An observational cohort study of interstitial lung abnormalities (ILAs) in a large Japanese health screening population (Kumamoto ILA study in Japan: KILA-J).

BACKGROUND: Interstitial lung abnormalities (ILAs) are subtle or mild parenchymal abnormalities observed in more than 5% of the lungs on computed tomography (CT) scans in patients in whom interstitial lung disease was not previously clinically suspected and is considered. ILA is considered to be partly undeveloped stages of idiopathic pulmonary fibrosis (IPF) or progressive pulmonary fibrosis (PPF). This study aims to clarify the frequency of subsequent IPF or PPF diagnosis, the natural course from the preclinical status of the diseases, and the course after commencing treatment. METHODS: This is an ongoing, prospective, multicentre observational cohort study of patients with ILA referred from general health screening facilities with more than 70,000 annual attendances. Up to 500 participants will be enrolled annually over 3 years, with 5-year assessments every six months. Treatment intervention including anti-fibrotic agents will be introduced in disease progression cases. The primary outcome is the frequency of subsequent IPF or PPF diagnoses. Additionally, secondary and further endpoints are associated with the efficacy of early therapeutic interventions in cases involving disease progression, including quantitative assessment by artificial intelligence. DISCUSSION: This is the first prospective, multicentre, observational study to clarify (i) the aetiological data of patients with ILA from the largest general health check-up population, (ii) the natural course of IPF or PPF from the asymptomatic stage, and (iii) the effects and outcomes of early therapeutic intervention including anti-fibrotic agents for progressive cases of ILA. The results of this study could significantly impact the clinical practice and treatment strategy for progressive fibrosing interstitial lung diseases. TRIAL REGISTRATION NUMBER: UMIN000045149.

Serum surfactant protein D as a predictive biomarker for the efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis: a post-hoc analysis of the phase 3 trial in Japan.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease course. The recent advancement of antifibrotic therapy has increased the need for reliable and specific biomarkers. This study aimed to assess alveolar epithelial biomarkers as predictors for the efficacy of the antifibrotic drug pirfenidone. METHODS: We conducted a post-hoc analysis of the prospective, multicenter, randomized, placebo-controlled, phase 3 trial of pirfenidone in Japan (total, n = 267; pirfenidone, n = 163; placebo, n = 104). Logistic regression analysis was performed to extract parameters that predicted disease progression, defined by a ≥ 10% relative decline in vital capacity (VC) from baseline and/or death, at week 52. For assessment of serum surfactant protein (SP)-D, SP-A and Krebs von den Lungen (KL)-6, all patients were dichotomized by the median concentration of each biomarker at baseline to the high and low biomarker subgroups. Associations of these concentrations were examined with changes in VC at each time point from baseline up to week 52, along with progression-free survival (PFS). Additionally, the effect of pirfenidone treatment on serial longitudinal concentrations of these biomarkers were evaluated. RESULTS: In the multivariate logistic regression analysis, body mass index (BMI), %VC and SP-D in the pirfenidone group, and BMI and %VC in the placebo group were indicated as predictors of disease progression. Pirfenidone treatment reduced the decline in VC with statistical significance in the low SP-D and low SP-A subgroups over most of the treatment period, and also prolonged PFS in the low SP-D and low KL-6 subgroups. Furthermore, SP-D levels over time course were reduced in the pirfenidone group from as early as week 8 until the 52-week treatment period compared with the placebo group. CONCLUSIONS: Serum SP-D was the most consistent biomarker for the efficacy of pirfenidone in the cohort trial of IPF. Serial measurements of SP-D might have a potential for application as a pharmacodynamic biomarker. Trial registration The clinical trial was registered with the Japan Pharmaceutical Information Center (JAPIC) on September 13, 2005 (registration No. JapicCTI-050121; http://Clinicaltrials.jp ).

Monocyte count and the risk for acute exacerbation of fibrosing interstitial lung disease: A retrospective cohort study.

Recent studies have suggested that an increased peripheral monocyte count predicts a poor outcome in fibrosing interstitial lung disease (ILD). However, the association between an increased monocyte count and acute exacerbations (AEs) of fibrosing ILD remains to be elucidated. Our retrospective cohort study aimed to assess the impact of peripheral monocyte count on AEs of fibrosing ILD. We analyzed the electronic medical records of 122 consecutive patients with fibrosing ILD and no prior history of an AE, who were treated with anti-fibrotic agents from August 2015 to December 2018. We determined their peripheral monocyte counts at anti-fibrotic agent initiation and performed univariate and multivariate Cox regression analyses of time-to-first AE after anti-fibrotic agent initiation to assess the impact of monocyte count on AEs of fibrosing ILD. Twenty-six patients developed an AE during the follow-up period, and there was an increased monocyte count at anti-fibrotic agent initiation in these patients compared to those who did not develop an AE. There was also a significantly shorter time-to-first AE of fibrosing ILD in patients with a higher absolute monocyte count. Subgroup analyses indicated similar results regardless of the idiopathic pulmonary fibrosis diagnoses. This association was independently significant after adjusting for the severity of the fibrosing ILD. Using our results, we developed a simple scoring system consisting of two factors-monocyte count (<>380 µL-1) and ILD-gender, age, physiology score (<>4 points). Our findings suggest that the absolute monocyte count is an independent significant risk factor for AE in patients with fibrosing ILD. Our simple scoring system may be a predictor for AEs of fibrosing ILD, although further studies are needed to verify our findings.

