Cause of mortality and sarcopenia in patients with idiopathic pulmonary fibrosis receiving antifibrotic therapy.

BACKGROUND AND OBJECTIVE: Recent research has highlighted the fundamental role of sarcopenia, characterized by loss of skeletal muscle mass and strength, with a risk of poor outcomes. AFT preserves lung function by preventing the annual decline in FVC and is associated with improved outcomes in patients with IPF. However, altered cause of death and prognostic implications of sarcopenia in patients with IPF receiving AFT remain unknown. METHODS: This study comprised two cohorts of patients with IPF receiving AFT, historical cohort of IPF patients without AFT and controls. The cause of mortality was compared with a historical cohort. Sarcopenia was assessed by measuring the ESMCSA and ESMMA via CT. RESULTS: Patients with IPF had smaller ESMCSA and lower ESMMA but similar BMI than controls, suggesting patients with IPF had skeletal muscle loss without any obvious body weight loss. The most common cause of mortality in patients receiving AFT was chronic respiratory failure, accounting for approximately 60%, and decreased proportions of LC were found. Subsequently, low ESMCSA was an independent prognostic factor associated with worse survival rates. Furthermore, combined assessment of ESMCSA , %FVC predicted and BMI values provided clear prognostic distinction. CONCLUSION: Patients with IPF receiving AFT showed skeletal muscle loss without obvious weight loss. These patients mostly died by chronic respiratory failure, and skeletal muscle wasting has prognostic significance, suggesting that preventing sarcopenia as well as preserving lung function are important for managing these patients.

Author Correction: Macrophage Mannose Receptor CD206 Predicts Prognosis in Community-acquired Pneumonia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Macrophage Mannose Receptor CD206 Predicts Prognosis in Community-acquired Pneumonia.

CD206, a mannose receptor, is mainly expressed on the surface of alternatively activated macrophages where it acts as a pattern recognition receptor and plays a role in innate and adaptive immunity. This study investigated serum soluble CD206 (sCD206) levels in community-acquired pneumonia (CAP) and examined their clinical significance. sCD206 concentrations were measured in the sera of two independent cohorts with CAP (127 and 125 patients, respectively) and 42 controls. The expression of CD206 in the lung from autopsied cases was also examined. Patients with CAP showed significantly elevated sCD206 levels than did the controls (p < 0.0001). Notably, fatal CAP patients had more than two-fold higher sCD206 concentrations than survivors in both cohorts (p < 0.0001). Serum sCD206 concentrations were associated with Pneumonia Severity Index (PSI) and CURB-65 values. Importantly, even fatal CAP patients classified as PSI I-IV, CURB65 0-2 or age <75 years had comparatively higher levels of sCD206 than those classified as PSI V, CURB-65 3-5 or age ≥75 years. Immunohistochemically, the infiltration of CD206+ macrophages was found in the lungs of fatal cases. Elevated levels of sCD206 are associated with CAP prognosis, suggesting sCD206 might be a potential biomarker to predict severity for CAP.

Effect of PD-1 inhibitor on exhaled nitric oxide and pulmonary function in non-small cell lung cancer patients with and without COPD.

Background: Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor, has been shown to improve survival in non-small cell lung cancer (NSCLC). The possible involvement of PD-1 axis in the pathogenesis of inflammatory lung disease, such as chronic obstructive pulmonary disease (COPD) has also been reported. However, effects of PD-1 blockade on the respiratory system remain unknown. Objectives: This prospective study aimed to investigate whether inhibition of the PD-1 axis altered lung inflammation and pulmonary function in NSCLC patients with and without COPD. Method: This was a prospective multi-center study. Measurements of fractioned exhaled nitric oxide (FeNO) and pulmonary function were performed before and after 4 cycles of nivolumab therapy. Results: A total of 137 patients with NSCLC were initially enrolled, and subsequently 95 patients (41 COPD and 54 non-COPD) receiving 4 cycles of nivolumab administration were included. After anti-PD-1 therapy, FeNO levels were significantly elevated together with increase in peripheral eosinophils. Interestingly, significant FeNO elevation was only found in COPD patients without increased peripheral eosinophils, but this was not the case in non-COPD patients. Additionally, COPD patients exhibited significant increases in FVC and FEV1 but no changes in dyspnea scales, and acute exacerbation did not occur during the therapy. Conclusion: Our observations suggest that anti-PD-1 therapy changed FeNO levels and pulmonary function in NSCLC patients. This therapy does not worsen COPD in terms of symptoms, pulmonary function, or acute exacerbation.

