IL20Rb aggravates pulmonary fibrosis through enhancing bone marrow derived profibrotic macrophage activation.

Idiopathic pulmonary fibrosis (IPF) is one of the most fatal chronic interstitial lung diseases with unknown pathogenesis, current treatments cannot truly reverse the progression of the disease. Pulmonary macrophages, especially bone marrow derived pro-fibrotic macrophages, secrete multiple kinds of profibrotic mediators (SPP1, CD206, CD163, IL-10, CCL18…), thus further promote myofibroblast activation and fibrosis procession. IL20Rb is a cell-surface receptor that belongs to IL-20 family. The role of IL20Rb in macrophage activation and pulmonary fibrosis remains unclear. In this study, we established a bleomycin-induced pulmonary fibrosis model, used IL4/13-inducing THP1 cells to induce profibrotic macrophage (M2-like phenotype) polarization models. We found that IL20Rb is upregulated in the progression of pulmonary fibrosis, and its absence can alleviate the progression of pulmonary fibrosis. In addition, we demonstrated that IL20Rb promote the activation of bone marrow derived profibrotic macrophages by regulating the Jak2/Stat3 and Pi3k/Akt signaling pathways. In terms of therapeutic strategy, we used IL20Rb neutralizing antibodies for animal administration, which was found to alleviate the progression of IPF. Our results suggest that IL20Rb plays a profibrotic role by promoting profibrotic macrophage polarization, and IL20Rb may become a potential therapeutic target for IPF. Neutralizing antibodies against IL20Rb may become a potential drug for the clinical treatment of IPF.

Evaluation of post-dilatation on longitudinal stent deformation and postprocedural stent malapposition in the left main artery by optical coherence tomography (OCT): an in vitro study.

BACKGROUND: The diameter of the ostial and proximal left main coronary artery can be greater than 5.0 mm. However, the diameters of the mostly available coronary drug-eluting stents (DESs) are ≤ 4.0 mm. Whether high-pressure dilatation can increase the diameter of stents from 4.0 to 5.0 mm and whether post-dilatation leads to longitudinal stent deformation (LSD) of 4.0-mm-diameter stents have rarely been studied. Therefore, this study aims to evaluate LSD and stent malapposition of six types of commercially available 4.0-mm-diameter stents in China in a 5.0-mm-diameter artificial blood vessel model by optical coherence tomography (OCT) in vitro. METHODS: The left main coronary artery was simulated by a truncated cone-shaped silicone tube. The internal diameters were 4.0 mm at one end of the silicone tube and 5.0 mm at the other end. Six different types of coronary stents widely used in China were selected for this study. Each stent was respectively implanted into the simulated blood vessel and dilated to a diameter of 4.2 mm according to the stent-balloon pressure compliance table. The stents were subjected to post-dilatation with a 5.0 × 15-mm noncompliant balloon. The LSD ratio of the longitudinal axis of each stent and stent malapposition were measured through OCT, and any fractures of the stents were determined. RESULTS: None of the six types of stents fractured following post-dilatation. The longitudinal axes of the BuMA and Excrossal stents were slightly shortened, while the other stents were elongated after high-pressure post-dilatation. All stents expanded to a diameter of 5.0 mm without incomplete stent apposition, except for the Nano Plus stent, which remained malapposed after high-pressure post-dilatation. CONCLUSION: All 4.0-mm-diameter stents can be expanded to a diameter of 5.0 mm by noncompliant balloon post-dilatation without stent strut fracture. Most stents were found to be well apposed after high-pressure post-dilatation. However, LSD was observed after post-balloon dilatation. Stent malapposition might be positively correlated with the percentage change in stent length.

Risk factors associated with COVID-19 pneumonia in Chinese patients with pre-existing interstitial lung disease during the SARS-CoV-2 pandemic.

In China, the emergence of a nationally widespread epidemic infection of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has appeared within a month since December 7, 2022. To evaluate the risk factors for suffering from coronavirus disease 2019 (COVID-19) pneumonia due to infection with SARS-CoV-2 in different kinds of interstitial lung disease (ILD) patients with diverse immunizations, we conducted this retrospective study on 525 patients with ILDs who underwent regular follow-up in our ILD clinic. Among them, 128 ILD patients (24.4%) suffered from COVID-19 pneumonia after SARS-CoV-2 infection. Patients were older with a male predominance in the pneumonia group than in the nonpneumonia group (65.0 ± 10.0 years vs. 56.4 ± 11.7 years, p < 0.001, 55.5% vs. 39.5%, p = 0.002, respectively). Connective tissue disease-associated ILD (CTD-ILD) (25%), idiopathic pulmonary fibrosis (23.4%), and interstitial pneumonia with autoimmune features (21.1%) were the main pre-existing ILDs in the pneumonia group. In Cox multivariable analysis, only male sex and corticosteroid use were risk factors for COVID-19 pneumonia after infection. Two or three doses of vaccination were a protective factor for pre-existing ILD patients suffering from COVID-19 pneumonia. More than two doses of vaccination were strongly recommended for pre-existing ILD patients, particularly for males who were administered corticosteroids.

