An Investigation of O-Demethyl Tramadol/Tramadol Ratio for Cytochrome P450 2D6 Phenotyping: The CYTRAM Study.

Cytochrome P450 2D6 (CYP2D6) gene polymorphisms influence the exposure to tramadol (T) and its pharmacologically active metabolite, O-demethyl tramadol (O-dT). Tramadol has been considered as a candidate probe drug for CYP2D6 phenotyping. The objective of the CYTRAM study was to investigate the value of plasma O-dT/T ratio for CYP2D6 phenotyping. European adult patients who received IV tramadol after surgery were included. CYP2D6 genotyping was performed and subjects were classified as extensive (EM), intermediate (IM), poor (PM), or ultra-rapid (UM) CYP2D6 metabolizers. Plasma concentrations of tramadol and O-dT were determined at 24 h and 48 h. The relationship between O-dT/T ratio and CYP2D6 phenotype was examined in both a learning and a validation group. Genotype data were obtained in 301 patients, including 23 PM (8%), 117 IM (39%), 154 EM (51%), and 7 UM (2%). Tramadol trough concentrations at 24 h were available in 297 patients. Mean value of O-dT/T ratio was significantly lower in PM than in non-PM individuals (0.061 ± 0.031 versus 0.178 ± 0.09, p < 0.01). However, large overlap was observed in the distributions of O-dT/T ratio between groups. Statistical models based on O-dT/T ratio failed to identify CYP2D6 phenotype with acceptable sensitivity and specificity. Those results suggest that tramadol is not an adequate probe drug for CYP2D6 phenotyping.

Pediatric-Adult Care Transition: Perceptions of Adolescent and Young Adult Patients with Sickle Cell Disease and Their Healthcare Providers.

Introduction: The pediatric-adult care transition, which takes place during adolescence, is a high-risk period for medical care adherence in chronic diseases, this encompasses treatment adherence, attending medical consultations and following healthcare advice. Studying perceptions is needed to get a more comprehensive picture of this care transition and to propose interventions to address the gaps. The authors analyzed perceptions from patients and caregivers in adolescents with sickle cell disease. Although this is the first step to improving the actual care management, to our knowledge, no study has explored perceptions from healthcare providers and compared it to patients' perceptions. The purpose of this study was to provide an insight on the experience of adolescent and adult patients, pediatric and adult healthcare providers in the context of pediatric to adult care transition, and analyze those concerns in order to better understand medical care adherence and improve patient care. Material and Methods: Semi-structured interviews were conducted with adolescent and adult patients, as well as healthcare professionals (HCPs) in pediatric and adult departments. These interviews were audiotaped and transcribed before manual inductive content analysis. Results: A total of 15 adolescent patients, 10 adult patients, 9 pediatric HCPs and 13 adult HCPs - including 12 nurses - were interviewed. Patients and healthcare providers all agreed that the pediatric-adult care transition was poorly experienced. This was mainly due to various changes in habits, physicians, and care organization. Anticipating this transition and acquiring new skills both for patients and HCPs are essential steps for improving medical care adherence during this challenging pediatric-adult care transition. Conclusion: Propositions emerged from patients and healthcare providers to improve care and subsequently to improve medical care adherence in patients with sickle cell disease during and after the pediatric to adult care transition.

Agreement between a regional pharmacovigilance centre and an adjudication committee regarding adverse drug reactions on a cohort of hospitalised children.

BACKGROUND AND PURPOSE: The EREMI project was set up to collect data on adverse drug reactions (ADRs) occurring due to off-label and/or unlicensed drugs prescribed to hospitalised children in France. These events were evaluated by a regional pharmacovigilance centre (RPC) and an adjudication committee (AC). The aim of this study was to assess the agreement between these two different entities on their evaluation of ADRs. EXPERIMENTAL APPROACH: The RPC first validated the ADRs and assessed their causality using the Naranjo scale. The AC assessed then ADRs using all available information, including the RPC evaluation. The agreement on severity and nature of ADRs, role of treatment (suspect or concomitant) and drug causality was calculated using Cohen's nonparametric kappa coefficient (k). KEY RESULTS: Three hundred and eighty-six events were reported in 219 children. The RPC excluded 65 events and validated 321 ADRs. Agreement was very good on nature of ADRs (k=0.85) and role of treatment (k=0.81), moderate on severity of ADRs (k=0.60) and very poor on drug causality (k=0.05). CONCLUSION AND IMPLICATIONS: Agreement between the RPC and the AC was not constant throughout this evaluation. They troubled to agree on severe ADRs and on drug causality.

