Focal-adhesion kinase regulates the sialylation of N-glycans via the PI4KIIα-PI4P pathway.

Sialylation is a terminal glycosylated modification of glycoproteins that regulates critical biological events such as cell adhesion and immune response. Our previous study showed that integrin α3ß1 plays a crucial role in regulating the sialylation of N-glycans. However, the underlying mechanism for the regulation remains unclear. This study investigated how sialylation is affected by focal adhesion kinase (FAK), which is a critical downstream signal molecule of integrin ß1. We established a stable FAK knockout (KO) cell line using the CRISPR/Cas9 system in HeLa cells. The results obtained from lectin blot, flow cytometric analysis, and MS showed that the sialylation levels were significantly decreased in the KO cells compared with that in wild-type (WT) cells. Moreover, phosphatidylinositol 4-phosphate (PI4P) expression levels were also reduced in the KO cells due to a decrease in the stability of phosphatidylinositol 4-kinase-IIα (PI4KIIα). Notably, the decreased levels of sialylation, PI4P, and the complex formation between GOLPH3 and ST3GAL4 or ST6GAL1, which are the main sialyltransferases for modification of N-glycans, were significantly restored by the re-expression of FAK. Furthermore, the decreased sialylation and phosphorylation of Akt and cell migration caused by FAK deficiency all were restored by overexpressing PI4KIIα, which suggests that PI4KIIα is one of the downstream molecules of FAK. These findings indicate that FAK regulates sialylation via the PI4P synthesis pathway and a novel mechanism is suggested for the integrin-FAK-PI4KIIα-GOLPH3-ST axis modulation of sialylation in N-glycans.

[A CASE OF REPEATED DRUG-INDUCED LUNG DISEASES DUE TO MULTIPLE HERBAL MEDICINES CONTAINING COMMON INGREDIENTS].

We present a rare case of repetitive lung disease caused by various herbal medicines containing common ingredients. In June 201X-2, an 81-year-old man with chronic sinusitis was treated with Shini-seihai-to. One month later, the patient experienced liver dysfunction, and pulmonary opacity was observed on a chest radiograph; this condition improved following the discontinuation of Shini-seihai-to. In October 201X-2, the patient developed fever and dyspnea after treatment with Saiko-keishi-to, which was administered to treat irritable bowel syndrome, and was diagnosed with pneumonia. His condition did not improve with antimicrobial treatment but did improve with systemic corticosteroids. Following discharge from the hospital, the patient took both Shini-seihai-to and Hochu-ekki-to. He developed a fever two days later, which improved after discontinuing the medicines. The patient developed a cough after taking Sairei-to in February 201X and was subsequently admitted to our hospital with respiratory failure; pulmonary opacity was observed on a chest computed tomography scan. On the basis of clinical course, lymphocytosis in bronchoalveolar lavage fluid, and drug-induced lymphocyte stimulation tests, we diagnosed the patient with Sairei-to-induced lung disease. The patient's condition improved after discontinuing Sairei-to. We conclude that common ingredients in different herbal medicines may cause drug-induced lung injury. Therefore, we recommend that scrupulous attention should be paid to Chinese herbal medicine use in patients with a history of lung injury induced by herbal medicines.

Differences in clinical features of acute exacerbation between connective tissue disease-associated interstitial pneumonia and idiopathic pulmonary fibrosis.

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a devastating condition that frequently occurs in the advanced stage of IPF. However, the clinical features in AE of connective tissue disease-associated interstitial pneumonia (AE-CTD-IP) have not been well-established. The aim of this study was to clarify the clinical features of AE-CTD-IP and to compare them with those of AE-IPF. Fifteen AE-CTD-IP patients and 48 AE-IPF patients who were diagnosed and treated at our hospital were retrospectively studied. Compared with AE-IPF patients, AE-CTD-IP patients had a significantly higher %FVC (median, 94.8 vs. 56.3%; p < 0.001) and a lower extent of honeycombing on HRCT ( p = 0.020) within 1 year before AE. At AE, AE-CTD-IP patients showed higher white blood cell counts (12.0 vs. 9.9 × 103/µL; p = 0.023), higher CRP (10.2 vs. 6.7 mg/dL; p = 0.027), and longer period from admission to the beginning of AE treatment (4 vs. 1 days; p = 0.003) than AE-IPF patients. In addition, patients with AE-CTD-IP had poor prognosis as in those with AE-IPF (log-rank; p = 0.171). In conclusion, AE-CTD-IP occurred even in the early stage of IP and had more inflammatory status than in AE-IPF.

