The immunodynamics of pulmonary fibrosis.

Progressive pulmonary fibrosis (PPF) corresponds to any fibrotic interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis (IPF) that presents clinical, physiological and/or radiological evidence of disease progression similar to IPF. Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of pulmonary fibrosis and are associated with disease progression and reduced survival in IPF and other fibrotic ILDs. This study aimed to investigate the role of serum levels of MMP-1 and MMP-7 in patients with fibrotic non-IPF ILD as possible biomarkers of patients at risk of developing PPF. Newly diagnosed patients with fibrotic non-IPF ILD were included in this study. Serum levels of MMP-1 and MMP-7 were quantified at baseline and disease progression was monitored. PPF was defined according to the recent European Respiratory Society, American Thoracic Society, Japanese Respiratory Society and the Latin American Thoracic Society Clinical Practice Guidelines. 79 patients with fibrotic non-IPF ILDs were included and classified as having PPF or non-PPF. Significantly higher levels of MMP-7, but not MMP-1, were detected in the PPF group (p=0.01). MMP-7 was independently associated with PPF (adjusted OR 1.263, 95% CI 1.029-1.551; p=0.026) after adjustment for sex, age and smoking history. A cut-off value of 3.53 ng·mL-1 for serum MMP-7 levels had a sensitivity of 61% and a specificity of 74% for predicting PPF in non-IPF ILDs. In patients with fibrotic non-IPF ILDs, serum MMP-7 levels were significantly greater in the subgroup of patients meeting the PPF criteria at follow-up. This can be considered and further investigated as a possible biomarker to identify fibrotic ILD patients at risk of PPF.

This Year in Review paper, the first in a series of three review papers, highlights the most relevant articles published in 2013 in Respirology and other respiratory medicine journals on acute lung injury, interstitial lung disease (ILD), sleep and pulmonary physiology. Yuanlin Song The outbreak of H7N9 avian influenza pneumonia in east China highlighted the significance of virus assortment in birds and the role played by transmission from birds to humans. Meanwhile, Middle East respiratory syndrome coronavirus has been an inhabitant in bats for many years and transmitted to humans with person-to-person transmission.1, 2 Analysis of 111 patients who had confirmed H7N9 infection showed high mortality with the majority of deaths due to severe pneumonia and acute respiratory distress syndrome (ARDS).1 Novel coronavirus infection showed respiratory distress and multiple organ damage with mortality around 65% in affected patients.2 Influenza virus infection is still a severe challenge to public health warranting continuous efforts on vaccine development. Sepsis is also a major cause of ARDS, and it is associated with high mortality in intensive care unit patients. A recent study showed prolonged hospitalization but no increased mortality in a group of ARDS patients who had positive blood stream culture.3 However, this finding needs further investigation in a large group of ARDS patients at multiple sites. Unlike traditional ARDS, influenza-induced ARDS features both epithelial and endothelial injury with the injured epithelium and endothelium being orchestrated to provoke massive inflammation in the lungs. This leads to capillary leakage and eventual inhomogeneous alveolar flooding.4, 5 Alveolar flooding is a process of fluid leakage with active/passive transport driven by ion movement or hydrostatic pressure. Cystic fibrosis transmembrane regulation conductance has shown participation in alveolar fluid transport to the capillary compartment. Inhibition of chloride transport worsens lung injury induced by lipopolysaccharide in a rodent model, suggesting inhibition of active fluid transport may delay lung injury recovery.6 Among various risk factors, bile acid aspiration induces lung injury through p38 and c-Jun N-terminal kinase phosphorylation, as well as cytosolic phospholipase A2 and cyclooxygenase-2 production, which results in attenuation of junctional proteins such as occludin, zonula occludens-1 and E-cadherin.7 Similarly in a Pseudomonas aeruginosa-induced lung injury model, claudins -3, -4 and -18 are significantly upregulated with the degree of bronchoalveolar lavage claudin level being associated with lung injury score.8 These results strongly suggested protection against lung injury occurs through junctional protein expression in alveolar epithelium. Angiotensin-converting enzyme (ACE) plays a role in the pathogenesis of ARDS. bronchoalveolar lavage samples from ARDS patients showed increased ACE-1 but decreased ACE-2 levels.9 ACE-2 cleaves Angiotensin II to form Angiotensin, while ACE-1 cleaves Angiotensin I to form Angiotensin II. An angiostatin inhibitor reduced lung injury in a lipopolysaccharide-induced mouse model,10 suggesting imbalance of ACE expression in ARDS and potential therapy through downregulation of ACE-1. Different manoeuvres have been developed to quantify lung oedema and extravascular lung water to guide management of ARDS.11 A recent study using computed tomography imaging showed inhomogeneous distribution of lung injury in ARDS patients, and the level of inhomogeneity was associated with mortality.12 Chest ultrasound has been applied in ARDS to quantify lung oedema through B-line and subpleural consolidation measurement.13 These imaging techniques provide additional information on lung water that may help clinical evaluation and management of fluid administration and mechanical ventilation setting. Low tidal volume (6 mL/kg) ventilation strategy has been shown to reduce mortality in ARDS. Does an even lower tidal volume provide additional benefit? A recent study showed ventilation with 3 mL/kg combined with extracorporeal CO2 removal significantly increased ventilation free days in severe hypoxic patients.14 Prone position ventilation has shown improved survival in severe ARDS, although the protocol might not be applicable in most medical centres.15 Regarding ventilation mode, adaptive support ventilation is equivalent to volume control ventilation on mortality in patients with ARDS,16 which is consistent with previous reports. The lung is eventually healed through organ-derived stem cell mobilization/repopulation and tissue regeneration. Exogenous stem cell has been extensively studied in different lung injury animal model to test the efficacy, administration route and underlying mechanism. So far, it is known that exogenous stem cells heal lung injury through engraftment, paracrine secretion, immune modulation, growth factor production and antibiotic peptide synthesis pathway.17 So far, there are more than 300 on-going clinical trials assessing stem cell therapies.18, 19 A number of respiratory conditions are being considered as targets for stem cell treatment including ARDS and chronic progressive diseases such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).17, 20-22 The outcomes of these trials should be known in next few years. Bronchiectasis is characterized as vicious cycle of chronic purulent airway inflammation with bronchodilation. Neutrophils play an important role in airway inflammation, and so the activity of neutrophils has been studied in idiopathic bronchiectasis and control patients.23 The result showed similar response of neutrophils to granulocyte macrophage–colony stimulating factor in these two groups, suggesting neutrophil phagocytosis and generation of oxidative species have been preserved in bronchiectasis patients,23 although the exhaled condensation may not detect the difference.24, 25 Macrolide antibiotics including azithromycin has been shown to be beneficial in reducing symptoms and exacerbations,26 with an underlying mechanism thought to be biofilm disruption (which helps antibiotics penetration) and suppressive activity on airway inflammation. Toby M. Maher Chronic fibrotic ILD, encompassing a range of conditions including IPF and connective tissue disease-associated ILD, has gained increasing prominence over the last 2 or 3 years following the emergence of effective therapies such as pirfenidone and rituximab.27-29 Despite a rise in clinical trial activity, the pathobiology of fibrotic lung disease remains poorly understood.30 The development of IPF has previously been linked to abnormalities in lymphatic drainage and lymphangiogenesis.31 Data presented in Respirology, by Egashira et al. on the differential