Browsing by Author "Zavadska, Dace"
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Item A 5-transcript signature for discriminating viral and bacterial etiology in pediatric pneumonia(2025-02-21) Viz-Lasheras, Sandra; Gómez-Carballa, Alberto; Pardo-Seco, Jacobo; Zavadska, Dace; DIAMONDS; GENDRES; PERFORM consortia; Rīga Stradiņš UniversityPneumonia stands as the primary cause of death among children under five, yet current diagnosis methods often result in inadequate or unnecessary treatments. Our research seeks to address this gap by identifying host transcriptomic biomarkers in the blood of children with definitive viral and bacterial pneumonia. We performed RNA sequencing on 192 prospectively collected whole blood samples, including 38 controls and 154 pneumonia cases, uncovering a 5-transcript signature (genes FAM20A, BAG3, TDRD9, MXRA7, and KLF14) that effectively distinguishes bacterial from viral pneumonia (area under the curve (AUC): 0.95 [0.88–1.00]). Initial validation using combined definitive and probable cases yielded an AUC of 0.87 [0.77–0.97], while full validation in a new prospective cohort of 32 patients achieved an AUC of 0.92 [0.83–1.00]. This robust signature holds significant potential to enhance diagnostics accuracy for pediatric pneumonia, reducing diagnostic delays and unnecessary treatments and potentially transforming clinical practice.Item A grupas ß hemolītiskā streptokoka infekcija bērniem Latvijā. Promocijas darba kopsavilkums(Rīgas Stradiņa universitāte, 2010) Zavadska, Dace; Gardovska, DaceItem A grupas ß hemolītiskā streptokoka infekcija bērniem Latvijā. Promocijas darbs(Rīgas Stradiņa universitāte, 2010) Zavadska, Dace; Gardovska, DaceItem Adeno-associated virus 2 infection in children with non-A–E hepatitis(2023-05-18) Ho, Antonia; Orton, Richard; Tayler, Rachel; Thomson, Emma C.; DIAMONDS Consortium; ISARIC4C Investigators; Zavadska, Dace; Laivacuma, Sniedze; Rudzate, Aleksandra; Stoldere, Diāna; Barzdina, Arta; Barzdina, Elza; Madelane, Monta; Grāvele, Dagne; Rīga Stradiņš UniversityAn outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland 1 in April 2022 and has now been identified in 35 countries2. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case–control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4+ T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10−12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a ‘helper virus’ to support AAV2 replication) and disease susceptibility related to HLA class II status.Item Are children with prolonged fever at a higher risk for serious illness? : A prospective observational study(2023-04-25) Nijman, Ruud G; Tan, Chantal D; Hagedoorn, Nienke N; Nieboer, Daan; Balode, Anda; Zavadska, Dace; PERFORM consortium; Rīga Stradiņš UniversityObjectives: To describe the characteristics and clinical outcomes of children with fever ≥5 days presenting to emergency departments (EDs). Design: Prospective observational study. Setting: 12 European EDs. Patients: Consecutive febrile children <18 years between January 2017 and April 2018. Interventions: Children with fever ≥5 days and their risks for serious bacterial infection (SBI) were compared with children with fever <5 days, including diagnostic accuracy of non-specific symptoms, warning signs and C-reactive protein (CRP; mg/L). Main outcome measures: SBI and other non-infectious serious illness. Results: 3778/35 705 (10.6%) of febrile children had fever ≥5 days. Incidence of SBI in children with fever ≥5 days was higher than in those with fever <5 days (8.4% vs 5.7%). Triage urgency, life-saving interventions and intensive care admissions were similar for fever ≥5 days and <5 days. Several warning signs had good rule in value for SBI with specificities >0.90, but were observed infrequently (range: 0.4%-17%). Absence of warning signs was not sufficiently reliable to rule out SBI (sensitivity 0.92 (95% CI 0.87-0.95), negative likelihood ratio (LR) 0.34 (0.22-0.54)). CRP <20 mg/L was useful for ruling out SBI (negative LR 0.16 (0.11-0.24)). There were 66 cases (1.7%) of non-infectious serious illnesses, including 21 cases of Kawasaki disease (0.6%), 28 inflammatory conditions (0.7%) and 4 malignancies. Conclusion: Children with prolonged fever have a higher risk of SBI, warranting a careful clinical assessment and diagnostic workup. Warning signs of SBI occurred infrequently but, if present, increased the likelihood of SBI. Although rare, clinicians should consider important non-infectious causes of prolonged fever.Item Availability and use of rapid diagnostic tests for the management of acute childhood infections in Europe : A cross-sectional survey of paediatricians(2022-12) Dewez, Juan