Originally scheduled to take place in Philadelphia in May, the 2020 congress of the American Thoracic Society (ATS) was held virtually between 5th–10th August. Welcoming delegates to the congress, ATS President, Juan Celedón, and Immediate Past President, James Beck, explained that ATS 2020 Virtual would feature a rich and diverse platform of online content, including a blend of both pre-recorded and live sessions.
As always, the congress’s cutting-edge clinical and scientific programme offered delegates the opportunity to deep dive into important topics and the latest advancements in pulmonary, critical care and sleep medicine. In this in-depth report, sessions covering the diagnosis and management of interstitial lung disease are summarised.
INTERSTITIAL LUNG DISEASE
Interstitial lung disease, idiopathic pulmonary fibrosis, diagnosis, treatment
Early Detection and Diagnosis of Idiopathic Pulmonary Fibrosis
This ‘Clinical Topics in Pulmonary Medicine’ symposium focused on the clinical significance of early detection and diagnosis of idiopathic pulmonary fibrosis (IPF).
Luca Richeldi, Rome, Italy, explained that while antifibrotic drugs have turned IPF into a treatable disease - slowing decline in forced vital capacity (FVC) by ~50% versus placebo - they cannot completely stop disease progression. Earlier diagnosis is therefore critical, particularly as the INMARK biomarker study suggests greater efficacy of nintedanib in patients with early-stage IPF and more preserved lung volume. The INBUILD trial in progressive fibrosing interstitial lung diseases (ILDs) has also shown that the effect size of nintedanib is comparable across different groups of ILD. Indeterminate patterns detectable on high resolution computed tomography (HRCT) may be indicative of early usual interstitial pneumonia (UIP) and a recent position paper from the Fleischner Society specifically addresses these incidentally-detected interstitial lung abnormalities (ILAs). Chest auscultation is another early diagnostic approach undergoing intense clinical research. Overall, Dr Richeldi encouraged clinicians to think of pulmonary fibrosis as spectrum of different stages, with IPF the most progressive and deadly ‘tip if the iceberg’.
“If we want to achieve early diagnosis and treatment of IPF we need to focus our attention in coming years on ILA.”
Luca Richeldi, Rome, Italy
In steps towards achieving these goals, the Fleischner Society has attempted to create standards for imaging characterisation and reporting, suggesting a pathway to evaluate those with ILA based on the updated definition.
Updated definition of ILA
Incidental identification of non-dependent abnormalities, including ground-glass, reticular abnormalities, lung distortion, traction bronchiectasis, honeycombing and non-emphysematous cysts, involving at least 5% of a lung zone, in individuals in whom ILD is not suspected
Screening for early stages of pulmonary fibrosis also appears achievable in selected populations. For example, the CGS-PF study which screened 105 first-degree relatives of patients with familial pulmonary fibrosis/IPF showed 31% had ILAs and 18% had ILD. Future directions should help move us towards early detection of pulmonary fibrosis, concluded Dr Matthew, although key areas of uncertainty still exist.
Anna Podolanczuk, New York, USA, defined subclinical ILD as cellular proliferation, interstitial inflammation and/or fibrosis of the lung parenchyma not due to infection or neoplasia in the absence of symptoms and physiological impairment. Quantitative computed tomography (CT) imaging can be used to complement visual scoring of ILAs and other biomarkers in studies of subclinical ILD. The large, population-based, multi-ethnic study of atherosclerosis (MESA) examined subclinical ILD in 6814 patients with no respiratory selection criteria. MESA revealed high attenuation areas to be a key CT-based biomarker of early lung injury and remodelling associated with reduced exercise capacity, lower FVC, increased risk of ILA, and higher all-cause, ILD-related mortality and hospitalisation. Other early ILD risk factors identified in MESA included circulating adhesion molecule levels, obstructive sleep apnoea and air pollution. Strategies that focus on these modifiable risk factors and prevention of progression from subclinical to clinical ILD are key for both primary and secondary ILD prevention, noted Dr Podolanczuk - although better risk prediction models and biomarkers for disease development are still needed.
Rachel Kate, Boston, USA, pondered the question of when and why ILAs are clinically important. She outlined evidence showing that ILAs are associated with measures of decreased pulmonary function and exercise capacity, as well as an increased risk of death. Pathological characteristics of ILA are similar to those seen in IPF. Like IPF, ILAs also progress over time and this progression is associated with a decline in FVC and increased mortality. The AGES-Reykjavik study followed ILA progression in a longitudinal birth cohort of 5700 participants and identified key imaging features associated with ILD progression and mortality. In everyday practice, these radiological features can be used to help narrow a clinically important phenotype, Dr Kate suggested.