Model-Based Comparative Analysis of Rifampicin and Rifabutin Drug-Drug Interaction Profile.

Rifamycins are widely used for treating mycobacterial and staphylococcal infections. Drug-drug interactions (DDI) caused by rifampicin (RIF) are a major issue. We used a model-based approach to predict the magnitude of DDI with RIF and rifabutin (RBT) for 217 cytochrome P450 (CYP) substrates. On average, DDI caused by low-dose RIF were twice as potent as those caused by RBT. Contrary to RIF, RBT appears unlikely to cause severe DDI, even with sensitive CYP substrates.

A Clinical Decision Support Tool to Find the Best Initial Intravenous Cyclosporine Regimen in Pediatric Hematopoietic Stem Cell Transplantation.

To optimize cyclosporine A (CsA) dosing regimen in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT), we aimed to provide clinicians with a validated decision support tool for determining the most suitable first dose of intravenous CsA. We used a 10-year monocentric data set of pediatric patients undergoing HSCT. Discretization of all variables was performed according to literature or thanks to algorithms using Shannon entropy (from information theory) or equal width intervals. The first 8 years were used to build the Bayesian network model. This model underwent a 10-fold cross-validation, and then a prospective validation with data of the last 2 years. There were 3.3% and 4.1% of missing values in the training and the validation data set, respectively. After prospective validation, the Tree-Augmented Naïve Bayesian network shows interesting prediction performances with an average area under the receiver operating characteristic curve of 0.804, 32.8% of misclassified patients, a true-positive rate of 0.672, and a false-positive rate of 0.285. This validated model allows good predictions to propose an optimized and personalized initial CsA dose for pediatric patients undergoing HSCT. The clinical impact of its use should be further evaluated.

Pharmacokinetic/Pharmacodynamic Dosage Individualization of Cefepime in Critically Ill Patients: A Case Study.

OBJECTIVE: The authors report on a case of a 59-year-old man hospitalized in the intensive care unit because of severe SARS-COV-2 infection (COVID-19). BACKGROUND: The patient had several comorbidities, including liver cirrhosis. He developed ventilation-associated bacterial pneumonia for which he was administered cefepime at an initial dose of 2 g/8 hours. Therapeutic drug monitoring was performed, showing overexposure with an initial trough concentration of >60 mg/L. METHODS: Analysis of pharmacokinetic data and model-based dose adjustment was performed using BestDose software. RESULTS: The patient had unexpected pharmacokinetic parameter values. Serum creatinine was only moderately increased, whereas measured creatinine clearance based on urine collection showed impaired renal function. Bacterial minimum inhibitory concentration was also considered in the dosing decisions. After dose reduction to 0.5 g/8 hours, the cefepime trough concentration progressively declined and reached the target values by the end of the therapy. A post-hoc analysis provided a different interpretation of drug overexposure. CONCLUSION: This case report illustrates how physiological, microbiological, and drug concentration data can be used for model-based dosage individualization of cefepime in intensive care unit patients.

Proton Pump Inhibitors are Risk Factors for Viral Infections: Even for COVID-19?

During the ongoing pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), more attention should be paid to the balance of risks and benefits associated with proton pump inhibitors for the following reasons. One of the main functions of gastric juice is to inactivate swallowed microorganisms, thereby inhibiting infectious agents from reaching the intestine. Studies have documented that proton pump inhibitors are a risk factor for rotavirus, influenza virus, norovirus, and Middle East respiratory syndrome coronavirus infections, and are associated with an increased risk of acute gastroenteritis during periods of highest circulation of enteric viruses. In light of the evidence for gastrointestinal infection implying a fecal-oral transmission of SARS-CoV-2 and given the magnitude of the SARS-CoV-2/coronavirus disease 2019 pandemic, associated with the widespread misuse of proton pump inhibitors, this suggests that we should not rule out the hypothesis that patients treated with proton pump inhibitors may be more at risk of being infected by SARS-CoV-2.

Sickle cell disease perceptions of caregivers, adolescent, and adult patients: Barriers and facilitators to medical care adherence.

