Long-term effect of pulmonary rehabilitation in idiopathic pulmonary fibrosis: a randomised controlled trial.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterised by worsening dyspnoea and exercise intolerance. RESEARCH QUESTION: Does a long-term pulmonary rehabilitation improve exercise tolerance in patients with IPF treated with standard antifibrotic drugs, which are expected to reduce disease progression? METHODS: This open-label randomised controlled trial was performed at 19 institutions. Stable patients receiving nintedanib were randomised into pulmonary rehabilitation and control groups (1:1). The pulmonary rehabilitation group underwent initial rehabilitation which included twice-weekly sessions of monitored exercise training for 12 weeks, followed by an at-home rehabilitation programme for 40 weeks. The control group received usual care only, without pulmonary rehabilitation. Both groups continued to receive nintedanib. The primary and main secondary outcomes were change in 6 min walking distance (6MWD) and change in endurance time (using cycle ergometry) at week 52. RESULTS: Eighty-eight patients were randomised into pulmonary rehabilitation (n=45) and control (n=43) groups. Changes in 6MWD were -33 m (95% CI -65 to -1) and -53 m (95% CI -86 to -21) in the pulmonary rehabilitation and control groups, respectively, with no statistically significant difference (mean difference, 21 m (95% CI -25 to 66), p=0.38). Changes in endurance time were significantly better in the pulmonary rehabilitation (64 s, 95% CI -42.3 to 171)) than in the control (-123 s (95% CI -232 to -13)) group (mean difference, 187 s (95% CI 34 to 153), p=0.019). INTERPRETATION: Although pulmonary rehabilitation in patients taking nintedanib did not improve 6MWD in the long term, it led to prolonged improvement in endurance time. TRIAL REGISTRATION NUMBER: UMIN000026376.

Impact of bronchoalveolar lavage lymphocytosis on the effects of anti-inflammatory therapy in idiopathic non-specific interstitial pneumonia, idiopathic pleuroparenchymal fibroelastosis, and unclassifiable idiopathic interstitial pneumonia.

BACKGROUND: Idiopathic non-specific interstitial pneumonia (iNSIP), idiopathic pleuroparenchymal fibroelastosis (iPPFE), and unclassifiable idiopathic interstitial pneumonia (IIP) are IIPs with chronic fibrotic phenotypes, and unlike idiopathic pulmonary fibrosis, they have often been treated with anti-inflammatory drugs, including corticosteroids and immunosuppressants. However, the impact of bronchoalveolar lavage (BAL) lymphocytosis on the effects of anti-inflammatory therapy has never been evaluated. This study aimed to elucidate whether BAL lymphocytosis can be used to predict the efficacy of anti-inflammatory drugs for iNSIP, iPPFE, and unclassifiable IIP. METHODS: Japanese patients diagnosed with iNSIP, iPPFE, and unclassifiable IIP by multidisciplinary discussion were identified using the nationwide registry. Eligible patients were stratified into four groups with and without BAL lymphocytosis and anti-inflammatory therapy to compare overall survival (OS) and changes in lung function. BAL lymphocytosis was defined as a lymphocyte differential count > 15%, and the cut-off was corroborated by survival classification and regression tree analysis. RESULTS: Overall, 186 patients (37 iNSIP, 16 iPPFE, and 133 unclassifiable IIP) were analyzed. Limited to patients treated with anti-inflammatory drugs (n = 123), patients with BAL lymphocytosis had a better prognosis [hazard ratio (HR), 0.26; 95% confidence interval (CI), 0.11-0.63; P = 0.003], higher slope of forced vital capacity (FVC) % predicted for 2 years, and longer OS (log-rank test, P = 0.012) than those without BAL lymphocytosis. On multivariate analysis, BAL lymphocytosis (HR 0.31; 95% CI 0.13-0.75; P = 0.009) was a prognostic factor for OS, along with age and FVC % predicted. Conversely, for patients managed without anti-inflammatory therapy (n = 63), the presence or absence of BAL lymphocytosis had no prognostic value. CONCLUSIONS: BAL lymphocytosis is associated with good outcomes in patients treated with anti-inflammatory drugs, but has no prognostic value when anti-inflammatory drugs are not used. BAL lymphocytosis may provide a predictive biomarker for identifying patients with iNSIP, iPPFE and unclassifiable IIP who are likely to benefit from anti-inflammatory drugs.

