Diagnostic models predicting paediatric viral acute respiratory infections: a systematic review.

OBJECTIVES: To systematically review and evaluate diagnostic models used to predict viral acute respiratory infections (ARIs) in children. DESIGN: Systematic review. DATA SOURCES: PubMed and Embase were searched from 1 January 1975 to 3 February 2022. ELIGIBILITY CRITERIA: We 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 SYNTHESIS: Study 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). RESULTS: Of 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. CONCLUSIONS: Diagnostic 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 NUMBER: CRD42022308917.

Circulation of Rhinoviruses and/or Enteroviruses in Pediatric Patients With Acute Respiratory Illness Before and During the COVID-19 Pandemic in the US.

Importance: Rhinoviruses and/or enteroviruses, which continued to circulate during the COVID-19 pandemic, are commonly detected in pediatric patients with acute respiratory illness (ARI). Yet detailed characterization of rhinovirus and/or enterovirus detection over time is limited, especially by age group and health care setting. Objective: To quantify and characterize rhinovirus and/or enterovirus detection before and during the COVID-19 pandemic among children and adolescents seeking medical care for ARI at emergency departments (EDs) or hospitals. Design, Setting, and Participants: This cross-sectional study used data from the New Vaccine Surveillance Network (NVSN), a multicenter, active, prospective surveillance platform, for pediatric patients who sought medical care for fever and/or respiratory symptoms at 7 EDs or hospitals within NVSN across the US between December 2016 and February 2021. Persons younger than 18 years were enrolled in NVSN, and respiratory specimens were collected and tested for multiple viruses. Main Outcomes and Measures: Proportion of patients in whom rhinovirus and/or enterovirus, or another virus, was detected by calendar month and by prepandemic (December 1, 2016, to March 11, 2020) or pandemic (March 12, 2020, to February 28, 2021) periods. Month-specific adjusted odds ratios (aORs) for rhinovirus and/or enterovirus-positive test results (among all tested) by setting (ED or inpatient) and age group (<2, 2-4, or 5-17 years) were calculated, comparing each month during the pandemic to equivalent months of previous years. Results: Of the 38 198 children and adolescents who were enrolled and tested, 11 303 (29.6%; mean [SD] age, 2.8 [3.7] years; 6733 boys [59.6%]) had rhinovirus and/or enterovirus-positive test results. In prepandemic and pandemic periods, rhinoviruses and/or enteroviruses were detected in 29.4% (9795 of 33 317) and 30.9% (1508 of 4881) of all patients who were enrolled and tested and in 42.2% (9795 of 23 236) and 73.0% (1508 of 2066) of those with test positivity for any virus, respectively. Rhinoviruses and/or enteroviruses were the most frequently detected viruses in both periods and all age groups in the ED and inpatient setting. From April to September 2020 (pandemic period), rhinoviruses and/or enteroviruses were detectable at similar or lower odds than in prepandemic years, with aORs ranging from 0.08 (95% CI, 0.04-0.19) to 0.76 (95% CI, 0.55-1.05) in the ED and 0.04 (95% CI, 0.01-0.11) to 0.71 (95% CI, 0.47-1.07) in the inpatient setting. However, unlike some other viruses, rhinoviruses and/or enteroviruses soon returned to prepandemic levels and from October 2020 to February 2021 were detected at similar or higher odds than in prepandemic months in both settings, with aORs ranging from 1.47 (95% CI, 1.12-1.93) to 3.01 (95% CI, 2.30-3.94) in the ED and 1.36 (95% CI, 1.03-1.79) to 2.44 (95% CI, 1.78-3.34) in the inpatient setting, and in all age groups. Compared with prepandemic years, during the pandemic, rhinoviruses and/or enteroviruses were detected in patients who were slightly older, although most (74.5% [1124 of 1508]) were younger than 5 years. Conclusions and Relevance: Results of this study show that rhinoviruses and/or enteroviruses persisted and were the most common respiratory virus group detected across all pediatric age groups and in both ED and inpatient settings. Rhinoviruses and/or enteroviruses remain a leading factor in ARI health care burden, and active ARI surveillance in children and adolescents remains critical for defining the health care burden of respiratory viruses.

A Diagnostic Prediction Model to Distinguish Multisystem Inflammatory Syndrome in Children.

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.

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.

Comparison of clinical presentations and burden of respiratory syncytial virus in infants across three distinct healthcare settings in Davidson County, Tennessee.

