Provider-ordered viral testing and antibiotic administration practices among children with acute respiratory infections across healthcare settings in Nashville, Tennessee.

Objective: 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). Design: Active, prospective ARI surveillance study from November 2017 to February 2020. Setting: Pediatric hospital and emergency department in Nashville, Tennessee. Participants: Children 30 days to 17 years old seeking medical care for fever and/or respiratory symptoms. Methods: 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. Results: 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. Conclusions: 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.

Principal Component Patterns of Pediatric Respiratory Viral Testing Across Health Care Settings.

BACKGROUND AND OBJECTIVES: Factors prompting clinicians to request viral testing in children are unclear. We assessed patterns prompting clinicians to perform viral testing in children discharged from an emergency department (ED) or hospitalized with an acute respiratory infection (ARI). METHODS: Using active ARI surveillance data collected from November 2017 through February 2020, children aged between 30 days and 17 years with fever or respiratory symptoms who had a research respiratory specimen tested were included. Children's presentation patterns from their initial evaluation at each health care setting were analyzed using principal components (PCs) analysis. PC-specific models using logistic regression with robust sandwich estimators were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) between PCs and provider-ordered viral testing. PCs were assigned respiratory virus/viruses names a priori based on the patterns represented. RESULTS: In total, 4107 children were enrolled and tested, with 2616 (64%) discharged from the ED and 1491 (36%) hospitalized. In the ED, children with a coviral presentation pattern had a 1.44-fold (95% CI, 1.24-1.68) increased odds of receiving a provider-ordered viral test than children showing clinical symptoms less representative of coviral-like infection. Whereas children in the ED and hospitalized with rhinovirus-like symptoms had 71% (OR, 0.29; 95% CI, 0.24-0.34) and 39% (OR, 0.61; 95% CI, 0.49-0.76) decreased odds, respectively, of receiving a provider-ordered viral test during their medical encounter. CONCLUSIONS: Viral tests are frequently ordered by clinicians, but presentation patterns vary by setting and influence the initiation of testing. Additional assessments of factors affecting provider decisions to use viral testing in pediatric ARI management are needed to maximize patient benefits of testing.

Clinical characteristics and outcomes of children with single or co-detected rhinovirus-associated acute respiratory infection in Middle Tennessee.

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 χ2 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.

Respiratory pathogens during the COVID-19 pandemic: Alterations in detection and seasonality in Nashville, Tennessee.

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.

Clinical presentations of adult and pediatric SARS-CoV-2-positive cases in a community cohort, Nashville, Tennessee.

Compared to adults, the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) illness in children has been lower and less severe. However, reports comparing SARS-CoV-2 infection among children and adults are limited. As part of our longitudinal cohort study of adults and children with SARS-CoV-2 infection and their household contacts in Nashville, Tennessee, we compared the clinical characteristics and outcomes of SARS-CoV-2 infections between children and adults. Children were more likely to be asymptomatically infected and had a shorter illness duration compared to adults. The differences observed in clinical presentation across ages may inform symptom-specific testing, screening, and management algorithms.

SARS-CoV-2 vaccine safety and immunogenicity in patients with hematologic malignancies, transplantation, and cellular therapies.

Individuals with hematological malignancies and hematopoietic stem cell transplant (HCT) recipients are immunologically heterogenous groups with varying degrees of immunosuppression at increased risk of severe disease and mortality from SARS-CoV-2 infection. SARS-CoV-2 vaccines are key interventions to preventing severe COVID-19 and its complications. While these individuals were excluded from initial vaccine trials, there is now a growing body of acceptable safety and immunogenicity data among these individuals. A consistent signal for new or worsening graft versus host disease in allogeneic HCT recipients has not been demonstrated post-vaccination. Immunogenicity in these populations is variable depending on disease and treatment factors. However, serological responses may not accurately reflect vaccine protection as correlates of protection within these populations are not yet established. Large-scale studies powered to identify rare serious events, resolve differences in vaccine responses between different vaccination strategies, and identify immune correlates of protection within these populations are needed.

The impact of community closures among nonessential and essential workers, Nashville, Tennessee: A cross-sectional study.