AIMS: To provide an understanding of medical care adherence factors as reported by caregivers, adolescent, and adult patients with sickle cell disease and to analyse those concerns to identify barriers and facilitators about medical care adherence. Three topics influenced medical care adherence: the disease itself, therapeutics, and the healthcare system. This study will focus on the first topic. DESIGN: Qualitative explorative study, using semi-structured and life-experience interviews and manual inductive content analysis. METHODS: From December 2016 - March 2017, one semi-structured interview was conducted by a researcher with each of the 15 adolescent patients, 10 adult patients, and 19 caregivers in a French public hospital. Interviews were audio-taped and transcribed before a content analysis. Perceptions were classified into barriers and facilitators of medical care adherence. RESULTS: This article presents disease perceptions of caregivers and patients (adolescents and adults): daily management and social representations. These perceptions differ among parents, adolescent patients, and adult patients. However, all report important disease-related "limitations" in their lives. The objective for adults (parents and patients) is to "live with the disease" and to achieve this, they find coping resources. Two major resources expressed by adults emerged: social resources (support from friends, patients' association, and social visibility) and disease knowledge (theoretical and derived from experience). This is not the case of adolescents for whom social normality was the main concern. CONCLUSION: Care management adherence is partly based on coping with the disease. Given the lower number of facilitators expressed by adolescents, it is essential to propose interventions in this population. It will help them cope with the disease and, consequently, optimize care management adherence. IMPACT: Showing differences among caregivers, adult, and adolescent patient perceptions, this study impact future care practices. It revealed needs of intervention for adolescents.

A decision support tool to find the best cyclosporine dose when switching from intravenous to oral route in pediatric stem cell transplant patients.

PURPOSE: Managing the pharmacokinetic variability of immunosuppressive drugs after pediatric hematopoietic stem cell transplantation (HSCT) is a clinical challenge. Thus, the aim of our study was to design and validate a decision support tool predicting the best first cyclosporine oral dose to give when switching from intravenous route. METHODS: We used 10-years pediatric HSCT patients' dataset from 2008 to 2018. A tree-augmented naïve Bayesian network model (method belonging to artificial intelligence) was built with data from the first eight-years, and validated with data from the last two. RESULTS: The Bayesian network model obtained showed good prediction performances, both after a 10-fold cross-validation and external validation, with respectively an AUC-ROC of 0.89 and 0.86, a percentage of misclassified patients of 28.7% and 35.2%, a true positive rate of 0.71 and 0.65, and a false positive rate of 0.12 and 0.14 respectively. CONCLUSION: The final model allows the prediction of the most likely cyclosporine oral dose to reach the therapeutic target specified by the clinician. The clinical impact of using this model needs to be prospectively warranted. Respecting the decision support tool terms of use is necessary as well as remaining critical about the prediction by confronting it with the clinical context.

Intra-individual Pharmacokinetic Variability of Intravenous Busulfan in Hematopoietic Stem Cell-Transplanted Children.

BACKGROUND: Busulfan therapeutic drug monitoring (TDM) is necessary to better achieve the target exposure in children before hematopoietic stem cell transplantation (HSCT). However, TDM-based dosing may be challenging if intra-individual pharmacokinetic variability (also denoted inter-occasion variability [IOV]) occurs during therapy. OBJECTIVES: The objectives of this study were to describe and quantify busulfan IOV in children, and to investigate its potential determinants. METHODS: We performed a new analysis of published data from children who received intravenous busulfan over 4 days before HSCT. We calculated individual pharmacokinetic parameters on each day of therapy using a published population pharmacokinetic model of busulfan and analyzed their changes. Population estimation of IOV was also performed with non-linear mixed effects (NLME) modeling. Potential predictors of significant decrease in busulfan clearance (CL) were assessed by using machine learning approaches. RESULTS: IOV could be assessed in 136 children. Between day (D) 1 and D2, most patients (80%) experienced a decrease in busulfan CL, with a median change of - 7.9%. However, both large decreases (minimum, - 48.5%) and increases in CL (maximum, + 44%) were observed. Over D1-D3 of therapy, mean CL significantly decreased (- 15%), with a decrease of ≥ 20% in 22% of patients. Some patients also showed unstable CL from day to day. NLME modeling of IOV provided a coefficient of variation of 10.6% and 13.1% for volume of distribution (Vd) and CL, respectively. Some determinants of significant decreases in busulfan CL were identified, but predictive performance of the models was limited. CONCLUSIONS: Significant busulfan intra-individual variability may occur in children who receive a HSCT and is hardly predictable. The main risk is busulfan overexposure. Performing TDM repeatedly over therapy appears to be the best way to accurately estimate busulfan exposure and perform precision dosing.

