Respiratory Virus Surveillance Among Children with Acute Respiratory Illnesses - New Vaccine Surveillance Network, United States, 2016-2021.

The New Vaccine Surveillance Network (NVSN) is a prospective, active, population-based surveillance platform that enrolls children with acute respiratory illnesses (ARIs) at seven pediatric medical centers. ARIs are caused by respiratory viruses including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), human parainfluenza viruses (HPIVs), and most recently SARS-CoV-2 (the virus that causes COVID-19), which result in morbidity among infants and young children (1-6). NVSN estimates the incidence of pathogen-specific pediatric ARIs and collects clinical data (e.g., underlying medical conditions and vaccination status) to assess risk factors for severe disease and calculate influenza and COVID-19 vaccine effectiveness. Current NVSN inpatient (i.e., hospital) surveillance began in 2015, expanded to emergency departments (EDs) in 2016, and to outpatient clinics in 2018. This report describes demographic characteristics of enrolled children who received care in these settings, and yearly circulation of influenza, RSV, HMPV, HPIV1-3, adenovirus, human rhinovirus and enterovirus (RV/EV),* and SARS-CoV-2 during December 2016-August 2021. Among 90,085 eligible infants, children, and adolescents (children) aged <18 years† with ARI, 51,441 (57%) were enrolled, nearly 75% of whom were aged <5 years; 43% were hospitalized. Infants aged <1 year accounted for the largest proportion (38%) of those hospitalized. The most common pathogens detected were RV/EV and RSV. Before the emergence of SARS-CoV-2, detected respiratory viruses followed previously described seasonal trends, with annual peaks of influenza and RSV in late fall and winter (7,8). After the emergence of SARS-CoV-2 and implementation of associated pandemic nonpharmaceutical interventions and community mitigation measures, many respiratory viruses circulated at lower-than-expected levels during April 2020-May 2021. Beginning in summer 2021, NVSN detected higher than anticipated enrollment of hospitalized children as well as atypical interseasonal circulation of RSV. Further analyses of NVSN data and continued surveillance are vital in highlighting risk factors for severe disease and health disparities, measuring the effectiveness of vaccines and monoclonal antibody-based prophylactics, and guiding policies to protect young children from pathogens such as SARS-CoV-2, influenza, and RSV.

Clinical Presentation and Severity of Adenovirus Detection Alone vs Adenovirus Co-detection With Other Respiratory Viruses in US Children With Acute Respiratory Illness from 2016 to 2018.

BACKGROUND: Human adenovirus (HAdV) is commonly associated with acute respiratory illnesses (ARI) in children and is also frequently co-detected with other viral pathogens. We compared clinical presentation and outcomes in young children with HAdV detected alone vs co-detected with other respiratory viruses. METHODS: We used data from a multicenter, prospective, viral surveillance study of children seen in the emergency department and inpatient pediatric settings at seven US sites. Children less than 18 years old with fever and/or respiratory symptoms were enrolled between 12/1/16 and 10/31/18 and tested by molecular methods for HAdV, human rhinovirus/enterovirus (HRV/EV), respiratory syncytial virus (RSV), parainfluenza (PIV, types 1-4), influenza (flu, types A-C), and human metapneumovirus (HMPV). Our primary measure of illness severity was hospitalization; among hospitalized children, secondary severity outcomes included oxygen support and length of stay (LOS). RESULTS: Of the 18,603 children enrolled, HAdV was detected in 1,136 (6.1%), among whom 646 (56.9%) had co-detection with at least one other respiratory virus. HRV/EV (n = 293, 45.3%) and RSV (n = 123, 19.0%) were the most frequent co-detections. Children with HRV/EV (aOR = 1.61; 95% CI = [1.11-2.34]), RSV (aOR = 4.48; 95% CI = [2.81-7.14]), HMPV (aOR = 3.39; 95% CI = [1.69-6.77]), or ≥ 2 co-detections (aOR = 1.95; 95% CI = [1.14-3.36]) had higher odds of hospitalization compared to children with HAdV alone. Among hospitalized children, HAdV co-detection with RSV or HMPV was each associated with higher odds of oxygen support, while co-detection with PIV or influenza viruses was each associated with higher mean LOS. CONCLUSIONS: HAdV co-detection with other respiratory viruses was associated with greater disease severity among children with ARI compared to HAdV detection alone.

