Computed tomography findings as determinants of pulmonary function tests in fibrotic interstitial lung diseases—Network-analyses and multivariate models

Abstract

The aim was to evaluate the impact of multiple high-resolution computed tomography (HRCT) features on pulmonary function test (PFT) biomarkers in fibrotic interstitial lung disease (FILD) patients. HRCT of subsequently ILD-board-discussed FILD patients were semi-quantitatively evaluated in a standardized approach: 18 distinct lung regions were scored for noduli, reticulation, honeycombing, consolidations, ground glass opacities (GGO), traction bronchiectasis (BRK) and emphysema. Total lung capacity (TLC), forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1/FVC, diffusion capacity for carbon monoxide (DLCO) and transfer coefficient (KCO) were assessed. Interactions between each PFT biomarker and all HRCT scores were visualized by network analyses, modeled according to the Schwarz Bayesian Information Criterion and incorporated in uni- and multivariate stepwise regression analyses. Among 108 FILD patients (mean age 67 years, 77% male), BRK extent was a major significant uni- or multivariate determinant of all PFT analyzed. Besides that, diffusion-based variables DLCO and KCO showed a larger dependency on reticulation, emphysema and GGO, while forced expiratory volume-based measures FEV1, FVC and FEV1/FVC were more closely associated with consolidations. For TLC, the only significant multivariate determinant was reticulation. In conclusion, PFT biomarkers derived from spirometry, body plethysmography and diffusion capacity in FILD patients are differentially influenced by semi-quantified HRCT findings.

Clinical, imaging, and blood biomarkers to assess 1-year progression risk in fibrotic interstitial lung diseases—Development and validation of the honeycombing, traction bronchiectasis, and monocyte (HTM)-score

“…In our cohort, DLCO decline was the most frequent indicator of disease progression. However, DLCO had not been widely adopted as biomarker of disease progression in ILD until recently ( 12 ), due to its known methodologically determined variability and a variety of confounding factors like emphysema or pulmonary hypertension ( 12 , 30 , 51 – 53 ). We have analyzed progression-risk in association with presence and extent of emphysema as well as with pulmonary artery to aorta diameter as a surrogate for pulmonary hypertension and did not find statistically significant or clinically meaningful interactions as shown in Table 1 .…”

“…As described in previous publications ( 30 , 31 ), all patients discussed by the local ILD-board were included into a prospective registry between 2017 and 2021. Patients enregistered had undergone standardized baseline evaluation including high-resolution computed tomography (HRCT), blood analyses including autoimmune antibody screening, and pulmonary functions tests (PFT).…”

“…If clinically feasible, prone imaging was preferred to differ opacities in dependent lung areas from true interstitial lung abnormalities ( 33 ). During the respective ILD-board session, a specialist ILD-radiologist assessed the presence of parenchymal nodules, reticular abnormalities, honeycombing, consolidations, ground glass opacities, emphysema, mosaic attenuation, and traction bronchi(-ol)ectasis in an upper-, middle- and lower-lung area as defined by thirds of the largest cranio-caudal diameter in the sagittal reconstructions, leading to scores from zero to six, as described for our previously reported evaluations ( 30 , 31 ). Each finding was then scored as absent, limited or abundant using cut-off values based on statistical modeling of the leading variables as explicated below.…”

The influence of age and sex in sarcoidosis

“…It is well established that lung fibrosis can impair normal lung function [59], and ageing promotes lung fibrosis Patients with sarcoidosis experience an upregulation in these same pro-fibrotic cytokines [60]. Although not specifically studied, it is reasonable to posit that the effects of ageing on lung remodeling would amplify the damaging effects of sarcoidosis In this regard, ageing and sarcoidosis share immunological features, described below, that would support this claim…”

“…Currently, first world countries are experiencing an increase in populations over the age of 60 as never seen before Approximately 16% of the US population is over the age of 65 [42], while 22% is over the age of 60 in the United Kingdom [43]; 24% of German citizens are age 60 or older [44] Notably, Germany experienced their largest number of centenarians in 2020 at over 20 000 individuals [44], emphasizing the growing importance of understanding the biological complexities of ageing Additionally, respiratory diseases are a leading cause of death worldwide whether chronic such as chronic obstructive pulmonary disorder (COPD) or acute such as a lower respiratory infection [45,46] Age-related changes of the lung encompass reduction in thoracic cavity size and respiratory force [47] as well as changes which disrupt cellular and molecular homeostasis [48], culminating in an increased risk of respiratory failure for individuals over the age of 60 [49] As we age, there is an exponential atrophy of skeletal muscle function surrounding the thoracic cavity [50,51] reducing its total volume capacity and reducing inspiratory and expiratory strength [52] The strength of the thoracic diaphragm, the dominant muscle involved in respiration, is significantly reduced in adults 67 and over [53] Pathogen clearance and response is significantly reduced as we age The first line of defense within the upper and lower airways is mucociliary clearance which also becomes impaired with age [54,55] This is particularly impactful when considering that expiratory strength is required for adequate clearance of particulates that cannot be cleared through mucociliary action [56,57] These structural changes demonstrate a reduced ability for elderly individuals to meet respiratory needs should pulmonary stress occur (Fig. 1) In normal ageinglungs, transcriptomic studies have revealed permanent re-modeling of the extracellular matrix Parenchymal tissue composition in mice 24 months old (aged), as opposed to 8 week-old mice (young), exhibit increased expression of the pro-fibrotic cytokines IL-1b, IL-6, and TNF-a [58 ] It is well established that lung fibrosis can impair normal lung function [59], and ageing promotes lung fibrosis Patients with sarcoidosis experience an upregulation in these same pro-fibrotic cytokines [60]. Although not specifically studied, it is reasonable to posit that the effects of ageing on lung remodeling would amplify the damaging effects of sarcoidosis In this regard, ageing and sarcoidosis share immunological features, des...…”