distribution of lymphatic drainage between upper and lower regions of the lung, are of particular interest for researchers trying to understand the development of fibrotic lung disease.32 Egashira and colleagues observed that lymphatic drainage in the upper lobes follows a bronchovascular distribution, while in the lower lobes, the lymphatics tend to be found in the subpleural regions. These differences may go some way to explain the typical pattern of distribution of fibrosis in individuals with IPF and merits further investigation in the context of fibrotic ILD. Cigarette smoking is a recognized risk factor for the development of a range of ILD including IPF, respiratory bronchiolitis-ILD and desquamative interstitial pneumonitis. Active smoking has also been associated with an increased risk of developing ILD in individuals with rheumatoid arthritis.33, 34 Furthermore, it is increasingly being recognized that ILD develops in a significant subset of individuals with emphysema.35 To explore the link between cigarette smoking, ILD and emphysema, Antoniou et al. compared the high-resolution computed tomography scans of individuals with IPF, RA-ILD and COPD.36 The authors found emphysema in a significant proportion of the patients with IPF and RA-ILD (35% and 48%, respectively). Interestingly, when compared with individuals with COPD, those with ILD and emphysema had significantly lower pack-year smoking histories. Although requiring prospective validation, this observation suggests that emphysema and pulmonary fibrosis share pathogenetic mechanisms.37 Individuals with fibrotic ILD, especially those with IPF, demonstrate highly variable rates of disease progression.38 This can make it challenging for clinicians to accurately convey information regarding prognosis at the point patients are diagnosed with the condition. In patients with early disease and preserved lung function determining prognosis can be especially challenging. Kondoh et al. have demonstrated that as is the case for individuals with more advanced disease, a typical computed tomography appearance of usual interstitial pneumonia and the extent of honeycombing identify individuals at a high risk of early progression.39 In IPF, it has previously been shown that the profusion of fibroblastic foci seen on surgical lung biopsy predicts subsequent disease progression.40 In a study of 50 subjects, Harada et al. extended this observation, demonstrating that the extent of fibroblastic foci in surgical lung biopsies correlates with disease severity and subsequent progression in both IPF and fibrotic NSIP.41 While of interest, this finding lacks clinical utility because of the requirement for biopsy material. Serum markers make an attractive target for biomarker development in ILD because of the ease of repeated sampling. Inokoshi et al. explored the potential of the extracellular matrix component, hyaluronan, as a diagnostic and prognostic biomarker in chronic fibrotic ILD.42 In their study of 49 subjects, hyluronan was elevated compared with healthy controls and rose further in individuals undergoing acute exacerbations. Procalcitonin, a small circulating amino acid precursor of calcitonin, has been investigated as a marker of bacterial pneumonia.43 Nagata et al. have shown that procalcitonin levels may be a useful discriminator between acute exacerbations of IPF (in which levels remain low) and bacterial-driven episodes of ARDS and pneumonia (in which, procalcitonin levels are markedly elevated).44 These observations, however, require validation in large prospective cohorts of patients.45 Sarcoidosis remains an enigmatic and multifaceted condition of unknown aetiology. A number of groups have previously reported a negative correlation between active cigarette smoking and the development of sarcoid.46-49 Hattori et al. sought to assess the relationship between sarcoidosis and cigarette smoking in Japan.50 In contrast with other studies undertaken, they found a strikingly high rate of smoking in their sarcoid patients (59.6% in men and 27.9% of women). Smoking was commoner in sarcoid patients than in age-matched controls in almost all deciles of age apart from men in their 30s. Interestingly, Hattori and colleagues noted a trend towards increased parenchymal involvement is sarcoid patients who smoked compared with those who had never smoked.50 While these data are thought provoking, they need to be caveated with the fact that the study was retrospective and relied on smoking prevalence data for the general Japanese population that was drawn from separately conducted research. Suchankova et al. undertook a study of myeloid cells isolated from the bronchoalveolar lavage of patients with sarcoid.51 They explored the expression pattern of triggering receptor expressed on myeloid cells-1 and -2. These two receptors belong to the immunoglobulin superfamily, play a role in the innate immune response to infection, and act to drive cell fusion and granuloma formation. Both triggering receptor expressed on myeloid cells-1 and -2 expressions were increased on the cell surface of bronchoalveolar lavage cells in sarcoid when compared with bronchoalveolar lavage cells isolated from individuals with other forms of ILD. These observations support a role for infection as a trigger for the development of sarcoid. They also suggest that triggering receptor expressed on myeloid cells-1 and -2 expression levels might be effective biomarkers for discriminating between individuals with sarcoid-related ILD and ILDs of other causes. Rare (or orphan) lung diseases are often overlooked in the medical literature, and yet some of the most striking treatment advances in the last decade have come in ultra-rare diseases. As such, insights derived from rare diseases have often revealed disease mechanisms that contribute to the understanding of more common disorders. During 2013, Respirology published a state-of-the-art review of treatment options in pulmonary alveolar proteinosis.52 The paper by Leth et al. explores in detail current understanding regarding the role of granulocyte macrophage-colony stimulating factor autoantibodies as the key pathogenetic mechanism in the majority of individuals with pulmonary alveolar proteinosis and the complementary role played by novel therapeutics and whole lung lavage. A disorder that has been increasingly recognized in the last few years is immunoglobulin G4-related disease (IgG4-RD).53 The condition is characterized by raised serum IgG4, multiorgan deposits of IgG4-positive plasma cells with associated fibrosis and a good therapeutic response to corticosteroids. It has become increasingly clear that IgG4-RD results in a number of specific pulmonary abnormalities. Matsui et al. provide an excellent overview of the constellation of lung manifestations of IgG4-RD in their large case series of 48 individuals with IgG4-RD and lung involvement.54 The most frequently observed findings were mediastinal adenopathy, thickening of the perilymphatic interstitium (intralobular septae), and, in a proportion of cases, subpleural or peribronchovascular consolidation. The apparent lymphatic spread of the disease resembles the appearances of pulmonary lymphoproliferative disease, and so the authors emphasize the importance of obtaining histological confirmation in suspected cases of IgG4-related lung disease. Obliterative bronchiolitis is an extremely debilitating condition that is associated with a wide range of underlying factors including transplant rejection, autoimmune disease, viral infection and occupational exposures.55-57 The mechanism by which these diverse conditions lead to the development of obliterative bronchiolitis remains unknown. Hashimoto et al. sought to understand how environmental exposure to Sauropus androgynous, a vegetable commonly eaten in Thailand, results in some individuals developing obliterative bronchiolitis.58 The aqueous fraction of Sauropus androgynous extract triggers cytokine release from monocytes. The release of the pro-inflammatory cytokine tumour necrosis factor-α was increased by Sauropus androgynous extract in monocytes from healthy controls but was increased even further in monocytes derived from individuals with S. androgynous-induced obliterative bronchiolitis. This observation suggests that both host and environmental factors are important in the development of obliterative bronchiolitis. Amanda Piper Recent years have seen an increasing number of publications highlighting the association between sleep-disordered