Health-related quality of life following aortopexy for tracheomalacia: a cross-sectional study.

OBJECTIVES: The objective was to measure health-related quality of life (HRQoL) of children following treatment of all-cause tracheomalacia with aortopexy. METHODS: Children ≥5 years and parents of children <18 years who had undergone aortopexy completed the Paediatric Quality of Life Inventory (PedsQL4.0). Scores were compared to published norms. RESULTS: Completed questionnaires were received from 35 parents (65%) and 10 children (38%). Median age at aortopexy was 9.8 months (1 month-12.7 years) and median years of follow-up was 2.6 (4 months-6.9 years). Children who completed questionnaires had a median age of 8.4 (5.7-13.4) years. Parent and child-reported total PedsQL scores were 69.61 (SD : 19.74), and 63.15 (SD : 20.40) respectively. Half of parents and 80% of children reported scores suggesting poor HRQoL outcomes. Parent-reported total, physical and psycho-social scores were lower than those of healthy children and those with acute illness but comparable to children with chronic health conditions and cardiovascular disease. Similarly, children themselves reported comparable total scores to children with chronic illness but child-reported psycho-social scores were lower in the aortopexy group than any other group. There was no association between PedsQL scores and cause of malacia, age or time since aortopexy. The presence of complex congenital comorbidities had a significant (p < 0.05) impact on HRQoL scores. CONCLUSIONS: Following aortopexy children remain at risk of poor HRQoL, especially those with complex comorbidities. HRQoL reported by both parent and child provides important insight into the lives of children following this procedure. Further longitudinal and qualitative study are required to better understand this complex group.

Novel approach for tracheal resection in Morquio a syndrome with end-stage critical airway obstruction: a UK case series.

BACKGROUND: Mucopolysaccharidosis (MPS) type IVA is a rare lysosomal storage disorder caused by aberrations of the N-acetyl-galactosamine-6-sulfatase (GALNS) enzyme. MPS IVA is associated with a wide gamut of respiratory and airway disorders that manifest in a continuum of severity. In individuals exhibiting severe phenotypic expression, terminal stages of the disease frequently culminate in life-threatening, critical airway obstruction. These manifestations of end-stage disease are engendered by an insidious progression of multi-level airway pathologies, comprising of tracheomalacia, stenosis, tortuosity and 'buckling'. Historically, the management of end-stage airway disease has predominantly leaned towards palliative modalities. However, contemporary literature has posited that the potential benefits of tracheal resection with aortopexy, performed under cardiopulmonary bypass (CPB), may offer a promising therapeutic option. In this context, we report on outcomes from patients undergoing a novel approach to tracheal resection that is combined with manubrial resection, leading to improved airway calibre, obviating the requisition for CPB. RESULTS: In this study, seven patients with severe MPS IVA exhibited clinical symptoms and radiological evidence indicative of advanced airway obstruction. All patients had a tracheal resection with a partial upper manubriectomy via transcervical approach, which did not require CPB. The surgical cohort consisted of 5 females and 2 males, the median age was 16 years (range 11-19) and the median height was 105.6cm (range 96.4-113.4). Postoperatively, significant improvements were seen in forced expiratory volume in 1 second (FEV1), with a mean increase of 0.68 litres (95% CI: 0.45-0.91; SD: 0.20). Notably, other spirometry variables also showed meaningful improvements, providing evidence of positive treatment effects. Furthermore, there were no major long-term complications, and the procedure resulted in a significant enhancement in patient-reported domains using PedsQL (version 4.0). CONCLUSIONS: This study represents the largest case series to date, on tracheal resection in patients with severe MPS IVA. Our findings demonstrate the effectiveness of the transcervical approach with partial manubriectomy for improving respiratory function and quality of life for individuals with advanced airway obstruction. Tracheal resection presents a promising treatment modality for severe cases of MPS IVA. Successful outcomes rely on meticulous multidisciplinary assessment, judicious decision-making, and appropriate timing of tracheal surgery. Further research and long-term follow-up studies are warranted to validate the long-term efficacy and safety of this approach.