Body size-adjusted dose analysis of pirfenidone in patients with interstitial pneumonia.

BACKGROUND AND OBJECTIVE: Pirfenidone is an effective anti-fibrotic agent for idiopathic pulmonary fibrosis (IPF). Although adverse events (AE) sometimes prevent patients from continuing treatment, current dose adjustment guidance does not consider patient body size or weight (BW). The aim of this study was to evaluate the importance of pirfenidone dose adjustment by body surface area (BSA) or BW for preventing AE and permitting continuous treatment in patients with interstitial pneumonia (IP). METHODS: Sixty-seven Japanese patients with IP including 46 patients with IPF treated with pirfenidone between 2009 and 2015 were retrospectively evaluated. Pirfenidone doses were adjusted by BSA or BW and were compared with clinical parameters. RESULTS: Forty-two of 67 patients (62.7%) with IP showed AE, most commonly gastrointestinal symptoms (77.5%). Patients having AE received significantly higher adjusted doses of pirfenidone by both BSA and BW (P = 0.024 and P = 0.010, respectively), while unadjusted doses did not differ. BSA-adjusted dose discriminated patients with AE from those without (area under the curve = 0.666 at 1085 mg/m2 ). Six of seven patients (85.7%) who discontinued pirfenidone due to AE took ≥1085 mg/m2 of pirfenidone. In a subgroup with IPF, patients taking a medium dose (median: 876 median-1085 mg/m2 ) showed a lower annual decline in % forced vital capacity than patients taking a lower dose (P = 0.025). CONCLUSION: BSA-adjusted pirfenidone dosing may be useful to prevent AE whilst achieving a long-term treatment effect in patients with IP.

Persistent impairment on spirometry in chronic eosinophilic pneumonia: A longitudinal observation study (Shizuoka-CEP study).

BACKGROUND: Chronic eosinophilic pneumonia (CEP) is characterized by the accumulation of eosinophils in the lung with unknown etiology. Although systemic corticosteroid administration leads to dramatic improvement, nearly half the patients with CEP experience relapse and some develop persistent impairment of pulmonary function. However, predictive factors for this persistent impairment have not been determined. OBJECTIVE: To investigate the occurrence of persistent impairment of pulmonary function in CEP and determine its predictive factors. METHODS: This observational study consisted of 133 consecutive patients with CEP who were followed for longer than 1 year. Spirometry was performed at the time of diagnosis and at follow-up. RESULTS: During the observational period (6.1 ± 4.1 years), relapse occurred in 75 patients (56.4%). Remarkably, 42 patients (31.6%) had a persistent pulmonary function defect (27 obstructive, 10 restrictive, and 4 obstructive and restrictive cases) at the last evaluation. Logistic analyses showed that the relapse was associated with neither persistent obstructive nor restrictive defects. Persistent obstructive defect was significantly associated with the comorbidity of asthma and obstructive defect at the initial CEP diagnosis, whereas persistent restrictive defect was significantly related to reticulation at high-resolution computer tomography and restrictive defect at diagnosis. CONCLUSION: Persistent impairment of pulmonary function is common in CEP. Concurrent asthma and obstructive defects at diagnosis were predictors for persistent obstructive impairments, whereas reticulation at high-resolution computer tomography and restrictive defect at diagnosis predicted persistent restrictive impairment. Attention should be paid to these persistent impairments in the management of CEP. TRIAL REGISTRATION: http://www.umin.ac.jp/ctr/index-j.htm Identifier: UMIN000019092 (principal investigator, Takafumi Suda, MD, PhD).

Clinical Implication of Proteinase-3-antineutrophil Cytoplasmic Antibody in Patients with Idiopathic Interstitial Pneumonias.

