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      Viral Detection by Reverse Transcriptase Polymerase Chain Reaction in Upper Respiratory Tract and Metagenomic RNA Sequencing in Lower Respiratory Tract in Critically Ill Children With Suspected Lower Respiratory Tract Infection

      research-article
      , MD 1 , 2 , , , MD, PhD 3 , 4 , , PhD 4 , , MS 5 , , PhD 6 , 7 , , PhD 8 , , MSPH 8 , , PhD 9 , , PhD 5 , , MD, MSCS 1 , , BA 4 , , BS 4 , , BS 5 , , MD, DCH 2 , , MD 1 , , MD 1 , , MD 10 , , MD 11 , , MD 12 , , MD 13 , , MD 14 , , MD 15 , , MD 16 , , PhD 4 , , MD 17
      Pediatric Critical Care Medicine
      Lippincott Williams & Wilkins
      diagnostics, metagenomic next-generation sequencing, RNA sequencing, viral lower respiratory tract infection

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          Abstract

          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.

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          Most cited references27

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          The measurement of observer agreement for categorical data.

          This paper presents a general statistical methodology for the analysis of multivariate categorical data arising from observer reliability studies. The procedure essentially involves the construction of functions of the observed proportions which are directed at the extent to which the observers agree among themselves and the construction of test statistics for hypotheses involving these functions. Tests for interobserver bias are presented in terms of first-order marginal homogeneity and measures of interobserver agreement are developed as generalized kappa-type statistics. These procedures are illustrated with a clinical diagnosis example from the epidemiological literature.
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            Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study

            Summary Background We have previously estimated that respiratory syncytial virus (RSV) was associated with 22% of all episodes of (severe) acute lower respiratory infection (ALRI) resulting in 55 000 to 199 000 deaths in children younger than 5 years in 2005. In the past 5 years, major research activity on RSV has yielded substantial new data from developing countries. With a considerably expanded dataset from a large international collaboration, we aimed to estimate the global incidence, hospital admission rate, and mortality from RSV-ALRI episodes in young children in 2015. Methods We estimated the incidence and hospital admission rate of RSV-associated ALRI (RSV-ALRI) in children younger than 5 years stratified by age and World Bank income regions from a systematic review of studies published between Jan 1, 1995, and Dec 31, 2016, and unpublished data from 76 high quality population-based studies. We estimated the RSV-ALRI incidence for 132 developing countries using a risk factor-based model and 2015 population estimates. We estimated the in-hospital RSV-ALRI mortality by combining in-hospital case fatality ratios with hospital admission estimates from hospital-based (published and unpublished) studies. We also estimated overall RSV-ALRI mortality by identifying studies reporting monthly data for ALRI mortality in the community and RSV activity. Findings We estimated that globally in 2015, 33·1 million (uncertainty range [UR] 21·6–50·3) episodes of RSV-ALRI, resulted in about 3·2 million (2·7–3·8) hospital admissions, and 59 600 (48 000–74 500) in-hospital deaths in children younger than 5 years. In children younger than 6 months, 1·4 million (UR 1·2–1·7) hospital admissions, and 27 300 (UR 20 700–36 200) in-hospital deaths were due to RSV-ALRI. We also estimated that the overall RSV-ALRI mortality could be as high as 118 200 (UR 94 600–149 400). Incidence and mortality varied substantially from year to year in any given population. Interpretation Globally, RSV is a common cause of childhood ALRI and a major cause of hospital admissions in young children, resulting in a substantial burden on health-care services. About 45% of hospital admissions and in-hospital deaths due to RSV-ALRI occur in children younger than 6 months. An effective maternal RSV vaccine or monoclonal antibody could have a substantial effect on disease burden in this age group. Funding The Bill & Melinda Gates Foundation.
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              Community-acquired pneumonia requiring hospitalization among U.S. children.