Imaging features associated with ILD progression and mortality
Imaging features associated with the progression and mortality of ILD
Lida Hariri, Boston, USA, explored novel methods for the early diagnosis of UIP, focusing on endobronchial optical coherence tomography (EB-OCT). After developing and validating key EB-OTC features of ILD, Dr Hariri’s group carried out a prospective diagnostic accuracy study in 30 patients undergoing surgical lung biopsy (SLB) for ILD diagnosis. The primary outcome of this study showed EB-OCT was 100% sensitive and specific for histopathologic UIP and clinical IPF. These results highlight the potential of EB-OCT as a low-risk, non-surgical method for the microscopic diagnosis of UIP and other ILDs as a complement to HRCT and a potential replacement of SLB.
The ability of EB-OCT to identify microscopic features not visible on HRCT offers the potential for earlier diagnosis and treatment of UIP, as well as a tool for monitoring disease progression and therapy response over time. In the diagnostic workflow for ILD, Dr Hariri suggested EB-OCT be used as step after HRCT for patients with a low confidence diagnosis.
“It is incredibly important to distinguish UIP/IPF from other ILDs because of the survival implications and the design of therapeutic strategies.”
Lida Hariri, Boston, USA
Clinical Year in Review: Interstitial Lung Disease
The Clinical Year in Review symposia required speakers to conduct a literature review of the prior year’s scientific publications and highlight the top five most important and influential papers on specific clinical topics. Leading clinical research publications on ILDs were reviewed by Anna Podolanczuk, New York, USA. In the treatment arena, two separate, large, welldesigned Phase III clinical trials have shown nintedanib to be effective in slowing the annual rate of FVC decline in patients with systemic sclerosis-associated ILD and a broad range of progressive fibrosing ILDs.
Figure: 1 year decline in FVC with nintedanib versus placebo
Mean change from baseline in FVC with nintedanib vs. placebo for patients with systemic sclerosis-associated ILD and progressive fibrosing ILD
The COLDICE multicentre study showed good agreement in histopathological assessment and final multidisciplinary discussion (MDD) diagnosis between transbronchial lung cryobiopsy and SLB, however high or definite confidence in final MDD diagnosis was reached more often with the traditional surgical approach (60% of cryobiopsy cases versus 74% of SLB cases). A further study evaluating diagnostic likelihood thresholds that define a working diagnosis of ILD provided validity for the incorporation of levels of uncertainty into the decision-making process. This study showed no mortality difference between those patients with a provisional high confidence diagnosis of IPF versus a definite diagnosis. In the ongoing search for an easily measurable and quantifiable prognostic biomarker, a large, retrospective, multicentre cohort study has revealed increased peripheral blood monocyte count to be a key cellular biomarker for poor outcomes in fibrotic lung diseases.
Cellular Plasticity and Lung Tissue Bioengineering: Novel Approaches to Advanced Respiratory Disease
This session focused on the regenerative capacity of lung cells and the use of bioengineering techniques as novel approaches to repairing or replacing injured lungs.
The exciting potential of lung regeneration strategies as novel treatments for IPF were explored by Janette Burgess, Groningen, the Netherlands. Dr Burgess explained that decellularising lungs by removing the extracellular matrix (ECM) scaffold - and then recellularising them - may represent a novel way of creating new functional lung tissue. A central player in this process is the ECM which drives cell responses by directing RNA profiles and protein deposition. Both collagen organisation and ECM stiffness changes in lung fibrosis, becoming more organised and stiff, respectively, which can influence ensuing cellular responses. Hydrogels provide a novel approach to regulating the scaffold that is presented for recellularisation. These are naturally derived (e.g. from native lung tissue) or synthetic polymers which provide the optimal mechanical and functional properties for regeneration of lung tissue. The next step beyond hydrogels is 3D bioprinting to create anatomical, spatially organised structures. Three central approaches are currently used for 3D printing in lung regeneration. Increased understanding of changing stem cell populations in the lung is also helping to fuel hopes for regeneration of fibrotic tissue. Successful Phase I safety trials of bone marrow-derived mesenchymal stem cells have been already carried out in IPF. Retaining stem cells in the lung (e.g. by optimised encapsulation), harnessing the secretome they produce and maximising delivery to the lung tissue will be key to enhancing therapeutic efficacy.
