Multi-center evaluation of baseline neutrophil-to-lymphocyte (NLR) ratio as an independent predictor of mortality and clinical risk stratifier in idiopathic pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease trajectory. The aim of this study was to assess the potential of neutrophil-to-lymphocyte ratio (NLR) to predict outcomes in IPF. Methods: We adopted a two-stage discovery (n = 71) and validation (n = 134) design using patients from the UCL partners (UCLp) cohort. We then combined discovery and validation cohorts and included an additional 794 people with IPF, using real-life data from 5 other UK centers, to give a combined cohort of 999 patients. Data were collected from patients presenting over a 13-year period (2006-2019) with mean follow up of 3.7 years (censoring: 2018-2020). Findings: In the discovery analysis, we showed that high values of NLR (>/ = 2.9 vs < 2.9) were associated with increased risk of mortality in IPF (HR 2.04, 95% CI 1.09-3.81, n = 71, p = 0.025). This was confirmed in the validation (HR 1.91, 95% CI 1.15-3.18, n = 134, p = 0.0114) and combined cohorts (HR 1.65, n = 999, 95% CI 1.39-1.95; p < 0·0001). NLR correlated with GAP stage and GAP index (p < 0.0001). Stratifying patients by NLR category (low/high) showed significant differences in survival for GAP stage 2 (p < 0.0001), however not for GAP stage 1 or 3. In a multivariate analysis, a high NLR was an independent predictor of mortality/progression after adjustment for individual GAP components and steroid/anti-fibrotic use (p < 0·03). Furthermore, incorporation of baseline NLR in a modified GAP-stage/index, GAP-index/stage-plus, refined prognostic ability as measured by concordance (C)-index. Interpretation: We have identified NLR as a widely available test that significantly correlates with lung function, can predict outcomes in IPF and refines cohort staging with GAP. NLR may allow timely prioritisation of at-risk patients, even in the absence of lung function. Funding: Breathing Matters, GSK, CF Trust, BLF-Asthma, MRC, NIHR Alpha-1 Foundation.

Validity and repeatability of cardiopulmonary exercise testing in interstitial lung disease.

BACKGROUND: Cardiopulmonary exercise testing (CPET), and its primary outcome of peak oxygen uptake (VO2peak), are acknowledged as biomarkers in the diagnostic and prognostic management of interstitial lung disease (ILD). However, the validity and repeatability of CPET in those with ILD has yet to be fully characterised, and this study fills this evidence gap. METHODS: Twenty-six people with ILD were recruited, and 21 successfully completed three CPETs. Of these, 17 completed two valid CPETs within a 3-month window, and 11 completed two valid CPETs within a 6-month window. Technical standards from the European Respiratory Society established validity, and repeatability was determined using mean change, intraclass correlation coefficient and typical error. RESULTS: Every participant (100%) who successfully exercised to volitional exhaustion produced a maximal, and therefore valid, CPET. Approximately 20% of participants presented with a plateau in VO2, the primary criteria for establishing a maximal effort. The majority of participants otherwise presented with secondary criteria of respiratory exchange ratios in excess of 1.05, and maximal heart rates in excess of their predicted values. Repeatability analyses identified that the typical error (expressed as percent of coefficient of variation) was 20% over 3-months in those reaching volitional exhaustion. CONCLUSION: This work has, for the first time, fully characterised how patients with ILD respond to CPET in terms of primary and secondary verification criteria, and generated novel repeatability data that will prove useful in the assessment of disease progression, and future evaluation of therapeutic regimens where VO2peak is used as an outcome measure.

Use of peripheral neutrophil to lymphocyte ratio and peripheral monocyte levels to predict survival in fibrotic hypersensitivity pneumonitis (fHP): a multicentre retrospective cohort study.

The factors determining disease course and survival in fibrotic hypersensitivity pneumonitis (fHP) have not been fully elucidated.The aim of this study was to describe the characteristics of patients with fHP in a real-world cohort and investigate factors associated with worse outcomes. We aimed to explore the use of neutrophil to lymphocyte ratio (NLR) and peripheral blood monocyte levels in predicting mortality. METHODS: A retrospective, multicentre, observational UK cohort study. RESULTS: Patients with fHP were significantly younger than those with idiopathic pulmonary fibrosis (IPF) (median age fHP 73 vs IPF 75 years) and were much more likely to be woman (fHP 61% vs IPF 26%). In almost half of all fHP cases (49%, n=104/211), no causative antigen was identified from either the history or specific antigen testing. Overall, fHP was associated with a better survival than IPF, although median survival of both groups was poor (fHP 62 months vs IPF 52 months).IPF survival in patients with a high NLR was significantly lower than those with a low NLR (44 vs 83 months). A monocyte count ≥0.95 K/uL also predicted significantly poorer outcomes for patients with IPF compared with <0.95 K/uL (33 vs 57 months). In contrast, NLR and monocyte count did not predict survival in the fHP cohort. CONCLUSIONS: Although fHP has a statistically lower mortality than IPF, absolute survival time of both conditions is poor. High baseline NLR and absolute monocyte counts predict worse survival in IPF but not in fHP, highlighting the potential for divergence in their pathogenic mechanisms.

Feasibility of cardiopulmonary exercise testing in interstitial lung disease: the PETFIB study.

INTRODUCTION: Cardiopulmonary exercise testing (CPET) provides a series of biomarkers, such as peak oxygen uptake, which could assess the development of disease status in interstitial lung disease (ILD). However, despite use in research and clinical settings, the feasibility of CPET in this patient group has yet to be established. METHODS: Twenty-six patients with ILD (19 male) were recruited to this study. Following screening for contraindications to maximal exercise, participants underwent an incremental CPET to volitional exhaustion. Feasibility of CPET was assessed by the implementation, practicality, acceptability and demand, thus providing clinical-driven and patient-driven information on this testing procedure. RESULTS: Of the 26 recruited participants, 24 successfully completed at least one CPET, with 67/78 prospective tests being completed. Contraindications included hypertension, low resting oxygen saturation and recent pulmonary embolism. Of the CPETs undertaken, 63% successfully reached volitional exhaustion, with 31% being terminated early by clinicians due to excessive desaturation. Quantitative and qualitative feedback from participants revealed a positive experience of CPET and desire for it to be included as a future monitoring tool. CONCLUSION: CPET is feasible in patients with ILD. Identification of common clinical contraindications, and understanding of patient perspectives will allow for effective design of future studies utilising CPET as a monitoring procedure.