What is precision medicine? König, Inke R; Fuchs, Oliver; Hansen, Gesine ...
The European respiratory journal
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The term "precision medicine" has become very popular over recent years, fuelled by scientific as well as political perspectives. Despite its popularity, its exact meaning, and how it is different ...from other popular terms such as "stratified medicine", "targeted therapy" or "deep phenotyping" remains unclear. Commonly applied definitions focus on the stratification of patients, sometimes referred to as a novel taxonomy, and this is derived using large-scale data including clinical, lifestyle, genetic and further biomarker information, thus going beyond the classical "signs-and-symptoms" approach.While these aspects are relevant, this description leaves open a number of questions. For example, when does precision medicine begin? In which way does the stratification of patients translate into better healthcare? And can precision medicine be viewed as the end-point of a novel stratification of patients, as implied, or is it rather a greater whole?To clarify this, the aim of this paper is to provide a more comprehensive definition that focuses on precision medicine as a process. It will be shown that this proposed framework incorporates the derivation of novel taxonomies and their role in healthcare as part of the cycle, but also covers related terms.
Human rhinovirus infection (HRVI) plays an important role in asthma exacerbations and is thought to be involved in asthma development during early childhood. We hypothesized that HRVI causes ...differential DNA methylation and subsequently differential mRNA expression in epithelial cells of children with asthma. Primary nasal epithelial cells from children with (n = 10) and without (n = 10) asthma were cultivated up to passage two and infected with Rhinovirus-16 (RV-16). HRVI-induced genome-wide differences of DNA methylation in asthmatics (vs. controls) and resulting mRNA expression were analyzed by the HumanMethylation450 BeadChip Kit (Illumina) and RNA sequencing. These results were further verified by pyrosequencing and quantitative PCR, respectively. 471 CpGs belonging to 268 genes were identified to have HRVI-induced asthma-specifically modified DNA methylation and mRNA expression. A minimum-change criteria was applied to restrict assessment of genes with changes in DNA methylation and mRNA expression of at least 3% and least 0.1 reads/kb per million mapped reads, respectively. Using this approach we identified 16 CpGs, including HLA-B-associated transcript 3 (BAT3) and Neuraminidase 1 (NEU1), involved in host immune response against HRVI. HRVI in nasal epithelial cells leads to specific modifications of DNA methylation with altered mRNA expression in children with asthma. The HRVI-induced alterations in DNA methylation occurred in genes involved in the host immune response against viral infections and asthma pathogenesis. The findings of our pilot study may partially explain how HRVI contribute to the persistence and progression of asthma, and aid to identify possible new therapeutic targets. The promising findings of this pilot study would benefit from replication in a larger cohort.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Only few data on safety during high-dose, accelerated escalation schedules during subcutaneous allergen immunotherapy (AIT) are available. The aim of this study was to assess the safety and ...tolerability of an accelerated dose escalation schedule of AIT in adult patients with moderate to severe seasonal rhinoconjunctivitis in a multicenter, open-label, randomized phase II trial. The dose escalation scheme for patients in Group I (1 strength) included 3 injections with 1 strength, B (10,000 TU/mL), whereas the dose escalation scheme for Group II (standard) included 7 injections with 2 strengths, A (1,000 TU/mL) and B (10,000 TU/mL), of an aluminum hydroxide-adsorbed allergoid grass pollen preparation. Overall, 72 of 87 randomized patients (83.7%) reported at least 1 treatment-emergent adverse event (TEAE; 82.2 Group I vs. 85.4% Group II); 58.8% of all reported TEAEs were assessed as being related to AIT (60.0 vs. 48.8%). The most frequently reported AIT-related TEAEs were swelling (46.7 vs. 34.1%), erythema (28.9 vs. 36.6%), and pruritus (31.1 vs. 17.1%) at the site of the injection. Systemic allergic reactions occurred in 5 (5.8%) patients overall, with more being reported in the 1-strength group (4 8.9% vs. 1 2.4%). All systemic allergic reactions were classified as World Allergy Organization (WAO) Grade 1 or Grade 2 reactions. Accelerated high-dose escalation with an aluminum hydroxide-adsorbed grass pollen allergoid can be initiated with a safety and tolerability profile comparable to the standard dose escalation schedule in patients with allergic rhinitis with or without asthma.
