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Shortly after the implementation of community mitigation measures in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), sharp declines in respiratory syncytial virus and influenza circulation were noted; post-mitigation circulation of other respiratory pathogens has gone unexplored. We retrospectively analyzed all records of a provider-ordered multiplex test between April 1, 2018, and July 31, 2021, in Nashville, Tennessee, and we noted disrupted historical seasonal patterns for common respiratory pathogens during the SARS-CoV-2 pandemic.

Background Rhinovirus (RV) is one of the most common etiologic agents of acute respiratory infection (ARI), which is a leading cause of morbidity and mortality in young children. The clinical significance of RV co-detection with other respiratory viruses, including respiratory syncytial virus (RSV), remains unclear. We aimed to compare the clinical characteristics and outcomes of children with ARI-associated RV-only detection and those with RV co-detection—with an emphasis on RV/RSV co-detection. Methods We conducted a prospective viral surveillance study (11/2015–7/2016) in Nashville, Tennessee. Children < 18 years old who presented to the emergency department (ED) or were hospitalized with fever and/or respiratory symptoms of < 14 days duration were eligible if they resided in one of nine counties in Middle Tennessee. Demographics and clinical characteristics were collected by parental interviews and medical chart abstractions. Nasal and/or throat specimens were collected and tested for RV, RSV, metapneumovirus, adenovirus, parainfluenza 1–4, and influenza A–C using reverse transcription quantitative polymerase chain reaction assays. We compared the clinical characteristics and outcomes of children with RV-only detection and those with RV co-detection using Pearson’s χ 2 test for categorical variables and the two-sample t -test with unequal variances for continuous variables. Results Of 1250 children, 904 (72.3%) were virus-positive. RV was the most common virus ( n  = 406; 44.9%), followed by RSV ( n  = 207; 19.3%). Of 406 children with RV, 289 (71.2%) had RV-only detection, and 117 (28.8%) had RV co-detection. The most common virus co-detected with RV was RSV ( n  = 43; 36.8%). Children with RV co-detection were less likely than those with RV-only detection to be diagnosed with asthma or reactive airway disease both in the ED and in-hospital. We did not identify differences in hospitalization, intensive care unit admission, supplemental oxygen use, or length of stay between children with RV-only detection and those with RV co-detection. Conclusion We found no evidence that RV co-detection was associated with poorer outcomes. However, the clinical significance of RV co-detection is heterogeneous and varies by virus pair and age group. Future studies of RV co-detection should incorporate analyses of RV/non-RV pairs and include age as a key covariate of RV contribution to clinical manifestations and infection outcomes.

The World Health Organization created the Severe Acute Respiratory Infection (SARI) criteria in 2011 to monitor influenza (flu)-related hospitalization. Many studies have since used the SARI case definition as inclusion criteria for surveillance studies. We sought to determine the sensitivity, specificity, positive predictive value, and negative predictive value of the SARI criteria for detecting ten different respiratory viruses in a Middle Eastern pediatric cohort. The data for this study comes from a prospective acute respiratory surveillance study of hospitalized children <2 years in Amman, Jordan from March 16, 2010 to March 31, 2013. Participants were recruited if they had a fever and/or respiratory symptoms. Nasal and throat swabs were obtained and tested by real-time RT-PCR for eleven viruses. Subjects meeting SARI criteria were determined post-hoc. Sensitivity, specificity, positive predictive value, and negative predictive value of the SARI case definition for detecting ten different viruses were calculated and results were stratified by age. Of the 3,175 patients enrolled, 3,164 were eligible for this study, with a median age of 3.5 months, 60.4% male, and 82% virus-positive (44% RSV and 3.8% flu). The sensitivity and specificity of the SARI criteria for detecting virus-positive patients were 44% and 77.9%, respectively. Sensitivity of SARI criteria for any virus was lowest in children <3 months at 22.4%. Removing fever as a criterion improved the sensitivity by 65.3% for detecting RSV in children <3 months; whereas when cough was removed, the sensitivity improved by 45.5% for detecting flu in same age group. The SARI criteria have poor sensitivity for detecting RSV, flu, and other respiratory viruses-particularly in children <3 months. Researchers and policy makers should use caution if using the criteria to estimate burden of disease in children.

