The case of huge simple pulmonary aspergilloma that responded remarkably to drug therapy.

The first choice of treatment for simple pulmonary aspergilloma is surgery, but in clinical practice, many cases find surgery difficult. We report a case of simple pulmonary aspergilloma in which significant improvement was observed with pharmacological treatment alone, despite initially presenting with a large fungus ball.

A randomized double-blind placebo-controlled trial of an inhibitor of plasminogen activator inhibitor-1 (TM5614) in mild to moderate COVID-19.

An inhibitor of plasminogen activator inhibitor (PAI)-1, TM5614, inhibited thrombosis, inflammation, and fibrosis in several experimental mouse models. To evaluate the efficacy and safety of TM5614 in human COVID-19 pneumonia, phase IIa and IIb trials were conducted. In an open-label, single-arm trial, 26 Japanese COVID-19 patients with mild to moderate pneumonia were treated with 120-180 mg of TM5614 daily, and all were discharged without any notable side effects. Then, a randomized, double-blind, placebo-controlled trial was conducted in Japanese COVID-19 patients with mild to moderate pneumonia. The number of study participants was set to be 50 in each arm. Even after extension of the enrollment period, the number of study participants did not reach the initially intended sample size, and 75 patients were enrolled in the study. The total oxygenation scale from Day 1 to Day 14 as the primary endpoint was 1.5 in the TM5614 group vs 4.0 in the placebo group (p = 0.22), and the number of days of oxygen administration required as the secondary endpoint was 2.0 days in the TM5614 group vs 3.5 days in the placebo group (p = 0.34). Further studies will be necessary to verify the efficacy of PAI-1 inhibition for the treatment of COVID-19 pneumonia.Clinical trial registration: Two studies were conducted: a prospective, multicenter, open-label phase II study at https://jrct.niph.go.jp (jRCT2021200018) (First registration date 18/08/2020) and a prospective, multicenter, randomized, double-blind, placebo-controlled, phase II study at https://jrct.niph.go.jp (jRCT2021210006) (First registration date 28/05/2021).

Japanese clinical practice guide 2022 for hypersensitivity pneumonitis.

Considering recently published two guidelines for the diagnosis of hypersensitivity pneumonitis (HP), the Japanese Respiratory Society (JRS) has now published its own Japanese clinical practice guide for HP. Major types of HP in Japan include summer-type, home-related, bird-related, farmer's lung, painter's lung, humidifier lung, and mushroom grower's lung. Identifying causative antigens is critical for increasing diagnostic confidence, as well as improving prognosis through appropriate antigen avoidance. This guide proposes a comprehensive antigen questionnaire including the outbreak sources reported in Japan. Drawing on the 2021 CHEST guideline, this guide highlights the antigen identification confidence level and adaptations for environmental surveys. The detection of specific antibodies against causative antigens is an important diagnostic predictor of HP. In Japan, the assessments of bird-specific IgG (pigeons, budgerigars) and the Trichosporon asahii antibody are covered by medical insurance. Although this guide adopts the 2020 ATS/JRS/ALAT guideline diagnostic criteria based on the combination of imaging findings, exposure assessment, bronchoalveolar lavage lymphocytosis, and histopathological findings, it added some annotations to facilitate the interpretation of the content and correlate the medical situation in Japan. It recommends checking biomarkers; seasonal changes in the KL-6 concentration (increase in winter for bird-related HP/humidifier lung and in summer for summer-type HP) and high KL-6 concentrations providing a basis for the suspicion of HP. Antigen avoidance is critical for disease management of HP. This guide also addresses the pharmacological management of HP, highlighting the treatment strategy for fibrotic HP including combination therapies with anti-inflammatory/immunosuppressive and antifibrotic drugs.

A case of pulmonary nocardiosis with Nocardia brasiliensis spread from a post-traumatic cutaneous infection in an immunocompetent patient.

