Gene-based drug therapy for children and youth treated with psychoactive medications.

Psychoactive medications are increasingly used to treat children and youth with mental health conditions, but individual variations in response highlight the need for precision medicine. Pharmacogenetic (PGx) testing is a key component of precision medicine. The number of commercial pharmacogenetic testing companies promoting PGx, with the promise of achieving individualized and effective treatment of mental health conditions, has grown exponentially in recent years. Scientific evidence supporting the use of PGx to manage mental health conditions is limited, especially for paediatric populations. This practice point outlines steps guiding the use and interpretation of PGx testing for psychoactive medications in clinical settings, along with key supportive resources. Practice guidelines have been developed for variants in pharmacogenes encoding cytochrome P450 drug-metabolizing enzymes (e.g., CYP2C19, CYP2D6, CYP2C9) as one determinant of drug concentrations in blood, which can support both drug choice and dosing strategy for certain anti-psychotics, anti-depressants, and anti-epileptics. Adverse drug reactions to some anti-epileptic drugs (e.g., carbamazepine and phenytoin) have been associated with certain human leukocyte antigen types and variants in DNA polymerase gamma (POLG; valproic acid). Evidence remains limited for genetic variants of drug target proteins, making it challenging to identify patients with altered treatment responses at a therapeutic blood concentration.

La pharmacothérapie en fonction des gènes chez les enfants et les adolescents qui prennent des médicaments psychoactifs.

Les médicaments psychoactifs sont de plus en plus utilisés pour traiter les enfants et les adolescents ayant des troubles de santé mentale, mais la variabilité des réponses individuelles fait ressortir l'importance d'une médecine personnalisée. Les tests pharmacogénétiques sont un volet important d'un tel type de médecine. Le nombre d'entreprises de tests pharmacogénétiques commerciaux qui font la promotion de tests de ce genre et promettent un traitement efficace et individualisé des troubles de santé mentale se multiplie depuis quelques années. Les preuves scientifiques en appui à l'utilisation de la pharmacogénétique sont limitées, particulièrement dans les populations pédiatriques. Le présent point de pratique souligne les étapes qui orientent le recours à ces tests pour la prise de médicaments psychoactifs en milieu clinique et présente des ressources de soutien importantes. Il existe des directives cliniques sur les variants des pharmacogènes qui encodent les enzymes de métabolisation du cytochrome P450 (p. ex., CYP2C19, CYP2D6, CYP2C9), lesquels sont l'un des déterminants des concentrations pharmacologiques dans le sang et peuvent appuyer à la fois le choix du médicament et la stratégie posologique de certains antipsychotiques, antidépresseurs et antiépileptiques. Les effets indésirables de certains médicaments antiépileptiques (p. ex., la carbamazépine et la phénytoïne) sont associés à certains types d'antigènes d'histocompatibilité humaine et à des variants de l'ADN polymérase gamma (POLG; acide valproïque). Les données probantes sont limitées à l'égard des variants génétiques des protéines qui ciblent les médicaments, et c'est pourquoi il est difficile de déterminer quels patients présenteraient une réponse altérée au traitement à une concentration sanguine thérapeutique.

Interleukin (IL)-1/IL-6-Inhibitor-Associated Drug Reaction With Eosinophilia and Systemic Symptoms (DReSS) in Systemic Inflammatory Illnesses.

BACKGROUND: After introducing IL-1/IL-6 inhibitors, some patients with Still and Still-like disease developed unusual, often fatal, pulmonary disease. This complication was associated with scoring as DReSS (drug reaction with eosinophilia and systemic symptoms) implicating these inhibitors, although DReSS can be difficult to recognize in the setting of systemic inflammatory disease. OBJECTIVE: To facilitate recognition of IL-1/IL-6 inhibitor-DReSS in systemic inflammatory illnesses (Still/Still-like) by looking at timing and reaction-associated features. We evaluated outcomes of stopping or not stopping IL-1/IL-6 inhibitors after DReSS reaction began. METHODS: In an international study collaborating primarily with pediatric specialists, we characterized features of 89 drug-reaction cases versus 773 drug-exposed controls and compared outcomes of 52 cases stopping IL-1/IL-6 inhibitors with 37 cases not stopping these drugs. RESULTS: Before the reaction began, drug-reaction cases and controls were clinically comparable, except for younger disease-onset age for reaction cases with preexisting cardiothoracic comorbidities. After the reaction began, increased rates of pulmonary complications and macrophage activation syndrome differentiated drug-reaction cases from drug-tolerant controls (P = 4.7 × 10-35 and P = 1.1 × 10-24, respectively). The initial DReSS feature was typically reported 2 to 8 weeks after initiating IL-1/IL-6 inhibition. In drug-reaction cases stopping versus not stopping IL-1/IL-6-inhibitor treatment, reaction-related features were indistinguishable, including pulmonary complication rates (75% [39 of 52] vs 76% [28 of 37]). Those stopping subsequently required fewer medications for treatment of systemic inflammation, had decreased rates of macrophage activation syndrome, and improved survival (P = .005, multivariate regression). Resolution of pulmonary complications occurred in 67% (26 of 39) of drug-reaction cases who stopped and in none who continued inhibitors. CONCLUSIONS: In systemic inflammatory illnesses, recognition of IL-1/IL-6-inhibitor-associated reactions followed by avoidance of IL-1/IL-6 inhibitors significantly improved outcomes.