              Incidence estimates of hospitalizations for community-acquired pneumonia among children in the United States that are based on prospective data collection are limited. Updated estimates of pneumonia that has been confirmed radiographically and with the use of current laboratory diagnostic tests are needed.
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                Author and article information

                Journal
                Pediatr Crit Care Med
                Pediatr Crit Care Med
                PCC
                Pediatric Critical Care Medicine
                Lippincott Williams & Wilkins (Hagerstown, MD )
                1529-7535
                21 September 2023
                January 2024
                : 25
                : 1
                : e1-e11
                Affiliations
                [1 ] Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO.
                [2 ] Department of Pediatrics, Section of Infectious Diseases, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO.
                [3 ] Division of Infectious Diseases, Department of Medicine, University of California San Francisco, San Francisco, CA.
                [4 ] Chan Zuckerberg Biohub, San Francisco, CA.
                [5 ] Department of Biostatistics and Informatics, University of Colorado, Colorado School of Public Health, Aurora, CO.
                [6 ] Department of Epidemiology, University of Colorado School of Medicine, Aurora, CO.
                [7 ] Department of Pediatrics, Section of Emergency Medicine, University of Colorado School of Medicine, Aurora, CO.
                [8 ] Department of Pediatrics, University of Utah, Salt Lake City, UT.
                [9 ] Department of Pediatrics, Section of Pulmonary Medicine, University of Colorado School of Medicine, Aurora, CO.
                [10 ] Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children’s Hospital and The Ohio State University College of Medicine, Columbus, OH.
                [11 ] Anesthesiology and Critical Care, Hospital of the University of Pennsylvania and the Children’s Hospital of Philadelphia, Philadelphia, PA.
                [12 ] Department of Anesthesia and Critical Care Medicine, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, PA.
                [13 ] Department of Pediatrics, Critical Care Medicine, Children’s Hospital of Michigan, Central Michigan University, Detroit, MI.
                [14 ] Department of Pediatrics, Critical Care Medicine, Children’s National Hospital, Washington, DC.
                [15 ] Department of Pediatrics, Benioff Children’s Hospital, University of California, San Francisco, San Francisco, CA.
                [16 ] Department of Molecular Biology, Princeton University, Princeton, NJ.
                [17 ] Department of Pediatrics, Critical Care, University of Arkansas for Medical Sciences and Arkansas Children’s Research Institute, Little Rock, AR.
                Author notes
                For information regarding this article, E-mail: osbornec1@ 123456chop.edu ; lilliam.ambroggio@ 123456childrenscolorado.org
                Article
                00013
                10.1097/PCC.0000000000003336
                10756702
                37732845
                204fa2ff-3609-4505-9638-487c5e78d1cc
                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.

                This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Funding
                Funded by: National Institute of Child Health and Human Development, doi 10.13039/100000071;
                Award ID: UG1HD083171
                Award Recipient : Peter M Mourani
                Funded by: National Institute of Child Health and Human Development, doi 10.13039/100000071;
                Award ID: UG1HD049983
                Award Recipient : Joseph A Carcillo
                Funded by: National Institute of Child Health and Human Development, doi 10.13039/100000071;
                Award ID: UG01HD049934
                Award Recipient : Charles Langelier
                Funded by: National Institute of Child Health and Human Development
                Award ID: UG1HD083170
                Award Recipient : Mark W Hall
                Funded by: National Institute of Child Health and Human Development, doi 10.13039/100000071;
                Award ID: UG1HD050096
                Award Recipient : Kathleen Meert
                Funded by: National Institute of Child Health and Human Development, doi 10.13039/100000071;
                Award ID: UG1HD63108
                Award Recipient : Athena Zuppa
                Funded by: National Institute of Child Health and Human Development, doi 10.13039/100000071;
                Award ID: UG1HD083166
                Award Recipient : Patrick S McQuillen
                Funded by: National Institute of Child Health and Human Development, doi 10.13039/100000071;
                Award ID: UG1HD049981
                Award Recipient : Murray M Pollack
                Funded by: NHLBI Division of Intramural Research, doi 10.13039/100017540;
                Award ID: 1R01HL124103
                Award Recipient : Peter M Mourani
                Funded by: NHLBI Division of Intramural Research, doi 10.13039/100017540;
                Award ID: K23HL138461-01A1
                Award Recipient : Charles Langelier
                Funded by: NHLBI Division of Intramural Research, doi 10.13039/100017540;
                Award ID: 5R01HL155418-03
                Award Recipient : Charles Langelier
                Categories
                Online Clinical Investigations
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                diagnostics,metagenomic next-generation sequencing,rna sequencing,viral lower respiratory tract infection

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