914

Onco Targets Ther. 2022 Jun 7;15:637-642. doi: 10.2147/OTT.S361467. eCollection 2022.

ABSTRACT

Pembrolizumab is an immune checkpoint inhibitor (ICI) that targets programmed death-1. Although ICIs have shown efficacy in the treatment of lung cancer, they have also been reported to cause a variety of immune-related adverse events (irAEs). Hepatotoxicity is a known irAEs, but currently, there is not enough information on its pathological characteristics and treatment. We report the case of a 70-year-old man with advanced squamous-cell lung cancer who developed severe grade 4 hepatitis on day 8 after receiving carboplatin, nab-paclitaxel, and pembrolizumab as fourth-line therapy. We treated him with steroid therapy the day after a liver biopsy was performed to investigate his pathological features, which led to a rapid and remarkable improvement. Confirmation of immune-related hepatotoxicity by pathological findings allowed the early tapering and discontinuation of steroid therapy. Performing a liver biopsy and verifying histological characteristics are needed for successful treatment with short-term steroids when drug-induced hepatitis caused by anti-cancer therapy including pembrolizumab is considered.

PMID:35698605 | PMC:PMC9188365 | DOI:10.2147/OTT.S361467

Vaccine. 2022 Jul 29;40(31):4262-4269. doi: 10.1016/j.vaccine.2022.06.001. Epub 2022 Jun 10.

ABSTRACT

Encouraging vaccine uptake is important to reducing the impact of infectious disease. However, negative attitudes and vaccine hesitancy, due in part to worry about side effects, are obstacles to achieving high vaccination rates. Provided vaccine information sheets typically include a list of side effects without numeric information about their likelihoods, but providing such numbers may yield benefits. We investigated the effect of providing numeric information about side-effect likelihood (e.g., "1%") and verbal labels (e.g., "uncommon") on intentions to get a hypothetical vaccine, reasons for the vaccination decision, and risk overestimation. In a diverse, online, convenience sample (N = 595), providing numeric information increased vaccine intentions-70% of those who received numeric information were predicted to be moderately or extremely likely to vaccinate compared to only 54% of those who did not receive numeric information (p<.001), controlling for age, gender, race, education, and political ideology. Participants receiving numeric information also were less likely to overestimate side-effect likelihood. Verbal labels had additional benefits when included with numeric information, particularly among the vaccine hesitant. For these participants, verbal labels increased vaccine intentions when included with numeric information (but not in its absence). Among the vaccine-hesitant, 43% of those provided numeric information and verbal labels were predicted to be moderately or extremely likely to get vaccinated vs. only 24% of those given a list of side effects (p<.001). We conclude that the standard practice of not providing numeric information about side-effect likelihood leads to a less-informed public who is less likely to vaccinate.

PMID:35697576 | DOI:10.1016/j.vaccine.2022.06.001

BMC Geriatr. 2022 Jun 13;22(1):502. doi: 10.1186/s12877-022-03171-8.

ABSTRACT

BACKGROUND: Polypharmacy increases with age and is associated with serious health and economic costs. This study reports changes over a decade in medication-use patterns and polypharmacy, in Israeli community-dwelling older adults aged ≥ 65 years.

METHODS: Demographic and health data from two representative national health cross-sectional surveys - MABAT ZAHAV 1 (MZ1) in 2005-2006, and MZ2 in 2014-2015 were analyzed. Polypharmacy was defined as use of ≥ 5 medications. Risk factors for polypharmacy were estimated by multivariable logistic regression with adjusted odds ratios (aOR) and their 95% confidence intervals (CI).

RESULTS: Self-reported data on medications taken were available for 1647 participants (91.5%) in MZ1, and for 833 participants (80.2%) in MZ2, 55% women, and about 20% aged ≥ 80, in both surveys. The prevalence of polypharmacy was significantly lower in MZ2 than in MZ1: 64.2% versus 56.3%, p = .0001; with an aOR (95%CI) of 0.64 (0.52, 0.80). The most commonly taken drugs were for hypertension (27.0%, 25.3%), dyslipidemia (9.7%, 12.4%) and anticoagulation (9.2%, 9.8%). For approximately 10% of drugs, indications were either unknown or incorrect. Polypharmacy was significantly associated with poor self-health assessment 2.47 (1.99, 3.06), ≥ 4 versus 1-3 chronic illnesses 6.36 (3.85, 10.50), and age ≥ 80 versus younger 1.72 (1.32, 2.24). Similar associations were observed with major polypharmacy of ≥ 8 medications.

CONCLUSION: Polypharmacy, although reduced in the last decade, requires constant attention, especially concerning lack of knowledge of indications which leads to poor adherence and adverse side effects. Health-care teams should carry out regular medicine reconciliation in at-risk elderly patients.

