Search

Objectives: Viral lower respiratory tract infection (vLRTI) contributes to substantial morbidity and mortality in children. Diagnosis is typically confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) of nasopharyngeal specimens in hospitalized patients; however, it is unknown whether nasopharyngeal detection accurately reflects presence of virus in the lower respiratory tract (LRT). This study evaluates agreement between viral detection from nasopharyngeal specimens by RT-PCR compared with metagenomic next-generation RNA sequencing (RNA-Seq) from tracheal aspirates (TAs)., Design: This is an analysis of of a seven-center prospective cohort study., Setting: Seven PICUs within academic children's hospitals in the United States., Patients: Critically ill children (from 1 mo to 18 yr) who required mechanical ventilation via endotracheal tube for greater than or equal to 72 hours., Interventions: We evaluated agreement in viral detection between paired upper and LRT samples. Results of clinical nasopharyngeal RT-PCR were compared with TA RNA-Seq. Positive and negative predictive agreement and Cohen's Kappa were used to assess agreement., Measurements and Main Results: Of 295 subjects with paired testing available, 200 (68%) and 210 (71%) had positive viral testing by RT-PCR from nasopharyngeal and RNA-Seq from TA samples, respectively; 184 (62%) were positive by both nasopharyngeal RT-PCR and TA RNA-Seq for a virus, and 69 (23%) were negative by both methods. Nasopharyngeal RT-PCR detected the most abundant virus identified by RNA-Seq in 92.4% of subjects. Among the most frequent viruses detected, respiratory syncytial virus demonstrated the highest degree of concordance (κ = 0.89; 95% CI, 0.83-0.94), whereas rhinovirus/enterovirus demonstrated lower concordance (κ = 0.55; 95% CI, 0.44-0.66). Nasopharyngeal PCR was more likely to detect multiple viruses than TA RNA-Seq (54 [18.3%] vs 24 [8.1%], p ≤ 0.001)., Conclusions: Viral nucleic acid detection in the upper versus LRT reveals good overall agreement, but concordance depends on the virus. Further studies are indicated to determine the utility of LRT sampling or the use of RNA-Seq to determine LRTI etiology., Competing Interests: This work was supported by the following cooperative agreements from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): (UG1HD083171 to Dr. Pollack), (UG1HD049983 to Dr. Carcillo) (UG01HD049934 to Drs. Reeder, Locandro, and DeRisi), (UG1HD083170 to Dr. Hall), (UG1HD050096 to Dr. Meert), (UG1HD63108 to Dr. Zuppa), (UG1HD083166 to Dr. McQuillen), (UG1HD049981 to Dr. McQuillen); the National Heart Lung Blood Institute (1R01HL124103 to Dr. Pollack) and (K23HL138461-01A1 and 5R01HL155418-03 to Dr. Langelier), and National Institutes of Health (NIH). Dr. Maddux’s institution received funding from the National Institute for Child Health and Human Development (NICHD) (K23HD096018) and the Francis Family Foundation. Dr. Caldera disclosed work for hire and she disclosed that she is a staff research associate employed through University of California San Francisco. Dr. Hall received funding from Abbvie, Kiadis, and the American Board of Pediatrics. Drs. Zuppa, Carcillo, and McQuillen’s institutions received funding from the NICHD. Dr. Carcillo’s institution received funding from the National Institute of General Medical Sciences. Dr. DeRisi received funding from Public Health Company and Allen & Co; he disclosed that he is a scientific founder and advisor for Delve Bio; he received support for article research from Chan Zuckerberg Biohub. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: Tobacco smoke exposure increases the risk and severity of lower respiratory tract infections in children, yet the mechanisms remain unclear. We hypothesized that tobacco smoke exposure would modify the lower airway microbiome., Methods: Secondary analysis of a multicenter cohort of 362 children between ages 31 days and 18 years mechanically ventilated for >72 h. Tracheal aspirates from 298 patients, collected within 24 h of intubation, were evaluated via 16 S ribosomal RNA sequencing. Smoke exposure was determined by creatinine corrected urine cotinine levels ≥30 µg/g., Results: Patients had a median age of 16 (IQR 568) months. The most common admission diagnosis was lower respiratory tract infection (53%). Seventy-four (20%) patients were smoke exposed and exhibited decreased richness and Shannon diversity. Smoke exposed children had higher relative abundances of Serratia spp., Moraxella spp., Haemophilus spp., and Staphylococcus aureus. Differences were most notable in patients with bacterial and viral respiratory infections. There were no differences in development of acute respiratory distress syndrome, days of mechanical ventilation, ventilator free days at 28 days, length of stay, or mortality., Conclusion: Among critically ill children requiring prolonged mechanical ventilation, tobacco smoke exposure is associated with decreased richness and Shannon diversity and change in microbial communities., Impact: Tobacco smoke exposure is associated with changes in the lower airways microbiome but is not associated with clinical outcomes among critically ill pediatric patients requiring prolonged mechanical ventilation. This study is among the first to evaluate the impact of tobacco smoke exposure on the lower airway microbiome in children. This research