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.

Paediatric hospital visit with laboratory-confirmed influenza improved family members' influenza vaccination.

OBJECTIVES: Vaccination is the primary intervention to prevent influenza infection, yet vaccine uptake remains low among children and other at-risk patients. The aim of the study is to investigate the impact of a paediatric hospital visit with laboratory-confirmed influenza on the influenza vaccination behaviour of participants and their family members in the subsequent influenza season. METHODS: This study compared the influenza vaccination coverage for participants < 18 years of age with a clinical suspicion of influenza in 2017-2018 during a hospital visit, in two subsequent influenza seasons. Data was retrieved from the hospital electronic medical record and a follow-up questionnaire (2018-2019) to ascertain the common reason(s) that families did not vaccinate their children the following year (2018-2019). The children were distributed into positive- (antigen and/or PCR) and negative-influenza groups. RESULTS: A total of 133 children were enrolled in our study. Participants' mean age was 4.6 years and 74 (55.6%) were males. Overall, 47 (35.3%) had confirmed influenza virus. A significant increase in influenza immunization was found among both positive- and negative-influenza participants between 2017-2018 and 2018-2019 (6.4% vs. 27.7%, p < 0.001; 8.1% vs. 29.1%, p < 0.001, respectively), as well as among family members of positive-influenza participants - siblings and parents (6.4% vs. 19.6%, p = 0.003; 0% vs. 17%, p < 0.001, respectively). Common reasons for failure to vaccinate included doubt in vaccine effectiveness, unlikely to get "flu", busy, and side effects. CONCLUSIONS: Our findings suggest that a paediatric hospital visit with laboratory-confirmed influenza increases vaccine uptake among families. Future studies should aim to evaluate evidence-based interventions to improve influenza vaccine uptake among children.

Association of viral load with TRAIL, IP-10, CRP biomarker signature and disease severity in children with respiratory tract infection or fever without source: A prospective, multicentre cohort study.

BACKGROUND: To investigate the association of viral load (VL) with (i) tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma-induced protein-10, C-reactive protein, and a combinatorial score (BV score), and (ii) clinical severity. STUDY DESIGN: In this prospective, multicentre cohort substudy, children with respiratory tract infection or fever without source were enrolled. VL for influenza virus, rhinovirus, respiratory syncytial virus, and adenovirus was measured from nasopharyngeal swabs. The reference standard diagnosis was established based on expert panel adjudication. RESULTS: Of 1140 recruited patients, 333 had a virus monodetection. VL for the aggregated data set correlated with TRAIL and IP-10 levels, with the length of oxygen therapy, and inversely with the BV score. At a single viral level, only the influenza VL yielded a correlation with TRAIL, IP-10 levels, and the BV score. Children with a viral reference standard diagnosis had significantly higher VL than those with bacterial infection (p = 0.0005). Low TRAIL (incidence rate ratio [IRR] 0.6, 95% confidence interval [CI] 0.39-0.91) and young age (IRR 0.62, 95% CI 0.49-0.79) were associated with a longer hospital stay, while young age (IRR 0.33, 95% CI 0.18-0.61), low TRAIL (IRR 0.25, 95% CI 0.08-0.76), and high VL (IRR 1.16, 95% CI 1.00-1.33) were predictive of longer oxygen therapy. CONCLUSION: These findings indicate that VL correlates with biomarkers and may serve as a complementary tool pertaining to disease severity.

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.

The diagnostic value of nasal microbiota and clinical parameters in a multi-parametric prediction model to differentiate bacterial versus viral infections in lower respiratory tract infections.

