Increased levels of GM-CSF and CXCL10 and low CD8+ memory stem T Cell count are markers of immunosenescence and severe COVID-19 in older people.

BACKGROUND: Ageing leads to altered immune responses, resulting in higher susceptibility to certain infections in the elderly. Immune ageing is a heterogeneous process also associated with inflammaging, a low-grade chronic inflammation. Altered cytotoxic T cell responses and cytokine storm have previously been described in severe COVID-19 cases, however the parameters responsible for such immune response failures are not well known. The aim of our study was to characterize CD8+ T cells and cytokines associated with ageing, in a cohort of patients aged over 70 years stratified by COVID-19 severity. RESULTS: One hundred and four patients were included in the study. We found that, in older people, COVID-19 severity was associated with (i) higher level of GM-CSF, CXCL10 (IP-10), VEGF, IL-1ß, CCL2 (MCP-1) and the neutrophil to lymphocyte ratio (NLR), (ii) increased terminally differentiated CD8+T cells, and (ii) decreased early precursors CD8+ T stem cell-like memory cells (TSCM) and CD27+CD28+. The cytokines mentioned above were found at higher concentrations in the COVID-19+ older cohort compared to a younger cohort in which they were not associated with disease severity. CONCLUSIONS: Our results highlight the particular importance of the myeloid lineage in COVID-19 severity among older people. As GM-CSF and CXCL10 were not associated with COVID-19 severity in younger patients, they may represent disease severity specific markers of ageing and should be considered in older people care.

Derivation and validation of a simple multidimensional index incorporating exercise capacity parameters for survival prediction in idiopathic pulmonary fibrosis.

INTRODUCTION: The gender-age-physiology (GAP) index is an easy-to-use baseline mortality prediction model in idiopathic pulmonary fibrosis (IPF). The GAP index does not incorporate exercise capacity parameters such as 6 min walk distance (6MWD) or exertional hypoxia. We evaluated if the addition of 6MWD and exertional hypoxia to the GAP index improves survival prediction in IPF. METHODS: Patients with IPF were identified at a tertiary care referral centre. Discrimination and calibration of the original GAP index were assessed. The cohort was then randomly divided into a derivation and validation set and performance of the GAP index with the addition of 6MWD and exertional hypoxia was evaluated. A final model was selected based on improvement in discrimination. Application of this model was then evaluated in a geographically distinct external cohort. RESULTS: There were 562 patients with IPF identified in the internal cohort. Discrimination of the original GAP index was measured by a C-statistic of 0.676 (95% CI 0.635 to 0.717) and overestimated observed risk. 6MWD and exertional hypoxia were strongly predictive of mortality. The addition of these variables to the GAP index significantly improved model discrimination. A revised index incorporating exercise capacity parameters was constructed and performed well in the internal validation set (C-statistic: 0.752; 95% CI 0.701 to 0.802, difference in C-statistic compared with the refit GAP index: 0.050; 95% CI 0.004 to 0.097) and external validation set (N=108 (C-statistic: 0.780; 95% CI 0.682 to 0.877)). CONCLUSION: A simple point-based baseline-risk prediction model incorporating exercise capacity predictors into the original GAP index may improve prognostication in patients with IPF.

Proteomic biomarkers for survival in systemic sclerosis-associated pulmonary hypertension.

