High risk of lung cancer in surfactant-related gene variant carriers.

BACKGROUND: Several rare surfactant-related gene (SRG) variants associated with interstitial lung disease are suspected to be associated with lung cancer, but data are missing. We aimed to study the epidemiology and phenotype of lung cancer in an international cohort of SRG variant carriers. METHODS: We conducted a cross-sectional study of all adults with SRG variants in the OrphaLung network and compared lung cancer risk with telomere-related gene (TRG) variant carriers. RESULTS: We identified 99 SRG adult variant carriers (SFTPA1 (n=18), SFTPA2 (n=31), SFTPC (n=24), ABCA3 (n=14) and NKX2-1 (n=12)), including 20 (20.2%) with lung cancer (SFTPA1 (n=7), SFTPA2 (n=8), SFTPC (n=3), NKX2-1 (n=2) and ABCA3 (n=0)). Among SRG variant carriers, the odds of lung cancer was associated with age (OR 1.04, 95% CI 1.01-1.08), smoking (OR 20.7, 95% CI 6.60-76.2) and SFTPA1/SFTPA2 variants (OR 3.97, 95% CI 1.39-13.2). Adenocarcinoma was the only histological type reported, with programmed death ligand-1 expression ≥1% in tumour cells in three samples. Cancer staging was localised (I/II) in eight (40%) individuals, locally advanced (III) in two (10%) and metastatic (IV) in 10 (50%). We found no somatic variant eligible for targeted therapy. Seven cancers were surgically removed, 10 received systemic therapy, and three received the best supportive care according to their stage and performance status. The median overall survival was 24 months, with stage I/II cancers showing better survival. We identified 233 TRG variant carriers. The comparative risk (subdistribution hazard ratio) for lung cancer in SRG patients versus TRG patients was 18.1 (95% CI 7.1-44.7). CONCLUSIONS: The high risk of lung cancer among SRG variant carriers suggests specific screening and diagnostic and therapeutic challenges. The benefit of regular computed tomography scan follow-up should be evaluated.

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.

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.

Patients Hospitalized for COVID-19 in the Periods of Delta and Omicron Variant Dominance in Greece: Determinants of Severity and Mortality.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has been a pandemic since 2020, and depending on the SARS-CoV-2 mutation, different pandemic waves have been observed. The aim of this study was to compare the baseline characteristics of patients in two phases of the pandemic and evaluate possible predictors of mortality. METHODS: This is a retrospective multicenter observational study that included patients with COVID-19 in 4 different centers in Greece. Patients were divided into two groups depending on the period during which they were infected during the Delta and Omicron variant predominance. RESULTS: A total of 979 patients (433 Delta, 546 Omicron) were included in the study (median age 67 years (54, 81); 452 [46.2%] female). Compared to the Omicron period, the patients during the Delta period were younger (median age [IQR] 65 [51, 77] vs. 70 [55, 83] years, p < 0.001) and required a longer duration of hospitalization (8 [6, 13] vs. 7 [5, 12] days, p = 0.001), had higher procalcitonin levels (ng/mL): 0.08 [0.05, 0.17] vs. 0.06 [0.02, 0.16], p = 0.005, ferritin levels (ng/mL): 301 [159, 644] vs. 239 [128, 473], p = 0.002, C- reactive protein levels (mg/L): 40.4 [16.7, 98.5] vs. 31.8 [11.9, 81.7], p = 0.003, and lactate dehydrogenase levels (U/L): 277 [221, 375] vs. 255 [205, 329], p < 0.001. The Charlson Comorbidity Index was lower (3 [0, 5] vs. 4 [1, 6], p < 0.001), and the extent of disease on computed tomography (CT) was greater during the Delta wave (p < 0.001). No evidence of a difference in risk of death or admission to the intensive care unit was found between the two groups. Age, cardiovascular events, acute kidney injury during hospitalization, extent of disease on chest CT, D-dimer, and neutrophil/lymphocyte ratio values were identified as independent predictors of mortality for patients in the Delta period. Cardiovascular events and acute liver injury during hospitalization and the PaO2/FiO2 ratio on admission were identified as independent predictors of mortality for patients in the Omicron period. CONCLUSIONS: In the Omicron wave, patients were older with a higher number of comorbidities, but patients with the Delta variant had more severe disease and a longer duration of hospitalization.

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.

Eosinopenia as a Prognostic Biomarker for Noninvasive Ventilation Use in COPD Exacerbations.

