Monocyte Count as a Prognostic Biomarker in Patients with Idiopathic Pulmonary Fibrosis

Michael Kreuter, Joyce S Lee, Argyrios Tzouvelekis, Justin M Oldham, Philip L Molyneaux, Derek Weycker, Mark Atwood, Klaus-Uwe Kirchgaessler, Toby M Maher, Michael Kreuter, Joyce S Lee, Argyrios Tzouvelekis, Justin M Oldham, Philip L Molyneaux, Derek Weycker, Mark Atwood, Klaus-Uwe Kirchgaessler, Toby M Maher

Abstract

Rationale: There is an urgent need for simple, cost-effective prognostic biomarkers for idiopathic pulmonary fibrosis (IPF); biomarkers that show potential include monocyte count. Objectives: We used pooled data from pirfenidone and IFNγ-1b trials to explore the association between monocyte count and prognosis in patients with IPF. Methods: This retrospective pooled analysis included patients (active and placebo arms) from the following four phase III, randomized, placebo-controlled trials: ASCEND (NCT01366209), CAPACITY (NCT00287729 and NCT00287716), and INSPIRE (NCT00075998). Outcomes included IPF progression (≥10% absolute decline in FVC% predicted, ≥50 m decline in 6-minute-walk distance, or death), all-cause hospitalization, and all-cause mortality over 1 year. The relationship between monocyte count (defined as time-dependent) and outcomes was assessed using bivariate and multivariable models. Measurements and Main Results: This analysis included 2,067 patients stratified by monocyte count (at baseline: <0.60 × 109 cells/L [n = 1,609], 0.60 to <0.95 × 109 cells/L [n = 408], and ≥0.95 × 109 cells/L [n = 50]). In adjusted analyses, a higher proportion of patients with monocyte counts of 0.60 to <0.95 × 109 cells/L or ≥0.95 × 109 cells/L versus <0.60 × 109 cells/L experienced IPF progression (P = 0.016 and P = 0.002, respectively), all-cause hospitalization (P = 0.030 and P = 0.003, respectively), and all-cause mortality (P = 0.005 and P < 0.001, respectively) over 1 year. Change in monocyte count from baseline was not associated with any of the outcomes over 1 year and did not appear to be affected by study treatment. Conclusions: In patients with IPF, elevated monocyte count was associated with increased risks of IPF progression, hospitalization, and mortality. Monocyte count may provide a simple and inexpensive prognostic biomarker in IPF.

Keywords: biomarkers; prognosis; pulmonary fibrosis.

Figures

Figure 1.
Figure 1.
Kaplan-Meier curves for time to first (A) IPF progression (≥10% absolute decline in FVC% predicted, ≥50 m decline in 6-minute-walk distance, or death), (B) all-cause hospitalization, and (C) all-cause mortality over 1 year by monocyte count, in which monocyte count was defined as a time-dependent variable. IPF = idiopathic pulmonary fibrosis.
Figure 2.
Figure 2.
Adjusted hazard ratios for IPF progression, all-cause hospitalization, and all-cause mortality by monocyte count. Monocyte count and other model covariates were defined as time-dependent variables, as appropriate. CI = confidence interval; IPF = idiopathic pulmonary fibrosis.