Emmanuel; Pembrey, Lucy; Nijman, Ruud G.; del Torso, Stefano; Grossman, Zachi; Hadjipanayis, Adamos; Van Esso, Diego; Lim, Emma; Emonts, Marieke; Burns, James; Gras-LeGuen, Christèle; Kohlfuerst, Daniela; Dornbusch, Hans Jürgen; Brengel-Pesce, Karen; Mallet, Francois; von Both, Ulrich; Tsolia, Maria; Eleftheriou, Irini; Zavadska, Dace; de Groot, Ronald; van der Flier, Michiel; Moll, Henriëtte; Hagedoorn, Nienke; Borensztajn, Dorine; Oostenbrink, Rianne; Kuijpers, Taco; Pokorn, Marko; Vincek, Katarina; Martinó n-Torres, Federico; Rivero, Irene; Agyeman, Philipp; Carrol, Enitan D.; Paulus, Stéphane; Cunnington, Aubrey; Herberg, Jethro; Levin, Michael; Mujkić, Aida; Geitmann, Karin; Da Dalt, Liviana; Valiulis, Arunas; Lapatto, Risto; Syridou, Garyfallia; Altorjai, Péter; Torpiano, Paul; Størdal, Ketil; Illy, Károly; Mazur, Artur; Spreitzer, Mateja Vintar; Rios, Joana; Wyder, Corinne; Romankevych, Ivanna; Basmaci, Romain; Ibanez-Mico, Salvador; Yeung, ShunmayBackground Point-of-care-tests (POCTs) have been advocated to optimise care in patients with infections but their actual use varies. This study aimed to estimate the variability in the adoption of current POCTs by paediatricians across Europe, and to explore the determinants of variability. Methods and findings A cross-sectional survey was conducted of hospital and primary care paediatricians, recruited through professional networks. Questions focused on the availability and use of currently available POCTs. Data were analysed descriptively and using Median Odds Ratio (MOR) to measure variation between countries. Multilevel regression modelling using changes in the area under the receiver operating characteristic curve of models were used to assess the contribution of individual or workplace versus country level factors, to the observed variation. The commonest POCT was urine dipsticks (UD) which were available to >80% of primary care and hospital paediatricians in 68% (13/19) and 79% (23/29) countries, respectively. Availability of all POCTs varied between countries. In primary care, the country (MOR) varied from 1.61 (95%CI: 1.04-2.58) for lactate to 7.28 (95%CI: 3.04-24.35) for UD. In hospitals, the country MOR varied from 1.37 (95%CI:1.04-1.80) for lactate to 11.93 (95% CI:3.35-72.23) for UD. Most paediatricians in primary care (69%, 795/1154) and hospital (81%, 962/1188) would use a diagnostic test in the case scenario of an infant with undifferentiated fever. Multilevel regression modelling showed that the country of work was more important in predicting both the availability and use of POCTs than individual or workplace characteristics. Conclusion There is substantial variability in the adoption of POCTs for the management of acute infections in children across Europe. To inform future implementation of both existing and innovative tests, further research is needed to understand what drives the variation between countries, the needs of frontline clinicians, and the role of diagnostic tests in the management of acute childhood infections.Item Biobanking and consenting to research : a qualitative thematic analysis of young people’s perspectives in the North East of England(2023-12) van der Velden, Fabian J.S.; Lim, Emma; Gills, Lily; DIAMONDS Consortium; Zavadska, Dace; Laivacuma, Sniedze; Rudzate, Aleksandra; Barzdina, Arta; Madelane, Monta; Stoldere, Diāna; Barzdina, Elza; Grāvele, Dagne; Rīga Stradiņš UniversityBackground: Biobanking biospecimens and consent are common practice in paediatric research. We need to explore children and young people’s (CYP) knowledge and perspectives around the use of and consent to biobanking. This will ensure meaningful informed consent can be obtained and improve current consent procedures. Methods: We designed a survey, in co-production with CYP, collecting demographic data, views on biobanking, and consent using three scenarios: 1) prospective consent, 2) deferred consent, and 3) reconsent and assent at age of capacity. The survey was disseminated via the Young Person’s Advisory Group North England (YPAGne) and participating CYP’s secondary schools. Data were analysed using a qualitative thematic approach by three independent reviewers (including CYP) to identify common themes. Data triangulation occurred independently by a fourth reviewer. Results: One hundred two CYP completed the survey. Most were between 16–18 years (63.7%, N = 65) and female (66.7%, N = 68). 72.3% had no prior knowledge of biobanking (N = 73). Acceptability of prospective consent for biobanking was high (91.2%, N = 93) with common themes: ‘altruism’, ‘potential benefits outweigh individual risk’, 'frugality', and ‘(in)convenience’. Deferred consent was also deemed acceptable in the large majority (84.3%, N = 86), with common themes: ‘altruism’, ‘body integrity’ and ‘sample frugality’. 