PURPOSE: The clinical significance of proteinase-3-antineutrophil cytoplasmic antibody (PR3-ANCA) positivity is not well established in idiopathic interstitial pneumonia (IIP) patients. We aimed to determine the clinical features of PR3-ANCA-positive IIP patients. METHODS: We retrospectively reviewed 377 consecutive IIP patients; of these, 360 patients had PR3-ANCA and myeloperoxidase-antineutrophil cytoplasmic antibody test results available. The clinical features of PR3-ANCA-positive IIP patients and control ANCA-negative idiopathic pulmonary fibrosis patients (ANCA-negative IPF) were compared. RESULTS: Sixteen patients (4.4 %) were PR3-ANCA-positive IIP and 94 (26 %) were ANCA-negative IPF. The median age at diagnosis (72 vs. 70 years, P = 0.17) and proportion of males (75 vs. 89 %, P = 0.12) in PR3-ANCA-positive IIP and ANCA-negative IPF patients, respectively, were not significantly different. Radiologically, the HRCT patterns of PR3-ANCA-positive IIP patients varied (UIP, n = 3, 18.8 %; possible UIP, n = 3, 18.8 %; NSIP, n = 5, 31.3 %; unclassifiable CT pattern, n = 5, 31.3 %) more than those of ANCA-negative IPF patients (UIP, n = 69, 73.4 %; possible UIP, n = 25, 26.6 %; P < 0.001). No PR3-ANCA-positive IIP patients developed ANCA-associated vasculitis. The 5-year survival rate was 50 % in PR3-ANCA-positive IIP patients and 52 % in ANCA-negative IPF patients with no significant difference (P = 0.96 by log-rank test). CONCLUSIONS: The HRCT patterns of PR3-ANCA-positive IIP patients varied more than those of the IPF patients, but the clinical features of high IIP-onset age and male predominance were similar between the groups. Furthermore, PR3-ANCA-positive IIP patients had a poor prognosis similar to that of IPF patients.

Clinical Significance of Forced Oscillation Technique for Evaluation of Small Airway Disease in Interstitial Lung Diseases.

PURPOSE: Small airway disease (SAWD) in patients with interstitial lung disease (ILD) is often assessed by high-resolution computed tomography (HRCT). However, frequent HRCT examinations result in a high level of radiographic exposure. This study investigated the utility of the forced oscillation technique (FOT) to evaluate SAWD in patients with ILD. METHODS: Broadband FOT using a commercially available device (MostGraph-01) and pulmonary function tests (PFT) were performed in 90 patients with ILD. HRCT images taken within 3 months were reviewed. The patients were divided into two groups according to the presence or absence of SAWD findings detected by HRCT. Clinical characteristics, PFT, and FOT between the two groups were compared. RESULTS: Of the 90 patients with ILD, 19 were classified as having SAWD findings (the presence group) and 71 as not having SAWD findings (the absence group). There were no significant differences in parameters of PFT between the two groups. The presence group had higher absolute values of reactance at 5 Hz (X5), resonant frequency (Fres), and low-frequency reactance area (ALX) than did the absence group. A within-breath change analysis demonstrated that the change in X5, Fres, and ALX between expiration and inspiration (ΔX5, ΔFres, ΔALX, respectively) was significantly different between the groups. A univariate analysis revealed that X5, Fres, ALX, ΔX5, ΔFres, ΔALX were significantly associated with the presence of SAWD findings. Multivariate analysis validated that Fres was related to the presence of SAWD findings. CONCLUSIONS: The FOT may be useful in detecting and evaluating SAWD in patients with ILD. TRIAL REGISTRATION: UMIN 000020733.

Efficacy of short-term prednisolone treatment in patients with chronic eosinophilic pneumonia.

In patients with chronic eosinophilic pneumonia (CEP), dramatic improvements are seen in response to corticosteroid therapy; however, relapse is common after treatment has ceased. The optimal duration of corticosteroid therapy remains unclear. In a randomised, open-label, parallel group study, eligible patients with CEP received oral prednisolone for either 3 months (3-month group) or 6 months (6-month group), followed by 2 years observation. All patients were treated with an initial dose of prednisolone of 0.5 mg·kg(-1)·day(-1), which was then tapered and discontinued at either 3 or 6 months. The primary end-point was relapse during the follow-up period. In the final analysis, there were 23 patients in the 3-month group and 21 patients in the 6-month group. All patients showed a good response to prednisolone treatment. There were 12 (52.1%) relapses in the 3-month group and 13 (61.9%) relapses in the 6-month group. No significant difference was found in the cumulative rate of relapse (p=0.56). All relapse cases showed improvement upon resumption of prednisolone treatment. No difference was observed in the rate of relapse between the 3- and 6-month prednisolone treatment groups for patients with CEP.

