Pulmonary embolism (PE) is a serious and sometimes life-threatening condition that refers to a blood clot that occludes the arteries of the lung. Despite all improvements over the past decades,... Show morePulmonary embolism (PE) is a serious and sometimes life-threatening condition that refers to a blood clot that occludes the arteries of the lung. Despite all improvements over the past decades, diagnosing PE is still a difficult process due to the non-specific symptoms, which can frequently overlap with symptoms of other cardiopulmonary diseases. Currently recommended diagnostic strategies for suspected acute PE consist of standardized assessment of the clinical pre-test probability (CPTP) using validated clinical decision rules (CDRs) and D-dimer testing. PE is considered safely ruled out in patients with a non-high CPTP and a normal D-dimer test. Imaging tests as computed tomography pulmonary angiography (CTPA) are required in the case of a high CPTP and/or abnormal D-dimer test to confirm the diagnosis. The first part of this thesis describes the challenges of diagnosing PE in general and in specific clinically relevant patient subgroups. Moreover, this part evaluates the diagnostic performance of non-invasive diagnostic strategies for suspected PE in specific relevant patient subgroups. The second part of this thesis focuses on venous thrombotic complications in hospitalized patients with COVID-19. Show less
Purpose The 14th Acromegaly Consensus Conference was convened to consider biochemical criteria for acromegaly diagnosis and evaluation of therapeutic efficacy.Methods Fifty-six acromegaly experts... Show morePurpose The 14th Acromegaly Consensus Conference was convened to consider biochemical criteria for acromegaly diagnosis and evaluation of therapeutic efficacy.Methods Fifty-six acromegaly experts from 16 countries reviewed and discussed current evidence focused on biochemical assays; criteria for diagnosis and the role of imaging, pathology, and clinical assessments; consequences of diagnostic delay; criteria for remission and recommendations for follow up; and the value of assessment and monitoring in defining disease progression, selecting appropriate treatments, and maximizing patient outcomes.Results In a patient with typical acromegaly features, insulin-like growth factor (IGF)-I > 1.3 times the upper limit of normal for age confirms the diagnosis. Random growth hormone (GH) measured after overnight fasting may be useful for informing prognosis, but is not required for diagnosis. For patients with equivocal results, IGF-I measurements using the same validated assay can be repeated, and oral glucose tolerance testing might also be useful. Although biochemical remission is the primary assessment of treatment outcome, biochemical findings should be interpreted within the clinical context of acromegaly. Follow up assessments should consider biochemical evaluation of treatment effectiveness, imaging studies evaluating residual/recurrent adenoma mass, and clinical signs and symptoms of acromegaly, its complications, and comorbidities. Referral to a multidisciplinary pituitary center should be considered for patients with equivocal biochemical, pathology, or imaging findings at diagnosis, and for patients insufficiently responsive to standard treatment approaches.Conclusion Consensus recommendations highlight new understandings of disordered GH and IGF-I in patients with acromegaly and the importance of expert management for this rare disease. Show less
BackgroundThe recently published 4-level Pulmonary Embolism Clinical Probability Score (4PEPS) integrates different aspects from currently available diagnostic strategies to further reduce imaging... Show moreBackgroundThe recently published 4-level Pulmonary Embolism Clinical Probability Score (4PEPS) integrates different aspects from currently available diagnostic strategies to further reduce imaging testing in patients with clinically suspected pulmonary embolism (PE).AimTo externally validate the performance of 4PEPS in an independent cohort.MethodsIn this post-hoc analysis of the prospective diagnostic management YEARS study, the primary outcome measures were discrimination, calibration, efficiency (proportion of imaging tests potentially avoided), and failure rate (venous thromboembolism (VTE) diagnosis at baseline or follow-up in patients with a negative 4PEPS algorithm). Multiple imputation was used for missing 4PEPS items. Based on 4PEPS, PE was considered ruled out in patients with a very low clinical pre-test probability (CPTP) without D-dimer testing, in patients with a low CPTP and D-dimer <1000 μg/L, and in patients with a moderate CPP and D-dimer below the age-adjusted threshold.ResultsOf the 3465 