breathing and cardiovascular disorders such as hypertension, heart failure and stroke. If left untreated, severe obstructive sleep apnoea (OSA) is associated with an increased risk of premature cardiovascular death.59, 60 A number of pathophysiological mechanisms linking OSA to cardiovascular morbidity have been proposed. Recurrent episodes of intermittent hypoxia arising from upper airway closure could activate inflammatory pathways impairing vascular endothelial function. Lui et al. provided an excellent review of the various pathways connecting endothelial dysfunction to OSA and the development of vascular abnormalities.61 In their review, evidence regarding the potential of early and effective intervention to prevent or possibly even reverse altered endothelial function associated with sleep-disordered breathing was discussed. In addition to the oxidative stress produced by apnoeic episodes, large negative pressures generated by inspiratory efforts against a closed airway create mechanical stresses on the tissues of the thorax. Kawano et al. tested the hypothesis that OSA could lead to pulmonary artery In their study of patients with suspected an association between severe OSA and an in the pulmonary artery was In addition to cardiovascular a number of studies have demonstrated an association between OSA and However, OSA is an risk factor for the development of II remains In their of prospective and colleagues found a significant association between OSA and with the risk increasing with OSA To the degree to which treatment of OSA this risk has yet to be although the results from the of on in 2 trial help this A wide range of have also been associated with most arising from the of sleep and intermittent However, which of are affected by OSA and the extent to which can be with continuous positive airway are not due to the wide range of that have been and colleagues sought to this by a the OSA was found to be associated with in and and function. with was most to and function. Data from a published trial of in with OSA over a found that active had a significant on and However, of three tested showed and even this was function was in the at 2 with the being for those with more severe A major with the study was the high and of of the As highlighted by et al. and of controls significant in data in this is to prevalence rates of and evidence of the health of disease has rise to interest in developing and of care to assess and The review by et al. an excellent synthesis of the data of care for their and potential The paper also some around the role of in the management of and provide a review of the current the relationship between obstructive lung such as and and While the is applied to the of OSA and COPD, similar between and the at in between and on clinical and these authors for obstructive lung diseases and OSA a more general of obstructive lung diseases and increasing rates with between these the authors emphasize the importance of OSA in patients with lung disease and in to understand response to therapy and to disease have been for determining an effective therapeutic for or for management of patients with OSA for more than years. 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significantly lower than the severe OSA However, no in mortality between patients with or was seen even patients with had a compared with individuals While the results from this study are consistent with the findings from a recent trial to therapy in patients with the of OSA As with the health outcomes were similar being in the As in the by the in outcomes between the two therapies from with lower To a major with has been the to However, this with the recent development of to be these more Although OSA is a common finding in the majority of patients with is not in sleep-disordered breathing in this et al. provide useful clinical insights the of sleep-disordered breathing in patients with and factors that could be to those to on the first treatment and at were useful in following 3 of An finding of this study was the progressive in these over the study results from an study that to may over During 2013, Respirology published two other excellent in the of sleep and In the first of the relationship between syndrome and sleep-disordered and provided a overview of the of on OSA and The paper by and the of highlighting the more of these on the respiratory not on sleep-disordered but including immune cell airway and pulmonary the increasing of in the this review is a of the these respiratory and using a mouse model, demonstrated differential of on the synthesis of in the regulation of sleep and the most OSA have on studies the role of these and their response to in humans may further on the pathogenesis of function has been to the and treatment of respiratory disease and, similar to to be a in While there is an drive to for this is not the case for other common lung function et highlighted that many of the for lung were years and in lung by volume and the of data in the a number of in the As such, and data for lung and airway in individuals and provided for these The findings demonstrate that lung the need for The and for pulmonary function have regarding how for et that 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Insulin-Like Growth Factor-II Is Increased in Systemic Sclerosis-Associated Pulmonary Fibrosis and Contributes to the Fibrotic Process via Jun N-Terminal Kinase- and Phosphatidylinositol-3 Kinase-Dependent Pathways

The incremental changes made in the definition of acute lung injury/adult respiratory distress syndrome (ARDS) over the last two decades represent a series of landmark events in the history of the condition. The first description of ARDS established the recognition of this syndrome;1 the 1994 America-European Consensus Conference definition set the standard for acute lung injury/ARDS clinical trials;2 while the new Berlin definition, which has revised the America-European Consensus Conference version, is based on 18 years clinical investigation and mechanism exploration, and as a result is a more precise and practical3 guide for clinical evaluation. The essential components of the new Berlin definition of ARDS are: removal of acute lung injury and division of ARDS into three successive stages (mild, moderate and severe) based on timing, chest imaging, partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FiO2) ratio and level of positive end expiratory pressure applied, with, as previously, exclusion of heart failure or fluid overload. The new definition is based on two large-scale databases from seven medical centres and unifies the understanding of ARDS and establishes a new standard for future clinical trials. Being continuously open to the air makes the respiratory system particularly vulnerable to environmental changes and thus predisposes the lung to inflammation and injury. Of various aerosols and particles, diesel particulate matter and engineered nanoparticles are two major concerns when it comes to assessing the pulmonary risks posed by air pollution.4, 5 diesel particulate matter provokes oxidative stress through particle surface area, transition metal and constituent organics and stimulation of cytokine production which further induce inflammation.4 Air pollution including diesel particulate matter induces cellular epigenetic changes including DNA methylation and histone modification which may eventually lead to gene silencing or microRNA changes and which in some case ultimately lead to cell proliferation and cancer development.6 Understanding the mechanisms involved in cellular injury by air pollution using genome, epigenome, transcriptome and microRNAome assays may help to dissect the molecular pathways that might become potential prophylactic or therapeutic targets.6 Engineered nanoparticles arise as a consequence of modern nanomaterial production, and humans are exposed to engineered nanoparticles through daily life, working place or professional exposure. The toxicity of engineered nanoparticles depends on their size, shape, surface and corona. Engineered nanoparticles can enter into cell organelles and induce oxidative stress, inflammation and immune responses.5 Evaluation and understanding of the mechanisms by which air pollution affects human health not only provides approaches for potential intervention, but also helps to establish a legal framework for production, consumption and environmental protection.5 Another important environment hazard is radiation. Medical