Core outcome measurement set for research and clinical practice in post-COVID-19 condition (long COVID) in children and young people: an international Delphi consensus study "PC-COS Children".

The coronavirus disease 2019 (COVID-19) pandemic substantially impacted different age groups, with children and young people not exempted. Many have experienced enduring health consequences. Presently, there is no consensus on the health outcomes to assess in children and young people with post-COVID-19 condition. Furthermore, it is unclear which measurement instruments are appropriate for use in research and clinical management of children and young people with post-COVID-19. To address these unmet needs, we conducted a consensus study, aiming to develop a core outcome set (COS) and an associated core outcome measurement set (COMS) for evaluating post-COVID-19 condition in children and young people. Our methodology comprised of two phases. In phase 1 (to create a COS), we performed an extensive literature review and categorisation of outcomes, and prioritised those outcomes in a two-round online modified Delphi process followed by a consensus meeting. In phase 2 (to create the COMS), we performed another modified Delphi consensus process to evaluate measurement instruments for previously defined core outcomes from phase 1, followed by an online consensus workshop to finalise recommendations regarding the most appropriate instruments for each core outcome. In phase 1, 214 participants from 37 countries participated, with 154 (72%) contributing to both Delphi rounds. The subsequent online consensus meeting resulted in a final COS which encompassed seven critical outcomes: fatigue; post-exertion symptoms; work/occupational and study changes; as well as functional changes, symptoms, and conditions relating to cardiovascular, neuro-cognitive, gastrointestinal and physical outcomes. In phase 2, 11 international experts were involved in a modified Delphi process, selecting measurement instruments for a subsequent online consensus workshop where 30 voting participants discussed and independently scored the selected instruments. As a result of this consensus process, four instruments met a priori consensus criteria for inclusion: PedsQL multidimensional fatigue scale for "fatigue"; PedsQL gastrointestinal symptom scales for "gastrointestinal"; PedsQL cognitive functioning scale for "neurocognitive" and EQ-5D for "physical functioning". Despite proposing outcome measurement instruments for the remaining three core outcomes ("cardiovascular", "post-exertional malaise", "work/occupational and study changes"), a consensus was not achieved. Our international, consensus-based initiative presents a robust framework for evaluating post-COVID-19 condition in children and young people in research and clinical practice via a rigorously defined COS and associated COMS. It will aid in the uniform measurement and reporting of relevant health outcomes worldwide.

International Care programs for Pediatric Post-COVID Condition (Long COVID) and the way forward.

BACKGROUND: Pediatric Post-COVID-Condition (PPCC) clinics treat children despite limited scientific substantiation. By exploring real-life management of children diagnosed with PPCC, the International Post-COVID-Condition in Children Collaboration (IP4C) aimed to provide guidance for future PPCC care. METHODS: We performed a cross-sectional international, multicenter study on used PPCC definitions; the organization of PPCC care programs and patients characteristics. We compared aggregated data from PPCC cohorts and identified priorities to improve PPCC care. RESULTS: Ten PPCC care programs and six COVID-19 follow-up research cohorts participated. Aggregated data from 584 PPCC patients was analyzed. The most common symptoms included fatigue (71%), headache (55%), concentration difficulties (53%), and brain fog (48%). Severe limitations in daily life were reported in 31% of patients. Most PPCC care programs organized in-person visits with multidisciplinary teams. Diagnostic testing for respiratory and cardiac morbidity was most frequently performed and seldom abnormal. Treatment was often limited to physical therapy and psychological support. CONCLUSIONS: We found substantial heterogeneity in both the diagnostics and management of PPCC, possibly explained by scarce scientific evidence and lack of standardized care. We present a list of components which future guidelines should address, and outline priorities concerning PPCC care pathways, research and international collaboration. IMPACT: Pediatric Post-COVID Condition (PPCC) Care programs have been initiated in many countries. Children with PPCC in different countries are affected by similar symptoms, limiting many to participate in daily life. There is substantial heterogeneity in diagnostic testing. Access to specific diagnostic tests is required to identify some long-term COVID-19 sequelae. Treatments provided were limited to physical therapy and psychological support. This study emphasizes the need for evidence-based diagnostics and treatment of PPCC. The International Post-COVID Collaboration for Children (IP4C) provides guidance for guideline development and introduces a framework of priorities for PPCC care and research, to improve PPCC outcomes.

