RESUMEN
The co-administration of venetoclax, a BCL-2 inhibitor, with a mould-active azole, such a posaconazole, has potential to both prevent invasive fungal infection (IFI) and reduce the required treatment dose, and cost, of venetoclax. Posaconazole drug-level monitoring is critical to ensuring adequate mould prophylaxis. A retrospective audit of 99 patients at a tertiary cancer centre, with myeloid malignancies co-prescribed venetoclax and posaconazole between January 2018 and April 2022, was undertaken to evaluate the adequacy of posaconazole prescribing and the rate of breakthrough IFI. Seventy-six patients (77%) had at least one posaconazole level measured in the study period, with 37% requiring a dose adjustment based on steady-state trough levels. Breakthrough IFI occurred in 4% of patients, typically within 1 month of commencing anti-mould prophylaxis. Close monitoring of posaconazole levels in venetoclax-treated patients, particularly in the early, outpatient setting, is critical.
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Infecciones Fúngicas Invasoras , Leucemia Mieloide Aguda , Humanos , Antifúngicos/uso terapéutico , Estudios Retrospectivos , Leucemia Mieloide Aguda/tratamiento farmacológico , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/prevención & controlRESUMEN
Revaccination after receipt of a hematopoietic cell transplant (HCT) or cellular therapies is a pillar of patient supportive care, with the potential to reduce morbidity and mortality linked to vaccine-preventable infections. This review synthesizes national, international, and expert consensus vaccination schedules post-HCT and presents evidence regarding the efficacy of newer vaccine formulations for pneumococcus, recombinant zoster vaccine, and coronavirus disease 2019 in patients with hematological malignancy. Revaccination post-cellular therapies are less well defined. This review highlights important considerations around poor vaccine response, seroprevalence preservation after cellular therapies, and the optimal timing of revaccination. Future research should assess the immunogenicity and real-world effectiveness of new vaccine formulations and/or vaccine schedules in patients post-HCT and cellular therapy, including analysis of vaccine response that relates to the target of cellular therapies.
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Enfermedades Transmisibles , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Vacunas , Humanos , Enfermedades Transmisibles/etiología , Neoplasias Hematológicas/terapia , Inmunoterapia Adoptiva , Estudios SeroepidemiológicosRESUMEN
Infection remains a significant contributor to morbidity and mortality in patients with myeloma. This guideline was developed by a multidisciplinary group of clinicians who specialise in the management of patients with myeloma and infection from the medical and scientific advisory group from Myeloma Australia and the National Centre for Infections in Cancer. In addition to summarising the current epidemiology and risk factors for infection in patients with myeloma, this guideline provides recommendations that address three key areas in the prevention of infection: screening for latent infection, use of antimicrobial prophylaxis and immunoglobulin replacement and vaccination against leading respiratory infections (severe acute respiratory syndrome coronavirus 2, influenza and Streptococcus pneumoniae) and other preventable infections. This guideline provides a practical approach to the prevention of infection in patients with myeloma and harmonises the clinical approach to screening for infection, use of prophylaxis and vaccination to prevent infectious complications.
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Antiinfecciosos , COVID-19 , Mieloma Múltiple , Humanos , Consenso , COVID-19/complicaciones , Mieloma Múltiple/complicaciones , Mieloma Múltiple/tratamiento farmacológico , VacunaciónRESUMEN
The objective of the study is to assess the efficacy and tolerability of penicillins compared to anti-staphylococcal beta-lactams for treatment of penicillin-susceptible Staphylococcus aureus bloodstream infections (PSSA BSI). A retrospective cohort study was conducted of 140 sequential PSSA BSI presenting to a local health district (90 cases included). Penicillin susceptibility was confirmed by disc diffusion, Vitek® and Nitrocefin beta-lactamase methods. Clinical information regarding comorbidities and infection complexity was recorded. Antibiotic choice, dosage and duration were reviewed. Outcomes were compared according to the definitive treatment with either penicillin or ASBLs. The primary outcome was 30-day mortality. Secondary outcomes included renal injury, microbiological relapse and treatment tolerability. Ninety patients met inclusion criteria and were included in subsequent analysis. Of PSSA BSI, 69% were community acquired. Eighty-two percent had complex PSSA infections. The average duration of bacteraemia was 2.8 days (SD = 1.8 days). Sixty-six patients received definitive penicillin treatment, with a mean of 3.5 days of empiric antibiotics prior to penicillin. Twenty-four patients received definitive ASBL treatment (11 cefazolin, 13 flucloxacillin). There was no difference in 30-day mortality between groups (p = 1). There was no difference in renal injury (p > 0.5), hospital length of stay (p = 0.59) or microbiological relapse within 1 year (p = 0.17). Penicillin treatment was well tolerated. Our data supports penicillin as a suitable and well-tolerated alternative to ASBL in managing complex PSSA BSI.