BACKGROUND: Interstitial lung disease (ILD) and pulmonary hypertension (PH) represent the major causes of mortality in systemic sclerosis (SSc). Patients with systemic sclerosis and combined PH and ILD (SSc-PH-ILD) generally have a poor prognosis. Predictors of survival and of potential benefit of treatment are lacking in patients with SSc-PH-ILD. OBJECTIVE: To identify specific plasma protein expression patterns associated with survival in patients with SSc-PH-ILD. MATERIALS AND METHODS: Post-hoc analysis of a prospective multicenter French study in patients with PH-ILD. An untargeted proteomic analysis using mass spectrometry was performed to identify plasma protein changes associated with long-term overall survival in patients with SSc-PH-ILD. RESULTS: Thirty two patients were included in the analysis, of whom 13 died during follow-up (median survival: 76.5 months). At baseline, survivors had less severe hemodynamic impairment [pulmonary vascular resistance of 4.4 Wood Units (IQR 3-5.2) vs. 6.2 Wood Units (IQR 4.2-10.7)] and higher carbon monoxide diffusing capacity [median 39% (IQR 35-44%) vs. 25% (IQR 22-30.5%)], than the 13 patients who died. Seven proteins, associated with haemostasis and fibrosis, were differentially expressed according to patients' survival. In the survivor group, two proteins were increased (ADAMTS13, SERPIND1) and five were decreased (PTGDS, OLFM1, C7, IGFBP7, FBN1) compared to the non-survivor groups. CONCLUSION: The prognosis of SSc-PH-ILD patients is poor. This proteomic approach found 7 plasma proteins (involved in haemostasis and fibrosis pathways) associated with survival. These potential biomarkers may be good candidates to prognostic enrichment.

Psychometric Properties of a Machine Learning-Based Patient-Reported Outcome Measure on Medication Adherence: Single-Center, Cross-Sectional, Observational Study.

BACKGROUND: Medication adherence plays a critical role in controlling the evolution of chronic disease, as low medication adherence may lead to worse health outcomes, higher mortality, and morbidity. Assessment of their patients' medication adherence by clinicians is essential for avoiding inappropriate therapeutic intensification, associated health care expenditures, and the inappropriate inclusion of patients in time- and resource-consuming educational interventions. In both research and clinical practices the most extensively used measures of medication adherence are patient-reported outcome measures (PROMs), because of their ability to capture subjective dimensions of nonadherence. Machine learning (ML), a subfield of artificial intelligence, uses computer algorithms that automatically improve through experience. In this context, ML tools could efficiently model the complexity of and interactions between multiple patient behaviors that lead to medication adherence. OBJECTIVE: This study aimed to create and validate a PROM on medication adherence interpreted using an ML approach. METHODS: This cross-sectional, single-center, observational study was carried out a French teaching hospital between 2021 and 2022. Eligible patients must have had at least 1 long-term treatment, medication adherence evaluation other than a questionnaire, the ability to read or understand French, an age older than 18 years, and provided their nonopposition. Included adults responded to an initial version of the PROM composed of 11 items, each item being presented using a 4-point Likert scale. The initial set of items was obtained using a Delphi consensus process. Patients were classified as poorly, moderately, or highly adherent based on the results of a medication adherence assessment standard used in the daily practice of each outpatient unit. An ML-derived decision tree was built by combining the medication adherence status and PROM responses. Sensitivity, specificity, positive and negative predictive values (NPVs), and global accuracy of the final 5-item PROM were evaluated. RESULTS: We created an initial 11-item PROM with a 4-point Likert scale using the Delphi process. After item reduction, a decision tree derived from 218 patients including data obtained from the final 5-item PROM allowed patient classification into poorly, moderately, or highly adherent based on item responses. The psychometric properties were 78% (95% CI 40%-96%) sensitivity, 71% (95% CI 53%-85%) specificity, 41% (95% CI 19%-67%) positive predictive values, 93% (95% CI 74%-99%) NPV, and 70% (95% CI 55%-83%) accuracy. CONCLUSIONS: We developed a medication adherence tool based on ML with an excellent NPV. This could allow prioritization processes to avoid referring highly adherent patients to time- and resource-consuming interventions. The decision tree can be easily implemented in computerized prescriber order-entry systems and digital tools in smartphones. External validation of this tool in a study including a larger number of patients with diseases associated with low medication adherence is required to confirm its use in analyzing and assessing the complexity of medication adherence.

Risk stratification and treatment of pulmonary embolism with intermediate-risk of mortality.