Acute exacerbation of chronic fibrosing interstitial pneumonia in patients receiving antifibrotic agents: incidence and risk factors from real-world experience.

BACKGROUND AND OBJECTIVE: Here, we present real-world data on the incidence and risk factors of acute exacerbation (AE) in patients with chronic fibrotic interstitial pneumonia (CFIP) treated with antifibrotic agents, which has been previously poorly documented. METHODS: We retrospectively examined clinical characteristics, incidence and risk factors of AE in a cohort of 100 patients with CFIP (n = 75, idiopathic pulmonary fibrosis [IPF]; n = 25, other conditions), all of whom received antifibrotic agents in a real-world setting. RESULTS: The median follow-up was 17.4 months (interquartile range [IQR], 6.6 to 26.7 months). During the follow-up periods, 21 patients experienced AE after starting antifibrotic agents. The estimated 1-, 2-, and 3-year AE incidence rates were 11.4% (95% confidence interval [95%CI], 6.2-20.3%), 32% (95%CI, 20.7-47.4%), and 36.3% (95%CI 23.5-53.1%), respectively. Decreased baseline lung function (forced vital capacity and carbon monoxide diffusing capacity of the lung), existence of pulmonary hypertension estimated from an echocardiogram, higher Interstitial Lung Disease-Gender, Age, and Physiology (ILD-GAP) score, supplementary oxygen, and concomitant corticosteroid and proton-pump inhibitor (PPI) use upon starting the antifibrotic agent were risk factors of AE. Concomitant corticosteroid and PPI use and corticosteroid dose were risk factor of AE in a multivariate Cox regression hazard model adjusting for ILD-GAP score. CONCLUSION: AE of CFIP is more common in patients with physiologically and functionally advanced disease under antifibrotic agents. Prudent use of corticosteroids and PPIs when initiating antifibrotic agents may be recommended. Further studies are warranted.

The negative effect of initial high-dose methylprednisolone and tapering regimen for acute respiratory distress syndrome: a retrospective propensity matched cohort study.

BACKGROUND: The efficacy of corticosteroid use in acute respiratory distress syndrome (ARDS) remains controversial. Generally, short-term high-dose corticosteroid therapy is considered to be ineffective in ARDS. On the other hand, low-dose, long-term use of corticosteroids has been reported to be effective since they provide continued inhibition of the systemic inflammatory response syndrome (SIRS) that accompanies ARDS. Thus far, no reports have been published on the efficacy of initiating treatment with a high-dose corticosteroid regimen with tapering. METHODS: We conducted a retrospective observational study involving 186 patients treated at a teaching hospital (68% had sepsis, pneumonia, or aspiration pneumonia). ARDS was diagnosed according to the Berlin definition. Patients were divided into a high-dose (n = 21) or low-dose corticosteroid group (n = 165) to compare the effectiveness of a down-titration regimen. The primary medical team chose which treatment a patient would receive. We were careful to conduct a differential diagnosis of interstitial pneumonia (e.g., acute eosinophilic pneumonia) since corticosteroid treatment has been proven effective in that patient population. The primary outcome was the 60-day mortality rate. The secondary outcome was the number of ventilator-free days (VFD). RESULTS: Those started on a high-dose regimen had a significantly higher 60-day mortality rate (P = 0.031) with significantly fewer VFD (P = 0.021). Propensity scores were used to adjust patient backgrounds in a variable analysis that also showed the high-dose regimen was a factor in decreasing VFD (OR, 95.63; 95% CI, 1.74-5271.07; P = 0.026) and worsening the 60-day mortality rate (OR, 2.54; 95% CI, 0.92-7.02; P = 0.072). CONCLUSIONS: A tapering regimen after high-dose corticosteroids is likely to increase ventilator dependency and might aggravate the prognosis of patients with ARDS diagnosed according to the Berlin definition.

Azithromycin for idiopathic acute exacerbation of idiopathic pulmonary fibrosis: a retrospective single-center study.