Approaches to 3D bioprinting
Key approaches to 3D bioprinting
Lung regeneration is being pursued as a potential therapeutic approach to ILD and centres on the regrowth of functional lung tissue. Overcoming the challenges associated with translating new lung structure into functional benefits was discussed by Connie Hsia, Dallas, USA. Although lung growth can be successfully reinitiated, it requires mechanical signals in an optimal supra-threshold range plus physical space. Similarly, amplification of lung regrowth is possible but requires balanced stimulation of all components and remodelling without distortion to produce a thin diffusional barrier, normal acinar architecture and redistribution of mechanical support that minimises the work of breathing.
Proportionally enhanced bronchovascular support is also important to match ventilation, perfusion and diffusion, thereby improving gas exchange which is the pivotal function of the lung. Looking at potential therapeutic applications, pharmacological stimulation should be broad-based and cover all major components of the lung at a modest dose but for a sustained duration. Selective or overstimulation should be avoided, cautioned Dr Hsai, who highlighted cocktail agents and stem cells and their products as among the most promising therapeutic approaches in this field.
“Can lung regrowth be re-initiated? The answer is yes - but there are conditions”
Connie Hsia, Dallas, USA
Advancing Care Quality for Adult Home Oxygen Patients
Benefits of oxygen therapy in ILD/IPF
The benefits of oxygen therapy for patients with ILD/IPF
Currently there are over 1.4 million oxygen users in the US and even more worldwide. However, unmet needs still remain in the provision of equipment, education and support to patients and many important care quality issues are yet to be addressed. As part of this perennially popular ATS session, Christopher Ryerson, Vancouver, Canada, reviewed standards-of-care for meeting the oxygen needs of patients with ILD during rest, exercise and sleep. Continuous oxygen has shown well-established mortality benefits in chronic obstructive pulmonary disease (COPD) and - although ILDs constitute a unique patient population - the severity of hypoxaemia is also known to predict outcomes in IPF. Dr Ryerson presented evidence showing that oxygen therapy has particular benefits during acute exercise and with short-term outpatient use for sufferers of fibrotic ILDs, although robust long-term data are lacking. Barriers to oxygen therapy such as access, cost, canister weight and stigma are often outweighed by the benefits, and perceptions typically change after oxygen initiation. Although concrete guidance is currently lacking on oxygen therapy in ILDs, there is a strong recommendation for long-term oxygen therapy in patients with IPF and clinically significant resting hypoxaemia, albeit more limited evidence supporting ambulatory or nocturnal oxygen supplementation. New guidelines are on the horizon, revealed Dr Ryerson, and may prove particularly pertinent given results of recent study which shows that ILD clinicians currently have incomplete access to supplemental ambulatory oxygen for patients meeting prescription criteria.
A panel of 'mythbusters' debating the validity of the hypothesis that new insights from single cell profiling technologies may transform the management of pulmonary fibrosis.
The Impact of Novel Single Cell Profiling Technologies on the Understanding and Management of Pulmonary Fibrosis
Using the popular ATS ‘mythbusters’ format, this provocative and interactive live session examined the hypothesis that new insights from single cell profiling technologies have the scope to transform our understanding and management of pulmonary fibrosis. Leading researchers presented the latest findings in the field before appointed ‘mythbusters’ debated the validity of the overall hypothesis.
The IPF cell atlas is a multicentre, grassroots effort to create a comprehensive map of all human cells in the lungs of patients with IPF and other fibrosing ILDs, with the aim of understanding and accelerating the development of novel tools for diagnosis, monitoring and treatment. Data derived from the atlas has thus far proved both sensible and reproducible, said Naftali Kaminski, New Haven, USA, and identified several key cell populations with a role in IPF aetiology. Insights from the atlas have shown that profibrotic macrophages dominate immune populations in the fibrotic lung, while epithelial cell populations are markedly shifted. A novel endothelial cell population is also evident in the IPF lung and archetype analysis suggests a continuous fibrosis-related trajectory within fibroblasts or myofibroblasts but not across them. Cellular changes in the IPF lung appear to share a common theme, explained Dr Kaminski, proximalisation of the distal lung where the lung tries to rebuild itself without a blueprint. This proximalisation of the distal lung and the shift of cell and gene regulatory networks represent important conceptual frameworks for future exploration.
“While you may slow down fibrosis by affecting one pathway or cell type - to stop it you need to reprogramme the organ.”
