Can monocytes predict prognosis of idiopathic pulmonary fibrosis?
Authors: Michael Kreuter, Toby M Maher
Journal: The Lancet Respiratory Medicine (2019)

Idiopathic pulmonary fibrosis is a chronic, progressive, fibrosing interstitial lung disease with an unfavourable prognosis.1Raghu G Remy-Jardin M Myers JL et al.American Thoracic SocietyEuropean Respiratory SocietyJapanese Respiratory SocietyLatin American Thoracic SocietyDiagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline.Am J Respir Crit Care Med. 2018; 198: e44-e68Crossref PubMed Scopus (1823) Google Scholar Although substantial progress has been made in the treatment of this devastating condition, the course of the disease and prognosis for patients is challenging to predict. Thus, there is an urgent need to identify prognostic biomarkers in idiopathic pulmonary fibrosis. Several study groups have reported protein and RNA biomarkers with the potential to determine risk of progression and worsening of fibrosis in patients with idiopathic pulmonary fibrosis.2Neighbors M Cabanski CR Ramalingam TR et al.Prognostic and predictive biomarkers for patients with idiopathic pulmonary fibrosis treated with pirfenidone: post hoc assessment of the CAPACITY and ASCEND trials.Lancet Respir Med. 2018; 6: 615-626Summary Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 3Kahn N Rossler A-K Hornemann K et al.C-proSP-B: a possible biomarker for pulmonary diseases?.Respiration. 2018; 96: 117-126Crossref PubMed Scopus (12) Google Scholar, 4Tzouvelekis A Herazo-Maya JD Slade M et al.Validation of the prognostic value of MMP-7 in idiopathic pulmonary fibrosis.Respirology. 2017; 22: 486-493Crossref PubMed Scopus (57) Google Scholar, 5Maher TM Oballa E Simpson JK et al.An epithelial biomarker signature for idiopathic pulmonary fibrosis: an analysis from the multicentre PROFILE cohort study.Lancet Respir Med. 2017; 5: 946-955Summary Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 6Jenkins RG Simpson JK Saini G et al.Longitudinal change in collagen degradation biomarkers in idiopathic pulmonary fibrosis: an analysis from the prospective, multicentre PROFILE study.Lancet Respir Med. 2015; 3: 462-472Summary Full Text Full Text PDF PubMed Scopus (209) Google Scholar, 7Raghu G Richeldi L Jagerschmidt A et al.Idiopathic pulmonary fibrosis: prospective, case-controlled study of natural history and circulating biomarkers.Chest. 2018; 154: 1359-1370Summary Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 8Herazo-Maya JD Sun J Molyneaux PL et al.Validation of a 52-gene risk profile for outcome prediction in patients with idiopathic pulmonary fibrosis: an international, multicentre, cohort study.Lancet Respir Med. 2017; 5: 857-868Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar However, measurement of these markers is often costly and, in many cases, is not easily available outside research laboratories. Therefore, simpler approaches are needed. One lesson that can be learned from other respiratory disorders is that routinely measured cellular biomarkers, such as blood eosinophil counts in chronic obstructive pulmonary disease (COPD), can predict treatment responses.9Suissa S Dell'Aniello S Ernst P Comparative effectiveness of LABA-ICS versus LAMA as initial treatment in COPD targeted by blood eosinophils: a population-based cohort study.Lancet Respir Med. 2018; 6: 855-862Summary Full Text Full Text PDF PubMed Scopus (62) Google Scholar Is it possible that there is a comparable cellular biomarker in idiopathic pulmonary fibrosis? With this question in mind, Scott and colleagues10Scott MKD Quinn K Li Q et al.Increased monocyte count as a cellular biomarker for poor outcomes in fibrotic diseases: a retrospective, multicentre cohort study.Lancet Respir Med. 2019; (published online March 29.)http://dx.doi.org/10.1016/S2213-2600(18)30508-3Summary Full Text Full Text PDF PubMed Scopus (101) Google Scholar report their interesting yet unexpected finding of an association between absolute and relative numbers of circulating monocytes and survival in individuals with idiopathic pulmonary fibrosis. In an analysis of transcriptome data from 120 peripheral blood mononuclear cell (PBMC) samples of patients with idiopathic pulmonary fibrosis, estimated CD14+ classic monocyte percentages above the mean were associated with shorter transplantation-free survival times (HR 1·82, 95% CI 1·05–3·14), whereas higher percentages of T cells and B cells were not (0·97, 0·59–1·66; and 0·78, 0·45–1·34 respectively). In two validation cohorts (the COMET trial and the Yale cohort), patients with higher monocyte counts were at higher risk for poor outcomes (COMET Wilcoxon p=0·025; Yale Wilcoxon p=0·049). Monocyte counts of 0·95 K/μL or greater were associated with mortality after adjusting for forced vital capacity (HR 2·47, 95% CI 1·48–4·15; p=0·0063), and the gender, age, and physiology index (HR 2·06, 95% CI 1·22–3·47; p=0·0068) across the COMET, Stanford, and Northwestern datasets. Furthermore, the investigators also report that higher absolute monocyte counts were significantly associated with shortened survival in patients with other fibrotic disorders such as systemic sclerosis, myelofibrosis, and hypertrophic cardiomyopathy. Several conclusions can be reached from these data. Methodologically, the investigators should be applauded: they made strenuous efforts to incorporate multiple validation cohorts and also used a range of methods to identify monocytes. Additionally, they verified their findings in large, real-world datasets and took steps to confirm that patients identified by coding did indeed have a clinical diagnosis of idiopathic pulmonary fibrosis or other fibrotic disease after case-note review. However, their findings might not be quite as unexpected as initially thought. Monocytes and macrophages are essential components of the innate immune system, are important in the identification of antigens, and are capable of initiating robust inflammatory and profibrotic responses. Findings from other studies have shown that circulating monocytes translocate to regions of tissue injury where they differentiate to macrophages and contribute to tissue remodelling, and can exhibit specific genetic modifications in their expression of profibrotic genes.11Guilliams M Mildner A Yona S Developmental and functional heterogeneity of monocytes.Immunity. 