Similarities and differences of interstitial lung disease associated with pathogenic variants in SFTPC and ABCA3 in adults.

BACKGROUND AND OBJECTIVE: Variants in surfactant genes SFTPC or ABCA3 are responsible for interstitial lung disease (ILD) in children and adults, with few studies in adults. METHODS: We conducted a multicentre retrospective study of all consecutive adult patients diagnosed with ILD associated with variants in SFTPC or ABCA3 in the French rare pulmonary diseases network, OrphaLung. Variants and chest computed tomography (CT) features were centrally reviewed. RESULTS: We included 36 patients (median age: 34 years, 20 males), 22 in the SFTPC group and 14 in the ABCA3 group. Clinical characteristics were similar between groups. Baseline median FVC was 59% ([52-72]) and DLco was 44% ([35-50]). An unclassifiable pattern of fibrosing ILD was the most frequent on chest CT, found in 85% of patients, however with a distinct phenotype with ground-glass opacities and/or cysts. Nonspecific interstitial pneumonia and usual interstitial pneumonia were the most common histological patterns in the ABCA3 group and in the SFTPC group, respectively. Annually, FVC and DLCO declined by 1.87% and 2.43% in the SFTPC group, respectively, and by 0.72% and 0.95% in the ABCA3 group, respectively (FVC, p = 0.014 and DLCO , p = 0.004 for comparison between groups). Median time to death or lung transplantation was 10 years in the SFTPC group and was not reached at the end of follow-up in the ABCA3 group. CONCLUSION: SFTPC and ABCA3-associated ILD present with a distinct phenotype and prognosis. A radiologic pattern of fibrosing ILD with ground-glass opacities and/or cysts is frequently found in these rare conditions.

CSF2RB mutation-related hereditary pulmonary alveolar proteinosis: the "long and winding road" into adulthood.

Genetic analysis pre-lung transplantation diagnosed a case of hereditary pulmonary alveolar proteinosis (PAP) complicated by fibrosis in adulthood. The need for genetic testing in GM-CSF autoantibody negative and unclassifiable PAP is highlighted. https://bit.ly/3QcsYwM.

Expression of PD-1/PD-L1 axis in mediastinal lymph nodes and lung tissue of human and experimental lung fibrosis indicates a potential therapeutic target for idiopathic pulmonary fibrosis.

BACKGROUND: Mediastinal lymph node enlargement is prevalent in patients with idiopathic pulmonary fibrosis (IPF). Studies investigating whether this phenomenon reflects specific immunologic activation are lacking. METHODS: Programmed cell death-1 (PD-1)/ programmed cell death ligand-1 (PD-L1) expression in mediastinal lymph nodes and lung tissues was analyzed. PD-1, PD-L1 mRNA expression was measured in tracheobronchial lymph nodes of mice following bleomycin-induced injury on day 14. Finally, the effect of the PD-1 inhibitor, pembrolizumab, in bleomycin-induced pulmonary fibrosis was investigated. RESULTS: We analyzed mediastinal lymph nodes of thirty-three patients (n = 33, IPF: n = 14, lung cancer: n = 10, concomitant IPF and lung cancer: n = 9) and lung tissues of two hundred nineteen patients (n = 219, IPF: 123, controls: 96). PD-1 expression was increased, while PD-L1 expression was decreased, in mediastinal lymph nodes of patients with IPF compared to lung cancer and in IPF lungs compared to control lungs. Tracheobronchial lymph nodes isolated on day 14 from bleomycin-treated mice exhibited increased size and higher PD-1, PD-L1 mRNA levels compared to saline-treated animals. Pembrolizumab blunted bleomycin-induced lung fibrosis, as indicated by reduction in Ashcroft score and improvement in respiratory mechanics. CONCLUSIONS: Mediastinal lymph nodes of patients with IPF exhibit differential expression profiles than those of patients with lung cancer indicating distinct immune-mediated pathways regulating fibrogenesis and carcinogenesis. PD-1 expression in mediastinal lymph nodes is in line with lung tissue expression. Lower doses of pembrolizumab might exert antifibrotic effects. Clinical trials aiming to endotype patients based on mediastinal lymph node profiling and accordingly implement targeted therapies such as PD-1 inhibitors are greatly anticipated.

