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BACKGROUND: Progress in rare and interstitial lung disease in childhood can most usefully be achieved through systematic, registry-based collection. QUESTION AND METHODS: What are the practicalities and benefits of participating in the pediatric lung registry/chILD-EU project? We report our clinical experiences. RESULTS: Pediatricians and pediatric pulmonologists identify children with rare lung diseases. These are reported to the Kid's Lung Register after parental consent. Clinical data, imaging, and blood are sent to the registry. Genetic analysis can be arranged if desired. With completeness of the data, a peer-review process by pediatric radiology, possibly lung pathology, clinical and possibly genetic experts takes place in an interdisciplinary conference. A working diagnosis is established and communicated to the responsible physician via the registry and, if necessary, further discussed in case-related discussions. Assistance in entering the data is provided by the registry. Follow-ups are performed annually, and all registered physicians are invited to regular, web-based case discussions. Significant questions are answered in scientific projects and jointly published (>110 publications to date). CONCLUSIONS: Due to voluntary additional work of all participants beyond clinical routine, more than 1000 children with rare lung diseases have been included in the registry with biobank to date. A deeper understanding of the clinical courses of large cohorts of rare diseases and the initial description of new entities contributes to better care for these children.
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Doenças Pulmonares Intersticiais , Criança , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/terapia , Pulmão/diagnóstico por imagem , Sistema de Registros , Doenças Raras/diagnósticoRESUMO
OBJECTIVE: Medication is commonly used in anorexia nervosa (AN) despite largely missing high grade evidence. Olanzapine (OLZ) is the best-evidenced substance used off-label in this group, with conflicting outcome regarding BMI, clinical and safety parameters. Therefore, it is important to strictly assure quality of treatment with OLZ in AN by using 'Therapeutic Drug Monitoring' according to AGNP-guidelines, including serum levels and adverse drug reactions (ADRs) to support safety for adolescents with AN and attempt to generate an initial age- and disorder-specific therapeutic reference range. METHOD: Sixty-five adolescents with AN (aged 10-18) treated with OLZ (98% female; 97.5% AN-restricting-type) were prospectively observed, ADRs reported, and correlations between dosage and serum levels measured at trough level were calculated, a preliminary therapeutic range defined. RESULTS: Mean dosage of OLZ was 8.15 (SD: 2.91) mg and 0.19 (SD: 0.07) mg/kg respectively, average concentration was 26.57 (SD: 13.46) ng/mL. Correlation between daily dosage/dosage per kg and serum level was 0.72 (**p < 0.001)/0.65 (**p < 0.001), respectively. ADRs with impairment were rare (6.3%). 75% improved clinically (CGI). BMI increased significantly by 1.5 kg/m2 (t = 10.6, p < 0.001). A preliminary therapeutic reference range is 11.9 and 39.9 ng/mL. CONCLUSIONS: OLZ in the hands of specialists is a well-tolerated and safe treatment adjunct for adolescents with AN.
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INTRODUCTION: Despite the growing evidence base for psychotropic drug treatment in pediatric patients, knowledge about the benefit-risk ratio in clinical practice remains limited. The 'Therapeutic Drug Monitoring (TDM)-VIGIL' study aimed to evaluate serious adverse drug reactions (ADRs) in children and adolescents treated with antidepressants and/or antipsychotics in approved ('on-label'), and off-label use in clinical practice. METHODS: Psychiatric pediatric patients aged 6-18 years treated with antidepressants and/or antipsychotics either on-label or off-label were prospectively followed between October 2014 and December 2018 within a multicenter trial. Follow-up included standardized assessments of response, serious ADRs and therapeutic drug monitoring. RESULTS: 710 youth (age=14.6±2.2 years, female=66.6%) were observed for 5.5 months on average; 76.3% received antidepressants, 47.5% antipsychotics, and 25.2% both. Altogether, 55.2% of the treatment episodes with antidepressants and 80.7% with antipsychotics were off-label. Serious ADRs occurred in 8.3% (95%CI=6.4-10.6%) of patients, mainly being psychiatric adverse reactions (77.4%), predominantly suicidal ideation and behavior. The risk of serious ADRs was not significantly different between patients using psychotropics off-label and on-label (antidepressants: 8.1% vs. 11.3%, p=0.16; antipsychotics: 8.7% vs 7.5%, p=0.67). Serious ADRs occurred in 16.6% of patients who were suicidal at enrollment versus 5.6% of patients who were not suicidal (relative risk 3.0, 95%CI=1.9-4.9). CONCLUSION: Off-label use of antidepressants and antipsychotics in youth was not a risk factor for the occurrence of serious ADRs in a closely monitored clinical setting. Results from large naturalistic trials like ours can contribute to bridging the gap between knowledge from randomized controlled trials and real-world clinical settings.
