Triage performance in adolescent patients with SARS-CoV-2 infection in Israel.

OBJECTIVE: The aim of this study was to assess the performance of the Pediatric Canadian Triage and Acuity Scale (PaedCTAS) in adolescent patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: A time-series study was conducted in the Emergency Departments (EDs) of 17 public hospitals during the Delta (B.1.617.2) variant spread in Israel. Data were collected prospectively from June 11, 2021 to August 15, 2021. Multivariate regression analyses were performed to identify independent variables associated with hospital admission and with admission to an Intensive Care Unit (ICU). RESULTS: During the study period, 305 SARS-CoV-2 patients ages 12-18 years presenting to the ED were included, and 267 (87.5%) were unvaccinated. Sixty-seven (22.0%) and 12 (3.9%) patients were admitted to pediatric wards and ICUs, respectively. PaedCTAS level 1-2 and the presence of chronic disease increased the odds of hospital admission (adjusted odds ratio (aOR) 5.74, 95% CI, 2.30-14.35, p < 0.0001), and (aOR 2.9, 95% CI, 1.48-5.67, p < 0.02), respectively. PaedCTAS level 1-2 and respiratory symptoms on presentation to ED increased the odds of ICU admission (aOR 27.79; 95% CI, 3.85-176.91, p < 0.001), and (aOR 26.10; 95% CI, 4.47-172.63, p < 0.0001), respectively. PaedCTAS level 3-5 was found in 217/226 (96%) of the patients who were discharged home from the ED. CONCLUSIONS: The findings suggest that PaedCTAS level 1-2 was the strongest factor associated with hospital and ICU admission. Almost all the patients who were discharged home had PaedCTAS level 3-5. Study findings suggest good performance of the PaedCTAS in this cohort.

Antibiotic misuse in respiratory tract infections in children and adults-a prospective, multicentre study (TAILORED Treatment).

Respiratory tract infections (RTI) are more commonly caused by viral pathogens in children than in adults. Surprisingly, little is known about antibiotic use in children as compared to adults with RTI. This prospective study aimed to determine antibiotic misuse in children and adults with RTI, using an expert panel reference standard, in order to prioritise the target age population for antibiotic stewardship interventions. We recruited children and adults who presented at the emergency department or were hospitalised with clinical presentation of RTI in The Netherlands and Israel. A panel of three experienced physicians adjudicated a reference standard diagnosis (i.e. bacterial or viral infection) for all the patients using all available clinical and laboratory information, including a 28-day follow-up assessment. The cohort included 284 children and 232 adults with RTI (median age, 1.3 years and 64.5 years, respectively). The proportion of viral infections was larger in children than in adults (209(74%) versus 89(38%), p < 0.001). In case of viral RTI, antibiotics were prescribed (i.e. overuse) less frequently in children than in adults (77/209 (37%) versus 74/89 (83%), p < 0.001). One (1%) child and three (2%) adults with bacterial infection were not treated with antibiotics (i.e. underuse); all were mild cases. This international, prospective study confirms major antibiotic overuse in patients with RTI. Viral infection is more common in children, but antibiotic overuse is more frequent in adults with viral RTI. Together, these findings support the need for effective interventions to decrease antibiotic overuse in RTI patients of all ages.

Diagnostic Accuracy of a Real-Time Host-Protein Test for Infection.

