Advanced Interstitial Lung Disease Research Articles

Deep-learning CT imaging algorithm to detect usual interstitial pneumonia pattern in patients with systemic sclerosis-associated interstitial lung disease: association with disease progression and survival.

Interstitial lung disease (ILD) is the most common cause of death in patients with systemic sclerosis (SSc), although disease behavior is highly heterogeneous. While a usual interstitial pneumonia (UIP) pattern is associated with worse survival in other ILDs, its significance in SSc-ILD is unclear. We sought to assess the prognostic utility of a deep-learning HRCT algorithm of UIP probability in SSc-ILD. Patients with SSc-ILD were included if HRCT images, concomitant lung function tests, and follow-up data were available. We used the Systematic Objective Fibrotic Imaging analysis Algorithm (SOFIA), a convolution neural network algorithm which provides probabilities of a UIP pattern on HRCT images. These were converted into the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED)-based UIP probability categories. Decline in lung function was assessed by mixed-effect model analysis and relationship with survival by Cox proportional hazards analysis. 522 patients were included in the study. 19.5% were classified as UIP not in the differential, 53.5% as low probability of UIP, 25.7% as intermediate probability of UIP, and 1.3% as high probability of UIP. A higher likelihood of UIP probability expressed as PIOPED categories was associated with worse baseline FVC, as well as with decline in FVC (p= 0.008), and worse 15-year survival (p= 0.001), both independently of age, gender, ethnicity, smoking history, and baseline FVC or Goh et al. staging system. A higher probability of a SOFIA-determined UIP pattern is associated with more advanced ILD, disease progression, and worse survival, suggesting that it may be a useful prognostic marker in SSc-ILD.

Correlation of FAPI PET Uptake with Immunohistochemistry in Explanted Lungs from Patients with Advanced Interstitial Lung Disease.

Recent studies have demonstrated promising results of fibroblast activation protein (FAP) inhibitor (FAPI) PET in prognosticating and monitoring interstitial lung diseases (ILDs). As a first step toward successful translation, our primary aim was to validate the FAPI PET uptake through immunohistochemistry in patients with advanced ILD who underwent lung transplantation after a FAPI PET scan. Methods: This is a preliminary analysis of a single-center, open-label, single-arm, prospective exploratory biodistribution study of 68Ga-FAPI-46 PET imaging in patients with ILD (NCT05365802). Patients with ILD confirmed by high-resolution CT and scheduled for lung transplant were included. Tissue samples of explanted lungs were obtained from both the central and peripheral lung parenchyma of each lobe. Additional samples were obtained from areas of the lung corresponding to regions of FAPI PET activity. Immunohistochemical staining was performed with an anti-FAP antibody. Percentages of FAP immunohistochemistry-positive area were measured semiautomatically using QuPath software. SUVs in the areas of pathologic samples were measured on FAPI PET/CT by referencing the gross photomap of the explanted lung. A Spearman correlation coefficient test was used to assess the relationship between FAPI PET uptake and FAP immunohistochemical expression in each specimen. Results: Four patients with advanced ILD who underwent FAPI PET/CT before lung transplantation were included. The types of ILD were idiopathic pulmonary fibrosis (n = 2), rheumatoid arthritis-associated ILD (n = 1), and nonspecific interstitial pneumonia (n = 1). FAPI uptake was visualized mainly in the fibrotic area on CT. Twenty-nine surgical pathology samples from 3 patients were analyzed. FAP staining was predominantly positive in fibroblastic foci. FAPI PET SUVmax and SUVmean showed a positive correlation with the immunohistochemical FAP expression score (SUVmax: r = 0.57, P = 0.001; SUVmean: r = 0.54, P = 0.002). Conclusion: In this analysis conducted in patients who underwent lung transplantation after a FAPI PET scan, FAPI PET uptake was positively correlated with FAP immunohistochemistry. These findings provide a rationale for further investigation of FAPI PET as a potential imaging biomarker for ILD.

Converging Pathways: A Review of Pulmonary Hypertension in Interstitial Lung Disease.