Nationwide Outbreak of Candida auris Infections Driven by COVID-19 Hospitalizations, Israel, 2021-2022

We report an outbreak of Candida auris across multiple healthcare facilities in Israel. For the period of May 2014-May 2022, a total of 209 patients with C. auris infection or colonization were identified. The C. auris incidence rate increased 30-fold in 2021 (p = 0.00015), corresponding in time with surges of COVID-19-related hospitalization. Multilocus sequence typing revealed hospital-level outbreaks with distinct clones. A clade III clone, imported into Israel in 2016, accounted for 48.8% of typed isolates after January 2021 and was more frequently resistant to fluconazole (100% vs. 63%; p = 0.00017) and voriconazole (74% vs. 5.2%; p<0.0001) than were non-clade III isolates. A total of 23% of patients had COVID-19, and 78% received mechanical ventilation. At the hospital level, outbreaks initially involved mechanically ventilated patients in specialized COVID-19 units and then spread sequentially to ventilated non-COVID-19 patients and nonventilated patients.

Effectiveness of BNT162b2 Vaccination During Pregnancy in Preventing Hospitalization for Severe Acute Respiratory Syndrome Coronavirus 2 in Infants.

OBJECTIVE: To assess the clinical effectiveness of the BNT162b2 vaccine during pregnancy in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hospitalizations of infants. STUDY DESIGN: A retrospective, multicenter, 1:3 case-control (test-negative) study. Symptomatic hospitalized infants less than 6 months of age, with a positive SARS-CoV-2 polymerase chain reaction test between January 3, 2021, and March 11, 2021, were matched by age and time to negative controls, hospitalized with symptoms compatible with SARS-CoV-2 infection. Mothers were defined as fully vaccinated who received 2 doses of BNT162b2 with the second given 2 weeks to 6 months before delivery; or partially vaccinated, if they received only 1 dose or 2 doses with the second given more than 6 months or less than 2 weeks before delivery. Severe SARS-CoV-2 was defined as a need for assisted ventilation. RESULTS: We matched 116 SARS-CoV-2 positive infants with 348 negative controls with symptoms compatible with SARS-CoV-2 infection. The effectiveness of fully vaccinated mothers was 61.6% (95% CI, 31.9-78.4) and the effectiveness of partially vaccinated mothers was not significant. Effectiveness was higher in infants 0-2 vs 3-6 months of age. The effectiveness (57.1%; 95% CI, 22.8-76.4) was similar when excluding mothers who were infected with SARS-CoV-2 during pregnancy. The OR of severe infection in infants born to unvaccinated vs fully vaccinated mothers was 5.8. CONCLUSIONS: At least 2 doses of BNT162b2 vaccine administered during the second or third trimester of pregnancy had an effectiveness of 61.6% in decreasing hospitalization for SARS-CoV-2 infection in infants less than 6 months of age.

Mental health among children with long COVID during the COVID-19 pandemic.

A growing number of studies report that persons of all ages, infected with SARS-CoV-2, may experience long-term persistent symptoms, known as long COVID (LC) or post COVID-19 condition. This is one of the first studies examining the consequences of LC on children's mental health. In this case-control study, we compared select mental health aspects of 103 children diagnosed with LC to a control group of 113 children uninfected with SARS-COV-2; all 4-18 years old. Both groups were assessed via parents' questionnaires. In comparison to the control group, children with LC exhibited more memory difficulties. However, no group differences emerged in other functional aspects (connection with friends and engagement in physical activities), problems with concentration, or levels of emotional-behavioral problems (externalizing, internalizing, ADHD, and PTSD symptoms). We also found that children with LC had greater exposure to COVID-19-related stressors. Higher levels of parental worries regarding their children's functioning and economic difficulties at home significantly predicted higher levels of children's emotional-behavioral problems and were better predictors than the child's age, social functioning, or LC diagnosis.    Conclusion: LC was associated with impairments in some aspects of children's memory which may relate to academic functioning, but not with higher rates of emotional-behavioral problems, thus warranting interventional programs addressing school functioning and cognitive abilities in this population. Additionally, parents' economic stress and worries regarding their child's emotional adjustment during the pandemic, are important factors affecting pandemic-related emotional-behavioral problems among children, regardless of COVID-19 infection, that should be addressed. What is Known: • Children may have long COVID (LC) after being infected with SARS-COV-2. What is New: • LC may be associated to impairments in some aspects of children's memory, as reported by parents. • Parents' economic stress and worries concerning their children's emotional adjustment during the pandemic are associated with more distress in their children.