radiation therapy or accidental overexposure can initiate lung inflammation, injury and fibrosis.7 Captopril, an angiotensin-converting enzyme inhibitor, may mitigate lung injury and improve survival after radiation exposure, which is very promising even 1 week after radiation exposure. Angiotensin-converting enzyme inhibitors could be potential drug candidates for prophylaxis against radiation-induced lung injury, although the exact molecular mechanism by which they exert their effects is still under investigation. Tracheal transplant is a standard process in lung transplantation. A reproducible tracheal transplant animal model would be very useful for the study of epithelium and submucosal gland regeneration after acute hypoxia-ischaemia injury. In a tracheal graft model in mice, the basal and duct cells initially proliferate to re-epithelialize the basement membrane, then these cells proliferate further and differentiate to restore the function of the epithelium, while serous cells differentiate 4–5 days before club (Clara) cells and ciliated epithelium.8 These sequential cellular changes represent a dynamic cell regeneration process which can be used as a therapeutic guide for repair of airway disease. Chronic airway inflammation is common in chronic obstructive lung disease and may lead to airway remodelling. Lipopolysaccharide is one of the common factors that induce airway inflammation. Three aquaporins have been reported to be expressed in airway epithelium and to play an important role in airway rehydration.9 Lipopolysaccharide downregulates AQP5 expression, but not AQP3 and AQP4, through the p38/JNK pathway. It is known that AQP5 deletion or downregulation may decrease fluid secretion/osmotic fluid transport10 associated with thick mucus production.11 Thus, the mechanism of lipopolysaccharide induced downregulation of AQP5 may provide insight in to airway disease management based on water channel expression. The last decade has seen a rapid increase in clinical and preclinical research activity in the interstitial lung diseases (ILD), in particular idiopathic pulmonary fibrosis (IPF).12 Despite this, there have been relatively few developments in our understanding or treatment of sarcoidosis. Although the basic patho-mechanisms are understood, there remains much that is unknown; what is the initial disease trigger, what determines disease chronicity and end-organ fibrosis, why is the disease phenotype so enormously variable between individuals? With this in mind, it was welcoming to see a number of important papers relating to sarcoidosis being published in Respirology during 2012. Shaffiq et al. presented data demonstrating that the soluble form of A Disintegrin and Metalloprotease (ADAM) 33 protein is raised in the bronchoalveolar lavage fluid of individuals with sarcoid when compared with controls.13 ADAM 33 forms part of a family of transmembrane glycoproteins that play diverse roles in modulating cell surface remodelling, mediation of cell–cell and cell–matrix interactions and ectodomain shedding of growth factors and receptors. Transforming growth factor-β-induced post-translational modification results in ectodomain shedding of ADAM 33, thus giving rise to a soluble form. Polymorphisms in the gene for ADAM 33 have been shown to alter susceptibility to the development of asthma. Furthermore, increased levels of soluble ADAM 33 have been shown in the bronchoalveolar lavage of asthma patients, suggesting that the protein plays an important role in the airway inflammation and fibrosis that characterize the disease. Shaffiq et al. as well as demonstrating increased levels of soluble ADAM 33 in sarcoidosis, were able to show that soluble ADAM 33 levels inversely correlate with both forced vital capacity (FVC) and diffusing capacity of carbon monoxide (DLco). Soluble ADAM 33 may therefore be a biomarker of disease severity in sarcoidosis, but more importantly the results presented by this group raise interesting questions about the role played by ADAM 33 in the pathogenesis and progression of pulmonary sarcoid. In a questionnaire study, Wilsher et al. also probed the overlap that possibly exists between asthma and sarcoidosis.14 The authors hoped to disentangle whether the pathogenesis of sarcoidosis is driven by a skewed T helper 1/T helper 2 immuno-phenotype. Preclinical data suggest that individuals with sarcoid are likely to exhibit a predominantly T helper 1 phenotype. Asthma, by contrast, is known to be driven by T helper 2 cytokines. One might therefore expect individuals with sarcoid to be protected against asthma. The authors however found an identical incidence of asthma symptoms and atopy in 136 sarcoid subjects when compared with previously reported New Zealand population data. As argued, in an accompanying editorial by Zappala and Wells, there are a number of important confounders that make these results challenging to interpret.15 Nonetheless, they concur that the lack of a clear T helper 1/T helper 2 dichotomy supports the notion that autoimmune disease (including sarcoid) results from a loss of immune regulation in genetically and environmentally predisposed individuals following antigenic exposure. Sarcoidosis causes significant morbidity to sufferers as a consequence of organ-specific symptoms and also through constitutional upset.16 Both these aspects of sarcoid were explored in papers published in Respirology in 2012. Young et al. assessed 52 individuals with sarcoid and well-preserved lung function and demonstrated that 11% showed airway hyperresponsiveness following nebulization of hypertonic saline and 44% showed airway hyperresponsiveness in response to histamine.17 airway hyperresponsiveness was associated, in univariate analysis, with conglomerate perihilar fibrosis and a reticular pattern on high-resolution computed tomography. On multivariate analysis, airway hyperresponsiveness was inversely correlated with baseline forced expiratory volume in 1 s (FEV1). Overall, these findings suggest that airway hyperresponsiveness is an important problem in sarcoidosis that is likely to reflect the consequences of airway remodelling following inflammation. De Boer and Wilsher published a validation of the Sarcoidosis Health Questionnaire in a non-US population.18 In keeping with earlier studies utilizing this questionnaire, they were able to show that in a New Zealand population of predominant European origin that the Sarcoidosis Health Questionnaire correlated well with health-related quality of life and fatigue scores. IPF, with a median survival of 2.8–4.2 years, remains one of the most devastating of the ILD. This is despite recent advances in disease understanding and the publication of a number of landmark clinical trials. While pirfenidone has recently been licensed as a treatment for IPF in Japan and Europe,19 some guidelines, on the basis of the positive findings of the IFIGENIA trial,20 recommend the use of the anti-oxidant N-acetyl-cysteine.21 The study of Homma et al. published in Respirology during 2012 represents an interesting addition to our understanding of the potential role of N-acetyl-cysteine as a therapy for IPF.22 The authors undertook a 48-week study, in 76 subjects of nebulized N-acetyl-cysteine monotherapy (352.4 mg twice daily) compared with placebo. At 48 weeks, there was no overall difference in the primary end-point of FVC change. However, there were a number of positive trends particularly in patients with more severe disease at baseline. Pending the results of the PANTHER trial (a study comparing oral N-acetyl-cysteine to placebo) in the USA, these data suggest that a larger, appropriately powered study of nebulized N-acetyl-cysteine may be warranted in the future. As well as clinical trials, another area of research interest in IPF is biomarker discovery. Fahim et al. reported that serum carcinoembryonic antigen levels correlated with baseline disease severity in 41 patients with IPF.23 Tasaka et al. looked at potential biomarkers in the bronchoalveolar lavage fluid of individuals with IPF alone and IPF combined with emphysema.24 They were able to demonstrate that the pro-inflammatory CXC chemokines CXCL5 and CXCL8 are associated with the presence of emphysema on high-resolution computed tomography. Levels of fibrocytes, circulating fibroblast progenitor cells, have previously been shown to predict prognosis in individuals with IPF.25 Interestingly, Fujiwara et al. were able to show that fibrocyte levels correlate with baseline disease severity