FSTL1 promotes alveolar epithelial cell aging and worsens pulmonary fibrosis by affecting SENP1-mediated DeSUMOylation.

Alveolar epithelial cell (AEC) senescence-induced changes of lung mesenchymal cells are key to starting the progress of pulmonary fibrosis. Follistatin-like 1 (FSTL1) plays a central regulatory role in the complex process of senescence and pulmonary fibrosis by enhancing transforming growth factor-ß1 (TGF-ß1) signal pathway activity. Activation of Smad4 and Ras relies on SUMO-specific peptidase 1 (SENP1)-mediated deSUMOylation during TGF-ß signaling pathway activation. We hypothesized that SENP1-mediated deSUMOylation may be a potential therapeutic target by modulating FSTL1-regulated cellular senescence in pulmonary fibrosis. In verifying this hypothesis, we found that FSTL1 expression was upregulated in the lung tissues of patients with idiopathic pulmonary fibrosis and that SENP1 was overexpressed in senescent AECs. TGF-ß1-induced FSTL1 not only promoted AEC senescence but also upregulated SENP1 expression. Interfering with SENP1 expression inhibited FSTL1-dependent promotion of AEC senescence and improved pulmonary fibrosis in mouse lungs. FSTL1 enhancement of TGF-ß1 signaling pathway activation was dependent on SENP1 in senescent AEC. Our work identifies a novel mechanism by which FSTL1 is involved in AEC senescence. Inhibition of SENP1 in epithelial cells alleviated pulmonary fibrosis by blocking FSTL1-enhanced TGF signaling.

Nintedanib in Asian patients with progressive fibrosing interstitial lung diseases: Results from the INBUILD trial.

BACKGROUND AND OBJECTIVE: In the INBUILD trial in patients with progressive fibrosing interstitial lung diseases (ILDs), nintedanib reduced the rate of decline in forced vital capacity (FVC) with an adverse event profile characterized mainly by gastrointestinal events. We analysed the effects of nintedanib in the subset of Asian subjects. METHODS: Subjects with fibrosing ILDs other than idiopathic pulmonary fibrosis who had shown progression of ILD at any time within the prior 24 months despite management deemed appropriate in clinical practice were randomized to receive nintedanib or placebo. We analysed the rate of decline in FVC (ml/year) over 52 weeks in all Asian subjects and in Asian subjects with a usual interstitial pneumonia (UIP)-like fibrotic pattern on high-resolution computed tomography (HRCT). RESULTS: One hundred sixty-four subjects in the INBUILD trial were of Asian race. The rate of decline in FVC (ml/year) over 52 weeks in this subgroup was -116.8 in the nintedanib group and -207.9 in the placebo group (difference: 91.0 [95% CI: 8.1, 173.9]; nominal p = 0.03). In Asian subjects with a UIP-like fibrotic pattern on HRCT, the rate of decline in FVC (ml/year) over 52 weeks was -130.1 in the nintedanib group and -224.2 in the placebo group (difference: 94.1 [5.5, 182.7]; nominal p = 0.04). Adverse events led to treatment discontinuation in 19.0% of the nintedanib group and 13.8% of the placebo group. CONCLUSION: In Asian patients with progressive fibrosing ILDs, nintedanib reduced the rate of decline in FVC with adverse events that were manageable for most patients.

Myositis specific antibodies are associated with isolated anti-Ro-52 associated interstitial lung disease.

OBJECTIVES: Anti-Ro-52 antibody positivity might be associated with the presence of interstitial lung disease (ILD) among patients with autoimmune features. However, the clinical significance of isolated anti-Ro-52 positivity (i.e. the presence of anti-Ro-52 antibodies but the absence of anti-Ro-60 antibodies; anti-Ro-52+Ro-60-) in patients with ILD is not clear. METHODS: This is a prospective and observational study of Chinese ILD patients with isolated anti-Ro-52 positivity. According to their myositis specific antibody (MSA) status, patients were split into groups, and their clinical and radiological features were compared. RESULTS: Of the 158 enrolled patients with ILD and isolated anti-Ro-52 positivity (isolated anti-Ro-52-ILD), there were 130 patients with a positive MSA status and 28 patients with a negative MSA status. Anti-synthetase antibodies (ASAs) were found in 61.5% of patients with MSA+-ILD, and anti-melanoma differentiation associated protein 5 (anti-MDA-5) antibodies were found in the remaining 38.5% of patients. The anti-nuclear antibody (ANA) pattern was associated with ASA and anti-MDA-5 positivity (x2 = 70.7, P < 0.001; Cramer's value 0.47, P < 0.001): ANA negativity was associated with anti-MDA-5 positivity, and cytoplasmic ANA positivity was associated with ASA positivity. There were statistically significant differences in the high-resolution CT patterns between patients with isolated anti-Ro-52 positivity with different MSA statuses (x2 = 29.8, P < 0.001; Cramer's value 0.31, P < 0.001): OP pattern was more common in patients with anti-MDA-5 antibodies than in those without anti-MDA-5 antibodies. CONCLUSIONS: Patients with isolated anti-Ro-52-ILD showed high positivity of MSA. Isolated anti-Ro-52 positivity with cytoplasmic ANA positivity was strongly associated with ASA+-ILD, while ANA negativity was associated with anti-MDA-5+-ILD.