Nocardia is an aerobic Gram-positive bacterium found in the environment, including soil and water. Nocardia brasiliensis is reportedly associated with cutaneous infections, and disseminated disease is typically detected in immunocompromised individuals. We present a rare case of disseminated nocardiosis with N. brasiliensis in an immunocompetent patient. An 82-year-old male, who had a left elbow injury 2 months prior to the first visit, presented with bilateral multiple lung nodules. N. brasiliensis was identified in both sputum and pus specimens, we concluded that the N. brasiliensis had spread from the primary cutaneous lesion. The patient was treated with antibiotics and had a favourable clinical course. As the present case report demonstrates, disseminated nocardiosis caused by this species can progress from a primary cutaneous lesion even in immunocompetent individuals, if the initiation of appropriate treatment is delayed. Therefore, careful evaluation is warranted when Nocardia species are detected.

Unilateral acute eosinophilic pneumonia on the operative side: A case 9 years after lung lobectomy.

The typical clinical manifestation of acute eosinophilic pneumonia is acute onset of respiratory symptoms due to smoking or medication use, accompanied by bilateral ground-glass opacity with consolidations on chest radiography. However, differential diagnosis with acute eosinophilic pneumonia should not be excluded in cases of unilateral pneumonia of postoperative lung.

Exploratory phase 2 study of the novel oral multi-kinase inhibitor TAS-115 in patients with idiopathic pulmonary fibrosis.

BACKGROUND: TAS-115, a novel oral multi-kinase inhibitor, showed antifibrotic effects in in vitro and in vivo animal models of idiopathic pulmonary fibrosis (IPF). METHODS: In this exploratory phase 2 study, IPF patients with a percent predicted forced vital capacity (%FVC) decline ≥5% acquired within the previous 6 months were enrolled. Patients were divided into three pre-treatment cohorts, namely, treatment-naïve, pirfenidone, or nintedanib. TAS-115 was administered orally at 200 mg/day with a 5-day on and 2-day off regimen. After 13 weeks of treatment, patients entered a 13-week extension treatment period where the efficacy was evaluated. The primary endpoint was the difference in slope of %FVC decline at Week 13 from baseline. Safety was also evaluated. RESULTS: Between June 2018 and July 2019, 46 patients were enrolled, and 30 (65.2%) patients completed the 13-week treatment. Of these, 22 (47.8%) proceeded to extension treatment. For the primary endpoint, TAS-115 treatment lowered the slope of the %FVC decline of 0.0750%/day (95% confidence interval: 0.0341-0.1158%/day) at Week 13. Efficacy was also demonstrated at Week 26. Treatment-related adverse events were reported in 40 (88.9%) patients, but most were manageable by dose reduction, dose interruption, or symptomatic treatment. CONCLUSIONS: TAS-115 treatment was effective, assessed using intra-patient change in slope of %FVC decline as a surrogate endpoint in patients with IPF pre-treated with pirfenidone or nintedanib and treatment-naïve patients. TAS-115 showed acceptable tolerability and a manageable safety profile. TRIAL REGISTRATION: Japic-Clinical Trials Information, JapicCTI-183898 (first registered: March 15, 2018).

Exertional Desaturation Is More Severe in Idiopathic Pulmonary Fibrosis Than in Other Interstitial Lung Diseases.

OBJECTIVE: Interstitial lung disease (ILD) is classified into several disease groups. Among them, idiopathic pulmonary fibrosis (IPF) has higher incidence and poor prognosis; therefore, it is important to characterize specific IPF symptoms. Exercise desaturation is a strong factor related to mortality in patients with ILD. Thus, the purpose of this study was to compare the degree of oxygen desaturation between IPF and other ILD (non-IPF ILD) patients during exercise, using the 6-minute walk test (6MWT). METHODS: This retrospective study included 126 stable patients with ILD who underwent 6MWT in our outpatient department. The 6MWT was used to assess desaturation during exercise, 6-minute walk distance (6MWD), and dyspnea at the end of exercise. In addition, patient characteristics and pulmonary function test results were recorded. RESULTS: Study subjects were divided into 51 IPF patients and 75 non-IPF ILD patients. The IPF group had significantly lower nadir oxygen saturation determined by pulse oximetry (SpO2) during 6MWT than the non-IPF ILD group (IPF, 86.5 ± 4.6%; non-IPF ILD, 88.7 ± 5.3%; p = 0.02). The significant association between the nadir SpO2 and IPF or non-IPF ILD grouping remained even after adjusting for gender, age, body mass index, lung function, 6MWD, and dyspnea (ß = -1.62; p <0.05). CONCLUSION: Even after adjusting for confounding factors, IPF patients had lower nadir SpO2 during 6MWT. Early assessment of exercise desaturation using the 6MWT may be more important in patients with IPF compared with patients with other ILDs.