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Antibacterianos/uso terapéutico , Bacteriemia/tratamiento farmacológico , Penicilinas/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , beta-Lactamas/uso terapéutico , Bacteriemia/microbiología , Bacteriemia/mortalidad , Cefazolina/uso terapéutico , Femenino , Humanos , Masculino , Estudios Retrospectivos , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/mortalidad , Staphylococcus aureus/enzimología , Vancomicina/uso terapéuticoRESUMEN
PURPOSE: Contention surrounds how best to screen patients for latent and undiagnosed infection prior to cancer treatment. Early treatment and prophylaxis against reactivation may improve infection-associated morbidity. This study sought to examine rates of screening and prevalence of latent infection in overseas-born patients receiving cancer therapies. METHODS: A single-centre retrospective audit of 952 overseas-born patients receiving chemotherapy, targeted agents and immunotherapy between January 1 and December 31 2019 was undertaken at Peter MacCallum Cancer Centre. Pre-treatment screening for hepatitis B (HBV), hepatitis C (HCV), human immunodeficiency virus (HIV), latent tuberculosis (LTBI), toxoplasmosis and strongyloidiasis was audited. RESULTS: Approximately half of our overseas-born patients were screened for HBV (58.9%) and HCV (50.7%). Fewer patients were screened for HIV (30.5%), LTBI (18.3%), strongyloidiasis (8.6%) or toxoplasmosis (8.1%). Although 59.7% of our patients were born in countries with high epidemiological risk for latent infection, according to World Health Organization data, 35% were not screened for any infection prior to commencement of therapy. CONCLUSION: The prevalence of latent infections amongst overseas-born patients with cancer, and complexities associated with risk-based screening, likely supports universal latent infection screening amongst this higher-risk cohort.
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Hepatitis B , Infección Latente , Neoplasias , Australia/epidemiología , Detección Precoz del Cáncer , Humanos , Tamizaje Masivo , Neoplasias/tratamiento farmacológico , Neoplasias/epidemiología , Prevalencia , Estudios RetrospectivosRESUMEN
Invasive fungal disease (IFD) due to moulds other than Aspergillus is a significant cause of mortality in patients with malignancies or post haemopoietic stem cell transplantation. The current guidelines focus on the diagnosis and management of the common non-Aspergillus moulds (NAM), such as Mucorales, Scedosporium species (spp.), Lomentospora prolificans and Fusarium spp. Rare but emerging NAM including Paecilomyces variotii, Purpureocillium lilacinum and Scopulariopsis spp. are also reviewed. Culture and histological examination of tissue biopsy specimens remain the mainstay of diagnosis, but molecular methods are increasingly being used. As NAM frequently disseminate, blood cultures and skin examination with biopsy of any suspicious lesions are critically important. Treatment requires a multidisciplinary approach with surgical debridement as a central component. Other management strategies include control of the underlying disease/predisposing factors, augmentation of the host response and the reduction of immunosuppression. Carefully selected antifungal therapy, guided by susceptibility testing, is critical to cure. We also outline novel antifungal agents still in clinical trial which offer substantial potential for improved outcomes in the future. Paediatric recommendations follow those of adults. Ongoing epidemiological research, improvement in diagnostics and the development of new antifungal agents will continue to improve the poor outcomes that have been traditionally associated with IFD due to NAM.