OBJECTIVE: Determining infection etiology can be difficult because viral and bacterial diseases often manifest similarly. A host protein test that computationally integrates the circulating levels of TNF-related apoptosis-induced ligand, interferon γ-induced protein-10, and C-reactive protein to differentiate between bacterial and viral infection (called MMBV) demonstrated high performance in multiple prospective clinical validation studies. Here, MMBV's diagnostic accuracy is evaluated in febrile children for whom physicians were uncertain about etiology when applied at the physician's discretion. METHODS: Patients aged 3 months to 18 years were retrospectively recruited (NCT03075111; SPIRIT study; 2014-2017). Emergency department physician's etiological suspicion and certainty level were recorded in a questionnaire at blood-draw. MMBV results are based on predefined score thresholds: viral/non-bacterial etiology (0 ≤ score <35), equivocal (35 ≤ score ≤65), and bacterial or coinfection (65 < score ≤100). Reference standard etiology (bacterial/viral/indeterminate) was adjudicated by 3 independent experts based on all available patient data. Experts were blinded to MMBV. MMBV and physician's etiological suspicion were assessed against the reference standard. RESULTS: Of 3003 potentially eligible patients, the physicians were uncertain about infection etiology for 736 of the cases assigned a reference standard (128 bacterial, 608 viral). MMBV performed with sensitivity 89.7% (96/107; 95% confidence interval 82.4-94.3) and specificity 92.6% (498/538; 95% confidence interval 90.0-94.5), significantly outperforming physician's etiological suspicion (sensitivity 49/74 = 66.2%, specificity 265/368 = 72.0%; P < .0001). MMBV equivocal rate was 12.4% (91/736). CONCLUSIONS: MMBV was more accurate in determining etiology compared with physician's suspicion and had high sensitivity and specificity according to the reference standard.

BV score differentiates viral from bacterial-viral co-infection in adenovirus PCR positive children.

Background and objectives: Adenovirus causes acute respiratory illness that can mimic bacterial infection, making it challenging to differentiate adenoviral infection from adenoviral-bacterial co-infection. A host-protein score (BV score) for differentiating bacterial from viral infection that combines the expression levels of TNF-related apoptosis-induced ligand, interferon gamma-induced protein-10, and C-reactive protein exhibited a negative predictive value (NPV) of 98% in prior studies. Here we evaluate BV score's diagnostic accuracy in pediatrics with adenovirus PCR detection. Methods: This is a sub-analysis of children aged 3 months to 20 years with adenovirus PCR-positive infection recruited prospectively in two previous cohort studies. Reference standard diagnosis (bacterial, viral or indeterminate) was based on expert adjudication. BV score ranges from 0 to 100 and provides three results based on predefined cutoffs: viral or other non-bacterial etiology (0 ≤ score < 35), equivocal (35 ≤ score ≤ 65), and bacterial or co-infection (65 < score ≤ 100). Experts were blinded to BV results. Results: Out of 1,779 children, 142 had an adenovirus PCR-positive nasopharyngeal swab. Median age was 1.2 years (interquartile range 0.6-1.8), 50.7% were male and 52.8% were hospitalized. 12 cases were reference standard bacterial, 115 reference standard viral and 15 were indeterminate. BV score attained sensitivity of 100.0% (no false negatives), specificity of 89.5% (95% confidence interval: 83.2-95.8), and NPV of 100.0% (92.6-100.0). Equivocal rate was 19.7%. Conclusions: BV score accurately differentiated between adenoviral and bacterial-adenoviral co-infection in this cohort of children with PCR-positive adenovirus detection. This performance supports a potential to improve appropriate antibiotic use.

Expert panel diagnosis demonstrated high reproducibility as reference standard in infectious diseases.

OBJECTIVE: If a gold standard is lacking in a diagnostic test accuracy study, expert diagnosis is frequently used as reference standard. However, interobserver and intraobserver agreements are imperfect. The aim of this study was to quantify the reproducibility of a panel diagnosis for pediatric infectious diseases. STUDY DESIGN AND SETTING: Pediatricians from six countries adjudicated a diagnosis (i.e., bacterial infection, viral infection, or indeterminate) for febrile children. Diagnosis was reached when the majority of panel members came to the same diagnosis, leaving others inconclusive. We evaluated intraobserver and intrapanel agreement with 6 weeks and 3 years' time intervals. We calculated the proportion of inconclusive diagnosis for a three-, five-, and seven-expert panel. RESULTS: For both time intervals (i.e., 6 weeks and 3 years), intrapanel agreement was higher (kappa 0.88, 95%CI: 0.81-0.94 and 0.80, 95%CI: NA) compared to intraobserver agreement (kappa 0.77, 95%CI: 0.71-0.83 and 0.65, 95%CI: 0.52-0.78). After expanding the three-expert panel to five or seven experts, the proportion of inconclusive diagnoses (11%) remained the same. CONCLUSION: A panel consisting of three experts provides more reproducible diagnoses than an individual expert in children with lower respiratory tract infection or fever without source. Increasing the size of a panel beyond three experts has no major advantage for diagnosis reproducibility.