in other fibrotic ILD.26 It remains to be seen, however, whether fibrocyte levels also predict prognosis in ILD other than IPF. While sarcoidosis and IPF are the commonest of the ILD, the combined incidence of other ILD, while significant, is less well recognized. In this regard, a work by Amar et al. utilizing the UK general practice database has provided interesting data on the burden of iatrogenic ILD in the UK.27 The authors report an incidence of drug- and radiation-induced ILD of 4.1 per million person years (this figure is likely to be an underestimate given the poor specificity of current coding systems in separating iatrogenic from other causes of ILD). Importantly, individuals with drug- or radiation-induced ILD had an all-cause mortality risk that was four times higher than age-matched cases. Another challenge with rarer ILD is in defining natural history. Kawabata et al. are therefore to be congratulated on their longitudinal study of individuals with desquamative interstitial pneumonia DIP.28 Of 31 patients studied, 14 were followed for over 5 years, and of these, five developed significant fibrosis and four developed lung cancer. These findings suggest that desquamative interstitial pneumonia is not the benign condition that other case series may have suggested. Estimating the effects of ILD on sufferers is another area that remains understudied. While there have been recent efforts to develop bespoke ILD quality of life tools such as the King's Brief Interstitial Lung Disease Questionnaire, other groups have sought to modify existing tools.29 Nagata et al. report that the chronic obstructive pulmonary disease (COPD) assessment test, a short quality of life questionnaire developed for COPD, shows a strong correlation with the St George's Respiratory Questionnaire in 55 individuals with ILD.30 In terms of treating ILD, rapidly progressive disease with respiratory failure represents a frequent challenge to pulmonologists. Decisions about the level of supportive care to provide in such instances are often coloured by the poor outcomes seen in the intensive care unit in individuals with IPF. Yokoyama and colleagues have provided timely data on the use of non-invasive ventilation (NIV) in this patient group.31 In a retrospective analysis of 38 patients admitted to their unit over 5 years with rapidly progressive interstitial pneumonia, they were able to show that early intervention with NIV was associated with a significantly improved chance of survival at 30 days. Connective tissue disease-associated ILD is a growing problem for pulmonologists, especially as rheumatological interventions for articular and non-pulmonary disease manifestations are improving. Nonetheless, understanding of the natural history of ILD in some of the rarer connective tissue disease is limited. Maldonado et al. assessed the outcome of autopsies in patients with known idiopathic inflammatory myopathy.32 Over a 29-year period, they identified 39 deaths with autopsy in individuals with idiopathic inflammatory myopathies. Of these cases, 33% died from respiratory complications, 28% from infectious disease and 26% from cardiovascular complications. Importantly, in a third of cases, the ultimate cause of death was not suspected ante-mortem. While improved diagnostics may reduce this issue in contemporary studies, this paper nonetheless highlights the importance of the need for prompt and correct diagnosis of respiratory complications and infectious disease in this patient group.33 The past few years has seen an increasing interest in the impact of abnormal breathing during sleep on daytime function and general health across a range of medical disorders. With increasing obesity in both developed and developing economies, and the well-recognized relationship between body mass index and sleep disordered breathing (SDB), understanding the mechanisms underpinning abnormal sleep breathing and its health consequences will be of increasing clinical importance. Over the course of 2012, Respirology published a number of articles in the area of sleep, with a particular emphasis on obesity and its impact on respiratory disease. Given the prevalence of obstructive sleep apnoea (OSA), it was not surprising that the focus of many of the papers was on this disorder. Isono34 provided a comprehensive review of the role obesity plays in the pathogenesis of upper airway collapse, with a particular emphasis on the consequences of fat deposition in the neck and surrounding the pharyngeal airway, as well as intra-abdominal fat distribution. The paper by Sutherland and colleagues35 discussed the interplay between obesity and craniofacial morphology in determining OSA risk. Craniofacial factors, particularly skeletal restriction, may be of greater importance for OSA risk in Asians, who develop more severe OSA at lower bodyweights than Caucasians. This has significant clinical consequences considering the increasing obesity levels in the Asia–Pacific region. Understanding the pathogenic aspects of OSA and how this is influenced by ethnicity may allow more targeted assessment and treatment strategies in OSA management in different regions. The complexity of factors contributing to OSA was further underscored in the article by Joosten and colleagues,36 who investigated a large cohort of patients with mild–moderate OSA. Using polysomnographic data, these authors identified six separate phenotypes, confirming the heterogeneity of this disorder and the need to consider these variations in analysing outcomes and therapies in patients with mild to moderate OSA. OSA and metabolic syndrome are both closely related to obesity and their frequent coexistence in the same individual has garnered significant interest in the role OSA plays in the development and worsening of cardiometabolic dysfunction. A review of this topic by Lam and colleagues37 provides an excellent analysis of the current state of knowledge in the area and highlights the complex relationship between obesity, OSA and metabolic syndrome. While it is known that obesity is closely related to OSA, it has been hypothesized that OSA could influence fat accumulation and deposition, and through the promotion of central obesity, contribute to metabolic dysfunction. Although continuous positive airway pressure (CPAP) remains the mainstay of therapy for OSA, obesity is the only major modifiable risk factor for OSA. Lam et al.37 stress the importance of diet, increased physical activity and weight loss in addition to CPAP in managing individuals with OSA and the metabolic syndrome. However, accomplishing weight loss is not easily achieved with conservative measures alone, and many severely obese individuals now look to surgical approaches for more permanent weight management. The paper by Schachter38 provides a valuable overview of the assessment and management of possible respiratory and sleep problems encountered by individuals undergoing bariatric surgery. Although weight loss achieved through surgery can have a significant impact on comorbid conditions including type II diabetes, we are reminded that OSA is rarely cured by bariatric surgery; postoperative monitoring of sleep breathing should be undertaken before considering cessation of CPAP therapy.38 Epidemiological evidence has shown that OSA is an independent predictor of mortality.39 In disorders such as obesity hypoventilation syndrome (OHS) and COPD, the presence of daytime hypercapnia is associated with reduced blood are not during sleep studies for OSA. the report by et was in that a cohort of patients with who sleep studies with and blood were followed for to In this study, the development of hypercapnia in to partial arterial carbon of and were of increased independent of obesity or disease. As identified in the accompanying editorial by it was from the study this group of individuals clinical practice in or intervention, given the increased mortality associated with these changes in individuals and therapy and would OSA has been to a range of cardiovascular disorders. Chronic plays an important role in this Using a model to of over different et found that chronic induced oxidative stress in the and the severity of the oxidative stress was significantly correlated with the of Over this response to likely a mechanism being into The authors that a understanding of such mechanisms could lead to new approaches in the management of cardiovascular complications of OSA. The role and arterial carbon plays in another type of central sleep was