Treatment of acute exacerbation of idiopathic pulmonary fibrosis with direct hemoperfusion using a polymyxin B-immobilized fiber column improves survival.

BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) has an extremely poor prognosis and there is currently no effective treatment for this condition. Direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) improves oxygenation, but it is unclear whether treatment of AE-IPF with PMX-DHP affects survival. This study elucidated the effectiveness and safety of PMX-DHP for the treatment of AE-IPF. METHODS: This study included 31 patients with 41 episodes of AE-IPF. All patients received steroids. Of 31, 14 patients (20 episodes) were treated with PMX-DHP. The laboratory and physiological test results after the start of therapy and survival were retrospectively compared between patients treated with and without PMX-DHP. RESULTS: Patients treated with PMX-DHP had a significantly greater change in PaO2/FiO2 ratio (mean ± SEM, 58.2 ± 22.5 vs. 0.7 ± 13.3, p = 0.034) and a smaller change in white blood cell count (-630 ± 959 /µL vs. 4500 ± 1190 /µL, p = 0.002) after 2 days of treatment than patients treated without PMX-DHP. The 12-month survival rate was significantly higher in patients treated with PMX-DHP (48.2% vs. 5.9%, p = 0.041). PMX-DHP was effective in patients with more severe underlying disease (GAP stages II or III; 12-month survival rate 57.1% with PMX-DHP vs. 0% without PMX-DHP, p = 0.021). Treatment with PMX-DHP was an independent predictor of better prognosis (hazard ratio 0.345, p = 0.037). Mild pulmonary thromboembolism occurred in one patient treated with PMX-DHP. CONCLUSIONS: Treatment of AE-IPF with PMX-DHP is tolerable and improves 12-month survival.

Quantitative analysis of lung elastic fibers in idiopathic pleuroparenchymal fibroelastosis (IPPFE): comparison of clinical, radiological, and pathological findings with those of idiopathic pulmonary fibrosis (IPF).

BACKGROUND: The pathological appearance of idiopathic pleuroparenchymal fibroelastosis (IPPFE) with hematoxylin-eosin staining is similar to that of usual interstitial pneumonia (UIP) in patients with idiopathic pulmonary fibrosis (IPF). The amount of elastic fibers (EF) and detailed differences between IPPFE and IPF have not been fully elucidated. The aim of this study was to quantify the EF and identify the differences between IPPFE and IPF. METHODS: We evaluated six patients with IPPFE and 28 patients with IPF who underwent surgical lung biopsy or autopsy. The patients' clinical history, physical findings, chest high-resolution computed tomography (HRCT) findings, and pathological features of lung specimens were retrospectively evaluated. The amounts of EF in lung specimens were quantified with Weigert's staining using a camera with a charge-coupled device and analytic software in both groups. RESULTS: Fewer patients with IPPFE than IPF had fine crackles (50.0% vs. 96.4%, p = 0.012). Patients with IPPFE had a lower forced vital capacity (62.7 ± 10.9% vs. 88.6 ± 21.9% predicted, p = 0.009), higher consolidation scores on HRCT (1.7 ± 0.8 vs. 0.3 ± 0.5, p < 0.0001), lower body mass indices (17.9 ± 0.9 vs. 24.3 ± 2.8, p < 0.0001), and more pneumothoraces than did patients with IPF (66.7 vs. 3.6%, p = 0.002). Lung specimens from patients with IPPFE had more than twice the amount of EF than did those from patients with IPF (28.5 ± 3.3% vs. 12.1 ± 4.4%, p < 0.0001). The amount of EF in the lower lobes was significantly lower than that in the upper lobes, even in the same patient with IPPFE (23.6 ± 2.4% vs. 32.4 ± 5.5%, p = 0.048). However, the amount of EF in the lower lobes of patients with IPPFE was still higher than that of patients with IPF (23.6 ± 2.4% vs. 12.2 ± 4.4%, p < 0.0001). CONCLUSION: More than twice the amount of EF was found in patients with IPPFE than in those with IPF. Even in the lower lobes, the amount of EF was higher in patients with IPPFE than in those with IPF, although the distribution of lung EF was heterogeneous in IPPFE specimens.

