Presenting clinical and imaging features of patients with clinically amyopathic interstitial lung disease associated with myositis-specific autoantibodies.

Background: Lung involvement in the context of idiopathic inflammatory myopathies has significant impact on outcome; early and accurate diagnosis is important but can be difficult to achieve. In particular, patients without clinically evident muscle involvement pose a significant diagnostic challenge. Methods: A computer-assisted search was conducted to identify patients with amyopathic interstitial lung disease associated with the presence of myositis-specific autoantibodies. Medical records and chest imaging studies were reviewed to identify clinical and radiologic features at presentation. Results: Of the 35 patients with amyopathic interstitial lung disease associated with myositis-specific autoantibodies, the median age was 65 years (range 43-78) and 20 were women (57%). Of the patients, 34% had previously visited the rheumatology department. Presenting symptoms consisted of dyspnea (94%), cough (43%), and arthritis (23%). Raynaud phenomenon, "mechanic hands," Gottron papules, and inspiratory crackles were present in 23, 31, 9, and 74% of patients, respectively. After a detailed history, none of the patients reported muscle weakness, while four (11%) exhibited increased CK levels; of these four, two had a concomitant increase in aldolase levels. Median FVC was 79% predicted (range: 49-135) and median DLco was 50% predicted (range: 17-103). HRCT pattern was suggestive of an alternative to UIP pattern in 31/33 (94%) patients; the most common imaging patterns were NSIP (49%) and NSIP/OP (39%). Conclusion: In patients with NSIP and NSIP/OP pattern, the presence of amyopathic interstitial lung disease associated with myositis-specific autoantibodies should be considered even in the absence of clinical evident myositis.

Bronchoscopy-related outbreaks and pseudo-outbreaks: A systematic review.

OBJECTIVE: To identify and report the pathogens and sources of contamination associated with bronchoscopy-related outbreaks and pseudo-outbreaks. DESIGN: Systematic review. SETTING: Inpatient and outpatient outbreaks and pseudo-outbreaks after bronchoscopy. METHODS: PubMed/Medline databases were searched according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, using the search terms "bronchoscopy," "outbreak," and "pseudo-outbreak" from inception until December 31, 2022. From eligible publications, data were extracted regarding the type of event, pathogen involved, and source of contamination. Pearson correlation was used to identify correlations between variables. RESULTS: In total, 74 studies describing 23 outbreaks and 52 pseudo-outbreaks were included in this review. The major pathogens identified in these studies were Pseudomonas aeruginosa, Mycobacterium tuberculosis, nontuberculous mycobacteria (NTM), Klebsiella pneumoniae, Serratia marcescens, Stenotrophomonas maltophilia, Legionella pneumophila, and fungi. The primary sources of contamination were the use of contaminated water or contaminated topical anesthetics, dysfunction and contamination of bronchoscopes or automatic endoscope reprocessors, and inadequate disinfection of the bronchoscopes following procedures. Correlations were identified between primary bronchoscope defects and the identification of P. aeruginosa (r = 0.351; P = .002) and K. pneumoniae (r = 0.346; P = .002), and between the presence of a contaminated water source and NTM (r = 0.331; P = .004) or L. pneumophila (r = 0.280; P = .015). CONCLUSIONS: Continued vigilance in bronchoscopy disinfection practices remains essential because outbreaks and pseudo-outbreaks continue to pose a significant risk to patient care, emphasizing the importance of stringent disinfection and quality control measures.

Coexistence of Autoimmune Pulmonary Alveolar Proteinosis With Small Cell Lung Cancer in a Man Presenting With Acute Onset Respiratory Failure.

A 60-year-old man was referred to our Respiratory Department with progressive dyspnea on exertion and productive cough over the past two months. High-resolution computed tomography showed diffuse ground glass opacities with superimposed interlobular and intralobular septal thickening mainly in the middle and lower lobes, compatible with crazy paving pattern. Serology tests revealed positive antibody transcriptional intermediary factor-γ1 (TIF-1γ) in myositis panel and bronchoalveolar lavage revealed milky appearance and positive periodic acid-Schiff (PAS) stain. Pulmonary function tests showed moderate reduction in diffusing capacity for carbon monoxide. The working diagnosis of autoimmune pulmonary alveolar proteinosis was established by high detectable levels of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies. Despite clinical and radiological improvement following treatment with whole lung lavage and inhaled sargramostim, patient's follow-up chest computed tomography revealed an enlargement of lower left paratracheal lymph node 4L. Endobronchial ultrasound bronchoscopy (EBUS) biopsy was compatible with small cell lung cancer (SCLC). Chemotherapeutic agents were promptly administrated, with no adverse events up until now.