BACKGROUND: Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is a fatal condition without an established pharmaceutical treatment. Most patients are treated with high-dose corticosteroids and broad-spectrum antibiotics. Azithromycin is a macrolide with immunomodulatory activity and may be beneficial for treatment of acute lung injury. The objective of this study was to determine the effect of azithromycin on survival of patients with idiopathic AE of IPF. METHODS: We evaluated 85 consecutive patients hospitalized in our department for idiopathic AE of IPF from April 2005 to August 2016. The initial 47 patients were treated with a fluoroquinolone-based regimen (control group), and the following 38 consecutive patients were treated with azithromycin (500 mg/day) for 5 days. Idiopathic AE of IPF was defined using the criteria established by the 2016 International Working Group. RESULTS: Mortality in patients treated with azithromycin was significantly lower than in those treated with fluoroquinolones (azithromycin, 26% vs. control, 70%; p < 0.001). Multivariate analysis revealed that the two variables were independently correlated with 60-day mortality as determined by the Acute Physiology and Chronic Health Evaluation II score (p = 0.002) and azithromycin use (p < 0.001). CONCLUSION: Azithromycin may improve survival in patients with idiopathic AE of IPF.

Efficacy of azithromycin for treatment of acute exacerbation of chronic fibrosing interstitial pneumonia: a prospective, open-label study with historical controls.

BACKGROUND: Acute exacerbation of chronic fibrosing interstitial pneumonia (AE-CFIP) is an often fatal condition with no established treatment. Recently, macrolides were found to be beneficial in cases of acute lung injury. OBJECTIVES: To examine the clinical effectiveness and safety of intravenous azithromycin in patients hospitalized for AE-CFIP. METHODS: A prospective, open-label study with historical controls was conducted. Twenty consecutive patients with AE-CFIP received azithromycin. They were compared with a historical cohort treated with fluoroquinolone (n = 56). All patients received high-dose steroid pulse therapy. The primary end point was mortality at 60 days. The secondary end point was safety of intravenous azithromycin in patients with AE-CFIP. Inverse probability of treatment weighting (IPTW) using the propensity score was performed to investigate the relationship between azithromycin use and survival time. RESULTS: Mortality was significantly lower in the patients treated with azithromycin than in those treated with fluoroquinolone (mortality rate at 60 days: 20 vs. 69.6%, p < 0.001; median survival time: not reached vs. 29.5 days, p < 0.001). The IPTW adjusted hazard of mortality at 60 days in patients receiving azithromycin was 0.17 (95% CI 0.05-0.61). No serious adverse events were observed. CONCLUSIONS: Azithromycin was associated with improved outcomes in patients with AE-CFIP. Further studies are needed to verify this finding (Clinical trial JMA-IIA00095).

Lung miliary micro-nodules in human T-cell leukemia virus type I carriers.

Human T-cell leukemia virus type 1 (HTLV-1) carriers are rarely subject to inflammatory disorders in multiple organs, other than the well-known complication, adult T-cell leukemia/lymphoma (ATLL). HTLV-1 associated bronchiolo-alveolar disorder (HABA) has been proposed as an immune mediated pulmonary reaction seen rarely in HTLV-1 carriers. The reported clinico-pathological patterns of HABA are diffuse panbronchiolitis (DPB) and lymphoid interstitial pneumonia (LIP). We here report three cases of HTLV-1 carriers showing miliary micro-nodules throughout both lungs. Microscopic examination in the video assisted thoracic surgery biopsies demonstrated that all cases had multiple discrete micro-nodules which consisted of marked lymphoid infiltration, granulomas, eosinophils and a few foci of necrosis inside the granuloma. No findings indicating ATLL, other neoplastic conditions, infection or interstitial pneumonia, including DPB and LIP, were present following panels of special staining and immunohistochemical examinations. Two patients improved without treatment within one month, with no evidence of recurrence after 7 years. One patient showed slow deterioration of lung reticular shadows in spite of a low dose corticosteroid therapy (prednisolone 10 mg/day). We believe these cases may be a newly recognized variant of HABA.

The ROX index (Index combining the respiratory rate with oxygenation) is a prognostic factor for acute respiratory distress syndrome.