Naftali Kaminski, New Haven, USA
Cell Population Discoveries from the IPF Cell Atlas
Cell population discoveries from the IPF cell atlas
Louise Wain, Leicester, UK, suggested that understanding the genetics of individuals with IPF will increase the value of individual cell profiling - and vice versa. Early genetic research in IPF highlighted the key role of telomerase mutations and the MUC5B promoter single nucleotide polymorphism (SNP). Subsequent genome-wide association studies (GWAS) of IPF have identified multiple common signals of association clustered in pathways related to host defense, cell-cell adhesion, DNA repair/telomere activity and signalling. For example, one recently published large GWAS meta-analysis by Dr Wain’s group uncovered 14 separate genetic signals for IPF. However, it remains critically important to integrate genetic studies with gene expression data, stressed Dr Wain. If both risk of disease and expression of the gene are confirmed then a particular SNP may be pinpointed as the causal gene for a GWAS signal, although the same SNP can show different directions of effect on gene expression dependent on the tissue/organ. Single cell profiling therefore remains important and, moving forward, should focus on large expression quantitative trait loci datasets, single cell genomics to better understand somatic effects and improved integration across different ‘omics’ datasets.
Rachel Zemans, Ann Arbor, USA, highlighted that arrested ACE2-to-ACE1 differentiation in the KRT8hi transitional state was a critical regenerative defect in IPF. Persistent TGF-β activation causes cells to become frozen in the transitional state, which is associated with fibroblast activation and matrix deposition. However, the critical question remains causality. If these persistent transitional cells - identified by single cell RNA sequencing - prove causative of fibrosis then it will be hard to bust the myth, Dr Zemans concluded.
Telomere attrition is the most common mechanism driving pulmonary fibrosis, with inherited telomerase and telomere maintenance gene mutations found in 35% of familial cases. This is not just an academic genetic discovery, stressed Mary Armanios, Baltimore, USA, but denotes a definable disease pattern which is clinically recognisable and highly relevant for informing and improving patient care. Patients with IPF have uniformly short telomeres which impacts T-cell function and replicative potential. This premature ageing in the T-cell compartment can manifest as severe cytomegalovirus infection, which is one of the key indications for telomere testing and precision medicine-derived patient management. Telomere length has a definable normal range and patients with IPF typically fall on the lowest decile of the population - more so than any other disease. Flow cytometry and fluorescence in situ hybridisation are the current “gold standards” for telomere testing in clinical settings and combine both diagnostic and prognostic utility.
The session culminated in an interactive debate between the mythbusters, presenters and chairs. Martin Kolb, Hamilton, Canada, noted that the most compelling discoveries so far have stemmed from the IPF atlas, whereas single cell profiling has simply confirmed ‘things we already knew’. Dr Kolb felt that single-cell RNA sequencing may have most application in the repurposing of existing molecules and drugs as therapies.
“It is important to keep in mind the ‘big picture’ as IPF is not a cell, a molecule or a mechanism but rather a conglomerate of all of these.”
Martin Kolb, Hamilton, Canada
Single cell profiling has had a clear impact on our understanding of the complex interplay between cell types and how these contribute to usual interstitial pneumonia lesions characteristic of IFP, agreed Joyce Lee, Aurora, USA. However, she remained more skeptical regarding the impact on management as, ultimately, it is the interaction of cell types that needs to be targeted rather than individual cells themselves.
Zea Borok, Los Angeles, USA insisted that single cell profiling would need to identify new cell types or show causative cell types that we were previously unknown in order to be deemed ‘revolutionary’. Cells are known to possess plasticity so it’s not surprising that they can adopt many different phenotypes depending on the microenvironment.
Overall, the panel agreed that while single-cell RNA sequencing has had an obvious impact on disease understanding, its implications for management are still unfolding. Moving forward, discovering the types of cell changes which happen earlier in the disease process - e.g. in familial patients - will prove key. The impact of the microenvironment, the role of the genetic background, the interplay between different cell types and individual variability are also critical considerations.
“This is only the beginning of the impact of single cell data. We cannot think of the lung in the same way as we did before knowing the craziness of the macrophages, the strangeness of these aberrant basaloid cells, the endothelial cells and others. This is going to keep changing and I think it’s going to lead us to start thinking about curing IPF.”
Naftali Kaminski, New Haven, USA
Looking ahead to next year, ATS 2021 is due to take place in San Diego, USA, from 14th–19th of May.
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