BACKGROUND: The ability to accurately distinguish bacterial from viral infection would help clinicians better target antimicrobial therapy during suspected lower respiratory tract infections (LRTI). Although technological developments make it feasible to rapidly generate patient-specific microbiota profiles, evidence is required to show the clinical value of using microbiota data for infection diagnosis. In this study, we investigated whether adding nasal cavity microbiota profiles to readily available clinical information could improve machine learning classifiers to distinguish bacterial from viral infection in patients with LRTI. RESULTS: Various multi-parametric Random Forests classifiers were evaluated on the clinical and microbiota data of 293 LRTI patients for their prediction accuracies to differentiate bacterial from viral infection. The most predictive variable was C-reactive protein (CRP). We observed a marginal prediction improvement when 7 most prevalent nasal microbiota genera were added to the CRP model. In contrast, adding three clinical variables, absolute neutrophil count, consolidation on X-ray, and age group to the CRP model significantly improved the prediction. The best model correctly predicted 85% of the 'bacterial' patients and 82% of the 'viral' patients using 13 clinical and 3 nasal cavity microbiota genera (Staphylococcus, Moraxella, and Streptococcus). CONCLUSIONS: We developed high-accuracy multi-parametric machine learning classifiers to differentiate bacterial from viral infections in LRTI patients of various ages. We demonstrated the predictive value of four easy-to-collect clinical variables which facilitate personalized and accurate clinical decision-making. We observed that nasal cavity microbiota correlate with the clinical variables and thus may not add significant value to diagnostic algorithms that aim to differentiate bacterial from viral infections.

Impact of rotavirus vaccine implementation on Israeli children: a comparison between pre- and post-vaccination era.

BACKGROUND: Worldwide rotavirus vaccination has resulted in a substantial decrease in rotavirus-induced severe gastroenteritis and related hospitalizations among children. Still, the characterization of patients warranting hospitalization needs to be further elucidated. The purpose of the study is to compare the clinical and laboratory features of children hospitalized with acute rotavirus infection before and after the introduction of routine vaccination. METHODS: This is a retrospective observational study. Participants were pediatric patients who presented to the Bnai Zion Medical Center pediatric emergency department and were diagnosed with rotavirus acute gastroenteritis between 2017 and 2019. RESULTS: During the pre-vaccination period (2007-2009), 114 infants and young children (median age: 14 months, range: 1-72 months; 59 male, 55 female) were hospitalized for rotavirus-induced acute gastroenteritis with a rate of 11.71 positive rotavirus tests per 1000 emergency room visits. In the post-vaccination period (2012-2019), 168 infants and young children (median age: 17 months, range: 0-84 months; 90 male, 78 female) were hospitalized with a rate of 4.18 positive rotavirus tests per 1000 emergency room visits. There were no statistical differences between the two groups in gender, breast-feeding rates and sibling(s). The proportion of cases with moderate-to-severe dehydration was higher in the post-vaccination children than in the pre-vaccination children. CONCLUSIONS: Rates of rotavirus-attributed acute gastroenteritis hospitalizations declined from the pre- to the post-vaccination period. Higher rates of dehydration were found in the post-vaccination children. Ongoing surveillance is warranted to better understand the implications of the vaccine.

Evaluation of Israeli healthcare workers knowledge and attitudes toward the COVID-19 vaccine.

OBJECTIVES: Healthcare workers (HCWs) are considered an important target group for the COVID-19 vaccines. The current study assesses the knowledge and attitudes of Israeli HCWs regarding COVID-19 immunization, and how various occupational and demographic factors may underlie COVID-related knowledge and attitudes differences. METHODS: Following a pre-test to validate measures, a cross-sectional online anonymous survey was distributed to HCWs using a snowball sampling method. RESULTS: The survey was completed by 714 participants (mean age 39.9; range 18-74; 447 female), 52% doctors, 32% nurses, and the remainder by paramedical staff. Of the respondents, 553 (77.4%) answered the question are you in favor of getting the COVID-19 vaccine, 105 (14.7%) were not sure, and 56 (7.8%) were not in favor. Doctors had higher odds of agreement as compared to both nurses (p < .025) and paramedical staff (p < .001). Multivariate logistic regression analysis revealed that increased age (OR: 1.075; 95% CI: 1.04-1.11, p < .001), profession (physician vs. nurse; OR: 2.73; 95% CI: 1.32-5.65; p < .007), and getting the current influenza vaccine (OR: 4.96; 95% CI: 2.47-9.95) were significant predictors of agreement. CONCLUSIONS: A high level of HCWs knowledge and in favor attitudes were observed. Yet negative attitudes were also noted, particularly among nurses, paramedical staff, and young employees.

A host signature based on TRAIL, IP-10, and CRP for reducing antibiotic overuse in children by differentiating bacterial from viral infections: a prospective, multicentre cohort study.

