Toshiki Yokoyama

The radiological patterns of interstitial change at an early phase: Over a 4-year follow-up

OBJECTIVES The identification of early phase interstitial changes may influence the understanding of idiopathic interstitial pneumonitis. This study aimed to clarify its radiological patterns and the association with smoking. METHODS The subjects underwent low-dose computed tomography to screen lung cancer. The selected subjects with interstitial changes were monitored for the precise morphology of interstitial changes using a high-resolution computed tomography (HRCT) scan. The subjects were classified into normal and abnormal HRCT subjects. The radiological findings on the HRCT scan, serum Klebs von der Lungen-6 (KL-6), surfactant protein (SP)-A, SP-D, pulmonary function, and computed tomography (CT) scores were analyzed. Abnormal HRCT subjects were classified based on the radiological patterns, and were followed-up over a 4-year period. RESULTS HRCT abnormalities suggesting interstitial changes were identified in 80 of 3079 subjects. Seven subjects with honeycombing and 14 with combined pulmonary fibrosis and emphysema (CPFE) were identified. The frequencies of sex (male) and smoking in the subjects with honeycombing was higher than that of other patterns. The smoking history and the levels of serum KL-6, SP-A, and SP-D in abnormal HRCT subjects were significantly higher than those in normal HRCT subjects. Thirty-two of 73 abnormal HRCT subjects showed a progression of the CT scores in a chest HRCT over a 4-year period. Eighteen abnormal HRCT current smokers were included in the progression of CT scores. CONCLUSIONS HRCT patterns, excluding interlobular septal thickening, show the progression of CT scores. Smokers with CT abnormalities may have a tendency to demonstrate worsening interstitial changes.

Recombinant Human Thrombomodulin in Acute Exacerbation of Idiopathic Pulmonary Fibrosis

BACKGROUND Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) presents as episodes of acute respiratory worsening closely associated with endothelial damage and disordered coagulopathy. Recombinant human soluble thrombomodulin (rhTM) regulates the coagulation pathway mainly by reducing thrombin-mediated clotting and enhancing protein C activation. We investigated the efficacy of rhTM for the treatment of patients with AE-IPF. METHODS This historical control study comprised 40 patients with AE-IPF. Twenty patients treated with rhTM (0.06 mg/kg/d) for about 6 days (rhTM group) and 20 patients treated without rhTM (control group) were evaluated. The predictors of 3-month mortality (logistic regression model) were evaluated. RESULTS There was no difference in baseline characteristics between the control group and the rhTM group. Three-month mortality of the rhTM group and control group was 30.0% and 65.0%, respectively. In univariate analysis, C-reactive protein and rhTM therapy were significant determinants for 3-month survival. In multivariate analysis, rhTM therapy (OR, 0.219; 95% CI, 0.049-0.978; P = 0.047) was an independent significant determinant for 3-month survival. CONCLUSIONS We found that rhTM therapy improved 3-month survival of AE-IPF. The results observed here warrant further investigation of rhTM in randomized control trials.

Thrombomodulin for acute exacerbations of idiopathic pulmonary fibrosis: A proof of concept study

INTRODUCTION The mortality of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is high. Anticoagulation therapy (recombinant human soluble thrombomodulin (rhTM)) is recognized as a potential new strategy for treating disseminated intravascular coagulation in Japan. This preliminary study was to evaluate whether the coagulation factors increase or decrease in AE-IPF-patients, and whether the additional administration of rhTM for AE-IPF-patients has any beneficial effects on inflammatory mediators and activated coagulation. METHODS We retrospectively compared the clinical data of AE-IPF-patients, idiopathic pulmonary fibrosis (IPF) with pneumonia-patients and slowly progressive IPF-patients. As a subsequent study, AE-IPF-patients were prospectively treated with a bolus of rhTM intravenously for six days under mechanical ventilation. We historically investigated the improvement of the serial clinical data in both oxygenation and intravascular coagulation disturbance between treated AE-IPF-patients and untreated AE-IPF-patients. RESULTS Eleven AE-IPF, 21 IPF with pneumonia and 16 slowly progressive IPF-patients were enrolled, and the coagulatory levels of the AE-IPF-patients were found to be significantly higher than in the other patients. In 20 treated AE-IPF-patients, the 28-day mortality and in-hospital mortality were 35% and 45%, respectively. The levels of oxygenation rapidly increased on day 1 and continued to improve until day 7 in the survival AE-IPF-patients. The thrombin-antithrombin complex levels and inflammatory cytokine levels in the survivors on day 7 were significantly different from those observed in the nonsurvivors. CONCLUSION AE-IPF-patients were found to have significantly higher levels of coagulation. The rhTM administration in the surviving AE-IPF-patients led to significant differences in the oxygenation and intravascular coagulation disturbance.