Pediatric Congenital Anterior Skull Base Encephaloceles and Surgical Management: A Comparative Review of 22 Patients Treated With Transnasally, Transcranially, or Combined Approach With a Review of the Literature.

BACKGROUND AND OBJECTIVES: Anterior basal encephaloceles are considered a rare entity and are often associated with midline cerebral abnormalities. Those with a large skull base defect and herniation of brain parenchyma in the neonate or young infant present unique challenges for surgical management. METHODS: We analyzed the neurosurgical administrative and operative databases between 1986 and 2022 to determine clinical presentation, operative approach, and outcome of basal encephaloceles. RESULTS: Over the 36-year period, 27 pediatric anterior basal encephaloceles were managed, of which 22 had full documentation and images allowing comprehensive review. Mean age at presentation was 5 years (SD 4.94). The majority were transethmoidal encephaloceles (59%), followed by the transsphenoidal-sphenoethmoidal type (32%). Overall, 91% were managed surgically by a transcranial, endoscopic, or combined approach. Four children required subsequent procedures, predominantly for persistent cerebrospinal fluid leak. No significant differences in proportion of patients requiring interval/revision surgery after initial conservative, endoscopic endonasal, or transcranial surgery was identified. Neither age at surgery nor size of the defect on computed tomography scan was associated with the need for revision surgery. Size of cranial defect was significantly smaller in the endoscopic group (P = .01). There was a historic tendency for younger children with larger defects to have a transcranial approach. With the addition of endoscopic skull base expertise, smaller defects in older children were more recently treated endoscopically. CONCLUSION: Basal encephaloceles are rare and complex lesions and are optimally managed within a skull base multidisciplinary team able to provide multiple approaches. Large skull base defects with brain parenchymal involvement often require a transcranial or combined transcranial-endoscopic approach.

Mast cell activation disrupts interactions between endothelial cells and pericytes during early life allergic asthma.

Allergic asthma generally starts during early life and is linked to substantial tissue remodeling and lung dysfunction. Although angiogenesis is a feature of the disrupted airway, the impact of allergic asthma on the pulmonary microcirculation during early life is unknown. Here, using quantitative imaging in precision-cut lung slices (PCLSs), we report that exposure of neonatal mice to house dust mite (HDM) extract disrupts endothelial cell/pericyte interactions in adventitial areas. Central to the blood vessel structure, the loss of pericyte coverage was driven by mast cell (MC) proteases, such as tryptase, that can induce pericyte retraction and loss of the critical adhesion molecule N-cadherin. Furthermore, spatial transcriptomics of pediatric asthmatic endobronchial biopsies suggests intense vascular stress and remodeling linked with increased expression of MC activation pathways in regions enriched in blood vessels. These data provide previously unappreciated insights into the pathophysiology of allergic asthma with potential long-term vascular defects.

Is air pollution exposure linked to household income? Spatial analysis of Community Multiscale Air Quality Model results for Madrid.

This study explores the potential correlation between income and exposure to air pollution for the city of Madrid, Spain and its neighboring municipalities. Madrid is a well-known European air pollution hotspot with a high mortality burden attributable to nitrogen dioxide (NO2) and fine particulate matter (PM2.5). Statistical analyses were carried out using electoral district level data on gross household income (GHI), and NO2 and PM2.5 concentrations in air obtained from a mesoscale air quality model for the study area. We applied linear regression, bivariate spatial correlation analysis, spatial autoregression and geographically weighted regression to explore the relationship between contaminants and income. Three different strategies were adopted to harmonize data for analysis. While some strategies suggested a link between income and air pollution, others did not, highlighting the need for multiple different approaches where uncertainty is high. Our findings offer important lessons for future spatial geographical studies of air pollution in cities worldwide. In particular we highlight the limitations of census-scale socio-economic data and the lack of non-model derived high-resolution air quality measurement data for many cities and offers lessons for policy makers on improving the integration of these types of essential public information.