PMID:35698037 | DOI:10.1186/s12877-022-03171-8

Sci Rep. 2022 Jun 13;12(1):9748. doi: 10.1038/s41598-022-13626-y.

ABSTRACT

The treatment of acute myeloid leukemia (AML) with unfavorable cytogenetics treatment remains a challenge. We previously established that ex vivo exposure of AML blasts to eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or fish oil emulsion (FO) induces Nrf2 pathway activation, metabolic switch, and cell death. The FILO group launched a pilot clinical study to evaluate the feasibility, safety, and efficacy of the adjunction of a commercial FO emulsion to 3 + 7 in untreated AML with unfavorable cytogenetics. The primary objective was complete response (CR). Thirty patients were included. FO administration raised the plasma levels of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids (p < 0.001). The pharmacokinetics of cytarabine and daunorubicin were unaffected. A historical comparison to the LAM2001 trial (Lioure et al. Blood 2012) found a higher frequency of grade 3 serious adverse events, with no drug-related unexpected toxicity. The CR rate was 77%, and the partial response (PR) 10%, not significantly superior to that of the previous study (CR 72%, PR 1%). RT-qPCR analysis of Nrf2 target genes and antioxidant enzymes did not show a significant in vivo response. Overall, FO emulsion adjunction to 3 + 7 is feasible. An improvement in CR was not shown in this cohort of high-risk patients. The present data does not support the use of FO in adjunction with 3 + 7 in high-risk AML patients.ClinicalTrials.gov identifier: NCT01999413.

PMID:35697729 | DOI:10.1038/s41598-022-13626-y

J Hepatol. 2022 Jun 10:S0168-8278(22)00348-8. doi: 10.1016/j.jhep.2022.05.027. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Nucleos(t)ide reverse transcriptase inhibitors do not completely suppress hepatitis B virus (HBV) DNA in chronic HBV infection (cHBV). Vebicorvir (VBR) is an investigational core inhibitor which interferes with multiple aspects of HBV replication. This phase 2 trial (NCT03577171) evaluated the efficacy and safety of VBR in combination with entecavir (ETV) in treatment-naïve patients with cHBV.

METHODS: Hepatitis B "e" antigen positive, treatment-naïve patients without cirrhosis were randomised 1:1 in a double-blind manner, to once-daily VBR 300 mg+ETV 0.5 mg or placebo (PBO)+ETV for 24 weeks (W). The primary endpoint was change in mean log10 HBV DNA from Baseline to W12 and W24.

RESULTS: All patients in both treatment groups (PBO+ETV: 12/12; VBR+ETV: 13/13) completed the study. At W12, VBR+ETV led to a greater mean (SD) reduction from Baseline in log10 IU/mL HBV DNA (-4.45 [1.03]) vs PBO+ETV (-3.30 [1.18]; p=0.0077). At W24, VBR+ETV led to a greater reduction from Baseline in log10 IU/mL HBV DNA (-5.33 [1.59]) vs PBO+ETV (-4.20 [0.98]; p=0.0084). Greater mean reductions in pregenomic RNA were observed at W12 and W24 in patients receiving VBR+ETV vs PBO+ETV (p<0.0001 and p<0.0001). Changes in viral antigens were similar in both groups. No drug interaction between VBR and ETV was observed. Two patients experienced HBV DNA rebound during treatment, with no resistance breakthrough detected. Safety of VBR+ETV was similar to PBO+ETV. All treatment-emergent adverse events and laboratory abnormalities were Grade 1/2. There were no deaths, serious AEs, or evidence of drug-induced liver injury.

CONCLUSIONS: In this 24-week study, VBR+ETV provided additive antiviral activity over PBO+ETV in treatment-naïve patients with cHBV with a favourable safety and tolerability profile.

LAY SUMMARY: Hepatitis B is a long-lasting viral infection of the liver. This study demonstrates that vebicorvir (a core inhibitor) with entecavir is generally safe, well tolerated, and demonstrates greater antiviral activity compared with entecavir alone in treatment-naïve patients chronically infected with hepatitis B virus. This study supports continued evaluation of vebicorvir in the treatment of chronic hepatitis B.

CLINICAL TRIAL NUMBER: NCT03577171.

PMID:35697332 | DOI:10.1016/j.jhep.2022.05.027

Immunotherapy. 2022 Jun 13. doi: 10.2217/imt-2021-0342. Online ahead of print.