OBJECTIVES: Identifying infection aetiology is essential for appropriate antibiotic use. Previous studies have shown that a host-protein signature consisting of TNF-related apoptosis-induced ligand (TRAIL), interferon-γ-induced protein-10 (IP-10), and C-reactive protein (CRP) can accurately differentiate bacterial from viral infections. METHODS: This prospective, multicentre cohort study, entitled AutoPilot-Dx, aimed to validate signature performance and to estimate its potential impact on antibiotic use across a broad paediatric population (>90 days to 18 years) with respiratory tract infections, or fever without source, at emergency departments and wards in Italy and Germany. Infection aetiology was adjudicated by experts based on clinical and laboratory investigations, including multiplex PCR and follow-up data. RESULTS: In total, 1140 patients were recruited (February 2017-December 2018), of which 1008 met the eligibility criteria (mean age 3.5 years, 41.9% female). Viral and bacterial infections were adjudicated for 628 (85.8%) and 104 (14.2%) children, respectively; 276 patients were assigned an indeterminate reference standard outcome. For the 732 children with reference standard aetiology, the signature discriminated bacterial from viral infections with a sensitivity of 93.7% (95%CI 88.7-98.7), a specificity of 94.2% (92.2-96.1), positive predictive value of 73.0% (65.0-81.0), and negative predictive value of 98.9% (98.0-99.8); in 9.8% the test results were equivocal. The signature performed consistently across different patient subgroups and detected bacterial immune responses in viral PCR-positive patients. CONCLUSIONS: The findings validate the high diagnostic performance of the TRAIL/IP-10/CRP signature in a broad paediatric cohort, and support its potential to reduce antibiotic overuse in children with viral infections.

Outcomes of Migraine and Tension-Type Headache in Children and Adolescents.

The aim of our study was to evaluate the long-term outcomes of pediatric migraine and TTH in a clinical setting. We conducted a cohort study. Pediatric patients who visited the pediatric neurology clinic due to diagnoses of migraine or TTH were contacted by phone 8-10 years after their initial diagnosis and interviewed about their outcomes. Of 147 children, we were able to reach 120 (81%) patients. Of these 120 patients, 59 were seen initially due to migraine and 61 due to TTH. For the migraine patients, headaches improved in 48 (81.4%) and worsened in four (6.8%). Regarding diagnosis at follow-up, 59% still had migraine, 17% had TTH, and 23% were headache-free. Aura and photophobia were significantly associated with persistence of a migraine diagnosis. For the TTH patients, headaches improved in 49 (81.7%) and worsened in nine (15.0%). Regarding diagnosis at follow-up, 36.7% still had TTH, 18.3% had migraine, and 45% were headache-free. Of the patients with TTH, 36.7% retained their initial diagnosis compared to 59.3% among the migraine patients. Most pediatric patients presenting with migraine or TTH will experience a favorable outcome over 10 years, with TTH patients having twice the chance of complete resolution.

COVID-19 in a Subset of Hospitalized Children in Israel.

BACKGROUND: Most pediatric coronavirus disease 2019 (COVID-19) is mild. We assessed nationally severe COVID-19, including pediatric inflammatory multisystem syndrome (PIMS), in hospitalized children. METHODS: An ongoing, prospective, national surveillance was conducted from March 2020 through March 2021, at 20 hospitals treating children <18 years across Israel (~75% of Israeli hospitals). RESULTS: Overall, 1007 cases (439 outpatients and 568 hospitalized) identified represent 0.35% of pediatric COVID-19 nationwide (n = 291 628). Of hospitalized cases, 464 (82%), 48 (8%), and 56 (10%) had mild, moderate/severe, and PIMS disease, respectively. The mean ± SD age was 5.6 ± 6.4 years. In mild, moderate/severe, and PIMS disease, 55%, 23%, and 4% of patients were <1 year old, respectively. Obesity was reported in 1%, 4%, and 13% of patients, respectively (P < .001). The most common symptom was fever in 67%, 60%, and 100%, respectively, whereas respiratory symptoms were documented in 33%, 41%, and 38% of patients, respectively. Lymphopenia was recorded in 25%, 60%, and 86% of cases, respectively. PIMS diagnosis was mainly serology-based (in 59%). Gastrointestinal symptoms, cardiovascular involvement, rash, and conjunctivitis were noted in 82%, 61%, 57%, and 34% of PIMS episodes, respectively. Elevated C-reactive protein (100%), ferritin, troponin, D-dimer, low albumin, and thrombocytopenia were common in PIMS. Echocardiography revealed pathological findings in 33% of patients. PIMS mainstay treatment included corticosteroids (77%) and intravenous immunoglobulin (53%). No mortality was recorded. CONCLUSIONS: At a national level, pediatric COVID-19 is mild, even in hospitalized cases, with only a third presenting with respiratory involvement. PIMS is rare, but necessitates a high index of suspicion, and with suitable treatment prognosis is favorable.