76.5% preferred to reconsent when cognitively mature enough to give assent (N = 78), even if parental consent was previously in place. 79.2% wanted to be informed if their biobanked biospecimen is reused (N = 80). Conclusion: Prospective and deferred consent acceptability for biobanking is high among CYP in the UK. Altruism, frugality, body integrity, and privacy are the most important themes. Clear communication and justification are paramount to obtain consent. Any CYP with capacity should be part of the consenting procedure, if possible.Item Biomarkers for the Discrimination of Acute Kawasaki Disease From Infections in Childhood(2020-07-22) Zandstra, Judith; Zavadska, Dace; EUCLIDS Consortium, PERFORM Consortium and UK Kawasaki Disease Genetics Study Network; Department of PaediatricsBackground: Kawasaki disease (KD) is a vasculitis of early childhood mimicking several infectious diseases. Differentiation between KD and infectious diseases is essential as KD's most important complication—the development of coronary artery aneurysms (CAA)—can be largely avoided by timely treatment with intravenous immunoglobulins (IVIG). Currently, KD diagnosis is only based on clinical criteria. The aim of this study was to evaluate whether routine C-reactive protein (CRP) and additional inflammatory parameters myeloid-related protein 8/14 (MRP8/14 or S100A8/9) and human neutrophil-derived elastase (HNE) could distinguish KD from infectious diseases. Methods and Results: The cross-sectional study included KD patients and children with proven infections as well as febrile controls. Patients were recruited between July 2006 and December 2018 in Europe and USA. MRP8/14, CRP, and HNE were assessed for their discriminatory ability by multiple logistic regression analysis with backward selection and receiver operator characteristic (ROC) curves. In the discovery cohort, the combination of MRP8/14+CRP discriminated KD patients (n = 48) from patients with infection (n = 105), with area under the ROC curve (AUC) of 0.88. The HNE values did not improve discrimination. The first validation cohort confirmed the predictive value of MRP8/14+CRP to discriminate acute KD patients (n = 26) from those with infections (n = 150), with an AUC of 0.78. The second validation cohort of acute KD patients (n = 25) and febrile controls (n = 50) showed an AUC of 0.72, which improved to 0.84 when HNE was included. Conclusion: When used in combination, the plasma markers MRP8/14, CRP, and HNE may assist in the discrimination of KD from both proven and suspected infection.Item Burden of varicella in Central and Eastern Europe : findings from a systematic literature review(2019-03-04) Mészner, Zsófia; Wysocki, Jacek; Richter, Darko; Zavadska, Dace; Ivaskeviciene, Inga; Usonis, Vytautas; Pokorn, Marko; Mangarov, Atanas; Jancoriene, Ligita; Man, Sorin C.; Kristufkova, Zuzana; Jesenak, Milos; Tešović, Goran; Pluta, Justyna; Wolfson, Lara J.; Department of PaediatricsIntroduction: Vaccination against varicella rapidly reduces disease incidence, resulting in reductions in both individual burden and societal costs. Despite these benefits, there is no standardization of varicella immunization policies in Europe, including countries in Central and Eastern Europe (CEE). Areas covered: This systematic literature review identified publications on the epidemiology of varicella, its associated health and economic burden, and vaccination strategies within the CEE region, defined as Albania, Bosnia-Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Serbia, Slovakia, and Slovenia. Twenty-six studies were identified from a search of PubMed, Embase®, and MEDLINE® biomedical literature databases, supplemented by gray literature and country-specific/global websites. Expert commentary: Limited information exists in published studies on the burden of varicella in CEE. The wide variability in incidence rates between countries is likely explained by a lack of consistency in reporting systems. Funded universal varicella vaccination (UVV) in CEE is currently available only in Latvia as a one-dose schedule, but Hungary together with Latvia are introducing a two-dose strategy in 2019. For countries that do not provide UVV, introduction of vaccination is predicted to provide substantial reductions in cases and rates of associated complications, with important economic benefits.Item Characteristics and management of adolescents attending the ED with fever : A prospective multicentre study(2022-01-19) Borensztajn, Dorine; Hagedoorn, Nienke N.; Carrol, Enitan; Von Both, Ulrich; Dewez, Juan