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Antipsicóticos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Adolescente , Antidepressivos/efeitos adversos , Antipsicóticos/efeitos adversos , Criança , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Uso Off-Label , Psicotrópicos/uso terapêuticoRESUMO
BACKGROUND: Sertraline is a selective serotonin reuptake inhibitor with specific indications in child and adolescent psychiatry. Notwithstanding its frequent use and clinical benefits, the relationship between pharmacokinetics, pharmacodynamics, efficacy, and tolerability of sertraline across indications, particularly in non-adult patients, is not fully understood. METHOD: This naturalistic therapeutic drug monitoring (TDM) study was conducted in a transdiagnostic sample of children and adolescents treated with sertraline (n = 78; mean age, 14.22 ± 2.39; range, 7-18 years) within the prospective multicenter "TDM-VIGIL" project. Associations between dose, serum concentration, and medication-specific therapeutic and side effects based on the Clinical Global Impression scale were examined. Tolerability was measured qualitatively with the 56-item Pediatric Adverse Event Rating Scale. RESULTS: A strong linear positive dose-serum concentration relationship (with dose explaining 45% of the variance in concentration) and significant effects of weight and co-medication were found. Neither dose nor serum concentration were associated with side effects. An overall mild-to-moderate tolerability profile of sertraline was observed. In contrast with the transdiagnostic analysis that did not indicate an effect of concentration, when split into depression (MDD) and obsessive-compulsive disorder (OCD) diagnoses, the probability of clinical improvement significantly increased as both dose and concentration increased for OCD, but not for MDD. CONCLUSIONS: This TDM-flexible-dose study revealed a significant diagnosis-specific effect between sertraline serum concentration and clinical efficacy for pediatric OCD. While TDM already guides clinical decision-making regarding compliance, dose calibration, and drug-drug interactions, combining TDM with other methods, such as pharmacogenetics, may facilitate a personalized medicine approach in psychiatry.
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Transtorno Obsessivo-Compulsivo , Sertralina , Adolescente , Criança , Monitoramento de Medicamentos/métodos , Humanos , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Estudos Prospectivos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Sertralina/uso terapêuticoRESUMO
BACKGROUND: Children's interstitial lung diseases (chILD) cover many rare entities, frequently not diagnosed or studied in detail. There is a great need for specialised advice and for internationally agreed subclassification of entities collected in a register.Our objective was to implement an international management platform with independent multidisciplinary review of cases at presentation for long-term follow-up and to test if this would allow for more accurate diagnosis. Also, quality and reproducibility of a diagnostic subclassification system were assessed using a collection of 25 complex chILD cases. METHODS: A web-based chILD management platform with a registry and biobank was successfully designed and implemented. RESULTS: Over a 3-year period, 575 patients were included for observation spanning a wide spectrum of chILD. In 346 patients, multidisciplinary reviews were completed by teams at five international sites (Munich 51%, London 12%, Hannover 31%, Ankara 1% and Paris 5%). In 13%, the diagnosis reached by the referring team was not confirmed by peer review. Among these, the diagnosis initially given was wrong (27%), imprecise (50%) or significant information was added (23%).The ability of nine expert clinicians to subcategorise the final diagnosis into the chILD-EU register classification had an overall exact inter-rater agreement of 59% on first assessment and after training, 64%. Only 10% of the 'wrong' answers resulted in allocation to an incorrect category. Subcategorisation proved useful but training is needed for optimal implementation. CONCLUSIONS: We have shown that chILD-EU has generated a platform to help the clinical assessment of chILD. TRIAL REGISTRATION NUMBER: Results, NCT02852928.