PURPOSE OF REVIEW: Intermediate-risk pulmonary embolisms (PE) represent a heterogeneous group at the high end of hemodynamically stable patients, characterized by a higher mortality rate. This challenging population gathers many unsolved question regarding its therapeutic management. The purpose of this review is to provide an updated overview of the literature regarding further risk stratification and treatment options in this population. RECENT FINDINGS: If anticoagulation represents the undisputed first line of treatment, some patients especially in the intermediate-high risk subgroup may necessitate or could benefit from therapeutic escalation with reperfusion therapies. This includes systemic thrombolysis (ST) or catheter-directed therapies (CDT). ST, despite its high efficacy, is not recommended in this population because of prohibitive bleeding complications. Therefore, reduced-dose ST appears to be a promising option and is actually under evaluation. CDT are percutaneous reperfusion techniques developed to acutely decrease pulmonary vascular obstruction with lower-dose or no thrombolytic agents and, thus, potentially improved safety compared to ST. SUMMARY: Great progress has been made in the recent years providing a wide range of therapeutic options. Optimal selection of patients who could benefit from these treatments is the key and is based on clinical, biological and radiological parameters evaluating right ventricle function and allowing accurate risk stratification. Pulmonary Embolism Response Team represents an efficient modality for therapeutic management especially in the intermediate-high risk subgroup.

Idiopathic pulmonary fibrosis patients with severe physiologic impairment: characteristics and outcomes.

RESEARCH QUESTION: There is no widely accepted grading system for IPF disease severity, although physiologic impairment based on pulmonary function testing is frequently employed. We sought to describe clinical and functional characteristics as well as outcomes of patients with severe physiologic impairment. PATIENTS AND METHODS: IPF patients with severe physiologic impairment defined by FVC ≤ 50% and/or DLco ≤ 30% predicted evaluated in the Inova Advanced Lung Disease Program between 2011 and 2019 were included. Demographic, physiologic, functional treatment and outcome data were collated. RESULTS: There were 531 patients with IPF evaluated of whom 242 (46%) had severe physiologic impairment. Mean age was 72 ± 8 years; baseline FVC was 53 ± 17% and DLCO 28 ± 9% of predicted. The mean 6 min walks test (6MWT) distance was 304 ± 121 m with 59% of the patients requiring supplemental oxygen ([Formula: see text] group). There was a poor correlation between the 6MWT distance and both FVC% and DLco%. Patients in the 6MWTRA group had a better transplant-free survival than the [Formula: see text] group (p = 0.002). Patients managed before October 2014 and not receiving antifibrotic therapy had worse outcomes with reduced transplant-free survival compared with patients presenting after this date who did receive antifibrotic therapy (n = 113) (log rank p < 0.0001). CONCLUSION: IPF patients often present with severe physiologic impairment which may be poorly correlated with their functional status. Assessment of IPF disease severity should not be based on physiologic impairment alone, but should also encompass functional status as well as need for supplemental oxygen. Antifibrotic therapy in patients with severe physiologic impairment is associated with improved outcomes.

Prevalence of Pulmonary Embolism Among Patients With COPD Hospitalized With Acutely Worsening Respiratory Symptoms.