Pulmonary hypertension (PH) in interstitial lung disease (ILD) is relatively common, affecting up to 50% of patients with idiopathic pulmonary fibrosis (IPF). It occurs more frequently in advanced fibrotic ILD, although it may also complicate milder disease and carries significant clinical implications in terms of morbidity and mortality. Key pathological processes driving ILD-PH include hypoxic pulmonary vasoconstriction and pulmonary vascular remodelling. While current understanding of the complex cell signalling pathways and molecular mechanisms underlying ILD-PH remains incomplete, there is evidence for an interplay between the disease pathogenesis of fibrotic ILD and PH, with interest in the role of the pulmonary endothelium in driving pulmonary fibrogenesis more recently. This review examines key clinical trials in ILD-PH therapeutics, including recent research showing promise for the treatment of both ILD-PH and the underlying pulmonary fibrotic process, further supporting the hypothesis of interrelated pathogenesis. Other important management considerations are discussed, including the value of accurate phenotyping in ILD-PH and the success of the "pulmonary vascular" phenotype. This article highlights the close and interconnected nature of fibrotic ILD and PH disease pathogenesis, a perspective likely to improve our understanding and therapeutic approach to this complex condition in the future.

Ischaemic Strokes Caused by Spontaneous Cerebral Air Embolism, A Rare Complication of Interstitial Lung Disease.

This case demonstrates a mechanism of stroke in patients with severe interstitial lung disease (ILD) that has not been previously described, and we suggest that in cases of advanced ILD, clinicians should consider this as a possible mechanism of stroke. The management of these patients should include transferring them to hyperbaric facilities to prevent further air emboli.

Acute Exacerbation of Interstitial Lung Disease: Definitions, Epidemiology, Prognosis and Management.

Abstract Acute exacerbation of interstitial ling disease (AE-ILD) denotes a rapid deterioration of respiratory function often leading to ICU admission due to severe hypoxemia. Definitions encompass the diverse spectrum of interstitial lung diseases and specific criteria for AE-ILD, originally established for idiopathic pulmonary fibrosis (IPF) and later expanded to other interstitial lung diseases. The incidence varies among the various interstitial lung disease subtypes, with around 10% of interstitial lung disease patients experiencing acute exacerbations within the initial two years of diagnosis. Clinical risk factors encompass advanced interstitial lung disease, compromised pulmonary function, and coexisting conditions. Prognostic markers include baseline pulmonary parameters, blood markers, and a newly developed Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) staging system. However, due to the scarcity of randomized studies, optimal treatment strategies remain uncertain. Current guidelines propose supportive care and oxygen therapy, with cautious use of corticosteroids in AE-IPF. Antibiotics are employed to manage infections, with procalcitonin-guided therapy showing potential. Management involves exposure elimination, targeted antibiotics, and antacid and antifibrotic use. For severe cases, mechanical ventilation, extracorporeal membrane oxygenation (ECMO), and even transplantation are considered. To conclude, AE-ILD poses formidable challenges and high mortality rates. Given the lack of standardized approaches, the pursuit of randomized trials is vital to enhance the understanding and management of AE-ILD, optimizing patient outcomes within the ICU setting. Keywords: acute exacerbation, interstitial lung disease, idiopathic pulmonary fibrosis, intensive care unit, definition.

The acute effect of inhaled nitric oxide on the exercise capacity of patients with advanced interstitial lung disease: a randomized controlled trial