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Doenças Pulmonares Intersticiais/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Sistema de Registros , Reprodutibilidade dos Testes , Adulto JovemRESUMO
Fluoxetine is the recommended first-line antidepressant in many therapeutic guidelines for children and adolescents. However, little is known about the relationships between drug dose and serum level as well as the therapeutic serum reference range in this age group. Within a large naturalistic observational prospective multicenter clinical trial ("TDM-VIGIL"), a transdiagnostic sample of children and adolescents (n = 138; mean age, 15; range, 7-18 years; 24.6% males) was treated with fluoxetine (10-40 mg/day). Analyses of both the last timepoint and all timepoints (n = 292 observations), utilizing (multiple) linear regressions, linear mixed-effect models, and cumulative link (mixed) models, were used to test the associations between dose, serum concentration, outcome, and potential predictors. The receiver operating curve and first to third interquartile methods, respectively, were used to examine concentration cutoff and reference values for responders. A strong positive relationship was found between dose and serum concentration of fluoxetine and its metabolite. Higher body weight was associated with lower serum concentrations, and female sex was associated with lower therapeutic response. The preliminary reference ranges for the active moiety (fluoxetine+norfluoxetine) were 208-328 ng/mL (transdiagnostically) and 201.5-306 ng/mL (depression). Most patients showed marked (45.6%) or minimal (43.5%) improvements and reported no adverse effects (64.9%). This study demonstrated a clear linear dose-serum level relationship for fluoxetine in youth, with the identified reference range being within that established for adults.
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BACKGROUND: No results of controlled trials are available for any of the few treatments offered to children with interstitial lung diseases (chILD). We evaluated hydroxychloroquine (HCQ) in a phase 2, prospective, multicentre, 1:1-randomized, double-blind, placebo-controlled, parallel-group/crossover trial. HCQ (START arm) or placebo were given for 4 weeks. Then all subjects received HCQ for another 4 weeks. In the STOP arm subjects already taking HCQ were randomized to 12 weeks of HCQ or placebo (= withdrawal of HCQ). Then all subjects stopped treatment and were observed for another 12 weeks. RESULTS: 26 subjects were included in the START arm, 9 in the STOP arm, of these four subjects participated in both arms. The primary endpoint, presence or absence of a response to treatment, assessed as oxygenation (calculated from a change in transcutaneous O2-saturation of ≥ 5%, respiratory rate ≥ 20% or level of respiratory support), did not differ between placebo and HCQ groups. Secondary endpoints including change of O2-saturation ≥ 3%, health related quality of life, pulmonary function and 6-min-walk-test distance, were not different between groups. Finally combining all placebo and all HCQ treatment periods did not identify significant treatment effects. Overall effect sizes were small. HCQ was well tolerated, adverse events were not different between placebo and HCQ. CONCLUSIONS: Acknowledging important shortcomings of the study, including a small study population, the treatment duration, lack of outcomes like lung function testing below age of 6 years, the small effect size of HCQ treatment observed requires careful reassessments of prescriptions in everyday practice (EudraCT-Nr.: 2013-003714-40, www.clinicaltrialsregister.eu , registered 02.07.2013). Registration The study was registered on 2 July 2013 (Eudra-CT Number: 2013-003714-40), whereas the approval by BfArM was received 24.11.2014, followed by the approval by the lead EC of the University Hospital Munich on 20.01.2015. At clinicaltrials.gov the trial was additionally registered on November 8, 2015 (NCT02615938).