by et These authors investigated changes in (a of during partial to In to at to moderate of breathing over a significant increase in at This increase in was correlated with an increase in central sleep Furthermore, a relationship between the increase in central sleep apnoea and a in arterial carbon was The authors the more at may a of compared with lower This study with that of et the importance of the of to sleep disordered breathing and its This syndrome at the end of the of and is associated with significant and health diagnosis is often or The prevalence of cardiovascular morbidity seen in is in keeping with the greater of inflammatory blood and of the found in patients compared with obese In their and the importance not only of treating in but also the need to the of weight and in to impact on cardiometabolic NIV may have an important but still role in in this In a study, and looked at the effects of NIV in severe therapy with a significant in pulmonary pressure and increase in in capacity could not be to but to be related to in As by et the of NIV is associated with reduced and improved this may be the to at physical activity and While the clinical of CPAP therapy in patients with moderate to severe OSA are well with therapy remains an One of the many factors that may influence to therapy is improved sleep quality on CPAP in rapid and sleep baseline can and have been with to However, what sleep and factors this have not been Using data from and CPAP studies, et found that an increase in sleep of and of in rapid sleep during the sleep and rapid Furthermore, they identified factors of sleep and rapid during pressure this may help to patients less likely to to therapy monitoring should be et reported and effects related to NIV in patients with chronic respiratory Although overall was at patients a greater the number of effects lower the need to strategies to and reduce effects that may on the use of daytime is a frequent by sleep and while it is associated with other causes need to be The sleep disorder is excellent review of this disorder by the interesting that have been found between and OSA, with evidence suggesting this may arise from to of the respiratory and systems are closely The of this for patient care was sleep quality is another by patients with a of medical disorders including et a large retrospective study sleep quality in patients with moderate to severe OSA. results of studies, these authors found sleep quality was poor with reduced sleep increased sleep and reduced rapid sleep compared with of In to some daytime than was associated with sleep the use of oxygen significantly sleep quality in these patients further investigation. The of clinical in the treatment and of patients with respiratory disease has increased over the last has also our understanding of how can help the severity and of disease and allow of prognosis and The of initial research in this area was on incremental in the but more there has been interest in that can be of the or such as the the and the incremental The primary of these are they are and less than the standard and may clinical and In Respirology in 2012, a number of studies made significant to this important area of and investigated the to three the incremental and the in patients with range and compared with a on a and ventilation were using a analysis system while and heart were also Importantly, the authors for the known with by the patients The primary of the study were that a oxygen and heart were achieved in while a significantly greater was during the compared with the These findings that can to the and provide results with As these may some important for assessing the of pulmonary and for to the more complex and In more common respiratory disorders COPD, interstitial pulmonary fibrosis and lung cancer the and of the have been relatively well However, two studies this investigated the of the in more conditions in patients undergoing upper and lung et the in patients the before undergoing upper surgery and investigated whether in the could predict pulmonary complications pneumonia, acute respiratory failure and However, in this relatively of patients, there were only pulmonary complications and the difference in could not the patients at higher risk. Wilsher et the and of the in patients with lung disease. It was demonstrated that there was between two 1 week correlation However, while the was reproducible and it not reflect the severity of lung disease as by lung function and high-resolution computed for of the The authors also demonstrate that was not in patients with

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease (ILD) with limited treatment options and poor prognosis. Differentiating IPF from connective tissue disease–associated ILD (CTD-ILD) is clinically challenging due to overlapping features, and reliable circulating biomarkers are lacking. Recent studies suggest that multi-marker proteomic models combined with machine learning may enhance diagnostic precision and prognostic assessment in fibrotic ILDs. We prospectively analyzed plasma samples from Taiwanese patients with fibrotic ILDs (IPF, n = 22; CTD-ILD, n = 66) using the Olink inflammation panel (92 proteins). Differentially expressed proteins were identified and subjected to integrative network analyses. Predictive classification models were developed using generalized linear modeling (GLM), decision tree, and random forest approaches. Prognostic relevance was evaluated with Kaplan–Meier and Cox regression analyses, and findings were validated in public transcriptomic datasets. Among 92 proteins profiled, 23 showed significant differences between IPF and CTD-ILD. Four candidates—MMP-10, FGF-19, ADA, and TWEAK (TNFSF12)—consistently emerged as key discriminatory markers. The GLM model incorporating FGF-19, ADA, and TWEAK achieved the highest diagnostic accuracy (AUC 0.870; sensitivity 0.97; specificity 0.82), outperforming decision tree and random forest models. Transcriptomic validation confirmed TWEAK downregulation in ILD lung tissues and in TGF-β1–stimulated fibroblasts, linking it to canonical profibrotic signaling. Survival analysis showed significantly worse outcomes in IPF versus CTD-ILD (log-rank p < 0.001), with MMP-10 associated with poor prognosis (HR 2.08, p = 0.007) and TWEAK with favorable prognosis (HR 0.04, p < 0.001). This study identifies distinct plasma proteomic signatures that differentiate IPF from CTD-ILD and highlights TWEAK as both a diagnostic and prognostic biomarker. A multi-marker GLM model demonstrated excellent diagnostic performance, supporting the clinical utility of plasma proteomics combined with machine learning to improve disease classification and risk stratification in fibrotic ILDs. Integrating plasma proteomics with machine learning enables development of a multi-marker model that enhances diagnostic accuracy and prognostic evaluation in fibrotic interstitial lung diseases, supporting more precise disease classification and risk stratification in clinical practice. Plasma proteomics combined with machine learning improves IPF vs CTD-ILD classification and identifies prognostic biomarkers, advancing precision diagnosis in fibrotic interstitial lung disease.

The aim of this study was to summarize quantitative computed tomography (CT) and machine learning data in fibrotic lung disease and to explore the potential application of these technologies in pulmonary sarcoidosis. Recent data in the use of quantitative CT in fibrotic interstitial lung disease (ILD) are covered. Machine learning includes deep learning, a branch of machine learning particularly suited to medical imaging analysis. Deep learning imaging biomarker research in ILD is currently undergoing accelerated development, driven by technological advances in image processing and analysis. Fundamental concepts and goals related to deep learning imaging research in ILD are discussed. Recent work highlighted in this review has been performed in patients with idiopathic pulmonary fibrosis (IPF). Quantitative CT and deep learning have not been applied to pulmonary sarcoidosis, although there are recent deep learning data in cardiac sarcoidosis. Pulmonary sarcoidosis presents unsolved problems for which quantitative CT and deep learning may provide unique solutions: in particular, the exploration of the long-standing question of whether sarcoidosis should be viewed as a single disease or as an umbrella term for disorders that might usefully be considered as separate diseases.