Lentiviral expression of wild-type LAMA3A restores cell adhesion in airway basal cells from children with epidermolysis bullosa.

The hallmark of epidermolysis bullosa (EB) is fragile attachment of epithelia due to genetic variants in cell adhesion genes. We describe 16 EB patients treated in the ear, nose, and throat department of a tertiary pediatric hospital linked to the United Kingdom's national EB unit between 1992 and 2023. Patients suffered a high degree of morbidity and mortality from laryngotracheal stenosis. Variants in laminin subunit alpha-3 (LAMA3) were found in 10/15 patients where genotype was available. LAMA3 encodes a subunit of the laminin-332 heterotrimeric extracellular matrix protein complex and is expressed by airway epithelial basal stem cells. We investigated the benefit of restoring wild-type LAMA3 expression in primary EB patient-derived basal cell cultures. EB basal cells demonstrated weak adhesion to cell culture substrates, but could otherwise be expanded similarly to non-EB basal cells. In vitro lentiviral overexpression of LAMA3A in EB basal cells enabled them to differentiate in air-liquid interface cultures, producing cilia with normal ciliary beat frequency. Moreover, transduction restored cell adhesion to levels comparable to a non-EB donor culture. These data provide proof of concept for a combined cell and gene therapy approach to treat airway disease in LAMA3-affected EB.

Pedicled pericardial patch in tracheal reconstruction in children - Novel technique to provide vascularized tissue for salvaging difficult airways.

BACKGROUND: Management of large central airway defects are often complex. Children who present with these defects have multiple co-morbidities or have had previous surgeries. Surgical options include various tissue cover for these defects without longer term benefits. Vascularized autologous pericardial patch offers a better solution to these defects by providing vascularity and potential for remodelling in future. METHODS: 41 children (M:F of 24:17) were operated for large trachea-bronchial defects between January 2015 and August 2022. The median age of was 12 months with median weight of 8.9 kg (IQR 3.3 kg-17.7 kg) Causes leading to the central tracheal defect include failed repair of previous trachea-oesophageal fistula (TOF) (n = 21) and acquired fistula due to button battery injury (n = 11). Surgical repair consisted of autologous pedicled pericardial patch repair for the airway defect under cardiopulmonary bypass. RESULTS: There were two operative deaths related to extensive sepsis and necrosis of reconstructed trachea. Four children had further reoperation with additional patch. Bronchoscopy was used as surveillance in all these children, with use of airway stents (biodegradable stent) in 9 children. The median ventilation time was 8 days, with tracheostomy being needed in 5 for long term support. CONCLUSIONS: Autologous pericardial patch is a versatile technique and can be used to salvage large tracheal defects when other method have failed or not feasible. Tracheomalacia at the site of repair could be managed with biodegradable stents. Vascularity and ciliary function of the patch still needs to be evaluated.

Revisiting the Great Ormond Street Hospital protocol for ward decannulation of children with tracheostomy.

INTRODUCTION: Tracheostomy decannulation is an important and final step in managing patients once the underlying issue requiring a tracheostomy resolves. However, no consensus exists on the optimal method to decannulate a paediatric patient. We revisit the Great Ormond Street Hospital (GOSH) tracheostomy decannulation protocol, a 5-day process involving downsizing the tracheostomy tube, capping, and observation, to evaluate its effectiveness and assess if changes to the protocol are required. METHOD: This is a retrospective study, reviewing patient records between April 2018 and April 2023 from a single quaternary care centre. Data extracted include comorbidities, age at the time of decannulation, duration of tracheostomy, reason for tracheostomy insertion, whether a decannulation attempt was successful or not, and the timings of decannulation failure. RESULTS: 66 patients that met the selection criteria underwent a decannulation trial between April 2018 and April 2023. 32 patients were male, and 34 patients were female. Age at attempted decannulations ranged from 1 year to 18 years, with an average age of 6.1 years. There were a total of 93 attempts at decannulation, with 51 (54.8%) successful attempts, 35 (56.5%) first decannulation attempt successes, and 42 (45.2%) unsuccessful attempts. 17 patients had 2 attempts at decannulation, and 4 patients had 3 or more attempts at decannulation. Of the unsuccessful attempts, patients mostly failed on capping of the tracheostomy tube with 33 failures (35.5%). CONCLUSION: The GOSH protocol achieved similar success rates to comparable protocols. The protocol's multi-step approach provides thorough evaluation and support for patients during the decannulation process, and its success on a complex patient cohort supports its continued use.