C/EBP homologous protein promotes Sonic Hedgehog secretion from type II alveolar epithelial cells and activates Hedgehog signaling pathway of fibroblast in pulmonary fibrosis.

BACKGROUND: Endoplasmic reticulum (ER) stress is involved in the pathological process of pulmonary fibrosis, including IPF. It affects a broad scope of cellular types during pulmonary fibrosis but the role in epithelial-mesenchymal crosstalk has not been fully defined. The present study aimed to investigate the effects of Shh secretion by ER  stress-challenged type II alveolar epithelial cells (AECII) on fibroblast and pulmonary fibrosis. METHODS: Conditioned medium (CM) from tunicamycin (TM)-treated AECII was collected and incubated with fibroblast. Short hairpin RNA (shRNA) was used for RNA interference of C/EBP homologous protein (CHOP). The effects of CHOP and HH signaling were evaluated by TM administration under the background of bleomycin-induced pulmonary fibrosis in mice. RESULTS: Both expression of CHOP and Shh in AECII, and HH signaling in mesenchyme were upregulated in IPF lung. TM-induced Shh secretion from AECII activates HH signaling and promotes pro-fibrotic effects of fibroblast. Interfering CHOP expression reduced ER stress-induced Shh secretion and alleviated pulmonary fibrosis in mice. CONCLUSIONS: Our work identified a novel mechanism by which ER stress is involved in pulmonary fibrosis. Inhibition of ER stress or CHOP in epithelial cells alleviated pulmonary fibrosis by suppressing Shh/HH signaling pathway of fibroblasts.

SENP1 regulates the transformation of lung resident mesenchymal stem cells and is associated with idiopathic pulmonary fibrosis progression.

BACKGROUND: Lung resident mesenchymal stem cells (LR-MSCs) play an important role in idiopathic pulmonary fibrosis (IPF) by transforming into myofibroblasts, thereby losing their repair ability. Evidence suggests that key proteins of multiple signaling pathways are involved in myofibroblast differentiation of LR-MSCs, such as ß-Catenin and GLI family zinc finger 1 (GLI1). These proteins are regulated by SUMO (small ubiquitin-like modifier) modification, which is a post-translational modification that promotes protein degradation, while Sumo specific protein 1 (SENP1)-mediated deSUMOylation produces the opposite biological effects. Therefore, we speculated that SENP1 might be a potential target for treating pulmonary fibrosis by preventing the myofibroblast differentiation of LR-MSCs. METHODS: LR-MSCs were isolated from mice by using immunomagnetic beads. The extracted LR-MSCs were identified by flow cytometric analysis and multilineage differentiation assays. Lentivirus packaged shRNA silenced the expression of SENP1 in vitro and vivo. The silencing efficacy of SENP1 was verified by real-time quantitative PCR. The effect of down-regulated SENP1 on the myofibroblast differentiation of LR-MSCs was assessed by Immunofluorescence and Western blot. Immunoprecipitation was used to clarify that SENP1 was a key target for regulating the activity of multiple signaling pathways in the direction of LR-MSCs differentiation. LR-MSCs resident in the lung was analyzed with in vivo imaging system. HE and Masson staining was used to evaluate the therapeutic effect of LR-MSCs with SENP1 down-regulation on the lung of BLM mice. RESULTS: In this study, we found that the myofibroblast differentiation of LR-MSCs in IPF lung tissue was accompanied by enhanced SENP1-mediated deSUMOylation. The expression of SENP1 increased in LR-MSCs transition of bleomycin (BLM)-induced lung fibrosis. Interfering with expression of SENP1 inhibited the transformation of LR-MSCs into myofibroblasts in vitro and in vivo and restored their therapeutic effect in BLM lung fibrosis. In addition, activation of the WNT/ß-Catenin and Hedgehog/GLI signaling pathways depends on SENP1-mediated deSUMOylation. CONCLUSIONS: SENP1 might be a potential target to restore the repair function of LR-MSCs and treat pulmonary fibrosis. Video Abstract.

Predictive value of LDL/HDL ratio in coronary atherosclerotic heart disease.