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COVID-19 , Doenças Pulmonares Intersticiais , Criança , Método Duplo-Cego , Humanos , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Estudos Prospectivos , Qualidade de Vida , SARS-CoV-2 , Resultado do TratamentoRESUMO
INTRODUCTION: Hypersensitivity pneumonitis (HP) in children is a severe interstitial lung disease and potentially, a chronic condition, if not treated appropriately. No evidence-based guidelines are available; in particular, the role of systemic glucocorticoid therapy is unclear. METHODS: The aim of this randomized, double-blind, placebo-controlled, parallel-group, multi-center, phase II trial in pediatric HP was to assess the outcome of HP in children after 6 months of treatment and to compare 3 months of treatment with oral prednisolone or placebo. RESULTS: After 1.5 years and the inclusion of only four children, we terminated the study prematurely. Two of the children randomized to prednisolone did not achieve the predefined response of FVC to normal. One child treated with placebo recovered to normal, similar to another child treated with prednisolone. All children treated with steroids developed drug-related side effects. DISCUSSION: This uncompleted study illustrates the urgent medical need for evidence-based treatment protocols for this condition. We discuss the hurdles which were specific for completion of this trial in a rare condition. Among other options, we suggest the inclusion of children into an all-age study of HP, as in adults the same questions are unanswered.
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Alveolite Alérgica Extrínseca , Doenças Pulmonares Intersticiais , Adulto , Alveolite Alérgica Extrínseca/diagnóstico , Alveolite Alérgica Extrínseca/tratamento farmacológico , Criança , Método Duplo-Cego , Glucocorticoides/uso terapêutico , Humanos , Prednisolona/uso terapêuticoRESUMO
BACKGROUND: Interstitial lung diseases in children (chILD) are rare and consist of many different entities that affect the parenchyma of the lungs, leading to a chronic lung disease. The natural course of many of these diseases is connected with a high morbidity and significant mortality. Symptomatic treatment consists of oxygen supplementation, adequate nutrition adapted to the high energy demand generated by the disease due to the increased breathing effort required, as well as immunization against respiratory pathogens to prevent exacerbations through respiratory infections. No proven pharmacological treatments are available to date. This placebo-controlled study aims to evaluate the efficacy and safety of the mid-term use of hydroxychloroquine in chILD. METHODS AND DESIGN: The study is an explorative, prospective, randomized, double-blind, placebo-controlled investigation of hydroxychloroquine (HCQ) in chILD. Patients can be included into the trial when diagnosed with a chronic (≥ 3 weeks' duration) diffuse parenchymal lung disease (chILD) (1) genetically defined, (2) histologically defined or (3) diagnosed with idiopathic pulmonary hemorrhage (hemosiderosis). The study contains of two different study blocks, a START and a STOP block, which can be initiated in any sequence. Each patient can participate in each block only once. In the START block subjects are randomized to parallel groups for 4 weeks treatment, then the placebo group is switched to the active drug. In the STOP block, subjects taking HCQ are randomized into parallel groups treated with placebo or HCQ. DISCUSSION: This study is the first international, investigator-initiated, prospective and controlled investigation of a pharmacological treatment in chILD. The block design was selected as it has the advantage of accommodating patients who are initiating or withdrawing from HCQ therapy, thus allowing the participation of those who were previously started on off-label HCQ. The cross-over design and selected outcome parameters enables us to include appropriate numbers of patients of all age groups from neonates to adults suffering from these rare diseases. TRIAL REGISTRATION: This is an exploratory, Phase 2a, randomized, double-blind, placebo-controlled, parallel-group, multinational study investigating the initiation or withdrawal of hydroxychloroquine in subjects with chILD. Study title: Hydroxychloroquine in pediatric ILD: START randomized controlled in parallel groups, then switch placebo to the active drug, and STOP randomized controlled in parallel groups to evaluate the efficacy and safety of hydroxychloroquine (HCQ). Short title: HCQ in pediatric ILD, particularly 4surfdefect. EudraCT, ID: 2013-003714-40. Registered on 2 July 2013. ClinicalTrials.gov, ID: NCT02615938. Registered on 8 November 2015. IZKS trial code: 2013-006; Sponsor: University Hospital, Ludwig-Maximilians University of Munich. Responsible Party: Prof. Dr. med. Matthias Griese, University Hospital, Ludwig-Maximilians University of Munich, Germany.