Lung transplantation outcome in adult surfactant-related interstitial lung disease: first evidence to move on.

A new study reports the first evidence to "move on" with lung transplantation in adult surfactant-related fibrotic ILDs. It highlights the need for better genetic characterisation of transplant candidates and cancer screening for these patients. https://bit.ly/3QxG73Z.

Effects of short-term air pollution exposure on symptoms development in the course of idiopathic pulmonary fibrosis.

BACKGROUND: Lately a potential detrimental effect of air pollution to idiopathic pulmonary fibrosis emerged. We aimed to assess the effects of short-term air pollution exposure to the clinical course of IPF. RESEARCH DESIGN AND METHODS: IPF patients were followed intensively for four nonconsecutive study periods between 13 July 2020 and 5 September 2021. Short-term exposure to O3, NO2 and PM10 concentrations was estimated using spatio-temporal land use regression models. Associations among symptoms, lung function, oxygen saturation, and short-term personal air pollutant exposure were assessed through multiple mixed effects logistic regression models. RESULTS: Data for up to 24 IPF patients (mean age: 72.2 ± 7.6 years) were analyzed. We detected positive significant associations between cough and a 10 µg/m3 increase in same day mean level of NO2 (OR = 1.59, 95%CI: 1.00-2.53), PM10 (OR = 2.42, 95%CI: 1.54-3.79), and O3 (OR = 1.63, 95%CI: 1.14-2.32). A 10 µg/m3 increase in same day mean level of NO2 was also associated with the risk of appearance of wheezing (OR = 3.01, 95%CI: 1.00-9.04), while exposure to O3 was associated with common cold (OR = 6.30, 95%CI: 3.59-11.07). No significant associations were detected between short-term exposure to air pollutants and forced vital capacity or saturation of oxygen. CONCLUSIONS: Short-term exposure to increased concentrations of air pollutants is an independent risk factor for IPF symptoms' aggravation.

From Karl Wurm and Guy Scadding's staging to 18F-FDG PET/CT scan phenotyping and far beyond: perspective in the evading history of phenotyping in sarcoidosis.

Sarcoidosis is an inflammatory granulomatous disease of unknown etiology involving any organ or tissue along with any combination of active sites, even the most silent ones clinically. The unpredictable nature of the sites involved in sarcoidosis dictates the highly variable natural history of the disease and the necessity to cluster cases at diagnosis based on clinical and/or imaging common characteristics in an attempt to classify patients based on their more homogeneous phenotypes, possibly with similar clinical behavior, prognosis, outcome, and therefore with therapeutic requirements. In the course of the disease's history, this attempt relates to the availability of a means of detection of the sites involved, from the Karl Wurm and Guy Scadding's chest x-ray staging through the ACCESS, the WASOG Sarcoidosis Organ Assessment Instruments, and the GenPhenReSa study to the 18F-FDG PET/CT scan phenotyping and far beyond to new technologies and/or the current "omics." The hybrid molecular imaging of the 18F-FDG PET/CT scan, by unveiling the glucose metabolism of inflammatory cells, can identify high sensitivity inflammatory active granulomas, the hallmark of sarcoidosis-even in clinically and physiologically silent sites-and, as recently shown, is successful in identifying an unexpected ordered stratification into four phenotypes: (I) hilar-mediastinal nodal, (II) lungs and hilar-mediastinal nodal, (III) an extended nodal supraclavicular, thoracic, abdominal, inguinal, and (IV) all the above in addition to systemic organs and tissues, which is therefore the ideal phenotyping instrument. During the "omics era," studies could provide significant, distinct, and exclusive insights into sarcoidosis phenotypes linking clinical, laboratory, imaging, and histologic characteristics with molecular signatures. In this context, the personalization of treatment for sarcoidosis patients might have reached its goal.

