Diagnostic yield of flexible bronchoscopy for immunocompromised patients with lung infiltrates: A single-center, retrospective study.

BACKGROUND: Pulmonary complications are associated with mortality in immunocompromised patients. The usefulness of bronchoscopy has been reported. However, clinical factors and procedures that influence diagnostic yield are still not established. MATERIALS AND METHODS: We retrospectively analyzed 115 bronchoscopies performed on 108 immunocompromised patients, defined as those who take corticosteroids and/or immunosuppressants. We evaluated clinical factors, sampling procedures, final diagnosis, and severe complications of bronchoscopy. RESULTS: The clinical diagnosis was obtained in 51 patients (44%). Of those, 33 cases were diagnosed as infectious diseases and 18 as non-infectious diseases. Nine out of 115 cases (7.8%) initiated new immunosuppressive treatment for an underlying disorder based on the negative microbiological results obtained with bronchoscopy. Collagen vascular disease was the most common underlying disorders (62 patients, 54%). Bronchoscopy was useful regardless of whether the patient was immunosuppressed to treat collagen vascular disease (P = 0.47). Performing transbronchial biopsy correlated with better diagnostic yield of bronchoscopy (54.7% vs 35.5%, P = 0.049). Other clinical factors, such as radiological findings, respiratory failure or antibiotic use at the time of bronchoscopy did not significantly influence diagnostic yield. Respiratory failure requiring intubation after bronchoscopy occurred only in one case (0.9%). CONCLUSIONS: Our study implied the transbronchial biopsy may be a useful procedure for reaching a diagnosis in immunocompromised patients with pulmonary infiltrates. In addition, our data suggest the usefulness of bronchoscopy for immunocompromised patients due to the treatment of collagen vascular disease as well as other underlying disorders.

Endoscopic reflux esophagitis and decline in pulmonary function in nonsmokers: A retrospective cohort study.

BACKGROUND: The association between reflux esophagitis and pulmonary function remains controversial. Thus, evaluating the relationship between endoscopic reflux esophagitis and changes in pulmonary function over time in a nonsmoking population is an important clinical issue. METHODS: In this single-center retrospective cohort study, a medical examination database at Kameda Medical Center Makuhari was employed to identify nonsmokers who underwent upper gastrointestinal endoscopy and spirometry in 2010 and were followed up in 2015. Gastroenterologists carefully double-checked the diagnosis of reflux esophagitis. Multiple linear regression analyses were performed to compare the decline in the percentage of predicted vital capacity (%VC), forced vital capacity (%FVC), and forced expiratory volume in 1 s (%FEV1) between participants with reflux esophagitis and those without. Furthermore, using multivariable logistic regression analyses, we evaluated the factors associated with rapid decline in %VC, %FVC, and %FEV1, which is defined as a decrease of >10% in each parameter over the 5-year observation period. RESULTS: We identified 3098 eligible subjects, including 72 and 44 participants who had a Los Angeles classification grade A and B-C (severe) reflux esophagitis in 2010, respectively. The decline in %VC was significantly larger in the participants with severe reflux esophagitis than in the control subjects (standardized coefficient, -0.037; 95% confidence interval, -0.071 to -0.004). Moreover, reflux esophagitis was significantly associated with a rapid decline in %VC and %FVC but not in %FEV1 (P for trend: 0.009, 0.009, and 0.276, respectively). CONCLUSIONS: Severe reflux esophagitis among nonsmokers had clinical disadvantages in terms of a decline in %VC.

Secondary analysis of preoperative predictors for acute postoperative exacerbation in interstitial lung disease.

This study assessed whether perioperative management is associated with postoperative acute exacerbations (AEs) in interstitial lung disease (ILD) patients. Using secondary data from the study "Postoperative acute exacerbation of interstitial lung disease: a case-control study," we compared the perioperative clinical management of the AE and non-AE groups (1:4 case-control matching) selected by sex, year of surgery (2009-2011, 2012-2014, and 2015-2017), and multiple surgeries within 30 days. We compared 27 and 108 patients with and without AEs, respectively. Rates of one lung ventilation (OLV) cases (70 vs. 29%; OR, 5.9; 95%CI, 2.34-14.88; p < 0.001) and intraoperative steroid administration (48 vs. 26%; OR, 2.65; 95%CI, 1.11-6.33; p = 0.028), and average mean inspiratory pressure (9.2 [1.8] vs. 8.3 [1.7] cmH2O; OR, 1.36; 95%CI, 1.04-1.79; p = 0.026), were significantly higher in the AE group. There was a significant difference in OLV between the groups (OR, 4.99; 95%CI, 1.90-13.06; p = 0.001). However, the fraction of inspired oxygen > 0.8 lasting > 1 min (63 vs. 73%, p = 0.296) was not significantly different between the groups. OLV was significantly associated with postoperative AEs in patients with ILD undergoing both pulmonary and non-pulmonary surgeries. Thus, preoperative risk considerations are more important in patients who require OLV.