IMPORTANCE: The prevalence of pulmonary embolism in patients with chronic obstructive pulmonary disease (COPD) and acutely worsening respiratory symptoms remains uncertain. OBJECTIVE: To determine the prevalence of pulmonary embolism in patients with COPD admitted to the hospital for acutely worsening respiratory symptoms. DESIGN, SETTING, AND PARTICIPANTS: Multicenter cross-sectional study with prospective follow-up conducted in 7 French hospitals. A predefined pulmonary embolism diagnostic algorithm based on Geneva score, D-dimer levels, and spiral computed tomographic pulmonary angiography plus leg compression ultrasound was applied within 48 hours of admission; all patients had 3-month follow-up. Patients were recruited from January 2014 to May 2017 and the final date of follow-up was August 22, 2017. EXPOSURES: Acutely worsening respiratory symptoms in patients with COPD. MAIN OUTCOMES AND MEASURES: The primary outcome was pulmonary embolism diagnosed within 48 hours of admission. Key secondary outcome was pulmonary embolism during a 3-month follow-up among patients deemed not to have venous thromboembolism at admission and who did not receive anticoagulant treatment. Other outcomes were venous thromboembolism (pulmonary embolism and/or deep vein thrombosis) at admission and during follow-up, and 3-month mortality, whether venous thromboembolism was clinically suspected or not. RESULTS: Among 740 included patients (mean age, 68.2 years [SD, 10.9 years]; 274 women [37.0%]), pulmonary embolism was confirmed within 48 hours of admission in 44 patients (5.9%; 95% CI, 4.5%-7.9%). Among the 670 patients deemed not to have venous thromboembolism at admission and who did not receive anticoagulation, pulmonary embolism occurred in 5 patients (0.7%; 95% CI, 0.3%-1.7%) during follow-up, including 3 deaths related to pulmonary embolism. The overall 3-month mortality rate was 6.8% (50 of 740; 95% CI, 5.2%-8.8%). The proportion of patients who died during follow-up was higher among those with venous thromboembolism at admission than the proportion of those without it at admission (14 [25.9%] of 54 patients vs 36 [5.2%] of 686; risk difference, 20.7%, 95% CI, 10.7%-33.8%; P < .001). The prevalence of venous thromboembolism was 11.7% (95% CI, 8.6%-15.9%) among patients in whom pulmonary embolism was suspected (n = 299) and was 4.3% (95% CI, 2.8%-6.6%) among those in whom pulmonary embolism was not suspected (n = 441). CONCLUSIONS AND RELEVANCE: Among patients with chronic obstructive pulmonary disease admitted to the hospital with an acute worsening of respiratory symptoms, pulmonary embolism was detected in 5.9% of patients using a predefined diagnostic algorithm. Further research is needed to understand the possible role of systematic screening for pulmonary embolism in this patient population.

Peripheral arterial disease and systematic detection of circulating tumor cells: rationale and design of the DETECTOR prospective cohort study.

BACKGROUND: Smoking is a strong risk factor for cancer and atherosclerosis. Cancer mortality, especially from lung cancer, overtakes cardiovascular (CV) death rate in patients with peripheral arterial disease (PAD). Only a few patients with lung cancer after PAD management may benefit from surgical excision. Circulating tumor cells (CTC) associated with low-dose chest CT (LDCT) may improve early cancer detection. This study focuses on a screening strategy that can address not only lung cancer but all tobacco-related cancers in this high-risk population. METHODS: DETECTOR Project is a prospective cohort study in two French University hospitals. Participants are smokers or former smokers (≥30 pack-years, quitted ≤15 years), aged ≥55 to 80 years, with atherosclerotic PAD or abdominal aortic aneurysm. After the first screening round combining LDCT and CTC search on a blood sample, two other screening rounds will be performed at one-year interval. Incidental lung nodule volume, volume doubling time and presence of CTC will be taken into consideration for adapted diagnostic management. In case of negative LDCT and presence of CTC, a contrast enhanced whole-body PET/CT will be performed for extra-pulmonary malignancy screening. Psychological impact of this screening strategy will be evaluated in population study using a qualitative methodology. Assuming 10% prevalence of smoking-associated cancer in the studied population, a total of at least 300 participants will be enrolled. DISCUSSION: Epidemiological data underline an increase incidence in cancer and related death in the follow-up of patients with PAD, compared with the general population, particularly for tobacco-related cancers. The clinical benefit of a special workup for neoplasms in patients with PAD and a history of cigarette smoking has never been investigated. By considering CTCs detection in this very high-risk selected PAD population for tobacco-induced cancer, we expect to detect earlier pulmonary and extra-pulmonary malignancies, at a potentially curable stage. TRIAL REGISTRATION: The study was registered in the French National Agency for Medicines and Health Products Safety (No N° EUDRACT_ID RCB: 2016-A00657-44) and was approved by the ethics Committee for Persons Protection (IRB number 1072 and n° initial agreement 2016-08-02; ClinicalTrials.gov identifier NCT02849041).

