Severe Paediatric Asthma Collaborative in Europe (SPACE):protocol for a European registry

The development of new asthma biologics and receptor blockers for the treatment of paediatric severe asthma raises challenges. It is unclear whether there are sufficient children in Europe to recruit into randomised placebo-controlled trials to establish efficacy and safety in this age group. In February 2016, the European Respiratory Society funded a clinical research collaboration entitled “Severe Paediatric Asthma Collaborative in Europe” (SPACE). We now report the SPACE protocol for a prospective pan-European observational study of paediatric severe asthma. Inclusion criteria are: 1) age 6–17 years, 2) severe asthma managed at a specialised centre for ≥6 months, 3)clinical and spirometry evidence of asthma, and 4) reaching a pre-defined treatment threshold. The exclusion criterion is the presence of conditions which mimic asthma symptoms. Eligible children will be prospectively recruited into a registry, recording demographics, comorbidities, quality of life, family history, neonatal history, smoking history, asthma background, investigations, and treatment. Follow-up will provide longitudinal data on asthma control and treatment changes. The SPACE registry, by identifying well-phenotyped children eligible for clinical trials, and the amount of overlap in eligibility criteria, will inform the design of European trials in paediatric severe asthma, and facilitate observational research where data from single centres are limited

recommendations by the Conect4Children expert advice group

Funding Information: Competing interests: A.V.R. has received Speaker fees/Consultant for Abbvie, Novartis, UCB, SOBI, Eli Lilly and Roche. N.M. reports grants outside the submitted work in the last five years from the Medical Research Council, National Institute of Health Research, March of Dimes, British Heart Foundation, HCA international, Health Data Research UK, Shire Pharmaceuticals, Chiesi Pharmaceuticals, Prolacta Life Sciences, and Westminster Children’s Research Fund; N.M. is a member of the Nestle Scientific Advisory Board and accepts no personal remuneration for this role. N.M. reports travel and accommodation reimbursements from Chiesi, Nestle and Shire. N.M. is a member of C4C, International Neonatal Collaboration (INC), UK National Research Ethics Advisory Service and MHRA advisory groups and/or working parties. S.W. has received compensation as a member of the scientific advisory board of AM Pharma, Novartis and Khondrion and receives research funding from IMI2 for the Conect4children project. B.A. has worked for GlaxoSmithKline between October 2006 and September 2009 and holds company shares. Between October 2009 and May 2015, she has worked for Novartis. M.S. has recieved research grant and honoraria for meetings and Advisory Boards from Alexion, Sanofi/Genzyme, Takeda, CHIESI, Ultragenix, Orchard, Orphazyme. P.I. is a permanent employee of Bayer AG, Germany. M.V. has received compensation for Advisory boards or Steering committes from Roche, Novartis, Achillion, Apellis, Retrophin/Travere, Alexion pharmaceuticals. C.M. has been a consultant to or has received honoraria from Janssen, Angelini, Servier, Nuvelution, Otsuka, Lundbeck, Pfizer, Neuraxpharm and Esteve outside the submitted work. She declares conflicts of interest unrelated to the present work. M.C. had advisory roles for AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Lilly, and Roche in the last 2 years (outside the topic of the submitted work, for oncology drugs). M.J. has received research grants from Shire and has been engaged as a speaker or consultant by Shire, Ginsana, PCM Scientific Evolan, and New Nordic, all unrelated to the present work. P.S. has received speaker fees and participated at advisory boards for Biomarin, Zogenyx, GW Pharmaceuticals, and has received research funding by ENECTA BV, GW Pharmaceuticals, Kolfarma srl., Eisai. E.R. has received speaker fees and participated at advisory boards for Eisai and has received research funding by GW Pharmaceuticals, Pfizer, Italian Ministry of Health (MoH) and the Italian Medicine Agency (AIFA). This work was developed within the framework of the DINOGMI Department of Excellence of MIUR 2018-2022 (legge 232 del 2016). M.A.R. is a member of the c4c Ethics Expert Group and received compensation for ethical consulting activities from Bayer AG Wallace Crandall is employee of Eli Lilly and Co. P.C. is an employee of UCB, and owns stock in the company. She was previously an employee of GSK and owns stock in the company. N.R. has received honoraria for consultancies or speaker bureaus from the following pharmaceutical companies in the past 3 years: Ablynx, Amgen, Astrazeneca-Medimmune, Aurinia, Bayer, Bristol Myers and Squibb, Cambridge Healthcare Research (CHR), Celgene, Domain therapeutic, Eli-Lilly, EMD Serono, Glaxo Smith and Kline, Idorsia, Janssen, Novartis, Pfizer, Sobi, UCB. The IRCCS Istituto Giannina Gaslini (IGG), where NR works as full-time public employee has received contributions from the following industries in the last 3 years: Bristol Myers and Squibb, Eli-Lilly, F Hoffmann-La Roche, Novartis, Pfizer, Sobi. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment with third parties. M.L. receives/has received consultation fees from CSL Behring, Novartis, Roche and Octopharma, travel grants from Merck Serono, and been awarded educational grants to organise meetings by Novartis, Biogen Idec, Merck Serono and Bayer. All other authors have no disclosures. Funding Information: Conect4children has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777389. The Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. The views expressed in this article are the personal views of the author(s) and should not be interpreted as made on behalf of, or reflecting the position of, the regulatory agency/agencies or organisations with which the author(s) is/are employed/affiliated . Publisher Copyright: © 2021, The Author(s).Background: The COVID-19 pandemic has had a devastating impact on multiple aspects of healthcare, but has also triggered new ways of working, stimulated novel approaches in clinical research and reinforced the value of previous innovations. Conect4children (c4c, www.conect4children.org) is a large collaborative European network to facilitate the development of new medicines for paediatric populations, and is made up of 35 academic and 10 industry partners from 20 European countries, more than 50 third parties, and around 500 affiliated partners. Methods: We summarise aspects of clinical research in paediatrics stimulated and reinforced by COVID-19 that the Conect4children group recommends regulators, sponsors, and investigators retain for the future, to enhance the efficiency, reduce the cost and burden of medicines and non-interventional studies, and deliver research-equity. Findings: We summarise aspects of clinical research in paediatrics stimulated and reinforced by COVID-19 that the Conect4children group recommends regulators, sponsors, and investigators retain for the future, to enhance the efficiency, reduce the cost and burden of medicines and non-interventional studies, and deliver research-equityWe provide examples of research innovation, and follow this with recommendations to improve the efficiency of future trials, drawing on industry perspectives, regulatory considerations, infrastructure requirements and parent–patient–public involvement. We end with a comment on progress made towards greater international harmonisation of paediatric research and how lessons learned from COVID-19 studies might assist in further improvements in this important area.publishersversionepub_ahead_of_prin