BackgroundInhaled nitric oxide (iNO) selectively acts on the pulmonary vasculature of ventilated lung tissue by reducing pulmonary vascular resistance and intrapulmonary shunt. This effect may reduce ventilation/perfusion mismatch and decrease pulmonary hypertension in patients with interstitial lung disease.MethodsIn a prospective, single-blinded, randomized, placebo-controlled trial, participants with advanced interstitial lung disease, underwent two separate six-minute walk tests (6MWT): one with iNO and the other with a placebo. The primary outcome measured the difference in meters between the distances covered in the two tests. Secondary outcomes included oxygen saturation levels, distance-saturation product, and Borg dyspnea score. A predefined subgroup analysis was conducted for patients with pulmonary hypertension.ResultsOverall, 44 patients were included in the final analysis. The 6MWT distance was similar for iNO treatment and placebo, median 362 m (IQR 265-409) vs 371 m (IQR 250-407), respectively (p = 0.29). Subgroup analysis for patients with pulmonary hypertension showed no difference in 6MWT distance with iNO and placebo, median 339 (256-402) vs 332 (238-403) for the iNO and placebo tests respectively (P=0.50). No correlation was observed between mean pulmonary artery pressure values and the change in 6MWT distance with iNO versus placebo (spearman correlation Coefficient 0.24, P=0.33).ConclusionIn patients with advanced interstitial lung disease, both with and without concurrent pulmonary hypertension, the administration of inhaled nitric oxide failed to elicit beneficial effects on the six-minute walk distance and oxygen saturation. The use of inhaled NO was found to be safe and did not lead to any serious side effects.Trial registration(NCT03873298, MOH_2018-04-24_002331).

Vasoactive drugs for the treatment of pulmonary hypertension associated with interstitial lung diseases: a systematic review

ObjectivesVasoactive drugs have exhibited clinical efficacy in addressing pulmonary arterial hypertension, manifesting a significant reduction in morbidity and mortality. Pulmonary hypertension may complicate advanced interstitial lung disease (PH-ILD) and is...

Association between the cardiothoracic ratio on chest X-rays and the respiratory function in patients with interstitial lung diseases: A cross-sectional study

Objective Patients with advanced interstitial lung disease (ILD) struggle to undergo spirometry to evaluate the respiratory function. The cardiothoracic ratio (CTR) on chest radiography can potentially reflect the lung volume; however, this has not yet been fully established. This study aimed to clarify the relationship between the CTR and the respiratory function in patients with interstitial lung diseases. Patients and Methods We reviewed 120 consecutive patients with idiopathic interstitial lung disease who were admitted to our department between April 2018 and March 2023 and who underwent chest radiography, spirometry, and echocardiography. A multiple linear regression analysis was used to identify the factors associated with the CTR. Correlations between the CTR and the respiratory or cardiac function were assessed using Pearson's correlation coefficient. Results A multiple linear regression analysis showed the percent vital capacity (β = -0.598, p <0.001), age (β = 0.405, p <0.001), and female sex (β = 0.177, p = 0.047) to be independently associated with the CTR, whereas no relationship was observed between the left ventricular ejection fraction, body mass index, and smoking habits. The CTR was significantly negatively correlated with the vital capacity (r = -0.490, p <0.001). Conclusions An increased CTR might reflect a decreased vital capacity, but not a decreased cardiac function, in patients with interstitial lung diseases. Measuring the CTR can thus be beneficial for predicting progression in patients with ILD.

A Reversible Case of Advanced Interstitial Lung Disease in a Patient with HER2 Low Metastatic Breast Cancer Treated with Trastuzumab Deruxtecan

A Reversible Case of Advanced Interstitial Lung Disease in a Patient with HER2 Low Metastatic Breast Cancer Treated with Trastuzumab Deruxtecan

Ways to predict interstitial lung disease in patients with systemic sclerosis: results of an observational study