Prognostic value of right ventricular dilatation in patients with low-risk pulmonary embolism.

The prognosis of multidetector computed tomography (MDCT) assessed right ventricular dilatation (RVD) is unclear in patients with pulmonary embolism (PE) and a simplified Pulmonary Embolism Severity Index (sPESI) of 0. We investigated in these patients whether MDCT-assessed RVD, defined by a right to left ventricular ratio (RV/LV) ≥0.9 or ≥1.0, is associated with worse outcomes.We combined data from three prospective cohorts of patients with PE. The main study outcome was the composite of 30-day all-cause mortality, haemodynamic collapse or recurrent PE in patients with sPESI of 0.Among 779 patients with a sPESI 0, 420 (54%) and 299 (38%) had a RV/LV ≥0.9 and ≥1.0 respectively. No difference in primary outcome was observed, 0.95% (95% CI 0.31-2.59) versus 0.56% (95% CI 0.10-2.22; p=0.692) and 1.34% (95% CI 0.43-3.62) versus 0.42% (95% CI 0.07-1.67; p=0.211) with RV/LV ≥0.9 and ≥1.0 respectively. Increasing the RV/LV threshold to ≥1.1, the outcome occurred more often in patients with RVD (2.12%, 95% CI 0.68-5.68 versus 0.34%, 95% CI 0.06-1.36; p=0.033).MDCT RV/LV ratio of ≥0.9 and ≥1.0 in sPESI 0 patients is frequent but not associated with a worse prognosis but higher cut-off values might be associated with worse outcome in these patients.

Evaluation of endothelial biomarkers as predictors of organ failures in septic shock patients.

BACKGROUND: Endothelial injury is recognized to trigger organ failures during the first 48h of septic shock. We evaluate endothelial biomarkers at ICU admission in their ability to predict severity, outcome, and organ failures in septic shock patients. METHODS: This prospective observational pilot study was conducted in a medical intensive care unit of a university hospital. Plasma levels of endothelial biomarkers as angiopoietin-2, sE-selectin or endocan were measured at ICU admission of 20 patients presenting with septic shock. Clinical and biological data were recorded at inclusion and each day during the first week. RESULTS: Significant correlations were found between angiopoietin-2 and severity scores at Day 1: SAPS2 (r(2)=0.620; p=0.004) and LOD score (r(2)=0.681; p=0.001). The angiopoietin-2 level was significantly higher in patients presenting with organ failure such as hemodynamic, renal or hepatic failure. It correlated with catecholamine infusion dose and was higher in non survivors compared with survivors (33.5 [28.9-51.4] vs. 12.4 [6.4-14.7]ng/ml; p=0.001). In contrast, in that population presenting with septic shock, endocan level at inclusion was not related to any organ failure at inclusion or Day 1 but appeared lower in patients presenting with respiratory failure at Day 3 compared to those who do not (1.9 [0.99-3.1] vs 5.2 [3.1-17.2]ng/ml; p=0.032). The endocan level at inclusion was correlated with the decrease in PaO2/FiO2 ratio at Day 2 (r(2)=0.628; p=0.0004) and Day 3 (r(2)=0.645; p=0.005). Endocan level <2.54ng/ml at admission is predictive of a respiratory failure presence at Day 3. CONCLUSION: In septic shock patients, angiopoietine-2 is related with clinical severity during the first 24h but only endocan is able to predict the presence of respiratory failure at Day 3.

Different KCO and VA combinations exist for the same DLCO value in patients with diffuse parenchymal lung diseases.