Pooled saliva CMV DNA detection: A viable laboratory technique for universal CMV screening of healthy newborns.

BACKGROUND: Most infants with congenital cytomegalovirus (cCMV) have no overt manifestations at birth, yet may later develop CMV-related sensorineural hearing loss (SNHL). With targeted screening, many asymptomatic neonates are missed and lose the opportunity for timely anti-viral treatment to ameliorate SNHL. Saliva is the preferred screening specimen given its ease of collection. OBJECTIVES: Assess a pooled saliva CMV DNA detection technique for cCMV screening of healthy full-term neonates. STUDY DESIGN: We conducted a prospective laboratory CMV PCR screening study in a secondary hospital from March-June 2019. Saliva specimens were obtained from 1000 newborns two-four hours after birth. Specimens were analyzed for CMV DNA with a real-time PCR platform (Altona) in pools of 10 and individually (40 µL and 400 µL, respectively). Neonates with positive saliva CMV DNA detection required urine CMV PCR testing to confirm cCMV diagnosis. RESULTS: From the 1000 saliva samples, there were 6 urine-confirmed cCMV cases, yielding a prevalence rate of 0.6 %. The specificity was high for both pooled and individual saliva sampling (99.9 % and 98.1 %, respectively). The positive predictive value of the pooled sample was 85.7 %, compared to 24.0 % for a single saliva sample. CONCLUSIONS: Pooling saliva of healthy newborns appears to be a reliable method to identify asymptomatic cCMV infection when positive results are confirmed by urine CMV DNA. Pooling in sizes appropriate to the cCMV prevalence rate may improve the laboratory workflow and decrease costs. Further studies should evaluate the clinical implications of this widespread cCMV pooled screening technique.

The yield of CSF molecular testing in febrile neonates.

We retrospectively examined the yield of a cerebrospinal fluid (CSF) multiplex real-time PCR assay of febrile young infants undergoing a full sepsis work-up. Eighty infants were included in the study: Forty-nine (61%) neonates and 31 (39%) 29-90 day-old patients were included in the study. A viral pathogen was detected in 59% (47/80) of the samples, human enterovirus in 53% (42/80) and Human parechovirus in 6% (5/80). The CSF of nearly half of the subjects with CNS infection was without pleocytosis; all CSF cultures were negative. Multiplex PCR CSF testing enhances the diagnosis of pathogen-specific viral CNS infection among febrile young infants.

The Sesame-Peanut Conundrum in Israel: Reevaluation of Food Allergy Prevalence in Young Children.

BACKGROUND: Food allergies (FAs) are on the rise worldwide. A previous cross-sectional study from 2002 in Israel estimated the prevalence of IgE-mediated FA among young children at 0.85%. Although sesame was found to be a common allergen, peanuts were found to be a rare allergen. OBJECTIVE: To determine the prevalence and distributions of IgE-mediated FAs among young children in Israel compared with previous data. METHODS: A total of 1932 young children (56% males, 44% females) with a mean age of 22.4 months (range, 18-30 months) were sequentially recruited from 15 government family health care centers in north Israel. Parents completed a questionnaire with 2 screening questions for suspected FA. Subjects with suspected FA underwent further evaluation including telephone interview, skin prick tests, and oral food challenge as needed. RESULTS: After analyzing the questionnaires, 146 subjects were suspected to have FA. Seventy-nine subjects were excluded by telephone interview and 13 were excluded on the basis of negative oral food challenge. We identified 54 of 1932 (2.8%) young children with 75 IgE-mediated FAs. Thirty-nine of 54 (72.2%) had allergy to 1 food and 9 (16.6%) to 2 foods. The most common food allergens were cow's milk (1%), eggs (0.88%), sesame (0.93%), tree nuts (0.57%), peanuts (0.2%), and fish (0.2%). CONCLUSIONS: The prevalence of IgE-mediated FA among young children in Israel has increased dramatically from 0.85% to 2.8%. The relative prevalence of the most common food allergens is similar to that identified in 2002, with a high prevalence of sesame FA and low prevalence of peanut FA.