Development of Core Outcome Measures sets for paediatric and adult Severe Asthma (COMSA)

BACKGROUND: Effectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) working group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies.METHODS: COMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult, and paediatric clinicians, pharmaceutical representatives and health regulators from across Europe. Evidence included a systematic review of development, validity, and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients' and carers' views about outcome measures. It was discussed using a modified GRADE Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria.RESULTS: Both adult and paediatric COM sets include forced expiratory volume in 1 s (FEV1) as z scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire, and Asthma Control Test (ACT) or Childhood-ACT while the adult COM includes the Severe Asthma Questionnaire and the Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately).CONCLUSIONS: This patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma.</p

Pancreatic Masses: Not All of Them are Pancreatic Adenocarcinoma: Differential Diagnosis

Primary pancreatic lymphoma (PPL) is a very rare tumor of the pancreas and can mimic pancreatic adenocarcinoma (PAC) clinically and radiographically. The rarity of PPL and its similarity to PAC can potentially lead to misdiagnosis of a minority of potentially curable patients. However, the management of PPL differs greatly from that of PAC. The most appropriate way of diagnosis in these patients is fine-needle aspiration biopsy before surgery. We report two cases with PPL presenting with a mass in the pancreas. One the patients was diagnosed after major open surgery and the other one was diagnosed by fine-needle aspiration biopsy

Assessment of platelet aspirin responsiveness in Turkish Population with PFA-100, serum thromboxane B-2, soluble CD40 ligand and soluble P-Selectin]

Aim: Recurrent thromboembolic vascular events have been reported in 5.5 to 60% of the population despite aspirin therapy. We aimed to determine the frequency of aspirin non-responsiveness in our population with "Platelet Function Analyzer-100 Closure Time" (PFA-100 CT) and serum tromboxane B-2, soluble CD40 Ligand and soluble P-selectin levels

Usage of Plasma Presepsin, C-Reactive Protein, Procalcitonin and Proadrenomedullin to Predict Bacteremia in Febril Neutropenia of Pediatric Hematological Malignancy Patients

Objective: To investigate the value of presepsin and proadrenomedullin (proADM) as new markers for febrile neutropenia, by comparing them with conventional markers. Methods: Plasma specimens for presepsin, proADM, C-reactive protein (CRP), and procalcitonin (PCT) were collected every 3 days during each episode of febrile neutropenia. Results: A total of 39 patients experiencing a collective 47 episodes of febrile neutropenia with hematological malignant neoplasms, as well as 40 healthy control patients without infectious disease, were enrolled in this study. Levels of the studied analytes in the presepsin 1 group (with baseline values taken at admission), presepsin 2 group (values recorded on the 3rd day of febrile neutropenia), and presepsin 3 group (values recorded on the 6th day of hospitalization) were all higher in the subgroups with bacteremia. C-reactive protein 1 (baseline value taken at admission), procalcitonin 1 (as recorded at admission), and procalcitonin 2 (recorded on the 3rd day of febrile neutropenia) were higher in the subroups with bacteremia (P =.03, P =. 04, and P =. 04, respectively). In multivariate logistic regression analysis, presepsin 1 and/or PCT 1/CRP 1 combined analysis was superior in predicting bacteremia. Conclusion: Presepsin could be used in combination with other biomarkers to detect bacteremia