helps elucidate the relationship between tobacco smoke exposure and the lower airway microbiome and may provide a possible mechanism by which tobacco smoke exposure increases the risk for poor outcomes in children., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Lower respiratory tract infections (LRTI) are a leading cause of critical illness and mortality in mechanically ventilated children; however, the pathogenic microbes frequently remain unknown. We combined traditional diagnostics with metagenomic next generation sequencing (mNGS) to evaluate the cause of LRTI in critically ill children., Methods: We conducted a prospective, multicentre cohort study of critically ill children aged 31 days to 17 years with respiratory failure requiring mechanical ventilation (>72 h) in the USA. By combining bacterial culture and upper respiratory viral PCR testing with mNGS of tracheal aspirate collected from all patients within 24 h of intubation, we determined the prevalence, age distribution, and seasonal variation of viral and bacterial respiratory pathogens detected by either method in children with or without LRTI., Findings: Between Feb 26, 2015, and Dec 31, 2017, of the 514 enrolled patients, 397 were eligible and included in the study (276 children with LRTI and 121 with no evidence of LRTI). A presumptive microbiological cause was identified in 255 (92%) children with LRTI, with respiratory syncytial virus (127 [46%]), Haemophilus influenzae (70 [25%]), and Moraxella catarrhalis (65 [24%]) being most prevalent. mNGS identified uncommon pathogens including Ureaplasma parvum and Bocavirus. Co-detection of viral and bacterial pathogens occurred in 144 (52%) patients. Incidental carriage of potentially pathogenic microbes occurred in 82 (68%) children without LRTI, with rhinovirus (30 [25%]) being most prevalent. Respiratory syncytial virus (p<0·0001), H influenzae (p=0·0006), and M catarrhalis (p=0·0002) were most common in children younger than 5 years. Viral and bacterial LRTI occurred predominantly during winter months., Interpretation: These findings demonstrate that respiratory syncytial virus, H influenzae, and M catarrhalis contribute disproportionately to severe paediatric LRTI, co-infections are common, and incidental carriage of potentially pathogenic microbes occurs frequently. Further, we provide a framework for future epidemiological and emerging pathogen surveillance studies, highlighting the potential for metagenomics to enhance clinical diagnosis., Funding: US National Institutes of Health and CZ Biohub., Competing Interests: Declaration of interests JK reports support from Genentech, outside the submitted work. LA reports funding from Pfizer, outside the submitted work. ABM reports grants from the Francis Family Foundation and the US National Institutes of Health (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), outside the submitted work. EAFS reports grants from the US NIH during the conduct of the study. EAFS reports grants, personal fees, and non-financial support from AstraZeneca, Merck, Regeneron, Pfizer, and Roche; personal fees, non-financial support, and other support from AbbVie; personal fees from Alere; other support from GSK; grants from Johnson and Johnson; and grants and non-financial support from Novavax, outside the submitted work. MWH reports grants from NIH NICHD, during the conduct of the study; and personal fees from La Jolla Pharmaceuticals, outside the submitted work. AFZ received NICHD funding through the Collaborative Pediatric Critical Care Research Network during the conduct of the study. KLM reports grants from NIH, during the conduct of the study. AS reports grants from NIH, outside the submitted work. MMP reports grants from NIH, during the conduct of the study. PSM reports grants from NIH NICHD, during the conduct of the study. JMD reports grants from NIH, during the conduct of the study. MSZ reports grants from National Heart, Lung, and Blood Institute (NHLBI; K23HL146936), outside the submitted work. PMM reports grants from NIH, during the conduct of the study. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

We sought to determine whether temporal changes in the lower airway microbiome are associated with ventilator-associated pneumonia (VAP) in children.Using a multicentre prospective study of children aged 31 days to 18 years requiring mechanical ventilation support for >72 h, daily tracheal aspirates were collected and analysed by sequencing of the 16S rRNA gene. VAP was assessed using 2008 Centers for Disease Control and Prevention paediatric criteria. The association between microbial factors and VAP was evaluated using joint longitudinal time-to-event modelling, matched case-control comparisons and unsupervised clustering.Out of 366 eligible subjects, 66 (15%) developed VAP at a median of 5 (interquartile range 3-5) days post intubation. At intubation, there was no difference in total bacterial load (TBL), but Shannon diversity and the relative abundance of Streptococcus , Lactobacillales and Prevotella were lower for VAP subjects versus non-VAP subjects. However, higher TBL on each sequential day was associated with a lower hazard (hazard ratio 0.39, 95% CI 0.23-0.64) for developing VAP, but sequential values of diversity were not associated with VAP. Similar findings were observed from the matched analysis and unsupervised clustering. The most