Do Circulating Monocytes Promote and Predict Idiopathic Pulmonary Fibrosis Progression?

Despite the availability of pharmacologic therapies, idiopathic pulmonary fibrosis (IPF) is still a clinical challenge. It is a lethal disease with a clinical course that cannot be predicted at the time of diagnosis. The high burden of suffering in IPF, the need to prioritize a select few for transplantation, and the high mortality highlight the need for better, simpler, and clinically applicable prognostic tools. In airways disease, for example (1, 2), eosinophil counts are routinely used for subphenotyping, directed therapy, and assessment of therapy responses. Is there an IPF equivalent to eosinophils?

Growing evidence supports that innate and adaptive immune cells disrupt normal lung repair. Some key studies have brought to light that several circulating immune populations have the potential to reflect and predict disease outcome either by RNA (3), protein (4), or cellular counts (5). Scott and colleagues (5), by performing cell deconvolution analysis of transcriptome data, reported an unexpected finding of an association between absolute and relative numbers of circulating monocytes and survival in individuals with IPF. In their study, patients with high monocyte counts were at higher risk for poor outcomes. Monocyte counts of 0.95×10⁹/L or greater were associated with mortality after adjusting for FVC, sex, age, and physiology index. These associations were validated in 7,000 patients with IPF through five different cohorts.

Supporting these findings, in this issue of the Journal, Kreuter and colleagues (pp. 74–81) (6) performed a retrospective pooled analysis in 2,067 patients from randomized double blinded phase III studies, ASCEND (Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis) (7), CAPACITY (Clinical Studies Assessing Pirfenidone in IPF: Research of Efficacy and Safety Outcomes) (8), and INSPIRE (Effect of Interferon gamma-1b on Survival in Patients with Idiopathic Pulmonary Fibrosis) (9), to determine whether monocyte count at baseline was associated with IPF progression. The determinants of progression were defined as ⩾10% absolute decline in percent predicted FVC, ⩾50 m decline in 6-minute-walk distance, all-cause hospitalization, and all-cause mortality over 1 year. The differential blood counts used for the analysis were pooled data from routine assessment at local institutions. In addition to a monocyte count higher than 0.95×10⁹/L, which was investigated in Scott and colleagues (5), Kreuter and colleagues found that monocyte counts higher than 0.95×10⁹/L and lower counts between 0.60 and 0.95×10⁹/L were associated with worse 1-year outcomes. Elevated monocyte counts of 0.60–0.95 and >0.95×10⁹/L were associated with significantly increased risks of IPF progression, hospitalization, and mortality over 1 year. This persisted also after adjustment for demographics, physiologic function, comorbidity profile, and chronic immunosuppressant use. Dynamic changes in monocyte counts were, however, not associated with outcomes, and antifibrotic treatments were not associated with significant changes in monocyte counts.

Validation of the prior Scott study by Kretuer and colleagues should bolster our collective confidence that monocyte counts do indeed track with mortality. Assessing the performance of monocyte counts needs to be considered in the context of other leukocyte lineage counts. Here, the authors observed, as with monocytes, that a high neutrophil count was associated with a higher risk of worse outcomes and a high lymphocyte count with lower risk of worse outcomes. These data raise all sorts of questions. What is the precise role of monocytes in disease? Can monocyte counts reflect response to treatment? Are lymphocytes “good” and monocytes (and neutrophils) “bad”? Can elevated monocyte counts predict patients at risk of acute exacerbations? Can monocyte counts subphenotype patients with IPF? And how do monocyte counts perform when compared with other biomarkers in IPF?

The data used for the analysis were differential blood counts measured by routine laboratory testing. This argues that clinical implementation of monocyte counts as predictive of IPF prognosis, if further validated, would be easy. Complete blood counts are, however, unable to differentiate between progenitor and immature monocytes, monocyte subtypes, or myeloid-derived monocyte-like cells, all phenotypically alike. Is, perhaps, one of these subtypes the pathologic actor? This is an important question because cells from the myeloid lineage, immature progenitors and end-differentiated cells, circulating in the peripheral blood may be implicated in the pathogenesis and prognostic in IPF. Fibrocytes are matrix-producing, bone marrow–derived monocyte-like cells that are increased in stable IPF and during acute exacerbations (10). Initial indications also demonstrate that myeloid-derived suppressor cells, a population of early released immature monocyte progenitors, are abundant in the peripheral blood and might contribute to disease and reflect progression (11). CCL18 (CC-chemokine ligand 18) secreted by activated human myeloid cells was reported as a soluble serum biomarker to predict mortality in IPF (12). Single-cell RNA sequencing studies have allowed unbiased, high-throughput, and high-resolution views of individual cell compartments in the IPF lung. These studies have identified heterogeneous myeloid subpopulations of monocytes, macrophages, and dendritic cells that uniquely emerge during lung fibrosis (13–15). The data from Scott and colleagues, and now from Kreuter and colleagues, underscore the critical importance of inflammation in IPF. These findings reveal that peripheral blood myeloid cells have the potential to not only predict disease outcome but also to reveal active disease processes in the lung. Whether there is an etiological role for monocytes in IPF or whether they can alter the natural history of IPF are fundamental questions that still need to be conclusively answered. Even considering early decision-making for antifibrotic therapy initiation or pretransplant evaluation in patients with high monocyte counts may not be far off. Hence, more studies that explore in depth the mechanistic role of monocytes in lung fibrosis are urgently required.

Another important aspect to emphasize here is how large IPF clinical trials are equipped to address biological and mechanistic questions. Ancillary studies from large clinical trials, as both Scott and colleagues and Kreuter and colleagues have now shown, are highly valuable treasures that should serve to advance, from multiple angles, the knowledge in the field. Unquestionably, the results presented in this study, we hope, will generate enthusiasm toward validation of monocytes as a biomarker and implementation of monocyte count to answer the questions that vex us as providers who care for patients with IPF.