Pathological findings and patterns of feline infectious peritonitis in the respiratory tract of cats.

Feline infectious peritonitis (FIP) is an important cause of death in cats. Thoracic manifestations are less common than abdominal manifestations, and FIP-associated respiratory disease is poorly documented. This study aimed to investigate pathological findings in the respiratory tract of cats with FIP and the occurrence and distribution of feline coronavirus antigen in the respiratory tract using immunohistochemistry. A retrospective study was carried out on 112 cats with FIP, of which 66 had inflammatory histological lesions in the respiratory tract (58.9%) and were included in this study. Three major gross patterns were defined: marked fibrin deposition in the thoracic cavity with lung atelectasis; marked fibrin deposition in the thoracic cavity with lung pyogranulomas; and lung pyogranulomas without thoracic effusion. Histological analysis revealed primary lesions in the visceral pleura and lung parenchyma at a similar frequency, with multifocal to diffuse presentations. Marked lesions were commonly observed. Five major histological patterns were defined: pleuritis; pleuritis and vasculitis/perivascular injury in the lung parenchyma; pleuritis and pneumonia; perivascular injury in the parenchyma without pleuritis; and pneumonia without pleuritis. In the pleura and pulmonary parenchyma, FIP virus antigen was detected in perivascular and peribronchial macrophages and in macrophages within bronchial-associated lymphoid tissue and foci of necrosis and inflammation in the pleura and lung parenchyma. Co-infections with retroviruses were detected in 47 cats (71.2%), mainly with feline leukemia virus (62.2%). Although FIP is a systemic disease, some cats developed significant lesions in the thoracic cavity, including involvement of the upper respiratory tract and presenting respiratory signs, without other classic signs of FIP. This work advances our knowledge of FIP in the respiratory system, helping veterinarians to recognize the various presentations of this disease.

New insights into autophagy in inflammatory subtypes of asthma.

Asthma is a heterogeneous airway disease characterized by airway inflammation and hyperresponsiveness. Autophagy is a self-degrading process that helps maintain cellular homeostasis. Dysregulation of autophagy is involved in the pathogenesis of many diseases. In the context of asthma, autophagy has been shown to be associated with inflammation, airway remodeling, and responsiveness to drug therapy. In-depth characterization of the role of autophagy in asthma can enhance the understanding of the pathogenesis, and provide a theoretical basis for the development of new biomarkers and targeted therapy for asthma. In this article, we focus on the relationship of autophagy and asthma, and discuss its implications for asthma pathogenesis and treatment.

Morphological Effects of Cigarette Smoking on Respiratory System and Related Functions Based on AQPs Expression

SUMMARY: A great deal of attention of air pollution on respiratory health is increasing, particularly in relation to haze days. It is that exposure to cigarette smoke augments the toxicity of common air contaminants, thereby increasing the complexity of respiratory diseases. Although there are various mechanisms involved to respiratory diseases caused or worsen by cigarette smoking, in which the role of AQPs in the lung with regard to fluid homeostasis still remains elusive. In this paper, we copied the rat models based on smoke generator, and investigated the morphological changes of mucosa and related functions depending on the balance of lining liquid of alveoli via AQPs expression. Compared with normal group, weak labelling of AQP1 and AQP5 protein abundance were clearly detected in the corresponding part of smoke exposure groups compared with normal group. Hence, it is suggested that the contribution of AQPs in the lung is diminished, thereby causing perturbed balancing between resorptive and secretory fluid homeostasis under cigarette smoking.