patients, 474 (14 %) were diagnosed with VTE at baseline or during 3-month follow-up. Discriminatory performance of the 4PEPS items was good (area under ROC-curve, 0.82; 95%CI, 0.80–0.84) as was calibration. Based on 4PEPS, PE could be considered ruled out without imaging in 58 % (95%CI 57–60) of patients (efficiency), for an overall failure rate of 1.3 % (95%CI 0.86–1.9).ConclusionIn this retrospective external validation, 4PEPS appeared to safely rule out PE with a high efficiency. Nevertheless, although not exceeding the failure rate margin by ISTH standards, the observed failure rate in our analysis appeared to be higher than in the original 4PEPS derivation and validation study. This highlights the importance of a prospective outcome study. Show less
Slobbe, M. van; Haeringen, A. van; Vissers, L.E.L.M.; Bijlsma, E.K.; Rutten, J.W.; Suerink, M.; ... ; Koene, S. 2023
This study aims to inform future genetic reanalysis management by evaluating the yield of whole-exome sequencing (WES) reanalysis in standard patient care in the Netherlands. Single-center data of... Show moreThis study aims to inform future genetic reanalysis management by evaluating the yield of whole-exome sequencing (WES) reanalysis in standard patient care in the Netherlands. Single-center data of 159 patients with a neurodevelopmental disorder (NDD), in which WES analysis and reanalysis were performed between January 1, 2014, and December 31, 2021, was retrospectively collected. Patients were included if they were under the age of 18 years at initial analysis and if this initial analysis did not result in a diagnosis. Demographic, phenotypic, and genotypic characteristics of patients were collected and analyzed. The primary outcomes of our study were (i) diagnostic yield at reanalysis, (ii) reasons for detecting a new possibly causal variant at reanalysis, (iii) unsolicited findings, and (iv) factors associated with positive result of reanalysis. In addition, we conducted a questionnaire study amongst the 7 genetic department in the Netherlands creating an overview of used techniques, yield, and organization of WES reanalysis. The single-center data show that in most cases, WES reanalysis was initiated by the clinical geneticist (65%) or treating physician (30%). The mean time between initial WES analysis and reanalysis was 3.7 years. A new (likely) pathogenic variant or VUS with a clear link to the phenotype was found in 20 initially negative cases, resulting in a diagnostic yield of 12.6%. In 75% of these patients, the diagnosis had clinical consequences, as for example, a screening plan for associated signs and symptoms could be devised. Most (32%) of the (likely) causal variants identified at WES reanalysis were discovered due to a newly described gene-disease association. In addition to the 12.6% diagnostic yield based on new diagnoses, reclassification of a variant of uncertain significance found at initial analysis led to a definite diagnosis in three patients. Diagnostic yield was higher in patients with dysmorphic features compared to patients without clear dysmorphic features (yield 27% vs. 6%; p = 0.001).Conclusions: Our results show that WES reanalysis in patients with NDD in standard patient care leads to a substantial increase in genetic diagnoses. In the majority of newly diagnosed patients, the diagnosis had clinical consequences. Knowledge about the clinical impact of WES reanalysis, clinical characteristics associated with higher yield, and the yield per year after a negative WES in larger clinical cohorts is warranted to inform guidelines for genetic reanalysis. These guidelines will be of great value for pediatricians, pediatric rehabilitation specialists, and pediatric neurologists in daily care of patients with NDD. Show less
Webers, C.; Grimm, S.; Tubergen, A. van; Gaalen, F. van; Heijde, D. van der; Joore, M.; Boonen, A. 2023
ObjectiveTo demonstrate the value of diagnosing axSpA, by comparing health and costs associated with available diagnostic algorithms and perfect diagnosis.MethodsUsing data from SPACE and other... Show moreObjectiveTo demonstrate the value of diagnosing axSpA, by comparing health and costs associated with available diagnostic algorithms and perfect diagnosis.MethodsUsing data from SPACE and other cohorts, a model was developed to estimate health (quality-adjusted life-years, QALYs) and costs (healthcare consumption and work productivity losses) of different diagnostic algorithms for axSpA amongst patients with low back pain referred to a rheumatologist, over a 60-year horizon. The model combined a decision-tree (diagnosis) with a state-transition model (treatment). The three algorithms (Berlin [BER, highest specificity], Modification 1 [M1; less strict inflammatory