Hypersensitivity pneumonitis (HP) is a complex form of interstitial lung disease (ILD) characterized by immune-mediated inflammation following an inciting antigen exposure in a susceptible individual.1 Chronic exposure leads to progression of inflammation with evolution of fibrotic response in the lung and progressive pulmonary fibrosis (PPF). Knowledge of key features of disease presentation is critical in distinguishing HP from other idiopathic interstitial pneumonias, allowing for subsequent appropriate interventions including exposure avoidance and treatment. Recently, two anticipated guidelines have emerged, one published by the American Thoracic Society/Japanese Respiratory Society/Asociación Latinoamericana de Tórax (ATS/JRS/ALAT) and the second by the American College of Chest Physicians (ACCP), establishing standardized diagnostic approaches to HP.2, 3 These guidelines provide similar diagnostic algorithms, in addition to establishing clinical, radiographic and histopathologic features of two clinical phenotypes known as fibrotic and nonfibrotic HP, with separate recommendations for each. Both guidelines emphasize the importance of classification of diagnosis of fibrotic HP (fHP) or nonfibrotic HP (nfHP), the distinction of which is made by the presence or absence of radiographic or histopathologic fibrosis. Prior time-based classification (acute, subacute, chronic) was deemed inferior by both working groups due to unreliable association with clinical outcomes. The new approach was adapted to objectively define disease presentation and to allow for more consistent association with disease prognostication, as well as to better inform treatment decisions. Diagnosis of HP is often challenging given the heterogeneity in clinical presentation, in addition to overlap with other non-fibrotic and fibrotic ILDs. Establishing a clinical profile may help inform pre-test probability when distinguishing between fibrotic ILDs, though an indeterminate clinical profile with overlapping features that may be compatible with both idiopathic pulmonary fibrosis (IPF) and fHP (such as male >60 years of age, former smoker with a possible exposure) can make distinction difficult.4 As a result, misdiagnosis is not infrequent, as a proportion of patients labelled as having IPF are often found to have fHP on explant studies or case re-evaluation.5-7 Furthermore, a causative antigen exposure is not identified in up to 60% of patients with HP, despite thorough evaluation.2, 8-10 Nonetheless, the index of suspicion for HP must remain high in a clinician's mind during evaluation of ILD, and an integrated approach implementing multidisciplinary discussion is particularly important in cases with clinical overlap. The diagnosis of HP requires an integrative approach with collaboration among expert pulmonologists, radiologists and pathologists in order to optimize diagnostic accuracy (Figure 1A). Both guidelines highlight the importance of three primary clinical domains including (1) exposure identification, (2) high resolution computed tomography (HRCT) imaging and (3) BAL lymphocytosis. The need for histopathology should be limited to patients in whom the confidence of the clinical diagnosis of HP is low and in whom risks for obtaining surgical lung biopsy are low.2 Antigen identification can be investigated initially through a comprehensive patient history. Regrettably, there is no validated recommended questionnaire available to date, and as a result, the clinician must approach patients with a detailed environmental exposure history with awareness of usual and unusual HP inducers.1 Serum-specific IgG testing detects immunologic sensitization without establishing causality, though can be helpful in generating supportive data in cases with some diagnostic uncertainty.5 Exposure tests such as the specific inhalation challenge can only be performed at centres with the appropriate expertise and have limited widespread implementation.3, 5 The importance of recognizing the distribution and patterns of HRCT chest imaging is emphasized in both guidelines. These are categorized as ‘typical’ or ‘compatible with HP’, for both nonfibrotic and fHP and include ‘indeterminate for HP’ for fHP.2, 3 The indeterminate category is used when any pattern of pulmonary fibrosis is present without specific features of HP.3 The distinction between fibrotic and nfHP has clinical significance, as there is clear demonstration that the presence of radiographic or histopathological fibrosis are associated with worse outcomes.11-19 While the specific radiographic features of the ‘typical’ nfHP and fHP patterns are described in the guidelines and have an upper lobe predominance, the three-density pattern is highly specific for fHP. This pattern is a combination of three attenuations on inspiratory CT images: normal appearing lung, high attenuation (GGO) corresponding to infiltrative disorder and regions of decreased attenuation related to the obstructive abnormality seen in small airway disease (Figure 1B).2 BAL lymphocytosis raises the probability of HP, with thresholds of 30% or greater demonstrating a high specificity for fHP.2, 20 This can help to distinguish fHP from other forms of fibrotic ILD such as IPF, though the absence of BAL lymphocytosis does not exclude a diagnosis of HP (Figure 1A). In patients in whom a confident diagnosis of HP cannot be made despite multidisciplinary review of clinical, radiographic and BAL findings (typically in patients with indeterminate imaging pattern for HP), the diagnosis of HP can only be ascertained with histopathology features found on lung biopsy (Figure 1A). The guidelines emphasize that lung biopsy must be considered as a last resort only in patients whose risk for the procedure are relatively low and all other diagnostic evaluation/intervention has been exhausted. The ATS/JRS/ALAT guideline suggests that transbronchial lung cryobiopsy (TBLC) be considered by capable medical centres with expertise in performing TBLC to patients with suspected fHP.2 Both guidelines offer similar criteria for histopathologic findings in fibrotic and nfHP.2, 3 Typical features of nfHP are accentuated around airways (‘bronchiolocentric’), with lymphocyte predominance, and poorly formed nonnecrotizing granulomas and/or multinucleated giant cells. Histopathologic features typical for fHP are (1) chronic fibrosing interstitial pneumonia with fibrotic NSIP or UIP-like pattern, (2) airway-centred fibrosis with or without peribronchiolar metaplasia, (3) poorly formed non-necrotizing granulomas and (4) absence of features to suggest alternative diagnosis. In cases where an inciting antigen is identified, avoidance and remediation are essential aspects of HP management. Importantly, lack of clinical improvement following antigen avoidance does not exclude a diagnosis of HP or rule out the antigen as causal. Currently, there are no established guidelines for pharmacologic management of HP. Immunomodulating medications such as prednisone, mycophenolate mofetil (MMF) or azathioprine are commonly used, though without the support of clinical trials. Although limited data does suggest the strongest benefit of corticosteroid (CS) in patients with nfHP, evidence to support long-term benefit of CS is lacking. Few retrospective studies have shown improvement in forced vital capacity (FVC) or diffusion capacfity for carbon monoxide (DLCO) with the use of MMF and azathioprine with significant reduction in prednisone dose and decreased incidence of treatment-emergent adverse effects when compared with prednisone alone.21-24 A retrospective study of rituximab in 20 patients with chronic HP suggested that rituximab may lead to stabilization of lung function in some patients.25 The 2022 ATS/ERS/JRS/ALAT guideline on PPF suggests therapeutic benefit with the antifibrotic nintedanib for patients with PPF, irrespective of the specific ILD diagnosis. Thus, nintedanib may be tried for patients with fHP manifesting PPF.26 Despite the lack of standardized treatment guidelines for HP, a reasonable approach based on limited data may be a trial of immunomodulating medications (i.e., CSs in addition to steroid-sparing agent such as MMF) in symptomatic patients with nf/fHP, with consideration of the addition of nintedanib as either combination or monotherapy without immunosuppression in cases of fHP with progressive disease. Collectively, the available data (largely from observational studies) suggest that clinical improvement is more common in nfHP than fHP, however, clinicians should not rely solely on clinical improvement (or lack of) with medical therapy to confirm or exclude a diagnosis of HP as suggested in the ACCP guideline.3 HP is a complex disease with a heterogeneous presentation and clinical course, often leading to diagnostic challenges. Guidelines published by both the ATS/JRS/ALAT and ACCP provide clinicians with similar diagnostic algorithms to aid in the diagnostic approach to patients with newly recognized ILD. Research is needed to improve diagnostic certainty in various aspects including genetic predisposition, validated regionally relevant exposure questionnaires, establishing BAL thresholds and specific antibody testing, in addition to differentiating histopathologic similarities of UIP and UIP-like patterns and genomic classifiers of UIP in patients with fHP and IPF. The possibility of HP as a primary entity or ‘cryptogenic HP’ when an antigen is not identified in the patient's environment despite thorough investigation (including inspection and microbiology testing by an environmental hygienist) will need to be pursued. Finally, data to guide treatment of HP is limited, with a strong need for clinical trials and other research to address treatment of both fHP and nfHP. None declared.