2018; 49: 595-613Summary Full Text Full Text PDF PubMed Scopus (356) Google Scholar, 12Misharin AV Morales-Nebreda L Reyfman PA et al.Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span.J Exp Med. 2017; 214: 2387-2404Crossref PubMed Scopus (488) Google Scholar Furthermore, another study8Herazo-Maya JD Sun J Molyneaux PL et al.Validation of a 52-gene risk profile for outcome prediction in patients with idiopathic pulmonary fibrosis: an international, multicentre, cohort study.Lancet Respir Med. 2017; 5: 857-868Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar has shown changes in the transcriptomic profile of circulating leucocytes in individuals with idiopathic pulmonary fibrosis that predict prognosis. Similarly, two other studies13Molyneaux PL Willis-Owen SAG Cox MJ et al.Host-microbial interactions in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2017; 195: 1640-1650Crossref PubMed Scopus (125) Google Scholar, 14Huang Y Ma SF Espindola MS et al.Microbes are associated with host innate immune response in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2017; 196: 208-219Crossref PubMed Scopus (94) Google Scholar independently showed that circulating immune cell transcriptional profiles appeared to change in response to the lung microbiome. It is therefore not surprising that a change in circulating leucocyte profile is linked with outcomes in idiopathic pulmonary fibrosis. With this concept in mind, better understanding of the contribution of monocytes to the pathophysiology of idiopathic pulmonary fibrosis might provide important mechanistic insights with relevance to therapy. Similar to the concept of, for example circulating tumour cells in lung cancer,15Krebs MG Sloane R Priest L et al.Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer.J Clin Oncol. 2011; 29: 1556-1563Crossref PubMed Scopus (712) Google Scholar or perhaps high eosinophil counts in asthma, a high blood monocyte count in idiopathic pulmonary fibrosis might reflect disease activity and thus explain the outcome differences observed by Scott and colleagues.10Scott MKD Quinn K Li Q et al.Increased monocyte count as a cellular biomarker for poor outcomes in fibrotic diseases: a retrospective, multicentre cohort study.Lancet Respir Med. 2019; (published online March 29.)http://dx.doi.org/10.1016/S2213-2600(18)30508-3Summary Full Text Full Text PDF PubMed Scopus (101) Google Scholar Yet, as highlighted by the investigators themselves, before introducing assessment of monocyte counts as part of routine clinical care for individuals with idiopathic pulmonary fibrosis, the limitations of this research should be taken into account. These include uncertainty around diagnosis and disease severity in a substantial subset of the patients, and the unknown effect of medical therapies (including corticosteroids and immunosuppressant and antifibrotic drugs) on monocyte counts and prognosis. Nonetheless, this first report on the clinical value of measuring blood monocyte counts in idiopathic pulmonary fibrosis calls for future research. Besides further validation in existing and future cohorts, monocyte counts should be assessed as therapeutic biomarkers in upcoming clinical trials; especially where compounds (such as PBI-4050 and TD139)16Khalil N Manganas H Ryerson CJ et al.Phase 2 clinical trial of PBI-4050 in patients with idiopathic pulmonary fibrosis.Eur Respir J. 2018; (published online Dec 21.)DOI:10.1183/13993003.00663-2018PubMed Google Scholar might be acting, at least partly, on macrophages. In conclusion, Scott and colleagues10Scott MKD Quinn K Li Q et al.Increased monocyte count as a cellular biomarker for poor outcomes in fibrotic diseases: a retrospective, multicentre cohort study.Lancet Respir Med. 2019; (published online March 29.)http://dx.doi.org/10.1016/S2213-2600(18)30508-3Summary Full Text Full Text PDF PubMed Scopus (101) Google Scholar provide evidence of a novel, simple, and inexpensive prognostic biomarker in idiopathic pulmonary fibrosis which, conceivably, could help to pave the way towards personalised medicine for this disease in the future. Thus, at least hypothetically, the fate of monocytes moving from the circulation and differentiating into profibrotic macrophages in the lung might determine the fate of individuals with idiopathic pulmonary fibrosis, but detailed future research is required to assess this. MK reports personal fees from GlaxoSmithKline (GSK) and Galapagos, and grants and personal fees from Boehringer and Roche. TMM has, via his institution, received industry-academic funding from GSK R&D and UCB, and consultancy or speakers fees from Apellis, Astra Zeneca, aTyr Pharma, Bayer, Biogen Idec, Boehringer Ingelheim, Galapagos, GSK R&D, ProMetic, Roche, Sanumed, and UCB. Increased monocyte count as a cellular biomarker for poor outcomes in fibrotic diseases: a retrospective, multicentre cohort studyMonocyte count could be incorporated into the clinical assessment of patients with idiopathic pulmonary fibrosis and other fibrotic disorders. Further investigation into the mechanistic role of monocytes in fibrosis might lead to insights that assist the development of new therapies. Full-Text PDF Open Access