In patients with systemic sclerosis (SSc), interstitial lung disease (ILD) is a factor in the decline of functional capacity up to disability and is also the leading cause of death. Therefore, one of the most important tasks in the treatment of this group of patients is not only to detect involvement of respiratory system, but also to predict the likelihood of its development.Objective: to study the possibility of predicting the development of ILD and advanced ILD in patients with SSc.Material and methods. The study included 79 patients with SSc (mean age 64.4±11.5 years; 94.9% women) from the Registry of myositis, SSc and Mixed Connective Tissue Diseases (РЕМИССиС) who underwent high-resolution computed tomography (HRCT) of the lungs. Classification trees (CTr) were constructed to predict the development of widespread ILD using the CHAID algorithm (exhaustive). All patients were tested for antibodies against Scl-70 (anti-Scl-70), CENP-B (anti-CENP-B), and PmScl (anti-PmScl).Results and discussion. ILD signs according to HRCT were detected in 53 patients. Fibrotic (34.2%) and cellular (15.2%) types of nonspecific interstitial pneumonia were the most common, and common interstitial pneumonia was less frequent (11.4%).The presence of ILD and advanced ILD (involvement of more than 20% of the lung parenchyma) were significantly associated with the detection of any autoantibodies, except anti-centromere antibodies, an increase in pulmonary artery systolic pressure, a decrease in forced vital capacity, diffusing capacity of the lungs, blood oxygen saturation at rest, and all parameters of six-minute walk test (6MWT), and complaints of shortness of breath. In addition, the presence of extensive ILD was also significantly associated with diffuse SSc and with SSc without skin manifestations.In establishing the CTr, it was found that the development of widespread ILD was unlikely in individuals who were able to walk more than 440 m in 6MWT and had neither anti-Scl-70 nor anti-PmScl.Significant associations were also found between the radiological pattern of ILD and the types of disease-specific antibodies.Conclusion. The 6MWT data in conjunction with the results of testing for SSc-specific autoantibodies provide a very accurate prediction of the presence and extent of ILD. It is advisable to include these indicators in the algorithm for screening and monitoring patients with SSc.

Treatment of pulmonary fibrosis through normalization of alveolar macrophages

Abstract Idiopathic pulmonary fibrosis (IPF) is a chronically advanced interstitial lung disease with unclear etiology and poor prognosis. Despite numerous studies, the pathogenesis of IPF has not been completely understood. In this study, we searched for a drug that can decrease chronic lung inflammation without deteriorating lung fibrosis. We found that fenofibrate, a PPARα agonist that is clinically used to control dyslipidemia, had therapeutic effects on pulmonary fibrosis through normalization of alveolar macrophages. We first showed that 6 days of oral administration of fenofibrate blocked the progression of bleomycin-induced pulmonary fibrosis and resolved inflammation. In addition, fenofibrate suppressed the LPS-induced pro-inflammatory mediators in bone marrow-derived macrophages in a PPARα-independent manner; however, it promoted the expression of tissue repair and anti-inflammatory genes. Finally, we examined the expression of the pro-inflammatory, tissue-repair, and anti-inflammatory genes in alveolar macrophages at days 2 or 6 after oral administration of fenofibrate in mice with advancing pulmonary fibrosis. Administration of fenofibrate resulted in decreased expression of proinflammatory cytokines and increased expression of tissue repair and anti-inflammatory genes at day 2. However, the gene expression pattern of alveolar macrophages of fenofibrate-treated mice at day 6 became similar to that of naïve alveolar macrophages. Taken together, this study suggests that fenofibrate can rapidly reprogram inflammatory macrophage polarization toward normal state through a transient resolving and anti-inflammatory macrophage polarization stage, which is linked to amelioration of pulmonary fibrosis.

A nomogram for the prediction of the survival of patients with advanced non-small cell lung cancer and interstitial lung disease.

Lung cancer is frequently accompanied by interstitial lung disease (ILD), and the overall survival (OS) of patients with these comorbidities is poor. Thus, we developed a nomogram for the prediction of the OS of patients with advanced non-small cell lung cancer (NSCLC) and ILD. Patients with wild-type gene advanced NSCLC with and without ILD who underwent chemotherapy between 2014 and 2019 were enrolled in the present study. The 0.5- and 1-year progression-free survival (PFS) and overall survival (OS) times of patients with and without ILD were determined using the Kaplan-Meier method. Cox regression was used to assess the prognostic value of clinical factors for patients with ILD. Based on the multivariate regression results, a nomogram for survival prediction was developed. The nomogram was validated using calibration curve. Data from 155 patients with lung cancer and ILD and 118 matched patients with lung cancer alone who were receiving first-line chemotherapy were analyzed. The first-line chemotherapy regimens were paclitaxel + carboplatin, pemetrexed + carboplatin, gemcitabine + carboplatin, and other. The median PFS and OS were significantly shorter in patients with than in those without ILD (3.0 vs. 7.0 months [p < 0.001] and 7.0 vs. 15.0 months (p < 0.001), respectively). Multivariate analysis showed that the lymphocyte count (hazard ratio [HR] 2.38; 95% confidence interval [CI], 1.44-3.94; p = 0.01), partial pressure of oxygen (PaO2 ; HR, 1.37; 95% CI, 1.03-1.82; p = 0.03), and chemotherapy regimen were independently associated with prognosis. The nomogram showed good discriminatory ability [C-index = 0.69 (95% CI, 0.49-0.82)]. Calibration curves showed that predicted and actual prognoses were consistent. This nomogram can aid the prediction of the OS of patients with advanced NSCLC and ILD.