Lysophosphatidylcholine Acyltransferase 1 Deficiency Promotes Pulmonary Emphysema via Apoptosis of Alveolar Epithelial Cells.

Chronic obstructive pulmonary disease (COPD) is primarily caused by inhalation of cigarette smoke and is the third leading cause of death worldwide. Pulmonary surfactant, a complex of phospholipids and proteins, plays an essential role in respiration by reducing the surface tension in the alveoli. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) is an enzyme that catalyzes the biosynthesis of surfactant lipids and is expressed in type 2 alveolar epithelial cells. Its dysfunction is suggested to be involved in various lung diseases; however, the relationship between LPCAT1 and COPD remains unclear. To investigate the role of LPCAT1 in the pathology of COPD, we analyzed an elastase-induced emphysema model using Lpcat1 knockout (KO) mice. In Lpcat1 KO mice, elastase-induced emphysema was significantly exacerbated with increased apoptotic cells, which was not ameliorated by supplementation with dipalmitoylphosphatidylcholine, which is a major component of the surfactant synthesized by LPCAT1. We subsequently evaluated the effects of cigarette smoking on primary human type 2 alveolar epithelial cells (hAEC2s) and found that cigarette smoke extract (CSE) downregulated the expression of Lpcat1. Furthermore, RNA sequencing analysis revealed that the apoptosis pathway was significantly enriched in CSE-treated primary hAEC2s. Finally, we downregulated the expression of Lpcat1 using small interfering RNA, which resulted in enhanced CSE-induced apoptosis in A549 cells. Taken together, cigarette smoke-induced downregulation of LPCAT1 can promote the exacerbation of pulmonary emphysema by increasing the susceptibility of alveolar epithelial cells to apoptosis, thereby suggesting that Lpcat1 is a novel therapeutic target for irreversible emphysema.

Predictors of postoperative acute exacerbation of interstitial lung disease: a case-control study.

INTRODUCTION: Patients with interstitial lung disease (ILD) are known to develop an acute exacerbation (AE) after surgery. Previous studies have evaluated the predictors of postoperative AE. However, it remains unclear whether the results of those studies can be generalised to patients with different types of ILD and/or extrapolated to those who undergo non-pulmonary surgery. This study aimed to elucidate the predictors of the development of AE after surgery with general anaesthesia in patients with ILD. METHODS: We conducted a nested matched case-control study of 700 patients from an initial cohort of 50 840 patients. We excluded those who underwent solid organ or bone marrow transplantation. The cases were patients with ILD who developed AE within 30 days postoperatively, whereas the controls did not develop AE. Each case (n=28) was matched with four controls (n=112) for sex, year of surgery and multiple operations within 30 days. Furthermore, a multivariable conditional logistic regression analysis was used to identify significant predictors, as indicated by a p value of <0.05. RESULTS: After adjusting for potential confounders, the multivariable conditional logistic regression analysis identified honeycombing on CT (OR 3.09; 95% CI 1.07 to 8.92), a per cent predicted FVC <80% (OR 4.21; 95% CI 1.46 to 12.2) and an ARISCAT score ≥45 (OR 6.14; 95% CI 2.10 to 18.0) significantly associated with the development of postoperative AE. CONCLUSIONS: We found that the three factors were independent predictors for the development of postoperative AE in patients with ILD. These predictors are advantageous because they can be readily evaluated before surgery by surgeons and anaesthesiologists even without consulting experienced pulmonologists.

Naftopidil reduced the proliferation of lung fibroblasts and bleomycin-induced lung fibrosis in mice.

Naftopidil, an α-1 adrenoceptor antagonist with few adverse effects, is prescribed for prostate hyperplasia. Naftopidil inhibits prostate fibroblast proliferation; however, its effects on lung fibroblasts and fibrosis remain largely unknown. Two normal and one idiopathic pulmonary fibrosis human lung fibroblast lines were cultured with various naftopidil concentrations with or without phenoxybenzamine, an irreversible α-1 adrenoceptor inhibitor. We examined the incorporation of 5-bromo-2'-deoxyuridine into DNA and lactic acid dehydrogenase release by enzyme-linked immunosorbent assay, cell cycle analysis by flow cytometry, scratch wound-healing assay, and mRNA expressions of type IV collagen and α-smooth muscle actin by polymerase chain reaction. Effects of naftopidil on bleomycin-induced lung fibrosis in mice were evaluated using histology, micro-computed tomography, and surfactant protein-D levels in serum. Naftopidil, dose-dependently but independently of phenoxybenzamine, inhibited 5-bromo-2'-deoxyuridine incorporation in lung fibroblasts. Naftopidil induced G1 cell cycle arrest, but lactic acid dehydrogenase release and migration ability of lung fibroblasts were unaffected. Naftopidil decreased mRNA expressions of type IV collagen and α-smooth muscle actin in one normal lung fibroblast line. Histological and micro-computed tomography examination revealed that naftopidil attenuated lung fibrosis and decreased serum surfactant protein-D levels in bleomycin-induced lung fibrosis in mice. In conclusion, naftopidil may have therapeutic effects on lung fibrosis.