In developing countries where point-of-care testing is limited, providers rely on clinical judgement to discriminate between viral and bacterial respiratory infections. We performed a cross-sectional cohort study of hospitalized Jordanian children to evaluate antibiotic use for respiratory syncytial virus (RSV) infections. Admitting diagnoses from a prior viral surveillance cohort of hospitalized Jordanian children were dichotomized into suspected viral-like, non-pulmonary bacterial-like, and pulmonary bacterial-like infection. Stratifying by sex, we performed a polytomous logistic regression adjusting for age, underlying medical condition, maternal education, and region of residence to estimate prevalence odds ratios (PORs) for antibiotic use during hospitalization. Sensitivity and specificity of admission diagnoses and research laboratory results were compared. Children with a suspected viral-like admission diagnosis, compared to those with suspected non-pulmonary bacterial-like, were 88% and 86% less likely to be administered an empiric/first-line antibiotic (male, aPOR: 0.12; female, aPOR: 0.14; p-value = <0.001). There were slight differences by sex with males having a lower prevalence than females in being administered an expanded coverage antibiotic; but they had a higher prevalence of macrolide administration than males with non-pulmonary bacterial-like infection. Overall, children with RSV had a 34% probability (sensitivity) of being assigned to a suspected viral-like diagnosis; whereas RSV-negative children had a 76% probability (specificity) of being assigned to a suspected pulmonary bacterial-like diagnosis. Hospitalized children with a suspected viral-like admission diagnosis were less likely to receive an empiric/first-line and expanded coverage antibiotic compared to suspected non-pulmonary and pulmonary infections; however, when evaluating the accuracy of admission diagnosis to RSV-laboratory results there were considerable misclassifications. These results highlight the need for developing antibiotic interventions for Jordan and the rest of the Middle East.

ObjectivesTo systematically review and evaluate diagnostic models used to predict viral acute respiratory infections (ARIs) in children.DesignSystematic review.Data sourcesPubMed and Embase were searched from 1 January 1975 to 3 February 2022.Eligibility criteriaWe included diagnostic models predicting viral ARIs in children (<18 years) who sought medical attention from a healthcare setting and were written in English. Prediction model studies specific to SARS-CoV-2, COVID-19 or multisystem inflammatory syndrome in children were excluded.Data extraction and synthesisStudy screening, data extraction and quality assessment were performed by two independent reviewers. Study characteristics, including population, methods and results, were extracted and evaluated for bias and applicability using the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies and PROBAST (Prediction model Risk Of Bias Assessment Tool).ResultsOf 7049 unique studies screened, 196 underwent full text review and 18 were included. The most common outcome was viral-specific influenza (n=7; 58%). Internal validation was performed in 8 studies (44%), 10 studies (56%) reported discrimination measures, 4 studies (22%) reported calibration measures and none performed external validation. According to PROBAST, a high risk of bias was identified in the analytic aspects in all studies. However, the existing studies had minimal bias concerns related to the study populations, inclusion and modelling of predictors, and outcome ascertainment.ConclusionsDiagnostic prediction can aid clinicians in aetiological diagnoses of viral ARIs. External validation should be performed on rigorously internally validated models with populations intended for model application.PROSPERO registration numberCRD42022308917.