Goal-Oriented Monitoring of Cyclosporine Is Effective for Graft-versus-Host Disease Prevention after Hematopoietic Stem Cell Transplantation in Sickle Cell Disease and Thalassemia Major.

Graft-versus-host disease (GVHD) is an important challenge and a major cause of morbidity and mortality in children after hematopoietic stem cell transplant (HSCT). Herein we report our institution's experience of goal-oriented Bayesian monitoring for cyclosporine (CsA) used alone as GVHD prophylaxis during the post-transplant period in pediatric patients with thalassemia major (TM) or sickle cell anemia (SCA) undergoing HLA-matched HSCT. We also studied evolution of chimerism. Twenty-six consecutive patients (SCA, 14; TM, 12) underwent matched sibling donor (MSD) HSCT from 2004 to 2014. All patients received a myeloablative conditioning regimen. GVHD prophylaxis consisted of 20 mg/kg antithymocyte globulin in the conditioning regimens and then CsA alone in the post-transplant period. Target CsA trough blood concentration (TBC) was 150 ± 20 ng/mL. At last follow-up, all patients were alive and free of disease, even in cases of mixed chimerism. Engraftment occurred in all patients. No patient developed grades II to IV acute GVHD, 4 patients developed acute grade I skin GVHD, and only 1 presented with chronic pulmonary GVHD. A better control of GVHD and immunosuppression by a strict monitoring of CsA TBC as described herein is promising and could play a crucial role. Further investigations are required, but this study opens new perspectives to improve survival and safety of HSCT from alternative donors in TM and SCA to levels compatible with that obtained with MSDs.

Impact of a paediatric-adult care transition programme on the health status of patients with sickle cell disease: study protocol for a randomised controlled trial (the DREPADO trial).

BACKGROUND: Thanks to advancements in medical care, a majority of patients with sickle cell disease (SCD) worldwide live beyond 18 years of age, and therefore, patients initially followed in paediatric departments are then transferred to adult departments. This paediatric-adult care transition is a period with an increased risk of discontinuity of care and subsequent morbidity and mortality. During this period, the patient will have to manage new interlocutors and places of care, and personal issues related to the period of adolescence. To take into consideration all these aspects, an interesting approach is to use the whole system approach to the patient, as presented in the biopsychosocial approach. The aim of this trial is to evaluate the impact of the proposed biopsychosocial paediatric-adult transition programme. METHODS: The DREPADO study is a multicentre randomised control trial comparing a control group (Arm A) to an interventional group with a paediatric-adult transition programme based on a biopsychosocial approach (Arm B). To be included, patients should have the SS, SC, or Sß form of sickle cell disease and be aged between 16 and 17 years. The randomisation in a 1:1 ratio assigns to Arm A or B. The primary outcome is the number of hospital admissions and emergencies for complications in the index hospital, in the 2 years after the first consultation in the adult department of care. Secondary outcomes consider the quality of life, but also include coping skills such as sense of self-efficacy and disease knowledge. To provide patient and parent knowledge and coping skills, the transition programme is composed of three axes: educational, psychological, and social, conducted individually and in groups. DISCUSSION: By providing self-care knowledge and coping skills related to SCD and therapeutics, helping empower patientsin relation to pain management and emotions, and facilitating the relationship to oneself, others, and care in Arm B of the DREPADO study, we believe that the morbidity and mortality of patients with SCD may be reduced after the proposed paediatric-adult transition programme. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03786549; registered on 17 December 2018; https://clinicaltrials.gov/.

Methylprednisolone-related liver injury: A descriptive study using the French pharmacovigilance database.