Cada vez se presta más atención a la contaminación del aire en la salud respiratoria, particularmente, en relación con los días de neblina. En consecuencia la exposición al humo del cigarrillo aumenta la toxicidad de los contaminantes comunes del aire, lo que además aumenta la complejidad de las enfermedades respiratorias. Aunque existen varios mecanismos involucrados en las enfermedades respiratorias causadas o empeoradas por el tabaquismo, en las que el papel de las AQP en el pulmón respecto a la homeostasis de líquidos sigue siendo difícil de alcanzar. En este artículo, copiamos los modelos de rata basados en el generador de humo e investigamos los cambios morfológicos de la mucosa y las funciones relacionadas según el equilibrio del líquido de revestimiento de los alvéolos a través de la expresión de AQP. En comparación con el grupo normal, se detectó claramente un etiquetado débil de la abundancia de proteínas AQP1 y AQP5 en la parte correspondiente de los grupos de exposición al humo en comparación con el grupo control. Por lo tanto, se sugiere que la contribución de las AQP en el pulmón está disminuida, provocando así un equilibrio perturbado entre la homeostasis del líquido secretor y de reabsorción bajo el hábito de fumar cigarrillos.

Human Airway Basal Cells Undergo Reversible Squamous Differentiation and Reshape Innate Immunity.

Histological and lineage immunofluorescence examination revealed that healthy conducting airways of humans and animals harbor sporadic poorly differentiated epithelial patches mostly in the dorsal noncartilage regions that remarkably manifest squamous differentiation. In vitro analysis demonstrated that this squamous phenotype is not due to intrinsic functional change in underlying airway basal cells. Rather, it is a reversible physiological response to persistent Wnt signaling stimulation during de novo differentiation. Squamous epithelial cells have elevated gene signatures of glucose uptake and cellular glycolysis. Inhibition of glycolysis or a decrease in glucose availability suppresses Wnt-induced squamous epithelial differentiation. Compared with pseudostratified airway epithelial cells, a cascade of mucosal protective functions is impaired in squamous epithelial cells, featuring increased epithelial permeability, spontaneous epithelial unjamming, and enhanced inflammatory responses. Our study raises the possibility that the squamous differentiation naturally occurring in healthy airways identified herein may represent "vulnerable spots" within the airway mucosa that are sensitive to damage and inflammation when confronted by infection or injury. Squamous metaplasia and hyperplasia are hallmarks of many airway diseases, thereby expanding these areas of vulnerability with potential pathological consequences. Thus, investigation of physiological and reversible squamous differentiation from healthy airway basal cells may provide critical knowledge to understand pathogenic squamous remodeling, which is often nonreversible, progressive, and hyperinflammatory.

SARS-CoV-2 infection and persistence in the human body and brain at autopsy.

Coronavirus disease 2019 (COVID-19) is known to cause multi-organ dysfunction1-3 during acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some patients experiencing prolonged symptoms, termed post-acute sequelae of SARS-CoV-2 (refs. 4,5). However, the burden of infection outside the respiratory tract and time to viral clearance are not well characterized, particularly in the brain3,6-14. Here we carried out complete autopsies on 44 patients who died with COVID-19, with extensive sampling of the central nervous system in 11 of these patients, to map and quantify the distribution, replication and cell-type specificity of SARS-CoV-2 across the human body, including the brain, from acute infection to more than seven months following symptom onset. We show that SARS-CoV-2 is widely distributed, predominantly among patients who died with severe COVID-19, and that virus replication is present in multiple respiratory and non-respiratory tissues, including the brain, early in infection. Further, we detected persistent SARS-CoV-2 RNA in multiple anatomic sites, including throughout the brain, as late as 230 days following symptom onset in one case. Despite extensive distribution of SARS-CoV-2 RNA throughout the body, we observed little evidence of inflammation or direct viral cytopathology outside the respiratory tract. Our data indicate that in some patients SARS-CoV-2 can cause systemic infection and persist in the body for months.

Biofilm aggregates and the host airway-microbial interface.