Open and Thoracoscopic Aortopexy for Airway Malacia in Children: 15 Year Single Centre Experience.

OBJECTIVES: The objective was to report and analyse the characteristics and results of open aortopexy and thoracoscopic aortopexy for the treatment of airway malacia in a paediatric population. METHODS: We report a retrospective consecutive case series of paediatric patients undergoing aortopexy for the treatment of airway malacia at a quaternary referral centre between December 2006 and January 2021. Outcome measures included days to extubation, continued need for non-invasive ventilation, further intervention in the form of tracheostomy and death. RESULTS: 169 patients underwent aortopexy: 147 had open procedures (135 via median/limited median sternotomy and 12 thoracotomy) and 22 thoracoscopic. Mean follow up was 8.46 yrs (range 1-20 yrs). Most common site of airway malacia was the trachea (n = 106, 62.7 %), and 48 (28.4 %) had additional involvement at the bronchi with tracheobronchomalacia (TBM). 15 (8.9 %) had bronchomalacia (BM) only. Incidence of bronchial disease was lower in the thoracoscopic than open group (13.6 % vs 40.82 %; p < 0.0001). Mean time to extubation was 1.45 days, 2.59 days, 5.23 days in tracheomalacia, TBM and BM groups, respectively (p = 0.0047). Mean time to extubation was 1.35 days, 2 days, 3.67 days, and 5 days in patients with external vascular compression, TOF/OA, primary airway malacia, and laryngeal reconstruction, respectively (p = 0.0002). There were 21 deaths across the cohort, and all were in the open group. 71.4 % (n = 15) had bronchial involvement of their airway malacia. CONCLUSIONS: Open and thoracoscopic aortopexy are effective treatments for airway malacia in children. We have identified that involvement of the bronchi is a risk factor for adverse outcomes, and the optimum treatment for this patient cohort is still debatable. LEVEL OF EVIDENCE: IV. TYPE OF STUDY: Retrospective Study.

Lung extracellular matrix modulates KRT5+ basal cell activity in pulmonary fibrosis.

Aberrant expansion of KRT5+ basal cells in the distal lung accompanies progressive alveolar epithelial cell loss and tissue remodelling during fibrogenesis in idiopathic pulmonary fibrosis (IPF). The mechanisms determining activity of KRT5+ cells in IPF have not been delineated. Here, we reveal a potential mechanism by which KRT5+ cells migrate within the fibrotic lung, navigating regional differences in collagen topography. In vitro, KRT5+ cell migratory characteristics and expression of remodelling genes are modulated by extracellular matrix (ECM) composition and organisation. Mass spectrometry- based proteomics revealed compositional differences in ECM components secreted by primary human lung fibroblasts (HLF) from IPF patients compared to controls. Over-expression of ECM glycoprotein, Secreted Protein Acidic and Cysteine Rich (SPARC) in the IPF HLF matrix restricts KRT5+ cell migration in vitro. Together, our findings demonstrate how changes to the ECM in IPF directly influence KRT5+ cell behaviour and function contributing to remodelling events in the fibrotic niche.

Airway soluble CSF1R predicts progression in patients with idiopathic pulmonary fibrosis.

