ABSTRACT
Introduction: In the randomised double-blind placebo-controlled CounterCovid study, imatinib reduced mortality in COVID-19 patients. High levels of alpha-1 acid glycoprotein (AAG) were associated with increased total imatinib concentrations in COVID-19 patients. Aim(s): We aimed to explore possible relationships between pharmacokinetic(PK) profiles of oral imatinib in COVID19 patients and pharmacodynamic (PD) outcomes. We hypothesize that high total imatinib concentrations may be associated with improved clinical outcomes in COVID-19 patients, when adjusted for AAG. Method(s): PK profiles were expressed as trough concentration at steady state(Css). PD responses were the ratio between partial oxygen pressure and fraction of inspired oxygen(P/F), WHO ordinal scale for clinical improvement(WHO-score) and oxygen supplementation liberation(O2lib). Linear regression, linear mixed effects models and time-to-event analysis were performed and adjusted for possible confounders. Result(s): Individual Css could be determined from 168 patients. Css did associate significantly with P/F (beta=-199,42;p-value=0.013) and O2lib (HR 0.75;p-value= 0.021), adjusted for sex, age, neutrophil-lymphocyte ratio, dexamethasone usage, AAG and baseline P/F-and WHO-score. Css did not significantly associate with WHO-score. Concusion: Higher total exposure following oral imatinib in COVID-19 patients did not associate with improved clinical outcomes. Total Css showed an inverse association with PD-outcomes. This association may be biased by disease-course and variability in metabolic rate and protein binding. Therefore, additional PKPD analyses into unbound imatinib and its main metabolite at Css may better explain exposure-response associations.
ABSTRACT
RATIONALE4,4-44,4% of children suffer from post-COVID syndrome, commonly known as long- COVID, after an acute SARS-CoV-2 infection. However, an uniform clinical definition, and guidelines to diagnose or treat children suspected of long-COVID are lacking. Multiple careprograms have been initiated worldwide. In this study, we aimed to assess the currently available pediatric international long-COVID care programs and explore the characteristics of their patient cohorts.METHODSWe established an international network (IP4C) and performed a crosssectional analysis from aggregated data collected by its members using a survey. Topics included: the used definition for long-covid in children, the organization of pediatric long-COVID clinics and long-COVID patients characteristics. Descriptive analysis of the aggregated data was used to summarize and compare each of these categories across countries. RESULTSWe included data concerning organization of care from 17 cohorts based in 13 different countries. A wide range of definitions for long COVID was used, which differed mostly in duration of symptoms and the necessity of microbiologically proven SARS-COV-2 infection. 66,6-100% of patients in the long- COVID cohorts suffered from complaints for more than twelve weeks, and 49,5-97,3% of patients had a positive RT-PCR or serology for SARS-CoV-2. Most long-COVID care programs consisted of real-life visits with multidisciplinary teams, consisting of general pediatricians, pediatric lung specialists, cardiologists and infectiologist, a physiotherapist and psychologist. The type of investigations performed at the long-COVID clinics ranged from assessment of medical history (100%) and standardized questionnaires (91%) to in depth evaluation of organ functioning (e.g. spirometry performed in 0-100% of patients). Aggregated data of 431 long-COVID patients from 11 dedicated long-COVID care programs were analyzed. Mean age of patients ranged from 6,5-16,4 years old. Girls were overrepresented in most cohorts (20-65%). 28-81,8% of patient had a positive medical history, most commonly atopic syndrome, asthma and prematurity. Most patients (90- 100%) suffered from asymptomatic or mild acute COVID-19. Frequent long-COVID symptoms were fatigue, headaches, concentration difficulties, dyspnea and sleep disturbances. 5-37% of patients had severe limitations in daily life. CONCLUSIONSThis is the first study to describe the organization of pediatric long-COVID care. It demonstrates that pediatric long-COVID is recognized worldwide as a multisystemic disease, but its definition and care programs for pediatric long- COVID patients differ between cohorts. A clear definition of pediatric long-COVID is needed to improve international scientific collaboration and patient care. Our international network will facilitate further collaboration in investigation pathophysiology and therapeutic interventions in order to provide evidence based medical care for these patients.