BACKGROUND: There is no existing reliable and practical method for predicting the prognosis of acute respiratory distress syndrome (ARDS). OBJECTIVE: We aimed to clarify the association between the ROX index, which is calculated as the ratio of peripheral oxygen saturation divided by the fraction of inspired oxygen to the respiratory rate, and the prognosis of patients with ARDS under ventilator support. METHODS: In this single-center retrospective cohort study from prospectively collected database, eligible patients were categorized into three groups based on ROX tertiles. The primary outcome was the 28-day survival, and the secondary outcome was 28-day liberation from ventilator support. We performed multivariable analysis using the Cox proportional hazards model. RESULTS: Among 93 eligible patients, 24 (26%) patients died. The patients were divided into three groups according to the ROX index (< 7.4, 7.4-11, ≥ 11), with 13, 7, and 4 patients dying in the groups, respectively. A higher ROX index was associated with lower mortality; adjusted hazard ratios [95% CIs] for increasing tertiles of ROX index: 1[reference], 0.54[0.21-1.41], 0.23[0.074-0.72] (P = 0.011 for trend) and a higher rate of successful 28-day liberation from ventilator support; adjusted hazard ratios [95% CIs] for increasing tertiles of ROX index: 1[reference], 1.41[0.68-2.94], 2.80[1.42-5.52] (P = 0.001 for trend). CONCLUSIONS: The ROX index at 24 h after initiating ventilator support is a predictor of outcomes in patients with ARDS and might inform initiation of more advanced treatments.

Pneumocyte biomarkers KL-6 and surfactant protein D reflect the distinct findings of high-resolution computed tomography in nonspecific interstitial pneumonia.

BACKGROUND: Serum levels of pneumocyte biomarkers KL-6 and surfactant protein D (SP-D) are useful diagnostic markers for interstitial lung diseases. However, associations of serum KL-6 and SP-D with radiologic findings in nonspecific interstitial pneumonia (NSIP) remain unclear. OBJECTIVES: To determine whether serum levels of KL-6 and SP-D reflect fibrotic and/or inflammatory processes in NSIP, we investigated the correlation between high-resolution computed tomography (HRCT) findings and serum KL-6 and SP-D levels. METHODS: Serum levels of KL-6 and SP-D were measured in 21 patients with biopsy-confirmed NSIP. The radiographic extent of 6 HRCT patterns and total HRCT score, defined as the scored fibrotic index, were assessed. Changes in the levels of serum markers and CT findings during follow-up were also monitored. RESULTS: Serum levels of KL-6 in NSIP positively correlated with the total HRCT score and overall extent of interstitial disease. Serum levels of SP-D in NSIP showed a positive correlation with the area of ground-glass attenuation without traction bronchiectasis and the inflammatory CT pattern, but the levels were inversely correlated with the area of ground-glass attenuation with traction bronchiectasis and the fibrotic CT pattern. The follow-up CT and serum marker changes after treatment showed that percent change of disease extent was reflected in both markers, especially KL-6. Further, the decreased fibrotic pattern correlated with both biomarkers. CONCLUSIONS: The results indicate that serum levels of KL-6 in NSIP reflect the overall extent of interstitial lesions, which include both inflammatory and fibrotic lesions, while the levels of SP-D mainly reflect the extent of inflammatory lesions.

The clinical significance of 5% change in vital capacity in patients with idiopathic pulmonary fibrosis: extended analysis of the pirfenidone trial.

BACKGROUND: Our phase III clinical trial of pirfenidone for patients with idiopathic pulmonary fibrosis (IPF) revealed the efficacy in reducing the decline of vital capacity (VC) and increasing the progression-free survival (PFS) time by pirfenidone. Recently, marginal decline in forced VC (FVC) has been reported to be associated with poor outcome in IPF. We sought to evaluate the efficacy of pirfenidone from the aspects of 5% change in VC. METHODS: Improvement ratings based on 5% change in absolute VC, i.e., "improved (VC ≥ 5% increase)", "stable (VC < 5% change)", and "worsened (VC ≥ 5% decrease)" at month 3, 6, 9 and 12 were compared between high-dose pirfenidone (1800 mg/day; n = 108) and placebo (n = 104) groups, and (high-dose and low-dose (1200 mg/day; n = 55)) pirfenidone (n = 163) and placebo groups. PFS times with defining the disease progression as death or a ≥ 5% decline in VC were also compared between high-dose pirfenidone and placebo groups, and low-dose pirfenidone and placebo groups. Furthermore, considering "worsened" and "non-worsened (improved and stable)" of the ratings at months 3 and 12 as "positive" and "negative", respectively, and the positive and negative predictive values of the ratings were calculated in each group. RESULTS: In the comparison of the improvement ratings, the statistically significant differences were clearly revealed at months 3, 6, 9, and 12 between pirfenidone and placebo groups. Risk reductions by pirfenidone to placebo were approximately 35% over the study period. In the comparison of the PFS times, statistically significant difference was also observed between pirfenidone and placebo groups. The positive/negative predictive values in placebo and pirfenidone groups were 86.1%/50.8% and 87.1%/71.7%, respectively. Further, the baseline characteristics of patients worsened at month 3 had generally severe impairment, and their clinical outcomes including mortality were also significantly worsened after 1 year. CONCLUSIONS: The efficacy of pirfenidone in Japanese phase III trial was supported by the rating of 5% decline in VC, and the VC changes at month 3 may be used as a prognostic factor of IPF. TRIAL REGISTRATION: This clinical trial was registered with the Japan Pharmaceutical Information Center (JAPIC) on September 13th, 2005 (REGISTRATION NUMBER: JAPICCTI-050121).