This study provides the first evidence for a role of airway sCSF1R in IPF https://bit.ly/3KTBrCA.

Facial deformation following treatment for pediatric head and neck rhabdomyosarcoma; the difference between treatment modalities. Results of a trans-Atlantic, multicenter cross-sectional cohort study.

BACKGROUND: The four different local therapy strategies used for head and neck rhabdomyosarcoma (HNRMS) include proton therapy (PT), photon therapy (RT), surgery with radiotherapy (Paris-method), and surgery with brachytherapy (AMORE). Local control and survival is comparable; however, the impact of these different treatments on facial deformation is still poorly understood. This study aims to quantify facial deformation and investigates the differences in facial deformation between treatment modalities. METHODS: Across four European and North American institutions, HNRMS survivors treated between 1990 and 2017, more than 2 years post treatment, had a 3D photograph taken. Using dense surface modeling, we computed facial signatures for each survivor to show facial deformation relative to 35 age-sex-ethnicity-matched controls. Additionally, we computed individual facial asymmetry. FINDINGS: A total of 173 HNRMS survivors were included, survivors showed significantly reduced facial growth (p < .001) compared to healthy controls. Partitioned by tumor site, there was reduced facial growth in survivors with nonparameningeal primaries (p = .002), and parameningeal primaries (p ≤.001), but not for orbital primaries (p = .080) All patients were significantly more asymmetric than healthy controls, independent of treatment modality (p ≤ .001). There was significantly more facial deformation in orbital patients when comparing RT to AMORE (p = .046). In survivors with a parameningeal tumor, there was significantly less facial deformation in PT when compared to RT (p = .009) and Paris-method (p = .007). INTERPRETATION: When selecting optimal treatment, musculoskeletal facial outcomes are an expected difference between treatment options. These anticipated differences are currently based on clinicians' bias, expertise, and experience. These data supplement clinician judgment with an objective analysis highlighting the impact of patient age and tumor site between existing treatment options.

Tracheal Resection for Critical Airway Obstruction in Morquio A Syndrome.

Introduction: The primary cause of death in Morquio A syndrome (mucopolysaccharidosis (MPS) IVA) is airway obstruction, brought about by an inexorable and pathognomonic multilevel airway tortuosity, buckling, and obstruction. The relative pathophysiological contributions of an inherent cartilage processing defect versus a mismatch in longitudinal growth between the trachea and the thoracic cage are currently a subject of debate. Enzyme replacement therapy (ERT) and multidisciplinary management continue to improve life expectancy for Morquio A patients by slowing many of the multisystem pathological consequences of the disease but are not as effective at reversing established pathology. An urgent need has developed to consider alternatives to palliation of progressive tracheal obstruction to preserve and maintain these patients' hard-won good quality of life, as well as to facilitate spinal and other required surgery. Case Report. Following multidisciplinary discussion, transcervical tracheal resection with limited manubriectomy was successfully performed, without the need for cardiopulmonary bypass, in an adolescent male on ERT with the severe airway manifestations of Morquio A syndrome. His trachea was found to be under significant compressive forces at surgery. On histology, chondrocyte lacunae appeared enlarged, but intracellular lysosomal staining and extracellular glycosaminoglycan staining was comparable to control trachea. At 12 months, this has resulted in a significant improvement in respiratory and functional status, with corresponding enhancement to his quality of life. Conclusion: This addressing of tracheal/thoracic cage dimension mismatch represents a novel surgical treatment approach to an existing clinical paradigm and may be useful for other carefully selected individuals with MPS IVA. Further work is needed to better understand the role and optimal timing of tracheal resection within this patient cohort so as to individually balance considerable surgical and anaesthetic risks against the potential symptomatic and life expectancy benefits.