BACKGROUND: In recent years, blood eosinophils have been evaluated as a surrogate biomarker for eosinophilic airway inflammation and as a prognostic indicator of the outcomes of hospitalized COPD subjects. During an exacerbation of COPD, eosinopenia has been proposed as a prognostic marker of adverse outcomes. OBJECTIVES: The aim of the present post hoc analysis was to elucidate the effectiveness of blood eosinophils for predicting the need of NIV in subjects with COPD exacerbation. METHODS: Consecutive subjects admitted to a hospital for COPD exacerbation were included in the analysis. The eosinophil count from the first complete blood count was used to designate the eosinophil groups. The relationship between the clinical characteristics and blood eosinophil counts, as dichotomized using 150 cells/µL, was evaluated. Results Subjects with blood eosinophil number < 150 k/µL had a more severe disease on admission compared to subjects with ≥150 k/µL, regarding pH 7.400 (7.36, 7.44) vs. 7.42 (7.38, 7.45), p = 0.008, PO2/FiO2 levels 238.1 (189.8, 278.6) vs. 276.2 (238.2, 305.6), p < 0.001, CRP (mg/L) levels 7.3 (3.1, 19.9) vs. 3.5 (0.7, 7.8), p < 0.001 and required a longer hospital stay (days) 10.0 (8.0, 14.0) vs. 5.0 (3.0, 7.0) p < 0.001 respectively. The number of blood eosinophils correlated with the levels of CRP upon admission (p < 0.001, r = -0.334), with arterial pH upon admission (p < 0.030, r = 0.121), with PO2/FiO2 (p < 0.001, r = -0.248), and with duration of hospital stay (p < 0.001, r = -0.589). In the multinomial logistic regression analysis, blood eosinophil count < 150 k/µL was an independent predictor of the use of NIV during hospital stay. CONCLUSION: During COPD exacerbation, low blood eosinophil levels upon admission are related to more severe disease and can be used as a predictor of the need of NIV. Further prospective studies are needed to identify the use of blood eosinophil levels as a predictor of unfavorable outcomes.

Diffuse alveolar haemorrhage in children: an international multicentre study.

Background: Paediatric diffuse alveolar haemorrhage (DAH) is a rare heterogeneous condition with limited knowledge on clinical presentation, treatment and outcome. Methods: A retrospective, descriptive multicentre follow-up study initiated from the European network for translational research in children's and adult interstitial lung disease (Cost Action CA16125) and chILD-EU CRC (the European Research Collaboration for Children's Interstitial Lung Disease). Inclusion criteria were DAH of any cause diagnosed before the age of 18 years. Results: Data of 124 patients from 26 centres (15 counties) were submitted, of whom 117 patients fulfilled the inclusion criteria. Diagnoses were idiopathic pulmonary haemosiderosis (n=35), DAH associated with autoimmune features (n=20), systemic and collagen disorders (n=18), immuno-allergic conditions (n=10), other childhood interstitial lung diseases (chILD) (n=5), autoinflammatory diseases (n=3), DAH secondary to other conditions (n=21) and nonspecified DAH (n=5). Median (IQR) age at onset was 5 (2.0-12.9) years. Most frequent clinical presentations were anaemia (87%), haemoptysis (42%), dyspnoea (35%) and cough (32%). Respiratory symptoms were absent in 23%. The most frequent medical treatment was systemic corticosteroids (93%), hydroxychloroquine (35%) and azathioprine (27%). Overall mortality was 13%. Long-term data demonstrated persistent abnormal radiology and a limited improvement in lung function. Conclusions: Paediatric DAH is highly heterogeneous regarding underlying causes and clinical presentation. The high mortality rate and number of patients with ongoing treatment years after onset of disease underline that DAH is a severe and often chronic condition. This large international study paves the way for further prospective clinical trials that will in the long term allow evidence-based treatment and follow-up recommendations to be determined.

Diffuse panniculitis in a teenage male with ZZ α1-antitrypsin deficiency.

Diffuse panniculitis is a rare manifestation of α1-ATD, albeit perhaps the most fulminant and life-threatening complication, associated usually with ZZ phenotype. Intravenous α1-AT treatment is lifesaving. https://bit.ly/3EDmCzT.

COVID-19 in patients with pulmonary alveolar proteinosis: a European multicentre study.

Adult PAP patients experience similar #COVID19 rates to the general population, and high rates of hospitalisation and deaths, underscoring their vulnerability and the need for measures to prevent infection. The impact of iGM-CSF must be considered. https://bit.ly/3M0wKnZ.