Fatal Neonatal Sepsis Associated with Human Adenovirus Type 56 Infection: Genomic Analysis of Three Recent Cases Detected in the United States.

BACKGROUND: Human adenovirus (HAdV)-D56 was first described in 2011 by genomics analysis of a strain isolated in France in 2008 from a fatal case of neonatal infection. Since then, it has been reported in cases of keratoconjunctivitis and male urethritis. Three epidemiologically unrelated fatal cases of neonatal sepsis associated with infection by HAdV-D strains with a similar genetic makeup were documented in the United States between 2014 and 2020. METHODS: Whole genome sequences were obtained for the isolated strains, and genomics analyses were conducted to compare them to phylogenetically related HAdV-D genomic sequences available in GenBank. RESULTS: The three new US strains were indistinguishable by in silico restriction enzyme analysis. Their genome sequences were 99.9% identical to one another and to the prototype strain isolated in 2008 from a similar context of disease. The phylogenetic reconstruction revealed a highly supported clustering of all HAdV-D56 strains isolated in various countries since 1982. Our comparison to serologically intermediate strains 15/H9 described in the literature indicated that HAdV-D56-like viruses have circulated worldwide since the late 1950s. CONCLUSION: As with other HAdV-D genotypes with the ability to infect ocular and genital mucosae, the risk of severe prenatal or perinatal HAdV-D56 infection must be considered.

Viral Etiology of Acute Gastroenteritis in <2-Year-Old US Children in the Post-Rotavirus Vaccine Era.

BACKGROUND: The rotavirus disease burden has declined substantially since rotavirus vaccine was introduced in the United States in 2006. The aim of this study was to determine the viral etiology of acute gastroenteritis (AGE) in US children aged <2 years. METHODS: The New Vaccine Surveillance Network (NVSN) of geographically diverse US sites conducts active pediatric population-based surveillance in hospitals and emergency departments. Stool samples were collected from children aged <2 years with symptoms of AGE (n = 330) and age-matched healthy controls (HCs) (n = 272) between January and December 2012. Samples were tested by real-time reverse-transcriptase polymerase chain reaction assays {adenovirus (type 40 and 41), norovirus, parechovirus A, enterovirus, sapovirus, and astrovirus} and an enzyme immunoassay (rotavirus). All samples that tested positive were genotyped. RESULTS: Detection rates of pathogens in children with AGE versus those of HCs were, respectively, 23.0% versus 6.6% for norovirus (P < .01), 23.0% versus 16.0% for adenovirus (P = .08), 11.0% versus 16.0% for parechovirus A (P = .09), 11.0% versus 9.0% for enterovirus (P = .34), 7.0% versus 3.0% for sapovirus (P = .07), 3.0% versus 0.3% for astrovirus (P = .01), and 3.0% versus 0.4% for rotavirus (P = .01). A high prevalence of adenovirus was detected at 1 surveillance site (49.0% for children with AGE and 43.0% for HCs). Norovirus GII.4 New Orleans was the most frequently detected (33.0%) norovirus genotype. Codetection of >1 virus was more common in children with AGE (16.0%) than in HCs (10.0%) (P = .03). CONCLUSIONS: Norovirus, astrovirus, sapovirus, and rotavirus were detected significantly more in children with AGE than in HCs, and norovirus was the leading AGE-causing pathogen in US children aged <2 years during the year 2012.

Comparison of three multiplex gastrointestinal platforms for the detection of gastroenteritis viruses.