Increased Levels of Galectin-3 in Critical COVID-19.

Severe COVID-19 is related to hyperinflammation and multiple organ injury, including respiratory failure, thus requiring intensive care unit (ICU) admission. Galectin-3, a carbohydrate-binding protein exhibiting pleiotropic effects, has been previously recognized to participate in inflammation, the immune response to infections and fibrosis. The aim of this study was to evaluate the relationship between galectin-3 and the clinical severity of COVID-19, as well as assess the prognostic accuracy of galectin-3 for the probability of ICU mortality. The study included 235 COVID-19 patients with active disease, treated in two different Greek hospitals in total. Our results showed that median galectin-3 serum levels on admission were significantly increased in critical COVID-19 patients (7.2 ng/mL), as compared to the median levels of patients with less severe disease (2.9 ng/mL, p = 0.003). Galectin-3 levels of the non-survivors hospitalized in the ICU were significantly higher than those of the survivors (median 9.1 ng/mL versus 5.8 ng/mL, p = 0.001). The prognostic accuracy of galectin-3 for the probability of ICU mortality was studied with a receiver operating characteristic (ROC) curve and a multivariate analysis further demonstrated that galectin-3 concentration at hospital admission could be assumed as an independent risk factor associated with ICU mortality. Our results were validated with galectin-3 measurements in a second patient cohort from a different Greek university hospital. Our results, apart from strongly confirming and advancing previous knowledge with two patient cohorts, explore the possibility of predicting ICU mortality, which could provide useful information to clinicians. Therefore, galectin-3 seems to establish its involvement in the prognosis of hospitalized COVID-19 patients, suggesting that it could serve as a promising biomarker in critical COVID-19.

Diagnostic Utility of Bronchoalveolar Lavage Lymphocytosis in Patients with Interstitial Lung Diseases.

BACKGROUND: Interstitial lung diseases (ILDs) are extremely challenging in terms of diagnosis. Extreme bronchoalveolar lavage (BAL) lymphocytosis is thought to strongly point towards the diagnosis of hypersensitivity pneumonitis (HP). OBJECTIVES: Explore the range of different ILD that can present with BAL lymphocytosis, including cases of pronounced lymphocytosis and its diagnostic utility. METHODS: Patients with ILD that were subjected to BAL were identified retrospectively from a cohort of consecutive patients. RESULTS: BAL lymphocytosis ≥20% was recorded in 106 patients (27%), while pronounced BAL lymphocytosis ≥40% was recorded in 49 patients (12.5%). The most common diagnoses in patients with BAL lymphocytosis ≥20% and ≥40%, were HP (32.1%), connective tissue disease (CTD)-ILD (26.4%), sarcoidosis (16%), and HP (38.8%), CTD-ILD (24.5%), sarcoidosis (14.3%), respectively. CONCLUSIONS: Neither the presence nor the degree of BAL lymphocytosis can point to a specific diagnosis.

The utility of diaphragm ultrasound thickening indices for assessing respiratory decompensation in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) leads to diaphragmatic weakness at some point during its course, which is a major cause of respiratory insufficiency. The aim of this study was to evaluate ultrasound-based measures for assessing the diaphragmatic competency and the need for ventilatory support. METHODS: Twenty-six subjects with ALS and 12 healthy controls were enrolled. All participants underwent B-mode diaphragm ultrasound (DUS). Diaphragm thickness and thickening indices were recorded. In the subjects with ALS, further assessments included functional scales and spirometry. We investigated the diagnostic accuracy of DUS thickening indices in predicting diaphragmatic dysfunction and the correlation between clinical, spirometric, and DUS data. RESULTS: Significant relationships were found between forced vital capacity and all diaphragmatic thickening indices. Similarly, all diaphragmatic thickening indices correlated with both Milano Torino staging and disease progression rate. Only thickening fraction (TFdi) correlated with score on the revised ALS Functional Rating Scale (r = 0.459, P = .024). TFdi had better accuracy in predicting diaphragmatic dysfunction (area under the curve [AUC] = 0.839, 95% confidence interval [CI] 0.643 to 0.953) and the need for initiation of noninvasive ventilation (NIV) (AUC = 0.989, 95% CI 0.847 to 1.000) compared with the other indices. A TFdi cut-off point of 0.50 was a sensitive threshold to consider NIV. DISCUSSION: DUS successfully identifies diaphragmatic dysfunction in ALS, being a valuable accessory modality for investigating respiratory symptoms. TFdi was found to be the most useful DUS index, which encourages further investigation.