common dominant VAP pathogens included Prevotella species (19%), Pseudomonas aeruginosa (14%) and Streptococcus mitis / pneumoniae (10%). Mycoplasma and Ureaplasma were also identified as dominant organisms in several subjects.In mechanically ventilated children, changes over time in microbial factors were marginally associated with VAP risk, although these changes were not suitable for predicting VAP in individual patients. These findings suggest that focusing exclusively on pathogen burden may not adequately inform VAP diagnosis., Competing Interests: Conflict of interest: P.M. Mourani reports grants from NIH NHLBI and NIH NICHD, during the conduct of the study. Conflict of interest: M.K. Sontag reports grants from NIH NHLBI, during the conduct of the study. Conflict of interest: K.M. Williamson has nothing to disclose. Conflict of interest: J.K. Harris has nothing to disclose. Conflict of interest: R. Reeder has nothing to disclose. Conflict of interest: C. Locandro has nothing to disclose. Conflict of interest: T.C. Carpenter reports grants from NIH NHLBI and NIH NICHD, during the conduct of the study. Conflict of interest: A.B. Maddux reports a grant from Parker B. Francis Foundation (Fellowship Award) and NIH/NICHD K23HD096018, outside the submitted work. Conflict of interest: K. Ziegler reports grants from NIH NHLBI during the conduct of the study. Conflict of interest: E.A.F. Simões reports grants from NIH NHLBI, during the conduct of the study. Conflict of interest: C.M. Osborne has nothing to disclose. Conflict of interest: L. Ambroggio has nothing to disclose. Conflict of interest: M.K. Leroue has nothing to disclose. Conflict of interest: C.E. Robertson has nothing to disclose. Conflict of interest: C. Langelier has nothing to disclose. Conflict of interest: J.L. DeRisi reports grants from NIH NHLBI, during the conduct of the study. Conflict of interest: J. Kamm has nothing to disclose. Conflict of interest: M.W. Hall reports grants from NIH NICHD, during the conduct of the study. Conflict of interest: A.F. Zuppa has nothing to disclose. Conflict of interest: J. Carcillo has nothing to disclose. Conflict of interest: K. Meert reports grants from NIH, during the conduct of the study. Conflict of interest: A. Sapru reports grants from NIH NICHD, during the conduct of the study. Conflict of interest: M.M. Pollack reports grants from NIH, during the conduct of the study. Conflict of interest: P. McQuillen reports grants from NIH NICHD, during the conduct of the study. Conflict of interest: D.A. Notterman has nothing to disclose. Conflict of interest: J.M. Dean reports grants from NIH, during the conduct of the study. Conflict of interest: B.D. Wagner reports grants from NIH NHLBI, during the conduct of the study., (Copyright ©ERS 2021.)

Importance: The Four Corners Youth Consortium was created to fill the gap in our understanding of youth concussion. This study is the first analysis of posttraumatic headache (PTH) phenotype and prognosis in this cohort of concussed youth., Objective: To describe the characteristics of youth with PTH and determine whether the PTH phenotype is associated with outcome., Design, Setting, and Participants: This cohort study examined outcomes from patients in a multi-institutional registry of traumatic brain injury (TBI) clinics from December 2017 to June 2019. Inclusion criteria included being between ages 5 and 18 years at enrollment and presentation within 8 weeks of a mild TBI. Data were analyzed between February 2019 and January 2021., Exposure: Mild TBI with standard care., Main Outcomes and Measures: Time to recovery and headache 3 months after injury; measurement device is the Postconcussion Symptom Inventory (PCSI). PTH with migraine phenotype was defined as moderate-severe headache that is new or significantly worse compared with baseline and associated with nausea and/or photophobia and phonophobia., Results: A total of 612 patients with 625 concussions were enrolled, of whom 387 patients with 395 concussions consented to participate in this study. One hundred nine concussions were excluded (concussions, rather than patients, were the unit of analysis), leaving 281 participants with 286 concussions (168 [58.7%] girls; 195 [75.6%] White; 238 [83.2%] aged 13-18 years). At the initial visit, 133 concussions (46.5%) were from patients experiencing PTH with a migraine phenotype, 57 (20%) were from patients experiencing PTH with a nonmigraine phenotype, and 96 (34%) were from patients with no PTH. Patients with any PTH after concussion were more likely to have prolonged recovery than those without PTH (median [interquartile range], 89 [48-165] days vs 44 [26-96] days; log-rank P < .001). Patients with PTH and a migraine phenotype took significantly longer to recover than those with nonmigraine phenotype (median [interquartile range], 95 [54-195] days vs 70 [46-119] days; log-rank P = .01). Within each phenotype, there was no significant difference between sexes in recovery or PTH at 3 months., Conclusions and Relevance: PTH with a migraine phenotype is associated with persistent symptoms following concussion compared with nonmigraine PTH or no PTH. Given that female sex is associated with higher rates of migraine and migraine PTH, our finding may be one explanation for findings in prior studies that girls are at higher risk for persistent postconcussion symptoms than boys.