Background Parainfluenza virus (PIV) is a leading cause of acute respiratory illness (ARI) in children. However, few studies have characterized the clinical features and outcomes associated with PIV infections among young children in the Middle East. Methods We conducted hospital-based surveillance for ARI among children < 2 years of age in a large referral hospital in Amman, Jordan. We systematically collected clinical data and respiratory specimens for pathogen detection using reverse transcription polymerase chain reaction. We compared clinical features of PIV-associated ARI among individual serotypes 1, 2, 3, and 4 and among PIV infections compared with other viral ARI and ARI with no virus detected. We also compared the odds of supplemental oxygen use using logistic regression. Results PIV was detected in 221/3168 (7.0%) children hospitalized with ARI. PIV-3 was the most commonly detected serotype (125/221; 57%). Individual clinical features of PIV infections varied little by individual serotype, although admission diagnosis of ‘croup’ was only associated with PIV-1 and PIV-2. Children with PIV-associated ARI had lower frequency of cough (71% vs 83%; p  < 0.001) and wheezing (53% vs 60% p < 0.001) than children with ARI associated with other viruses. We did not find a significant difference in supplemental oxygen use between children with PIV-associated infections (adjusted odds ratio [aOR] 1.12, 95% CI 0.66–1.89, p  = 0.68) and infections in which no virus was detected. Conclusions PIV is frequently associated with ARI requiring hospitalization in young Jordanian children. Substantial overlap in clinical features may preclude distinguishing PIV infections from other viral infections at presentation.

As public health and social distancing guidelines loosen in the setting of waning global natural and vaccine immunity, a deeper understanding of the immunological response to reexposure and reinfection to this highly contagious pathogen is necessary to maintain public health. Viral sequencing analysis provides a robust but unrealistic means to monitor reinfection globally. As public health guidelines throughout the world have relaxed in response to vaccination campaigns against SARS-CoV-2, it is likely that SARS-CoV-2 will remain endemic, fueled by the rise of more infectious SARS-CoV-2 variants. Moreover, in the setting of waning natural and vaccine immunity, reinfections have emerged across the globe, even among previously infected and vaccinated individuals. As such, the ability to detect reexposure to and reinfection by SARS-CoV-2 is a key component for global protection against this virus and, more importantly, against the potential emergence of vaccine escape mutations. Accordingly, there is a strong and continued need for the development and deployment of simple methods to detect emerging hot spots of reinfection to inform targeted pandemic response and containment, including targeted and specific deployment of vaccine booster campaigns. In this study, we identify simple, rapid immune biomarkers of reinfection in rhesus macaques, including IgG3 antibody levels against nucleocapsid and FcγR2A receptor binding activity of anti-RBD antibodies, that are recapitulated in human reinfection cases. As such, this cross-species analysis underscores the potential utility of simple antibody titers and function as price-effective and scalable markers of reinfection to provide increased resolution and resilience against new outbreaks. IMPORTANCE As public health and social distancing guidelines loosen in the setting of waning global natural and vaccine immunity, a deeper understanding of the immunological response to reexposure and reinfection to this highly contagious pathogen is necessary to maintain public health. Viral sequencing analysis provides a robust but unrealistic means to monitor reinfection globally. The identification of scalable pathogen-specific biomarkers of reexposure and reinfection, however, could significantly accelerate our capacity to monitor the spread of the virus through naive and experienced hosts, providing key insights into mechanisms of disease attenuation. Using a nonhuman primate model of controlled SARS-CoV-2 reexposure, we deeply probed the humoral immune response following rechallenge with various doses of viral inocula. We identified virus-specific humoral biomarkers of reinfection, with significant increases in antibody titer and function upon rechallenge across a range of humoral features, including IgG1 to the receptor binding domain of the spike protein of SARS-CoV-2 (RBD), IgG3 to the nucleocapsid protein (N), and FcγR2A receptor binding to anti-RBD antibodies. These features not only differentiated primary infection from reexposure and reinfection in monkeys but also were recapitulated in a sequencing-confirmed reinfection patient and in a cohort of putatively reinfected humans that evolved a PCR-positive test in spite of preexisting seropositivity. As such, this cross-species analysis using a controlled primate model and human cohorts reveals increases in antibody titers as promising cross-validated serological markers of reinfection and reexposure.