A comprehensive analysis of GATA3 expression in carcinomas of various origins with emphasis on lung carcinomas.

GATA3 is a transcription factor involved in embryogenesis of multiple human tissues and in maintaining cell differentiation and tissue homeostasis in the adult organism. GATA3 is also involved in carcinogenesis and regarded as a sensitive marker for urothelial and breast carcinomas, albeit expression in carcinomas of non-breast/urothelial origin has been frequently reported. We sought to examine the extent and intensity of GATA3 expression in various carcinomas, mainly lung, urothelial, and breast and various other primary sites. Patients with breast carcinoma (N=40), carcinoma of the urinary bladder/renal pelvis (N=40), lung carcinoma (N=110) and various other origins (N=45) were included in the study. One hundred and sixty-five patients had a primary tumor diagnosis, and 70 cases had a metastatic tumor diagnosis. Our results showed that GATA3 expression was significantly more common in carcinomas of the breast, urinary bladder and renal pelvis compared to all other origins. All primary and 93% of metastatic urinary bladder carcinomas and 94% of the primary and 80% of metastatic breast carcinomas expressed GATA3. Expression was lower in non-urothelial histology of urinary primaries and in triple negative breast carcinomas. Focal staining, mostly faint, was seen in 5.6% of the primary lung adenocarcinomas and 35% of the primary lung squamous cell carcinomas. More extensive and intense staining was seen in 3.7% of the primary lung adenocarcinomas and 12% of the primary lung squamous cell carcinomas. Expression, mostly focal was also seen in 30% of the metastatic lung carcinomas. Finally, high expression was seen in 12.5% of the other tumors (one metastatic pancreatic carcinoma, one metastatic salivary gland adenocarcinoma NOS, one metastatic squamous cell carcinoma of the skin, one primary uterine cervix serous carcinoma, and one squamous cell carcinoma of the head and neck) and focal expression was present in another 22% of them. No ideal cut-off for positivity for GATA3 staining could be identified. In conclusion our study shows that GATA3 staining has two caveats in its use: the first is that non classical histologies of urothelial carcinomas and TNBC may be negative for the marker and secondly carcinomas of various origins may show (although rarely) intense positivity.

SRC and TKS5 mediated podosome formation in fibroblasts promotes extracellular matrix invasion and pulmonary fibrosis.

The activation and accumulation of lung fibroblasts resulting in aberrant deposition of extracellular matrix components, is a pathogenic hallmark of Idiopathic Pulmonary Fibrosis, a lethal and incurable disease. In this report, increased expression of TKS5, a scaffold protein essential for the formation of podosomes, was detected in the lung tissue of Idiopathic Pulmonary Fibrosis patients and bleomycin-treated mice. Τhe profibrotic milieu is found to induce TKS5 expression and the formation of prominent podosome rosettes in lung fibroblasts, that are retained ex vivo, culminating in increased extracellular matrix invasion. Tks5+/- mice are found resistant to bleomycin-induced pulmonary fibrosis, largely attributed to diminished podosome formation in fibroblasts and decreased extracellular matrix invasion. As computationally predicted, inhibition of src kinase is shown to potently attenuate podosome formation in lung fibroblasts and extracellular matrix invasion, and bleomycin-induced pulmonary fibrosis, suggesting pharmacological targeting of podosomes as a very promising therapeutic option in pulmonary fibrosis.

Improvement of psoriatic skin lesions following pirfenidone use in patients with fibrotic lung disease.