Antisynthetase syndrome-related interstitial lung disease (ASyS-ILD): longitudinal imaging findings.

Interstitial lung disease (ILD) impacts mortality in antisynthetase syndrome (ASyS). Computed tomographic (CT) patterns and evolution in ASyS ILD are not well described. We report longitudinal CT patterns in ASyS-ILD and their impact on survival. This is a monocentric retrospective study of 47 patients with ASyS-ILD. Longitudinal CT patterns and fibrosis severity (severity of radiographic features indicating fibrosis) were analyzed by two radiologists in consensus. The association between imaging features and survival was examined using univariate Cox regression analysis. In total, 211 CT scans were analyzed with an average of 4 ± 2 CT scans/patient with a median follow-up of 79months in 47 patients. Non-fibrotic patterns were present initially in 63.8% (n = 30) of patients, while fibrotic patterns occurred in 36.2% (n = 17). The initial non-fibrotic patterns/abnormalities resolved in 23.3% (n = 7), evolved in 6.7% (n = 2), persisted in 13.3% (n = 4), and progressed in 56.7% (n = 17), while initial fibrotic patterns persisted in 82.4% (n = 14) and progressed in 17.6% (n = 3). Radiographic progression of ILD (progression in CT pattern or increased fibrosis severity) occurred in 53.2% (n = 25) of patients. Advanced age and radiographic progression were associated with decreased survival (all p < 0.05). The presence of ground-glass opacities (GGO) and predominant lower lung distribution of abnormalities on initial CTs were associated with increased survival (all p < 0.05). Progression occurred in 56.7% of ASyS-ILD patients presenting with non-fibrotic patterns. Fibrotic patterns tended to persist. Age and radiographic progression were associated with reduced survival while the initial presence of GGO and predominant lower lobe distribution were associated with increased survival. • In ASyS-ILD, initial non-fibrotic patterns such as OP, cNSIP, or OP-cNSIP tended to progress to fNSIP. • Fibrotic patterns such as fNSIP or UIP in ASyS-ILD tended to persist without pattern changes. • GGO and lower lung predominance on initial CT were associated with better survival while advanced baseline age and radiographic ILD progression during follow-up were associated with decreased survival.

Incidence and risk factors of venous thrombotic events in patients with interstitial lung disease during hospitalization