BACKGROUND: DLCO is the product of the CO transfer coefficient (KCO) by the "accessible" alveolar volume (VA). In theory, the same DLCO may result from various combinations of KCO and VA values, each of which reflect different injury sites and mechanisms. We sought to determine in this study the potential variability of both VA and KCO for fixed values of DLCO in diffuse parenchymal lung diseases (DPLD). METHODS: To this end, we designed a retrospective, cross-sectional study of three distinct types of DPLD and analysed pulmonary function test (PFT) datasets. RESULTS: We show here that for the same value of DLCO (50% predicted), KCO varied from 60 to 95% predicted and VA from 55 to 85% predicted in various types of DPLD idiopathic pulmonary fibrosis, sarcoidosis and connective tissue disease-associated DPLD, indicating distinct pathogenic mechanisms in these diseases. In addition, a comparison of VA with total lung capacity may help to evidence the distal airway obstruction sometimes associated with certain DPLD particularly sarcoidosis. CONCLUSION: Clinicians should take into account not only DLCO but also VA and KCO values when managing patients with DPLD.

[Diffuse interstitial lung disease: What is the role of bronchoalveolar lavage?]. / Pneumopathies interstitielles diffuses: quelle place pour le lavage bronchoalvéolaire?

Bonchoalveolar lavage is a safe and poorly invasive tool with a great diagnostic value particularly in diffuse infiltrative pulmonary diseases (IPD). In specific instances, it allows for a definite diagnosis (alveolar hemorrhage; alveolar proteinosis, lipidoses, infiltrative malignant diseases, opportunistic infections), obviating the need to perform more invasive diagnostic procedures like video-assisted surgical biopsy. In inflammatory IPD, either idiopathic, diagnostic or associated with inhaled antigens or with collagen vascular diseases for instance, it represents a crucial orientation diagnostic tool, considerably narrowing the spectrum of potential differential diagnosis.

Determinants of exercise capacity in cystic fibrosis patients with mild-to-moderate lung disease.

BACKGROUND: Adult patients with cystic fibrosis (CF) frequently have reduced exercise tolerance, which is multifactorial but mainly due to bronchial obstruction. The aim of this retrospective analysis was to determine the mechanisms responsible for exercise intolerance in patients with mild-to-moderate or severe disease. METHODS: Cardiopulmonary exercise testing with blood gas analysis at peak exercise was performed in 102 patients aged 28 ± 11 years: 48 patients had severe lung disease (FEV1 < 50%, group 1) and 54 had mild-to-moderate lung disease (FEV1 ≥ 50%, group 2). VO2 peak was measured and correlated with clinical, biological, and functional parameters. RESULTS: VO2 peak for all patients was 25 ± 9 mL/kg/min (65 ± 21% of the predicted value) and was < 84% of predicted in 82% of patients (100% of group 1, 65% of group 2). VO2 peak was correlated with body mass index, C-reactive protein, FEV1, FVC, RV, DLCO, VE/VCO2 peak, VD/VT, PaO2, PaCO2, P(A-a)O2, and breathing reserve. In multivariate analysis, FEV1 and overall hyperventilation during exercise were independent determinants of exercise capacity (R(2) = 0.67). FEV1 was the major significant predictor of VO2 peak impairment in group 1, accounting for 31% of VO2 peak alteration, whereas excessive overall hyperventilation (reduced or absent breathing reserve and VE/VCO2) accounted for 41% of VO2 alteration in group 2. CONCLUSION: Exercise limitation in adult patients with CF is largely dependent on FEV1 in patients with severe lung disease and on the magnitude of the ventilatory response to exercise in patients with mild-to-moderate lung disease.

Sarcoidosis-Associated Pulmonary Hypertension.