BACKGROUND: Dyslipidemia is one of independent risk factors for coronary atherosclerotic heart disease (CAHD). We determined whether the LDL/HDL ratio is better than LDL-C or HDL-C alone in predicting the severity of CAHD. METHODS: We performed a retrospective study of 1351 patients with myocardial ischemia who underwent coronary angiography between January 2018 and December 2019 in Shanghai Ninth People's Hospital. Spearman correlation analysis, logistic regression model, Cox proportional hazards model and multicollinearity were used to evaluate LDL/HDL ratio for predicting CAHD severity compared to LDL-C or HDL-C alone. RESULTS: Higher LDL/HDL ratio was seen in CAHD patients than controls (2.94 ± 1.06 vs 2.36 ± 0.78, P < 0.05). LDL/HDL ratio was significantly associated with the severity of coronary vascular stenosis. The area under the ROC curve of LDL-C, HDL-C, LDL/HDL ratio used to predict CAHD are 0.574 (95% CI 0.547-0.600, P < 0.001), 0.625 (95% CI 0.598-0.651, P < 0.001), 0.668 (95% CI 0.639-0.697, P = 0.000), respectively. The cut-off value of LDL/HDL ratio is 2.517, and the sensitivity and specificity are 65% and 61%, respectively. LDL/HDL ratio was related to the prevalence of CAHD and the odds ratio (OR) was 2.39 [95% confidence interval (CI) 1.698-2.593, P = 0.00] in multicollinearity regression model. CONCLUSION: LDL/HDL ratio may become a better predictor of CAHD severity, compared to LDL-C or HDL-C.

Severe asthma as the initial clinical manifestation of IgG4-related disease: a retrospective clinical study.

BACKGROUND: Respiratory involvement is common in immunoglobulin G4-related disease (IgG4-RD). However, severe asthma as the initial clinical manifestation of IgG4-RD is rare and might be neglected by respiratory clinicians. We aimed to explore the clinical characteristics and prognoses of patients with immunoglobulin G4-related disease (IgG4-RD) manifesting as severe asthma. METHODS: A retrospective analysis of the clinical characteristics and prognoses of patients with severe asthma who were eventually diagnosed with IgG4-RD was performed in the Peking Union Medical College Hospital from 2013 to 2019. RESULTS: Twelve patients (5males, 7 females) were included. The mean age at enrollment and age of asthma onset were 59.4 ± 10.1 and 53.8 ± 10.4 years, respectively. The mean duration of asthma symptoms was 5.7 ± 2.0 years. In all patients, the proportion (25.1 ± 10.3%) and count (2.0 ± 1.1) × 109/L of eosinophils in peripheral blood increased. Additionally, all patients exhibited elevated total immunoglobulin E [IgE, (1279.3 ± 1257.9) KU/L] and IgG4 (9155.8 ± 9247.6) mg/dL. Bronchial wall thickening (n = 11) and mediastinal/hilar lymphadenopathy (n = 11) were major chest CT manifestations. All were pathologically diagnosed through surgical biopsy; submandibular gland (n = 8), supraclavicular lymph node (n = 2), stomach (n = 1), rashes (n = 1), lacrimal gland (n = 1) and thoracoscopic lung (n = 1) biopsies were performed. Asthma was well controlled by oral glucocorticoids (GCs), but some patients relapsed during tapering (n = 11). The refractory condition was controlled after increasing the dosage of GCs and add-on immunosuppressants. CONCLUSIONS: For patients with middle age-onset severe asthma with elevated eosinophils, total IgE and IgG4 levels and available salivary gland ultrasound imaging, ruling out IgG4-RD is recommended. GCs used in combination with immunosuppressants is recommended to prevent relapse.

[Clinical characteristics of arrhythmia-onset sarcoidosis cases].

Objective: To describe the clinical characteristics of sarcoidosis patients with arrhythmia as the primary or main manifestation. Methods: We conducted a retrospective analysis of arrhythmia-onset sarcoidosis cases between January 2017 and December 2020. Their clinical manifestations, radiological features, treatment and prognosis were reviewed and analyzed. Results: This study consisted of 3 females and 1 male, with a mean age of 51 years (range from 42 to 58 years old). Arrhythmia was the first or main clinical manifestation for all 4 cases, involving Ⅲ° atrioventricular block (AVB) (n=1), Ⅱ° type Ⅱ AVB (n=1), and frequent ventricular premature beats and short array ventricular tachycardia (n=2). Three cases were diagnosed with respiratory sarcoidosis simultaneously during the diagnostic evaluation for arrhythmia. One case was diagnosed with sarcoidosis because of abnormal chest CT images due to cervical lymph node enlargement 5 years after arrhythmia. All 4 cases were confirmed as presenting epithelioid cell granulomatous inflammation by bronchoscopic biopsies. Late gadolinium enhancement with cardiac magnetic resonance (LGE-CMR) imaging was arranged for two cases. Both of them had typical imaging findings of cardiac sarcoidosis. Three cases were confirmed of cardiac involvement through positron emission computed tomography (PET)-CT. None of the enrolled four cases were arranged with endomyocardial biopsy. All four cases were improved with oral corticosteroids, immunosuppressants and anti-arrhythmic medications. Two cases underwent cardiac pacemaker implantation. Conclusions: The possibility of cardiac sarcoidosis should be considered in middle-aged and elderly patients with unexplained high-degree AVB or ventricular arrhythmia. Chest CT is recommended for routine screening for those cases. LGE-CMR and/or PET-CT is recommended for them to confirm the diagnosis of cardiac sarcoidosis. Corticosteroids and immunosuppressants are effective for these patients.