Exploratory analysis of a phase III trial of pirfenidone identifies a subpopulation of patients with idiopathic pulmonary fibrosis as benefiting from treatment.

BACKGROUND: A phase III trial in Japan showed that pirfenidone is effective for idiopathic pulmonary fibrosis (IPF). To find out which patients specifically benefit from pirfenidone, we analyzed in an exploratory manner the data from the phase III trial. METHODS: The patients in the phase III trial were stratified by baseline percentage predicted vital capacity (%VC), arterial oxygen partial pressure (PaO(2)), and the lowest oxygen saturation by pulse oximetry (SpO(2)) during the 6-minute steady-state exercise test (6MET). In the subpopulations, changes in VC and subjective symptoms (cough and dyspnea on the Fletcher, Hugh-Jones [F, H-J] Classification scale) were evaluated in patients treated with high-dose (1800 mg/day) pirfenidone, low-dose (1200 mg/day) pirfenidone, and placebo at week 52. RESULTS: Significant efficacy of pirfenidone in reducing the decline in VC could be seen in a subpopulation having %VC ≥ 70% and SpO(2) < 90% at baseline. This favorable effect was accompanied by categorical change in VC and progression-free survival time. In the subpopulation, pirfenidone significantly suppressed cough and dyspnea. CONCLUSIONS: IPF patients having %VC ≥ 70% and SpO(2) < 90% at baseline will most likely benefit from pirfenidone when evaluated using changes in VC (and %VC), and cough and dyspnea symptoms. This subpopulation could expect to benefit most from pirfenidone treatment. TRIAL REGISTRATION: This clinical trial was registered with the Japan Pharmaceutical Information Center (JAPIC) on September 13th, 2005 (REGISTRATION NUMBER: JAPICCTI-050121).

Clinical phenotypes from fatal cases of acute respiratory distress syndrome caused by pneumonia.

There have been no report of objective clinical characteristics or prognostic factors that predict fatal outcome of acute respiratory distress syndrome (ARDS) since the Berlin definition was published. The aim of this study is to identify clinically available predictors that distinguish between two phenotypes of fatal ARDS due to pneumonia. In total, 104 cases of Japanese patients with pneumonia-induced ARDS were extracted from our prospectively collected database. Fatal cases were divided into early (< 7 days after diagnosis) and late (≥ 7 days) death groups, and clinical variables and prognostic factors were statistically evaluated. Of the 50 patients who died within 180 days, 18 (36%) and 32 (64%) were in the early (median 2 days, IQR [1, 5]) and late (median 16 days, IQR [13, 29]) death groups, respectively. According to multivariate regression analyses, the APACHE II score (HR 1.25, 95%CI 1.12-1.39, p < 0.001) and the disseminated intravascular coagulation score (HR 1.54, 95%CI 1.15-2.04, p = 0.003) were independent prognostic factors for early death. In contrast, late death was associated with high-resolution computed tomography (HRCT) score indicating early fibroproliferation (HR 1.28, 95%CI 1.13-1.42, p < 0.001) as well as the disseminated intravascular coagulation score (HR 1.24, 95%CI 1.01-1.52, p = 0.039). The extent of fibroproliferation on HRCT, and the APACHE II scores along with coagulation abnormalities, should be considered for use in predictive enrichment and personalized medicine for patients with ARDS due to pneumonia.

[Solid malignancy in patients who received cyclosporine for fibrosing interstitial pneumonia].

OBJECTIVE: Since more solid malignancies are observed in transplant recipients treated with cyclosporine (CsA) than in healthy persons. We sought to describe the incidence of malignancy in patients treated with CsA for fibrosing interstitial pneumonia. METHODS: We prospectively reviewed 43 patients who received CsA and prednisolone for fibrosing interstitial pneumonia over 180 days at our hospital between April 2004 and October 2008. The duration of CsA treatment was 632 +/- 364 days. RESULTS: Malignancy developed in 6 (14.0%) patients. Time to diagnosis after medical intervention ranged from 394 days to 1325 days (mean, 783 days). Non-small cell lung cancer was diagnosed in 4 cases. These were discovered by routine computed tomography in all cases. Hepatocellular carcinoma and gastric cancer were each diagnosed in 1 case, respectively. Incidence of malignancy tended to be higher in patients who had been treated with CsA for 567 days or more than in those who had been treated for less than 567 days, but this was not statistically significant. CONCLUSION: Our results highlight the need for close follow-up for patients who receive CsA for over 2 years. This could lead to cancer detection at an early stage.