Psoriasis is an immune-mediated inflammatory disorder of the skin, characterised by uncontrolled proliferation and dysfunctional differentiation of keratinocytes. In our case series, pirfenidone was administered for the management of fibrotic lung disease and, serendipitously, we noticed remission of coexisting cutaneous psoriatic lesions few months after treatment initiation. Pirfenidone's antifibrotic and immunomodulatory properties have been well studied; yet, not fully elucidated. In line with this, pirfenidone may exert pleiotropic therapeutic effects in other immune-mediated diseases such as psoriasis, while, at the same time, spare immunosuppression-related side effects of current antipsoriatic drugs. Pirfenidone-mediated enhanced absorption of ultraviolet A and ultraviolet B by skin keratinocytes might represent a potential mechanism. The possible role of pirfenidone as an antipsoriatic drug requires large-scale and long-term study.

Increased lipocalin-2 expression in pulmonary inflammation and fibrosis.

Introduction: Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive interstitial lung disease with dismal prognosis. The underlying pathogenic mechanisms are poorly understood, resulting in a lack of effective treatments. However, recurrent epithelial damage is considered critical for disease initiation and perpetuation, via the secretion of soluble factors that amplify inflammation and lead to fibroblast activation and exuberant deposition of ECM components. Lipocalin-2 (LCN2) is a neutrophil gelatinase-associated lipocalin (NGAL) that has been suggested as a biomarker of kidney damage. LCN2 has been reported to modulate innate immunity, including the recruitment of neutrophils, and to protect against bacterial infections by sequestering iron. Methods: In silico analysis of publicly available transcriptomic datasets; ELISAs on human IPF patients' bronchoalveolar lavage fluids (BALFs); bleomycin (BLM)-induced pulmonary inflammation and fibrosis and LPS-induced acute lung injury (ALI) in mice: pulmonary function tests, histology, Q-RT-PCR, western blot, and FACS analysis. Results and discussion: Increased LCN2 mRNA expression was detected in the lung tissue of IPF patients negatively correlating with respiratory functions, as also shown for BALF LCN2 protein levels in a cohort of IPF patients. Increased Lcn2 expression was also detected upon BLM-induced pulmonary inflammation and fibrosis, especially at the acute phase correlating with neutrophilic infiltration, as well as upon LPS-induced ALI, an animal model characterized by neutrophilic infiltration. Surprisingly, and non withstanding the limitations of the study and the observed trends, Lcn2-/- mice were found to still develop BLM- or LPS-induced pulmonary inflammation and fibrosis, thus questioning a major pathogenic role for Lcn2 in mice. However, LCN2 qualifies as a surrogate biomarker of pulmonary inflammation and a possible indicator of compromised pulmonary functions, urging for larger studies.

Anti-Ro52/Anti-nuclear Matrix Protein 2 Positive Clinically Amyopathic Dermatomyositis Presented Only With Interstitial Lung Disease.

This report contemplates a unique case of clinically amyopathic dermatomyositis (CADM) that presented as interstitial lung disease. The patient was a 55-year-old woman who showed up with progressive exercise intolerance and a dry cough without muscular or dermatological clinical manifestations. Diagnostic workup and imaging revealed the presence of interstitial lung disease, and further evaluation led to a positive autoimmune panel for anti-nuclear matrix protein 2 (anti-NXP2) and anti-Ro52 antibodies, establishing the diagnosis of anti-NXP2 plus anti-Ro52 antibodies-positive amyopathic idiopathic inflammatory dermatomyositis. The patient was started on intravenous corticosteroids. She showed improvement on her chest X-ray (CXR) and was then switched to oral corticosteroids. After six months of steroid treatment, corticosteroids were stopped, and the patient was re-evaluated one month later disease relapse.

Radiologic Features of T10 Paravertebral Muscle Sarcopenia: Prognostic Factors in COVID-19.