Background and Aims: The effects of community closures and relaxing social distancing restrictions on severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) by occupational risk remain unclear. Therefore, we evaluated the impact of community closures and reopening phases with the prevalence of testing SARS-CoV-2-positive among nonessential and essential workers. Methods: We constructed a cross-sectional cohort from March 20 to July 31, 2020, of 344 adults from Metropolitan Nashville, Tennessee. We performed an unconditional logistic regression model to evaluate the impact of community closures and phase implementation on testing SARS-CoV-2 positive by occupation to estimate adjusted prevalence odds ratios (aPORs) and 95% confidence intervals (CIs). Results: During a stay-at-home/Phase I order, those with non-essential occupations had 59% decreased prevalence odds (aPOR:0.41; 95% CI: 0.20-0.84) of testing SARS-CoV-2-positive compared to when no restrictions were in place. Persons with essential occupations had four times the prevalence odds of testing SARS-CoV-2-positive (aPOR:4.19; 95% CI:1.57-11.18) compared with nonessential occupations when no community restrictions were established. Conclusion: Stay-at-home restrictions were associated with a lower risk of SARS-CoV-2 infection in the community for nonessential workers. Essential employees remained at increased risk for SARS-CoV-2, including when no community restrictions were in place and vaccines were not available. This study supports targeting prevention measures for these high-risk occupations.

Adenovirus Infection in Hospitalized Children with Acute Respiratory Infection in Jordan.

BACKGROUND: The most common clinical manifestation of adenovirus (AdV) infection is acute respiratory illness (ARI). Specific AdV species associated with ARI hospitalizations are not well defined in the Middle East. METHODS: A viral surveillance study was conducted among children <2 years hospitalized in Amman, Jordan, from March 2010 to March 2013. Nasal and throat respiratory specimens were obtained from enrolled children and tested for viruses using a real-time reverse-transcription quantitative polymerase chain reaction. AdV-positive specimens were typed by partial hexon gene sequencing. Demographic and clinical features were compared between AdV detected as single pathogen versus co-detected with other respiratory viruses, and between AdV-B and AdV-C species. RESULTS: AdV was detected in 475/3168 (15%) children hospitalized with ARI; of these, 216 (45%) specimens were successfully typed with AdV-C as the most common species detected (140/216; 65%). Children with AdV-single detection (88/475; 19%) had a higher frequency of fever (71% vs. 56%; P=0.015), diarrhea (18% vs. 11%; p=0.048), and/or seizures/abnormal movements (14% vs. 5%; p=0.003). Children with AdV co-detected with other viruses more likely required oxygen support [adjusted odds ratio (aOR) 1.91 (95% CI: 1.08, 3.39), P = 0.027] than those with AdV-single detection. Children with AdV-C had higher odds of co-detections with other viruses compared with those with AdV-B [aOR 4.00 (95% CI: 1.91, 8.44), P < 0.001]. CONCLUSION: Clinical differences were identified between AdV-single and AdV co-detected with other viruses, and between AdV-B and AdV-C. Larger studies with AdV typing are needed to determine additional epidemiological and clinical differences between specific AdV species and types.

Serological Markers of SARS-CoV-2 Reinfection.

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.

Humoral and cellular immune responses to the SARS-CoV-2 BNT162b2 vaccine among a cohort of solid organ transplant recipients and healthy controls.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with increased morbidity and mortality in solid organ transplant (SOT) recipients. Despite exclusion from SARS-CoV-2 vaccine clinical trials, these individuals were identified as high-risk and prioritized for vaccination in public health guidelines. METHODS: We prospectively evaluated humoral and cellular immune responses to two doses of the SARS-CoV-2 mRNA vaccine, BNT162b2, in 56 SOT recipients and 26 healthy controls (HCs). Blood specimens collected from participants prior to each dose and following the second dose were tested for SARS-CoV-2-specific antibodies, as well as CD4+ and CD8+ T-cell responses. RESULTS: SOT recipients demonstrated lower mean anti-SARS-CoV-2 antibody levels compared to HCs after each dose, and only 21.6% achieved an antibody response after the second dose within the range of HC responses. Similarly, the percentage of responsive CD4+ and CD8+ T cells in SOT recipients was lower than in HCs. While most HCs showed notable humoral and cellular responses, responses were less concordant in SOT recipients, with some showing evidence of either humoral or cellular response, but not both. CONCLUSION: Humoral and cellular immune responses to the BNT162b2 vaccine are markedly reduced in SOT recipients as compared to HCs, suggesting that SOT recipients may benefit from more tailored regimens such as higher dose and/or additional vaccinations.

Antibiotic use for respiratory syncytial virus in the Middle East: A surveillance study in hospitalized Jordanian children.