[Retrospective analysis and a cross-sectional questionnaire survey of lung cancer concomitant with interstitial lung disease].

Objective: To describe the clinical characteristics and prognosis of lung cancer concomitant with interstitial lung disease (LC-ILD), and to understand the current status of knowledge of LC-ILD by physicians in the departments related to the treatment of the disease. Methods: We conducted a retrospective analysis of in-hospitalized pathology identified lung cancer (LC) patients who were admitted to our hospital between January 2014 and December 2018. After reviewing their chest CT imagings and pathological reports, 70 patients who were concomitant with interstitial lung disease (ILD) were enrolled in our study. On the other hand, a cross-sectional survey using an online questionnaire was conducted in LC-ILD management doctors who came from 29 provincial hospitals. The perceptions of demographic features, LC characteristics and management, ILD characteristics and management, and the prognosis of LC-ILD were investigated. Results: Among the 70 enrolled LC-ILD cases, there were 52 males, and the mean age was (64.3±7.63) years (ranged from 49 years to 84 years). There were 51 patients who were older than 59 years. The most common pathological pattern of LC was adenocarcinoma. Most of them were diagnosed with LC and ILD simultaneously, and they were usually treated with chemotherapy while unresectable. There were 11 patients (15.7%) with positive EGFR or ALK mutation. Forty-five patients (64.3%) died during the follow-up, and 33 were died from LC progression. There were no significant differences between the surgical group and non-surgical group on age, pathological patterns, EGFR or ALK mutation. However, LC-ILD patients in the surgical group were diagnosed with earlier TNM classification and with better prognosis. A total of 1 014 doctors answered the questionnaire completely. In the feedback, patients aged 60 years and older (785 doctors/77.4%), and male patients (720 doctors/71%) were the predominant LC-ILD patients. Adenocarcinoma (390 doctors/38.5%), adenocarcinoma or squamous-cell cancer (SCC) (182 doctors/17.9%), and SCC (151 doctors/14.9%) were considered as the common pathological patterns of LC-ILD patients. In most doctors' feedback, the EGFR or ALK mutation was not common for LC-ILD: low (646 doctors/63.7%) or hardly (306 doctors/30.5%) positive mutation. The diagnosis of ILD was earlier than LC (506 doctors/49.9%) or there was no identified precedence of LC and ILD diagnosis (208 doctors/20.5%). Most of the doctors (693 doctors/68.3%) agreed that the vital factor for surgery or not was the severity of ILD for LC-ILD patients. There were great divergences on the treatment protocol both for the advanced LC and ILD. The patients with LC-ILD were died mostly from LC progression and ILD exacerbation (542 doctors/53.5%), followed by ILD exacerbation (237 doctors/23.4%) or LC progression (226 doctors/22.3%). Conclusions: The elderly male patients were predisposed to LC-ILD, and adenocarcinoma was the common pathological pattern. The LC-ILD patients with non-advanced LC who were performed with surgery had better prognosis. However, it is recommended to consider whether to perform surgery in combination with the severity of the ILD.

[Clinical analysis of autoimmune diseases associated with interstitial lung diseases initially presented with idiopathic pulmonary fibrosis].

Objectives: To describe the clinical characteristics of patients with autoimmune diseases associated interstitial lung diseases (AID-ILD) initially presented with idiopathic pulmonary fibrosis (IPF) in a tertiary Chinese hospital. Methods: We conducted a retrospective analysis of 14 patients diagnosed with AID-ILD during the IPF follow-up between January 2016 and December 2021. Among the 14 enrolled AID-ILD cases, there were 13 males and 1 female, (69.71±9.07) years old (range from 55 y to 87 y). Results: Detailed clinical consultation and further laboratory analysis were performed during the follow-up when the IPF patients showed exaggerated dyspnea (7 cases), fever of unknown causes (6 cases), microscopic hematuria (5 cases), arthralgia and swelling (4 cases), arthralgia (2 cases), morning stiffness (2 cases) and renal failure (2 cases). Finally, 6 patients showed positive MPO-ANCA, one patient showed positive PR3-ANCA and 7 patients showed positive anti-CCP. During the IPF periods, 7 patients had received antifibrotic agents and 5 patients had been prescribed with N-acetylcysteine, and 1 patient had received antifibrotic agents after N-acetylcysteine. Among them, no medication was prescribed for one IPF patient. After they were diagnosed with AID-ILD, glucocorticoids and/or immunosuppressants were added for 13 of them. Thirteen of cases improved or stable after these treatments, but one didn't show significant changes. Conclusions: AID-UIP, especially ANCA-UIP, AAV-UIP or RA-UIP should be considered when the IPF patients showed fever of unknown origin, microscopic hematuria and/or arthritis related symptoms. They might benefit from the add-on glucocorticoids and/or immunosuppressants.