A Retrospective Study of the Impact of Pneumococcal Conjugate Vaccine-13 Immunization in a Northern Israel Hospital.

BACKGROUND: The introduction of pneumococcal conjugate vaccine-13 (PCV-13) has reduced the burden of invasive pneumococcal disease. OBJECTIVES: To characterize true positive blood cultures of children who presented to our hospital following implementation of the PCV-13 vaccine. METHODS: A retrospective study was conducted on positive blood cultures of children presenting with fever from 2010-2017. Subjects were divided into two age groups: a younger group 3-36 months and an older group 3-18 years. Patients were classified as either having or not having a focus of infection at the time of their bacteremia. Pneumococcal isolates were typed at Israel's Streptococcal Reference Laboratory. RESULTS: The samples included 94 true positive blood cultures. Focal infection with concomitant bacteremia was more common than bacteremia without a focus both overall: 67/94 (71%) vs. 27/94 (28.7%), P <0.001 as well as in the two groups: 32/48 (66%) vs. 16/48 (33%), P = 0.02 in the younger group and 35/46 (76%) vs. 11/46 (24%), P = 0.001 in the older group. Streptococcus pneumoniae was the most common pathogen overall, 27/94 (29%), and in the younger group, 21/48 (44%), but rare in the older group, 6/46 (13%). In the latter, Brucella species predominated, 12/46 (26%), along with Staphylococcus aureus 12/46 (26%). CONCLUSIONS: Our findings are consistent with other studies reporting decreased pneumococcal bacteremia, bacteremia primarily accompanying focal infection, and changing etiological agents among PCV-13-vaccinated children. Brucella species was prominent in older children with osteoarticular infections. Ongoing surveillance is warranted to better understand the implications of PCV-13.

Respiratory Viruses Frequently Mimic Pertussis in Young Infants.

Bordetella pertussis is prevalent among infants, but its diagnosis is complicated by the fact that its signs and symptoms overlap with respiratory viruses. Indeed, when evaluating the etiology of infants less than 1 year of age suspected of having pertussis, we found that respiratory viruses frequently mimic B. pertussis and are more likely to be the causative agent.

Expressions of Gratitude and Medical Team Performance.

BACKGROUND AND OBJECTIVES: Exposure to negative social interactions (such as rudeness) has robust adverse implications on medical team performance. However, little is known regarding the effects of positive social interactions. We hypothesized that expressions of gratitude, a prototype of positive social interaction, would enhance medical teams' effectiveness. Our objective was to study the performance of NICU teams after exposure to expressions of gratitude from alternative sources. METHODS: Forty-three NICU teams (comprising 2 physicians and 2 nurses) participated in training workshops of acute care simulations. Teams were randomly assigned to 1 of 4 conditions: (1) maternal gratitude (in which the mother of a preterm infant expressed gratitude to NICU teams, such as the one that treated her child), (2) expert gratitude (in which a physician expert expressed gratitude to teams for participating in the training), (3) combined maternal and expert gratitude, or (4) control (same agents communicated neutral statements). The simulations were evaluated (5-point Likert scale: 1 = failed and 5 = excellent) by independent judges (blind to team exposure) using structured questionnaires. RESULTS: Maternal gratitude positively affected teams' performances (3.9 ± 0.9 vs 3.6 ± 1.0; P = .04), with most of this effect explained by the positive impact of gratitude on team information sharing (4.3 ± 0.8 vs 4.0 ± 0.8; P = .03). Forty percent of the variance in team information sharing was explained by maternal gratitude. Information sharing predicted team performance outcomes, explaining 33% of the variance in diagnostic performance and 41% of the variance in therapeutic performance. CONCLUSIONS: Patient-expressed gratitude significantly enhances medical team performance, with much of this effect explained by enhanced information sharing.