References

    1. Ley B, Collard HR, King TE., Jr Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;183:431–440.
    1. Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, et al. American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. Diagnosis of idiopathic pulmonary fibrosis: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018;198:e44–e68.
    1. Nathan SD, Shlobin OA, Weir N, Ahmad S, Kaldjob JM, Battle E, et al. Long-term course and prognosis of idiopathic pulmonary fibrosis in the new millennium. Chest. 2011;140:221–229.
    1. Vancheri C, Failla M, Crimi N, Raghu G. Idiopathic pulmonary fibrosis: a disease with similarities and links to cancer biology. Eur Respir J. 2010;35:496–504.
    1. King TE, Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, et al. ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083–2092.
    1. Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, et al. CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377:1760–1769.
    1. Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2071–2082.
    1. Scott MKD, Quinn K, Li Q, Carroll R, Warsinske H, Vallania F, et al. Increased monocyte count as a cellular biomarker for poor outcomes in fibrotic diseases: a retrospective, multicentre cohort study. Lancet Respir Med. 2019;7:497–508.
    1. Neighbors M, Cabanski CR, Ramalingam TR, Sheng XR, Tew GW, Gu C, 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;6:615–626.
    1. Kahn N, Rossler A-K, Hornemann K, Muley T, Grünig E, Schmidt W, et al. C-proSP-B: a possible biomarker for pulmonary diseases? Respiration. 2018;96:117–126.
    1. Tzouvelekis A, Herazo-Maya JD, Slade M, Chu JH, Deiuliis G, Ryu C, et al. Validation of the prognostic value of MMP-7 in idiopathic pulmonary fibrosis. Respirology. 2017;22:486–493.
    1. Maher TM, Oballa E, Simpson JK, Porte J, Habgood A, Fahy WA, et al. An epithelial biomarker signature for idiopathic pulmonary fibrosis: an analysis from the multicentre PROFILE cohort study. Lancet Respir Med. 2017;5:946–955.
    1. Jenkins RG, Simpson JK, Saini G, Bentley JH, Russell AM, Braybrooke R, et al. Longitudinal change in collagen degradation biomarkers in idiopathic pulmonary fibrosis: an analysis from the prospective, multicentre PROFILE study. Lancet Respir Med. 2015;3:462–472.
    1. Raghu G, Richeldi L, Jagerschmidt A, Martin V, Subramaniam A, Ozoux ML, et al. Idiopathic pulmonary fibrosis: prospective, case-controlled study of natural history and circulating biomarkers. Chest. 2018;154:1359–1370.
    1. Herazo-Maya JD, Sun J, Molyneaux PL, Li Q, Villalba JA, Tzouvelekis A, 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;5:857–868.
    1. Korthagen NM, van Moorsel CH, Barlo NP, Ruven HJ, Kruit A, Heron M, et al. Serum and BALF YKL-40 levels are predictors of survival in idiopathic pulmonary fibrosis. Respir Med. 2011;105:106–113.
    1. Stuart BD, Lee JS, Kozlitina J, Noth I, Devine MS, Glazer CS, et al. Effect of telomere length on survival in patients with idiopathic pulmonary fibrosis: an observational cohort study with independent validation. Lancet Respir Med. 2014;2:557–565.
    1. Richards TJ, Kaminski N, Baribaud F, Flavin S, Brodmerkel C, Horowitz D, et al. Peripheral blood proteins predict mortality in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2012;185:67–76.
    1. Organ LA, Duggan AR, Oballa E, Taggart SC, Simpson JK, Kang’ombe AR, et al. Biomarkers of collagen synthesis predict progression in the PROFILE idiopathic pulmonary fibrosis cohort. Respir Res. 2019;20:148.
    1. Kreuter M, Maher TM. Can monocytes predict prognosis of idiopathic pulmonary fibrosis? Lancet Respir Med. 2019;7:467–469.
    1. Suissa 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;6:855–862.
    1. Xu-Welliver M, Carbone DP. Blood-based biomarkers in lung cancer: prognosis and treatment decisions. Transl Lung Cancer Res. 2017;6:708–712.
    1. Håkansson KEJ, Rasmussen LJH, Godtfredsen NS, Tupper OD, Eugen-Olsen J, Kallemose T, et al. The biomarkers suPAR and blood eosinophils are associated with hospital readmissions and mortality in asthma - a retrospective cohort study. Respir Res. 2019;20:258.
    1. Teoh AKY, Jo HE, Chambers DC, Symons K, Walters EH, Goh NS, et al. Blood monocyte counts as a potential prognostic marker for idiopathic pulmonary fibrosis: analysis from the Australian IPF registry. Eur Respir J. 2020;55:1901855.
    1. Kreuter M, Lee JS, Tzouvelekis AE, Oldham JM, Molyneaux PL, Weycker D, et al. Monocyte count as a prognostic biomarker in patients with idiopathic pulmonary fibrosis (IPF): a retrospective, pooled analysis from Ascend, Capacity, and Inspire [abstract] Am J Respir Crit Care Med. 2020;201:A6207.
    1. King TE, Jr, Albera C, Bradford WZ, Costabel U, Hormel P, Lancaster L, et al. INSPIRE Study Group. Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial. Lancet. 2009;374:222–228.
    1. Gregory AD, Kliment CR, Metz HE, Kim K-H, Kargl J, Agostini BA, et al. Neutrophil elastase promotes myofibroblast differentiation in lung fibrosis. J Leukoc Biol. 2015;98:143–152.
