Tracheostomy in children is associated with neutrophilic airway inflammation

Background Tracheostomies in children are associated with significant morbidity, poor quality of life, excess healthcare costs and excess mortality. The underlying mechanisms facilitating adverse respiratory outcomes in tracheostomised children are poorly understood. We aimed to characterise airway host defence in tracheostomised children using serial molecular analyses. Methods Tracheal aspirates, tracheal cytology brushings and nasal swabs were prospectively collected from children with a tracheostomy and controls. Transcriptomic, proteomic and metabolomic methods were applied to characterise the impact of tracheostomy on host immune response and the airway microbiome. Results Children followed up serially from the time of tracheostomy up to 3 months postprocedure (n=9) were studied. A further cohort of children with a long-term tracheostomy were also enrolled (n=24). Controls (n=13) comprised children without a tracheostomy undergoing bronchoscopy. Long-term tracheostomy was associated with airway neutrophilic inflammation, superoxide production and evidence of proteolysis when compared with controls. Reduced airway microbial diversity was established pre-tracheostomy and sustained thereafter. Conclusions Long-term childhood tracheostomy is associated with a inflammatory tracheal phenotype characterised by neutrophilic inflammation and the ongoing presence of potential respiratory pathogens. These findings suggest neutrophil recruitment and activation as potential exploratory targets in seeking to prevent recurrent airway complications in this vulnerable group of patients.

[1]  Andrew J. Sims,et al.  National Cohort Study of Health Care Resource Use After Pediatric Tracheostomy. , 2022, JAMA pediatrics.

[2]  Jiang Zheng,et al.  Imbalanced GSH/ROS and sequential cell death , 2021, Journal of biochemical and molecular toxicology.

[3]  Kiran B. Hebbar,et al.  Mortality and Outcomes of Pediatric Tracheostomy Dependent Patients , 2021, Frontiers in Pediatrics.

[4]  T. Corte,et al.  Therapeutic targets in lung tissue remodelling and fibrosis. , 2021, Pharmacology & therapeutics.

[5]  E. Sanders,et al.  The respiratory microbiota during and following mechanical ventilation for respiratory infections in children , 2020, European Respiratory Journal.

[6]  J. Aran,et al.  Airway Redox Homeostasis and Inflammation Gone Awry: From Molecular Pathogenesis to Emerging Therapeutics in Respiratory Pathology , 2020, International journal of molecular sciences.

[7]  R. Agbeko,et al.  Pediatric tracheostomy: A large single‐center experience , 2020, The Laryngoscope.

[8]  A. Devin,et al.  Neutrophil Metabolic Shift during Their Lifecycle: Impact on Their Survival and Activation , 2019, International journal of molecular sciences.

[9]  Elizabeth L. Westwood,et al.  Quality of life in paediatric tracheostomy patients and their caregivers - A cross-sectional study. , 2019, International journal of pediatric otorhinolaryngology.

[10]  A. Herr,et al.  Feasibility of shotgun metagenomics to assess microbial ecology of pediatric tracheostomy tubes , 2018, The Laryngoscope.

[11]  J. Perry,et al.  Excess Mucin Impairs Subglottic Epithelial Host Defense in Mechanically Ventilated Patients , 2018, American journal of respiratory and critical care medicine.

[12]  O. Koren,et al.  Antibiotics in early life: dysbiosis and the damage done , 2018, FEMS microbiology reviews.

[13]  F. Culley,et al.  Innate Immunity to Respiratory Infection in Early Life , 2017, Front. Immunol..

[14]  E. Castro-Nallar,et al.  The temporal dynamics of the tracheal microbiome in tracheostomised patients with and without lower respiratory infections , 2017, PloS one.

[15]  M. Ochs,et al.  Development, remodeling and regeneration of the lung: coping with the structural and functional challenges of breathing , 2017, Cell and Tissue Research.