Successful osimertinib rechallenge without concomitant corticosteroids after osimertinib-induced pneumonitis.

A 60-year-old woman was diagnosed with cT4N3M1c stage IVB lung adenocarcinoma with epidermal growth factor receptor mutation of exon19 deletion. After one month of treatment with osimertinib, a cough and diffuse ground glass opacities were observed in the bilateral lung field. Based on the clinical course and the exclusion of other etiologies, osimertinib-induced pneumonitis was diagnosed. The shadows resolved after osimertinib was discontinued. However, brain metastasis and leptomeningeal metastasis developed 20 months later; therefore, osimertinib was re-administered without concomitant corticosteroids. The pulmonary lesion and leptomeningeal metastasis were successfully treated without recurrence of drug-induced pneumonitis for eight months.

Prognostic Role of Interferon-λ3 in Anti-Melanoma Differentiation-Associated Gene 5-Positive Dermatomyositis-Associated Interstitial Lung Disease.

OBJECTIVE: Interferon-λ3 (IFNλ3) is a cytokine with antiviral functions on barrier surfaces, and it is associated with disease activity in autoimmune diseases. This study assessed the clinical significance of serum IFNλ3 levels in polymyositis/dermatomyositis (PM/DM)-associated interstitial lung disease (ILD). METHODS: We measured serum IFNλ3 levels in 221 patients with PM/DM-ILD (155 in the derivation cohort, 66 in the validation cohort) and 38 controls. We evaluated factors associated with mortality risk among 79 patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive DM-ILD. RESULTS: Serum IFNλ3 levels at diagnosis were significantly higher in patients with PM/DM-ILD than in healthy controls. Remarkably, serum IFNλ3 levels were specifically increased in patients with anti-MDA5 antibody-positive DM-ILD in both the derivation and validation cohorts. In anti-MDA5 antibody-positive DM-ILD, patients with high IFNλ3 levels (>120 pg/mL) had significantly lower survival rates than those with low IFNλ3 levels (≤120 pg/mL). A multivariate analysis revealed that high IFNλ3 levels, as well as old age and low Pao2, were significantly associated with poor prognoses in patients with anti-MDA5 antibody-positive DM-ILD. In a classification analysis of patients with anti-MDA5 antibody-positive DM-ILD based on age, IFNλ3 level, and Pao2, patients with old age (>53 years), high IFNλ3 levels (>120 pg/mL), and low Pao2 (<75 mm Hg) had the worst survival. In lung pathologic analyses, IFNλ3-positive staining was observed in macrophages, airway epithelial cells, the pleural region, and intrapulmonary veins in patients with anti-MDA5 antibody-positive DM-ILD. CONCLUSION: Serum IFNλ3 is a promising biomarker for identifying patients at high risk of poor outcomes in anti-MDA5 antibody-positive DM-ILD.

Chemotherapy for patients with advanced lung cancer with interstitial lung disease: a prospective observational study.

Introduction: Although recent advances in chemotherapy for lung cancer are remarkable, most clinical trials have excluded patients with interstitial lung disease (ILD) due to the concern of developing acute exacerbation (AE) of ILD. Hence, accumulating original evidence of cancer treatment for this population is important. Methods: Between 2016 and 2020, a prospective observational study was conducted across 11 Japanese hospitals. Patients with chemotherapy-naïve, inoperable, advanced lung cancer with ILD were included. The primary outcome was the frequency of AE-ILD after registration; the secondary outcomes were the risk factor of AE-ILD and the efficacy of chemotherapy. Results: Among 124 patients enrolled, 109 patients who received chemotherapy were analyzed. The median age was 72 years, and the majority showed usual interstitial pneumonia (UIP)/probable UIP pattern upon chest computed tomography. The median percent-predicted forced vital capacity (%FVC) was 81% (interquartile range: 66-95%). After registration, 23 patients (21.1%; 95% confidence interval [CI]: 14.4-29.7%) developed AE-ILD. The logistic analysis revealed that lower %FVC slightly but significantly increased the risk of AE-ILD (odds ratio per 10% decrease: 1.27; 95% CI: > 1.00-1.62). Overall response rates/median overall survival times in non-small-cell lung cancer and small-cell lung cancer for the first-line chemotherapy were 41% (95% CI: 31-53)/8.9 months (95% CI: 7.6-11.8) and 91% (95% CI: 76-98)/12.2 months (95% CI: 9.2-14.5), respectively. Conclusion: AE-ILD during chemotherapy is a frequent complication among patients with lung cancer with ILD, particularly those with lower %FVC. Conversely, even in this population, passable treatment response can be expected.