Sarcoidosis-associated pulmonary hypertension (SAPH) is a very severe complication of the disease, largely impacting its morbidity and being one of its strongest predictors of mortality. With the recent modifications of the hemodynamic definition of pulmonary hypertension (mean arterial pulmonary pressure >20 instead of <25 mmHg,) its prevalence is presently not precisely known, but it affects from 3 to 20% of sarcoid patients; mostly, although not exclusively, those with an advanced, fibrotic pulmonary disease. Its gold-standard diagnostic tool remains right heart catheterization (RHC). The decision to perform it relies on an expert decision after a non-invasive work-up, in which echocardiography remains the screening tool of choice. The mechanisms underlying SAPH, very often entangled, are crucial to define, as appropriate and personalized therapeutic strategies will aim at targeting the most significant ones. There are no recommendations so far as to the indications and modalities of the medical treatment of SAPH, which is based upon the opinion of a multidisciplinary team of sarcoidosis, pulmonary hypertension and sometimes lung transplant experts.

A cystic and bullous lung disease associated with a PIK3CA-related overgrowth syndrome.

A bullous and cystic lung disease diagnosed in the context of a clinically and genetically diagnosed PROS https://bit.ly/48GnoJy.

High-Risk Sarcoidosis: A Focus on Pulmonary, Cardiac, Hepatic and Renal Advanced Diseases, as Well as on Calcium Metabolism Abnormalities.

Although sarcoidosis is generally regarded as a benign condition, approximately 20-30% of patients will develop a chronic and progressive disease. Advanced pulmonary fibrotic sarcoidosis and cardiac involvement are the main contributors to sarcoidosis morbidity and mortality, with failure of the liver and/or kidneys representing additional life-threatening situations. In this review, we discuss diagnosis and treatment of each of these complications and highlight how the integration of clinical, pathological and radiological features may help predict the development of such high-risk situations in sarcoid patients.

Transbronchial cryobiopsy proven amyloid diffuse cystic lung disease complicating a transthyretin mutated (ATTRm) amyloidosis: a case report.

We present a case report of transbronchial cryobiopsy proven diffuse amyloid cystic lung disease complicating a homozygous Val122Ile (V122I) transthyretin mutated amyloidosis (ATTRm). To the best of our knowledge, this is the first case in the literature reporting such pulmonary lesions in ATTRm amyloidosis, and notably diagnosed through cryobiopsy. A 51-year-old man from Mali with a past medical history of bilateral carpal tunnel syndrome presented erectile dysfunction, asthenia and worsening dyspnoea over the past year. He presented signs of cardiac failure; histological and radiological investigations diagnosed cardiac amyloidosis. He was found homozygote for the V122I mutation in transthyretin. A diffuse cystic lung disease (DCLD) was noted on computed tomography (CT) scan. We performed a transbronchial pulmonary cryobiopsy that revealed histological transthyretin amyloid deposits. This case report illustrates the safety and usefulness of cryobiopsy in the setting of DCLD and extends ATTRm amyloidosis as a possible cause of DCLD.

Pulmonary toxicity of mTOR inhibitors. Comparisons of two populations: Solid organ recipients and cancer patients.

INTRODUCTION: Mammalian target of rapamycin (mTOR) inhibitors-associated pneumonitis (mTOR-IP) has long been described in solid organ recipients (T) patients but more recently in cancer (K) patients. Its overall characteristics have never been compared between these 2 populations. The aim of this study was to compare them in terms of presentation, severity and outcome in T and in K patients. MATERIAL AND METHODS: We carried out a retrospective study in a single French tertiary center. Four databases were used to ensure the exhaustive collection of all mTOR-IP cases between 2001 and 2020. All clinical, biological, radiological, pathological and outcome data were reviewed. RESULTS: Thirty-nine patients with mTOR-IP were diagnosed during this period, 24T and 15K patients. The average dosage of everolimus and sirolimus was 2,65mg (±1,78) and 2,75mg (±0,96) in T patients, respectively, versus 8,75mg (±2,26) for everolimus in K patients. The overall prevalence of mTOR-IP was 6.4% with a median time of occurrence of 7 months [IQR 3-35 months]. mTOR-IP were significantly more frequent (P<0.001) and occurred earlier (P<0.001) in cancer patients. No clinical, functional, radiological, pathological nor outcome differences were otherwise observed between the 2 groups. Average everolimus blood levels at the time of mTOR-IP diagnosis were in the range of recommended therapeutic values. CONCLUSION: Our study shows that mTOR-IP is comparable in terms of presentation in T and in K patients but that it occurs significantly earlier after drug introduction in the latter. This raises questions as to the potential role of the higher doses used in K patients as well as that of co-treatments in the pathogeny of the disease.