Management and Long-Term Outcomes of Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS) in Children: A Scoping Review.

Drug reaction with eosinophilia and systemic symptoms (DReSS) is known to cause mortality and long-term sequelae in the pediatric population, however there are no established clinical practice guidelines for the management of pediatric DReSS. We conducted a scoping review, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to summarize the currently available data on treatment, mortality, and long-term sequelae of DReSS in children (aged 0-18 years). Data from 644 individuals revealed that various treatment strategies are being used in the management of pediatric DReSS, and strategies were often used in combination. The diversity in treatment approaches cannot be solely attributed to age or disease severity and reflects the lack of evidence-based management guidelines for DReSS. Children are also at risk of developing autoimmune sequelae following DReSS, most commonly thyroid disease and type 1 diabetes mellitus. We found that the eventual development of autoimmune disease was more often associated with DReSS caused by antibiotics, especially minocycline and sulfamethoxazole, in comparison with individuals who did not develop sequelae. In this study, we identify strengths and weaknesses in the currently available literature and highlight that future prospective studies with structured and long-term follow-up of children with DReSS are needed to better understand potential risk factors for mortality and development of sequelae after DReSS.

Clinical Presentation and Diagnosis of Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS) in Children: A Scoping Review.

Effective treatment of drug reactions with eosinophilia and systemic symptoms (DReSS) requires early diagnosis and close monitoring. Diagnosing DReSS is especially challenging in children due to a low incidence rate, heterogeneous clinical presentation, and a lack of (pediatric) diagnostic criteria and clinical practice guidelines. We performed a scoping review, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to summarize the clinical presentation and diagnostic process of DReSS in children (aged 0-18 years). Data from 644 individuals showed that DReSS manifests differently in children compared to adults. Children have a higher number of organs involved, including higher rates of cardiac and respiratory involvement compared to adults. Children < 6 years of age appear more prone to develop neurologic symptoms. Conversely, eosinophilia, edema, and kidney involvement are less frequently observed in children. Anti-seizure medications are by far the most common causative drug class, but the range of implicated drugs increases as children get older. This study highlights that children with DReSS not only differ from adults but also that differences exist between children of different ages. As such, there is a need to establish pediatric-specific diagnostic criteria. These efforts will promote earlier diagnosis of DReSS and likely lead to improved clinical care offered to children and their families.

Dosing Variation at Initiation of Adalimumab and Etanercept and Clinical Outcomes in Juvenile Idiopathic Arthritis: A Childhood Arthritis and Rheumatology Research Alliance Registry Study.

OBJECTIVE: To determine the dose-response relationship of tumor necrosis factor (TNF) inhibition in the treatment of juvenile idiopathic arthritis (JIA). METHODS: Participants of the Childhood Arthritis and Rheumatology Research Alliance Registry were eligible for inclusion in the analyses if they started TNF inhibition treatment for JIA. The primary treatment response was determined 3 to 7 months after the start of treatment, based on the JIA American College of Rheumatology Pediatric criteria for improvement, clinical Juvenile Arthritis Disease Activity Score, and persistence of treatment after 6 months. Subsequently, pooled logistic regression models were performed to include long-term follow-up data. The models were adjusted for risk factors associated with poor treatment response. Dosing was expressed by body weight, body surface area, ideal body weight, fat free mass, and lean body mass. RESULTS: Participants treated with adalimumab (n = 328) and etanercept (n = 437) were included in the analyses (median dose 0.82 mg/kg body weight [interquartile range (IQR) 0.66-1.04] and 0.83 mg/kg body weight [IQR 0.75-0.95], respectively). The majority of analyses did not show a relationship between dose and outcome. Where associations were found, results were conflicting. Alternative dosing characteristics based on ideal body weight, fat free mass, and lean body mass did not result in stronger or more consistent associations. CONCLUSION: This study was not able to confirm our hypothesis that increased dosing of TNF inhibitors results in improved treatment outcomes. Although adjustment was performed for risk factors of impaired treatment response, residual confounding by indication likely explains the negative associations found in this study.