back pain (IBP) criterion] and Modification 2 [M2; IBP not mandatory as entry criterion, highest sensitivity]) were compared. Changes in sensitivity/specificity were explored and the value of perfect diagnosis was investigated.ResultsFor each correctly diagnosed axSpA patient, up to 4.7 QALYs and €60,000 could be gained/saved, considering a societal perspective. Algorithm M2 resulted in more health and lower costs per patient (24.23 QALYs; €157,469), compared to BER (23.96 QALYs; €159,423) and M1 (24.15 QALYs; €158,417). Hypothetical improvements in M2 sensitivity resulted in slightly more value compared to improvements in specificity. Perfect diagnosis can cost €7,500 per patient and still provide enough value.ConclusionCorrect diagnosis of axSpA results in substantial health and cost benefits for patients and society. Not requiring IBP as mandatory for diagnosis of axSpA (algorithm M2) provides more value and would be preferable. A considerably more expensive diagnostic algorithm with better accuracy than M2 would still be considered good value for money. Show less
With back pain as one of the most common complaints in the population and with no single disease feature with sufficient sensitivity and specificity to diagnose axial spondyloarthritis (axSpA) on... Show moreWith back pain as one of the most common complaints in the population and with no single disease feature with sufficient sensitivity and specificity to diagnose axial spondyloarthritis (axSpA) on its own, diagnosing axSpA can be challenging. In this article, we discuss clinical, laboratory, and imaging spondyloarthritis features that can be used in diagnosis and explain the general principles underlying an axSpA diagnosis. Moreover, we discuss three pitfalls to avoid when diagnosing axSpA: i) using classification criteria as diagnostic criteria, ii) making a diagnosis by simple counting of spondyloarthritis features, and iii) overreliance on imaging findings. Finally, we have some advice on how to build diagnostic skills and discuss new developments that may help facilitate the diagnosis of axSpA in the future.(c) 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/). Show less
Delgado, V.; Marsan, N.; Waha, S. de; Bonaros, N.; Brida, M.; Burri, H.; ... ; ESC Sci Document Grp 2023
This paper aims to improve the diagnosis of syncope and transient loss of consciousness (TLOC) in children. Diagnostic problems stem, first, from some causes spanning various disciplines, e.g.... Show moreThis paper aims to improve the diagnosis of syncope and transient loss of consciousness (TLOC) in children. Diagnostic problems stem, first, from some causes spanning various disciplines, e.g. cardiology, neurology and psychiatry, while the most common cause, vasovagal syncope, is not embraced by any specialty. Second, clinical variability is huge with overlapping signs and symptoms. Third, the approach to TLOC/syncope of the European Society of Cardiology (ESC) is underused in childcare. We explain the ESC guidelines using an additional paediatric literature review. Classification of TLOC and syncope is hierarchic and based on history taking. Loss of consciousness (LOC) is defined using three features: abnormal motor control including falling, reduced responsiveness and amnesia. Adding a < 5 min duration and spontaneous recovery defines TLOC. TLOC simplifies diagnosis by excluding long LOC (e.g. some trauma, intoxications and hypoglycaemia) and focussing on syncope, tonic-clonic seizures and functional TLOC. Syncope, i.e. TLOC due to cerebral hypoperfusion, is divided into reflex syncope (mostly vasovagal), orthostatic hypotension (mostly initial orthostatic hypotension in adolescents) and cardiac syncope (arrhythmias and structural cardiac disorders). The initial investigation comprises history taking, physical examination and ECG; the value of orthostatic blood pressure measurement is unproven in children but probably low. When this fails to yield a diagnosis, cardiac risk factors are assessed; important clues are supine syncope, syncope during exercise, early death in relatives and ECG abnormalities.Conclusions: In adults, the application of the ESC guidelines reduced the number of absent diagnoses and costs; we hope this also holds for children. Show less
Hoeven, A. van der; Beek, M.T. van der; Bekker, V.; Meijers, E.; Ivens, M.J.R.; Wessels, E.; ... ; Boers, S.A. 2023