Background: Sarcopenia, defined as a small cross-sectional area (CSA) in computed tomography (CT) measurements of skeletal muscles, serves as a disease severity marker in various clinical scenarios, including pulmonary conditions and critical illness. Another parameter of sarcopenia, the level of myosteatosis, reflected by the tissue's radiodensity, in the thoracic skeletal muscles group, has been linked to disease progression in coronavirus disease 2019 (COVID-19) patients. We hypothesize that CT-derived measurements of the skeletal muscle density (SMD) and the CSA of thoracic skeletal muscles can predict outcomes in COVID-19 pneumonia. Methods: We retrospectively reviewed the CT scans of 84 patients with COVID-19 pneumonia admitted to two of Greece's largest academic teaching hospitals between April 2020 and February 2021. CSA and SMD at the level of the T10 vertebra were measured using computational imaging methods. The patient population was stratified according to survival status and CT severity score (CT-SS). Correlations were drawn between the radiologic features of sarcopenia, CT severity subgroups, serum inflammatory markers, and adverse events, e.g., death and intubation. Results: Thoracic muscles' CSA measurements correlate with CT-SS and prominent inflammatory markers, such as white blood cell (WBC), C-reactive protein (CRP), fibrinogen, and D-dimers. Moreover, according to linear regression analysis, CSA seems to predict CT-SS variation significantly (ß = -0.266, P = 0.018). CSA proved to differ significantly across survivors (P = 0.027) but not between CT severity categories and intubation subgroups. The AUC (area under the curve) of the receiver operating characteristic (ROC) curve for the predictive value of thoracic muscles' CSA in mortality is 0.774 (95% confidence interval (CI): 0.66 - 0.83, P < 0.000). The optimal cut-off value (Youden index = 0.57) for mortality prognosis, with a sensitivity of 66.7% and a specificity of 88.9%, is 15.55. Thoracic muscles' SMD analyses did not reveal any significant correlations. Conclusions: Easy to obtain and accurately calculated, radiologic features can provide a reliable alternative to laboratory methods for predicting survival in COVID-19. Thoracic muscles' CSA measurement in the level of the T10 vertebra, an acclaimed prognostic imaging assessment that relates directly to CT-SS and inflammatory markers in COVID-19 pneumonia, is a fairly specific tool for survival prognosis.

Remdesivir Use in the Real-World Setting: An Overview of Available Evidence.

In the years of Coronavirus Disease 2019 (COVID-19), various treatment options have been utilized. COVID-19 continues to circulate in the global population, and the evolution of the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has posed significant challenges to the treatment and prevention of infection. Remdesivir (RDV), an anti-viral agent with in vitro efficacy against coronaviruses, is a potent and safe treatment as suggested by a plethora of in vitro and in vivo studies and clinical trials. Emerging real-world data have confirmed its effectiveness, and there are currently datasets evaluating its efficacy and safety against SARS-CoV-2 infections in various clinical scenarios, including some that are not in the SmPC recommendations according for COVID-19 pharmacotherapy. Remdesivir increases the chance of recovery, reduces progression to severe disease, lowers mortality rates, and exhibits beneficial post-hospitalization outcomes, especially when used early in the course of the disease. Strong evidence suggests the expansion of remdesivir use in special populations (e.g., pregnancy, immunosuppression, renal impairment, transplantation, elderly and co-medicated patients) where the benefits of treatment outweigh the risk of adverse effects. In this article, we attempt to overview the available real-world data of remdesivir pharmacotherapy. With the unpredictable course of COVID-19, we need to utilize all available knowledge to bridge the gap between clinical research and clinical practice and be sufficiently prepared for the future.

SH2 Domain-Containing Phosphatase-SHP2 Attenuates Fibrotic Responses through Negative Regulation of Mitochondrial Metabolism in Lung Fibroblasts.