Background and Aims Respiratory syncytial virus (RSV) is a leading cause of acute respiratory infection (ARI) in children, particularly in low‐ and middle‐income countries. Rapid diagnosis is important for management and infection control. We aimed to evaluate diagnostic accuracy of Sofia 2 RSV fluorescent immunoassay (FIA) compared to reverse‐transcription quantitative PCR (RT‐qPCR) in children under 2 years hospitalized with ARI in Amman, Jordan. Methods We conducted a prospective viral surveillance study from January 26, 2020 to March 17, 2020, at Al‐Bashir Hospital. Sofia 2 RSV FIA was performed on nasal swabs and compared to RT‐qPCR. We calculated sensitivity, specificity, and Cohen's κ with 95% confidence intervals and assessed factors associated with RSV detection by FIA using logistic regression. Results Of 458 children enrolled, 356 (77.7%) had RSV detected by RT‐qPCR. Sofia 2 RSV FIA demonstrated 76.1% sensitivity (95% CI: 71.3, 80.5%) and 94.1% specificity (95% CI: 87.6, 97.8%) relative to RT‐qPCR. Lower RT‐qPCR cycle threshold value (inversely related to viral load) was significantly associated with Sofia 2 RSV FIA positivity (aOR = 0.75; 95% CI: 0.70, 0.81; p < 0.001). Conclusion Sofia 2 RSV FIA demonstrates potential as a rapid diagnostic test in resource‐limited settings. Further research on its clinical outcomes and cost‐effectiveness could enhance RSV management in children.

Evaluate the association between provider-ordered viral testing and antibiotic treatment practices among children discharged from an ED or hospitalized with an acute respiratory infection (ARI). Active, prospective ARI surveillance study from November 2017 to February 2020. Pediatric hospital and emergency department in Nashville, Tennessee. Children 30 days to 17 years old seeking medical care for fever and/or respiratory symptoms. Antibiotics prescribed during the child's ED visit or administered during hospitalization were categorized into (1) None administered; (2) Narrow-spectrum; and (3) Broad-spectrum. Setting-specific models were built using unconditional polytomous logistic regression with robust sandwich estimators to estimate the adjusted odds ratios and 95% confidence intervals between provider-ordered viral testing (ie, tested versus not tested) and viral test result (ie, positive test versus not tested and negative test versus not tested) and three-level antibiotic administration. 4,107 children were enrolled and tested, of which 2,616 (64%) were seen in the ED and 1,491 (36%) were hospitalized. In the ED, children who received a provider-ordered viral test had 25% decreased odds (aOR: 0.75; 95% CI: 0.54, 0.98) of receiving a narrow-spectrum antibiotic during their visit than those without testing. In the inpatient setting, children with a negative provider-ordered viral test had 57% increased odds (aOR: 1.57; 95% CI: 1.01, 2.44) of being administered a broad-spectrum antibiotic compared to children without testing. In our study, the impact of provider-ordered viral testing on antibiotic practices differed by setting. Additional studies evaluating the influence of viral testing on antibiotic stewardship and antibiotic prescribing practices are needed.

Objective Features of multisystem inflammatory syndrome in children (MIS‐C) overlap with other syndromes, making the diagnosis difficult for clinicians. We aimed to compare clinical differences between patients with and without clinical MIS‐C diagnosis and develop a diagnostic prediction model to assist clinicians in identification of patients with MIS‐C within the first 24 hours of hospital presentation. Methods A cohort of 127 patients (<21 years) were admitted to an academic children's hospital and evaluated for MIS‐C. The primary outcome measure was MIS‐C diagnosis at Vanderbilt University Medical Center. Clinical, laboratory, and cardiac features were extracted from the medical record, compared among groups, and selected a priori to identify candidate predictors. Final predictors were identified through a logistic regression model with bootstrapped backward selection in which only variables selected in more than 80% of 500 bootstraps were included in the final model. Results Of 127 children admitted to our hospital with concern for MIS‐C, 45 were clinically diagnosed with MIS‐C and 82 were diagnosed with alternative diagnoses. We found a model with four variables—the presence of hypotension and/or fluid resuscitation, abdominal pain, new rash, and the value of serum sodium—showed excellent discrimination (concordance index 0.91; 95% confidence interval: 0.85‐0.96) and good calibration in identifying patients with MIS‐C. Conclusion A diagnostic prediction model with early clinical and laboratory features shows excellent discrimination and may assist clinicians in distinguishing patients with MIS‐C. This model will require external and prospective validation prior to widespread use.