Computed tomography findings in pathological usual interstitial pneumonia: relationship to survival.

RATIONALE: Patients with a clinicopathological diagnosis of idiopathic pulmonary fibrosis (IPF) may have typical findings of usual interstitial pneumonia (UIP) on computed tomography (CT) or nonspecific or atypical findings, including those often seen in nonspecific interstitial pneumonia. OBJECTIVES: The aims of this study were to revisit the high-resolution CT findings of IPF and to clarify the correlation between the CT findings and mortality. METHODS: The study included 98 patients with a histologic diagnosis of UIP and a clinical diagnosis of IPF. Two observers evaluated the CT findings independently and classified each case into one of the following three categories: (1) definite UIP, (2) consistent with UIP, or (3) suggestive of alternative diagnosis. The correlation between the CT categories and mortality was evaluated using the Kaplan-Meier method and the log-rank test, as well as Cox proportional hazards regression models. MEASUREMENTS AND MAIN RESULTS: Thirty-three of the 98 CT scans were classified as definite UIP, 36 as consistent with UIP, 29 as suggestive of an alternative diagnosis. The mean survival was 45.7, 57.9, and 76.9 months, respectively. There was no significant difference in survival among the three categories (all P > 0.05). Traction bronchiectasis and fibrosis scores were significant predictors of outcome (hazard ratios: 1.30 and 1.10, respectively; 95% confidence intervals: 1.18-14.2 and 1.03-1.19, respectively). CONCLUSIONS: In patients with IPF and UIP pattern on the biopsy, the pattern of abnormality on thin-section CT, whether characteristic of UIP or suggestive of alternative diagnosis, does not influence prognosis. Prognosis is influenced by traction bronchiectasis and fibrosis scores.

Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study.

RATIONALE: Interstitial lung disease (ILD) occurs in Japanese patients with non-small cell lung cancer (NSCLC) receiving gefitinib. OBJECTIVES: To elucidate risk factors for ILD in Japanese patients with NSCLC during treatment with gefitinib or chemotherapy. METHODS: In a prospective epidemiologic cohort, 3,166 Japanese patients with advanced/recurrent NSCLC were followed for 12 weeks on 250 mg gefitinib (n = 1,872 treatment periods) or chemotherapy (n = 2,551). Patients who developed acute ILD (n = 122) and randomly selected control subjects (n = 574) entered a case-control study. Adjusted incidence rate ratios were estimated from case-control data by odds ratios (ORs) with 95% confidence intervals (CIs) using logistic regression. Crude (observed) incidence rates and risks were calculated from cohort data. MEASUREMENTS AND MAIN RESULTS: The observed (unadjusted) incidence rate over 12 weeks was 2.8 (95% CI, 2.3-3.3) per 1,000 person-weeks, 4.5 (3.5-5.4) for gefitinib versus 1.7 (1.2-2.2) for chemotherapy; the corresponding observed naive cumulative incidence rates at the end of 12-week follow-up were 4.0% (3.0-5.1%) and 2.1% (1.5-2.9%), respectively. Adjusted for imbalances in risk factors between treatments, the overall OR for gefitinib versus chemotherapy was 3.2 (1.9-5.4), elevated chiefly during the first 4 weeks (3.8 [1.9-7.7]). Other ILD risk factors in both groups included the following: older age, poor World Health Organization performance status, smoking, recent NSCLC diagnosis, reduced normal lung on computed tomography scan, preexisting chronic ILD, concurrent cardiac disease. ILD-related deaths in patients with ILD were 31.6% (gefitinib) versus 27.9% (chemotherapy); adjusted OR, 1.05 (95% CI, 0.3-3.2). CONCLUSIONS: ILD was relatively common in these Japanese patients with NSCLC during therapy with gefitinib or chemotherapy, being higher in the older, smoking patient with preexisting ILD or poor performance status. The risk of developing ILD was higher with gefitinib than chemotherapy, mainly in the first 4 weeks.

A Scoring System with High-Resolution Computed Tomography to Predict Drug-Associated Acute Respiratory Distress Syndrome: Development and Internal Validation.