Importance: Pediatric mild traumatic brain injury (TBI) and concussion are a public health challenge with up to 30% of patients experiencing prolonged recovery. Pediatric patients presenting to concussion clinics often have ongoing impairments and may be at increased risk for persistent symptoms. Understanding this population is critical for improved prognostic estimates and optimal treatment., Objective: To describe pediatric patients presenting to concussion clinics and characterize factors associated with their recovery., Design, Setting, and Participants: This prospective cohort study included patients enrolled at multicenter concussion specialty clinics from the Four Corners Youth Consortium from December 2017 to July 2019, with up to 12-month follow-up. Patients were eligible if they were aged 5 to 18.99 years with a diagnosis of mild TBI or concussion presenting to participating clinics within 8 weeks of injury. Patients were excluded if the patient or their parents were unable to read or sign the consent document, or if the patient had a Glasgow Coma Scale score less than 13 or a penetrating injury. Data were analyzed from February 2019 to April 2020., Exposures: Diagnosis of mild TBI or concussion., Main Outcomes and Measures: This study used National Institute of Neurological Disorders and Stroke common data elements, including data on demographic characteristics, injury details, history, neurological and neuropsychological assessments, and treatment., Results: A total of 600 patients were consecutively enrolled, among whom 324 (54.0%) were female and 435 (72.5%) were adolescents (ie, aged 13-18 years). A higher proportion of girls and women (248 patients [76.5%]) were adolescents compared with boys and men (187 patients [67.8%]) (P = .02), and girls and women reported significantly more preexisting anxiety compared with boys and men (80 patients [26.7%] vs 46 patients [18.7%]; P = .03). Significantly more adolescents reported preexisting migraines compared with preadolescents (82 patients [20.9%] vs 15 patients [10.9%]; P = .01). Girls and women recovered more slowly than boys and men (persistent symptoms after injury: week 4, 217 patients [81.6%] vs 156 patients [71.2%]; week 8, 146 patients [58.9%] vs 89 patients [44.3%]; week 12, 103 patients [42.6%] vs 58 patients [30.2%]; P = .01). Patients with history of migraine or anxiety or depression recovered more slowly than those without, regardless of sex., Conclusions and Relevance: These findings suggest that identification of subgroups of pediatric patients with mild TBI or concussion at risk for prolonged recovery could aid in better prognostic estimates and more targeted treatment interventions.

Aim: In-hospital cardiac arrest occurs in >5000 children each year in the US and almost half will not survive to discharge. Animal data demonstrate that an immediate post-resuscitation burst of hypertension is associated with improved survival. We aimed to determine if systolic and diastolic invasive arterial blood pressures immediately (0-20 min) after return of spontaneous circulation (ROSC) are associated with survival and neurologic outcomes at hospital discharge., Methods: This is a secondary analysis of the Pediatric Intensive Care Quality of CPR (PICqCPR) study of invasively measured blood pressures during intensive care unit CPR. Patients were eligible if they achieved ROSC and had at least one invasively measured blood pressure within the first 20 min following ROSC. Post-ROSC blood pressures were normalized for age, sex and height. "Immediate hypertension" was defined as at least one systolic or diastolic blood pressure >90th percentile. The primary outcome was survival to hospital discharge., Results: Of 102 children, 70 (68.6%) had at least one episode of immediate post-CPR diastolic hypertension. After controlling for pre-existing hypotension, duration of CPR, calcium administration, and first documented rhythm, patients with immediate post-CPR diastolic hypertension were more likely to survive to hospital discharge (79.3% vs. 54.5%; adjusted OR = 2.93; 95%CI, 1.16-7.69)., Conclusions: In this post hoc secondary analysis of the PICqCPR study, 68.6% of subjects had diastolic hypertension within 20 min of ROSC. Immediate post-ROSC hypertension was associated with increased odds of survival to discharge, even after adjusting for covariates of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)