Pharmacokinetic and pharmacodynamic principles: unique considerations for optimal design of neonatal clinical trials.

Core clinical pharmacology principles must be considered when designing and executing neonatal clinical trials. In this review, the authors discuss important aspects of drug dose selection, pharmacokinetics, pharmacogenetics and pharmacodynamics that stakeholders may consider when undertaking a neonatal or infant clinical trial.

Case report: Drug reaction with eosinophilia and systemic symptoms (DRESS)-induced hemophagocytic disorder.

Hemophagocytic disorders are severe and life-threatening conditions that can be genetic in origin [i.e., primary hemophagocytic lymphohistiocytosis (HLH)] or result from infections (i.e., secondary hemophagocytic lymphohistiocytosis), rheumatologic disease [i.e., macrophage activation syndrome (MAS)], and less frequently immunodeficiency or metabolic disease. Although rare, drug-induced hemophagocytosis needs to be considered in the work-up as it requires specific management strategies. Most drug-induced hemophagocytic disorders are related to Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). We present the case of a 7-year-old girl who initially presented with fever, maculopapular rash, and unilateral lymphadenopathy, who went on to develop hemophagocytosis secondary to DRESS caused by prolonged combination treatment with amoxicillin/clavulanic acid and trimethoprim/sulfamethoxazole. This case illustrates the importance of considering adverse drug reactions in the evaluations of patients with a hemophagocytic process.

Increased rate of respiratory symptoms in children with Down syndrome: a 2-year web-based parent-reported prospective study.

To compare the incidence of respiratory symptoms and short-term consequences between children with Down syndrome and children from the general population, we conducted a prospective parent-reported observational study. Children with Down syndrome (≤ 18 years) were included between March 2012 and June 2014. Caregivers received a baseline questionnaire with follow-up 1-2 years after inclusion. Caregivers received a weekly questionnaire about respiratory symptoms, fever, antibiotic prescriptions, doctor's visits, and consequences for school and work attendance. Children with Down syndrome were compared to a cohort of the general population ("Kind en Ziek" study) with similar weekly questionnaires. A total of 9,011 childweeks were reported for 116 participants with Down syndrome (75% response rate). The frequency of respiratory symptoms was higher in children with Down syndrome than in children from the general population (30% vs 15.2%). In addition, symptoms subsided later (around 8 vs 5 years of age). The seasonal influence was limited, both in children with Down syndrome and children from the general population. Consequences of respiratory disease were significant in children with Down syndrome compared to children from the general population, with a higher rate of doctor's visits (21.3% vs 11.8%), antibiotic prescriptions (47.8% vs 26.3%), and absenteeism from school (55.5% vs 25.4%) and work (parents, 9.4% vs 8.1%).  Conclusion: Children with Down syndrome have a higher frequency of respiratory symptoms and symptoms last until a later age, confirming the impression of professionals and caregivers. Individualized treatment plans might prevent unfavorable consequences of chronic recurrent respiratory disease in children with Down syndrome. What is Known: • Children with Down syndrome have an altered immune system and are prone to a more severe course of respiratory tract infections. • The overall conception is that patients with Down syndrome suffer from respiratory tract infections more often. What is New: • Children with Down syndrome suffer from respiratory symptoms more frequently than children from the general population. • The respiratory symptoms in children with Down syndrome subside at a later age compared to children from the general population.

Pediatric cannabis intoxication trends in the pre and post-legalization era.