Emmanuel; Emonts, Marieke; Van Der Flier, Michiel; De Groot, Ronald; Herberg, Jethro; Kohlmaier, Benno; Levin, Michael; Lim, Emma; Maconochie, Ian; Martinon Torres, Federico; Nijman, Ruud; Pokorn, Marko; Rivero-Calle, Irene; Tsolia, Maria; Vermont, Clementien; Zavadska, Dace; Zenz, Werner; Zachariasse, Joany; Moll, Henriette A.; Department of PaediatricsObjective Most studies on febrile children have focused on infants and young children with serious bacterial infection (SBI). Although population studies have described an increased risk of sepsis in adolescents, little is known about febrile adolescents attending the emergency department (ED). We aimed to describe patient characteristics and management of febrile adolescents attending the ED. Design and setting The MOFICHE/PERFORM study (Management and Outcome of Febrile Children in Europe/Personalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union), a prospective multicentre study, took place at 12 European EDs. Descriptive and multivariable regression analyses were performed, comparing febrile adolescents (12-18 years) with younger children in terms of patient characteristics, markers of disease severity (vital signs, clinical alarming signs), management (diagnostic tests, therapy, admission) and diagnosis (focus, viral/bacterial infection). Results 37 420 encounters were included, of which 2577 (6.9%) were adolescents. Adolescents were more often triaged as highly urgent (38.9% vs 34.5%) and described as ill appearing (23.1% vs 15.6%) than younger children. Increased work of breathing and a non-blanching rash were present less often in adolescents, while neurological signs were present more often (1% vs 0%). C reactive protein tests were performed more frequently in adolescents and were more often abnormal (adjusted OR (aOR) 1.7, 95% CI 1.5 to 1.9). Adolescents were more often diagnosed with SBI (OR 1.8, 95% CI 1.6 to 2.0) and sepsis/meningitis (OR 2.3, 95% CI 1.1 to 5.0) and were more frequently admitted (aOR 1.3, 95% CI 1.2 to 1.4) and treated with intravenous antibiotics (aOR 1.7, 95% CI 1.5 to 2.0). Conclusions Although younger children presented to the ED more frequently, adolescents were more often diagnosed with SBI and sepsis/meningitis. Our data emphasise the importance of awareness of severe infections in adolescents.Item Clinical characteristics of patients with tick-borne encephalitis (Tbe) : A European multicentre study from 2010 to 2017(2021-07) Kohlmaier, Benno; Schweintzger, Nina A.; Sagmeister, Manfred G.; Švendová, Vendula; Kohlfürst, Daniela S.; Sonnleitner, Astrid; Leitner, Manuel; Berghold, Andrea; Schmiedberger, Erich; Fazekas, Franz; Pichler, Alexander; Rejc-Marko, Jana; Růžek, Daniel; Dufková, Lucie; Čejková, Darina; Husa, Petr; Pýchová, Martina; Krbková, Lenka; Chmelík, Václav; Štruncová, Věra; Zavadska, Dace; Karelis, Guntis; Mickiene, Aukse; Zajkowska, Joanna; Bogovič, Petra; Strle, Franc; Zenz, Werner; Department of Paediatrics; Rīga Stradiņš UniversityTick-borne encephalitis (TBE) virus is a major cause of central nervous system infections in endemic countries. Here, we present clinical and laboratory characteristics of a large international cohort of patients with confirmed TBE using a uniform clinical protocol. Patients were recruited in eight centers from six European countries between 2010 and 2017. A detailed description of clinical signs and symptoms was recorded. The obtained information enabled a reliable classification in 553 of 555 patients: 207 (37.3%) had meningitis, 273 (49.2%) meningoencephalitis, 15 (2.7%) meningomyelitis, and 58 (10.5%) meningoencephalomyelitis; 41 (7.4%) patients had a peripheral paresis of extremities, 13 (2.3%) a central paresis of extremities, and 25 (4.5%) had single or multiple cranial nerve palsies. Five (0.9%) patients died during acute illness. Outcome at discharge was recorded in 298 patients. Of 176 (59.1%) patients with incomplete recovery, 80 (27%) displayed persisting symptoms or signs without recovery expectation. This study provides further evidence that TBE is a severe disease with a large proportion of patients with incomplete recovery. We suggest monitoring TBE in endemic European countries using a uniform protocol to record the full clinical spectrum of the disease.Item Comparative epidemiologic characteristics of pertussis in 10 Central and Eastern European countries, 2000-2013(2016-06-01) Heininger, Ulrich; André, Philippe; Chlibek, Roman; Kristufkova, Zuzana; Kutsar, Kuulo; Mangarov, Atanas; Mészner, Zsófia; Nitsch-Osuch, Aneta; Petrović, Vladimir; Prymula, Roman; Usonis, Vytautas; Zavadska, Dace; Department of PaediatricsWe undertook an epidemiological survey of the annual incidence of pertussis reported from 