PURPOSE: Hepatotoxicity associated with methylprednisolone (MP) is rarely reported in the literature. The aim of the present study was to review the characteristics of acute liver injury associated with intravenous (IV) or oral MP registered in the French pharmacovigilance database (FPD). METHODS: All cases with MP coded as suspected, concomitant, or interacting drug associated with liver injury as the adverse effect reported up to May 2016 were extracted from the FPD. Cases were identified using the "Drug related hepatic disorders" Standard Medical Query. RESULTS: A total of 97 cases of liver injury associated with MP were analysed; 58.8% were women and the median age was 46 years (range: 1-91). MP was used for an autoimmune disease in 47.6% of cases including 26 cases of multiple sclerosis, and was IV in 79.4% of cases. Nearly three-quarters of patients (73,2%) had a hepatocellular type of injury, the severity of which was mainly mild (45%) or moderate (31%). Most patients (92%) spontaneously and fully recovered within a mean 38.4 days. A rechallenge using the IV route was performed in 13 patients and for 10 (76.9%) this was positive (the initial type of injury was hepatocellular for all these cases). Regarding IV route of administration (n=77), MP was coded as the only suspected drug in 22% of cases. DISCUSSION: The results suggest that IV MP causality should be considered in case of acute liver injury while data for oral MP is insufficient; systematic liver monitoring for high-dose IV MP may be recommended.

Quantitative Prediction of Interactions Mediated by Transporters and Cytochromes: Application to Organic Anion Transporting Polypeptides, Breast Cancer Resistance Protein and Cytochrome 2C8.

BACKGROUND: The in vivo mechanistic static model (IMSM) is an effective method to predict the magnitude of drug-drug interactions (DDIs) mediated by cytochromes. OBJECTIVE: The aim of this study was to extend the IMSM paradigm to DDIs mediated by organic anion transporting polypeptide (OATP) 1Bs, breast cancer resistance protein (BCRP) and cytochrome 2C8. METHODS: First, a generic model for this kind of interaction was established, and a literature search was then conducted to retrieve the area under the concentration-time curve (AUC) ratio of a large set of DDIs involving OATP1B1, OATP1B3, BCRP and cytochromes 2C8 or 3A4. The model was fitted to the data to estimate the characteristic parameters (contribution ratios [CRs] and inhibition or induction potencies [IXs]) by nonlinear regression, and the model was qualified by external validation on a different dataset. Lastly, the model was used to identify the risks of overexposure by DDIs of this type. RESULTS: A total of 27 substrates, 26 inhibitors, 3 inducers and 3 genetic variants were considered in the regression analysis. The number of observations (AUC ratios, denoted as Robs) was 101. Forty-six CRs and 47 IXs were estimated. The proportions of predictions within 0.67- to 1.5-fold and 0.5- to twofold Robs were 90% and 99%, respectively, for the internal validation, and 78% and 96%, respectively, for the external validation. The median fold-error was 1.03 (the ideal value is 1). The interquartile range of fold-error was 0.31, and the relative standard error of parameter estimates was, at most, 17%. CONCLUSIONS: The IMSM approach was successfully extended to DDIs mediated by OATP1Bs, BCRP and cytochromes 2C8 or 3A4. The method revealed good predictive performances by internal and external validation.

Medication adherence in pediatric transplantation and assessment methods: a systematic review.

Background: Medication adherence is a major concern in public health. It is fully established that immunosuppressive therapy (IT) and concomitant medications affect transplant outcomes in the pediatric population, showing interest in adherence to this therapy. The aim of the present review was to report on medication adherence in pediatric population post-transplantation. This will enable us to know the situation in this particular population. Methods: A literature search was performed using the MEDLINE database. Studies that were published from January 1999 to January 2016 in English language and which investigated medication adherence in pediatric transplantation were included. The type of organ and the methods used to assess medication adherence were studied. Results: A total of 281 records were identified, from which 34 studies were selected: 38% (n=13) on kidney transplantation, 32% (n=11) on liver transplantation, and 23% (n=10) on the transplantation of other organs. Medication adherence was found to be lower than 80% in two-thirds of the studies (64%), and varied from 22% to 97%. This wide range was explained in part by the important heterogeneity of assessment methods among studies. The methods used were objective, non-objective, or combined both types. Most studies did not fully describe the data collected: the time since transplantation, the period over which adherence was assessed, the population, the medications, and the threshold discriminating adherence and non-adherence. Conclusion: The present study found poor medication adherence in the pediatric population post-transplantation. There was a wide range of medication adherence, explained largely by the heterogeneity of assessment methods. Future studies must consider the characteristics of each methodology, but also the threshold defining adherence should be chosen on the basis of clinical outcomes, and describe all data collected to gain precision. To improve adherence in this population, it is essential to identify factors influencing medication (IT and concomitant medications) adherence.