Epithelial senescence in idiopathic pulmonary fibrosis is propagated by small extracellular vesicles.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that affects 3 million people worldwide. Senescence and small extracellular vesicles (sEVs) have been implicated in the pathogenesis of IPF, although how sEVs promote disease remains unclear. Here, we profile sEVs from bronchial epithelial cells and determine small RNA (smRNA) content. METHODS: Conditioned media was collected and sEVs were isolated from normal human bronchial epithelial cells (NHBEs) and IPF-diseased human bronchial epithelial cells (DHBEs). RESULTS: Increased sEV release from DHBEs compared to NHBEs (n = 4; p < 0.05) was detected by nanoparticle tracking analysis. NHBEs co-cultured with DHBE-derived sEVs for 72 h expressed higher levels of SA-ß-Gal and γH2AX protein, p16 and p21 RNA and increased secretion of IL6 and IL8 proteins (all n = 6-8; p < 0.05). sEVs were also co-cultured with healthy air-liquid interface (ALI) cultures and similar results were observed, with increases in p21 and p16 gene expression and IL6 and IL8 (basal and apical) secretion (n = 6; p < 0.05). Transepithelial electrical resistance (TEER) measurements, a reflection of epithelial barrier integrity, were decreased upon the addition of DHBE-derived sEVs (n = 6; p < 0.05). smRNA-sequencing identified nineteen significantly differentially expressed miRNA in DHBE-derived sEVs compared to NHBE-derived sEVs, with candidate miRNAs validated by qPCR (all n = 5; p < 0.05). Four of these miRNAs were upregulated in NHBEs co-cultured with DHBE-derived sEVs and three in healthy ALI cultures co-cultured with DHBE-derived sEVs (n = 3-4; p < 0.05). CONCLUSIONS: This data demonstrates that DHBE-derived sEVs transfer senescence to neighbouring healthy cells, promoting the disease state in IPF.

International Pediatric Otolaryngology Group: Consensus guidelines on the diagnosis and management of non-tuberculous mycobacterial cervicofacial lymphadenitis.

INTRODUCTION: Non-tuberculous mycobacterial (NTM) infection commonly manifests as subacute or chronic cervicofacial lymphadenitis in immunocompetent children. The optimal management of this pathology remains controversial. OBJECTIVES: This international consensus guideline aims to understand the practice patterns for NTM cervicofacial lymphadenitis and to address the primary diagnostic and management challenges. METHODS: A modified three-iterative Delphi method was used to establish expert recommendations on the diagnostic considerations, expectant or medical management, and operative considerations. The recommendations herein are derived from current expert consensus and critical review of the literature. SETTING: Multinational, multi-institutional, tertiary pediatric hospitals. RESULTS: Consensus recommendations include diagnostic work-up, goals of treatment and management options including surgery, prolonged antibiotic therapy and observation. CONCLUSION: The recommendations formulated in this International Pediatric Otolaryngology Group (IPOG) consensus statement on the diagnosis and management of patients with NTM lymphadenitis are aimed at improving patient care and promoting future hypothesis generation.

Cell-intrinsic differences between human airway epithelial cells from children and adults.

The airway epithelium is a protective barrier that is maintained by the self-renewal and differentiation of basal stem cells. Increasing age is a principle risk factor for chronic lung diseases, but few studies have explored age-related molecular or functional changes in the airway epithelium. We retrieved epithelial biopsies from histologically normal tracheobronchial sites from pediatric and adult donors and compared their cellular composition and gene expression profile (in laser capture-microdissected whole epithelium, fluorescence-activated cell-sorted basal cells, and basal cells in cell culture). Histologically, pediatric and adult tracheobronchial epithelium was similar in composition. We observed age-associated changes in RNA sequencing studies, including higher interferon-associated gene expression in pediatric epithelium. In cell culture, pediatric cells had higher colony formation ability, sustained in vitro growth, and outcompeted adult cells in a direct competitive proliferation assay. Our results demonstrate cell-intrinsic differences between airway epithelial cells from children and adults in both homeostatic and proliferative states.