2000 to 2013 in ten Central and Eastern European countries to ascertain whether increased pertussis reports in some countries share common underlying drivers or whether there are specific features in each country. The annual incidence of pertussis in the participating countries was obtained from relevant government institutions and/or national surveillance systems. We reviewed the changes in the pertussis incidence rates in each country to explore differences and/or similarities between countries in relation to pertussis surveillance; case definitions for detection and confirmation of pertussis; incidence and number of cases of pertussis by year, overall and by age group; population by year, overall and by age group; pertussis immunization schedule and coverage, and switch from whole-cell pertussis vaccines (wP) to acellular pertussis vaccines (aP). There was heterogeneity in the reported annual incidence rates and trends observed across countries. Reported pertussis incidence rates varied considerably, ranging from 0.01 to 96 per 100,000 population, with the highest rates generally reported in Estonia and the lowest in Hungary and Serbia. The greatest burden appears for the most part in infants (<1 year) in Bulgaria, Hungary, Latvia, Romania, and Serbia, but not in the other participating countries where the burden may have shifted to older children, though surveillance of adults may be inappropriate. There was no consistent pattern associated with the switch from wP to aP vaccines on reported pertussis incidence rates. The heterogeneity in reported data may be related to a number of factors including surveillance system characteristics or capabilities, different case definitions, type of pertussis confirmation tests used, public awareness of the disease, as well as real differences in the magnitude of the disease, or a combination of these factors. Our study highlights the need to standardize pertussis detection and confirmation in surveillance programs across Europe, complemented with carefully-designed seroprevalence studies using the same protocols and methodologies.Item Comparison of Tick-borne Encephalitis (TBE) clinical disease in children and adults – population-based study in Latvia, 2018-2020(2023-10-22) Freimane, Zane; Karelis, Guntis; Harper, Lisa; Bender, Cody; Zhang, Pingping; Angulo, Frederick; Erber, Wilhelm; Bormane, Antra; Griškevica, Aija; Pilz, Andreas; Madhava, Harish; Zavadska, Dace; Department of Paediatrics; Department of Neurology and NeurosurgeryItem Development and validation of a prediction model for invasive bacterial infections in febrile children at European Emergency Departments : MOFICHE, a prospective observational study(2021-07-01) Hagedoorn, Nienke N.; Borensztajn, Dorine; Nijman, Ruud Gerard; Nieboer, Daan; Herberg, Jethro Adam; Balode, Anda; Von Both, Ulrich; Carrol, Enitan; Eleftheriou, Irini; Emonts, Marieke; Van Der Flier, Michiel; De Groot, Ronald; Kohlmaier, Benno; Lim, Emma; MacOnochie, Ian; Martinón-Torres, Federico; Pokorn, Marko; Strle, Franc; Tsolia, Maria; Zavadska, Dace; Zenz, Werner; Levin, Michael; Vermont, Clementien; Moll, Henriette A.; Rīga Stradiņš UniversityObjectives: To develop and cross-validate a multivariable clinical prediction model to identify invasive bacterial infections (IBI) and to identify patient groups who might benefit from new biomarkers. Design: Prospective observational study. Setting: 12 emergency departments (EDs) in 8 European countries. Patients: Febrile children aged 0-18 years. Main outcome measures: IBI, defined as bacteraemia, meningitis and bone/joint infection. We derived and cross-validated a model for IBI using variables from the Feverkidstool (clinical symptoms, C reactive protein), neurological signs, non-blanching rash and comorbidity. We assessed discrimination (area under the receiver operating curve) and diagnostic performance at different risk thresholds for IBI: sensitivity, specificity, negative and positive likelihood ratios (LRs). Results: Of 16 268 patients, 135 (0.8%) had an IBI. The discriminative ability of the model was 0.84 (95% CI 0.81 to 0.88) and 0.78 (95% CI 0.74 to 0.82) in pooled cross-validations. The model performed well for the rule-out threshold of 0.1% (sensitivity 0.97 (95% CI 0.93 to 0.99), negative LR 0.1 (95% CI 0.0 to 0.2) and for the rule-in threshold of 2.0% (specificity 0.94 (95% CI 0.94 to 0.95), positive LR 8.4 (95% CI 6.9 to 10.0)). The intermediate thresholds of 0.1%-2.0% performed poorly (ranges: sensitivity 0.59-0.93, negative LR 0.14-0.57, specificity 0.52-0.88, positive LR 1.9-4.8) and comprised 9784 patients (60%). Conclusions: The rule-out threshold of this model has potential to reduce antibiotic treatment