Central airway stenosis in a patient with autoimmune pancreatitis

Autoimmune pancreatitis is a unique form of chronic pancreatitis characterised by a high-serum immunoglobulin (Ig)G4 concentration involving various extra pancreatic lesions. A 63-yr-old female with autoimmune pancreatitis complained of cough. Chest computed tomography revealed an irregular stenosis of the central airway, lung hilar and mediastinal lymph node swelling, and a marked thickness of the bronchovascular bundle. Bronchoscopic examination revealed an irregular tracheobronchial stenosis accompanied with an oedematous mucosa and engorged vessels. Lung hilar and mediastinal lymph node swelling, central airway stenosis and bronchoscopic findings remarkably resembled those of sarcoidosis. Bronchial biopsy specimens demonstrated diffuse infiltrations of plasma cells, lymphocytes and eosinophils with fibrosis. Immunostaining showed infiltration of several IgG4-positive plasma cells. The patient was treated with oral prednisolone at 1 mg·kg−1·day−1 for pancreatic lesions. A month later, the lung lesions, including central airway stenosis, lung hilar and mediastinal lymph node swelling, and bronchovascular bundle thickness, had dramatically improved along with improvement of pancreatitis, thus indicating a close association between the two conditions. This is the first report of a patient with autoimmune pancreatitis showing central airway stenosis similar to that of sarcoidosis.

Potential benefits of early continuous positive pressure ventilation in patients with rapidly progressive interstitial pneumonia

Background and objective:  Rapidly progressive interstitial pneumonia (RPIP), including acute exacerbations of interstitial pneumonia, is associated with high rates of mortality. The present study was performed to examine the effects of respiratory management using non‐invasive ventilation (NIV) in patients with RPIP and to assess the prognostic factors for survival.

Elevated IgG4 levels in patients demonstrating sarcoidosis-like radiologic findings.

One of the radiologic patterns associated with IgG4-related systemic disease was similar to that of pulmonary sarcoidosis. We analyzed whether suspected pulmonary sarcoidosis might include unrecognized IgG4-related systemic disease. The enrolled patients had bilateral hilar lymphadenopathy and/or lung nodules on chest computed tomography, used to diagnose the patients who could either be compatible with or suggested as having pulmonary sarcoidosis. The IgG4 levels were retrospectively measured. Bronchoalveolar lavage (BAL) was analyzed for the presence of IgG subclasses, and specimens were stained by an antibody to IgG4. We compared these data in the suspected sarcoidosis patients, with or without elevated serum IgG4, with the laboratory data and bronchoscopy results in patients with definite sarcoidosis. All enrolled patients were followed for over 5 years.The patients were classified as 49 definite and 44 suspected sarcoidosis patients. Eight patients, including 6 suspected sarcoidosis patients, had elevated abnormal levels of serum IgG4. The suspected sarcoidosis patients had significantly lower percentages of lymphocytes and IgG in the BAL. One suspected sarcoidosis patient had positive IgG4 staining in a lung specimen. The elevated serum IgG4 patients among the patients with suspected sarcoidosis showed significantly higher levels of BAL IgG4, IgG4/IgG, and IgG4/IgG3 compared with the levels of the normal serum IgG4 patients. The follow-up study revealed that 1 patient with elevated serum IgG4 was complicated with other organ failure caused by IgG4-related systemic disease, and Castleman disease was diagnosed in 2 patients. IgG4-related systemic disease was, therefore, identified among the patients with elevated serum IgG4.Abbreviations: ACE = angiotensin-converting enzyme, BAL = bronchoalveolar lavage, BHL = bilateral hilar lymphadenopathy, CD= clusters of differentiation, CT = computed tomography, ELISA= enzyme-linked immunosorbent assay, Ga-67 = Gallium-67 citrate, sIL2r = soluble interleukin-2 receptor.

Clinical Predictors of Response to EGFR Tyrosine Kinase Inhibitors in Patients with EGFR-Mutant Non-Small Cell Lung Cancer

Background: The presence of EGFR (epidermal growth factor receptor) mutations is a robust predictor of EGFR tyrosine kinase inhibitor (TKI) responsiveness. Predictors of EGFR-TKI responsiveness in EGFR-mutant non-small cell lung cancer (NSCLC) patients, however, have not been well investigated. The purpose of this study is to examine predictors of EGFR-TKI responsiveness in EGFR-mutant NSCLC patients. Patients and Methods: Seventy EGFR-mutant NSCLC patients who received EGFR-TKIs in our institution between April 2007 and March 2013 were analyzed retrospectively. Results: The objective response rate was 50.0% (95% confidence interval, CI, 38.6-61.4%) and the disease control rate was 91.4% (95% CI, 82.5-96.0%). The median progression-free survival (PFS) and overall survival were 9.0 (95% CI, 3.92-14.08) and 20.8 months (95% CI, 14.56-27.04), respectively. In multivariate analysis, adenocarcinoma (hazard ratio, HR, 12.25; 95% CI, 37.7-41.10; p < 0.001) and major mutations (deletions in exon 19 and L858R point mutation in exon 21; HR, 2.46; 95% CI, 1.14-5.28; p = 0.022) were significant predictors of longer PFS. Conclusion: Major mutations and adenocarcinoma histology were independent predictors of better treatment outcome in EGFR-mutant NSCLC patients who received EGFR-TKIs. Further well-controlled prospective studies are warranted to confirm our findings.