Biofilms are multicellular microbial aggregates that can be associated with host mucosal epithelia in the airway, gut, and genitourinary tract. The host environment plays a critical role in the establishment of these microbial communities in both health and disease. These host mucosal microenvironments however are distinct histologically, functionally, and regarding nutrient availability. This review discusses the specific mucosal epithelial microenvironments lining the airway, focusing on: i) biofilms in the human respiratory tract and the unique airway microenvironments that make it exquisitely suited to defend against infection, and ii) how airway pathophysiology and dysfunctional barrier/clearance mechanisms due to genetic mutations, damage, and inflammation contribute to biofilm infections. The host cellular responses to infection that contribute to resolution or exacerbation, and insights about evaluating and therapeutically targeting airway-associated biofilm infections are briefly discussed. Since so many studies have focused on Pseudomonas aeruginosa in the context of cystic fibrosis (CF) or on Haemophilus influenzae in the context of upper and lower respiratory diseases, these bacteria are used as examples. However, there are notable differences in diseased airway microenvironments and the unique pathophysiology specific to the bacterial pathogens themselves.

ITGB4 Deficiency in Airway Epithelium Aggravates RSV Infection and Increases HDM Sensitivity.

Background: The heterogeneity of RSV-infected pathology phenotype in early life is strongly associate with increased susceptibility of asthma in later life. However, the inner mechanism of this heterogeneity is still obscure. ITGB4 is a down-regulated adhesion molecular in the airway epithelia of asthma patients which may participate in the regulation of RSV infection related intracellular pathways. Object: This study was designed to observe the involvement of ITGB4 in the process of RSV infection and the effect of ITGB4 deficiency on anti-RSV responses of airway epithelia. Results: RSV infection caused a transient decrease of ITGB4 expression both in vitro and in vivo. Besides, ITGB4 deficiency induced not only exacerbated RSV infection, but also enhanced HDM sensitivity in later life. Moreover, IFN III (IFN-λ) was significantly suppressed during RSV infection in ITGB4 deficient airway epithelial cells. Furthermore, the suppression of IFN-λ were regulated by IRF-1 through the phosphorylation of EGFR in airway epithelial cells after RSV infection. Conclusion: These results demonstrated the involvement of ITGB4 deficiency in the development of enhance RSV infection in early life and the increased HDM sensitivity in later life by down-regulation of IFN-λ through EGFR/IRF-1 pathway in airway epithelial cells.

FBXL7 Body Hypomethylation Is Frequent in Tumors from the Digestive and Respiratory Tracts and Is Associated with Risk-Factor Exposure.

Squamous cell carcinoma is the main histological tumor type in the upper aerodigestive tract (UADT), including the esophagus (ESCC) and the head and neck sites, as well as the oral cavity (OCSCC), larynx (LSCC) and oropharynx (OPSCC). These tumors are induced by alcohol and tobacco exposure, with the exception of a subgroup of OPSCC linked to human papillomavirus (HPV) infection. Few genes are frequently mutated in UADT tumors, pointing to other molecular mechanisms being involved during carcinogenesis. The F-box and leucine-rich repeat protein 7 (FBXL7) is a potential tumor-suppressing gene, one that is frequently hypermethylated in pancreatic cancer and where the encoded protein promotes the degradation of AURKA, BIRC5 and c-SRC. Thus, the aim of this study was to evaluate the methylation and expression profile of FBXL7 in the UADT and the gene's association with the clinical, etiological and pathological characteristics of patients, as well as the expression of its degradation targets. Here we show that the FBXL7 gene's body is hypomethylated in the UADT, independently of histology, but not in virus-associated tumors. FBXL7 body methylation and gene expression levels were correlated in the ESCC, LSCC, OCSCC and OPSCC. Immunohistochemistry analysis showed that FBXL7 protein levels are not correlated with the levels of its degradation targets, AURKA and BIRC5, in the UADT. The high discriminatory potential of FBXL7 body hypomethylation between non-tumor and tumor tissues makes it a promising biomarker.

Recapitulating infection, thermal sensitivity and antiviral treatment of seasonal coronaviruses in human airway organoids.