Medication adherence after pediatric allogeneic stem cell transplantation: Barriers and facilitators.

PURPOSE: Immunosuppressive therapy following pediatric hematopoietic stem cell transplantation is essential for the patient's prognosis, as the antibioprophylaxis and the isolation measures. But medication adherence is suboptimal for children and adolescents, from 52 to 73% in literature. The aim of this study is to provide an understanding of medication adherence after pediatric allogeneic stem cell transplantation (SCT), by identifying facilitators and barriers. METHOD: Semi-structured interviews were conducted by a pharmacist with caregivers and healthcare providers in a pediatric centre. Four topics were discussed: transplantation, post-transplantation therapies, caregivers' experience and the healthcare system. Interviews were audiotaped, transcribed and analysed by inductive approach. FINDINGS: Semi-structured interviews with 15 caregivers and 21 healthcare providers identified factors of medication adherence and hygiene measures. The long-term nature of therapy and difficult transitions of care were identified as major barriers. Recognizing the benefits of medication and parental involvement are facilitators. Furthermore, caregivers expressed the need to take into consideration the family entity. They would like also to receive earlier information from healthcare providers before hospital discharge. Those needs were not always identified by healthcare providers. CONCLUSION: This analysis revealed barriers and facilitators to the medication adherence and to the care. It demonstrated similarities and differences between caregivers and healthcare providers' perceptions and has thereby initiated an improvement process of the healthcare system. As part of this process, medical and paramedical healthcare providers at this French pediatric centre are currently working on a support program for post-alloSCT hospital-home transition.

Maximal concentration of intravenous busulfan as a determinant of veno-occlusive disease: a pharmacokinetic-pharmacodynamic analysis in 293 hematopoietic stem cell transplanted children.

Veno-occlusive disease (VOD) is a severe adverse reaction to busulfan-containing regimens used in the preparation of children for hematopoietic stem cell transplantation (HSCT). We conducted a retrospective analysis of data to examine determinants of VOD in children who received IV busulfan for HSCT conditioning. Busulfan PK parameters as well as various indices (maximal concentration-Cmax, area under the concentration-time curve-AUC) were estimated using a validated Bayesian approach. The influence of available PK, demographic, and clinical variables on the incidence of VOD was evaluated by using logistic regression and classification and regression tree (CART) analyses. Among the 293 patients included, the mean age was 6.5 years and the mean actual body weight was 26.3 kg. The incidence of VOD was 25.6%. Busulfan Cmax as well as weight <9 kg or age <3 years were identified as independent predictors of VOD in logistic regression analysis. CART analysis identified busulfan Cmax over the entire regimen as the strongest predictor of VOD. This study suggests that busulfan-associated VOD is in part a concentration-dependent reaction. In addition, the youngest children showed the highest risk of VOD. These findings may have important implications for busulfan dosing and therapeutic drug monitoring practice in HSCT children.

Increased Risk of Thrombosis Associated with Peripherally Inserted Central Catheters Compared with Conventional Central Venous Catheters in Children with Leukemia.

OBJECTIVE: To study the risk of catheter-associated thrombosis (CAT) between peripherally inserted central catheters (PICCs) and tunneled central venous catheters in children with leukemia. STUDY DESIGN: We analyzed all PICCs and conventional tunneled catheters placed in patients aged <18 years and admitted to our institute for leukemia treatment between February 2008 and April 2014. Cases of symptomatic CAT were confirmed by ultrasound and treated with low-molecular-weight heparin. RESULTS: During the study period, 157 PICCs and 138 conventional tunneled catheters were placed in 192 patients with leukemia. CAT incidence was 1.5% (n = 2) in the conventional tunneled catheter group and 10.2% (n = 16) in the PICC group. The OR for CAT occurrence after PICC vs conventional tunneled catheter placement was 5.6 (95% CI, 1.2-26.5). CONCLUSION: Our results suggest that the use of PICCs in children with leukemia increases the risk of CAT in comparison with the use of conventional tunneled catheters. Further randomized controlled studies are needed to characterize this risk and to better define indications.