Characteristics of pediatric recurrent acute mastoiditis: A case-control study.

BACKGROUND: Data on pediatric recurrent acute mastoiditis are lacking, despite its morbidity and clinical significance. Our aim was to describe the incidence, characteristics, and associated factors of recurrent mastoiditis in hospitalized children. METHODS: Using a case-control design, analyzing electronic data of hospitalized children with acute mastoiditis between June 2011 and December 2018, children with recurrent mastoiditis were compared to children with a single episode at the time of hospitalization. Recurrent episodes of mastoiditis were compared to the first episodes. Recurrent acute mastoiditis was defined as recurring mastoiditis ≥4-weeks after a completely resolved event. RESULTS: Of 347 children hospitalized with acute mastoiditis, 22 (6.3%) had recurrent mastoiditis; the median interval between episodes was 3 months (range: 1-36). The mean ± SD age was 2.3 ± 2.25 years. A comparison of first episodes in recurring cases to single episodes by univariate and multivariate analysis, showed no differences in the pre-admission management or in the isolated pathogens; however, a history of atopic dermatitis and percutaneous abscess drainage were more frequent in first episodes of recurring cases (27.3% vs. 1.2%, p < 0.001, and 27.3% vs. 10.0%, p = 0.026, respectively). The second episode of acute mastoiditis was characterized by a milder clinical course and shorter durations from symptoms to hospitalization, intravenous antibiotic therapy, and length of hospital stay. Linear regression showed that an increased interval from symptoms to hospitalization significantly increased length of hospital stay (regression coefficient of 0.215 [95% CI: 0.114-0.317], p < 0.001). CONCLUSIONS: Recurrent episodes of mastoiditis were clinically milder, with shorter length of hospital stay compared to first episodes, possibly because of early admission.

Skull Base Osteomyelitis in Children: Clinical Characteristics and Potential Implications.

OBJECTIVES: We describe 10 new cases of otogenic (n = 8) and nonotogenic (n = 2) skull base osteomyelitis (SBO) in previously healthy children and review the literature on SBO in the pediatric population. METHODS: We retrospectively analyzed the medical records of 10 children (age range 0.9-12.8 years) discharged with a diagnosis of SBO between 2015 and 2020 in 2 children's hospitals in central Israel. RESULTS: Five patients presented with fever and 5 with otological signs and symptoms. All 10 children underwent a comprehensive clinical evaluation, imaging studies (computerized tomography or magnetic resonance imaging) and laboratory investigations. The physical examination revealed neurologic findings, including nuchal rigidity, papilledema, and apathy, in 4 patients. All 8 otogenic patients underwent surgical intervention and the 2 nonotogenic patients, who were diagnosed as having deep neck and throat infections, responded well to treatment consisting of antibiotics without surgery. CONCLUSIONS: Early diagnosis of pediatric SBO can be challenging because the symptoms are often nonspecific. The final diagnosis relies mainly on imaging, preferably magnetic resonance imaging. Surgical intervention is usually mandatory in the otogenic patients, whereas the nonotogenic patients respond well to medical management alone.

Clinical Features and Comparison of Kingella and Non-Kingella Endocarditis in Children, Israel.

Kingella spp. have emerged as an important cause of invasive pediatric diseases. Data on Kingella infective endocarditis (KIE) in children are scarce. We compared the clinical features of pediatric KIE cases with those of Streptococcus species IE (StIE) and Staphylococcus aureus IE (SaIE). A total of 60 patients were included in the study. Throughout the study period, a rise in incidence of KIE was noted. KIE patients were significantly younger than those with StIE and SaIE, were predominately boys, and had higher temperature at admission, history of oral aphthae before IE diagnosis, and higher lymphocyte count (p<0.05). Pediatric KIE exhibits unique features compared with StIE and SaIE. Therefore, in young healthy children <36 months of age, especially boys, with or without a congenital heart defect, with a recent history of oral aphthae, and experiencing signs and symptoms compatible with endocarditis, Kingella should be suspected as the causative pathogen.