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.

Diffuse cryptococcal pneumonia in multicentric Castleman's disease with elevated serum IgG4.

A woman in her 60s with suspected multicentric Castleman's disease, who was receiving treatment with oral prednisolone, presented to our hospital with mild cough and malaise. Chest CT showed diffuse infiltrative and granular shadows, indicating exacerbation of lung lesions caused by steroid-resistant multicentric Castleman's disease. A video-assisted thoracoscopic lung and mediastinal lymph node biopsy was performed. The biopsy revealed mediastinal lymph node tissue consistent with multicentric Castleman's disease, as well as presence of Cryptococcus neoformans in the alveolar space. C. neoformans infection in immunocompromised individuals may present with diffuse lung lesions and should be noted as a mimicker of acute exacerbation of Castleman's disease.

Palliative care for interstitial lung disease: A nationwide survey of pulmonary specialists.

BACKGROUND AND OBJECTIVE: Interstitial lung disease (ILD) is progressive with high symptom burdens and poor prognosis. Patients with ILD need optimal palliative care to maintain their quality of life, however, few nationwide surveys have addressed palliative care for ILD. METHODS: A nationwide, self-administered questionnaire was conducted. Questionnaires were sent by mail to pulmonary specialists certified by the Japanese Respiratory Society (n = 3423). The current practices of PC for ILD, end-of-life communication, referral to a PC team, barriers to PC for ILD, and comparison of PC between ILD and lung cancer (LC). RESULTS: 1332 (38.9%) participants completed the questionnaire, and the data of 1023 participants who had cared for ILD patients in the last year were analysed. Most participants reported that ILD patients often or always complained of dyspnoea and cough, but only 25% had referred them to a PC team. The timing of end-of-life communication tended to be later than the physician-perceived ideal timing. The participants experienced significantly greater difficulty in symptomatic relief and decision-making in PC for ILD compared to LC. Prescription of opioids for dyspnoea was less frequent for ILD than for LC. ILD-specific barriers in PC included an 'inability to predict prognosis', 'lack of established treatments for dyspnoea', 'shortage of psychological and social support', and 'difficulty for patients/families to accept the disease's poor prognosis'. CONCLUSION: Pulmonary specialists experienced more difficulty in providing PC for ILD compared to LC and reported considerable ILD-specific barriers in PC. Multifaceted clinical studies are needed to develop optimal PC for ILD.

Weight loss in nintedanib-treated patients with idiopathic pulmonary fibrosis.