Background: The burden of respiratory syncytial virus (RSV)-associated acute respiratory illnesses among healthy infants (<1 year) in the inpatient setting is well established. The focus on RSV-associated illnesses in the outpatient (OP) and emergency department (ED) settings are however understudied. We sought to determine the spectrum of RSV illnesses in infants at three distinct healthcare settings. Methods: From 16 December 2019 through 30 April 2020, we performed an active, prospective RSV surveillance study among infants seeking medical attention from an inpatient (IP), ED, or OP clinic. Infants were eligible if they presented with fever and/or respiratory symptoms. Demographics, clinical characteristics, and illness histories were collected during parental/guardian interviews, followed by a medical chart review and illness follow-up surveys. Research nasal swabs were collected and tested for respiratory pathogens for all enrolled infants. Results: Of the 627 infants screened, 475 were confirmed eligible; 360 were enrolled and research tested. Within this final cohort, 101 (28%) were RSV-positive (IP = 37, ED = 18, and OP = 46). Of the RSV-positive infants, the median age was 4.5 months and 57% had ⩾2 healthcare encounters. The majority of RSV-positive infants were not born premature (88%) nor had underlying medical conditions (92%). RSV-positive infants, however, were more likely to have a lower respiratory tract infection than RSV-negative infants (76% vs 39%, p < 0.001). Hospitalized infants with RSV were younger, 65% required supplemental oxygen, were more likely to have lower respiratory tract symptoms, and more often had shortness of breath and rales/rhonchi than RSV-positive infants in the ED and OP setting. Conclusion: Infants with RSV illnesses seek healthcare for multiple encounters in various settings and have clinical difference across settings. Prevention measures, especially targeted toward healthy, young infants are needed to effectively reduce RSV-associated healthcare visits.

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.

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.

Clinical Presentations of Adult and Pediatric SARS-CoV-2-Positive Cases in a Community Cohort

OBJECTIVES/GOALS: The spectrum of disease caused by SARS-CoV-2 ranges from asymptomatic detection to severe illness, with varying presentations by age. Therefore, we aimed to compare the clinical characteristics between children and adults with SARS-CoV-2. METHODS/STUDY POPULATION: From March 20, 2020, to August 18, 2021, we conducted SARS-CoV-2 surveillance in individuals from metropolitan Nashville, TN. Children with multisystem inflammatory syndrome were excluded. Analyses were restricted to individuals with SARS-CoV-2 infection confirmed by detection of viral RNA in nasal specimens using reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and/or by detection of serum IgG to the SARS-CoV-2 spike and nucleocapsid proteins using enzyme-linked immunosorbent assay (ELISA). Those with negative RT-qPCR results, but a positive ELISA within 4-6 weeks of symptom onset, were classified as SARS-CoV-2 positive. Clinical characteristics between children and adults were compared with Pearson’s chi square. Illness duration was compared using Kaplan Meier estimators. RESULTS/ANTICIPATED RESULTS: Overall, 426/826 (49%) individuals (children: 57 [13%);adults: 369 [87%]) were SARS-CoV-2 positive, with median ages of 12 and 41 years, respectively. Most individuals were female (54%) and white, non-Hispanic (79%). Compared to adults, children were more likely to be asymptomatic (children: 16% vs. adults: 5%;p=0.001). In contrast, symptomatic adults were more likely to report cough (71% vs. 56%), wheezing (21% vs. 8%), shortness of breath (45% vs. 19%), ageusia (67% vs. 23%), and anosmia (64% vs 27%) than symptomatic children (p<0.05). Mean illness duration was shorter in children than adults: 7 days (95% CI: 5.1, 8.9) vs. 14 days (95% CI: 12.4,15.0), respectively. A total of 5% (18/352) of adults reported symptoms lasting ? 4 weeks (range: 31-96 days), whereas all symptoms in children resolved by 31 days. DISCUSSION/SIGNIFICANCE: Overall, children with SARS-CoV-2 present with a shorter and milder disease course compared to adults. Further studies are needed to understand SARS-CoV-2 illness severity across the lifespan.

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.