BackgroundStudies on the incidence of venous thromboembolism (VTE) events in patients with interstitial lung disease (ILD) are limited and the results are inconsistent. The aim of this research was to investigate the incidence and risk factors of VTE in ILD during hospitalization.Materials and methodsIn this retrospective, cross-sectional, observational study, a total of 5009 patients diagnosed with ILD from January 2016 to March 2022 in our hospital were retrospectively included. In ILD patients, VTE including pulmonary thromboembolism (PTE) and deep vein thrombosis (DVT) were screened from the electronic medical record system. Diagnosis of PTE and DVT were performed by CT pulmonary angiography (CTPA), CTV or ultrasound. And then the incidence and risk factors of VTE in different types of ILD were assessed.ResultsAmong 5009 patients with ILD, VTE was detected in 129 (2.6%) patients, including 15(0.3%) patients with both PTE and DVT, 34 (0.7%) patients with PTE and 80 (1.6%) patients with DVT. 85.1% of patients with APE were in the intermediate-low risk group. The incidence of VTE in Anti-Neutrophil Cytoplasmic Antibodies -associated vasculitis related ILD (ANCA-AV-ILD), hypersensitivity pneumonitis and idiopathic pulmonary fibrosis (IPF) respectively was 7.9% and 3.6% and 3.5%. In patients with connective tissue disease-associated ILD (CTD-ILD), the incidence of VTE, DVT, PTE, combined PTE and DVT respectively was 3.0%, 2.3%, 0.4% and 0.3%. Among the various risk factors, different ILD categories, age ≥ 80 years (OR 4.178, 95% CI 2.097–8.321, P < 0.001), respiratory failure (OR 2.382, 95% CI 1.533–3.702, P < 0.001) and varicose veins (OR 3.718, 95% CI 1.066–12.964, P = 0.039) were independent risk factors of VTE. The incidence of VTE in patients with ILD increased with the length of time in hospital from 2.2% (< 7 days) to 6.4% (> 21 days).ConclusionThe incidence of VTE during hospitalization in ILD patients was 2.6%, with a 1.6% incidence of DVT, higher than the 0.7% incidence of PTE. Advanced age, ILD categories, respiratory failure and varicose veins as independent risk factors for the development of VTE should be closely monitored.

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.

Indicaciones de trasplante pulmonar

In advanced stages of diffuse interstitial lung disease (DILD), the only treatment that may increase survival is lung transplantation. In Spain, 40% of all lung transplantations were performed in patients with DILD; it is the leading cause of transplantation in our country. The selection of candidates for lung transplantation continues to be a challenge for specialist physicians, especially due to ethical difficulties. In this protocol, we will analyze the criteria for referring patients with advanced interstitial lung disease to a lung transplantation center, the indications for their inclusion on the transplantation list, as well as the risk factors that we must take into account when evaluating this therapeutic measure and its contraindications in order to thus provide specific recommendations and optimize the management of these patients.

The 6-min walk test as a primary end-point in interstitial lung disease.

There is a need for clinical trial end-points to better assess how patients feel and function, so that interventions can be developed which alleviate symptoms and improve quality of life. Use of 6-min walk test (6MWT) outcomes as a primary end-point in interstitial lung disease (ILD) trials is growing, particularly for drugs targeting concurrent pulmonary hypertension. However, 6MWT outcomes may be influenced differentially by interstitial lung and pulmonary vascular components of ILD, making interpretation complicated. We propose that using 6MWT outcomes, including 6-min walk distance or oxygen desaturation, as primary end-points should depend upon the study population (how advanced the ILD is; whether vasculopathy is significant), the degree of disease progression, and, importantly, the effect of study treatment expected. We argue that the 6MWT as a single outcome measure is suitable as a primary end-point if the treatment goal is to improve functional performance or prevent disease progression within a study population of patients with advanced ILD or those with ILD and co-existent vasculopathy. In addition, we discuss the potential of composite primary end-points incorporating 6MWT outcomes, outlining important considerations to ensure that they are appropriate for the study population and treatment goals.

Inhibition of AHNAK nucleoprotein 2 alleviates pulmonary fibrosis by downregulating the TGF-β1/Smad3 signaling pathway.