ABSTRACT

Patients with cancer have a higher risk of severe COVID-19, and expert consensus advocates for COVID-19 vaccination in this population. Some cases of autoimmune hepatitis have been described after the administration of COVID-19 vaccine in the people in apparently good health. Immune checkpoint inhibitors (ICIs) are responsible for a wide spectrum of immune-related adverse events (irAEs). This article reports a case of hepatitis and colitis in a 52-year-old woman who was undergoing immunotherapy and was HBV positive 10 days after receiving the first Pfizer-BioNTech COVID-19 vaccine dose. Because both ICIs and the COVID-19 vaccines stimulate the immune response, the authors hypothesize that these vaccines may increase the incidence of irAEs during ICI treatment. There is a complex interplay between the immune-mediated reaction triggered by the vaccination and PD-L1 co-administration.

PMID:35694999 | DOI:10.2217/imt-2021-0342

Lancet Haematol. 2022 Jun 9:S2352-3026(22)00145-4. doi: 10.1016/S2352-3026(22)00145-4. Online ahead of print.

ABSTRACT

BACKGROUND: Early antibiotic discontinuation has been advocated in haematology patients with fever of unknown origin during chemotherapy-induced neutropenia, but its safety is unknown. We aimed to assess if short treatment with carbapenems is non-inferior to extended treatment.

METHODS: This non-inferiority, open-label, multicentre, randomised trial was done in six hospitals in the Netherlands. Adult patients (≥18 years) who were treated with intensive chemotherapy or haematopoietic stem-cell transplantation (HSCT) for a haematological malignancy, and had fever of unknown origin during high-risk neutropenia (<0·5 × 109/L expected for ≥7 days) were eligible. After onset of fever, patients received either 500 mg intravenous imipenem-cilastatin four times a day or 1000 mg intravenous meropenem three times a day. Between 48 h and 72 h of treatment, participants were randomly assigned (1:1) by a computer-generated sequence to receive a short-term (72 h [60-84]; short treatment group) or extended (≥9 days until being afebrile for 5 days or neutrophil recovery; extended treatment group) carbapenem regimen. The composite primary endpoint was treatment failure, defined as recurrent fever or a carbapenem-sensitive infection between day 4 and day 9 and septic shock or respiratory failure or death from day 4 until neutrophil recovery. The study was designed to assess the non-inferiority of the short treatment compared with the extended treatment regimen, with a non-inferiority margin of 10%. The primary outcome was adjudicated by an independent outcome committee, who were masked to treatment allocation, and was analysed in the intention-to-treat and per-protocol populations. The trial is completed and registered with ClinicalTrials.gov, NCT02149329.

FINDINGS: Between Dec 1, 2014, and July 1, 2019, 281 patients were included in the intention-to-treat analysis: 144 (51%) patients were assigned to the short treatment group and 137 (49%) to the extended treatment group. Median age was 59 years (IQR 52-65); 109 (39%) patients were women and 172 (61%) were men; 205 (73%) patients received HSCT. In the intention-to-treat analysis, 28 (19%) of 144 patients in the short treatment group versus 21 (15%) of 137 patients in the extended treatment group had treatment failure (adjusted risk difference [ARD] 4·0% [90% CI -1·7% to 9·7%]; p=0·25). In the per-protocol analysis (n=225), 24 (23%) of 104 patients in the short treatment group and 19 (16%) of 121 patients in the extended treatment group had treatment failure (ARD 7·3% [0·3% to 14·9%]; p=0·11). The most common grade 3-5 infection-related adverse events were mucositis (23 [20%] of 114 adverse events in the short treatment group vs 28 [29%] of 98 adverse events in the extended treatment group), fever of unknown origin (20 [18%] vs 16 [16%] events), and bacteraemia (15 [13%] vs 13 [13%] events). The number of serious adverse events were higher in the short treatment group (23 [16%] of 144 patients) than in the extended treatment group (14 [10%] of 137 patients), due to an increased rate of readmission (17 [12%] patients in the short treatment group vs ten [7%] in the extended treatment group). Death before 30 days after neutrophil recovery occurred in five (3%) participants in the short treatment group: two due to progressive leukaemia, two due to candidaemia, and one due to Enterococcus faecium bacteraemia and drug-induced pneumonitis. One (1%) patient died in the extended treatment group due to candidaemia. None of the deaths were related to carbapenem-sensitive infections.

INTERPRETATION: Early discontinuation of carbapenem treatment in patients with febrile neutropenia of unknown origin does not result in increased treatment failure. Our study supports short treatment if patients are afebrile after 3 days of carbapenem treatment. However, because secondary analyses suggested that serious adverse events and all-cause mortality occurred more often in patients who are presistantly febrile the short treatment group, we recommend vigilance for non-susceptible pathogens and early resumption of empirical therapy in patients who are deteriorating.

FUNDING: The Netherlands Organisation for Health Research and Development and Fonds NutsOhra.

PMID:35691326 | DOI:10.1016/S2352-3026(22)00145-4