[16]  M. Hall,et al.  Two‐year mortality, complications, and healthcare use in children with medicaid following tracheostomy , 2016, The Laryngoscope.

[17]  C. O'Brien,et al.  Description of Respiratory Microbiology of Children With Long-Term Tracheostomies , 2016, Respiratory Care.

[18]  P. Minneci,et al.  Tracheostomy Placement in Children Younger Than 2 Years: 30-Day Outcomes Using the National Surgical Quality Improvement Program Pediatric. , 2016, JAMA otolaryngology-- head & neck surgery.

[19]  H. Muntz,et al.  Emergency department use among children with tracheostomies: Avoidable visits. , 2015, Journal of pediatric rehabilitation medicine.

[20]  Aedín C. Culhane,et al.  A multivariate approach to the integration of multi-omics datasets , 2014, BMC Bioinformatics.

[21]  M. Pagala,et al.  Bronchoscopic and Nonbronchoscopic Methods of Airway Culturing in Tracheostomized Children , 2014, Respiratory Care.

[22]  Andreas Krämer,et al.  Causal analysis approaches in Ingenuity Pathway Analysis , 2013, Bioinform..

[23]  Sarah L. Westcott,et al.  Development of a Dual-Index Sequencing Strategy and Curation Pipeline for Analyzing Amplicon Sequence Data on the MiSeq Illumina Sequencing Platform , 2013, Applied and Environmental Microbiology.

[24]  Yan Zhang,et al.  Characterization of methionine oxidation and methionine sulfoxide reduction using methionine-rich cysteine-free proteins , 2012, BMC Biochemistry.

[25]  T. Dahms,et al.  Innate immunity mediating inflammation secondary to endotracheal intubation. , 2012, Archives of otolaryngology--head & neck surgery.

[26]  Ó. Asensio,et al.  Paediatric patients with a tracheostomy: a multicentre epidemiological study , 2012, European Respiratory Journal.

[27]  A. Zychlinsky,et al.  Neutrophil function: from mechanisms to disease. , 2012, Annual review of immunology.

[28]  Paul McNally,et al.  Decreased Levels of Secretory Leucoprotease Inhibitor in the Pseudomonas-Infected Cystic Fibrosis Lung Are Due to Neutrophil Elastase Degradation1 , 2009, The Journal of Immunology.

[29]  Dionne A. Graham,et al.  Predictors of Clinical Outcomes and Hospital Resource Use of Children After Tracheotomy , 2009, Pediatrics.

[30]  Corey D. DeHaven,et al.  Integrated, nontargeted ultrahigh performance liquid chromatography/electrospray ionization tandem mass spectrometry platform for the identification and relative quantification of the small-molecule complement of biological systems. , 2009, Analytical chemistry.

[31]  M. Mann,et al.  MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification , 2008, Nature Biotechnology.

[32]  J. Elborn,et al.  Neutrophils in cystic fibrosis , 2008, Thorax.

[33]  J. Clancy,et al.  A Novel Proteolytic Cascade Generates an Extracellular Matrix-Derived Chemoattractant in Chronic Neutrophilic Inflammation12 , 2008, The Journal of Immunology.

[34]  A. Kraneveld,et al.  A novel peptide CXCR ligand derived from extracellular matrix degradation during airway inflammation , 2006, Nature Medicine.

[35]  T. Nicolai,et al.  Airway inflammation in children with tracheostomy , 2004, Pediatric pulmonology.

[36]  D. Townsend,et al.  The importance of glutathione in human disease. , 2003, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[37]  Y. Benjamini,et al.  Controlling the false discovery rate in behavior genetics research , 2001, Behavioural Brain Research.

[38]  W. MacNee,et al.  Oxidative stress and regulation of glutathione in lung inflammation. , 2000, The European respiratory journal.

[39]  W. Vogt Oxidation of methionyl residues in proteins: tools, targets, and reversal. , 1995, Free radical biology & medicine.