Recovery of Endothelium-dependent vascular relaxation impairment in convalescent COVID-19 patients: Insight from a pilot study.

BACKGROUND: Endothelial dysfunction is a key-feature in acute COVID-19. However, follow-up data regarding endothelial dysfunction and injury after COVID-19 infection are lacking. We aimed to investigate the changes in endothelium-dependent vasorelaxation at baseline and four months after hospital discharge in COVID-19 patients. METHODS: Twenty COVID-19 patients were compared to 24 healthy controls. Clinical and morphological data were collected after hospital admission for SARS-CoV-2 infection and reactive hyperaemia index (RHI) measurement was performed with a delay between 24 and 48 h after hospital admission and four months after hospital discharge in the outpatient clinics. Blood tests including inflammatory markers and measurement of post-occlusive vasorelaxation by digital peripheral arterial tonometry were performed at both visits. RESULTS: At baseline, COVID-19 patients exhibited reduced RHI compared to controls (p < 0.001), in line with an endothelial dysfunction. At four months follow-up, there was a 51% increase in the RHI (1.69 ± 0.32 to 2.51 ± 0.91; p < 0.01) in favor of endothelium-dependent vascular relaxation recovery. RHI changes were positively correlated with baseline C-reactive protein (r = 0.68; p = 0.02). Compared to COVID-19 patients with a decrease in RHI, COVID-19 patients with an increase in RHI beyond the day-to-day variability (i.e. >11%) had less severe systemic inflammation at baseline. CONCLUSION: Convalescent COVID-19 patients showed a recovery of systemic artery endothelial dysfunction, in particular patients with lower inflammation at baseline. Further studies are needed to decipher the interplay between inflammation and endothelial dysfunction in COVID-19 patients.

Prognostic impact of venous thromboembolism on the course of sarcoidosis: A multicenter retrospective case-control study.

Sarcoidosis is an independent risk factor for venous thromboembolism (VTE). However, the characteristics and clinical evolution of sarcoidosis patients presenting a VTE (sarcoidosis/VTE group) in the course of their disease are not known. Consequently, if VTE occurrence is associated with a more severe disease is still pending. We conducted a retrospective case-control study of sarcoidosis/VTE patients compared to matched sarcoidosis controls without VTE in two French tertiary centers, analysed and compared the clinical, biological, functional, imaging and evolutive profiles of the two groups. Sixty-one patients were included with at least one episode of VTE during course of sarcoidosis. At sarcoidosis onset (before/at the time of VTE occurrence) the number of affected organs, radiological stages and pulmonary functional tests were not significantly different between the two groups. In contrast, we found that sarcoidosis/VTE patients required more frequently a systemic immunosuppressive therapy (corticosteroids and/or immunosuppressors, 79% versus 58%; p = 0.008). The functional course was also poorer in sarcoidosis/VTE patients with a more frequent decrease in functional vital capacity (33% versus 18% in sarcoidosis/VTE patients and controls, respectively, p = 0.008). Finally, sarcoidosis/VTE patients presented more frequently with pulmonary hypertension (10% versus 1% in patients and controls, respectively, p = 0.006), and their survival was significantly worse (log-rank p <0.001). The occurrence of VTE during sarcoidosis is associated with a more severe disease and a poorer prognosis. The occurrence of VTE during sarcoidosis might signal a more inflammatory and/or evolutive disease in sarcoidosis/VTE patients and should be taken in consideration when designing therapeutic strategies for them.