Diffuse alveolar hemorrhage in children with interstitial lung disease: Determine etiologies!

OBJECTIVE: Diffuse alveolar hemorrhage (DAH) in children is a rare condition resulting from different underlying diseases. This study aimed at describing characteristics and diagnostic measures in children with ILD (children's interstitial lung disease, chILD) and DAH to improve the diagnostic approach by increasing clinician's awareness of diagnostic shortcomings. PATIENTS AND METHODS: A retrospective data analysis of patients with ILD and DAH treated in our own or collaborating centers between 01/07/1997 and 31/12/2020 was performed. Data on clinical courses and diagnostic measures were systematically retrieved as case-vignettes and investigated. To assess suitability of diagnostic software-algorithms, the Human Phenotype Ontology (HPO) was revised and expanded to optimize conditions of its associated tool the "Phenomizer." RESULTS: For 97 (74%) of 131 patients, etiology of pulmonary hemorrhage was clarified. For 34 patients (26%), no underlying condition was found (termed as idiopathic pulmonary hemorrhage, IPH). Based on laboratory findings or clinical phenotype/comorbidities, 20 of these patients were assigned to descriptive clusters: IPH associated with autoimmune features (9), eosinophilia (5), renal disease (3) or multiorgan involvement (3). For 14 patients, no further differentiation was possible. CONCLUSION: Complete and sometimes repeated diagnostics are essential for establishing the correct diagnosis in children with DAH. We suggest assignment of patients with IPH to descriptive clusters, which may also guide further research. Digital tools such as the Phenomizer/HPO are promising, but need to be extended to increase diagnostic accuracy.

The Impact of COVID-19 Pandemic on Surgical Treatment of Resectable Non-Small Cell Lung Cancer in Greece.

Background: The coronavirus disease (COVID-19) pandemic has posed an unprecedented challenge to health systems, and has significantly affected the healthcare of lung cancer patients. The aim of our study was to assess the impact of COVID-19 on early lung cancer patients' surgical treatment. Methods: All consecutive patients with early-stage non-small cell lung cancer eligible for surgical treatment stage I/II and resectable stage III, referred to our department during the first wave of COVID-19 between February to May 2020, were included and compared with those on the exact corresponding quarter in 2019, one year before the pandemic. Waiting time to surgical treatment, increase of tumor's size and increase on lung cancer stage were recorded and compared. All subjects were followed up for 12 months. Multiple linear and logistic regression models were applied to assess the differences in the management of the studied groups adjusting for potential confounders. Results: Sixty-one patients with early-stage lung cancer were included in the study; 28 (median age 67 years, SD: 7.1) during the pandemic and 33 (median age 67.1 years, SD: 7.5) one year earlier. A significantly longer period of waiting for treatment and an increase in tumor size were observed during the pandemic compared to before the pandemic [median time 47 days, interquartile rate (IQR): 23−100] vs. [median time 18 days, IQR: 11−23], p < 0.001. No significant differences were detected in the increase of the stage of lung cancer between the subgroups. Conclusion: The COVID-19 pandemic had a significant impact on surgical and oncological care, leading to significant delays on treatment and an increase in tumor size in early-stage lung cancer patients.

Genetics in Idiopathic Pulmonary Fibrosis: A Clinical Perspective.

BACKGROUND: Unraveling the genetic background in a significant proportion of patients with both sporadic and familial IPF provided new insights into the pathogenic pathways of pulmonary fibrosis. AIM: The aim of the present study is to overview the clinical significance of genetics in IPF. PERSPECTIVE: It is fascinating to realize the so-far underestimated but dynamically increasing impact that genetics has on aspects related to the pathophysiology, accurate and early diagnosis, and treatment and prevention of this devastating disease. Genetics in IPF have contributed as no other in unchaining the disease from the dogma of a "a sporadic entity of the elderly, limited to the lungs" and allowed all scientists, but mostly clinicians, all over the world to consider its many aspects and "faces" in all age groups, including its co-existence with several extra pulmonary conditions from cutaneous albinism to bone-marrow and liver failure. CONCLUSION: By providing additional evidence for unsuspected characteristics such as immunodeficiency, impaired mucus, and surfactant and telomere maintenance that very often co-exist through the interaction of common and rare genetic variants in the same patient, genetics have created a generous and pluralistic yet unifying platform that could lead to the understanding of the injurious and pro-fibrotic effects of many seemingly unrelated extrinsic and intrinsic offending factors. The same platform constantly instructs us about our limitations as well as about the heritability, the knowledge and the wisdom that is still missing.

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.