Factors predicting efficacy of ethanol lock therapy as catheter salvage strategy for pediatric catheter-related infections.

AIM: Catheter-related infections are difficult to cure, and failure rates are high. We aimed to evaluate the efficacy and safety of ethanol lock therapy (ELT) as catheter salvage strategy in children with central-line-associated bloodstream infection (CLABSI), and to identify factors associated with treatment failure. METHODS: Data were collected of all the children who received ELT for treatment of CLABSI during 2013-2018 due to failure of standard therapy or multiple catheter-related infections. Univariate and multivariate analyses of risk-factors for ELT failure were performed. Catheter salvage rates were compared to those achieved using systemic antimicrobials alone in an historical control group. RESULTS: A total of 123 ELT episodes among 95 patients were analyzed. The majority of patients had underlying hemato-oncological disorders. Approximately half the episodes occurred in patients with implantable ports. Early and late treatment failure rates of ELT were 16% (20/123) and 7% (9/123), respectively. Overall, successful catheter salvage was achieved in 78% (96/123) of episodes, compared to 54% using systemic antimicrobials alone (P < .001), including mycobacterium, candida, and most staphylococcus aureus infections. Adverse events were reported in 9% (11/123) of episodes and were mostly mechanical. Multivariate analysis identified four risk factors for ELT failure: Gram-positive bacteria, elevated C-reactive protein, signs of tunnel infection, and low absolute neutrophil counts. CONCLUSIONS: Our findings support the use of ELT for catheter salvage in children with CLABSI who failed standard therapy or had multiple catheter-related infections. The identified variables associated with ELT failure may help identify patients who can most benefit from ELT.

[THE ROLE OF BONE SCINTIGRAPHY IN THE DIAGNOSIS OF CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS IN CHILDREN].

INTRODUCTION: This case report presents a teenage girl hospitalized due to fever, left wrist pain and elevated inflammatory markers. These clinical findings, as well as a lytic lesion seen on plain radiographs and MRI in the distal left radius, led to the working diagnosis of acute osteomyelitis. Following 4 weeks of antibiotic therapy, a bone scan was conducted due to inadequate clinical response. It showed additional skeletal lesions and led to the final diagnosis of chronic recurrent multifocal osteomyelitis (CRMO). Treatment was changed to anti-inflammatory medications with a good response. This article presents key features of CRMO and emphasizes the role of skeletal scintigraphy in establishing the diagnosis.

A host-protein signature is superior to other biomarkers for differentiating between bacterial and viral disease in patients with respiratory infection and fever without source: a prospective observational study.

Bacterial and viral infections often present with similar symptoms. Etiologic misdiagnosis can alter the trajectory of patient care, including antibiotic overuse. A host-protein signature comprising tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma-induced protein-10 (IP-10), and C-reactive protein (CRP) was validated recently for differentiating bacterial from viral disease. However, a focused head-to-head comparison of its diagnostic performance against other biomarker candidates for this indication was lacking in patients with respiratory infection and fever without source. We compared the signature to other biomarkers and prediction rules using specimens collected prospectively at two secondary medical centers from children and adults. Inclusion criteria included fever > 37.5 °C, symptom duration ≤ 12 days, and presentation with respiratory infection or fever without source. Comparator method was based on expert panel adjudication. Signature and biomarker cutoffs and prediction rules were predefined. Of 493 potentially eligible patients, 314 were assigned unanimous expert panel diagnosis and also had sufficient specimen volume. The resulting cohort comprised 175 (56%) viral and 139 (44%) bacterial infections. Signature sensitivity 93.5% (95% CI 89.1-97.9%), specificity 94.3% (95% CI 90.7-98.0%), or both were significantly higher (all p values < 0.01) than for CRP, procalcitonin, interleukin-6, human neutrophil lipocalin, white blood cell count, absolute neutrophil count, and prediction rules. Signature identified as viral 50/57 viral patients prescribed antibiotics, suggesting potential to reduce antibiotic overuse by 88%. The host-protein signature demonstrated superior diagnostic performance in differentiating viral from bacterial respiratory infections and fever without source. Future utility studies are warranted to validate potential to reduce antibiotic overuse.