The seventh “Future of the Allergists and Specific Immunotherapy (FASIT)” workshop held in 2019 provided a platform for global experts from academia, allergy clinics, regulatory authorities and ...industry to review current developments in the field of allergen immunotherapy (AIT). Key domains of the meeting included the following: (a) Biomarkers for AIT and allergic asthma; (b) visions for the future of AIT; (c) progress and data for AIT in asthma and the updates of GINA and EAACI Asthma Guidelines (separated for house dust mite SCIT, SLIT tablets and SLIT drops; patient populations) including a review of clinically relevant endpoints in AIT studies in asthma; (d) regulatory prerequisites such as the “Therapy Allergen Ordinance” in Germany; (e) optimization of trial design in AIT clinical research; (f) challenges planning and conducting phase III (field) studies and the future role of Allergen Exposure Chambers (AEC) in AIT product development from the regulatory point of view. We report a summary of panel discussions of all six domains and highlight unmet needs and possible solutions for the future.
Cystic fibrosis (CF) lung disease starts in early infancy, suggesting that preventive treatment may be most beneficial. Lung clearance index (LCI) and chest magnetic resonance imaging (MRI) have ...emerged as promising endpoints of early CF lung disease; however, randomized controlled trials testing the safety and efficacy of preventive therapies in infants with CF are lacking.
To determine the feasibility, safety, and efficacy of preventive inhalation with hypertonic saline (HS) compared with isotonic saline (IS) in infants with CF, including LCI and MRI as outcome measures.
In this randomized, double-blind, controlled trial, 42 infants with CF less than 4 months of age were randomized across five sites to twice-daily inhalation of 6% HS (
= 21) or 0.9% IS (
= 21) for 52 weeks.
Inhalation of HS and IS was generally well tolerated by infants with CF, and the number of adverse events did not differ between groups (
= 0.49). The change in LCI from baseline to Week 52 was larger in infants with CF treated with HS (-0.6) than in those treated with IS (-0.1;
< 0.05). In addition, weight gain was improved in infants with CF treated with HS (
< 0.05), whereas pulmonary exacerbations and chest MRI scores did not differ in the HS group versus the IS group.
Preventive inhalation with HS initiated in the first months of life was safe and well tolerated and resulted in improvements in LCI and weight gain in infants with CF. Our results support the feasibility of LCI as an endpoint in randomized controlled trials in infants with CF. Clinical trial registered with www.clinicaltrials.gov (NCT01619657).
A high-dose, accelerated escalation schedule during subcutaneous allergen-specific immunotherapy (AIT) is safe and well-tolerated in adults. However, there are no data in children and adolescents. ...The aim of the present trial was to assess safety and tolerability of an accelerated dose escalation schedule of an AIT with a grass pollen allergoid in children and adolescents with moderate to severe seasonal rhinoconjunctivitis in a multicenter, open-label, randomized phase II trial. The dose escalation scheme for patients in the One Strength Group included 3 injections with 1 strength B (10,000 TU/mL), whereas the dose escalation scheme for the Standard group included 7 injections with 2 strengths A (1,000 TU/mL) and B (10,000 TU/mL) of an allergoid grass pollen preparation. Overall, n = 50 children (n = 25 in each group; mean age 8.9 + 1.54 years) and n = 37 adolescents (n = 20 and n = 17; 14.2 + 1.62 years) were randomized. For all patients, the mean treatment duration was 59.4 days in the One Strength group and 88.6 days in the Standard group. Treatment-emergent adverse events (TEAEs) related to AIT were reported in 52 and 40% in children and 35 and 35.3% in adolescents, respectively. Systemic allergic reactions occurred in about 5% of our patients and were reported in more patients of the One Strength group (6.7 vs. 2.4%). All systemic reactions were classified as WAO Grade 1. Accelerated high-dose escalation with an aluminum hydroxide-adsorbed grass pollen allergoid can be initiated with a safety and tolerability profile comparable to the standard dose escalation schedule in children and adolescents with allergic rhinitis with or without asthma.
A recent single-centre study demonstrated that MRI is sensitive to detect early abnormalities in the lung and response to therapy in infants and preschool children with cystic fibrosis (CF) ...supporting MRI as an outcome measure of early CF lung disease. However, the feasibility of multicentre standardisation remains unknown.
To determine the feasibility of multicentre standardisation of chest MRI in infants and preschool children with CF.