International Pediatric Otolaryngology Group (IPOG) consensus recommendations: Evaluation and management of congenital tracheal stenosis.

OBJECTIVES: To outline an expert-based consensus of recommendations for the diagnosis and management of pediatric patients with congenital tracheal stenosis. METHODS: Expert opinions were sought from members of the International Pediatric Otolaryngology Group (IPOG) via completion of an 18-item survey utilizing an iterative Delphi method and review of the literature. RESULTS: Forty-three members completed the survey providing recommendations regarding the initial history, clinical evaluation, diagnostic evaluation, temporizing measures, definitive repair, and post-repair care of children with congenital tracheal stenosis. CONCLUSION: These recommendations are intended to be used to support clinical decision-making regarding the evaluation and management of children with congenital tracheal stenosis. Responses highlight the diverse management strategies and the importance of a multidisciplinary approach to care of these patients.

Lung cancer screening provides an opportunity for early diagnosis and treatment of interstitial lung disease.

Interstitial lung abnormalities (ILA) can be incidentally detected in patients undergoing low-dose CT screening for lung cancer. In this retrospective study, we explore the downstream impact of ILA detection on interstitial lung disease (ILD) diagnosis and treatment. Using a targeted approach in a lung cancer screening programme, the rate of de novo ILD diagnosis was 1.5%. The extent of abnormality on CT and severity of lung function impairment, but not symptoms were the most important factors in differentiating ILA from ILD. Disease modifying therapies were commenced in 39% of ILD cases, the majority being antifibrotic therapy for idiopathic pulmonary fibrosis.

Distinct airway epithelial immune responses after infection with SARS-CoV-2 compared to H1N1.

Children are less likely than adults to suffer severe symptoms when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), while influenza A H1N1 severity is comparable across ages except for the very young or elderly. Airway epithelial cells play a vital role in the early defence against viruses via their barrier and immune functions. We investigated viral replication and immune responses in SARS-CoV-2-infected bronchial epithelial cells from healthy paediatric (n = 6; 2.5-5.6 years old) and adult (n = 4; 47-63 years old) subjects and compared cellular responses following infection with SARS-CoV-2 or Influenza A H1N1. While infection with either virus triggered robust transcriptional interferon responses, including induction of type I (IFNB1) and type III (IFNL1) interferons, markedly lower levels of interferons and inflammatory proteins (IL-6, IL-8) were released following SARS-CoV-2 compared to H1N1 infection. Only H1N1 infection caused disruption of the epithelial layer. Interestingly, H1N1 infection resulted in sustained upregulation of SARS-CoV-2 entry factors FURIN and NRP1. We did not find any differences in the epithelial response to SARS-CoV-2 infection between paediatric and adult cells. Overall, SARS-CoV-2 had diminished potential to replicate, affect morphology and evoke immune responses in bronchial epithelial cells compared to H1N1.

Immuno-proteomic profiling reveals aberrant immune cell regulation in the airways of individuals with ongoing post-COVID-19 respiratory disease.

Some patients hospitalized with acute COVID-19 suffer respiratory symptoms that persist for many months. We delineated the immune-proteomic landscape in the airways and peripheral blood of healthy controls and post-COVID-19 patients 3 to 6 months after hospital discharge. Post-COVID-19 patients showed abnormal airway (but not plasma) proteomes, with an elevated concentration of proteins associated with apoptosis, tissue repair, and epithelial injury versus healthy individuals. Increased numbers of cytotoxic lymphocytes were observed in individuals with greater airway dysfunction, while increased B cell numbers and altered monocyte subsets were associated with more widespread lung abnormalities. A one-year follow-up of some post-COVID-19 patients indicated that these abnormalities resolved over time. In summary, COVID-19 causes a prolonged change to the airway immune landscape in those with persistent lung disease, with evidence of cell death and tissue repair linked to the ongoing activation of cytotoxic T cells.