[A case of non small cell lung cancer associated with multiple cerebral infarctions due to nonbacterial thrombotic endocarditis].

A 67-year-old woman was admitted to our hospital for weakness in her right hand. MRI showed multiple cerebral infarctions and ultrasonic cardiography revealed vegetation on her aortic valve, so embolic stroke was diagnosed. Though she was afebrile and her vital signs were normal, chest CT revealed several enlarged mediastinal lymph nodes and a small nodule in the left lower lobe of the lung. Stage III adenocarcinoma of the lung was diagnosed, and the cause of her cerebral infarctions was found to be nonbacterial thrombotic endocarditis (NBTE). NBTE is known as the cause of embolic stroke among patients with advanced cancer, particularly adenocarcinoma. Prompt initiation of continuous heparin administration is required to interrupt the progress of cerebral thromboembolism in NBTE. In cases of coexisting cancer and embolic stroke, we should consider the possibility of NBTE.

[Two cases of pneumonitis caused by Seishinrenshiin, Chinese herbal medicine].

We report two cases of pneumonitis caused by Seishinrenshiin. A 54-year-old woman and a 80-year-old man had taken Seishinrenshiin for cystitis and benign prostatic hypertrophy. Their chest radiograph showed diffuse ground-glass shadows in the whole lung fields and chest CT showed diffuse ground-glass-opacities predominantly in the lower lung fields of both lungs. Biochemical tests revealed mild liver dysfunction and inflammatory reactions. Their abnormal chest shadows disappeared after discontinuation of Seishinrenshiin. We should be aware that Seishinrenshiin, as well as other Chinese herbal medicine, could be cause of drug-induced pneumonitis.

[A case of pleural sarcoidosis with bilateral pleural effusion].

A 25-year-old man was referred to our hospital because of cough and an abnormal shadow on chest X-ray film showing bilateral hilar lymphadenopathy accompanied by multiple nodules in both lung fields. A transbronchial lung biopsy demonstrated non-caseating epithelioid cell granulomas, and we diagnosed sarcoidosis. He was observed without medication for 18 months, however, his chest X-ray film findings gradually worsened, and bilateral pleural effusion appeared. The pleural effusion consisted of exudative fluid with prominent lymphocytes, and ADA level was elevated to 57.0U/l. Thoracoscopy demonstrated multiple whitish granulations on the parietal and visceral pleura. The pleural biopsy specimens exhibited non-caseating epithelioid cell granulomas, and there was no evidence of acid-fast bacilli. Based on these findings, pleural sarcoidosis was diagnosed. He was treated with 30 mg oral prednisolone daily, and both pleural effusion and nodules of lung fields on chest X-ray film subsided. Sarcoidosis with bilateral pleural effusions is rare, and we discuss this condition in relation to the pertinent literature.

Analysis of serum adiponectin and leptin in patients with acute exacerbation of idiopathic pulmonary fibrosis.