Bronchoscopy-Guided Cooled Radiofrequency Ablation as a Novel Intervention Therapy for Peripheral Lung Cancer

Background: Our previous animal and preliminary human studies indicated that bronchoscopy-guided cooled radiofrequency ablation (RFA) for the lung is a safe and feasible procedure without major complications. Objectives: The present study was performed to evaluate the safety, effectiveness and feasibility of computed tomography (CT)-guided bronchoscopy cooled RFA in patients with medically inoperable non-small-cell lung cancer (NSCLC). Methods: Patients with pathologically diagnosed NSCLC, who had no lymph node involvement or distant metastases (T1-2aN0M0) but were not surgical candidates because of comorbidities (e.g. synchronous multiple nodules, advanced age, cardiovascular disease, poor pulmonary function, etc.) were enrolled in the present study. The diagnosis and location between the nearest bronchus and target tumor were made by CT-guided bronchoscopy before the treatment. A total of 28 bronchoscopy-guided cooled RFA procedures were performed in 20 patients. After treatment, serial CT imaging was performed as follow-up. Results: Eleven lesions showed significant reductions in tumor size and 8 lesions showed stability, resulting in a local control rate of 82.6%. The median progression-free survival was 35 months (95% confidence interval: 22-45 months), and the 5-year overall survival was 61.5% (95% confidence interval: 36-87%). Three patients developed an acute ablation-related reaction (fever, chest pain) and required hospitalization but improved with conservative treatment. There were no other adverse events in the present study. Conclusions: CT-guided bronchoscopy cooled RFA is applicable for only highly selected subjects; however, our trial may be an alternative strategy, especially for disease local control in medically inoperable patients with stage I NSCLC.

Clinical features of central airway involvement in autoimmune pancreatitis.

To the Editors: Autoimmune pancreatitis (AIP) is characterised by a high serum immunoglobulin (Ig)G4 concentration and various extrapancreatic complications, including those of the lung [1]. Therefore, AIP is currently not viewed as a separate disease entity, but as the pancreatic involvement of a systemic IgG4-related disease [2]. We previously reported a patient with AIP showing central airway stenosis and bilateral hilar lymphadenopathy (BHL) similar to sarcoidosis [3]. Following this case, we prospectively identified an additional five patients with AIP who revealed similar airway findings (and BHL) in our department from September 2007 to January 2009. The six patients (including the first patient) met the diagnostic criteria of AIP proposed by Japanese Pancreatic Society in 2006 [1]. In order to update the available clinical and therapeutic information on central airway involvement in AIP, we performed airway biopsies and other examinations in these six patients. All six patients gave their written informed consent for the performance of bronchoscopy and blood sampling. The angiotensin-converting enzyme (ACE) and IgG4 concentrations were measured at Special Reference Laboratories Inc. (Tokyo, Japan), and interleukin (IL)-6 was measured at Mitsubishi Kagaku Bio-Clinical Laboratories Inc. (Tokyo, Japan). Chest computed tomography (CT) was performed with a multidetector row helical CT scanner (LightSpeed VCT; GE Medical Systems, Milwaukee, WI, USA) with both inspiratory and expiratory views [4]. All CT images were reviewed by two radiologists (S. Kawakami and Y. Fujinaga, Shinshu University School of Medicine, Matsumoto, Japan) [4]. Fibreoptic bronchoscopy (BF 1T-240 or 1T-260; Olympus corporation, Tokyo, Japan) was performed, and bronchoalveolar lavage (BAL), transbronchial lung biopsy (TBLB) and bronchial biopsy were achieved according to our routine protocol [5]. The TBLB was carried out in the right upper lobe (S2 and S3) and the bronchial biopsy …

A case of severe ARDS caused by novel swine-origin influenza (A/H1N1pdm) virus: A successful treatment with direct hemoperfusion with polymyxin B-immobilized fiber

In 2009, a 35‐year‐old female with Down syndrome was admitted to our hospital because of severe pneumonia caused by an infection with the novel swine‐origin influenza (A/H1N1pdm) virus (S‐OIV). A chest X‐ray on admission revealed bilateral infiltration shadows. Although mechanical ventilation was administered because of the development of ARDS, the hypoxemia continued to progressed. We observed evidence of alveolar hemorrhage on evaluation of the patient using bronchofiberscopy. The bacterial examination was negative. Despite intensive care, including respiratory management with high‐frequency oscillatory ventilation (HFOV), the patients hypoxemia and hypotension progressed. We concluded that a cytokine storm due to the influenza infection with SIRS caused shock status, resulting in septic shock. We subsequently treated the patient with direct hemoperfusion with polymyxin B‐immobilized fiber (PMX‐DHP). The hypoxemia improved immediately. She was free from mechanical ventilation and discharged from the hospital by the 17th day of her hospitalization. PMX‐DHP seems to improve hypoxemia in patients with severe ARDS who cannot maintain sufficient respiratory control under mechanical ventilation. This case is the first report about severe and life‐threatening ARDS due to the novel influenza, in which PMX‐DHP showed beneficial effects. J. Clin. Apheresis 2010.