A standardised chest 1.5T MRI protocol was implemented across four specialised CF centres. Following training and initiation visits, 42 infants and preschool children (mean age 3.2±1.5years, range 0–6years) with clinically stable CF underwent MRI and chest X-ray (CXR). Image quality and lung abnormalities were assessed using a standardised questionnaire and an established CF MRI and CXR score.
MRI was successfully performed with diagnostic quality in all patients (100%). Incomplete lung coverage was observed in 6% and artefacts also in 6% of sequence acquisitions, but these were compensated by remaining sequences in all patients. The range of the MRI score in CF patients was similar across centres with a mean global MRI score of 13.3±5.8. Cross-validation of the MRI against the CXR score revealed a moderate correlation (r=0.43–0.50, p<0.01).
Our results demonstrate that multicentre standardisation of chest MRI is feasible and support its use as radiation-free outcome measure of lung disease in infants and preschool children with CF.
Improvement of paediatric healthcare is hampered by inefficient processes for generating new evidence. Clinical research often requires extra encounters with patients, is costly, takes place in an ...artificial situation with a biased selection of patients, and entails long delays until new evidence is implemented into health care. Electronic health records (EHR) contain detailed information on real patients and cover the entirety of patients. However, the use of EHR for research is limited because they are not standardised between hospitals. This leads to disproportionate amounts of work for extracting data of interest and frequently data are incomplete and of poor quality.
SwissPedData aims to lay the foundation for a paediatric learning health system in Switzerland by facilitating EHR-based research. In this project, we aimed to assess the way routine clinical data are currently recorded in large paediatric clinics in Switzerland and to develop a national EHR-based set of common data elements (CDEs) that covers all processes of routine paediatric care in hospitals.
A taskforce of paediatricians from large Swiss children's hospitals reviewed the current status of routine data documentation in paediatric clinical care and the extent of digitalisation. We then used a modified Delphi method to reach a broad consensus on a national EHR-based set of CDEs.
All Swiss children's hospitals use EHR to document some or all aspects of care. One hundred and nineteen paediatricians, representing eight hospitals and all paediatric subspecialties, participated in an extended Delphi process to create SwissPedData. The group agreed on a national set of CDEs that comprises a main module with general paediatric data and sub-modules relevant to paediatric subspecialties. The data dictionary includes 336 CDEs: 76 in the main module on general paediatrics and between 11 and 59 CDEs per subspecialty module. Among these, 266 were classified as mandatory, 52 as recommended and 18 as optional.
SwissPedData is a set of CDEs for information to be collected in EHR of Swiss children's hospitals. It covers all care processes including clinical and paraclinical assessment, diagnosis, treatment, disposition and care site. All participating hospitals agreed to implement SwissPedData in their clinical routine and clinic information systems. This will pave the way for a national paediatric learning health system in Switzerland that enables fast and efficient answers to urgent clinical questions by facilitating high-quality nationwide retrospective and prospective observational studies and recruitment of patients for nested prospective studies and clinical trials.
The massive increase of infections with Group A Streptococcus (GAS) in 2022-2023 coincided in Switzerland with a change of the recommendations for the management of GAS pharyngitis. Therefore, the ...objective of the present study was to investigate whether the clinical manifestations and management before hospitalization for GAS infection differed in 2022-2023 compared with 2013-2022.
Retrospective study of GAS infections requiring hospitalization in patients below 16 years. Preadmission illness (modified McIsaac score), oral antibiotic use, and outcome in 2022-2023 were compared with 2013-2022. Time series were compared with surveillance data for respiratory viruses.
In 2022-2023, the median modified McIsaac score was lower (2 IQR 2-3 vs. 3 IQR 2-4, p = < 0.0001) and the duration of preadmission illness was longer (4 days 3-7 vs. 3 2-6, p = 0.004) than in 2013-2022. In both periods, withholding of preadmission oral antibiotics despite a modified McIsaac score ≥ 3 (12% vs. 18%, n.s.) or ≥ 4 (2.4% vs. 10.0%, p = 0.027) was rare. Respiratory disease, skeletal/muscle infection, and invasive GAS disease were significantly more frequent in 2022-2023, but there were no differences in clinical outcome. The time course of GAS cases in 2022-2023 coincided with the activity of influenza A/B.
We found no evidence supporting the hypothesis that the 2022-2023 GAS outbreak was associated with a change in preadmission management possibly induced by the new recommendation for GAS pharyngitis. However, clinical manifestations before admission and comparative examination of time-series strongly suggest that viral co-circulation played an important role in this outbreak.
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