BACKGROUND: We have previously shown that SHP2 downregulation may predispose fibroblasts to differentiate into myofibroblasts and proposed a role for SHP2 downregulation in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Recent data have shown that SHP2 localizes to the mitochondrial intercristae, and its overexpression enhances mitochondrial metabolism leading to oxidative stress and senescence. OBJECTIVE: To determine the effect of SHP2 on fibrotic responses. METHODS AND RESULTS: Primary mouse lung fibroblasts derived from mice carrying a conditional knock-in mutation (D61G/+), rendering the SHP2 catalytic domain constitutively active, had reduced proliferation (1.6-fold, p < 0.05), migration (2-fold, p < 0.05), as well as reduced responsiveness of TGFB-1 induced fibroblasts-to-myofibroblasts differentiation, compared to wild-type ones. Electron microscope analysis revealed that SHP2 D61G/+ mouse lung fibroblasts were characterized by mitochondrial abnormalities, including swollen mitochondria with disrupted electron-lucent cristae and an increased number of autophagosomes compared to wild-type ones. SHP2 D61G/+ MLFs exhibited increased protein levels of autophagy markers, including LC3B-II and p-62, evidence that was confirmed by immunofluorescence analysis. Mitochondrial function analysis revealed that stable (genotype D61G/+) overexpression of SHP2 led to impaired mitochondrial function, as assessed by decreased mitochondrial membrane potential (1.29-fold, p < 0.05), coupling efficiency (1.82 fold, p < 0.05), oxygen consumption rate (1.9-fold, p < 0.05), and increased reactive oxygen species production both at baseline (1.75-fold, p < 0.05) and following H2O2 stimulation (1.63-fold, p < 0.05) compared to wild-type ones (SHP2+/+). SHP2 D61G/+ mouse lung fibroblasts showed enhanced AMPK activity, as well as decreased activation of the mTORC1 signaling pathway, potentially leading to ineffective mitochondrial metabolism and increased autophagy. CONCLUSIONS: SHP2 attenuates fibrotic responses in fibroblast cell lines through negative regulation of mitochondrial metabolism and induction of autophagy. SHP2 activation may represent a promising therapeutic strategy for patients with fibrotic lung diseases.

COVID-19 Pharmacotherapy in Pregnancy: A Literature Review of Current Therapeutic Choices.

The clinical management of COVID-19 in pregnant women, who are considered a vulnerable population, remains uncertain even as the pandemic subsides. SARS-CoV-2 affects pregnant individuals in multiple ways and has been associated with severe maternal morbidity and mortality, as well as neonatal complications. The unique anatomy and physiology of gestation make managing COVID-19 in this population a complex and challenging task, emphasizing the importance of spreading knowledge and expertise in this area. Therapeutic interventions require distinct clinical consideration, taking into account differences in pharmacokinetics, vertical transmission, drug toxicities, and postnatal care. Currently, there is limited data on antiviral and immunomodulating COVID-19 pharmacotherapy in pregnancy. Some medication has been shown to be safe and well tolerated among pregnant women with COVID-19; however, the lack of randomized clinical trials and studies in this patient population is evident. Available vaccines are considered safe and effective, with no evidence of harm to the fetus, embryo development, or short-term postnatal development. Pregnant women should be counseled about the risks of SARS-CoV-2 infection and informed of available ways to protect themselves and their families. Effective treatments for COVID-19 should not be withheld from pregnant individuals, and more research is needed to ensure the best outcomes.

Statins' still controversial role in pulmonary fibrosis: What does the evidence show?

Pulmonary fibrosis (PF) represents the end stage of a broad range of interstitial lung diseases (ILDs). Statins are among the compounds which have been implicated in drug-induced ILD development. However, recent studies (both in vitro and in vivo) have provided evidence that statins may exert anti-inflammatory and anti-fibrotic effects potentially offering benefits to patients with PF. Several protective molecular mechanisms including the suppression of mevalonic acid pathway, the inhibition of NADPH oxidase activation in macrophages and the inhibition of several profibrotic mediators have been proposed to explain the observed in vivo decrease of the oxidative stress in the lung and the preservation of lung function in patients. Earlier clinical studies relating statins with drug-induced ILD development are contradicted by increasing new data showing the beneficial effects of statins in clinical outcomes in ILD patients who receive statins for concomitant cardiovascular indications. Future research may further elucidate the wide spectrum of pathways of IPF pathogenesis, and genetic heterogeneity, identifying clinically applicable biomarkers and specific endotypes thus recognizing in which patients statins could confer benefit and in which they might cause detrimental effects.

Diagnostic Accuracy of Multiple D-Dimer Cutoff Thresholds and Other Clinically Applicable Biomarkers for the Detection and Radiographic Evaluation of Pulmonary Embolism.