Body composition changes successfully classify prognosis in patients with mycobacterium avium complex lung disease.

OBJECTIVES: Loss of body weight, a manifestation of cachexia, is frequently found in patients with Mycobacterium avium complex lung disease (MAC-LD) and known as a prognostic determinant. However, the involvement of body composition changes in the prognosis of patients with MAC-LD remains unclear. METHODS: The cross-sectional-area of the erector spinea muscle (ESMCSA) and mean attenuation of the erector spinae muscles (ESMMA) in patients with MAC-LD, as determined by computed tomography imaging, were measured in two independent cohorts (137 and 111 patients, respectively). RESULTS: Patients with MAC-LD showed significantly smaller ESMCSA together with lower body mass index (BMI), but no difference in ESMMA in both cohorts compared with controls. Smaller ESMCSA, body mass index decline, and decreased ESMMA were associated with worse survival in the patients. Among them, decreased ESMMA showed prognostic significance in the multivariate analyses. Importantly, assessment by ESMMA together with BMI successfully divided the patients into three groups with distinct prognoses. CONCLUSION: Changes in body composition, especially decreased ESMMA, had prognostic significance in patients with MAC-LD. Additionally, combined assessment of ESMMA and BMI accurately predicted the prognosis of MAC-LD, which may be a helpful tool for disease management.

Heterogeneity analysis of PD-L1 expression and copy number status in EBUS-TBNA biopsy specimens of non-small cell lung cancer: Comparative assessment of primary and metastatic sites.

OBJECTIVES: Most patients with non-small cell lung cancer (NSCLC) are diagnosed at advanced stages where small biopsy specimens obtained through endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are sometimes the only available samples for diagnosis. We aimed to determine whether EBUS-TBNA specimens are suitable for the evaluation of PD-L1 protein expression and copy number alterations (CNAs). MATERIALS AND METHODS: PD-L1 protein expression and CNAs in 71 EBUS-TBNA specimens of NSCLC were assessed. Sixty-eight corresponding transbronchial biopsy (TBB) specimens from primary sites, thirteen resected primary tumors, and six resected metastases were comparatively analyzed. PD-L1 expression in tumor cells was assessed by immunohistochemistry (E1L3N). Positivity of ≥1% was used as the cutoff. PD-L1 CNAs were assessed with fluorescent in situ hybridization and were classified into three categories: amplification, polysomy, and disomy. Concordance between EBUS-TBNA and other specimens was calculated. RESULTS: The cohort comprised 48 men (67.6%), 15 never-smokers (21.1%), and 39 adenocarcinomas (54.9%). The concordance of PD-L1 positivity between EBUS-TBNA and other specimens was moderate; κ = 0.63 for EBUS-TBNA vs. TBB, κ = 0.68 for EBUS-TBNA vs. resected primary tumors, and κ = 1.0 for EBUS-TBNA vs. resected metastases. The concordance of PD-L1 CNA status was comparable with that of PD-L1 expression: κ = 0.60 for EBUS-TBNA vs. TBB and κ = 0.74 for EBUS-TBNA vs. resected primary tumors. When PD-L1 copy number was assessed as a continuous variable, the correlation of PD-L1 CNAs was superior to that of PD-L1 expression. Intratumorally, PD-L1 copy number was less heterogeneous than protein expression in whole sections of resected tumors. CONCLUSION: EBUS-TBNA specimens can be used to assess PD-L1 CNAs and protein expression. Although spatial heterogeneity should be considered for accurate interpretation, the evaluation of PD-L1 CNAs provides more reproducible results than that of protein expression levels especially with regard to intratumoral heterogeneity.

Utility of serum Aspergillus-galactomannan antigen to evaluate the risk of severe acute exacerbation in chronic obstructive pulmonary disease.