BACKGROUND: Viruses are major etiological agents of childhood gastroenteritis. In recent years, several molecular platforms for the detection of viral enteric pathogens have become available. OBJECTIVE/STUDY DESIGN: We evaluated the performance of three multiplex platforms including Biofire's Gastrointestinal Panel (FilmArray), Luminex xTAG® Gastrointestinal Pathogen Panel (GPP), and the TaqMan Array Card (TAC) for the detection of five gastroenteritis viruses using a coded panel of 300 archived stool samples. RESULTS: The FilmArray detected a virus in 199 (96.1%) and the TAC in 172 (83.1%) of the 207 samples (187 samples positive for a single virus and 20 samples positive for more than one virus) whereas the GPP detected a virus in 100 (78.7%) of the 127 (97 positive for one virus and three positive for more than one virus) samples. Overall the clinical accuracy was highest for the FilmArray (98%) followed by TAC (97.2%) and GPP (96.9%). The sensitivity of the FilmArray, GPP and TAC platforms was highest for rotavirus (100%, 95.8%, and 89.6%, respectively) and lowest for adenovirus type 40/41 (97.4%, 57.9% and 68.4%). The specificity of the three platforms ranged from 95.6% (rotavirus) to 99.6% (norovirus/sapovirus) for the FilmArray, 99.6% (norovirus) to 100% (rotavirus/adenovirus) for GPP, and 98.9% (astrovirus) to 100% (rotavirus/sapovirus) for TAC. CONCLUSION: The FilmArray demonstrated the best analytical performance followed by TAC. In recent years, the availability of multi-enteric molecular testing platforms has increased significantly and our data highlight the strengths and weaknesses of these platforms.

Newborn screening for SCID in New York State: experience from the first two years.

PURPOSE: To describe the process and assess outcomes for the first 2 years of newborn screening for severe combined immunodeficiency (SCID NBS) in New York State (NYS). METHODS: The NYS algorithm utilizes a first-tier molecular screen for TRECs (T-cell receptor excision circles), the absence of which is indicative of increased risk of immunodeficiency. RESULTS: During the first 2 years, 485,912 infants were screened for SCID. Repeat specimens were requested from 561 premature and 746 non-premature infants with low or borderline TRECs. A total of 531 infants were referred for diagnostic evaluation leading to identification of 10 infants with SCID and 87 with a clinically significant non-SCID abnormality based on flow cytometry or CBC results (positive predictive value 20.3 %). Nine infants were diagnosed with typical SCID and one with leaky SCID. SCID diagnoses included two patients with adenosine deaminase deficiency, three patients with typical and one with leaky IL2RG-related SCID, one patient with IL7Rα-related SCID, and three cases of typical SCID, etiology unknown. TRECs were undetectable in eight of the nine babies with typical SCID. Infants with other non-SCID conditions included 27 patients with a syndrome that included T-cell impairment, 18 of which had DiGeorge syndrome. Seventeen infants had T-cell impairment secondary to another clinically significant condition, and 13 were classified as 'other'. Among 30 infants classified as idiopathic T-cell lymphopenia, 11 have since resolved, and the remainder continues to be followed. One infant with undetectable TRECs had normal follow-up studies. Molecular studies revealed the presence of two changes in the infant's DNA. CONCLUSIONS: Overall, ten infants with SCID were identified during the first 2 years of screening in NYS, yielding an incidence of approximately 1 in 48,500 live births, which is consistent with the incidence observed by other states screening for SCID. The incidence of any clinically significant laboratory abnormality was approximately 1 in 5,000; both estimates are higher than estimates prior to the onset of newborn screening for SCID. Improvements to the NYS algorithm included the addition of a borderline category that reduced the proportion of infants referred for flow cytometric analysis, without decreasing sensitivity. We identified a large number of infants with abnormal TRECs and subsequent idiopathic T-cell lymphopenia. Long-term follow-up studies are needed to determine the prognosis and optimal treatment for this group of patients, some of whom may present with previously unrecognized, transient lymphopenia of infancy.

Field evaluation of TaqMan Array Card (TAC) for the simultaneous detection of multiple respiratory viruses in children with acute respiratory infection.