BACKGROUND: Human seasonal coronaviruses usually cause mild upper-respiratory tract infection, but severe complications can occur in specific populations. Research into seasonal coronaviruses is limited and robust experimental models are largely lacking. This study aims to establish human airway organoids (hAOs)-based systems for seasonal coronavirus infection and to demonstrate their applications in studying virus-host interactions and therapeutic development. METHODS: The infections of seasonal coronaviruses 229E, OC43 and NL63 in 3D cultured hAOs with undifferentiated or differentiated phenotypes were tested. The kinetics of virus replication and production was profiled at 33 °C and 37 °C. Genome-wide transcriptome analysis by RNA sequencing was performed in hAOs under various conditions. The antiviral activity of molnupiravir and remdesivir, two approved medications for treating COVID19, was tested. FINDINGS: HAOs efficiently support the replication and infectious virus production of seasonal coronaviruses 229E, OC43 and NL63. Interestingly, seasonal coronaviruses replicate much more efficiently at 33 °C compared to 37 °C, resulting in over 10-fold higher levels of viral replication. Genome-wide transcriptomic analyses revealed distinct patterns of infection-triggered host responses at 33 °C compared to 37 °C temperature. Treatment of molnupiravir and remdesivir dose-dependently inhibited the replication of 229E, OC43 and NL63 in hAOs. INTERPRETATION: HAOs are capable of modeling 229E, OC43 and NL63 infections. The intriguing finding that lower temperature resembling that in the upper respiratory tract favors viral replication may help to better understand the pathogenesis and transmissibility of seasonal coronaviruses. HAOs-based innovative models shall facilitate the research and therapeutic development against seasonal coronavirus infections. FUNDING: This research is supported by funding of a VIDI grant (No. 91719300) from the Netherlands Organization for Scientific Research and the Dutch Cancer Society Young Investigator Grant (10140) to Q.P., and the ZonMw COVID project (114025011) from the Netherlands Organization for Health Research and Development to R.R.

Sex Steroids Effects on Asthma: A Network Perspective of Immune and Airway Cells.

A multitude of evidence has suggested the differential incidence, prevalence and severity of asthma between males and females. A compilation of recent literature recognized sex differences as a significant non-modifiable risk factor in asthma pathogenesis. Understanding the cellular and mechanistic basis of sex differences remains complex and the pivotal point of this ever elusive quest, which remains to be clarified in the current scenario. Sex steroids are an integral part of human development and evolution while also playing a critical role in the conditioning of the immune system and thereby influencing the function of peripheral organs. Classical perspectives suggest a pre-defined effect of sex steroids, generalizing estrogens popularly under the "estrogen paradox" due to conflicting reports associating estrogen with a pro- and anti-inflammatory role. On the other hand, androgens are classified as "anti-inflammatory," serving a protective role in mitigating inflammation. Although considered mainstream and simplistic, this observation remains valid for numerous reasons, as elaborated in the current review. Women appear immune-favored with stronger and more responsive immune elements than men. However, the remarkable female predominance of diverse autoimmune and allergic diseases contradicts this observation suggesting that hormonal differences between the sexes might modulate the normal and dysfunctional regulation of the immune system. This review illustrates the potential relationship between key elements of the immune cell system and their interplay with sex steroids, relevant to structural cells in the pathophysiology of asthma and many other lung diseases. Here, we discuss established and emerging paradigms in the clarification of observed sex differences in asthma in the context of the immune system, which will deepen our understanding of asthma etiopathology.

Cystic Fibrosis Airway Mucus Hyperconcentration Produces a Vicious Cycle of Mucin, Pathogen, and Inflammatory Interactions that Promotes Disease Persistence.