Risk factors for early invasive fungal infections in paediatric liver transplant recipients.

Invasive fungal infections (IFIs) postliver transplantation are a frequent cause of morbidity and mortality; however, studies reporting on these infections in the paediatric population are scarce. To investigate the incidence and risk factors of IFIs in paediatric liver transplant recipients during the early posttransplantation period (≤3 months). Data were collected for all paediatric liver transplant recipients registered in a national transplantation center from 2004 to 2014. Using a stepwise logistic regression to identify independent risk factors for IFIs, a predictive model was formulated. Ten IFIs were identified in 81 liver transplant recipients (12.3%) all occurring during the first month posttransplantation. Candida species were responsible for nine cases (90%), of which four were non-albicans Candida (44%). Significant risk factors were identified; recipient of multiple blood product transfusions during transplantation, prolonged use of indwelling intravenous catheter, prolonged IV antibiotic treatment, surgical complications, pulse steroid treatment and living donor liver transplantation. The predictive model used two clinical parameters to define high-risk patients: a living donor transplantation and duration of IV antibiotic treatment (area under the ROC curve 0.918). IFIs are a significant complication occurring in the first month posttransplantation. Future studies are required to assess efficacy of targeted antifungal prophylaxis in high risk patients.

Children after renal transplantation hospitalized for fever: Is empirical antibiotic treatment always justified?

Infections are a major cause of morbidity and mortality after renal transplantation. However, data focusing on children are scarce. The objective of this study was to investigate the frequency and predictors of bacterial infection in pediatric renal transplant recipients in a specific setting of hospitalization due to fever. Clinical and laboratory data were retrospectively collected for all pediatric renal transplant recipients hospitalized for fever in a national renal transplantation center from 2004 to 2012. One hundred and sixty-eight hospital admissions for fever of 52 children were analyzed. A bacterial etiology was diagnosed in 85 admissions (50.6%); 49 cases (57.6%) were documented microbiologically and 36 (42.4%) clinically. Risk factors and markers of bacterial infection included older age, presence of a central venous catheter, sonographic findings, and elevated inflammatory indices. C-reactive protein level was a more sensitive marker than white blood cell count and absolute neutrophil count. In patients without identified risk factors, no bacterial infections were diagnosed. Pediatric renal transplant recipients hospitalized for fever are at high risk of bacterial infections and usually require empirical antibiotic treatment at admission. However, there is a minority of low-risk patients in whom clinicians may consider withholding antibiotic treatment with close follow-up.

Real-life comparison of three general paediatric wards showed similar outcomes for children with bronchiolitis despite different treatment regimens.

AIM: This study evaluated the effectiveness of three different treatments for bronchiolitis in a tertiary paediatric facility. METHODS: Patients with bronchiolitis who were younger than two years of age and were randomly allocated to three general wards at Schneider Children's Medical Center, Israel, after admission were included. Different treatment protocols in the wards were retrospectively compared. RESULTS: The study comprised 286 children. The clinical and laboratory parameters on admission were similar between the wards. In Ward C where nebulised hypertonic saline was infrequently administered (6.7%), the mean number of days with oxygen saturation under 92% and the meanlength of hospital stay (1.8 and 3.8 days) were significantly lower than Ward A (2.8 and 5.3 days) and Ward B, (2.9 and 4.7 days) where nebulised hypertonic saline was given more frequently (38.7%-74.7%). Multivariate analysis indicated that low saturation on admission, leukocytosis and use of nebulised hypertonic saline or adrenalin were independent predictors of a longer period of desaturation and hospital stay. CONCLUSION: Different treatment protocols for bronchiolitis were used in three paediatric wards in this real-life study. No treatment regimen proved superior. Inhalations of hypertonic saline or adrenaline were associated with a longer hospital stay.

Pseudomonas aeruginosa identified as a key pathogen in hospitalised children with aspiration pneumonia and a high aspiration risk.