BACKGROUND: Recent studies have shown that the microbiome, namely Aspergillus species, play a previously unrecognized role in both stable and exacerbated chronic obstructive pulmonary disease (COPD). Galactomannan is a major component of the Aspergillus cell wall that has been widely used as a diagnostic marker. OBJECTIVES: To explore whether serum levels of Aspergillus-galactomannan antigen could be used to evaluate the risk of severe acute exacerbation of COPD (AE-COPD). METHODS: We measured the Aspergillus-galactomannan antigen levels of 191 patients with stable COPD, and examined its clinical relevance including AE-COPD. RESULTS: There were 77 (40.3%) patients who were positive for serum Aspergillus-galactomannan antigen (≥0.5). High Aspergillus-galactomannan antigen level (≥0.7) was associated with older age and presence of bronchiectasis and cysts on computed tomography images. Compared to patients with low Aspergillus-galactomannan antigen level (<0.7), patients with high Aspergillus-galactomannan antigen level had significantly higher incidence of severe AE-COPD (P = 0.0039, Gray's test) and respiratory-related mortality (P = 0.0176, log-rank test). Multivariate analysis showed that high Aspergillus-galactomannan antigen level was independently associated with severe AE-COPD (hazard ratio, 2.162; 95% confidence interval, 1.267-3.692; P = 0.005). CONCLUSION: Serum Aspergillus-galactomannan antigen was detected in patients with COPD, and elevated serum Aspergillus-galactomannan antigen was associated with severe AE-COPD.

Nonspecific interstitial pneumonia: prognostic significance of high-resolution computed tomography in 59 patients.

OBJECTIVE: To retrospectively analyze the prognostic implications of high-resolution computed tomography (HRCT) findings for patients with biopsy-proven nonspecific interstitial pneumonia (NSIP). METHODS: Fifty-nine patients with NSIP (25 idiopathic NSIP, 34 collagen-vascular disease-associated NSIP) were included. Two chest radiologists independently evaluated the extent, presence, and distribution of various HRCT findings. Cox hazards analysis was used to evaluate the relationship between HRCT findings and prognosis. RESULTS: The 5-year survival rate was 83% and the 10-year survival rate was 66%. Univariate analysis revealed that the extent of areas with ground-glass attenuation without traction bronchi-bronchiolectasis and that of airs-pace consolidation were associated with favorable outcome, whereas that of intralobular reticular opacities was associated with worse prognosis. Multivariate analysis showed that the extent of air-space consolidation was an independent factor of favorable outcome. CONCLUSION: In NSIP, the extent of areas with ground-glass attenuation without traction bronchi-bronchiolectasis, air-space consolidation, and intralobular reticular opacities correlate with survival.

Prognosis in adult patients with idiopathic pulmonary hemosiderosis.

BACKGROUND: Diffuse alveolar hemorrhage (DAH) of unknown cause has been characterized as idiopathic pulmonary hemosiderosis (IPH). IPH is a rare disease, which has a high prevalence in children and shows a poor prognosis. However, in adults, since there are few reports about collective cases, the details remain to be determined. METHODS: Between January 2003 and June 2008, consecutive adult patients strictly defined as unknown cause DAH by chest images, fiberoptic bronchoscopy, autoantibody testing, and exclusion of systemic disease were enrolled. We investigated the clinical characterization and course of the enrolled patients. RESULTS: Nine patients were included. All patients were middle-aged men (56.1 ± 4.2 year-old) with sudden onset. They did not present with anemia (the hemoglobin level was 13.9 ± 0.5 g/dL) despite the quantity of bleeding. In bronchoalveolar-lavage fluid analysis, the cell count was increased (7.6 ± 1.6×10(5) cells/mL) with neutorophilia (33.3 ± 13.3%). The illness resolved within 2 weeks with or without corticosteroid therapy. All of the patients were alive without recurrence during the follow-up period (45.2 ± 6.2 months) after diagnosis. CONCLUSION: Adult IPH patients showed good prognosis. However, the present patients are clinically slightly different from the previously characterized IPH.

[A case of pulmonary alveolar proteinosis presenting with miniscule ground-glass opacity in the apex of the left lung].

A 66-year-old man was found to have a very small ground-glass opacity in the apex of the left lung. Because the ground-glass opacity had slightly enlarged after 2 years, video-assisted thoracic surgery (VATS) biopsy was performed. The histological findings showed the alveolar spaces to be filled with PAS-positive granular materials, so pulmonary alveolar proteinosis was diagnosed. Although his bronchoalveolar lavage fluid (BALF) did not have a milky appearance, his serum and BALF GM-CSF autoantibody and serum KL-6 levels were elevated. Asymptomatic pulmonary alveolar proteinosis may appear as very small ground-grass opacities.

Serum activity of indoleamine 2,3-dioxygenase predicts prognosis of community-acquired pneumonia.