The dynamics describing the vicious cycle characteristic of cystic fibrosis (CF) lung disease, initiated by stagnant mucus and perpetuated by infection and inflammation, remain unclear. Here we determine the effect of the CF airway milieu, with persistent mucoobstruction, resident pathogens, and inflammation, on the mucin quantity and quality that govern lung disease pathogenesis and progression. The concentrations of MUC5AC and MUC5B were measured and characterized in sputum samples from subjects with CF (N = 44) and healthy subjects (N = 29) with respect to their macromolecular properties, degree of proteolysis, and glycomics diversity. These parameters were related to quantitative microbiome and clinical data. MUC5AC and MUC5B concentrations were elevated, 30- and 8-fold, respectively, in CF as compared with control sputum. Mucin parameters did not correlate with hypertonic saline, inhaled corticosteroids, or antibiotics use. No differences in mucin parameters were detected at baseline versus during exacerbations. Mucin concentrations significantly correlated with the age and sputum human neutrophil elastase activity. Although significantly more proteolytic cleavages were detected in CF mucins, their macromolecular properties (e.g., size and molecular weight) were not significantly different than control mucins, likely reflecting the role of S-S bonds in maintaining multimeric structures. No evidence of giant mucin macromolecule reflecting oxidative stress-induced cross-linking was found. Mucin glycomic analysis revealed significantly more sialylated glycans in CF, and the total abundance of nonsulfated O-glycans correlated with the relative abundance of pathogens. Collectively, the interaction of mucins, pathogens, epithelium, and inflammatory cells promotes proteomic and glycomic changes that reflect a persistent mucoobstructive, infectious, and inflammatory state.

Growth of the airway smooth muscle layer from late gestation to childhood is mediated initially by hypertrophy and subsequently hyperplasia.

BACKGROUND AND OBJECTIVE: The airway smooth muscle (ASM) layer thickens during development. Identifying the mechanism(s) for normal structural maturation of the ASM reveals pathways susceptible to disease processes. This study characterized thickening of the ASM layer from foetal life to childhood and elucidated the underlying mechanism in terms of hypertrophy, hyperplasia and extracellular matrix (ECM) deposition. METHODS: Airways from post-mortem cases were examined from seven different age groups: 22-24 weeks gestation, 25-31 weeks gestation, term (37-41 weeks gestation), <0.5 year, 0.5-1 year, 2-5 years and 6-10 years. The ASM layer area (thickness), the number and size of ASM cells and the volume fraction of ECM were assessed by planimetry and stereology. RESULTS: From late gestation to the first year of life, normalized ASM thickness more than doubled as a result of ASM hypertrophy. Thereafter, until childhood, the ASM layer grew in proportion to airway size, which was mediated by ASM hyperplasia. Hypertrophy and hyperplasia of ASM were accompanied by a proportional change in ECM such that the broad composition of the ASM layer was constant across age groups. CONCLUSION: These data suggest that the mechanisms of ASM growth from late gestation to childhood are temporally decoupled, with early hypertrophy and subsequent proliferation. We speculate that the developing airway is highly susceptible to ASM thickening in the first year of life and that the timing of an adverse event will determine structural phenotype.

Bovine coronavirus in the lower respiratory tract of cattle with respiratory disease.

Bovine coronavirus (BCoV) is a known cause of enteric disease in cattle; however, its role in bovine respiratory disease (BRD) is poorly understood, with a dearth of evidence of the detection of the virus in respiratory tract lesions. We coupled histologic evaluation of tracheal and lower airway tissues from 104 calves with BRD in which BCoV was detected in the lungs via PCR followed by direct detection of BCoV by immunohistochemistry and an RNA in situ hybridization assay (ISH; RNAscope technology). RNAscope ISH detected BCoV in respiratory epithelium in more cases than did IHC. Using both methods of direct detection, tracheal epithelial attenuation and identification of the virus within lesions were observed commonly. Our results confirm a role of BCoV in respiratory tract infection and pathology, and show that the virus likely plays a role in the development of BRD.

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.

lncRNA-NEAT1 Sponges miR-128 to Promote Inflammatory Reaction and Phenotypic Transformation of Airway Smooth Muscle Cells.