while the rule-in threshold could be used to target treatment in febrile children at the ED. In more than half of patients at intermediate risk, sensitive biomarkers could improve identification of IBI and potentially reduce unnecessary antibiotic prescriptions.Item Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature(2023-06-01) Jackson, Heather R.; Miglietta, Luca; Habgood-Coote, Dominic; D'souza, Giselle; Zavadska, Dace; Levin, Michael; PERFORM consortiumBackground: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections. Methods: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39). Results: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV. Conclusions: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C.Item A diagnostic host-specific transcriptome response for Mycoplasma pneumoniae pneumonia to guide pediatric patient treatment(2025-12) Viz-Lasheras, Sandra; Gómez-Carballa, Alberto; Bello, Xabier; Rivero-Calle, Irene; Dacosta, Ana Isabel; Kaforou, Myrsini; Zavadska, Dace; EUCLIDS, PERFORM, and DIAMONDS consortia; Rīga Stradiņš UniversityMycoplasma pneumoniae causes atypical pneumonia in children and young adults. Its lack of a cell wall makes it resistant to beta-lactams, which are the first-line treatment for typical pneumonia. Current diagnostic tests are time-consuming and have low specificity, leading clinicians to administer empirical antibiotics. Using a LASSO regression simulation approach and blood microarray data from 107 children with pneumonia (including 30 M. pneumoniae) we identify eight different transcriptomic signatures, ranging from 3-10 transcripts, that differentiate mycoplasma pneumonia from other bacterial/viral pneumonias with high accuracy (AUC: 0.84-0.95). Additionally, we demonstrate that existing signatures for broadly distinguishing viral/bacterial infections and viral/bacterial pneumonias are ineffective in distinguishing M. pneumoniae from viral pneumonia. The new signatures are successfully validated in an independent RNAseq cohort of children with pneumonia, demonstrating their robustness. The high sensibility of these signatures presents a valuable opportunity to guide the treatment and management of M. pneumoniae pneumonia patients.Item Diagnostic Value of Clinical Presentation, Parental Concern, and Clinician’s Non-Analytical Reasoning in Identifying Serious Bacterial Infections in Febrile Children. Doctoral Thesis(Rīga Stradiņš University, 2022) Urbāne, Urzula Nora; Pavāre, Jana; Zavadska, DaceFever is one of the main reasons for visits to paediatric emergency departments (ED). Although in most cases the underlying cause is self-limiting viral infections, 4 to 25 % of children visiting ED with fever develop serious bacterial infections (SBI), which are significant causes of childhood mortality, even in developed countries. Due to high number of patients visiting ED with febrile illness, rapid discrimination between children with and without possible SBI is challenging.This study aimed to improve early recognition of SBI in children who present to ED by assessing the diagnostic value of clinical signs at presentation, clinician’s non-analytical reasoning, defined as “gut feeling” of serious illness and “sense of reassurance”, and parental concern of different / more severe illness. Based on these variables, derivation and external validation of two clinical prediction models (CPMs) for SBI was performed, and the performance of a CPM based on clinical variables alone was compared to a model integrating clinical features together with variables of non-analytical reasoning. The models were derived from a dataset of 517 febrile patients presenting to the ED of Children’s Clinical University Hospital (CCUH) in Riga, and externally validated in a dataset of 188 patients prospectively enrolled in six regional hospitals in Latvia.While the prognostic value of clinician’s “gut feeling” as an independent variable for diagnosing SBI was limited, “sense of reassurance” was significantly predictive of absence of SBI, and the performance of the CPM 2 integrating the non-analytical variables with clinical features was superior in both derivation (Receiver Operating Characteristic curve (ROC) Area Under Curve (AUC) 0.783, 95 % confidence interval (CI) 0.727–0.839) and validation cohorts (ROC AUC 0.752, 95 % CI 0.674–0.830), when compared to the performance of the CPM 1, which was based solely on clinical variables (ROC AUC in derivation population 0.738, 95 % CI 0.688–0.788, in validation population 0.677, 95 % CI 0.586–0.767). Both CPMs had moderate ability to predict SBI in febrile children presenting to ED and acceptable performance in the validation cohort. A scoring system based on the