Cutaneous T-cell-attracting chemokine as a novel biomarker for predicting prognosis of idiopathic pulmonary fibrosis: a prospective observational study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease that leads to respiratory failure and death. Although there is a greater understanding of the etiology of this disease, accurately predicting the disease course in individual patients is still not possible. This study aimed to evaluate serum cytokines/chemokines as potential biomarkers that can predict outcomes in IPF patients. METHODS: A multi-institutional prospective two-stage discovery and validation design using two independent cohorts was adopted. For the discovery analysis, serum samples from 100 IPF patients and 32 healthy controls were examined using an unbiased, multiplex immunoassay of 48 cytokines/chemokines. The serum cytokine/chemokine values were compared between IPF patients and controls; the association between multiplex measurements and survival time was evaluated in IPF patients. In the validation analysis, the cytokines/chemokines identified in the discovery analysis were examined in serum samples from another 81 IPF patients to verify the ability of these cytokines/chemokines to predict survival. Immunohistochemical assessment of IPF-derived lung samples was also performed to determine where this novel biomarker is expressed. RESULTS: In the discovery cohort, 18 cytokines/chemokines were significantly elevated in sera from IPF patients compared with those from controls. Interleukin-1 receptor alpha (IL-1Rα), interleukin-8 (IL-8), macrophage inflammatory protein 1 alpha (MIP-1α), and cutaneous T-cell-attracting chemokine (CTACK) were associated with survival: IL-1Rα, hazard ratio (HR) = 1.04 per 10 units, 95% confidence interval (95% CI) 1.01-1.07; IL-8, HR = 1.04, 95% CI 1.01-1.08; MIP-1α, HR = 1.19, 95% CI 1.00-1.36; and CTACK, HR = 1.12 per 100 units, 95% CI 1.02-1.21. A replication analysis was performed only for CTACK because others were previously reported to be potential biomarkers of interstitial lung diseases. In the validation cohort, CTACK was associated with survival: HR = 1.14 per 100 units, 95% CI 1.01-1.28. Immunohistochemistry revealed the expression of CTACK and CC chemokine receptor 10 (a ligand of CTACK) in airway and type II alveolar epithelial cells of IPF patients but not in those of controls. CONCLUSIONS: CTACK is a novel prognostic biomarker of IPF. Trial registration None (because of no healthcare intervention).

Thrombomodulin Alfa for Acute Exacerbation of Idiopathic Pulmonary Fibrosis. A Randomized, Double-Blind Placebo-controlled Trial.

Rationale: Acute exacerbation during the course of idiopathic pulmonary fibrosis causes a poor prognosis. Coagulation abnormalities and endothelial damage are involved in its pathogenesis. Thrombomodulin alfa, a recombinant human soluble thrombomodulin, has anticoagulant and antiinflammatory effects. Several clinical studies have shown that thrombomodulin alfa may improve survival of acute exacerbation.Objectives: To determine the efficacy and safety of thrombomodulin alfa compared with placebo in acute exacerbation of idiopathic pulmonary fibrosis.Methods: This randomized, double-blind placebo-controlled phase 3 study conducted at 27 sites in Japan involved patients with an acute exacerbation of idiopathic pulmonary fibrosis. Subjects were randomized 1:1 to receive placebo or thrombomodulin alfa (380 U/kg/d for 14 d by intravenous drip infusion). All subjects were treated with high-dose corticosteroid therapy. The primary endpoint was the survival proportion on Day 90.Measurements and Main Results: Of the 82 randomized subjects, 77 completed the study and were included in the full analysis set (thrombomodulin alfa, n = 40; placebo, n = 37). The survival proportions on Day 90 were 72.5% (29 of 40) in the thrombomodulin alfa group and 89.2% (33 of 37) in the placebo group, a difference of -16.7 percentage points (95% confidence interval, -33.8 to 0.4%; P = 0.0863). In the safety population (n = 80), bleeding adverse events occurred in the thrombomodulin alfa group (10 of 42; 23.8%) and the placebo group (4 of 38; 10.5%).Conclusions: Thrombomodulin alfa did not improve the 90-day survival proportion. The present results suggest that the use of thrombomodulin alfa for the treatment of acute exacerbation of idiopathic pulmonary fibrosis not be recommended.Clinical trial registered with www.clinicaltrials.gov (NCT02739165).

Therapeutic plasma exchange for clinically amyopathic dermatomyositis (CADM) associated with rapidly progressive interstitial pneumonia.