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Hematología , Infecciones Fúngicas Invasoras , Adulto , Antifúngicos/uso terapéutico , Aspergillus , Niño , Hongos , Humanos , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/terapiaRESUMEN
A substantial body of research demonstrates the importance of sleep for emotional processing and learning as well as the association between sleep problems and heightened anxiety. However, there is currently no research exploring the impact of sleepiness on vicariously learned fear responses. Experiment 1 (N = 38) first demonstrated no effect of trait or state sleepiness on children's (7-11 years of age) subjective ratings of fear. Experiment 2 (N = 42) and Experiment 3 (N = 46) used an established vicarious learning paradigm to demonstrate that trait sleepiness facilitated vicariously acquired avoidance preferences for animals paired with fearful faces (fear-paired animals), whereas state sleepiness facilitated children's fear cognitions and attentional bias toward fear-paired animals. This study is the first to demonstrate the role of state and trait sleepiness in moderating vicarious fear learning in children.
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Trastornos Fóbicos , Somnolencia , Animales , Niño , Emociones , Miedo , Humanos , AprendizajeAsunto(s)
Antibacterianos , Hematología , Humanos , Antibacterianos/uso terapéutico , Profilaxis AntibióticaRESUMEN
OBJECTIVES: The objective of this study was to evaluate the effect of tumour necrosis factor-alpha inhibitors (TNF-αI) on Alzheimer's disease-associated pathology. DESIGN: A literature search of PubMed, Embase, PsychINFO, Web of Science, Scopus, and the Cochrane Library databases for human and animal studies that evaluated the use of TNF-αI was performed on 26 October 2016. RESULTS: The main outcomes assessed were cognition and behaviour, reduction in brain tissue mass, presence of plaques and tangles, and synaptic function. Risk of bias was assessed regarding blinding, statistical model, outcome reporting, and other biases. Sixteen studies were included, 13 of which were animal studies and 3 of which were human. All animal studies found that treatment with TNF-αI leads to an improvement in cognition and behaviour. None of the studies measured change in brain tissue mass. The majority of studies documented a beneficial effect in other areas, including the presence of plaques and tangles and synaptic function. The amount of data from human studies was limited. Two out of 3 studies concluded that TNF-αI are beneficial in Alzheimer's disease patients, with one being an observational study and the latter being a small pilot study, with a high risk of bias. CONCLUSION: It was concluded that a large-scale randomized controlled trial assessing the effectiveness of TNF-αI on humans is warranted.
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Enfermedad de Alzheimer/tratamiento farmacológico , Antiinflamatorios no Esteroideos/uso terapéutico , Factores Inmunológicos/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Animales , Cognición/fisiología , Humanos , Proyectos Piloto , Placa Amiloide/patologíaRESUMEN
Recent research has indicated that vicarious learning can lead to increases in children's fear beliefs and avoidance preferences for stimuli and that these fear responses can subsequently be reversed using positive modeling (counterconditioning). The current study investigated children's vicariously acquired avoidance behavior, physiological responses (heart rate), and attentional bias for stimuli and whether these could also be reduced via counterconditioning. Ninety-six (49 boys, 47 girls) 7- to 11-year-olds received vicarious fear learning for novel stimuli and were then randomly assigned to a counterconditioning, extinction, or control group. Fear beliefs and avoidance preferences were measured pre- and post-learning, whereas avoidance behavior, heart rate, and attentional bias were all measured post-learning. Control group children showed increases in fear beliefs and avoidance preferences for animals seen in vicarious fear learning trials. In addition, significantly greater avoidance behavior, heart rate responding, and attentional bias were observed for these animals compared to a control animal. In contrast, vicariously acquired avoidance preferences of children in the counterconditioning group were significantly reduced post-positive modeling, and these children also did not show the heightened heart rate responding to fear-paired animals. Children in the extinction group demonstrated comparable responses to the control group; thus the extinction procedure showed no effect on any fear measures. The findings suggest that counterconditioning with positive modelling can be used as an effective early intervention to reduce the behavioral and physiological effects of vicarious fear learning in childhood.