BACKGROUND: Multipathogen reverse transcription real-time PCR (RT-qPCR) platforms have proven useful in surveillance for acute respiratory illness (ARI) and study of respiratory outbreaks of unknown etiology. The TaqMan(®) Array Card (TAC, Life Technologies™), can simultaneously test 7 clinical specimens for up to 21 individual pathogens (depending on arrangement of controls and use of duplicate wells) by arrayed singleplex RT-qPCR on a single assay card, using minimal amounts of clinical specimens. A previous study described the development of TAC for the detection of respiratory viral and bacterial pathogens; the assay was evaluated against well-characterized analytical materials and a limited collection of human clinical specimens. OBJECTIVES: We wished to compare TAC assay performance against standard individual RT-qPCR assays for respiratory viral detection, focusing on 10 viruses (adenovirus, human metapneumovirus, human parainfluenza viruses 1-4, influenza viruses A and B, respiratory syncytial virus, and rhinovirus) from a larger collection of human specimens. STUDY DESIGN: We used specimens from 942 children with ARI enrolled systematically in a population-based, ARI surveillance study (New Vaccine Surveillance Network, NVSN). RESULTS: Compared with standard individual RT-qPCR assays, the sensitivity of TAC for the targeted viruses ranged from 54% to 95% (54%, 56%, and 75% for adenovirus, human parainfluenza viruses-1 and -2, respectively, and 82%-95% for the other viruses). Assay specificity was 99%, and coefficients of variation for virus controls ranged from 1.5% to 4.5%. CONCLUSION: The TAC assay should prove useful for multipathogen studies and rapid outbreak response.

Bacteremia in children with sickle hemoglobinopathies.

BACKGROUND: Bacteremia is one of the most feared infectious complications of sickle cell disease, and it is associated with a high mortality rate in children. The objective of our study was to investigate the proportion of bacteremia among febrile children with sickle hemoglobinopathies and the clinical factors associated with bacteremia. METHODS: Clinical and microbiological data from children with sickle hemoglobinopathies being followed up at the Pediatric Hematology Clinic at the University of Rochester Medical Center in Rochester, New York, were retrospectively analyzed. The data were collected from medical records covering the time period of June 1997 to December 2006, which included the periods before and after the introduction of routine heptavalent pneumococcal conjugate vaccine usage. Proportions of positive blood cultures among febrile children, the types of organisms causing bacteremia, and clinical and sociodemographic factors were analyzed by χ and t tests as appropriate. RESULTS: The overall proportion of positive blood cultures was 3.8%; 1% was considered to yield true pathogens. Pneumococcal bacteremia decreased from 0.7% in the pre-pneumococcal conjugate vaccine-7 era to 0.2% in the post-pneumococcal conjugate vaccine-7 era; however, the difference was not statistically significant. Pathogens other than pneumococcus were responsible for most bacteremic episodes. No clinical or social factors were found to have statistically significant associations with positive blood cultures. CONCLUSIONS: Approximately 1% of children with sickle hemoglobinopathies with fever have bacteremia despite current penicillin prophylaxis and pneumococcal immunization, although most episodes are due to nonpneumococcal pathogens. Prompt evaluation of such febrile children with sickle hemoglobinopathies remains warranted.

Safety of live attenuated influenza vaccine in mild to moderately immunocompromised children with cancer.