Antibiotic Overuse in Children with Respiratory Syncytial Virus Lower Respiratory Tract Infection.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections (LRTI) during the first year of life. Antibiotic treatment is recommended in cases suspected of bacterial coinfection. The aim of this prospective study was to estimate the incidence of bacterial coinfections and the amount of antibiotic overuse in children infected with RSV using expert panel diagnosis. METHODS: Children 1 month of age and over with LRTI or fever without source were prospectively recruited in hospitals in the Netherlands and Israel. Children with confirmed RSV infection by Polymerase Chain Reaction (PCR) on nasal swabs were evaluated by an expert panel as reference standard diagnosis. Three experienced pediatricians distinguished bacterial coinfection from simple viral infection using all available clinical information, including all microbiologic evaluations and a 28-day follow-up evaluation. RESULTS: A total of 188 children (24% of all 784 recruited patients) were positive for RSV. From these, 92 (49%) were treated with antibiotics. All 27 children (29%) with bacterial coinfection were treated with antibiotics. Fifty-seven patients (62%) were treated with antibiotics without a diagnosis of bacterial coinfection. In 8 of the 92 (9%), the expert panel could not distinguish simple viral infection from bacterial coinfection. CONCLUSION: This is the first prospective international multicenter RSV study using an expert panel as reference standard to identify children with and without bacterial coinfection. All cases of bacterial coinfections are treated, whereas as many as one-third of all children with RSV LRTI are treated unnecessarily with antibiotics.

Nasal intermittent mandatory ventilation versus nasal continuous positive airway pressure for respiratory distress syndrome: a randomized, controlled, prospective study.

OBJECTIVE: To evaluate whether nasal intermittent mandatory ventilation (NIMV) compared with nasal continuous positive airway pressure (NCPAP) would decrease the requirement for endotracheal ventilation in the treatment of respiratory distress syndrome (RDS) in preterm infants <35 weeks. STUDY DESIGN: Randomized, controlled, prospective, single-center study. Forty-one infants were randomized to NCPAP and 43 comparable infants to NIMV (birth weight 1533 +/- 603 vs 1616 +/- 494 g, gestational age 30.6 +/- 3.0 vs 31.1 +/- 2.3 weeks, P = .5, respectively). RESULTS: Infants treated with NIMV and with NCPAP had comparable cardio-respiratory status at study entry. In the total cohort, infants treated initially with NIMV needed less endotracheal ventilation than infants treated with NCPAP (25% vs 49%, P < .05) with a similar trend in infants <1500 g; 31% vs 62%, P =. 06). When controlling for weight and gestational age, NIMV was more successful in preventing endotracheal ventilation (P < .05). Infants treated with NIMV had a decreased incidence of bronchopulmonary dysplasia (BPD) compared with those treated with NCPAP (2% vs 17%, P <. 05, in the total cohort and 5% vs 33%, P <. 05, for infants <1500 g). CONCLUSIONS: NIMV compared with NCPAP decreased the requirement for endotracheal ventilation in premature infants with RDS. This was associated with a decreased incidence of BPD.

Occipital Headaches in Children: Are They a Red Flag?