BACKGROUND: Patients with clinically amyopathic dermatomyositis (CADM) with anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) frequently develop rapidly progressive interstitial pneumonia (RPIP), often with fatal outcomes. Therapeutic plasma exchange (TPE) has been reported as effective against CADM-RPIP refractory to conventional immunosuppressive therapy. However, the detailed mechanisms by which TPE improves disease activity of CADM-RPIP remain unclear. AIM: To elucidate the clinical and demographic characteristics of patients with anti-MDA5 Ab-positive CADM-RPIP treated with TPE and to analyze changes in laboratory findings before, during, and after TPE. MATERIALS & METHODS: Patients hospitalized for CADM-RPIP and treated with TPE in 2017 and 2018 were analyzed retrospectively. RESULTS: Three patients were successfully treated with TPE, with good tolerance. Anti-MDA5 Ab titers decreased significantly over the course of TPE. CONCLUSION: We emphasize that TPE could represent an effective treatment option for CADM-RPIP refractory to traditional therapy. Removal of anti-MDA5 Ab and other pathogenic factors may facilitate favorable outcomes.

Utility of procalcitonin for differentiating cryptogenic organising pneumonia from community-acquired pneumonia.

Background This study aimed to investigate the usefulness of inflammatory biomarkers such as white blood cell (WBC) count, C-reactive protein (CRP) and procalcitonin (PCT) for differentiating cryptogenic organising pneumonia (COP) from community-acquired pneumonia (CAP). Methods COP patients hospitalised in Kurashiki Central Hospital between January 2010 and December 2017 whose WBC counts and CRP and PCT levels were measured were investigated retrospectively, and their results were compared with those of hospitalised CAP patients who were prospectively enrolled between October 2010 and November 2017. Definite COP was defined by specific histopathological findings, and possible COP was defined as a consolidation shadow on chest computed tomography and lymphocyte dominance in bronchoalveolar lavage fluid in the absence of specific histopathological findings or lung specimens. The discriminatory abilities of WBC counts, CRP and PCT were evaluated by receiver operating characteristic (ROC) curve analysis. Results There were 56 patients in the entire COP group, 35 (61.4%) with definite COP, and 914 CAP patients. All three biomarkers were significantly lower in COP than in CAP. The AUC value of PCT in all COP patients was 0.79, significantly higher than of both CRP (AUC 0.59, p < 0.001) and WBC (AUC 0.69, p = 0.048). In definite COP patients, the AUC value of PCT was 0.79, which was also significantly higher than of both WBC (AUC 0.64, p = 0.006) and CRP (AUC 0.64, p = 0.001). Conclusions PCT is a more useful biomarker for differentiating COP from CAP than WBC count or CRP. However, PCT should be used as an adjunct to clinical presentation and radiological findings.

Prognostic significance of crazy paving ground grass opacities in non-HIV Pneumocystis jirovecii pneumonia: an observational cohort study.

BACKGROUND: In patients with non-HIV Pneumocystis jirovecii pneumonia (PjP), computed tomography imaging reveals ground grass opacities (GGO). Previous reports show that some patients with non-HIV PjP exhibit GGO with crazy paving. However, there have been no studies on the association between crazy paving GGO and non-HIV PjP clinical outcomes. Here, at the diagnosis of non-HIV PjP, we reviewed high-resolution computed tomography (HRCT) findings that included GGO types and evaluated the prognostic impact of crazy paving GGO on the clinical outcomes of non-HIV PjP immunocompromised patients. METHODS: We retrospectively reviewed the clinical information including the HRCT findings of patients diagnosed with non-HIV PjP from five institutions between 2006 and 2015. The GGO types included those with or without crazy paving. The associations between clinical factors such as HRCT findings and in-hospital mortality were assessed using the Cox regression model. RESULTS: Sixty-one patients were included in our study. Nineteen patients died at a hospital. All patients exhibited GGO on HRCT imaging at diagnosis of non-HIV PjP. The HRCT findings included crazy paving GGO (29 patients, 47.5%), consolidations (23 patients, 37.7%), bronchiectasis (14 patients, 23.0%), and centrilobular small nodules (30 patients, 49.2%). Cysts were not observed in any patient. Multivariate analysis revealed that crazy paving GGO and low serum albumin levels were independent risk factors for mortality. CONCLUSIONS: At the diagnosis of non-HIV PjP, patients with crazy paving GGO on HRCT imaging and low serum albumin levels may have a poor prognosis.

Radiological fibrosis score is strongly associated with worse survival in rheumatoid arthritis-related interstitial lung disease.