Drugs can cause acute respiratory distress syndrome (ARDS). However, there is no established clinical prediction rule for drug-associated ARDS (DARDS). We aimed to develop and validate a scoring system for DARDS prediction. We analysed data collected from a prospective, single-centre, cohort study that included ARDS patients. The ARDS diagnosis was based on the American-European Consensus Conference or Berlin definition. Drug-associated acute lung injury (DALI) was defined as previous exposure to drugs which cause ALI and presence of traditional risk factors for ALI. High-resolution computed tomography (HRCT; indicating extent of lung damage with fibroproliferation), Acute Physiology and Chronic Health Evaluation (APACHE) II, and disseminated intravascular coagulation (DIC; indicating multiorgan failure) scores and PaO2/FiO2 were evaluated for their ability to predict DARDS. Twenty-nine of 229 patients had DARDS. The HRCT, APACHE II, and DIC scores and PaO2/FiO2 were assessed. The model-based predicted probability of DARDS fitted well with the observed data, and discrimination ability, assessed through bootstrap with an area under the receiver-operating curve, improved from 0.816 to 0.875 by adding the HRCT score. A simple clinical scoring system consisting of the APACHE II score, PaO2/FiO2, and DIC and HRCT scores can predict DARDS. This model may facilitate more appropriate clinical decision-making.

[Granulomatous diseases and pathogenic microorganism].

Granuloma formation is a chronic inflammatory reaction where macrophage system and other inflammatory cells are involved. After some antigen exposure and processing, T cells, macrophages, epithelioid cells, and giant cell are activated, and granulomas are formed. Granuloma is considered as a defense mechanism against antigens, which stay in the organs without inactivation. Granulomas including fibroblasts extra-cellular matrix surround and isolate the antigens. Granulomas are classified to noninfectious granulomas and infectious granulomas. However recent studies revealed pathogenic microorganism are suspected to be a cause of granuloma in non-inflammatory diseases. Balance between pathogenic microorganisms and defense mechanisms of the host might be important in the special immunologic reaction. In some cases, it is hard to clearly classify infectious and noninfectious granulomas. Recently, Eishi et al. reported that latent infection of Propionibacterium acnes might be cause of sarcoidosis. Several hypersensitivity pneumonias are considered to be caused by exogenous microorganisms. The symposium was organized to know and clarify the new mechanisms of non-infectious granulomatous lung diseases and pathogenic microorganisms. This report is a summary of a symposium entitled "Granulomatous Diseases and Pathogenic Microorganism", organized in the 82nd Japanese Society for Tuberculosis (president Dr. Mitsunori Sakatani, M.D.). 1. Imaging of Granulomatous Lung Diseases: Masanori AKIRA (Department of Radiology, National Hospital Organization Kinki-chuo Chest Medical Center) High-resolution computed tomography (HRCT) is a useful tool in the evaluation of parenchymal changes in patients with a granulomatous lung disease. In sarcoidosis, the HRCT findings include small, well-defined nodules in relation to lymphatic roots, lymph node enlargement, and middle or upper lobe predominance. The appearances of subacute hypersensitivity pneumonitis include ill-defined centrilobular nodules, ground-glass opacity, and air trapping especially on expiratory CT scan. Those of Langerhans cell histiocytosis include bizarre thin-walled lung cysts, centrilobular nodules and upper lobe predominance. Each of granulomatous lung disease has some characteristic HRCT appearances, but they all are non-specific for diagnosis. HRCT is also useful for grading of parenchymal changes in granulomatous lung diseases. 2. Histopathology of granulomatous lung diseases with special reference to differential diagnosis of infectious disease: Tamiko TAKEMURA (Department of Pathology, Japanese Red Cross Medical Center) The lung is commonly involved by various granulomatous diseases of various etiology. It is difficult to pathologically differentiate these granuloumatous diseases to conduct appropriate therapy, because of morphological similarity of epithelioid cell granuloma, variable etiology, and difficulty of identification of causative agents. Granulomatous diseases generally are divided into infectious and non-infectious ones for treatment. Although infectious granulomas usually reveal necrosis and abscess, non-infectious ones occasionally also reveal necrosis. In cases with granulomas in the lung, it is necessary to explore the etiologic agents including environmental ones. 3. Sarcoidosis and Propionibacterium acnes: Yoshinobu EISHI (Department of Pathology, Tokyo Medical and Dental University) P. acnes can cause latent infection in peripheral lung tissue and the mediastinal lymph nodes and persist intracellularly in a cell-wall-deficient form. This dormant form of P. acnes can be activated endogenously under certain environmental conditions (hormones, stress, living habits, etc.) and proliferate in cells at the sites of latent infection. Granulomatous inflammation occurs in sarcoidosis patients with hypersensitivity to intracellular proliferation of the cell-wall-deficient bacteria, which can infect other cells or organs when spread via the lymphatic or blood streams. The timely use of antibiotics may not only kill the bacteria proliferating at the site of disease activity, but also prevent endogenous activation of P. acnes. If long term administration of antibiotics eradicates dormant forms of the bacteria persistent in organs, it may lead to complete remission of sarcoidosis. 4. Farmer's lung and thermophilic actinomycetes: Takashi MOURI (Pulmonary Division, Iwate Prefectural Kitakami Hospital), Kohei YAMAUCHI, Hiroshi INOUE (Third Department of Internal Medicine, Iwate Medical University, School of Medicine), Kazuki KONISHI (Morioka Tsunagi Onsen Hospital) Farmer's lung is caused by the allergic reaction to inhalation of thermophilic actinomycetes. Acute symptoms are chill, fever, cough and dyspnea. Fine crackles is characteristic. Pathologically, alveolitis with lymphocytes infiltration and epithelioid cell granuloma and Masson's body are characteristics. Bronchoalveolar lavage analysis shows elevated lymphocytes and diverse CD4/8 ratio (high in average). Isolation from the environment improves the symptoms. Sometimes patients need steroid therapy, 0.5 to 1.0 mg/kg of predonisolone. Pulse therapy can be applied for severe cases. SLX analogue can prevent lymphocytes infiltration and granuloma formation in mice model. Some of acute farmer's lung show poor long term prognosis, showing emphysematous, fine granular or small nodules in chest CT. These chronic farmer's lung might be diagnosed as IIPs. 5. Hot tub lung: Takashi OGURA (Kanagawa Cardiovascular and Respiratory Center) Hot Tub Lung (HTL) is a disorder caused by exposure to Mycobacterium avium complex (MAC) organisms contaminating hot tub water. Whether this disease represents true infection or hypersensitivity pneumonitis is contoroversial. Recent reports support the theory that this disease represents a hypersensitivity pneumonitis rather than infection. The physicians should suspect a hypersensitivity pneumonitis reaction to MAC in the investigation of patients with hypersensitivity pneumonitis of unknown cause.