Nintedanib is approved for the treatment of idiopathic pulmonary fibrosis (IPF). Weight loss is recognized as an adverse event during nintedanib treatment, and is a common complication exploitable as a prognostic indicator of IPF. Here, we report a single-center, retrospective cohort study to assess body weight changes during nintedanib therapy in patients with IPF. Sixty-one patients treated with nintedanib for >6 months were included (45 males, mean age ± standard deviation 73.1 ± 7.4 years). Baseline body weight and body mass index were 60.1 ± 12.0 kg and 23.2 ± 3.5 kg/m2, respectively. Mean weight loss during the first 6 months of nintedanib treatment was significant (-3.2 ± 3.4 kg, p < 0.0001) with Common Terminology Criteria for Adverse Events (CTCAE) grades 0,1,2 or 3 of 30, 17, 13 and 1, respectively. Pulmonary function test records 6 months before nintedanib administration were available in a subset of patients (n = 40). Significant differences in weight change over the 6 months before-vs-after nintedanib administration were also observed in these patients [mean differences -2.5 ± 3.4 kg, 95% confidence interval (CI) -3.6, -1.4, p < 0.0001]. Multivariate analysis showed that only baseline body weight was significantly associated with weight loss of CTCAE grade ≧2 (odds ratio 0.921, 95% CI 0.854, 0.994). Median follow-up from starting nintedanib was 34.8 months. There was a significant difference in overall survival between patients with CTCAE grade ≧2-vs-grade<2 (median survival of 25.5 months and 55.2 months, p = 0.014). In the model adjusting for age, sex and lung function, weight loss CTCAE grade ≧2 was an independent predictor for all-cause mortality (hazard ratio 2.448, 95% CI 1.080-5.551). In conclusion, weight loss is an important issue for the management of patients with IPF treated with nintedanib.

Design and rationale of the Japanese Idiopathic Interstitial Pneumonias (JIPS) Registry.

BACKGROUND: Numerous studies investigated patients with IPF; however, only a few examined patients with idiopathic interstitial pneumonias (IIPs). METHODS: The Japanese Idiopathic Interstitial Pneumonias (JIPS) Registry, which was initiated in December 2016, is a multicenter prospective observational study of patients newly diagnosed with IIPs from 86 facilities treating ILDs. The plan is to enroll more than 600 new patients during the 2-year enrolment period and to follow their progress for 3 years after the last case enrolment. If additional consent is obtained, the study will continue for another 2 years. Research questions mainly focus on identifying the frequency by IIP classification, patient background, and diagnostic methods during enrolment, survival, acute exacerbation rate, changes in high-resolution CT imaging, forced vital capacity, and interstitial pneumonia markers over time. Other research questions, including those regarding disease behavior in patients with progressive fibrosing-ILD and new biomarkers associated with genetic predispositions, will be investigated. DISCUSSION: The JIPS Registry will provide a comprehensive description of the disease progression, prognosis, treatment status, new biomarkers, and validity of guidelines and central multidisciplinary decisions for IPF and similar diseases that can be differentiated from IPF among IIPs. ETHICS AND DISSEMINATION: Ethical approval was obtained from the institutional review board of Kanagawa Cardiovascular and Respiratory Center (KCRC-16-0005), and that of Jichi Medical University approved the biobank part (I18-005). Results will be published in peer-reviewed journals and will be presented at national and international conferences. TRIAL REGISTRATION: ClinTrials.gov Registry (NCT03041623, first posted on February 3, 2017).

Impact of sarcopenia defined by carina-level skeletal muscle mass on the long-term prognosis of patients with idiopathic pulmonary fibrosis.

BACKGROUND: Sarcopenia, defined using abdominal computed tomography (CT), has been used as a prognostic marker for patients with idiopathic pulmonary fibrosis (IPF). However, no consensus on the impact of sarcopenia as defined using chest CT exists. Therefore, this study aimed to investigate the impact of sarcopenia, defined using CT at the carina-level, on the long-term prognosis of patients with IPF. METHODS: This single-center retrospective cohort study included 117 patients with IPF. Sarcopenia was defined as skeletal muscle mass measured at the carina-level on chest CT images. All-cause mortality was analyzed using the Kaplan-Meier method, and the log-rank test was used to evaluate the differences between sarcopenia and non-sarcopenia groups. A Cox proportional hazards regression model was used to analyze the impact of sarcopenia on all-cause mortality in model 1 with adjustment for body mass index and gender-age-physiology stage as a confounding factor and in model 2 with sex, age, and% forced vital capacity (FVC). RESULTS: The median follow-up period was 956 days, and 57 deaths were recorded. The sarcopenia group had a significantly lower survival rate than the non-sarcopenia group. The multivariate Cox proportional hazards analysis revealed that sarcopenia was a significant predictor of all-cause mortality in models 1 and 2. In patients with no diffusing capacity for carbon monoxide (DLCO) measurement, sarcopenia was a significant prognostic predictor of all-cause mortality independent of%FVC. CONCLUSION: Sarcopenia, defined at the carina level, is a risk factor for all-cause mortality in patients with IPF. Assessment of sarcopenia by CT imaging is useful and less burdensome in patients with IPF.