OBJECTIVE: Pediatric asthma is still a health threat to the children. Long noncoding RNA-NEAT1 (lncRNA-NEAT1) was reported to be positively correlated with the severity of asthma. We aimed to study the effects and mechanism of lncRNA-NEAT1on inflammatory reaction and phenotypic transformation of airway smooth muscle cells (ASMCs) in the bronchial asthma. METHOD: The degree of lncRNA-NEAT1 and miR-128 mRNA in children with bronchial asthma and healthy individuals was tested by qRT-PCR. After the inflammatory reaction and phenotypic transformation of PDGF-BB-induced ASMCs, the expression of lncRNA-NEAT1 or miR-128 in the AMSC was disturbed in the AMSC. Subsequently, the expression of lncRNA-NEAT1 and miR-128 was detected by the way of qRT-PCR, and western blot was applied to measure the expression of MMP-2, MMP-9, α-SMA, calponin, NF-κB, and so on in the cells. The content of TNF-α, IL-1ß, IL-6, and IL-8 in the cell culture supernatant was checked by ELISA. MTT, Transwell, and flow cytometry were used to detect cell proliferation, migration, and apoptosis. Further, the targeting relations between lncRNA-NEAT1 and miR-128 were evaluated by the dual-luciferase reporter assay. RESULT: In the sputum of children with bronchial asthma, lncRNA-NEAT1 was significantly upregulated while miR-128 was rapidly downregulated. Besides, lncRNA-NEAT1 and miR-128 were competitively combined and, for their expression, negatively correlated. CONCLUSION: lncRNA-NEAT1 sponges miR-128 to boost PDGF-BB-induced inflammatory reaction and phenotypic transformation of ASMCs to aggravate the occurrence and development of childhood bronchial asthma.

Plk1 Regulates Caspase-9 Phosphorylation at Ser-196 and Apoptosis of Human Airway Smooth Muscle Cells.

Airway smooth muscle thickening, a key characteristic of chronic asthma, is largely attributed to increased smooth muscle cell proliferation and reduced smooth muscle apoptosis. Polo-like kinase 1 (Plk1) is a serine/threonine protein kinase that participates in the pathogenesis of airway smooth muscle remodeling. Although the role of Plk1 in cell proliferation and migration is recognized, its function in smooth muscle apoptosis has not been previously investigated. Caspase-9 (Casp9) is a key enzyme that participates in the execution of apoptosis. Casp9 phosphorylation at Ser-196 and Thr-125 is implicated in regulating its activity in cancer cells and epithelial cells. Here, exposure of human airway smooth muscle (HASM) cells to platelet-derived growth factorfor 24 hours enhanced the expression of Plk1 and Casp9 phosphorylation at Ser-196, but not Thr-125. Overexpression of Plk1 in HASM cells increased Casp9 phosphorylation at Ser-196. Moreover, the expression of Plk1 increased the levels of pro-Casp9 and pro-Casp3 and inhibited apoptosis, demonstrating a role of Plk1 in inhibiting apoptosis. Knockdown of Plk1 reduced Casp9 phosphorylation at Ser-196, reduced pro-Casp9/3 expression, and increased apoptosis. Furthermore, Casp9 phosphorylation at Ser-196 was upregulated in asthmatic HASM cells, which was associated with increased Plk1 expression. Knockdown of Plk1 in asthmatic HASM cells decreased Casp9 phosphorylation at Ser-196 and enhanced apoptosis. Together, these studies disclose a previously unknown mechanism that the Plk1-Casp9/3 pathway participates in the controlling of smooth muscle apoptosis.

Short palate, lung, and nasal epithelial clone 1 (SPLUNC1) level determines steroid-resistant airway inflammation in aging.