IFN Regulatory Factor 3 Potentiates Emphysematous Aggravation by Lipopolysaccharide.

Acute exacerbation of chronic obstructive pulmonary disease (COPD) is often induced by infection and often has a poor prognosis. Bacterial LPS activates innate immune receptor TLR4 followed by activation of a transcriptional factor IFN regulatory factor-3 (IRF3) as well as NF-κB, resulting in upregulation of various inflammatory mediators. To clarify the role of IRF3 in the pathogenesis of LPS-triggered COPD exacerbation, porcine pancreatic elastase (PPE) followed by LPS was administered intranasally to wild-type (WT) or IRF3-/- male mice. Sequential quantitative changes in emphysema were evaluated by microcomputed tomography, and lung histology was evaluated at the sixth week. WT mice treated with PPE and LPS exhibited enlarged alveolar spaces, whereas this feature was attenuated in similarly treated IRF3-/- mice. Moreover, LPS-induced emphysema aggravation was detected only in WT mice. Analysis of acute inflammation induced by PPE plus LPS revealed that the lungs of treated IRF3-/- mice had decreased mRNA transcripts for MCP-1, MIP-1α, TNF-α, and IFN-γ-inducible protein-10 but had increased neutrophils. IRF3 was involved in the production of mediators from macrophages, alveolar epithelial cells, and neutrophils. Furthermore, compared with isolated WT neutrophils from inflamed lung, those of IRF3-/- neutrophils exhibited impaired autophagic activation, phagocytosis, and apoptosis. These results suggest that IRF3 accelerated emphysema formation based on distinct profiles of mediators involved in LPS-induced COPD exacerbation. Regulation of the IRF3 pathway can affect multiple cell types and contribute to ameliorate pathogenesis of infection-triggered exacerbation of COPD.

Ovary-dependent emphysema augmentation and osteopontin induction in adult female mice.

Biological differences between the sexes greatly impact the development and severity of pulmonary disorders such as emphysema. Recent studies have demonstrated crucial roles for osteopontin (OPN, also known as SPP1) in lung inflammation and alveolar destruction in human and experimental emphysema, but the impact of gender on OPN action remains unknown. Here, we report ovary-dependent induction of Opn mRNA with augmentation of experimental emphysema in adult female mice. Both male and female mice developed emphysematous lungs following intra-tracheal administration of porcine pancreatic elastase; however, compared with male mice, female mice developed more severe injury-related inflammation and pathologic alterations of the lungs. Notably, we observed female-specific induction of the Opn gene upon lung injury. Ovariectomy blocked this induction, with attenuation of lung inflammation and alveolar destruction, demonstrating the essential role of ovaries in injury-related Opn induction and augmentation of emphysema in adult female mice. Lastly, pre-treatment of adult female mice with pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid, which blocks ATP-mediated wound response, suppressed Opn mRNA induction upon lung injury, resulting in attenuation of enhanced lung inflammation. Together, our findings define a novel, ovary-dependent mechanism underlying gender-specific augmentation of emphysema through transcriptional control of the Opn gene.

Usefulness of low-dose methotrexate monotherapy for treating sarcoidosis.

OBJECTIVE: Methotrexate (MTX) is a cytotoxic agent that is commonly employed as an alternative to corticosteroids to treat sarcoidosis, although the proper use and efficacy of MTX as a single agent remain unclear. METHODS: The clinical records of patients newly diagnosed with sarcoidosis who were admitted to our institution between 2000 and 2009 were reviewed. Among these patients, 26 received 7.5 mg of MTX per week as a single agent, and the independent effects of MTX were analyzed. RESULTS: Six of the 26 patients (23%) exhibited an improvement of sarcoidosis-related lesions. The skin lesions demonstrated a relatively higher response rate (37%) than the pulmonary lesions (9%). Ten of the 26 patients (39%) experienced adverse effects, mostly mild hepatotoxicity. No severe adverse effects, including irreversible hepatotoxicity, were observed. CONCLUSION: Although the efficacy of low-dose MTX monotherapy for sarcoidosis in this study was not high (23%), some patients exhibited definite improvements, and the drug proved to be safe, suggesting its possible benefits as a single agent for treating sarcoidosis.

Angioimmunoblastic T-cell lymphoma developed with lymphocytic pleural effusion.

Angioimmunoblastic T-cell lymphoma (AILT) is a rare variant of nodal and aggressive lymphoma. It is sometimes difficult to distinguish AILT from reactive lymphoid hyperplasia from the histopathological aspect. We report a case of AILT which developed with bilateral pleural effusion. The effusion consisted predominately of small lymphoid cells. Analyses of the effusion showed trisomy 3, and rearranged bands of TCR beta gene. Flow cytometry showed a very small amount of CD10-positive cells. Although we could not further identify the tumor cells in this case, analysis of pleural effusion cells will increase our understanding of the pathogenesis and the pathophysiology of AILT.