End-of-life care for idiopathic pulmonary fibrosis patients with acute exacerbation.

BACKGROUND: Acute exacerbation (AE) is a major cause of death in patients with idiopathic pulmonary fibrosis (IPF). AE-IPF patients require optimal palliative care; however, the real-world clinical situations are poorly understood. We aimed to survey the palliative care received by AE-IPF patients, especially with respect to opioid use for dyspnea and the end-of-life discussions (EOLd). METHODS: Self-administered questionnaires were dispatched to 3423 of the certified pulmonary physicians in Japan. They were asked to report a care report form of one patient each with AE-IPF who died very recently about opioid use for dyspnea and EOLd. We further explored the factors associated with the early use of opioids for dyspnea. RESULTS: Among the 3423 physicians, 1226 (35.8%) returned the questionnaire with the report forms of 539 AE-IPF patients. Of 539 AE-IPF patients, 361 (67.0%) received opioids for dyspnea. Of the 361 patients, 72 (20.0%) received opioids during the initial treatment with an intention of recovery (early use), while 289 (80.0%) did when the recovery was deemed impossible. EOLd was held before the onset of AE in 124 patients (23.0%); however, the majority of patients had EOLd after the admission for AE-IPF. EOLd before the onset of AE was significantly associated with the early use of opioids. CONCLUSION: In terminally ill AE-IPF patients, opioids are usually administered when the recovery is deemed impossible, and EOLd are rarely held before the onset of AE. Further studies are warranted on the efficacy of opioids for dyspnea and the appropriate timing of EOLd.

Development and validation of a new scoring system for prognostic prediction of community-acquired pneumonia in older adults.

The discriminative power of CURB-65 for mortality in community-acquired pneumonia (CAP) is suspected to decrease with age. However, a useful prognostic prediction model for older patients with CAP has not been established. This study aimed to develop and validate a new scoring system for predicting mortality in older patients with CAP. We recruited two prospective cohorts including patients aged ≥ 65 years and hospitalized with CAP. In the derivation (n = 872) and validation cohorts (n = 1,158), the average age was 82.0 and 80.6 years and the 30-day mortality rate was 7.6% (n = 66) and 7.4% (n = 86), respectively. A new scoring system was developed based on factors associated with 30-day mortality, identified by multivariate analysis in the derivation cohort. This scoring system named CHUBA comprised five variables: confusion, hypoxemia (SpO2 ≤ 90% or PaO2 ≤ 60 mmHg), blood urea nitrogen ≥ 30 mg/dL, bedridden state, and serum albumin level ≤ 3.0 g/dL. With regard to 30-day mortality, the area under the receiver operating characteristic curve for CURB-65 and CHUBA was 0.672 (95% confidence interval, 0.607-0.732) and 0.809 (95% confidence interval, 0.751-0.856; P < 0.001), respectively. The effectiveness of CHUBA was statistically confirmed in the external validation cohort. In conclusion, a simpler novel scoring system, CHUBA, was established for predicting mortality in older patients with CAP.

2020 guide for the diagnosis and treatment of interstitial lung disease associated with connective tissue disease.