Background: Diagnostic work-up of pulmonary embolism (PE) remains a challenge. Methods: We retrospectively studied all patients referred for computed tomography pulmonary angiography (CTPA) with suspicion of PE during a 12-month period (2018). The diagnostic accuracy of different D-dimer (Dd) cutoff thresholds for ruling out PE was evaluated. Furthermore, the association of Dd and red cell distribution width (RDW) with embolus location, CTPA findings, and patient outcome was recorded. Results: One thousand seventeen (n = 1017) patients were finally analyzed (mean age: 64.6 years (SD = 11.8), males: 549 (54%)). PE incidence was 18.7%. Central and bilateral embolism was present in 44.7% and 59.5%, respectively. Sensitivity and specificity for conventional and age-adjusted Dd cutoff was 98.2%, 7.9%, and 98.2%, 13.1%, respectively. A cutoff threshold (2.1 mg/L) with the best (64.4%) specificity was identified based on Receiver Operating Characteristics analysis. Moreover, a novel proposed Dd cutoff (0.74 mg/L) emerged with increased specificity (20.5%) and equal sensitivity (97%) compared to 0.5 mg/L, characterized by concurrent reduction (17.2%) in the number of performed CTPAs. Consolidation/atelectasis and unilateral pleural effusion were significantly associated with PE (p < 0.05, respectively). Patients with consolidation/atelectasis or intrapulmonary nodule(s)/mass on CTPA exhibited significantly greater median Dd values compared to patients without the aforementioned findings (2.34, (IQR 1.29−4.22) vs. 1.59, (IQR 0.81−2.96), and 2.39, (IQR 1.45−4.45) vs. 1.66, (IQR 0.84−3.12), p < 0.001, respectively). RDW was significantly greater in patients who died during hospitalization (p = 0.012). Conclusions: Age-adjusted Dd increased diagnostic accuracy of Dd testing without significantly decreasing the need for imaging. The proposed Dd value (0.74 mg/L) showed promise towards reducing considerably the need of CTPA. Multiple radiographic findings have been associated with increased Dd values in our study.

Fanconi syndrome-associated interstitial lung disease.

A middle-aged man was referred to our respiratory department with dyspnoea progressively deteriorating and non-productive cough over the past 8 months. High-resolution CT revealed multiple bilateral consolidations, traction bronchiectasis, reticular pattern and honeycombing with basal and peripheral predominance. Serology tests were negative. Pulmonary function tests showed moderate restrictive functional impairment and severe reduction in diffusing capacity for carbon monoxide. Meticulous evaluation of patient's medical history revealed recent administration of oral corticosteroid due to pulmonary fibrosis potentially in the context of Fanconi syndrome diagnosed at childhood. The working diagnosis of interstitial lung disease (ILD) as a rare complication of Fanconi syndrome was proposed following multidisciplinary discussion. Despite combination treatment with low doses of corticosteroids and antifibrotic compound, the patient exhibited clinical, radiological and functional deterioration, was admitted to intensive care unit due to respiratory failure following infection-driven progression of fibrotic ILD and finally died.

Pulmonary adverse events following immune checkpoint inhibitors.

PURPOSE OF REVIEW: Immune checkpoint inhibitors (ICIs) have rapidly become a mainstay of cancer treatment. However, immune modulation resulting from checkpoint inhibition can cause inflammation in any organ system, with pneumonitis being one of the most severe immune-related adverse events (irAEs). Here, we review the most recent literature on pulmonary adverse events following ICIs. RECENT FINDINGS: Several systematic reviews and meta-analyses of data from trials of antiprogrammed death-1 (PD-1; nivolumab, pembrolizumab), anti-PD-ligand-1 (PD-L1; atezolizumab, avelumab, durvalumab) and anticytotoxic T lymphocyte antigen-4 (CTLA-4; ipilimumab or tremelimumab) in patients with advanced cancer have explored the relative risk and incidence of lung toxicity among different tumor types and therapeutic regimens. They have showed that the incidence of all-grade (1-4) and high-grade (3-4) pneumonitis is significantly higher in nonsmall cell lung cancer (NSCLC) compared with other tumor types. In addition, they have demonstrated that immunotherapy, especially monoimmunotherapy, has a significantly lower risk of irAEs compared to immune-chemotherapy. Treatment for lung cancer, preexisting interstitial lung disease, smoking history and male sex appear to increase the risk for ICI-related pneumonitis. SUMMARY: Lung toxicity is an uncommon but potentially severe and even fatal complication of ICIs. Timely recognition is critically important but challenging, particularly in patients with lung cancer wherein drug toxicity can mimic disease progression or recurrence.