Occipital headache is considered a risk factor for serious secondary headache pathology. The purpose of our study was to assess the etiology of occipital headaches among children visiting the emergency department. Subjects were children aged 5 to 18 years who were referred to the emergency department due to headaches during the years 2013 to 2014. A total of 314 patients with headaches were seen at our emergency department. Thirty-nine patients had occipital headaches. Viral infections were the most prevalent final diagnosis (97; 31%), followed by migraine (37; 11.8%). None of our patients had a brain tumor. There was no difference in final diagnosis between the occipital and nonoccipital groups. The most common causes of occipital headaches are viral infections and primary headaches. Serious intracranial disorders presenting solely as occipital headaches and not accompanied by other neurologic signs are uncommon. Thus, occipital headaches should be evaluated in the same manner as other headache locations.

A host-protein based assay to differentiate between bacterial and viral infections in preschool children (OPPORTUNITY): a double-blind, multicentre, validation study.

BACKGROUND: A physician is frequently unable to distinguish bacterial from viral infections. ImmunoXpert is a novel assay combining three proteins: tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma induced protein-10 (IP-10), and C-reactive protein (CRP). We aimed to externally validate the diagnostic accuracy of this assay in differentiating between bacterial and viral infections and to compare this test with commonly used biomarkers. METHODS: In this prospective, double-blind, international, multicentre study, we recruited children aged 2-60 months with lower respiratory tract infection or clinical presentation of fever without source at four hospitals in the Netherlands and two hospitals in Israel. A panel of three experienced paediatricians adjudicated a reference standard diagnosis for all patients (ie, bacterial or viral infection) using all available clinical and laboratory information, including a 28-day follow-up assessment. The panel was masked to the assay results. We identified majority diagnosis when two of three panel members agreed on a diagnosis and unanimous diagnosis when all three panel members agreed on the diagnosis. We calculated the diagnostic performance (ie, sensitivity, specificity, positive predictive value, and negative predictive value) of the index test in differentiating between bacterial (index test positive) and viral (index test negative) infection by comparing the test classification with the reference standard outcome. FINDINGS: Between Oct 16, 2013 and March 1, 2015, we recruited 777 children, of whom 577 (mean age 21 months, 56% male) were assessed. The majority of the panel diagnosed 71 cases as bacterial infections and 435 as viral infections. In another 71 patients there was an inconclusive panel diagnosis. The assay distinguished bacterial from viral infections with a sensitivity of 86·7% (95% CI 75·8-93·1), a specificity of 91·1% (87·9-93·6), a positive predictive value of 60·5% (49·9-70·1), and a negative predictive value of 97·8% (95·6-98·9). In the more clear cases with unanimous panel diagnosis (n=354), sensitivity was 87·8% (74·5-94·7), specificity 93·0% (89·6-95·3), positive predictive value 62·1% (49·2-73·4), and negative predictive value 98·3% (96·1-99·3). INTERPRETATION: This external validation study shows the diagnostic value of a three-host protein-based assay to differentiate between bacterial and viral infections in children with lower respiratory tract infection or fever without source. This diagnostic based on CRP, TRAIL, and IP-10 has the potential to reduce antibiotic misuse in young children. FUNDING: MeMed Diagnostics.

Immediate versus delayed umbilical cord clamping in premature neonates born < 35 weeks: a prospective, randomized, controlled study.

The purpose of this study was to test whether delayed versus immediate cord clamping would result in higher blood pressure (BP) and hematocrit (Hct), and to assess its clinical effects on the neonatal course in premature neonates (< 35 weeks). This was a prospective, masked, randomized, controlled study. Prior to delivery, 35 neonates were randomly assigned to immediate cord clamping (ICC) at 5 to 10 seconds, and a comparable group of 30 neonates were randomly assigned to delayed cord clamping (DCC) at 30 to 45 seconds. Intention-to-treat analyses revealed that the DCC group tended to have higher initial diastolic BP and higher Hct (especially in vaginally delivered neonates). Infants weighing < 1500 g with DCC tended to have higher mean BP, and needed less mechanical ventilation and surfactant compared with ICC neonates. Infants with DCC did not experience more polycythemia (Hct > 60%), but had a trend toward higher bilirubin levels with no differences in the phototherapy needs. DCC seems to be safe and may be beneficial when compared with ICC in premature neonates. However, the differences between the two methods were modest and the clinical relevance needs to be assessed further by larger studies and additional meta-analysis of randomized trials.

