Increased monocyte level is a risk factor for radiological progression in patients with early fibrotic interstitial lung abnormality

Discussion

This study shows that in an unselected cohort of patients undergoing thoracic CT scanning for all indications, in a 6-year period, 3.1% of patients showed evidence of EF-ILA. In a subset of patients who had more than one CT scan during this 6-year period, 43% progressed in extent of disease or demonstrated new traction bronchiectasis or honeycombing. Monocytes, MLR, NLR and SIRI were associated with progression in a multivariate analysis which included analysis of age and gender.

Our findings are comparable to ILA prevalence observed in large population-based cohorts [2, 3, 20] and lung cancer screening cohorts [21, 22] in which ILA ranged between 3% and 10%. Our definition of EF-ILA, which includes reticulation and GGO, but not traction bronchiectasis and honeycombing, probably encompassed “indeterminate UIP”, as defined in the 2018 IPF guidelines [17]. However, as we are unable to assess CT distribution of these ILAs in all cases for this large cohort, the terminology of EF-ILA was used. Since reticular abnormalities are common in older individuals and have previously been regarded as part of the normal spectrum of senescent lung [23], we limited inclusion to individuals aged 45–75 years at time of CT [24]. Comparable to other studies, gender was roughly of equal proportions across all cases in this cohort in those with EF-ILA, where traction bronchiectasis and honeycombing were excluded [2, 3].

The Age Gene/Environment Susceptibility (AGES) [3] and Framingham [2] population-based studies demonstrated ILA progression in 43% and 64% of cases, respectively, with associated risks of mortality similar to our cohort. In AGES, prevalence of indeterminate for UIP (iUIP) was estimated at 3.9%. iUIP was associated with mortality risk in univariate analysis (HR 1.6, p<0.0001), but nonsignificantly in multivariate analysis (HR 1.2, p=0.07). In our cohort, with a much higher number of cases, multivariate analysis showed that EF-ILA is associated with all-cause mortality (HR 1.87, p=0.002).

Importantly, we and others [6] demonstrate that radiographic progression is not observed in the majority of cases. It remains challenging to predict those cases that will progress to established fibrotic ILD. To address this, the Fleischner Society recently proposed a schema to facilitate triage, management and follow-up of ILAs [1]. This includes subcategorising cases according to ILA distribution on CT and presence (or absence) of ILAs indicative of established fibrosis.

ILA assessment in individuals with a history of familial ILD has identified associations with particulate exposures, age, positive smoking history, shorter telomere length and MUC5b risk allele [25, 26]. Associations among ageing-related biomarkers and ILA have been explored [27]; however, collectively these are costly and are not routinely available for large-scale use. Furthermore, with implementation of routine lung cancer screening pathways and greater use of thoracic CT for other diagnostic purposes, it is anticipated that ILA detection will increase. Patient follow-up could have a huge implication on clinical resources.

Peripheral blood leukocyte measurement is available as part of routine full blood count analysis and integrating this simple and cheap measure into risk stratification and ILA management is worthy of future consideration. This is supported by studies in IPF patients, where elevated peripheral blood monocyte count has been shown to be predictive of disease progression and mortality. The study by Scott et al. [13], a large multicentre retrospective cohort study, first demonstrated that monocyte counts ≥0.95×10⁹ cells·L⁻¹ were associated with all-cause mortality in IPF and non-IPF fibrotic lung disease. Since then, other retrospective clinical studies have documented similar findings [14, 15, 28]. In an analysis of multiple independent cohorts (the Multi-Ethnic Study of Atherosclerosis (MESA), AGES, COPDGene and Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE); n=7396), Kim et al. [29] reported association between higher absolute monocyte count and ILA progression.

There are subtle, but important, differences between our study and that of Kim et al. [29], who reported the findings of a pooled analysis of four population-based cohorts (two COPD-focused cohorts). In this heterogeneous population, Kim et al. do not discuss whether their observed association between monocytes and ILA progression is limited to specific ILAs, such as those with early evidence of fibrosis. In our study, the inclusion criteria were biased towards selection of cases with CT features potentially compatible with early fibrosis, and were thus population-based enriched for patients potentially at risk of progressing to pulmonary fibrosis [1]. In our cohort of progressors, we detail the proportion of cases with new CT features representative of established pulmonary fibrosis and report association between absolute monocyte count (and other leukocyte parameters) with progression and all-cause mortality. In addition, we adopted a different approach to data analysis, employing Cox proportional hazards modelling to take account of time until events occurred.