The prognosis of patients with connective tissue disease (CTD) has improved significantly in recent years, but interstitial lung disease (ILD) associated with connective tissue disease (CTD-ILD) remains a refractory condition, which is a leading cause of mortality. Because it is an important prognostic factor, many observational and interventional studies have been conducted to date. However, CTD is a heterogeneous group of conditions, which makes the clinical course, treatment responses, and prognosis of CTD-ILD extremely diverse. To summarize the current understanding and unsolved questions, the Japanese Respiratory Society and the Japan College of Rheumatology collaborated to publish the world's first guide focusing on CTD-ILD, based on the evidence and expert consensus of pulmonologists and rheumatologists, along with radiologists, pathologists, and dermatologists. The task force members proposed a total of 27 items, including 7 for general topics, 9 for disease-specific topics, 3 for complications, 4 for pharmacologic treatments, and 4 for non-pharmacologic therapies, with teams of 2-4 authors and reviewers for each item to prepare a consensus statement based on a systematic literature review. Subsequently, public opinions were collected from members of both societies, and a critical review was conducted by external reviewers. Finally, the task force finalized the guide upon discussion and consensus generation. This guide is expected to contribute to the standardization of CTD-ILD medical care and is also useful as a tool for promoting future research by clarifying unresolved issues.

COVID-19 and acute exacerbation of interstitial lung disease.

We conducted a study to examine the effect of COVID-19 on the acute exacerbation of interstitial lung disease (AE-ILD) early in the COVID-19 epidemic (January 1-April 30, 2020). An online questionnaire survey was conducted, which was completed by 134 hospitals. During this period, 854 patients with AE-ILD (including 12 cases of COVID-AE-idiopathic pulmonary fibrosis were hospitalized at 128 hospitals. In comparison, the total number of AE-ILD hospitalizations during the same period in 2019 was 894. The number of hospitalizations increased at 17 hospitals, decreased at 27, and remained the same at 88 hospitals in 2020 compared to the same period in 2019. In 2020, COVID-19-related acute exacerbations had a significantly worse prognosis than non-COVID-19-related acute exacerbations in both 30-day and 90-day mortality. Because the prognosis of AE-ILD associated with COVID-19 is extremely poor, prevention of COVID-19 is especially important for patients with ILD.

Pneumonia Caused by Severe Acute Respiratory Syndrome Coronavirus 2 and Influenza Virus: A Multicenter Comparative Study.

BACKGROUND: Detailed differences in clinical information between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia (CP), which is the main phenotype of SARS-CoV-2 disease, and influenza pneumonia (IP) are still unclear. METHODS: A prospective, multicenter cohort study was conducted by including patients with CP who were hospitalized between January and June 2020 and a retrospective cohort of patients with IP hospitalized from 2009 to 2020. We compared the clinical presentations and studied the prognostic factors of CP and IP. RESULTS: Compared with the IP group (n = 66), in the multivariate analysis, the CP group (n = 362) had a lower percentage of patients with underlying asthma or chronic obstructive pulmonary disease (P < .01), lower neutrophil-to-lymphocyte ratio (P < .01), lower systolic blood pressure (P < .01), higher diastolic blood pressure (P < .01), lower aspartate aminotransferase level (P < .05), higher serum sodium level (P < .05), and more frequent multilobar infiltrates (P < .05). The diagnostic scoring system based on these findings showed excellent differentiation between CP and IP (area under the receiver operating characteristic curve, 0.889). Moreover, the prognostic predictors were different between CP and IP. CONCLUSIONS: Comprehensive differences between CP and IP were revealed, highlighting the need for early differentiation between these 2 pneumonias in clinical settings.

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).

Diffuse Pulmonary Ossification with Connective Tissue Weakness Potentially Due to Vascular Ehlers-Danlos Syndrome.

A 30-year-old non-smoking man was referred to our hospital for the further examination of abnormal shadows revealed by chest X-ray. He had mild shortness of breath. Chest computed tomography revealed a fine-grained dendritic shadow with diffuse calcification in both lungs and as well as emphysematous changes in the upper lung lobes. A surgical lung biopsy histology revealed diffuse pulmonary ossification complicated with lung laceration, vascular disruption, hemosiderosis, and emphysema, suggesting vascular Ehlers-Danlos syndrome (vEDS). However, the patient had no external physical signs or family history of vEDS and no COL3A1 gene mutations. We are closely monitoring this patient in the clinic.