Distribution of Respiratory Viral Pathogens in Infants Across Different Clinical Settings from December 2019 to April 2020

Background. Acute respiratory infections (ARI) are a major cause of morbidity and mortality in young children, with viral pathogens being the most common etiologies. However, due to limited and inconsistent clinical diagnostic viral testing in the outpatient (OP) setting compared to the inpatient (IP) setting, the actual burden and distribution of viral pathogens across these clinical settings remain largely underreported. We aimed to evaluate the frequency of common respiratory viruses in medically attended ARI in infants. Methods. We conducted a prospective viral surveillance study in Davidson County, TN. Eligible infants under one year presenting with fever and/or respiratory symptoms were enrolled from OP, emergency department (ED), or IP settings. Nasal swabs were collected and tested for common viral pathogens using Luminex® NxTAG Respiratory Pathogen Panel and for SARS-CoV-2 using Luminex® NxTAG CoV extended panel. Results. From 12/16/2019 to 4/30/2020, 364 infants were enrolled, and 361 (99%) had nasal swabs collected and tested. Of those, 295 (82%) had at least one virus detected;rhinovirus/enterovirus (RV/EV) [124 (42%)], respiratory syncytial virus (RSV) [101 (32%)], and influenza (flu) [44 (15%)] were the three most common pathogens detected. No samples tested positive for SARS-CoV-2. Overall, the mean age was 6.1 months, 50% were male, 45% White and 27% Hispanic. Figure 1 shows the total number of PCR viral testing results by month. RSV was the most frequent virus detected in the IP (63%) and ED (37%) settings, while RV/EV was the most common in the OP setting (Figure 2). Figure 3 displays viral seasonality by clinical setting, showing an abrupt decrease in virus-positive cases following the implementation of a stay-at-home order on March 23, 2020 in Nashville, TN. Conclusion. Most medical encounters in infants are due to viral pathogens, with RSV, RV/EV, and flu being the most common. However, distributions differed by clinical setting, with RSV being the most frequently detected in the IP and ED settings, and second to RV/EV in the OP setting. Continued active viral ARI surveillance in various clinical settings is warranted. Preventative measures such as vaccines and infection control measures deserve study to reduce viral ARI burden.

Evaluating the diagnostic accuracy of the WHO Severe Acute Respiratory Infection (SARI) criteria in Middle Eastern children under two years over three respiratory seasons.

OBJECTIVE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Epidemiologic trends and characteristics of SARS-CoV-2 infections among children in the United States.

PURPOSE OF REVIEW: To review the epidemiological characteristics and clinical features associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections among children in the United States. RECENT FINDINGS: In the United States, the majority of SARS-CoV-2 infections in children have been mild illnesses, with those 5-17 years of age having the highest frequency. Specifically, the incidence of SARS-CoV-2 in children is two times higher in adolescents (12-17 years) than younger school-aged children (5-11 years). Despite the higher case counts in older children, 10% of pediatric hospitalizations have been in infants less than one year. In addition, severe respiratory and renal complications, hospitalization, and even death have been documented in children. SUMMARY: Clinical manifestations of SARS-CoV-2 infection in children range from asymptomatic to severe respiratory distress, with mild nonspecific symptoms being the most commonly reported. The broad clinical presentation and the frequency of asymptomatic or minimally symptomatic infections in children pose challenges for controlling and detecting SARS-CoV-2. However, severe disease has been noted in children with associated medical complications and death. Thus, additional active surveillance and research is needed to understand the burden children contribute to the SARS-CoV-2 pandemic in the United States.

Coronavirus Surveillance in a Pediatric Population in Jordan From 2010 to 2013: A Prospective Viral Surveillance Study.

BACKGROUND: Human coronaviruses (HCoVs) are a significant cause of acute respiratory illness (ARI) in children; however, the role of HCoVs in ARI among hospitalized children in the Middle East is not well defined. METHODS: Children under 2 years admitted with fever and/or respiratory symptoms were enrolled from 2010 to 2013 in Amman, Jordan. Nasal/throat swabs were collected and stored for testing. Demographic and clinical characteristics were collected through parent/guardian interviews and medical chart abstractions. Prior stored specimens were tested for HCoVs (HKU1, OC43, 229E and NL63) by qRT-PCR. RESULTS: Of the 3168 children enrolled, 6.7% were HCoVs-positive. Among HCoV-positive children, the median age was 3.8 (1.9-8.4) months, 59% were male, 14% were premature, 11% had underlying medical conditions and 76% had viral-codetection. The most common presenting symptoms were cough, fever, wheezing and shortness of breath. HCoVs were detected year-round, peaking in winter-spring months. Overall, 56%, 22%, 13% and 6% were OC43, NL63, HKU1 and 229E, respectively. There was no difference in disease severity between the species, except higher intensive care unit admission frequency in NL63-positive subjects. CONCLUSIONS: HCoVs were detected in around 7% of children enrolled in our study. Despite HCoV detection in children with ARI with highest peaks in respiratory seasons, the actual burden and pathogenic role of HCoVs in ARI merits further evaluation given the high frequency of viral codetection.