AIM: Data on the causative pathogens and optimal empirical therapy of aspiration pneumonia in children are limited. This study sought to describe the bacteriology of aspiration pneumonia in hospitalised children with a high aspiration risk. METHODS: Respiratory tract specimens were prospectively collected using the induced sputum technique from children with a high aspiration risk who were hospitalised for aspiration pneumonia in a tertiary paediatric medical centre from 2009 to 2014. Clinical, microbiological and treatment data were recorded and analysed for each admission. RESULTS: The cohort comprised 50 children with 235 hospital admissions. Of the 183 respiratory tract cultures performed, 110 were positive for bacteria, with 169 isolates, mostly Gram-negative. The most common Gram-negative pathogen was Pseudomonas aeruginosa. If patients had Pseudomonas aeruginosa isolation, the risk of them having the pathogen again was 81%. The multivariate analysis showed that the use of antibiotic prophylaxis and number of hospitalisations were significantly associated with Pseudomonas aeruginosa isolation. CONCLUSION: Gram-negative bacilli, especially Pseudomonas aeruginosa, were the major causative agents of paediatric aspiration pneumonia in our study. Empiric antipseudomonas treatment should be considered, particularly in patients who are receiving antibiotic prophylaxis, have experienced recurrent hospitalisations or with previous respiratory cultures that showed Pseudomonas aeruginosa isolation.

Using the Rochester criteria to evaluate infantile fever is more effective in males than females.

AIM: The reliability of low-risk and high-risk criteria in evaluating febrile infants aged up to 60 days has been well documented. The aim of this study was to evaluate gender differences in the reliability of these criteria in order to exclude serious bacterial infection (SBI) in febrile infants. METHODS: This study used the Rochester risk criteria, the study group was divided into low- or high-risk status for SBI, and the data were stratified by gender. SBI was defined as a urinary tract infection, bacteraemia, meningitis or bacterial enteritis. RESULTS: We enrolled 1896 infants (58.3% males), and SBIs were found in 10.6% of the males and 8% of the females (p = 0.21). The sensitivity of the risk criteria was 91.5% for the males and 73.4% (p < 0.05) for the females, and the positive likelihood ratio was 2.64 in the males versus 2.14 in the females (p < 0.001). A multivariable analysis showed that high-risk male patients were more than two times more likely to develop a bacterial infection than high-risk females. CONCLUSION: The Rochester risk criteria had a significantly higher sensitivity and positive likelihood ratio in males. Our findings suggest that clinicians should take gender into account when evaluating febrile infants.

Vancomycin Dosing and Its Association With Acute Kidney Injury in Pediatric Cardiac Intensive Care Patients Under 3 Months of Age.

BACKGROUND: The standard vancomycin regimen for term neonates is 45 mg/kg/day. However, the optimal starting vancomycin dosing for achieving therapeutic levels in young infants in cardiac intensive care units remains unknown. Moreover, data on the association of supratherapeutic vancomycin levels with acute kidney injury (AKI) are limited. METHODS: Retrospective study of infants ≤3 months old, receiving vancomycin following congenital heart surgery at postoperative intensive care unit admission. Assessed were vancomycin dosing, achievement of therapeutic trough concentration of 10-20 mg/L and development of AKI, based on the modified Kidney Disease Improving Global Outcomes criteria. RESULTS: Inclusion criteria were met by 109 patients with a median age of 8 days (IQR: 6-16). The mean (SD) vancomycin dose required for achieving therapeutic concentration was 28.9 (9.1) mg/kg at the first postoperative day. Multivariate logistic regression identified higher preoperative creatinine levels and shorter cardiopulmonary bypass time as predictors of supratherapeutic vancomycin concentrations (c-index 0.788). During the treatment course, 62 (56.9%) developed AKI. Length of stay and mortality were higher in those who developed AKI as compared with those who did not. Multivariate logistic regression identified higher vancomycin concentration as a predictor for postoperative AKI, OR, 3.391 (95% CI: 1.257-9.151), P = 0.016 (c-index 0.896). CONCLUSION: Our results support a lower starting vancomycin dose of ~30 mg/kg/day followed by an early personalized therapeutic approach, to achieve therapeutic trough concentrations of 10-20 mg/L in cardiac postoperative term infants. Supratherapeutic concentrations are associated with an increased risk for AKI, which is prevalent in this population and associated with adverse outcomes.