BACKGROUND: The safety of intranasal live-attenuated influenza vaccine (LAIV) in immunocompromised children with cancer is unknown. The objective of this study was to describe the safety and immunogenicity of LAIV in mild to moderately immunocompromised children with cancer. METHODS: We conducted a multicenter, randomized, double-blind study of LAIV versus placebo in children aged 5-17 years with cancer. LAIV (frozen formulation) or allantoic fluid/buffer was administered intranasally. Reactogenicity, adverse events, blood for immune assays, and nasal swabs for viral shedding were obtained during 5 visits over the first 42 days postvaccination; information concerning serious adverse events (SAEs) was collected for 180 days. RESULTS: 20 subjects were enrolled (LAIV, n=10; placebo, n=10) with a mean age of 12.2 years. Ten subjects had hematologic malignancy (LAIV, n=4; placebo, n=6); 10 subjects had solid tumors (LAIV, n=6; placebo, n=4). One subject was excluded from immunogenicity analysis for not receiving a full dose of LAIV. LAIV resulted in an increased incidence of runny nose/nasal congestion occurring in all LAIV recipients; no related SAEs were observed. Four of 10 LAIV recipients shed vaccine virus, with none exceeding 7-10 days duration. LAIV demonstrated modest immunogenicity by hemagglutination inhibition (≥ 4 fold rise for any strain, 33%) and microneutralization assays (≥ 4 fold rise for any strain, 44%). CONCLUSION: In this small pilot study conducted in mild to moderately immunocompromised children with cancer, runny nose/nasal congestion was increased in LAIV recipients, no related SAEs occurred, and prolonged viral shedding was not detected. Moderate immunogenicity was demonstrated in this small group of individuals.

The effect of a structured exercise program on nutrition and fitness outcomes in human immunodeficiency virus-infected children.

The feasibility and effectiveness of a hospital-based exercise-training program followed by a home-based program for improving fitness, strength, and changes in body composition in children and adolescents with HIV were evaluated. Subjects participated in nonrandomized 24-session, hospital supervised exercise training program followed by an 314 unsupervised home-based maintenance program. Outcome measurements included muscular strength/endurance, flexibility, relative peak VO(2), body composition, and lipids. Seventeen subjects (eight females) with a median age of 15.0 years (range: 6.0-22.6) and BMI z-score of 0.61 (range: -1.70-2.57) at entry completed the intervention. After 24 training sessions, the median increases in muscular strength were between 8% and 50%, depending on muscle group. The median increases in muscle endurance, relative peak VO(2), and lean body mass were 38.7% (95% CI: 12.5-94.7; p = 0.006), 3.0 ml/kg/min (95% CI: 1.5-6.0; p < 0.001), and 4.5% (95% CI: 2.4-6.6; p < 0.001), respectively. Twelve children completed the home-based maintenance program. Median changes in these outcomes between completion of the hospital-based intervention and a follow-up after completion of the home-based program were near zero. No adverse events occurred during the intervention. A supervised hospital-based fitness program is feasible, safe, and effective for improving general fitness and strength as well as lean body mass in children with HIV.

Rhinovirus-associated hospitalizations in young children.

BACKGROUND: Rhinoviruses frequently cause the common cold but have not been considered important causes of acute respiratory hospitalizations in children. METHODS: A population-based surveillance study was performed among children <5 years of age who were hospitalized with respiratory symptoms or fever and who resided within counties encompassing Nashville, Tennessee, or Rochester, New York, from October 2000 through September 2001. Data collected included questionnaires, nasal and throat swabs for viral culture and polymerase chain reaction testing, and chart review. Rates of rhinovirus-associated hospitalizations were calculated. RESULTS: Of 592 children enrolled, 156 (26%) were rhinovirus positive, representing 4.8 (95% confidence interval [CI], 4.3-5.2) rhinovirus-associated hospitalizations/1000 children. Age-specific rates per 1000 children were 17.6 (95% CI, 14.9-20.6) for 0-5-month-olds, 6.0 (95% CI, 5.0-7.0) for 6-23-month-olds, and 2.0 (95% CI, 1.6, 2.4) for 24-59-month-olds (P<.01). Children with a history of wheezing/asthma had significantly more rhinovirus-associated hospitalizations than those without a history (25.3/1000 children [95% CI, 21.6-29.5/1000 children] vs. 3.1/1000 children [95% CI, 2.7-3.5/1000 children]). CONCLUSIONS: Rhinoviruses were associated with nearly 5 hospitalizations/1000 children <5 years of age and were highest in children with a history of wheezing/asthma.