Idiopathic pulmonary fibrosis (IPF) is a chronic and advanced interstitial lung disease with poor prognosis. AHNAK nucleoprotein 2 (AHNAK2) is a macromolecular protein that is important for cell migration and muscle membrane repair. The protein acts via epithelial-mesenchymal transition (EMT), which is a key mechanism in the pathogenesis of IPF. However, very few studies have elucidated the effect of AHNAK2 in the development of IPF. Therefore, we aimed to determine the role of AHNAK2 in IPF development. C57BL/6 mice were induced with bleomycin, while A549 and Beas-2b pulmonary epithelial cell lines were treated with TGF-β1 to induce IPF model. The expression of AHNAK2 was detected using immunohistochemistry staining in vivo, and real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB) in vitro. C57BL/6 mice were injected with adeno-associated virus (AAV)-sh NC or AAV-sh AHNAK2 and the pulmonary function and EMT marker expression were measured. The migratory abilities of the two transforming growth factor beta 1 (TGF-β1)-induced cell lines were examined using wound-healing and Transwell assays after transfection with si-NC, si-AHNAK2-1 and -2. EMT marker expression was detected using RT-qPCR and WB. Smad3 and phosphorylated-Smad3 of the two cells were examined using WB. Following Smad3 inhibition by Smad3 phosphorylation inhibitor (SIS3), TGF-β1-induced cell migration and EMT marker expression were evaluated again after different transfections. AHNAK2 expression was higher in the IPF model than in the normal model in vivo and in vitro. Partial inhibition of AHNAK2 suppressed the EMT process and improved pulmonary ventilation and compliance in the mouse model of IPF. Similarly, knockdown of AHNAK2 suppressed the migration of pulmonary epithelial cells and reversed EMT. Furthermore, Smad3 of the two TGF-β1-induced cell lines was not activated when AHNAK2 was inhibited. When SIS3 inhibited the activation of Smad3, the suppression of AHNAK2 had no effect on A549 and Beas-2b, regardless of TGF-β1 induction. Inhibition of AHNAK2 alleviates pulmonary fibrosis and partially reverses EMT by inhibiting the TGF-β1/Smad3 signaling pathway. Therefore, AHNAK2 is a potential therapeutic target for IPF.

Bronchoalveolar Lavage as a Diagnostic Tool in an Atypical Pulmonary Langerhans Cell Histiocytosis.

Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon diffuse cystic lung disease that occurs almost exclusively in young adult smokers. High-resolution computed tomography of the chest allows a confident diagnosis of PLCH in typical presentation, when nodules, cavitating nodules, and cysts coexist and show a predominance for the upper and middle lung. Atypical presentations require histology for diagnosis. Histologic diagnosis rests on the demonstration of increased numbers of Langerhans cells and/or specific histological changes. PLCH is one of the few diseases in which bronchoalveolar lavage (BAL) has a high diagnostic value and can in some circumstances replace lung biopsy. We present a case of PLCH in an elderly non-smoker. Chest imaging revealed the presence of advanced interstitial lung disease with a fibrocystic pattern. BAL cellular analyses disclosed a macrophage pattern with CD1a phenotype that strongly supports the PLCH diagnosis, even in the setting of atypical clinical presentation and a lack of smoking exposure. PLCH is extremely rare in non-smokers and could represent a distinct phenotype.

Sleep architecture in patients with interstitial lung disease with and without pulmonary hypertension

Sleep disturbance is common in patients with advanced interstitial lung disease (ILD) often complicated by pulmonary hypertension (PH) and may contribute to poor quality of life. The etiology of sleep disturbance and the relationship between PH and sleep architecture in patients with ILD remains unknown. We performed a retrospective cohort study comparing sleep architecture on polysomnography in patients with ILD with and without PH, defined as mean pulmonary artery pressure on right heart catheterization ≥ 20mmHg. We tested the hypothesis that patients with ILD and PH would have increased wake time after sleep onset (WASO) compared to patients with ILD without PH using univariate analysis and multivariable linear regression. In our cohort of patients with ILD who underwent polysomnography (N = 49), patients with PH had lower total diffusion capacity for carbon monoxide (DLCO) (9.28 vs. 12.87ml/min/mmHg, P = 0.04) and percent DLCO (39% vs. 53%, P = 0.03). On polysomnography, patients with PH had increased percentage of total sleep time with saturation < 90% (T90) (17% vs. 6%, P = 0.03), decreased N2 sleep (181 vs. 233min, P = 0.03), decreased %N2 sleep (59% vs. 66%, P = 0.04), increased %N1 sleep (22% vs. 14%, P = 0.02), decreased sleep efficiency (62% vs. 72%, P = 0.03), and increased WASO (133 vs. 84min, P = 0.01). In multivariable analysis, PH was associated with a 43-min increase in WASO (95% CI 6.2-80.2, P = 0.02). Patients with ILD and PH have decreased total and %N2 sleep, increased %N1 sleep, decreased sleep efficiency, and increased WASO, likely indicating increased sleep fragmentation.