IntroductionBacterial meningitis in infants is an infrequent but life-threatening condition. Empiric therapy should begin as soon as meningitis is thought likely. Consequently, the causative... Show moreIntroductionBacterial meningitis in infants is an infrequent but life-threatening condition. Empiric therapy should begin as soon as meningitis is thought likely. Consequently, the causative microorganisms may not always be detected using culturing techniques, as cerebrospinal fluid (CSF) cultures are influenced by antibiotics. Nucleic acid amplification tests, such as polymerase chain reaction (PCR) (multiplex panels), may overcome this limitation but require a priori knowledge of the likely pathogen present within the sample. With this in mind, we investigated to what extent a culture-free, broad-range 16S rRNA gene next-generation sequencing (NGS) platform (MYcrobiota) could add to the microbiological diagnosis of meningitis.MethodsRetrospective cohort study at level III neonatal intensive care unit. Included were all infants with suspected meningitis admitted between 10 November 2017 and 31 December 2020. A comparison was made of the bacterial pathogen detection rate between MYcrobiota and conventional bacterial culture.ResultsIn a 3-year period, 37 CSF samples (diagnostic and follow-up) from 35 infants with proven or possible meningitis were available for MYcrobiota testing. MYcrobiota detected the presence of bacterial pathogens in 11 samples (30%), in contrast with the conventional CSF culture, which detected bacteria in 2 of 36 samples (5.6%).ConclusionAddition of 16S rRNA sequencing to conventional culturing greatly improved the identification of the aetiology of bacterial meningitis compared to culturing of CSF samples alone. Show less
Ginkel, N. van; Gennep, E.J. van; Oosterbaan, L.; Greidanus, J.; Boellaard, T.N.; Wondergem, M.; ... ; Mertens, L.S. 2023
The value of 18F-fluorodeoxyglucose positron-emission-tomography-computed tomography (FDG-PET/CT) for staging patients with (very) high-risk non-muscle invasive bladder cancer (NMIBC) is unknown.... Show moreThe value of 18F-fluorodeoxyglucose positron-emission-tomography-computed tomography (FDG-PET/CT) for staging patients with (very) high-risk non-muscle invasive bladder cancer (NMIBC) is unknown. In this study among NMIBC patients referred for RC, FDG-PET/CT detected metastases that were not detected by CT, leading to treatment changes in 10% of patients. However, the use of FDG-PET/CT should be weighed against its disad-vantages, including false-positive lesions. Introduction and Objectives: 18F-fluorodeoxyglucose positron-emission tomography-computed tomography (FDG-PET/CT) is increasingly used in the preoperative staging of patients with muscle-invasive bladder cancer. The clinical added value of FDG-PET/CT in high-risk non-muscle invasive bladder cancer (NMIBC) is unknown. In this study, the value of FDG-PET/CT in addition to contrast enhanced (CE)-CT was evaluated in high-risk NMIBC before radical cystec-tomy (RC). Materials and Methods: This is a retrospective analysis of consecutive patients with high risk and very-high risk urothelial NMIBC scheduled for RC in a tertiary referral center between 2011 and 2020. Patients underwent staging with CE-CT (chest and abdomen/pelvis) and FDG-PET/CT. We assessed the clinical disease stage before and after FDG-PET/CT and the treatment recommendation based on the stage before and after FDG-PET/CT. The accuracy of CT and FDG-PET/CT for identifying metastatic disease was defined by the receiver-operating curve using a reference -standard including histopathology/cytology (if available), imaging and follow-up. Results: A total of 92 patients were identified (median age: 71 years). In 14/92 (15%) patients, FDG-PET/CT detected metastasis (12 suspicious lymph nodes and 4 distant metastases). The disease stage changed in 11/92 (12%) patients based on additional FDG-PET/CT findings. FDG-PET/CT led to a different treatment in 9/92 (10%) patients. According to the reference standard, 25/92 (27%) patients had metastases. The sensitivit y, specificit y and accuracy of FDG-PET/CT was 36%, 93% and 77% respectively, versus 12%, 97% and 74% of CE-CT only. The area under the ROC curve was 0.643 for FDG-PET/CT and 0.545 for CT, P = .036. Conclusion: The addition of FDG-PET/CT to CE-CT imaging changed the treatment in 10% of patients and proved to be a valuable diagnostic tool in a selected subgroup of NMIBC patients scheduled for RC. Show less
There are long-standing unsolved issues regarding the diagnosis and classification of central disorders of hypersomnolence. These include delineating and identifying phenotypes and unique... Show moreThere are long-standing unsolved issues regarding the diagnosis and classification of central disorders of hypersomnolence. These include delineating and identifying phenotypes and unique conditions (“sui generis”), sleep deprivation’s impact on phenotypes and how to separate sleep deprivation as a trigger from other causes, as well as the association of excessive sleepiness with other disorders. We discuss these issues and present a novel, straightforward classification system with consistent terminology to get out of the impasse and do justice to people with hypersomnolence. Show less