Clinical differences between pulmonary and extrapulmonary acute respiratory distress syndrome: a retrospective cohort study of prospectively collected data in Japan.

BACKGROUND: Although acute respiratory distress syndrome (ARDS) reportedly shows various clinical phenotypes with different risk and prognostic factors, few studies have assessed the clinical features and prognosis of pulmonary and extrapulmonary ARDS. The aim of the present study was to investigate clinical differences between pulmonary and extrapulmonary ARDS. METHODS: In total, 200 patients who met the Berlin criteria and were diagnosed with ARDS between October 2004 and September 2017 were included. We classified the patients into pulmonary and extrapulmonary ARDS groups. Both groups were assessed for 60-day mortality, duration of ventilation, and other clinical features. RESULTS: There were 150 and 50 patients in the pulmonary and extrapulmonary ARDS groups, respectively. The two groups showed no significant differences in any assessment parameters except the serum lactate dehydrogenase (LDH) level, which was higher in the extrapulmonary ARDS group (P=0.01). After adjustment for potentially confounding covariates, there were no significant differences in 60-day mortality (P=0.99) and the duration of ventilation (P=0.45) between the two groups. Mortality was significantly associated with the disseminated intravascular coagulation (DIC) score, high-resolution computed tomography (HRCT) score, and serum LDH level in the pulmonary ARDS group and the DIC score and HRCT score in the extrapulmonary ARDS group. CONCLUSIONS: Pulmonary and extrapulmonary ARDS may be comparable in terms of the prognosis and duration of ventilation. DIC and HRCT scores may be common clinical predictors of mortality with ARDS.

Adjunctive therapy with azithromycin for moderate and severe acute respiratory distress syndrome: a retrospective, propensity score-matching analysis of prospectively collected data at a single center.

Effective pharmacological therapy has not been established for patients with acute respiratory distress syndrome (ARDS). Macrolides are antibiotics with potent immunomodulatory and anti-inflammatory effects that may be beneficial in ARDS treatment. The objective of this study was to determine the adjunctive effect of azithromycin on survival for patients with ARDS. This single-center, retrospective cohort evaluation of hospitalized patients with moderate or severe ARDS was conducted to assess the impact of intravenous azithromycin on clinical outcomes using a propensity score analysis. All data were collected prospectively as part of ongoing research on the utility of high-resolution computed tomography in ARDS. The primary outcome was 90-day mortality, and the secondary analysis assessed the effect of azithromycin on time to successful discontinuation of mechanical ventilation and 28-day mortality. Of 191 eligible patients with severe or moderate ARDS, 62 were treated with azithromycin. The 62 patients treated with azithromycin and 62 not treated with azithromycin were matched and analysed. Azithromycin use was associated with a statistically significant improvement in 90-day survival rate (Hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.27-0.87; P = 0.015) and a shorter time to successful discontinuation of mechanical ventilation (HR, 1.74; 95% CI, 1.07-2.81; P = 0.026). The 28-day mortality rate tended to be higher in the azithromycin cohort than in the non-azithromycin cohort, but this was not statistically significant. Adjunctive intravenous azithromycin therapy was effective in patients with moderate or severe ARDS. Further prospective randomized controlled trials are needed to confirm this result.