ABCA3-related interstitial lung disease beyond infancy.

BACKGROUND: The majority of patients with childhood interstitial lung disease (chILD) caused by pathogenic variants in ATP binding cassette subfamily A member 3 (ABCA3) develop severe respiratory insufficiency within their first year of life and succumb to disease if not lung transplanted. This register-based cohort study reviews patients with ABCA3 lung disease who survived beyond the age of 1 year. METHOD: Over a 21-year period, patients diagnosed as chILD due to ABCA3 deficiency were identified from the Kids Lung Register database. 44 patients survived beyond the first year of life and their long-term clinical course, oxygen supplementation and pulmonary function were reviewed. Chest CT and histopathology were scored blindly. RESULTS: At the end of the observation period, median age was 6.3 years (IQR: 2.8-11.7) and 36/44 (82%) were still alive without transplantation. Patients who had never received supplemental oxygen therapy survived longer than those persistently required oxygen supplementation (9.7 (95% CI 6.7 to 27.7) vs 3.0 years (95% CI 1.5 to 5.0), p=0.0126). Interstitial lung disease was clearly progressive over time based on lung function (forced vital capacity % predicted absolute loss -1.1% /year) and on chest CT (increasing cystic lesions in those with repetitive imaging). Lung histology pattern were variable (chronic pneumonitis of infancy, non-specific interstitial pneumonia, and desquamative interstitial pneumonia). In 37/44 subjects, the ABCA3 sequence variants were missense variants, small insertions or deletions with in-silico tools predicting some residual ABCA3 transporter function. CONCLUSION: The natural history of ABCA3-related interstitial lung disease progresses during childhood and adolescence. Disease-modifying treatments are desirable to delay such disease course.

Lung cancer in patients with idiopathic pulmonary fibrosis: A retrospective multicentre study in Europe.

BACKGROUND AND OBJECTIVE: There remains a paucity of large databases for patients with idiopathic pulmonary fibrosis (IPF) and lung cancer. We aimed to create a European registry. METHODS: This was a multicentre, retrospective study across seven European countries between 1 January 2010 and 18 May 2021. RESULTS: We identified 324 patients with lung cancer among 3178 patients with IPF (prevalence = 10.2%). By the end of the 10 year-period following IPF diagnosis, 26.6% of alive patients with IPF had been diagnosed with lung cancer. Patients with IPF and lung cancer experienced increased risk of all-cause mortality than IPF patients without lung cancer (HR: 1.51, [95% CI: 1.22-1.86], p < 0.0001). All-cause mortality was significantly lower for patients with IPF and lung cancer with a monocyte count of either <0.60 or 0.60-<0.95 K/µl than patients with monocyte count ≥0.95 K/µl (HR [<0.60 vs. ≥0.95 K/µl]: 0.35, [95% CI: 0.17-0.72], HR [0.60-<0.95 vs. ≥0.95 K/µl]: 0.42, [95% CI: 0.21-0.82], p = 0.003). Patients with IPF and lung cancer that received antifibrotics presented with decreased all cause-mortality compared to those who did not receive antifibrotics (HR: 0.61, [95% CI: 0.42-0.87], p = 0.006). In the adjusted model, a significantly lower proportion of surgically treated patients with IPF and otherwise technically operable lung cancer experienced all-cause mortality compared to non-surgically treated patients (HR: 0.30 [95% CI: 0.11-0.86], p = 0.02). CONCLUSION: Lung cancer exerts a dramatic impact on patients with IPF. A consensus statement for the management of patients with IPF and lung cancer is sorely needed.

Pulmonary hemorrhage in patients receiving anti-platelets- a case series and a suggested therapeutic algorithm.