[Host factors and characteristics of hospitalized patients with pneumocystis jirovecii pneumonia].

Objectives: To describe the underlying diseases, microbiologic examination and severity of hospitalized patients with Pneumocystis jirovecii pneumonia (PJP) in a tertiary Chinese hospital. Methods: We conducted a retrospective analysis of 485 identified PJP patients who were admitted to our hospital between January 2013 and December 2021. Results: Among the 485 enrolled PJP cases, there were 237 males and 248 females, aging (53.3±16.2) years (range from 14 y to 88 y). They were divided into 8 subgroups with variable underlying diseases. There were 209 cases with connective tissue diseases(CTD), 27 cases with non-hematologic malignancies, 38 cases with hematologic malignancies, 81 cases with kidney diseases, 33 cases with idiopathic interstitial pneumonia(IIP), 30 cases infected with human immunodeficiency virus (HIV), and 42 cases with miscellaneous underlying diseases. In the CTD group, there was more females than males, while male patients were predominant in both the malignant and the HIV groups. The Pneumocystis was identified in 44.95%(218/485) sputum samples and 92.01%(265/288) bronchoscopic samples. Pneumocystis asci were observed at direct microscopic examination with Grocott's methenamine silver stain in 4.95%(24/485)sputum samples and 9.72%(28/288)bronchoscopic samples. Pneumocystis DNA fragments were identified by PCR analysis in 43.09%(209/485)sputum samples and 90.63%(261/288)bronchoscopic samples. Among the 8 groups, cytomegaviremia and respiratory failure were most common in the HIV-infected PJP group, but the rates of mechanic ventilation, intensive care unit (ICU) admission and death were the lowest. There were less PJP patients in the IIP group (IIP-PJP) who received mechanic ventilation and admitted to ICU than the other groups except HIV-infected PJP group. However, the mortality rate was highest for the IIP-PJP group. Conclusions: CTD was the most common predisposed underlying disease for our enrolled PJP cases. Cytomegaviremia and respiratory failure were common in HIV-infected PJP patients, but the prognosis of HIV-PJP was slightly better than the others. The disease was more severe, rapidly progressive and fatal in the IIP-PJP group.

Prognosis of adult idiopathic inflammatory myopathy-associated interstitial lung disease: a retrospective study of 679 adult cases.

OBJECTIVES: Few studies have investigated the prognostic factors for idiopathic inflammatory myopathy-associated interstitial lung disease (IIM-ILD) across different clinical/serological phenotypes. METHODS: We conducted a retrospective analysis of patients diagnosed with IIM between January 2012 and December 2017. RESULTS: Of the 760 IIM cases registered, 679 adult cases were included in this study. ILD was present in 508 cases, and the presence of ILD in the clinically amyopathic DM, DM and PM groups was 92.7, 73.6 and 55.1%, respectively (P < 0.01). The prevalence of ILD in the anti-synthetase antibody (ASA)+-IIM group was higher than that in ASA--IIM group (95.2 vs 72.4%, P < 0.01); no such difference was found between the anti-histidyl-tRNA synthetase (Jo-1)+-IIM and Jo-1-ASA+-IIM groups (93.0 vs 98.5%, P > 0.05). The prevalence of ILD in the melanoma differentiation-associated protein-5 (MDA-5)+-IIM group was higher than that in MDA-5--IIM group (97.8 vs 72.1%, P < 0.01). Among adults with IIM, men with concurrent ILD, who were older than 50 years, were most likely to die. No significant difference was found in the all-cause mortality rates between DM-ILD and clinically amyopathic DM-ILD groups (33.3 vs 23%, P > 0.05), although both were higher than that in PM group (13.2%, P = 0.01 and P < 0.05, respectively). No difference was found in the all-cause mortality rates between MDA5-ASA--IM-ILD and MDA5-ASA+-IM-ILD groups (17.2 vs 12.8%, P > 0.05), and both were lower than that in MDA5+ASA--IM-ILD group (33.7%, P < 0.05). CONCLUSION: The prevalence of ILD in IIM and the prognosis of IIM-ILD patients may vary depending on the statuses of the ASA and MDA-5 antibodies.