Uncovering the Risk of Inhalational Exposures Across Interstitial Lung Diseases

BackgroundComorbidities are frequent and have been associated with poor quality of life, increased hospitalizations, and mortality in patients with interstitial lung disease (ILD). However, it is unclear how comorbidities lead to these negative outcomes and whether they could influence ILD disease progression. The goal of this study was to identify clusters of patients based on similar comorbidity profiles and to determine whether these clusters were associated with rate of lung function decline and/or mortality.MethodsPatients with a major fibrotic ILD (idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis, connective tissue disease-associated ILD, and unclassifiable ILD) from the CAnadian REgistry for Pulmonary Fibrosis (CARE-PF) were included. Hierarchical agglomerative clustering of comorbidities, age, sex, and smoking pack-years was conducted for each ILD subtype to identify combinations of these features that frequently occurred together in patients. The association between clusters and change in lung function over time was determined using linear mixed effects modeling, with adjustment for age, sex, and smoking pack-years. Kaplan Meier curves were used to assess differences in survival between the clusters.ResultsDiscrete clusters were identified within each fibrotic ILD. In IPF, males with obstructive sleep apnea (OSA) had more rapid decline in FVC %-predicted (− 11.9% per year [95% CI − 15.3, − 8.5]) compared to females without any comorbidities (− 8.1% per year [95% CI − 13.6, − 2.7]; p = 0.03). Females without comorbidities also had significantly longer survival compared to all other IPF clusters. There were no significant differences in rate of lung function decline or survival between clusters in the other fibrotic ILD subtypes.ConclusionsThe combination of male sex and OSA may portend worse outcomes in IPF. Further research is required to elucidate the interplay between sex and comorbidities in ILD, as well as the role of OSA in ILD disease progression.

Progressive fibrosing interstitial lung diseases (ILDs) involve similar pathophysiological processes, indicating the potential for common approaches to treatment. Nintedanib (Ofev®), an intracellular tyrosine kinase inhibitor (TKI) with antifibrotic properties, was one of the first drugs approved for use in idiopathic pulmonary fibrosis (IPF) and has more recently been approved for use in other chronic fibrosing ILDs with a progressive phenotype and systemic sclerosis-associated ILD (SSc-ILD). In multinational phase III trials, nintedanib significantly reduced the annual rate of decline in forced vital capacity (FVC) in adults with IPF, other progressive fibrosing ILDs and SSc-ILD. Reductions in FVC decline with nintedanib in patients with IPF and severe gas exchange impairment were comparable to those in patients with milder disease. Real-world experience in patients with IPF supports the effectiveness of nintedanib in slowing ILD progression. Nintedanib had a manageable tolerability profile in patients with fibrotic ILDs in clinical trials and real-world studies. No new safety signals have emerged from global pharmacovigilance data. Nintedanib continues to represent an important therapeutic option in patients with IPF and is the first drug to be approved for use in patients with other chronic fibrosing ILDs with a progressive phenotype or SSc-ILD, with these approvals expanding the range of fibrotic ILDs for which nintedanib can be prescribed.

Mice Lacking Neutrophil Elastase Are Resistant to Bleomycin-Induced Pulmonary Fibrosis

Physical activity limitations and cough are common in patients with interstitial lung disease (ILD), potentially leading to reduced health-related quality of life. We aimed to compare physical activity and cough between patients with subjective, progressive idiopathic pulmonary fibrosis (IPF) and fibrotic non-IPF ILD. In this prospective observational study, wrist accelerometers were worn for seven consecutive days to track steps per day (SPD). Cough was evaluated using a visual analog scale (VAScough) at baseline and weekly for six months. We included 35 patients (IPF: n = 13; non-IPF: n = 22; mean ± SD age 61.8 ± 10.8 years; FVC 65.3 ± 21.7% predicted). Baseline mean ± SD SPD was 5008 ± 4234, with no differences between IPF and non-IPF ILD. At baseline, cough was reported by 94.3% patients (mean ± SD VAScough 3.3 ± 2.6). Compared to non-IPF ILD, patients with IPF had significantly higher burden of cough (p = 0.020), and experienced a greater increase in cough over six months (p = 0.009). Patients who died or underwent lung transplantation (n = 5), had significantly lower SPD (p = 0.007) and higher VAScough (p = 0.047). Long-term follow up identified VAScough (HR: 1.387; 95%-CI 1.081-1.781; p = 0.010) and SPD (per 1000 SPD: HR 0.606; 95%-CI: 0.412-0.892; p = 0.011) as significant predictors for transplant-free survival. In conclusion, although activity didn't differ between IPF and non-IPF ILD, cough burden was significantly greater in IPF. SPD and VAScough differed significantly in patients who subsequently experienced disease progression and were associated with long-term transplant-free survival, calling for better acknowledgement of both parameters in disease management.

Transbronchial Cryobiopsy Is Superior to Forceps Biopsy for Diagnosing both Fibrotic and Non-Fibrotic Interstitial Lung Diseases

Acute exacerbation (AE) is recognized as a life-threatening condition with acute respiratory worsening in idiopathic pulmonary fibrosis (IPF). AE also occurs in fibrotic interstitial lung disease (ILD) other than IPF, including other types of idiopathic interstitial pneumonias (IIPs), ILD associated with collagen vascular disease (CVD-ILD), and chronic hypersensitivity pneumonia (CHP). However, the clinical impact after AE in those patients is still unclear. A retrospective review of 174 consecutive first-episodes with AE of ILD in our institution from 2002 to 2016 was performed. AE was defined according to the revised definition and diagnostic criteria proposed by an international working group in 2016. Clinical characteristics, 90-day survival, and the requirement of long-term oxygen therapy (LTOT) after AE were evaluated in each underlying ILD. There were 102 patients with AE of IPF (AE-IPF) and 72 with AE of ILD other than IPF, including non-IPF IIPs (n=29) and secondary ILD (n=43) [CVD-ILD (n=39), CHP (n=4)]. In CVD-ILD, rheumatoid arthritis (n=17) was most common. The 90-day mortality after AE was 57% in IPF, 29% in non-IPF IIPs, and 33% in secondary ILD. After AE, ILD other than IPF had a significantly better survival rate than IPF (P<0.001). Among survivors, the rates of patients requiring LTOT after AE were 63% in IPF, 35% in non-IPF IIPs, and 46% in secondary ILD, respectively. AE of ILD other than IPF might have a better prognosis than AE-IPF, but both are fatal conditions that cause chronic respiratory failure.

Prognostic value of transbronchial lung cryobiopsy for the multidisciplinary diagnosis of idiopathic pulmonary fibrosis: a retrospective validation study