Antiplatelet therapy including aspirin and thienopyridine agents (such as clopidogrel, prasugrel and ticagrelor) are often used in patients with coronary disease. Pulmonary hemorrhage due to antiplatelet therapy although very rare, when excessive, is a life-threatening event. So far, there is lack of specific guidelines for the management of these patients. We report a case series of 5 patients receiving antiplatelet therapy who were admitted to the hospital due to pulmonary hemorrhage related to antiplatelet therapy. We also propose an algorithm on the management of these patients taking into consideration the balance between thrombotic and bleeding risk and the severity of the hemorrhage.

Genotype-Phenotype Relationships in Inheritable Idiopathic Pulmonary Fibrosis: A Greek National Cohort Study.

BACKGROUND: Monogenic and polygenic inheritances are evidenced for idiopathic pulmonary fibrosis (IPF). Pathogenic variations in surfactant protein-related genes, telomere-related genes (TRGs), and a single-nucleotide polymorphism in the promoter of MUC5B gene encoding mucin 5B (rs35705950 T risk allele) are reported. This French-Greek collaborative study, Gen-Phen-Re-GreekS in inheritable IPF (iIPF), aimed to investigate genetic components and patients' characteristics in the Greek national IPF cohort with suspected heritability. PATIENTS AND METHODS: 150 patients with familial PF, personal-family extrapulmonary disease suggesting short telomere syndrome, and/or young age IPF were analyzed. RESULTS: MUC5B rs35705950 T risk allele was detected in 103 patients (90 heterozygous, 13 homozygous, allelic frequency of 39%), monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC, 2 RTEL1, 2 PARN, 1 NOP10, and 1 NHP2), and biallelic ABCA3 pathogenic variations in 3. Overlapping MUC5B rs35705950 T risk allele and TRG pathogenic variations were shown in 11 patients (5 TERT, 3 TERC, 1 PARN, 1 NOP10, and 1 NHP2), MUC5B rs35705950 T risk allele, and biallelic ABCA3 pathogenic variations in 2. In 38 patients, neither MUC5B rs35705950 T risk allele nor TRG pathogenic variations were detectable. Kaplan-Meier curves showed differences in time-to-death (p = 0.025) where patients with MUC5B rs35705950 T risk allele alone or in combination with TRG pathogenic variations presented better prognosis. CONCLUSION: The Gen-Phen-Re-GreekS in iIPF identified multiple and overlapping genetic components including the rarest, underlying disease's genetic "richesse," complexity and heterogeneity. Time-to-death differences may relate to diverse IPF pathogenetic mechanisms implicating "personalized" medical care driven by genotypes in the near future.

Long-term personal air pollution exposure and risk for acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Urban air pollution is involved in the progress of idiopathic pulmonary fibrosis (IPF). Its potential role on the devastating event of Acute Exacerbation of IPF (AE-IPF) needs to be clarified. This study examined the association between long-term personal air pollution exposure and AE- IPF risk taking into consideration inflammatory mediators and telomere length (TL). METHODS: All consecutive IPF-patients referred to our Hospital from October 2013-June 2019 were included. AE-IPF events were recorded and inflammatory mediators and TL measured. Long-term personal air pollution exposures were assigned to each patient retrospectively, for O3, NO2, PM2.5 [and PM10, based on geo-coded residential addresses. Logistic regression models assessed the association of air pollutants' levels with AE-IPF and inflammatory mediators adjusting for potential confounders. RESULTS: 118 IPF patients (mean age 72 ± 8.3 years) were analyzed. We detected positive significant associations between AE-IPF and a 10 µg/m3 increase in previous-year mean level of NO2 (OR = 1.52, 95%CI:1.15-2.0, p = 0.003), PM2.5 (OR = 2.21, 95%CI:1.16-4.20, p = 0.016) and PM10 (OR = 2.18, 95%CI:1.15-4.15, p = 0.017) independent of age, gender, smoking, lung function and antifibrotic treatment. Introduction of TL in all models of a subgroup of 36 patients did not change the direction of the observed associations. Finally, O3 was positively associated with %change of IL-4 (p = 0.014) whilst PM2.5, PM10 and NO2 were inversely associated with %changes of IL-4 (p = 0.003, p = 0.003, p = 0.032) and osteopontin (p = 0.013, p = 0.013, p = 0.085) respectively. CONCLUSIONS: Long-term personal exposure to increased concentrations of air pollutants is an independent risk factor of AE-IPF. Inflammatory mediators implicated in lung repair mechanisms are involved.