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Reacción de Prevención/fisiología , Frecuencia Cardíaca/fisiología , Niño , Femenino , Humanos , Masculino , Modelos EstadísticosRESUMEN
Research with children has demonstrated that both positive vicarious learning (modelling) and positive verbal information can reduce children's acquired fear responses for a particular stimulus. However, this fear reduction appears to be more effective when the intervention pathway matches the initial fear learning pathway. That is, positive verbal information is a more effective intervention than positive modelling when fear is originally acquired via negative verbal information. Research has yet to explore whether fear reduction pathways are also important for fears acquired via vicarious learning. To test this, an experiment compared the effectiveness of positive verbal information and positive vicarious learning interventions for reducing vicariously acquired fears in children (7-9 years). Both vicarious and informational fear reduction interventions were found to be equally effective at reducing vicariously acquired fears, suggesting that acquisition and intervention pathways do not need to match for successful fear reduction. This has significant implications for parents and those working with children because it suggests that providing children with positive information or positive vicarious learning immediately after a negative modelling event may prevent more serious fears developing.
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Miedo/psicología , Conducta Imitativa , Lenguaje , Aprendizaje , Niño , Femenino , Humanos , MasculinoRESUMEN
Vicarious fear learning refers to the acquisition of fear via observation of the fearful responses of others. The present study aims to extend current knowledge by exploring whether second-order vicarious fear learning can be demonstrated in children. That is, whether vicariously learnt fear responses for one stimulus can be elicited in a second stimulus associated with that initial stimulus. Results demonstrated that children's (5-11 years) fear responses for marsupials and caterpillars increased when they were seen with fearful faces compared to no faces. Additionally, the results indicated a second-order effect in which fear-related learning occurred for other animals seen together with the fear-paired animal, even though the animals were never observed with fearful faces themselves. Overall, the findings indicate that for children in this age group vicariously learnt fear-related responses for one stimulus can subsequently be observed for a second stimulus without it being experienced in a fear-related vicarious learning event. These findings may help to explain why some individuals do not recall involvement of a traumatic learning episode in the development of their fear of a specific stimulus.
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Miedo , Aprendizaje , Niño , Preescolar , Femenino , Humanos , Masculino , Estimulación LuminosaRESUMEN
INTRODUCTION: Penicillin allergy is common, and there is increased clinician interest in direct oral challenge (DOC) as a testing strategy for low-risk penicillin allergy. To aid wider implementation of DOC, consensus definitions of low-risk penicillin allergy phenotypes, and standardized approaches to assessment, DOC procedures, and evaluation, are required. AREAS COVERED: This review systematically reviews studies that have utilized penicillin DOC in healthcare settings to identify heterogeneity in implementation approaches and synthesize low-risk definitions, procedures, and evaluation. EXPERT OPINION: Opportunity exists to standardize penicillin DOC procedures in patients with a low-risk penicillin allergy to optimize antimicrobial prescribing and reduce the burden of penicillin allergy. Standardizing the definitions of 'low-risk' and 'positive challenge,' and improving the evaluation of patient safety, alongside the development of a unified approach to the structure of undertaking an oral challenge, is likely to increase uptake and confidence among non-allergist clinicians.
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Hipersensibilidad a las Drogas , Hipersensibilidad , Humanos , Antibacterianos/efectos adversos , Pruebas Cutáneas/métodos , Penicilinas/efectos adversos , Hipersensibilidad a las Drogas/diagnóstico , Hipersensibilidad a las Drogas/prevención & controlRESUMEN
Invasive fungal infections (IFI) are challenging to predict, diagnose and treat, and are associated with a particularly high mortality among patients with hematological malignancies. They are relatively uncommon in patients with lymphoma, compared with those with acute leukemia or undergoing allogeneic transplantation. We present a patient, autografted for recurrent lymphoma, with fever and refractory diarrhea persisting post engraftment, eventually attributable to disseminated mucor infection. This case illustrates the challenge of timely diagnosis and initiation of treatment for IFI in lymphoma patients, who do not routinely receive antifungal prophylaxis, and the importance of aggressive investigation and symptom-directed tissue sampling for evidence of IFI in febrile immunocompromised hosts not responding to broad-spectrum antibiotics.