The focus of this thesis is the improvement of diagnosis, early detection and treatment of CD in children. Increased knowledge, available guidelines and reliable diagnostics allow for timely... Show moreThe focus of this thesis is the improvement of diagnosis, early detection and treatment of CD in children. Increased knowledge, available guidelines and reliable diagnostics allow for timely diagnosis which can prevent complications and improve QoL, but the current healthcare approach is often unable to make the diagnosis in a timely manner. Moreover, despite timely diagnosis and effective therapy, there is a need to improve the follow up. Show less
BackgroundOwing to the rarity and heterogeneity in biology and presentation, there are multiple areas in the diagnosis, treatment and follow-up of soft tissue sarcoma (STS), with no, low-level or... Show moreBackgroundOwing to the rarity and heterogeneity in biology and presentation, there are multiple areas in the diagnosis, treatment and follow-up of soft tissue sarcoma (STS), with no, low-level or conflicting evidence.MethodsDuring the first Consensus Conference on the State of Science in Sarcoma (CSSS), we used a modified Delphi process to identify areas of controversy in the field of sarcoma, to name topics with limited evidence-based data in which a scientific and knowledge gap may remain and a consensus statement will help to guide patient management. We determined scientific questions which need to be addressed in the future in order to generate evidence and to inform physicians and caregivers in daily clinical practice in order to improve the outcomes of patients with sarcoma.We conducted a vote on STS key questions and controversies prior to the CSSS meeting, which took place in May 2022.ResultsSixty-two European sarcoma experts participated in the survey.Sixteen strong consensus (≥95%) items were identified by the experts, as well as 30 items with a ≥75% consensus on diagnostic and therapeutic questions. Ultimately, many controversy topics remained without consensus.ConclusionsIn this manuscript, we summarise the voting results and the discussion during the CSSS meeting. Future scientific questions, priorities for clinical trials, registries, quality assurance, and action by stakeholders are proposed. Platforms and partnerships can support innovative approaches to improve management and clinical research in STS. Show less
Background: Awareness and compliance with international guidelines for diagnosis and clinical management of Clostridioides difficile infection (CDI) are unknown.Aim: To compare the awareness and... Show moreBackground: Awareness and compliance with international guidelines for diagnosis and clinical management of Clostridioides difficile infection (CDI) are unknown.Aim: To compare the awareness and compliance with the recommended strategies for diagnosis and clinical management of CDI across Europe in 2018-2019.Methods: Hospital sites and their associated community practices across 12 European countries completed an online survey in 2018-2019, to report on their practices in terms of surveillance, prevention, diagnosis, and treatment of CDI. Responses were collected from 105 hospitals and 39 community general practitioners (GPs).Findings: Hospital sites of 11 countries reported participation in national surveillance schemes compared with six countries for international schemes. The European Society of Clinical Microbiology and Infectious Diseases (ESCMID)-recommended CDI testing meth-odologies were used by 82% (86/105) of hospitals, however countries reporting the highest incidence of CDI used non-recommended tests. Over 75% (80/105) of hospitals were aware of the most recent European CDI treatment guidelines at the time of this survey compared with only 26% (10/39) of surveyed GPs. However, up to 15% (16/105) of hospitals reported using the non-recommended metronidazole for recurrent CDI cases, sites in countries with lower awareness of CDI treatment guidelines. Only 37% (39/105) of hospitals adopted contact isolation precautions in case of suspected CDI.Conclusion: Good awareness of guidelines for the management of CDI was observed across the surveyed European hospital sites. However, low compliance with diagnostic testing guidelines, infection control measures for suspected CDI, and insufficient awareness of treatment guidelines continued to be reported in some countries. 2022 The Author(s). Published by Elsevier Ltd on behalf of The Healthcare Infection Society. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