Vedolizumab-induced acute interstitial lung injury in a 39-year-old male with ulcerative colitis.

Vedolizumab, an anti-integrin antibody, is effective for moderate to severe ulcerative colitis and Crohn's disease treatment with a good safety profile due to its gut selective mechanism of action. Upper respiratory tract vedolizumab adverse events are common; however, they are mild and do not require treatment withdrawal. Herein, we present a 39-year-old patient under vedolizumab treatment for ulcerative colitis who presented acute severe interstitial lung injury that necessitated vedolizumab withdrawal and systemic steroids administration.

Device use errors among patients with asthma and COPD and the role of training: a real-life study.

Background and objectives: Administration of inhaled medication for asthma and COPD is often difficult and incorrect device use is associated with unfavorable outcomes. We aimed to evaluate device use errors in asthma and COPD patients and to associate incorrect use with the patient's characteristics and medical history.Methods: Demographics and medical history were recorded. The use of each prescribed device was evaluated according to predefined steps.Results: 607 patients (49.9% male, median age (IQR) 63 (51, 70) years performed 663 demonstrations (56 patients were using 2 different types of devices). 51.4% were treated for asthma and 48.6% for COPD. 79.6% of demonstrations were performed using DPIs. Errors were documented on 41.2% of demonstrations and were associated with the type of device, p < 0.001. Elderly patients were less frequently using their devices correctly compared to younger patients, 50.8% vs 62.2%, respectively, p = 0.007. Correct demonstrations were more among asthmatics compared to COPD patients 63.1% vs 54.5%, p = 0.024. Incorrect use was associated with more acute exacerbations in the preceding year [median(IQR), 1(0, 2) vs 1(0, 1)], for incorrect and correct use, respectively, p < 0.001. Upon demonstration, 15.5% of patients have never been trained (i.e., undergone actual demonstrations and observation while using their device) by anyone. Errors occurred more frequently among patients who reported not to be trained compared to those who were trained, 67.0% vs 14.6%, respectively, p < 0.001. The commonest error was associated with the inspiration maneuver and accounted for the 48.3% of errors in the DPIs and 53.0% of errors in the MDIs.Conclusion: Device use errors are common and associated with unfavorable outcomes. Trained patients were more likely to use the device correctly.

Prevalence, distribution and clinical significance of joints, muscles and bones in sarcoidosis: an 18F-FDG-PET/CT study.

OBJECTIVES: In Sarcoidosis joints-muscles-bones (JMBs) localizations are of the least common. 18F-FDG-PET/CT imaging revolutionized detection of JMBs involvement by adding metabolic activity information and allowing for a comprehensive, whole-body mapping of the disease. AIM AND METHODS: This study investigated prevalence, distribution, and clinical significance of JMBs sarcoidosis in 195 consecutive patients that underwent 18F-FDG PET/CT examination. RESULTS: Joint and bone involvement were encountered in 15% of patients with a mean of the maximum-standardized-uptake-value (SUVmax) of 6.1. Most common location was the axial skeleton. Hypercalciuria was significantly more frequent in patients with osseous involvement (p = 0.003). Muscle activity (SUVmax = 2.4) was encountered in 20% of the patients, most frequently in treatment-naïve (p = 0.02). The muscles of the lower extremities were affected the most. Muscle and bone localization coexist in 50% of the cases. JMBs disease was almost asymptomatic, not related to chronicity but to pulmonary, nodal, and systemic disease. Long-term follow-up and treatment response of affected patients confirmed sarcoidosis. CONCLUSION: 18F-FDG-PET/CT revealed JMBs localizations and coexistence with other organ sites supporting the concept that sarcoidosis is a systemic disease. By allowing an integrative interpretation of multi-organ involvement in the context of a pattern highly suggestive of sarcoidosis, it strongly keeps-off the diagnosis of malignancy.