INTRODUCTION: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

The Clinical Characteristics, Severity, and Seasonality of RSV Subtypes Among Hospitalized Children in Jordan.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of acute respiratory infection (ARI) in young children worldwide. Multiple factors affect RSV disease severity, and data regarding differences between RSV subtypes severity are controversial. This study aimed to evaluate the clinical characteristics, seasonality and severity of RSV subtypes in children. METHODS: As part of a prospective ARI surveillance study conducted from March 2010 to March 2013 in Amman, Jordan, children less than 2 years with fever and/or respiratory symptoms were enrolled. Demographic and clinical characteristics were collected through parental interviews and medical chart review. The treating physician collected severity score data at admission. Nasal and throat swabs were collected and tested. Multivariable regression models were used to compare the odds of increased disease severity across a priori selected predictors of interest. RESULTS: Overall, 1397/3168 (44%) children were RSV positive, with a mean age of 5.3 months (±4.8 SD), 59.7% were male, 6.4% had an underlying medical condition (UMC), 63.6% were RSV-A positive, 25.2% were RSV-B positive, 0.6% were positive for both, and 10.6% could not be typed. Both RSV subtypes peaked in January-March of each year. RSV A-positive children were more likely to present with decreased appetite but less likely to have viral co-detection than RSV B-positive children. Independent factors associated with RSV disease severity included cycle threshold value, vitamin D level, age, UMC, prematurity and severity score, but not RSV subtypes. CONCLUSION: RSV subtypes co-circulated and had similar severity profiles; future preventive and treatment measures should target both subtypes.

Knowledge of, attitudes to and participation in clinical trials in Jordan: a population-based survey.

BACKGROUND: Clinical trials are important to improve public health care. However, recruiting participants for trials can be difficult. AIMS: This study assessed public knowledge of and willingness to participate in clinical trials in Jordan and examine the sociodemographic characteristics associated with knowledge and willingness and the reasons behind unwillingness to participate. METHODS: The questions were part of a representative, population-based survey in 2011 that included 3196 Jordanian individuals. In a home-based interview, participants were asked about: sociodemographic characteristics, and knowledge of and participation in clinical trials. RESULTS: Only 21.8% of respondents knew what a clinical trial was and (1.2%) had participated in a trial. About 25% of respondents indicated their willingness to enrol in a trial. Significantly more men (24.1%) than women (19.3%) knew what clinical trials were (P < 0.001), whereas more women (4.3%) than men (2.9%) said they would be very likely to agree to participate in trials. People aged 40-49 years had better knowledge of and greater willingness to participate in trials than other age groups. Income was positively associated with knowledge of trials but negatively associated with willingness to participate. Higher education was positively correlated with knowledge of and willingness to take part in trials. The main reasons for not participating in trials were concern about the risk to own health (61.1%) and not being convinced about the outcome and benefits of clinical trials (29.7%). CONCLUSION: The low level of knowledge of and willingness to participate in clinical trials indicates that strategies are needed to educate the public about the nature and importance of clinical trials.

The association between levels of inflammatory markers in autistic children compared to their unaffected siblings and unrelated healthy controls

Background/aim: Autism spectrum disorder (ASD) describes a range of neurodevelopmental disabilities that impair behavior and communication. Although it is relatively prevalent, the pathophysiology is still subject to speculation and debate. The aim of this study is to identify a possible association between interleukin-6, -8, -9, and -10 and tumor necrosis factor alpha (TNF-α) in autism among Jordanian children by comparing the plasma levels of these cytokines in autistic children with those of their unaffected siblings and unrelated healthy controls. Materials and methods: In this study, 80 Jordanian children under the age of 12 with diagnosed autism were selected. For comparison, 51 unaffected siblings and 86 unrelated healthy controls were also recruited. Venous blood was collected and interleukin levels in all three groups were investigated. Results: Interleukin-6 was found to be significantly higher in the plasma of both autistic children and their siblings compared with the unrelated healthy control group (P < 0.05). As for interleukin-8 and TNF-α, plasma levels were significantly higher exclusively in autistic children compared to their siblings and unaffected control subjects (P < 0.001, P < 0.001). There was no significant difference between plasma levels of the previously mentioned cytokines in the siblings and the unrelated control group. As for interleukin-9 and interleukin-10, no significant differences were found between all three groups (P = 0.15, P = 0.35). Conclusion: We found that interleukin-8 and TNF-α were exclusively elevated in autistic Jordanian children, while interleukin-6 was elevated in both autistic children and their siblings, potentially dismissing its significance. These results may lead to a better understanding of the disorder's pathophysiology, early testing, and diagnosis.