superior prediction model was created to distinguish between patients with high or low risk of SBI, as well as to identify patients in diagnostic “grey area”, in which the severity of manifestations of SBI and mild infections overlapped. Contrary to studies in primary care performed in other European countries, parental concern was not significantly predictive of SBI. Elements of fever-related anxiety were identified as factors influencig the level of parental concern and urging parents to present to healthcare early. A qualitative interview study including 34 parents of patients enrolled in derivation cohort revealed existing misconceptions regarding the possible negative effects of fever, which often were a result of unfulfilled educational and emotional needs when caring for a febrile child. This study suggests that educational intervention is necessary to reduce “fever phobia” in parents and to improve the diagnostic reliability of parental concern.Item Diagnostic Value of Clinical Presentation, Parental Concern, and Clinician’s Non-Analytical Reasoning in Identifying Serious Bacterial Infections in Febrile Children. Summary of the Doctoral Thesis(Rīga Stradiņš University, 2022) Urbāne, Urzula Nora; Pavāre, Jana; Zavadska, DaceFever is one of the main reasons for visits to paediatric emergency departments (ED). Although in most cases the underlying cause is self-limiting viral infections, 4 to 25 % of children visiting ED with fever develop serious bacterial infections (SBI), which are significant causes of childhood mortality, even in developed countries. Due to high number of patients visiting ED with febrile illness, rapid discrimination between children with and without possible SBI is challenging.This study aimed to improve early recognition of SBI in children who present to ED by assessing the diagnostic value of clinical signs at presentation, clinician’s non-analytical reasoning, defined as “gut feeling” of serious illness and “sense of reassurance”, and parental concern of different / more severe illness. Based on these variables, derivation and external validation of two clinical prediction models (CPMs) for SBI was performed, and the performance of a CPM based on clinical variables alone was compared to a model integrating clinical features together with variables of non-analytical reasoning. The models were derived from a dataset of 517 febrile patients presenting to the ED of Children’s Clinical University Hospital (CCUH) in Riga, and externally validated in a dataset of 188 patients prospectively enrolled in six regional hospitals in Latvia.While the prognostic value of clinician’s “gut feeling” as an independent variable for diagnosing SBI was limited, “sense of reassurance” was significantly predictive of absence of SBI, and the performance of the CPM 2 integrating the non-analytical variables with clinical features was superior in both derivation (Receiver Operating Characteristic curve (ROC) Area Under Curve (AUC) 0.783, 95 % confidence interval (CI) 0.727–0.839) and validation cohorts (ROC AUC 0.752, 95 % CI 0.674–0.830), when compared to the performance of the CPM 1, which was based solely on clinical variables (ROC AUC in derivation population 0.738, 95 % CI 0.688–0.788, in validation population 0.677, 95 % CI 0.586–0.767). Both CPMs had moderate ability to predict SBI in febrile children presenting to ED and acceptable performance in the validation cohort. A scoring system based on the superior prediction model was created to distinguish between patients with high or low risk of SBI, as well as to identify patients in diagnostic “grey area”, in which the severity of manifestations of SBI and mild infections overlapped. Contrary to studies in primary care performed in other European countries, parental concern was not significantly predictive of SBI. Elements of fever-related anxiety were identified as factors influencig the level of parental concern and urging parents to present to healthcare early. A qualitative interview study including 34 parents of patients enrolled in derivation cohort revealed existing misconceptions regarding the possible negative effects of fever, which often were a result of unfulfilled educational and emotional needs when caring for a febrile child. This study suggests that educational intervention is necessary to reduce “fever phobia” in parents and to improve the diagnostic reliability of parental concern.Item Divergent approaches in the vaccination of recently arrived migrants to europe : A survey of national experts from 32 Countries, 2017(2018-10-11) ESGITM Working Group on Vaccination in Migrants; Zavadska, Dace; Rīga Stradiņš UniversityBackground: Migrants within the European