Evaluation of multiplex real time polymerase chain reaction and procalcitonin in the diagnosis of sepsis

Background: Sepsis is one of the most serious and life-threatening clinical conditions of childhood. This study has been designed to evaluate how useful multiplex real-time polymerase chain reaction (PCR) is in the early diagnosis of responsible microorganisms of sepsis and to specify how serial procalcitonin level measurement is helpful to support diagnosis of sepsis. Methods: A total of 79 blood samples from 69 consecutive patients were collected for this prospective study between 01 Sept 2009-29 Feb 2012. Results: In the evaluation of patients who are diagnosed with sepsis out of 69 patients with 79 clinical sepsis, 24 (30.37%) had positive blood culture and 19 (24%) samples were positive for PCR. When blood culture and multiplex real-time PCR results were compared, multiplex real-time PCR had a sensitivity of 75% and specificity of 100%. When the 2 microorganisms that multiplex real-time PCR cannot detect are excluded sensitivity increased to 81.8% and specificity did not differ. Procalcitonin levels on the day sepsis is suspected had a mean level of 13.91 ng/mL (± 49.26), on the 1st day (after 24 hours) the mean level of procalcitonin was 15.05 ng/mL (± 43.95), on the 2nd day (after 48 hours) it was 14.89 ng/mL (± 41.57). Mean procalcitonin levels of 50 children admitted with complaints other than infection and systemic inflammation was 0.06 ng/mL (± 0.04). Conclusions: In conclusion, multiplex real-time PCR test would be useful in the early diagnosis of sepsis. Studying procalcitonin levels is helpful in the early diagnosis of sepsis but does not have any correlation with the isolation of microorganisms in blood culture and survival

Presepsin: A new marker of catheter related blood stream infections in pediatric patients

Background Catheter related blood stream infections (CRBSI) are mostly preventable hospital-acquired conditions. We aimed to investigate the value of presepsin in detection of CRBSI in hospitalized children. Methods Hospitalized pediatric patients who had clinical suspicion of CRBSI were followed. Results of peripheral blood cultures and blood cultures from central venous catheters, procalcitonin (PCT), C-reactive protein (CRP), total white blood cell (WBC) counts were recorded. Serum samples for presepsin were studied at the same time with the samples of healthy controls. The patients with positive blood cultures were defined as proven CRBSI and with negative cultures as suspected CRBSI. Results Fifty-eight patients and 80 healthy controls were included in the study. Proven CRBSI group consisted of 36 patients (62%) with positive blood cultures and compared with the suspected CRBSI group (n = 22, 36%) with negative culture results. There was no difference between proven and suspected CRBSI groups concerning WBC, PCT, CRP and presepsin. Presepsin was significantly higher in patient groups when compared with healthy controls. The receiver operating characteristic curve area under the curve was 0.98 (%95 CI: 0.97–1) and best cut-off value was 990 pg/ml. Conclusion In hospitalized pediatric patients with CRBSI, presepsin may be a helpful rapid marker in early diagnosis

Oxidant and Antioxidant Balance in Children with Community-Acquired Pneumonia

Objective The balance between oxidant and antioxidant defense mechanisms is crucial. In this article, we aimed to evaluate the role of this balance in community-acquired pneumonia (CAP) in children. Methods We analyzed serum oxidant and antioxidant stress parameters according to the clinical and demographic data of children with CAP and compared them with healthy controls. Serum total antioxidant status (TAS) and total oxidant status (TOS) were evaluated and compared between the groups, along with levels of ischemia-modified albumin (IMA), antioxidant enzymes, nonenzymatic antioxidant factors, and plasma thiol. Results Of 160 children evaluated, 106 had CAP (54 outpatients and 52 inpatients), and the other 54 were healthy (control group). Total thiol and native thiol levels were significantly lower in the inpatient group compared with the outpatient group (p = 0.004 and p = 0.005, respectively). Serum IMA differed significantly among the groups (p = 0.001), with inpatients showing the highest level. A positive correlation was found between serum IMA and C-reactive protein levels in patients with pneumonia (r = 0.351; p = 0.001). Conclusion Parameters that provide information about antioxidant capacity may be useful in the diagnosis and prognosis of pneumonia. Our results suggest that plasma thiol levels and IMA may be good candidate biomarkers to predict hospitalization for CAP in children