Circulating ANGPTL3 and ANGPTL4 levels predict coronary artery atherosclerosis severity.

BACKGROUND: We investigated the role of ANGPTL3 and ANGPTL4 in atherosclerosis development and determined whether plasma concentrations of ANGPTL3 and ANGPTL4 are related to the degree of coronary stenosis. METHODS: A total of 305 consecutive patients with angina who underwent diagnostic coronary angiography were enrolled in the study between August 2017 and August 2018. The levels of ANGPTL3 and ANGPTL4 were measured by using competitive ELISA kits. RESULTS: According to the degree of coronary artery stenosis, patients were classified into four types: coronary artery stenosis of < 10%, 10-50%, 50-75, and > 75%. The plasma ANGPTL3 level was higher (51.71 ± 52.67 vs. 24.65 ± 10.32 ng/mL, P < 0.001) and that of ANGPTL4 was lower (454.66 ± 269.05 vs. 875.49 ± 961.15 ng/mL, P < 0.001) in the coronary artery stenosis ≥ 10% group than in the < 10% group. ANGPTL3 and ANGPTL4 levels were significantly associated with the severity of coronary vascular stenosis. ROC curve analyses indicated that ANGPTL3 concentrations above 30.5 ng/mL can predict atherosclerosis with a sensitivity of 71.2% and specificity of 75.3%, and that ANGPTL4 levels below 497.5 ng/mL can predict atherosclerosis with a sensitivity of 63.9% and specificity of 74.5%. ANGPTL3 and ANGPTL4 were determined to be independent risk factors for coronary atherosclerosis with odds ratios (ORs) of 0.189 (95% CI 0.097-0.368, P < 0.001) and 3.625 (95% CI 1.873-7.016, P < 0.001), respectively. CONCLUSIONS: Increased ANGPTL3 or decreased ANGPTL4 shows an association with coronary atherosclerosis and, may become a predictor of coronary atherosclerosis in the future.

Pulmonary fibrosis in dyskeratosis congenita: a case report with a PRISMA-compliant systematic review.

BACKGROUND: Dyskeratosis congenita (DC) is a rare genetic disorder of poor telomere maintenance. Pulmonary fibrosis (PF) related to DC is rarely reported. CASE PRESENTATION: A 23-year-old student presented with a four-year history of progressive cough and exertional dyspnea. Physical examination was remarkable for typical mucocutaneous abnormalities. Chest computerized tomography scan revealed interstitial fibrosis. Testing of peripheral blood leukocytes confirmed that his telomeres were 30th percentile of age-matched controls. A heterozygous missense mutation located in exon 22 of PARN gene was identified in the patient by whole exome sequencing. The patient refused danazol therapy and lung transplantation, and died of respiratory failure 2 years later. In addition, this case and 26 reported cases of DC-related PF identified through the comprehensive search of PubMed, Web of Science, WANFANG and CNKI were reviewed. Later-onset PF was observed in 11 patients (40.7%). Radiological usual interstitial pneumonia (UIP) pattern or possible UIP pattern was noted only in half of patients. However, histopathological UIP or probable UIP patterns were found in 63.6% of patients. Age at bone marrow failure (BMF) and the frequency of normal to mild thrombocytopenia in later-onset patients was significantly higher than in early-onset patients (p = 0.017 and p = 0.021, respectively). Age at PF and age at BMF in DC patients with TERC/TERT variants was significantly higher than in those with TINF2 variants or DKC1/NHP2 variants (p = 0.004 and p = 0.003, respectively). The patients with TERT/TERC/RTEL1/PARN variants had a significantly better transplant-free survival than those with TINF2 variants or DKC1/NHP2 variants (p < 0.05). Patients who underwent surgical lung biopsy had significantly worse transplant-free survival than those without lung biopsy (p = 0.042). Worse survival was found in patients with immunosuppression therapy than in those without (p = 0.012). CONCLUSIONS: It is common for DC-associated PF to occur later in life without significant hematological manifestations. Mutations in the genes encoding different components of the telomere maintenance pathway were associated with clinical phenotypes and prognosis. PF caused by DC should be kept in mind by clinicians in the differential diagnosis of patients with unexplained PF and should be excluded before diagnostic surgical lung biopsy is undertaken or empirical immunosuppression therapy is prescribed.