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T/Natural killer (NK) cell lymphomas (TCL) represent a heterogenous subgroup of non-Hodgkin lymphoma, associated with poorer prognosis and higher treatment toxicity. A cohesive synthesis of infection outcomes among TCL patients is lacking. International guidelines offer no specific recommendations regarding prophylaxis or supportive infection care for TCL patients. This systematic narrative review highlights infection outcomes in TCL patients treated with conventional, and novel therapies. Recommendations for infection screening, antimicrobial prophylaxis and vaccination strategies are outined.
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Linfoma no Hodgkin , Linfoma de Células T , Humanos , Linfoma de Células T/complicaciones , Linfoma de Células T/diagnóstico , Linfoma de Células T/terapia , Células Asesinas Naturales/patología , Linfoma no Hodgkin/patologíaRESUMEN
BACKGROUND: Chimeric antigen receptor T cells (CAR-T cells) are increasingly used to treat haematological malignancies. Strategies for preventing infections in CAR-T-treated patients rely on expert opinions and consensus guidelines. OBJECTIVES: This scoping review aimed to identify risk factors for infections in CAR-T-treated patients with haematological malignancies. DATA SOURCES: A literature search utilized MEDLINE, EMBASE and Cochrane to identify relevant studies from conception until 30 September 2022. STUDY ELIGIBILITY CRITERIA: Trials and observational studies were eligible. PARTICIPANTS: Studies required ≥10 patients treated for haematological malignancy to report infection events (as defined by the study), and either (a) a descriptive, univariate or multivariate analysis of the relationship between infections event and a risk factors for infections, or (b) diagnostic performance of a biochemical/immunological marker in CAR-T-treated patients with infection. METHODS: A scoping review was conducted in accordance with PRISMA guidelines. DATA SOURCES: A literature search utilised MEDLINE, EMBASE and Cochrane to identify relevant studies from conception until September 30, 2022. Eligibility/Participants/Intervention: Trials and observational studies were eligible. Studies required ≥ 10 patients treated for haematological malignancy, to report infection events (as defined by the study), and either A) a descriptive, univariate or multivariate analysis of the relationship between infections event and a risk-factors for infections, or B) diagnostic performance of a biochemical/immunological marker in CAR-T treated patients with infection. ASSESSMENT OF RISK OF BIAS: Bias assessment was undertaken according to Joanna Brigg's Institute criteria for observational studies. METHODS OF DATA SYNTHESIS: Data were synthesized descriptively because of the heterogeneity of reporting. RESULTS: A total of 1522 patients across 15 studies were identified. All-cause infections across haematological malignancies were associated with lines of prior therapy, steroid administration, immune-effector cell-associated neurotoxicity and treatment-emergent neutropenia. Procalcitonin, C-reactive protein and cytokine profiles did not reliably predict infections. Predictors of viral, bacterial and fungal infections were poorly canvassed. DISCUSSION: Meta-analysis of the current literature is not possible because of significant heterogeneity in definitions of infections and risk factors, and small, underpowered cohort studies. Radical revision of how we approach reporting infections for novel therapies is required to promptly identify infection signals and associated risks in patients receiving novel therapies. Prior therapies, neutropenia, steroid administration and immune-effector cell-associated neurotoxicity remain the most associated with infections in CAR-T-treated patients.
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Neoplasias Hematológicas , Receptores Quiméricos de Antígenos , Humanos , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/terapia , Linfocitos T , EsteroidesRESUMEN
A registered (PROSPERO - CRD42022346462) systematic review and meta-analysis was conducted of all-grade infections amongst adult patients receiving CAR-T therapy for haematological malignancy. Meta-analysis of pooled incidence, using random effects model, was conducted. Cochran's Q test examined heterogeneity. 2678 patients across 33 studies were included in the primary outcome. Forty-percent of patients (95% CI: 0.33 - 0.48) experienced an infection of any grade. Twenty-five percent of infection events (95% CI: 0.16 - 0.34) were severe. Late infections were as common as early infections (IRR = 0.86, 95% CI: 0.38 - 1.98). All-grade infections, bacterial and viral infections were highest in myeloma patients at 57%, 37% and 28% respectively. Patients with NHL more commonly experienced late infections. Pooled rate of invasive candidiasis/yeast infections was 2% in studies utilizing anti-yeast prophylaxis. This review identified a high rate of all-grade infections, moderate rate of severe infections, and myeloma as a high-risk haematological group.