INTRODUCTION: On April 13, 2017, a bill to legalize cannabis was introduced to the Canadian Parliament and presented to the public. On October 17, 2018, Canada legalized recreational cannabis use. We assessed intoxication severity, reflected by ICU admission rates, risk factors and other characteristics in children who presented to the emergency department (ED) with cannabis intoxication, before and after legalization. METHODS: A retrospective cohort study of children 0-18 years who presented to a pediatric ED between January 1, 2008 and December 31, 2019 with cannabis intoxication. The pre-legalization period was defined from January 1, 2008 to April 12, 2017 and the peri-post legalization period from April 13, 2017 to December 31, 2019. RESULTS: We identified 298 patients; 232 (77.8%) presented in the pre legalization period and 66 (22.1%) in the peri-post legalization period; median age: 15.9 years (range: 11 months-17.99 years). A higher proportion of children were admitted to the ICU in the peri-post legalization period (13.6% vs. 4.7%, respectively; p = .02). While the median monthly number of cannabis-related presentations did not differ between the time periods (2.1 [IQR:1.9-2.5] in the pre legalization period vs. 1.7 [IQR:1.0-3.0] in the peri-post legalization period; p = .69), the clinical severity did. The proportions of children with respiratory involvement (65.9% vs. 50.9%; p = .05) and altered mental status (28.8% vs. 14.2%; p < .01) were higher in the peri-post legalization period. The peri-post legalization period was characterized by more children younger than 12 years (12.1% vs. 3.0%; p = .04), unintentional exposures (14.4% vs, 2.8%; p = .002) and edibles ingestion (19.7% vs. 7.8%; p = .01). Edible ingestion was an independent predictor of ICU admission (adjusted OR: 4.1, 95%CI: 1.2-13.7, p = .02). CONCLUSIONS: The recreational cannabis legalization in Canada is associated with increased rates of severe intoxications in children. Edible ingestion is a strong predictor of ICU admission in the pediatric population.

Infant drug exposure via breast milk.

More than half of women take medications during breastfeeding, predisposing their infants to medication exposure via breast milk. As a result, adverse drug reactions may emerge in the infant, although they are rarely reported. Disposition of maternal drugs in breast milk is described with several key parameters, which include relative infant dose (RID): infant drug intake via milk (weight- and time-adjusted) expressed as a percentage of the similarly adjusted mother's dose. Most drugs show RID values of <10%, indicating that drug concentrations in infant serum do not reach a level known to be therapeutic in adults unless drug clearance is markedly lower than the adult level on a weight basis. RID is a function of milk-to-(maternal) plasma drug concentration ratio (MP ratio) and maternal drug clearance. Therefore, MP ratio between drugs must be interpreted not by itself but with maternal drug clearance of each drug. This is why some drugs such as phenobarbital show an MP ratio of <1 but an RID as high as 50-70%, while morphine shows an MP ratio of 2 but an RID in the range of 5%. Using RID, we interpreted case reports of infant adverse outcomes, and we observed cases with relatively low infant serum concentrations of drug, consistent with low RID, as well as those with near- or above-adult therapeutic serum concentrations, with or without increased drug intake (i.e. high RID). It is important to consider both pharmacokinetic and pharmacodynamic factors in interpreting adverse outcomes in infants breastfed by a mother taking medications.

Effectiveness and Safety of High-Dose Biologics in Juvenile Idiopathic Arthritis in the Childhood Arthritis and Rheumatology Research Alliance.

OBJECTIVE: To describe high-dose biologic use when treating juvenile idiopathic arthritis (JIA). METHODS: Patients with JIA enrolled in the Childhood Arthritis and Rheumatology Research Alliance Registry and treated with a biologic after enrollment were eligible. We described the frequency of high-dose biologic use and characteristics of patients receiving high-dose biologics. We used regression modeling to compare 6-month outcomes (using disease activity measures) between those who increased their biologic from standard to high dose (high-dose group) to those who initiated and remained on standard dosing (no-change group), and to those who switched biologic agents (biologic-switch group). We also compared serious adverse events (SAEs) between groups. RESULTS: A total of 5,352 patients with JIA were treated with biologics following enrollment; 1,080 (20%) had ever received a high-dose biologic. There were no significant differences in outcomes between the high-dose group and the biologic-switch group; both improved disease activity measures, including the clinical Juvenile Arthritis Disease Activity Score 10 (-3.53 and -3.95, respectively; P = 0.68). Although the SAE rates in the high-dose group and the biologic-switch group were numerically higher than the no-change group, the event rates were similar, and neither rate was significantly higher than in the no-change group (unadjusted incident rate ratio 2.5 [95% confidence interval (95% CI) 0.7-8.5] and 1.8 [95% CI 0.7-4.6], respectively). CONCLUSION: Dosing escalation appears to be a reasonable choice to improve disease control, but large, prospective, randomized studies evaluating specific biologic agents are needed.

Population pharmacokinetics of vancomycin in paediatric patients with febrile neutropenia and augmented renal clearance: development of new dosing recommendations.