Postdischarge infant mortality among very low birth weight infants: a population-based study.

OBJECTIVE: The objective of this study was to identify factors that were associated with death after discharge from the NICU of very low birth weight infants in a population-based study. METHODS: From a national cohort of 13,430 very low birth weight infants who were born in Israel from 1995 to 2003, 10,602 infants were discharged from the hospital and composed the study population. Demographic and clinical data regarding the pregnancy, delivery, and neonatal course were obtained from the Israel national very low birth weight infant database. Data on each case of death during the postdischarge period until 1 year of age were provided by the Ministry of Health from national linked birth and death certificates. Univariate analyses and a multivariable logistic regression analyses were performed to examine the perinatal and neonatal risk factors for postdischarge death. RESULTS: The postdischarge mortality rate was 7.5 per 1000 (80 of 10,602 infants discharged from the hospital). The death rate was significantly higher in non-Jewish infants, infants who were born to young mothers, and infants who were born to low-educated mothers. After adjustment for demographic characteristics and perinatal and neonatal variables, postdischarge mortality was independently associated with congenital malformations, neonatal seizures, necrotizing enterocolitis, and bronchopulmonary dysplasia. CONCLUSION: Although the postdischarge death rate was relatively low in our cohort of very low birth weight infants, attention should be focused on the subgroups of infants who are at higher risk to decrease their mortality further.

Necrotizing enterocolitis in a premature infant as the presenting symptom of familial dysautonomia in the neonatal period: case report and review of the literature.

We present a case of a premature infant with early-onset necrotizing enterocolitis as the presenting symptom of familial dysautonomia. The diagnosis of familial dysautonomia in the neonatal period is usually rare and difficult, because many of the symptoms may be mild or nonspecific, whereas other characteristic signs and symptoms appear only later in life. The neonatologist should be aware of this rare diagnosis in the neonatal period, especially in the offspring of Ashkenazi Jews. The diagnosis is genetic. Preconception counseling to future parents belonging to populations at risk should include recommendation for genetic screening test to identify carriers of the mutations in the familial dysautonomia gene.

Prolonged resuscitation in a newborn recovering from meconium aspiration syndrome.

A complication during the course of meconium aspiration syndrome associated with persistent pulmonary hypertension in a newborn results in hypotension, bradycardia, and desaturation. The dilemmas and critical actions during the resuscitation are presented.

Auricular mild errors of morphogenesis: epidemiological analysis, local correlations and clinical significance.

BACKGROUND: The mild errors or morphogenesis (MEMs) are well known and accepted markers of alterations in embryonic development with predictive value in identification of major malformations, specific genetic syndromes, metabolic and psychiatric disease and childhood malignancy. OBJECTIVE: The goal of this study was to assess the contribution of auricular MEMs as part of total MEMs in an effort to study the factors influencing the different potential informative value of different types of MEMs and their variability with perinatal factors. METHOD: Three thousand one hundred and seven consecutive born neonates were screened for auricular and non-auricular MEMs, inregistered concomitantly with major malformations and postural defects. The study was accomplished by our specially designed computerized program in a relatively large nonhomogeneous ethnic population, in the metropolitan area of Haifa, Israel. RESULTS: The general prevalence of auricular MEMs was 43.1%; the most frequent pathogenetic type was the postural one. Significantly higher rates of auricular MEMs were associated with male sex, small- and large-for-gestational age, IVF pregnancy, triplet pregnancy, maternal diabetes and parental consanguinity. CONCLUSION: We conclude that the presence, number, and association or concomitance of auricular MEMs in the same neonate may have important clinical, diagnostic, pathogenetic, screening, and therapeutic value.