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Neoplasias Hematológicas , Hematología , Mieloma Múltiple , Receptores Quiméricos de Antígenos , Adulto , Humanos , Mieloma Múltiple/complicaciones , Mieloma Múltiple/terapia , Inmunoterapia Adoptiva/efectos adversos , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/epidemiología , Neoplasias Hematológicas/terapiaRESUMEN
Bispecific antibodies, a novel immunotherapy with promising efficacy against multiple myeloma, form immune synapses between T-cell surface marker CD3 and malignant cell markers, including B-cell maturation antigen (BCMA), FcRH5, and G protein-coupled receptor GPRC5D. These bispecific antibodies so effectively deplete plasma cells (and to some extent T-cells) that patients are at increased risk of developing infections. A systematic review and meta-analysis of infections in published studies of patients with myeloma treated with bispecific antibodies was conducted to better characterize the infection risks. A literature search used MEDLINE, EMBASE, and Cochrane to identify relevant studies between inception and February 10, 2023, including major conference presentations. Phase 1b-3 clinical trials and observational studies were included. Sixteen clinical trials comprising 1666 patients were included. Median follow-up was 7.6 months and 38% of the cohort had penta-drug refractory disease. Pooled prevalence of all-grade infections was 56%, whereas the prevalence of grade ≥3 infections was 24%. Patients who were treated with BCMA-targeted bispecifics had significantly higher rates of grade ≥3 infections than non-BCMA bispecifics (25% vs 20%). Similarly, patients treated with bispecifics in combination with other agents had significantly higher rate of all-grade infection than those receiving monotherapy (71% vs 52%). In observational studies (n = 293), excluded from the primary analysis to ensure no overlap with patients in clinical trials, several infections classically associated with T-cell depletion were identified. This systematic review identifies BCMA-targeted bispecifics and bispecific combination therapy as having higher infection risk, requiring vigilant infection screening and prophylaxis strategies.
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Anticuerpos Biespecíficos , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Anticuerpos Biespecíficos/efectos adversos , Antígeno de Maduración de Linfocitos B/uso terapéutico , Inmunoterapia , Linfocitos T , Complejo CD3RESUMEN
Background: The global COVID-19 pandemic disproportionately affected certain populations and its management differed between countries. This national study describes characteristics and outcomes of COVID-19 in patients with cancer in Australia. Methods: We performed a multicentre cohort study of patients with cancer and COVID-19 from March 2020 to April 2022. Data were analysed to determine varying characteristics between cancer types and changes in outcomes over time. Multivariable analysis was performed to determine risk factors associated with oxygen requirement. Findings: 620 patients with cancer from 15 hospitals had confirmed COVID-19. There were 314/620 (50.6%) male patients, median age 63.5 years (IQR 50-72) and majority had solid organ tumours (392/620, 63.2%). The rate of COVID-19 vaccination (≥1 dose) was 73.4% (455/620). Time from symptom onset to diagnosis was median 1 day (IQR 0-3), patients with haematological malignancy had a longer duration of test positivity. Over the study period, there was a significant decline in COVID-19 severity. Risk factors associated with oxygen requirement included male sex (OR 2.34, 95% CI 1.30-4.20, p = 0.004), age (OR 1.03, 95% CI 1.01-1.06, p = 0.005); not receiving early outpatient therapy (OR 2.78, 95% CI 1.41-5.50, p = 0.003). Diagnosis during the omicron wave was associated with lower odds of oxygen requirement (OR 0.24, 95% CI 0.13-0.43, p < 0.0001). Interpretation: Outcomes from COVID-19 in patients with cancer in Australia over the pandemic have improved, potentially related to changing viral strain and outpatient therapies. Funding: This study was supported by research funding from MSD.