Relation between sex hormones and leucocyte telomere length in men with idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: IPF is an ageing-related lung disorder featuring progressive lung scarring. IPF patients are frequently identified with short telomeres but coding mutations in telomerase can only explain a minority of cases. Sex hormones regulate telomerase activity in vitro and levels of sex hormones are related to LTL. The objective of this study was to explore whether sex hormones were associated with LTL, whether they interacted with genetic variants in telomerase and whether polymorphisms in the exon of androgen metabolism genes were associated with plasma testosterone concentrations in male IPF patients. METHODS: A case-control study was performed on 101 male IPF subjects and 51 age-matched healthy controls. Early morning plasma sex hormones were quantified, and whole-exome sequencing was used to identify rare protein-altering variants of telomerase and SNP in the exon of androgen metabolism genes. LTL was analysed by PCR and expressed as a T/S ratio. RESULTS: LTL, testosterone and DHT were decreased significantly in the IPF group. After adjustments for age and variant status in telomerase-related genes, only testosterone was positively associated with LTL (P = 0.001). No significant interaction (P = 0.661) was observed between rare protein-altering variants of telomerase and testosterone. No coding SNP in androgen metabolism genes were significantly associated with testosterone concentrations. CONCLUSION: Plasma testosterone is associated with LTL independent of age or rare protein-altering variants of telomerase. No genetic variations of androgen-related pathway genes are associated with androgen concentrations. Further studies are warranted to examine whether hormonal interventions might retard telomere loss in male IPF patients.

Long-term treatment with nintedanib in Asian patients with idiopathic pulmonary fibrosis: Results from INPULSIS®-ON.

BACKGROUND AND OBJECTIVE: The efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis (IPF) were investigated in the placebo-controlled INPULSIS® trials. All patients who completed an INPULSIS® trial could receive open-label nintedanib in the extension trial INPULSIS®-ON. METHODS: We assessed the long-term efficacy and safety of nintedanib in patients of Asian race who were treated in INPULSIS®-ON. Analyses were descriptive. RESULTS: A total of 215 Asian patients were treated in INPULSIS®-ON, of whom 121 continued nintedanib in INPULSIS®-ON and 94 initiated nintedanib in INPULSIS®-ON having received placebo in an INPULSIS® trial. At baseline of INPULSIS®-ON, the mean (SD) age of Asian patients was 66.3 (7.5) years, 80.5% were males and mean (SD) forced vital capacity (FVC) was 78.9 (19.3) % predicted. Median total exposure to nintedanib in both INPULSIS® and INPULSIS®-ON was 42.2 months; maximum exposure was 64.1 months. In INPULSIS®, the annual rate (SE) of decline in FVC over 52 weeks in Asian patients was -124 (20) mL/year in the nintedanib group and -218 (24) mL/year in the placebo group. In INPULSIS®-ON, the annual rate (SE) of decline in FVC over 192 weeks in Asian patients was -127 (11) mL/year. Diarrhoea was reported in Asian patients at event rates of 58.8 and 82.5 events per 100 patient exposure-years in patients who continued and initiated nintedanib in INPULSIS®-ON, respectively. CONCLUSION: The effect of nintedanib on slowing disease progression in Asian patients with IPF is sustained over the long term. Long-term treatment with nintedanib has an acceptable safety and tolerability profile.

The Association Between MUC5B Mutations and Clinical Outcome in Patients with Rheumatoid Arthritis-Associated Interstitial Lung Disease: A Retrospective Exploratory Study in China.

BACKGROUND Patients with rheumatoid arthritis (RA) who develop interstitial lung disease (RA-ILD), show features of usual interstitial pneumonia (UIP) on high-resolution computed tomography (HRCT). This retrospective exploratory clinical study aimed to investigate the association between mutations in the MUC5B gene and clinical outcome in patients with RA, with or without RA-ILD, using whole-exome sequencing (WES). MATERIAL AND METHODS WES was performed using peripheral blood samples for mutations in the MUC5B gene in 51 patients diagnosed with RA without ILD, and 45 patients with RA-ILD. The cumulative incidence in acute exacerbations of RA-ILD and variables associated with acute exacerbations of RA-ILD were analyzed. RESULTS In patients with RA-ILD, the main genetic variants of MUC5B were identified, with an odds ratio (OR) of 3.410 (p=0.013). Nine patients with RA without ILD (17.6%) and 19 patients with RA-ILD (42.2%) expressed MUC5B variants. Patients with RA-ILD carrying MUC5B variants had a significantly increased duration of RA-ILD (p=0.03) and showed a UIP pattern on lung HRCT (p=0.01). Acute exacerbations of RA-ILD occurred in 25 patients during follow-up, including 13 patients with mutant MUC5B and 12 patients with wildtype MUC5B. Univariate analysis showed that MUC5B mutations (p=0.043), older age of onset of RA (p=0.041), increased serum anti-citrullinated protein antibodies (ACPAs) (p=0.033), and a UIP imaging pattern on HRCT (p=0.015) were significantly correlated with acute exacerbations of RA-ILD. However, these findings were not supported by multivariate analysis (p=0.065). CONCLUSIONS The carrier status of MUC5B variants was an indicator of reduced prognosis and increased exacerbations of RA-ILD.