OBJECTIVES: High-resolution computed tomography (HRCT) parenchymal patterns have been used to predict prognosis in patients with interstitial lung disease (ILD). In idiopathic pulmonary fibrosis, the fibrosis score (i.e. the combined extent of reticulation and honeycombing) has been associated with worse survival. This study aimed to identify HRCT patterns and patient characteristics that can predict poor prognosis in rheumatoid arthritis-related ILD (RA-ILD). METHODS: We retrospectively analysed 65 patients with newly diagnosed RA-ILD from 2007 to 2016 at Kurashiki Central hospital. Using univariate and bivariate Cox regression analysis, associations with mortality, were identified. RESULTS: During a median follow-up of 56.5 months, 16/65 (24.6%) patients died. Univariate analysis identified six significant poor prognostic factors: lower baseline % predicted forced vital capacity, total interstitial disease score, reticulation score, traction bronchiectasis score, fibrosis score, and definite UIP pattern. Fibrosis score remained to be an independently significant poor prognostic factor of survival on bivariate analysis. Patients with a fibrosis score >20% had higher mortality (HR, 9.019; 95% CI, 2.87-28.35; p < .05). CONCLUSION: This study showed that fibrosis score is strongly associated with worse survival in RA-ILD, and patients with fibrosis score >20% had a 9.019-fold increased risk of mortality.

Radiographic fibrosis score predicts survival in systemic sclerosis-associated interstitial lung disease.

BACKGROUND AND OBJECTIVE: Interstitial lung disease (ILD) is a common pulmonary manifestation of systemic sclerosis (SSc). It is unknown whether radiographic fibrosis score predicts mortality in SSc-associated ILD (SSc-ILD). We retrospectively analysed patients with SSc-ILD to evaluate whether radiographic fibrosis score was a useful predictor of mortality. METHODS: We identified SSc-ILD patients evaluated at Kurashiki Central Hospital (Japan) from 2006 to 2016, and radiographic fibrosis scores based on the extent of reticulation and honeycombing on high-resolution computed tomography (HRCT) scanning were calculated by manually tracing around each fibrotic area. Independent predictors of overall survival were determined using the Cox proportional hazards model. RESULTS: The study included 48 patients, of whom 19 had usual interstitial pneumonia on HRCT. The median follow-up period was 56.6 months, and over the follow-up period 15 patients died. The 5-year survival was 72.4%. In the multivariate analysis, radiographic fibrosis score, age, being male and forced vital capacity were independently associated with an increased risk of death, while HRCT pattern was not. CONCLUSION: A high radiographic fibrosis score was a poor prognostic factor in SSc-ILD. More widespread fibrosis was associated with an increased risk of death, independent of HRCT pattern.

Comparison of clinical and pathological features of lung lesions of systemic IgG4-related disease and idiopathic multicentric Castleman's disease.

AIMS: The lung lesion [immunoglobulin (Ig)G4-L] of IgG4-related disease (IgG4-RD) is a condition that occurs together with IgG4-RD and often mimics the lung lesion [idiopathic multicentric Castleman's disease (iMCD-L)] of idiopathic multicentric Castleman's disease (iMCD). Because no clinical and pathological studies had previously compared features of these diseases, we undertook this comparison with clinical and histological data. METHODS AND RESULTS: Nine patients had IgG4-L (high levels of serum IgG4 and of IgG4+ cells in lung specimens; typical extrapulmonary manifestations). Fifteen patients had iMCD-L (polyclonal hyperimmunoglobulinaemia, elevated serum interleukin-6 levels and polylymphadenopathy with typical lymphadenopathic lesions). Mean values for age, serum haemoglobin levels and IgG4/IgG ratios were higher in the IgG4-L group and C-reactive protein levels were higher in the iMCD-L group. All IgG4-RD lung lesions showed myxomatous granulation-like fibrosis (active fibrosis), with infiltration of lymphoplasmacytes and scattered eosinophils within the perilymphatic stromal area, such as interlobular septa and pleura with obstructive vasculitis. All 15 lung lesions of iMCD, however, had marked accumulation of polyclonal lymphoplasmacytes in lesions with lymphoid follicles and dense fibrosis, mainly in the alveolar area adjacent to interlobular septa and pleura without obstructive vasculitis. CONCLUSIONS: Although both lesions had lymphoplasmacytic infiltration, lung lesions of IgG4-RD were characterized by active fibrosis with eosinophilic infiltration within the perilymphatic stromal area with obstructive vasculitis, whereas lung lesions of iMCD had lymphoplasmacyte proliferating lesions mainly in the alveolar area adjacent to the perilymphatic stromal area. These clinicopathological features may help to differentiate the two diseases.