Mechanistically, our findings could be explained by recent experimental evidence suggesting migration of monocytes from bone marrow to injured lung, then differentiating into macrophages with a pro-fibrotic phenotype [30]. Further support comes from translational studies that implicate distinct monocyte-derived alveolar macrophage populations in progression of fibrosis [31, 32].

Other studies have also implicated neutrophils and lymphocytes in pulmonary fibrosis. Akin to monocytes, neutrophils are recruited to areas of inflammation [33]. Similar to macrophages, they can alter their microenvironment by secreting proteases, oxidants, cytokines and chemokines [34]. Additionally, neutrophils are a substantial source of matrix metalloproteinases which are involved in collagen deposition and extracellular matrix formation [35]. Neutrophilic bronchoalveolar lavage specimens taken from patients with IPF have been associated with early mortality [36].

We have previously demonstrated in a cohort of patients with CT scans demonstrating iUIP that peripheral blood monocyte and neutrophil counts are implicated in progression to IPF [37], and the association of NLR, MLR and SIRI with mortality in IPF [38]. MLR has been used primarily to prognosticate in cancer studies in recognition that host systemic inflammatory responses influence tumour proliferation and disease progression [39]. NLR has been heavily studied as a systemic inflammatory marker [40]. It has been used to prognosticate systemic inflammatory diseases such as rheumatoid arthritis [41], and recently in connective tissue disease-related ILD and IPF [16]. SIRI integrates neutrophils, monocytes and lymphocytes into one composite measure and has shown promise as a prognosticator within oncology [19].

There are several limitations that should be considered when interpreting these results. We were unable to quantify extent of disease and extent of progression. Categorisation was based on qualitative information extracted from radiology reports and does not quantify individual ILA extent, which may contribute to rate of progression. Similarly, we were unable to capture indications for CT and we cannot account for clinical symptoms, which would have been interesting to explore. Therefore, interpretation of our findings is limited to association between CT features with blood leukocytes. The patients were selected because of their need for a thoracic CT, so the true prevalence in the population is unknown, only in those who requires a thoracic CT. In the group where we assessed progression, the interval between the first and last CT was longer in those who progressed compared to those who did not. It could be argued that those who did not progress would do so over a longer period of assessment. The nil-ILA group was identified by description of negative findings of keywords from CT reports (e.g. “no reticulation”). We acknowledge that this represents a smaller proportion of patients with normal CT scans and may have introduced bias to EF-ILA mortality risk calculation. However, selection criteria were identical and demographic and comorbidity profiles were comparable between nil-ILA and EF-ILA group. Furthermore, demographic profiles of the nil-ILA group are also comparable to the nil-ILA cohorts of other longitudinal studies [3].

A proportion of our EF-ILA cohort were subsequently seen in our ILD clinic. Mean time from first CT scan demonstrating EF-ILA to ILD clinic attendance was +3.1 years. As the ILD clinic was a first-attender clinic, it is likely (but not verified) that these were patients who became symptomatic or demonstrated progression after a follow-on CT scan and did not have a prior diagnosis of ILD. Therefore, there is a possibility of prior undiagnosed ILD. Under-reporting of ILA has been described previously [42]; as such, we cannot exclude the possibility that a degree of misclassification may have occurred. However, 80.7% of CT scans were reported by post-radiology fellowship specialist thoracic radiologists who attend ILD multidisciplinary team meetings, based at a single centre, which might mitigate interobserver difference. Excellent interobserver correlation between our thoracic radiologists in reporting ILD features (r=0.91; p<0.001) has been described previously [43]. The remaining 19.3% of CTs were reported by one out of 14 Oxford-based post-training radiologists. All radiologists collectively agree on descriptive reporting phrases, and there are regular local discrepancy meetings to check on accuracy of reporting.

World Health Organization International Classification of Diseases version 10 (ICD-10) coding was used to identify comorbidity during the 6 years of study follow-up, but without coding dates we were unable to align comorbidity events to first CT scan date. Smoking history was poorly captured using “ICD-10 coding”. Therefore, we elected not to include this information in our multivariate analysis, but acknowledge that patients who smoke may show a greater rate of ILA progression. Finally, the single-centre and retrospective nature of this study should be taken forward by prospective, intervention and validation studies in a different cohort.

Notwithstanding these limitations, our study, in a very large cohort with high proportion of specialist thoracic radiologist reporting, demonstrates that monocyte levels, MLR, NLR and SIRI are associated with progression in EF-ILA. Further prospective studies will help determine if these parameters could be used to help prioritise patients who might benefit from follow-up.