Weight loss progresses with the progression of idiopathic pulmonary fibrosis (IPF), and acute exacerbation of IPF (AE-IPF) frequently occurs in its advanced stage. Adiponectin and leptin are adipokines produced from adipose tissue, and are related to thinness and obesity, respectively. Additionally, these adipokines are implicated in the regulation of inflammation and fibrosis centering on peroxisome proliferator-activated receptor γ (PPARγ). However, the relationship between adiponectin/leptin and AE-IPF remains poorly known. We conducted this study to evaluate levels of serum adiponectin/leptin, and to elucidate the clinical importance of adiponectin and leptin in patients with AE-IPF. Thirty-two patients (39 episodes) who were diagnosed with AE-IPF at our hospital from 1997 to 2016 were retrospectively studied. Serum adiponectin and leptin concentrations were measured with enzyme-linked immunosorbent assay. Patients with AE-IPF showed higher levels of serum adiponectin and leptin than those at initial diagnosis of IPF (p = 0.007 and p = 0.027, respectively). Serum adiponectin/leptin (A/L) ratio was negatively correlated with body mass index at AE-IPF (r = -0.456, p = 0.003) and PaO2 before AE-IPF (r = -0.498, p = 0.034), and positively correlated with C-reactive protein at AE-IPF (r = 0.316, p = 0.049). Patients with higher A/L ratios had worse survival than those with lower A/L ratios (log-rank, p = 0.026). Further, in multivariate analysis, serum A/L ratio was a significant prognostic factor in patients with AE-IPF (HR 2.60, p = 0.042). In conclusion, the higher adiponectin/leptin ratio may be associated with a poor prognosis in patients with AE-IPF.

Clinical significance of myeloperoxidase-anti-neutrophil cytoplasmic antibody in idiopathic interstitial pneumonias.

OBJECTIVE: Although a possible association among myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA), microscopic polyangiitis (MPA), and idiopathic pulmonary fibrosis (IPF) has been suggested, the clinical significance of MPO-ANCA in idiopathic interstitial pneumonias (IIPs), including IPF and non-IPF, remains unclear. We aimed to investigate the frequency of MPO-ANCA positivity, as well as MPA incidence and risk factors for development in patients initially diagnosed with IIP. METHODS: We retrospectively analysed 305 consecutive patients who were initially diagnosed as IIP and had MPO-ANCA results available. RESULTS: Of the 305 patients, 26 (8.5%) were MPO-ANCA-positive. Baseline characteristics were similar between the MPO-ANCA-positive and -negative patients. The cumulative 5-year MPA incidence was 24.3% in the MPO-ANCA-positive patients and 0% in the -negative patients (P < 0.0001). MPO-ANCA was positive in 15 of 133 (11.3%) patients initially diagnosed with IPF and in 11 of 172 (6.3%) patients initially diagnosed with non-IPF (P = 0.56), with cumulative 5-year MPA incidence of 6.2% and 1.0%, respectively (P = 0.10). Multivariate analysis revealed that UIP pattern on HRCT (HR = 3.20, P < 0.01) and no treatment for IIP (HR = 3.52, P < 0.01) were independently associated with MPA development in MPO-ANCA-positive patients. CONCLUSION: MPO-ANCA positivity was uncommon, but was associated with subsequent MPA development in patients initially diagnosed with IIP, including both IPF and non-IPF cases. The study suggested that attention should be paid to MPA development in MPO-ANCA-positive IIP patients with UIP pattern on HRCT and those without treatment for IIP.

Prognostic evaluation of serum ferritin in acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) has an extremely poor prognosis. The role of ferritin in the pathogenesis of AE-IPF is not well known while serum ferritin is a key prognostic indicator for patients with clinically amyopathic dermatomyositis with rapidly progressive interstitial pneumonia. OBJECTIVE: To elucidate the clinical importance of serum ferritin in patients with AE-IPF. METHODS: Thirty-seven patients (48 episodes), who were diagnosed with AE-IPF and treated at our hospital between 1997 and 2015, were retrospectively studied. RESULTS: Patients with AE-IPF had significantly higher levels of serum ferritin than baseline levels at the first diagnosis of IPF (P = 0.0017). Receiver operating characteristic analysis showed the cut-off value 174 ng/mL for the separation of AE (area under the curve, 0.700). No patients with AE-IPF were positive for anti- melanoma differentiation-associated gene 5 antibody. Patients with AE-IPF and higher ferritin (≥174 ng/mL) had lower %FVC and %DLCO before AE, and those with much higher ferritin (≥500 ng/mL) had significantly worse prognosis than those with lower ferritin (log-rank, P = 0.024). Immunohistochemical staining in autopsy specimens showed alveolar macrophages that were producing ferritin. Finally, in multivariate Cox proportional hazards analyses, serum ferritin level of ≥500 ng/mL was a significant worse prognostic factor (hazard ratio 5.280, P = 0.046). CONCLUSION: Higher serum ferritin may be related to a worse prognosis in patients with AE-IPF.