Summary
The airway epithelium represents a physical barrier to the external environment acting as the first line of defence against potentially harmful environmental stimuli including microbes and ...allergens. However, lung epithelial cells are increasingly recognized as active effectors of microbial defence, contributing to both innate and adaptive immune function in the lower respiratory tract. These cells express an ample repertoire of pattern recognition receptors with specificity for conserved microbial and host motifs. Modern molecular techniques have uncovered the complexity of the lower respiratory tract microbiome. The interaction between the microbiota and the airway epithelium is key to understanding how stable immune homeostasis is maintained. Loss of epithelial integrity following exposure to infection can result in the onset of inflammation in susceptible individuals and may culminate in lung disease. Here we discuss the current knowledge regarding the molecular and cellular mechanisms by which the pulmonary epithelium interacts with the lung microbiome in shaping immunity in the lung. Specifically, we focus on the interactions between the lung microbiome and the cells of the conducting airways in modulating immune cell regulation, and how defects in barrier structure and function may culminate in lung disease. Understanding these interactions is fundamental in the search for more effective therapies for respiratory diseases.
The respiratory epithelium provides a highly effective barrier acting as the first line of defence against potentially harmful environmental stimuli including microbes and allergens.
The natural history of recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unknown. Because fibrosis with persistent physiological deficit is a previously described ...feature of patients recovering from similar coronaviruses, treatment represents an early opportunity to modify the disease course, potentially preventing irreversible impairment.
Determine the incidence of and describe the progression of persistent inflammatory interstitial lung disease (ILD) following SARS-CoV-2 when treated with prednisolone.
A structured assessment protocol screened for sequelae of SARS-CoV-2 pneumonitis. Eight hundred thirty-seven patients were assessed by telephone 4 weeks after discharge. Those with ongoing symptoms had outpatient assessment at 6 weeks. Thirty patients diagnosed with persistent interstitial lung changes at a multidisciplinary team meeting were reviewed in the interstitial lung disease service and offered treatment. These patients had persistent, nonimproving symptoms.
At 4 weeks after discharge, 39% of patients reported ongoing symptoms (325/837) and were assessed. Interstitial lung disease, predominantly organizing pneumonia, with significant functional deficit was observed in 35/837 survivors (4.8%). Thirty of these patients received steroid treatment, resulting in a mean relative increase in transfer factor following treatment of 31.6% (standard deviation SD ± 27.6,
< 0.001), and forced vital capacity of 9.6% (SD ± 13.0,
= 0.014), with significant symptomatic and radiological improvement.
Following SARS-CoV-2 pneumonitis, a cohort of patients are left with both radiological inflammatory lung disease and persistent physiological and functional deficit. Early treatment with corticosteroids was well tolerated and associated with rapid and significant improvement. These preliminary data should inform further study into the natural history and potential treatment for patients with persistent inflammatory ILD following SARS-CoV-2 infection.
Recent clinical trial successes have created an urgent need for earlier and more sensitive endpoints of disease progression in idiopathic pulmonary fibrosis (IPF). Domiciliary spirometry permits more ...frequent measurement of FVC than does hospital-based assessment, which therefore affords the opportunity for a more granular insight into changes in IPF progression.
To determine the feasibility and reliability of measuring daily FVC in individuals with IPF.
Subjects with IPF were given handheld spirometers and instruction on how to self-administer spirometry. Subjects recorded daily FEV
and FVC for up to 490 days. Clinical assessment and hospital-based spirometry was undertaken at 6 and 12 months, and outcome data were collected for 3 years.
Daily spirometry was recorded by 50 subjects for a median period of 279 days (range, 13-490 d). There were 18 deaths during the active study period. Home spirometry showed excellent correlation with hospital-obtained readings. The rate of decline in FVC was highly predictive of outcome and subsequent mortality when measured at 3 months (hazard ratio HR, 1.040; 95% confidence interval CI, 1.021-1.062; P ≤ 0.001), 6 months (HR, 1.024; 95% CI, 1.014-1.033; P < 0.001), and 12 months (HR, 1.012; 95% CI, 1.007-1.016; P = 0.001).
Measurement of daily home spirometry in patients with IPF is highly clinically informative and is feasible to perform for most of these patients. The relationship between mortality and rate of change of FVC at 3 months suggests that daily FVC may be of value as a primary endpoint in short proof-of-concept IPF studies.