OBJECTIVES: Indoleamine 2,3-dioxygenase (IDO) catalyzes the rate-limiting step of tryptophan (Trp) degradation in the kynurenine (Kyn) pathway. By depleting Trp, IDO plays a critical role in inducing immune suppression and tolerance. The aim of present study was to investigate serum IDO activity, determined by Kyn-to-Trp ratio (Kyn/Trp ratio), in community-acquired pneumonia (CAP) and to examine its clinical significance. METHODS: This study subjects consisted of 129 consecutive patients with CAP and 64 healthy controls. The concentrations of Kyn and Trp were measured simultaneously by liquid chromatography/electrospray ionization tandem mass spectrometry. RESULTS: The CAP patients had significantly higher Kyn concentrations and significant lower Trp concentrations than the controls (p < 0.0001 and p < 0.0001, respectively). Accordingly, IDO activity was significantly higher (2.4-fold) in the patients than in the controls (p < 0.0001). IDO activity correlated well with PSI (Pneumonia Severity Index) and CURB65 (p = 0.0005 and p < 0.0001, respectively). Moreover, the IDO activity and Kyn concentration were significantly higher in the nonsurvivors and were found to predict mortality in multivariate analysis. CONCLUSIONS: IDO activity was increased in CAP, and this activity was associated with the severity and outcome of this disease. These results suggest that IDO activity can predict prognosis of CAP.

Distinct prognosis of idiopathic nonspecific interstitial pneumonia (NSIP) fulfilling criteria for undifferentiated connective tissue disease (UCTD).

BACKGROUND: Although idiopathic nonspecific interstitial pneumonia (NSIP) was initially identified as a provisional diagnosis, the 2008 American Thoracic Society Project concluded that idiopathic NSIP is a distinct form of idiopathic interstitial pneumonia. However, an association between idiopathic NSIP and autoimmune diseases still attracts interest. In this context, a recent study proposed an intriguing concept that idiopathic NSIP is the pulmonary manifestation of undifferentiated connective tissue disease (UCTD). However, this has not been confirmed in a large number of patients with idiopathic NSIP. The present study was conducted to investigate the proportion and characteristics of patients with idiopathic NSIP who meet the criteria for UCTD. METHODS: We reviewed 47 consecutive patients with idiopathic NSIP and examined whether they met prespecified criteria for UCTD. Furthermore, we compared the clinical characteristics between patients fulfilling the UCTD criteria (UCTD-NSIP) and those not meeting them (Non-UCTD-NSIP). RESULTS: Of 47 patients with idiopathic NSIP, 22 (47%) met the UCTD criteria. Common symptoms associated with connective tissue diseases (CTDs) were skin change (50%) and Raynaud's phenomenon (41%) in UCTD-NSIP. UCTD-NSIP showed a female predominance and significantly higher percentages of lymphocytes with a lower CD4/CD8 ratio in bronchoalveolar lavage than Non-UCTD-NSIP. Interestingly, UCTD-NSIP had a significantly better survival than Non-UCTD-NSIP. CONCLUSIONS: Idiopathic NSIP included subjects who fulfilled the UCTD criteria, and these subjects had different clinical characteristics with significantly better outcome than those who did not meet the criteria. These data suggest that a part, but not all, of patients with idiopathic NSIP show CTD-like features with a distinct prognosis.

[A case of metastatic lung tumor with multiple ground glass opacities on chest CT].

A 70-year-old man was admitted to our hospital because of multiple ground-glass opacities on his chest CT scan. A transbronchial lung biopsy specimen revealed signet-ring cell carcinoma infiltrating into the alveolar septa. The histological findings of the carcinoma obtained from the lung were very similar to those of his gastric carcinoma which had been resected at age 66. Immunohistochemical staining of the cancer cells were positive for keratin 7 and keratin 20, therefore a metastatic lung tumor from gastric cancer was diagnosed. Although multiple, well-defined nodules are typically considered to be the presentation of pulmonary metastases, clinicians should also be aware that multiple, ill-defined ground-glass opacities can also be recognized as pulmonary metastasis.

[An adult case of asymptomatic congenital tracheal stenosis].

A 42-year-old woman was admitted with abnormal chest radiographs. Though interstitial pneumonia associated with dermatomyositis was diagnosed, her chest radiograph also revealed a narrowed trachea about 6 mm in diameter. Bronchoscopy showed that her trachea lacked a membranous posterior segment and O-shaped complete tracheal rings were present throughout the trachea, indicating congenital tracheal stenosis. Congenital tracheal stenosis is a rare disorder and is usually recognized in the first few weeks of life, but the patient had no history of dyspnea or recurrent pneumonia. This case suggests that among healthy people there are a very few who have asymptomatic congenital tracheal stenosis.