Union and European Economic Area (EU/EEA) may be underim-munised and lack documentation on previous vaccinations. We investigated approaches to vaccination in recently arrived adult and child migrants, and guideline availability and implementation. Methods: Between March and May 2017, a national vaccination expert from every EU/EEA country and Switzerland completed an electronic questionnaire. We used descriptive analyses to calculate percentages, and framework analysis to synthesise free-text responses. Results: We approached 32 countries (response rate 100%). Although 28 experts reported vaccination guidance at national level, specific guidelines for recently arrived migrants were only available in six countries and not consistently implemented. Twenty-three countries administered vaccinations during on-arrival health checks. Most experts recommended multiple vaccination opportunities be made available: at point of entry (n = 13) or at holding level (reception centres, migrant camps, detention centres) (n = 21). In 30 countries, child migrants without evidence of previous vaccination were re-vaccinated according to the national schedule. Diphtheria-pertussis-tetanus and polio vaccinations were given to migrant children in all countries, measles-mumps-rubella (MMR) in 31 countries, hepatitis B vaccination in 25. Low levels of catch-up vaccination were reported in adult migrants, with only 13 countries offering MMR and 10 countries charging fees. Conclusion: Existing guidance is often not migrant-specific and may not be applied in practice; clarification is needed on which vaccines should be given. Strategies are needed specifically for catch-up vaccination in adult migrants. Vaccinations should be offered in multiple settings, free of charge, with sufficient guidance and training provided to front-line healthcare professionals.Item Diversity in the emergency care for febrile children in Europe : A questionnaire study(2019-06-01) Borensztajn, Dorine; Yeung, Shunmay; Hagedoorn, Nienke N.; Balode, Anda; Von Both, Ulrich; Carrol, Enitan D.; Dewez, Juan Emmanuel; Eleftheriou, Irini; Emonts, Marieke; Van Der Flier, Michiel; De Groot, Ronald; Herberg, Jethro Adam; Kohlmaier, Benno; Lim, Emma; MacOnochie, Ian; Martinón-Torres, Federico; Nijman, Ruud; Pokorn, Marko; Strle, Franc; Tsolia, Maria; Wendelin, Gerald; Zavadska, Dace; Zenz, Werner; Levin, Michael; Moll, Henriette A.; Department of PaediatricsObjective To provide an overview of care in emergency departments (EDs) across Europe in order to interpret observational data and implement interventions regarding the management of febrile children. Design and setting An electronic questionnaire was sent to the principal investigators of an ongoing study (PERFORM (Personalised Risk assessment in Febrile illness to Optimise Real-life Management), www.perform2020.eu) in 11 European hospitals in eight countries: Austria, Germany, Greece, Latvia, the Netherlands, Slovenia, Spain and the UK. Outcome measures The questionnaire covered indicators in three domains: local ED quality (supervision, guideline availability, paper vs electronic health records), organisation of healthcare (primary care, immunisation), and local factors influencing or reflecting resource use (availability of point-of-care tests, admission rates). Results Reported admission rates ranged from 4% to 51%. In six settings (Athens, Graz, Ljubljana, Riga, Rotterdam, Santiago de Compostela), the supervising ED physicians were general paediatricians, in two (Liverpool, London) these were paediatric emergency physicians, in two (Nijmegen, Newcastle) supervision could take place by either a general paediatrician or a general emergency physician, and in one (München) this could be either a general paediatrician or a paediatric emergency physician. The supervising physician was present on site in all settings during office hours and in five out of eleven settings during out-of-office hours. Guidelines for fever and sepsis were available in all settings; however, the type of guideline that was used differed. Primary care was available in all settings during office hours and in eight during out-of-office hours. There were differences in routine immunisations as well as in additional immunisations that were offered; immunisation rates varied between and within countries. Conclusion Differences in local, regional and national aspects of care exist in the management of febrile children across Europe. This variability has to be considered when trying to interpret differences in the use of diagnostic tools, antibiotics and admission rates. Any future implementation of interventions or diagnostic tests will need to be aware of this European diversity.