Idiopathic pulmonary fibrosis (IPF) is a progressive, and invariably fatal, condition that is believed to arise in genetically susceptible individuals as a consequence of an aberrant wound-healing ...response following repetitive alveolar injury. The exact triggers, which initiate the fibrotic process, remain unknown. Infectious agents, including both viruses and bacteria, have the capacity to cause alveolar-epithelial cell injury and apoptosis. Relatively few studies have examined the role of infection in IPF. Those that have, point to viruses playing a key role as cofactors in the initiation and progression of IPF. There is also some evidence to suggest that viral infection may be responsible for a proportion of acute exacerbations of IPF. The role played by bacteria in the pathogenesis of IPF is less clear cut. Studies from other respiratory diseases suggest that alterations in the lung microbiome are associated with disease and that these changes influence disease behaviour. Emerging molecular microbiological techniques are making the study of microbial communities in the lung easier. It is hoped that by combining such techniques with the careful longitudinal phenotyping of patients with IPF, it will be possible to elucidate the role played by bacteria and viruses in the pathogenesis of the disease. If infection plays a causal role in IPF then it is possible that therapeutic strategies, utilising currently available antiviral or antibiotic drugs, may be effective in modifying the course of this devastating condition.
Pulmonary fibrosis (PF) encompasses a spectrum of chronic lung diseases that progressively impact the interstitium, resulting in compromised gas exchange, breathlessness, diminished quality of life ...(QoL), and ultimately respiratory failure and mortality. Various diseases can cause PF, with their underlying causes primarily affecting the lung interstitium, leading to their referral as interstitial lung diseases (ILDs). The current understanding is that PF arises from abnormal wound healing processes triggered by various factors specific to each disease, leading to excessive inflammation and fibrosis. While significant progress has been made in understanding the molecular mechanisms of PF, its pathogenesis remains elusive. This review provides an in-depth exploration of the latest insights into PF pathophysiology, diagnosis, treatment, and future perspectives.
Idiopathic pulmonary fibrosis (IPF) arises in genetically susceptible individuals as a result of an aberrant wound-healing response following repetitive alveolar injury. The clinical course of the ...disease remains both variable and unpredictable with periods of more rapid decline, termed acute exacerbation of IPF (AE-IPF), often punctuating the disease trajectory. Exacerbations carry a significant morbidity and mortality, and their exact pathogenesis remains unclear. Given the emerging evidence that disruption and alteration in the lung microbiome plays a role in the pathogenesis and progression of IPF, this review discusses the current knowledge of the contribution of infection and the respiratory microbiome to AE-IPF.
Proposed criteria for progressive fibrosing interstitial lung disease (PF-ILD) have been linked to increased mortality risk, but lung function trajectory after satisfying individual criteria remains ...unknown. Because survival is rarely employed as the primary end-point in therapeutic trials, identifying PF-ILD criteria that best predict subsequent change in forced vital capacity (FVC) could improve clinical trial design.
A retrospective, multicentre longitudinal cohort analysis was performed in consecutive patients with fibrotic connective tissue disease-associated ILD (CTD-ILD), chronic hypersensitivity pneumonitis and idiopathic interstitial pneumonia at three US centres (test cohort) and one UK centre (validation cohort). 1-year change in FVC after satisfying proposed PF-ILD criteria was estimated using joint modelling. Subgroup analyses were performed to determine whether results varied across key subgroups.
1227 patients were included, with CTD-ILD predominating. Six out of nine PF-ILD criteria were associated with differential 1-year change in FVC, with radiological progression of fibrosis, alone and in combination with other features, associated with the largest subsequent decline in FVC. Findings varied significantly by ILD subtype, with CTD-ILD demonstrating little change in FVC after satisfying most PF-ILD criteria, while other ILDs showed significantly larger changes. Findings did not vary after stratification by radiological pattern or exposure to immunosuppressant therapy. Near-term change in FVC after satisfying proposed PF-ILD criteria was heterogeneous depending on the criterion assessed and was strongly influenced by ILD subtype.
These findings may inform future clinical trial design and suggest ILD subtype should be taken into consideration when applying PF-ILD criteria.
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