    1. Hou Z, Ye Q, Qiu M, Hao Y, Han J, Zeng H. Increased activated regulatory T cells proportion correlate with the severity of idiopathic pulmonary fibrosis. Respir Res. 2017;18:170.
    1. Moore BB, Fry C, Zhou Y, Murray S, Han MK, Martinez FJ, et al. The COMET Investigators. Inflammatory leukocyte phenotypes correlate with disease progression in idiopathic pulmonary fibrosis. Front Med. 2014;1:56.
    1. Reilkoff RA, Peng H, Murray LA, Peng X, Russell T, Montgomery R, et al. Semaphorin 7a+ regulatory T cells are associated with progressive idiopathic pulmonary fibrosis and are implicated in transforming growth factor-β1-induced pulmonary fibrosis. Am J Respir Crit Care Med. 2013;187:180–188.
    1. Xue J, Kass DJ, Bon J, Vuga L, Tan J, Csizmadia E, et al. Plasma B lymphocyte stimulator and B cell differentiation in idiopathic pulmonary fibrosis patients. J Immunol. 2013;191:2089–2095.
    1. Misharin AV, Morales-Nebreda L, Reyfman PA, Cuda CM, Walter JM, McQuattie-Pimentel AC, et al. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J Exp Med. 2017;214:2387–2404.
    1. Ziegenhagen MW, Zabel P, Zissel G, Schlaak M, Müller-Quernheim J. Serum level of interleukin 8 is elevated in idiopathic pulmonary fibrosis and indicates disease activity. Am J Respir Crit Care Med. 1998;157:762–768.
    1. Lederer DJ, Martinez FJ. Idiopathic pulmonary fibrosis. N Engl J Med. 2018;378:1811–1823.
    1. Betensley A, Sharif R, Karamichos D. A systematic review of the role of dysfunctional wound healing in the pathogenesis and treatment of idiopathic pulmonary fibrosis. J Clin Med. 2016;6:E2.
    1. Boyette LB, Macedo C, Hadi K, Elinoff BD, Walters JT, Ramaswami B, et al. Phenotype, function, and differentiation potential of human monocyte subsets. PLoS One. 2017;12:e0176460.
    1. Duffield JS, Lupher M, Thannickal VJ, Wynn TA. Host responses in tissue repair and fibrosis. Annu Rev Pathol. 2013;8:241–276.
    1. Byrne AJ, Maher TM, Lloyd CM. Pulmonary macrophages: a new therapeutic pathway in fibrosing lung disease? Trends Mol Med. 2016;22:303–316.
    1. Greiffo FR, Viteri-Alvarez V, Frankenberger M, Dietel D, Ortega-Gomez A, Lee JS, et al. CX3CR1-fractalkine axis drives kinetic changes of monocytes in fibrotic interstitial lung diseases. Eur Respir J. 2020;55:pii1900460.
    1. Byrne AJ, Powell JE, O’Sullivan BJ, Ogger PP, Hoffland A, Cook J, et al. Dynamics of human monocytes and airway macrophages during healthy aging and after transplant. J Exp Med. 2020;217:e20191236.
    1. Aran D, Looney AP, Liu L, Wu E, Fong V, Hsu A, et al. Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat Immunol. 2019;20:163–172.
    1. Adams TS, Schupp JC, Poli S, Ayaub EA, Neumark N, Ahangari F, et al. Single Cell RNA-seq reveals ectopic and aberrant lung resident cell populations in Idiopathic Pulmonary Fibrosis [preprint] bioRxiv 2019. Available from:
    1. Nouno T, Okamoto M, Ohnishi K, Kaieda S, Tominaga M, Zaizen Y, et al. Elevation of pulmonary CD163+ and CD204+ macrophages is associated with the clinical course of idiopathic pulmonary fibrosis patients. J Thorac Dis. 2019;11:4005–4017.
    1. Allden SJ, Ogger PP, Ghai P, McErlean P, Hewitt R, Toshner R, et al. The transferrin receptor CD71 delineates functionally distinct airway macrophage subsets during idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2019;200:209–219.
    1. Walsh SM, Worrell JC, Fabre A, Hinz B, Kane R, Keane MP. Novel differences in gene expression and functional capabilities of myofibroblast populations in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2018;315:L697–L710.
    1. Heukels P, van Hulst JAC, van Nimwegen M, Boorsma CE, Melgert BN, van den Toorn LM, et al. Fibrocytes are increased in lung and peripheral blood of patients with idiopathic pulmonary fibrosis. Respir Res. 2018;19:90.
    1. Moeller A, Gilpin SE, Ask K, Cox G, Cook D, Gauldie J, et al. Circulating fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2009;179:588–594.
    1. Prasse A, Probst C, Bargagli E, Zissel G, Toews GB, Flaherty KR, et al. Serum CC-chemokine ligand 18 concentration predicts outcome in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2009;179:717–723.
    1. Cai M, Bonella F, He X, Sixt SU, Sarria R, Guzman J, et al. CCL18 in serum, BAL fluid and alveolar macrophage culture supernatant in interstitial lung diseases. Respir Med. 2013;107:1444–1452.
    1. Kawamura K, Ichikado K, Anan K, Yasuda Y, Sekido Y, Suga M, et al. Monocyte count and the risk for acute exacerbation of fibrosing interstitial lung disease: a retrospective cohort study. Chron Respir Dis. 2020;17:1479973120909840.
    1. Ji H, Li Y, Fan Z, Zuo B, Jian X, Li L, et al. Monocyte/lymphocyte ratio predicts the severity of coronary artery disease: a syntax score assessment. BMC Cardiovasc Disord. 2017;17:90.
    1. Yeager MP, Pioli PA, Collins J, Barr F, Metzler S, Sites BD, et al. Glucocorticoids enhance the in vivo migratory response of human monocytes. Brain Behav Immun. 2016;54:86–94.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