Suplatast tosilate alters DC1/DC2 balance in peripheral blood in bronchial asthma.

Suplatast tosilate is an antiallergic drug that selectively suppresses Th2-cytokine production and inhibits airway hyperresponsiveness and eosinophilic airway inflammation. This drug has been also shown to improve pulmonary function and symptoms in steroid-dependent asthma, resulting in a decrease in doses of inhaled corticosteroid. However, the precise mechanism by which suplatast tosilate exerts an antiasthmatic effect in vivo remains to be known. Our previous study showed the polarization of circulating type 1 dendritic cells (DC1)/type 2 dendritic cells (DC2) balance toward DC2 in asthma, which might be associated with its Th2-dominant immune response. In the present study, we attempted to clarify the effect of suplatast tosilate on DC1/DC2 balance in asthma. Using multicolor flow cytometry, we enumerated circulating DC1 and DC2 before and 8 weeks after treatment with suplatast tosilate in nine patients with asthma. Before the treatment, the patients with asthma had a significant higher percentage of DC2 together with a significant lower ratio of DC1/DC2 compared with normal subjects. Administration of suplatast tosilate significantly decreased the percentage of DC2, but not that of DC1, resulting in a significant raises of the ratio of DC1/DC2. Concomitantly, intracellular cytokine analysis showed that the percentage of IL-4 producing CD4+ T cells was significantly decreased after the treatment. These data suggest that suplatast tosilate normalizes the polarized DC1/DC2 balance toward DC2 in asthma, which may also alter its Th2-dominant Th1/Th2 balance toward Th1.

Increased expression of the 25-hydroxyvitamin D(3)-1alpha-hydroxylase gene in alveolar macrophages of patients with lung cancer.

25-Hydroxyvitamin D(3)-1alpha-hydroxylase (1alpha-hydroxylase) plays a central role in calcium metabolism by synthesizing the active hormone 1alpha,25-dihydroxyvitamin D(3) in the kidney. Its increased expression in the extrarenal tissues has been found in alveolar macrophages in sarcoidosis but not in any other pathological conditions. We found that 1alpha-hydroxylase-mRNA in alveolar macrophages measured by semiquantitative RT-PCR was 2-fold greater in patients with lung cancer than in control subjects (0.61 +/- 0.20 vs. 0.34 +/- 0.11, respectively; P < 0.0001). When the clinical stages of lung cancer were divided into early (stage IA-IIIA) and advanced (stage IIIB and IV) and the expression of 1alpha-hydroxylase gene was compared among the control, early, and advanced groups, the advanced group showed the highest expression, followed by the early group, then the control group (0.34 +/- 0.11, 0.52 +/- 0.11, and 0.69 +/- 0.23 for control, early, and advanced groups, respectively; P < 0.0001). The 1alpha-hydroxylase-mRNA level was well correlated with serum 1alpha,25-dihydroxylase D(3) concentration and the 1alpha,25-dihydroxylase D(3) to 25-hydroxyvitamin D(3) ratio, but none of the findings related to calcium metabolism among the patients with lung cancer. Increased local production of 1alpha,25-dihydroxyvitamin D(3) may be associated with the pathological conditions, such as immunosuppression, in lung cancer.

Alteration of balance between myeloid dendritic cells and plasmacytoid dendritic cells in peripheral blood of patients with asthma.

Asthma, a well-known helper T cell Type 2 (Th2)-mediated disease, has a polarized immune response toward a Th2 phenotype. However, the factors causing the Th2 polarization remain to be fully determined in this disease. Dendritic cells (DCs) are the most potent antigen-presenting cells that play a central role in initiating the primary immune response. In human blood, two functional distinct subsets of DCs, myeloid DCs and plasmacytoid DCs, have been identified. Myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) are also called Type 1 DCs (DC1) and Type 2 DCs (DC2), respectively, because mDCs and pDCs were shown to preferentially differentiate naive T cells into Th1 and Th2 cells, respectively. In asthma, it can thus be speculated that an altered balance of mDCs to pDCs toward pDCs may contribute to the Th2 polarization. To clarify this, we examined the numbers of mDCs and pDCs in the peripheral blood of 44 patients with asthma and 38 normal subjects, using multicolor flow cytometry. We found that the patients with asthma had a significantly higher number of pDCs, resulting in a significant decrease in the ratio of mDCs to pDCs compared with normal subjects. These data indicate that the patients with asthma had a polarization of the mDC:pDC balance toward pDCs, which may be involved in producing the Th2-dominant immune phenotype in asthma.