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Artificial intelligence quantitative CT (AIQCT) in idiopathic pulmonary fibrosis (IPF): enhances prognostication accuracy
IPF is a clinically and radiologically heterogenous condition. AIQCT is a novel tool developed, in part, to account for the interobserver variability seen when reporting parenchymal abnormalities on CT in IPF. Handa et al (Ann Am Thorac Soc 2022;19:399) used AIQCT in a training cohort of 304 CTs from patients with IPF to derive prognostic features, and then applied to 120 consecutively enrolled patients in a validation cohort. Patients required paired pulmonary function tests within 3 months of scanning, and scans could not demonstrate pleural effusion, pneumomediastinum or acute exacerbation of IPF (AE-IPF). Correlation coefficients outperformed those of texture-based analysis methods (p≤0.001 for 7/9 radiographic patterns), such as Canadian Laboratory Initiative on Paediatric Intervals, and reflects the reliability of AIQCT for quantification of lung abnormalities seen in other studies of the modality. Strengths of this protocol include the ability to differentiate traction bronchodilatation from honeycombing, and the automatic volumetric measurement of airways to include peripheral airways. AIQCT not only reliably identifies lung parenchymal patterns but also bronchial and central airways volumes. Multivariate Cox regression analysis including gender–age physiology staging found that bronchial volume (ie, the presence of traction bronchodilatation) and normal (non-interstitial lung disease (ILD)) lung volumes were independent prognostic factors in IPF (HRs 1.33, 95% CI 1.16 to 1.53, and 0.97, 95% CI 0.94 to 0.99, respectively). This study demonstrates the potential for novel software to enhance clinical care by providing better information to clinicians on longer-term outcomes but it requires further research prior to adoption into clinical practice.
Addition of cyclophosphamide (CYC) to steroid therapy in the treatment of AE-IPF: no evidence of benefit and worse 3-month mortality
CYC has been routinely used for the treatment of AE-IPF on the basis of retrospective studies and case series. In the phase III EXAFIP Study (CYC added to glucocorticoids in acute exacerbation of IPF), Naccache et al (Lancet Respir Med 2022;10:26) are the first to assess the safety and efficacy of CYC in AE-IPF within the confines of a randomised, placebo-controlled, double-blinded study. Adult patients with an investigator-led, guideline-based diagnosis of suspected or definite AE-IPF from 31 French sites were randomised to receive intravenous methylprednisolone 10 mg/kg/day for 3 days followed by an oral weaning regimen and Pneumocystis jiroveci prophylaxis and either CYC alongside haemorrhagic cystitis prophylaxis on days 0, 15, 30 and 60 (n=60) or placebo (n=59). Three-month mortality, the primary outcome of the study, was increased in the CYC cohort at 45% vs 31% with placebo (difference 14.5%, 95% CI −3.1 to 31.6; p=0.1) and the HR between CYC and placebo was 1.14 (95% CI 0.59 to 2.22). Increased mortality persisted despite adjustment for IPF severity (as defined by forced vital capacity ( FVC) <50% or diffusion capacity of the lungs for carbon monoxide (DLCO) <35%), OR 1.89, 95% CI 0.89 to 4.04, and was sustained at 6 months. The authors highlight the comparable adverse event rate between cohorts with similar incidence of infection-related adverse events and hypothesise that deleterious effects on fibrotic progression or lung dysbiosis may account for the poor outcomes of those receiving CYC in this study. Despite the likely underpowering of the study, the data should influence clinicians to review the use of CYC in AE-IPF.
Toll-like receptor 3 (TLR3) L412F polymorphism in IPF: leads to lung dysbiosis impaired immunity and worse clinical outcomes
Signalling by toll-like receptors such as TLR3 is a critical step in the body’s defence against invading microbes. Previous work has demonstrated that polymorphism on the TLR3 L412F nucleotide correlates with poorer survival and accelerated lung function decline in IPF. McElroy et al present a series of studies to further examine this relationship and elucidate underlying pathophysiology (Am J Respir Crit Care Med 2022; DOI: 10.1164/rccm.202010OC-3880OC). In the first of three IPF cohorts studied (n=228), L412F polymorphism was associated with a significant increase in AE-IPF-related death compared with the wild type (88% vs 13%; p=0.03). In a separate cohort, qPCR and 16s rRNA analysis of bronchoalveolar lavage (BAL) samples (n=47) demonstrated lung dysbiosis with L412F polymorphism, with a preponderance of Staphylococcus and Streptococcus spp and a significantly reduced overall bacterial burden (p=0.0024). Hierarchical heatmaps were created using a third cohort (n=55) of nasopharyngeal lavage samples collected during an AE-IPF to highlight similarities in the distribution of bacterial and viral populations in AE-IPF, which suggest the importance of bacterial–viral coinfection in the pathogenesis of AE-IPF. Finally, primary IPF fibroblasts were treated in vitro with agonists of TLRs2–8 and Pseudomonas aeruginosa and demonstrated attenuated production of inflammatory cytokines and chemokines including interleukin (IL)-6, IL-8 and Interferon-β where L412F polymorphism was present. Downstream cytosolic pathways mediated by retinoic acid -inducible gene 1 (RIG-1), melanoma differentiation-associated protein 5 (MDA-5) andprotein kinase R (PKR) are also affected. The authors present compelling data that L412F polymorphism is linked to increased AE-IPF mortality, and results from impaired immune activation in response to both viral and bacterial infections.
Transcriptomics of BAL cells in sarcoidosis: correlation between molecular endotype and clinical phenotypes
Pulmonary and multisystem sarcoidosis has a high morbidity with few therapeutic options. Despite improvement in understanding of the pathological mechanism the genetic traits of clinical phenotype are not well characterised. In this study, Vukmirovic et al attempt to link molecular endotypes with clinical phenotypes in patients with pulmonary sarcoidosis with or without multisystem involvement through analysis of genome-wide transcriptomic data from BAL samples obtained in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) Study (Eur Respir J 2021; DOI: 10.1183/13993003.02950-2020). Supervised analysis of BAL samples from the GRADS cohort (n=209) cross-correlated gene-expression profiles against predefined clinical parameters such as Scadding stage, BAL cell counts, and CT and pulmonary function test parameters. Transcriptomic programmes were identified to detect recognised pathways associated with airway (IL-2 and IL-7), parenchymal (transforming growth factor-beta 1 (TGF-β1) and mammalian target of rapamycin (mTOR)) or hilar nodal involvement (Th1 and Th17). Cluster analysis of the genetic profile was correlated to clinical traits and pathogenic environmental factors from the GRADS Study to generate four new endotypes; hilar lymphadenopathy with lymphocytic inflammation, extraocular involvement with PI3K activation, chronic sarcoidosis and multiorgan involvement with exaggerated immune responses. These were independently validated against a second cohort (n=50). Overall, this study identifies gene profiles correlated with disease severity and activity, advancing understanding of sarcoidosis biology, and identifies four new endotypes with applications for future research.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Commissioned; externally peer reviewed.