OBJECTIVES: The purpose of this study was to evaluate the influence of augmented renal clearance (ARC) on vancomycin clearance and provide dosage recommendations for paediatric patients with febrile neutropenia following HSCT. METHODS: A population pharmacokinetic analysis was performed based on a two-compartment model structure using a non-linear mixed-effect modelling approach. Monte Carlo simulations were conducted as a target attainment analysis of AUC between 400 mg·h/L and 650 mg·h/L for MRSA at an MIC of 1 mg/L. RESULTS: A total of 165 paediatric patients and 276 vancomycin serum concentrations were analysed in this study. Age, body weight, estimated glomerular filtration rate (eGFR) and fever (≥38.0°C) were identified as factors that significantly influenced vancomycin clearance. The median eGFR of the population was 143 mL/min/1.73 m2 and 34% of patients showed an eGFR ≥160 mL/min/1.73 m2, which may be classified as ARC. Our simulations showed that current dosing recommendations result in poor target attainment. In particular, children aged 6 months old to 6 years old with ARC require an initial vancomycin dose up to 35%-65% higher than the current dosing guidelines. CONCLUSIONS: ARC is frequently observed in paediatric patients with post-HSCT febrile neutropenia, resulting in a significant increase in vancomycin clearance. We propose a vancomycin dosing strategy for children with febrile neutropenia following HSCT based on eGFR, age, weight and body temperature.

Assessment of the Implementation of Pharmacogenomic Testing in a Pediatric Tertiary Care Setting.

Importance: Pharmacogenomic (PGx) testing provides preemptive pharmacotherapeutic guidance regarding the lack of therapeutic benefit or adverse drug reactions of PGx targeted drugs. Pharmacogenomic information is of particular value among children with complex medical conditions who receive multiple medications and are at higher risk of developing adverse drug reactions. Objectives: To assess the implementation outcomes of a PGx testing program comprising both a point-of-care model that examined targeted drugs and a preemptive model informed by whole-genome sequencing that evaluated a broad range of drugs for potential therapy among children in a pediatric tertiary care setting. Design, Setting, and Participants: This cohort study was conducted at The Hospital for Sick Children in Toronto, Ontario, from January 2017 to September 2020. Pharmacogenomic analyses were performed among 172 children who were categorized into 2 groups: a point-of-care cohort and a preemptive cohort. The point-of-care cohort comprised 57 patients referred to the consultation clinic for planned therapy with PGx targeted drugs and/or for adverse drug reactions, including lack of therapeutic benefit, after the receipt of current or past medications. The preemptive cohort comprised 115 patients who received exploratory whole-genome sequencing-guided PGx testing for their heart conditions from the cardiac genome clinic at the Ted Rogers Centre for Heart Research. Exposures: Patients received PGx analysis of whole-genome sequencing data and/or multiplex genotyping of 6 pharmacogenes (CYP2C19, CYP2C9, CYP2D6, CYP3A5, VKORC1, and TPMT) that have established PGx clinical guidelines. Main Outcomes and Measures: The number of patients for whom PGx test results warranted deviation from standard dosing regimens. Results: A total of 172 children (mean [SD] age, 8.5 [5.6] years; 108 boys [62.8%]) were enrolled in the study. In the point-of-care cohort, a median of 2 target genes (range, 1-5 genes) were investigated per individual, with CYP2C19 being the most frequently examined; genotypes in 21 of 57 children (36.8%) were incompatible with standard treatment regimens. As expected from population allelic frequencies, among the 115 children in the whole-genome sequencing-guided preemptive cohort, 92 children (80.0%) were recommended to receive nonstandard treatment regimens for potential drug therapies based on their 6-gene pharmacogenetic profile. Conclusions and Relevance: In this cohort study, among both the point-of-care and preemptive cohorts, the multiplex PGx testing program provided dosing recommendations that deviated from standard regimens at an overall rate that was similar to the population frequencies of relevant variants.

Inborn Errors of Adaptive Immunity in Down Syndrome.

Down syndrome fits an immunophenotype of combined immunodeficiency with immunodysregulation, manifesting with increased susceptibility to infections, autoimmunity, autoinflammatory diseases, and hematologic malignancies. Qualitative and quantitative alterations in innate and adaptive immunity are found in most individuals with Down syndrome. However, there is substantial heterogeneity and no correlation between immunophenotype and clinical presentation. Previously, it was thought that the immunological changes in Down syndrome were caused by precocious aging. We emphasize in this review that the immune system in Down syndrome is intrinsically different from the very beginning. The overexpression of specific genes located on chromosome 21 contributes to immunodeficiency and immunodysregulation, but gene expression differs between genes located on chromosome 21 and depends on tissue and cell type. In addition, trisomy 21 results in gene dysregulation of the whole genome, reflecting the complex nature of this syndrome in comparison to well-known inborn errors of immunity that result from monogenic germline mutations. In this review, we provide an updated overview focusing on inborn errors of adaptive immunity in Down syndrome.