Idiopathic Pulmonary Fibrosis: Best Practice in Monitoring and Managing a Relentless Fibrotic Disease.

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease that is, by definition, progressive. Progression of IPF is reflected by a decline in lung function, worsening of dyspnea and exercise capacity, and deterioration in health-related quality of life. In the short term, the course of disease for an individual patient is impossible to predict. A period of relative stability in forced vital capacity (FVC) does not mean that FVC will remain stable in the near future. Frequent monitoring using multiple assessments, not limited to pulmonary function tests, is important to evaluate disease progression in individual patients and ensure that patients are offered appropriate care. Optimal management of IPF requires a multidimensional approach, including both pharmacological therapy to slow decline in lung function and supportive care to preserve patients' quality of life.

18F-FDG PET/CT in Pulmonary Sarcoidosis:Quantifying Inflammation by the TLG index.

Objectives: In sarcoidosis progressive pulmonary disease affects prognosis. Pulmonary disease activity estimated by classic means poorly predicts severity and progressiveness. 18F-fluoro-2-deoxyglucose-positron-emission-tomography computed-tomography (18F-FDG-PET/CT) estimates pulmonary activity by inflammatory-cells metabolism. We aimed to investigate pulmonary sarcoidosis by 18F-FDG-PET/CT and evaluate the role of total-lesion-glycolysis (TLG) value, as an index quantifying the whole burden of lung inflammation.Methods: This is a retrospective study of sequentially gathered data. From a Greek cohort of 195 sarcoidosis-patients, 87 were identified with lung increased 18F-FDG uptake and further studied.Results: Visualizing lung by 18F-FDG-PET/CT identified new imaging patterns and revealed activity in all Scadding stages. Ever-smokers presented significantly higher TLG and lower DLCO compared to never-smokers. However, TLG value did not correlate with functional indices and did not differ between symptomatic and non-symptomatic patients. Among treatment-naïve patients, TLG did not differ significantly in those requiring therapy compared to those remained off.Conclusion: 18F-FDG PET/CT improved imaging and detection of pulmonary involvement and through TLG value revealed the deleterious smoking effect. The fact that TLG neither detected patients with clinical symptoms and functional impairment nor identified those requiring treatment once again confirms that in pulmonary sarcoidosis the link between activity, severity and decision to treat still eludes us.

Mycophenolate mofetil as an alternative treatment in sarcoidosis.

INTRODUCTION: In sarcoidosis although no better drug therapy than corticosteroids (CS) has emerged, alternative immunosuppressive agents are used when indicated. Mycophenolate mofetil (MMF) presents rapid action, a considerable safety profile and absence of lung toxicity. Few data exist so far on its use in patients with sarcoidosis. This is a retrospective study on the effectiveness and safety of MMF in patients with sarcoidosis. MATERIALS AND METHODS: All patients with biopsy proven sarcoidosis treated for at least 1 year with MMF from 2008 to 2017 in our department are evaluated. RESULTS: Eight patients with both pulmonary and extrapulmonary disease are included in the analysis. During follow-up, symptoms and chest radiological findings improved in all. A statistically significant improvement of FEV1 and FVC is reported (p = 0.010 and p = 0.021 respectively). Cardiac and renal disease resolved during treatment while dermal disease significantly improved. MMF permitted CS dose reduction from 15.0 (10.0, 35.0) to 2.5 (0.0, 5.0) mg prednisolone (or equivalent), p = 0.016. All patients but one, tolerated well MMF. CONCLUSION: MMF as an alternative drug in systemic sarcoidosis, proved safe and effective, permitting the reduction of the dose of oral CS and leading to clinical, functional and radiological improvement.