Asthma and its heterogeneity change with age. Increased airspace neutrophil numbers contribute to severe steroid-resistant asthma exacerbation in the elderly, which correlates with the changes seen in adults with asthma. However, whether that resembles the same disease mechanism and pathophysiology in aged and adults is poorly understood. Here, we sought to address the underlying molecular mechanism of steroid-resistant airway inflammation development and response to corticosteroid (Dex) therapy in aged mice. To study the changes in inflammatory mechanism, we used a clinically relevant treatment model of house-dust mite (HDM)-induced allergic asthma and investigated lung adaptive immune response in adult (20-22 wk old) and aged (80-82 wk old) mice. Our result indicates an age-dependent increase in airway hyperresponsiveness (AHR), mixed granulomatous airway inflammation comprising eosinophils and neutrophils, and Th1/Th17 immune response with progressive decrease in frequencies and numbers of HDM-bearing dendritic cells (DC) accumulation in the draining lymph node (DLn) of aged mice as compared with adult mice. RNA-Seq experiments of the aged lung revealed short palate, lung, and nasal epithelial clone 1 (SPLUNC1) as one of the steroid-responsive genes, which progressively declined with age and further by HDM-induced inflammation. Moreover, we found increased glycolytic reprogramming, maturation/activation of DCs, the proliferation of OT-II cells, and Th2 cytokine secretion with recombinant SPLUNC1 (rSPLUNC1) treatment. Our results indicate a novel immunomodulatory role of SPLUNC1 regulating metabolic adaptation/maturation of DC. An age-dependent decline in the SPLUNC1 level may be involved in developing steroid-resistant airway inflammation and asthma heterogeneity.

Quantifying Upper Aerodigestive Sequelae in Esophageal Atresia/Tracheoesophageal Fistula Neonates.

OBJECTIVES: We examined rates of upper aerodigestive tract (UADT) procedures in a multi-institutional cohort of neonates with esophageal atresia/tracheoesophageal fistula (EA/TEF) to estimate secondary UADT pathology. METHODS: A retrospective cohort study was performed using a previously-validated population of patients with EA/TEF within the Pediatric Health Information System (PHIS) between 2007 and 2015. ICD-9/10-CM codes for aerodigestive procedures were examined from 2007 to 2020: 1) diagnostic direct laryngoscopy and/or bronchoscopy (DLB), 2) DLB with intervention, 3) tracheostomy, 4) gastrostomy, 5) fundoplication, 6) aortopexy, 7) laryngotracheoplasty, and 8) esophageal dilation. Associations between procedures and demographics, length of gestation, and weight were estimated using generalized linear mixed models. RESULTS: We identified 2,509 patients with EA/TEF from 47 hospitals, 56.7% male and 43.3% female. Median length of stay for the first admission was 24 days (interquartile range: 12-55). Of these patients, 1,943 (77.4%) had at least one aerodigestive procedure within 14 admissions. Specifically, 1,635 (65.2%) underwent diagnostic DLB, 85 (3.4%) DLB with intervention, 167 (6.7%) tracheostomy, 1,043 (41.2%) gastrostomy, 211 (11.0%) fundoplication, 52 (2.1%) aortopexy, 161 (6.4%) laryngotracheoplasty, and 207 (8.3%) esophageal dilation. Preterm gestation increased odds of tracheostomy (adjusted odds ratio (OR) 2.4, 95% confidence interval (CI) 1.5-3.7), gastrostomy (OR 2.1, CI 1.7-2.7), fundoplication (OR 1.7, CI 1.1-2.4), aortopexy (OR 5.8, CI 2.1-16.1), and esophageal dilation (OR 2.0, CI 1.4-3.0). Very low birth weight (<1,500 g) increased odds of gastrostomy (OR 2.5, CI 1.6-3.8). CONCLUSION: Patients with EA/TEF frequently have aerodigestive sequelae. This work helps quantify aerodigestive needs in neonates with EA/TEF, suggesting early otolaryngology evaluation in their care. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:695-700, 2022.