Symptomatic post COVID patients have impaired alveolar capillary membrane function and high VE/VCO2.

BACKGROUND: Post COVID-19 syndrome is characterized by several cardiorespiratory symptoms but the origin of patients' reported symptomatology is still unclear. METHODS: Consecutive post COVID-19 patients were included. Patients underwent full clinical evaluation, symptoms dedicated questionnaires, blood tests, echocardiography, thoracic computer tomography (CT), spirometry including alveolar capillary membrane diffusion (DM) and capillary volume (Vcap) assessment by combined carbon dioxide and nitric oxide lung diffusion (DLCO/DLNO) and cardiopulmonary exercise test. We measured surfactant derive protein B (immature form) as blood marker of alveolar cell function. RESULTS: We evaluated 204 consecutive post COVID-19 patients (56.5 ± 14.5 years, 89 females) 171 ± 85 days after the end of acute COVID-19 infection. We measured: forced expiratory volume (FEV1) 99 ± 17%pred, FVC 99 ± 17%pred, DLCO 82 ± 19%, DM 47.6 ± 14.8 mL/min/mmHg, Vcap 59 ± 17 mL, residual parenchymal damage at CT 7.2 ± 3.2% of lung tissue, peakVO2 84 ± 18%pred, VE/VCO2 slope 112 [102-123]%pred. Major reported symptoms were: dyspnea 45% of cases, tiredness 60% and fatigability 77%. Low FEV1, Vcap and high VE/VCO2 slope were associated with persistence of dyspnea. Tiredness was associated with high VE/VCO2 slope and low PeakVO2 and FEV1 while fatigability with high VE/VCO2 slope. SPB was fivefold higher in post COVID-19 than in normal subjects, but not associated to any of the referred symptoms. SPB was negatively associated to Vcap. CONCLUSIONS: In patients with post COVID-19, cardiorespiratory symptoms are linked to VE/VCO2 slope. In these patients the alveolar cells are dysregulated as shown by the very high SPB. The Vcap is low likely due to post COVID-19 pulmonary endothelial/vasculature damage but DLCO is only minimally impaired being DM preserved.

Lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is an ultra-rare, slowly progressive neoplastic cystic disease, belonging to the group of PEComas. It can occur sporadically or associated to tuberous sclerosis complex disease and affects mainly women in child-birth age. Dyspnoea is the most frequent symptom referred to the time of diagnosis, however spontaneous pneumothorax may be a typical presentation associated to extrathoracic manifestations, such as renal angiomyolipomas. In the last decade, important advances in understanding molecular mechanisms underlying the LAM pathogenesis have been reached. It has allowed to obtain improvements in the research of novel biomarkers, treatment and a better management of the disease.

Comparison of clinical scoring to predict mortality risk in mild-to-moderate idiopathic pulmonary fibrosis.

BACKGROUND: During the last decade, a number of clinical scores, such as Gender-Age-Physiology (GAP) Index, TORVAN Score and Charlson Comorbidity Index (CCI), have been separately used to measure comorbidity burden in idiopathic pulmonary fibrosis (IPF). However, no previous study compared the prognostic value of these scores to assess mortality risk stratification in IPF patients with mild-to-moderate disease. METHODS: All consecutive patients with mild-to-moderate IPF who underwent high-resolution computed tomography, spirometry, transthoracic echocardiography and carotid ultrasonography at our Institution, between January 2016 and December 2018, were retrospectively analyzed. GAP Index, TORVAN Score and CCI were calculated in all patients. Primary endpoint was all-cause mortality, whereas secondary endpoint was the composite of all-cause mortality and rehospitalizations for all-causes, over medium-term follow-up. RESULTS: Seventy IPF patients (70.2±7.4 yrs, 74.3% males) were examined. At baseline, GAP Index, TORVAN Score and CCI were 3.4±1.1, 14.7±4.1 and 5.3±2.4, respectively. A strong correlation between coronary artery calcification (CAC) and common carotid artery (CCA) intima-media thickness (IMT) (r=0.88), CCI and CAC (r=0.80), CCI and CCA-IMT (r=0.81), was demonstrated in the study group. Follow-up period was 3.5±1.2 years. During follow-up, 19 patients died and 32 rehospitalizations were detected. CCI (HR 2.39, 95% CI: 1.31-4.35) and heart rate (HR 1.10, 95% CI: 1.04-1.17) were independently associated with primary endpoint. CCI (HR 1.54, 95% CI: 1.15-2.06) predicted secondary endpoint, also. A CCI ≥6 was the optimal cut-off for predicting both outcomes. CONCLUSIONS: Due to the increased atherosclerotic and comorbidity burden, IPF patients with CCI ≥6 at an early-stage disease have poor outcome over medium-term follow-up.

Prognostic role of CHA2DS2-VASc score for mortality risk assessment in non-advanced idiopathic pulmonary fibrosis: a preliminary observation.

During the last decade, the CHA2DS2-VASc score has been used for stratifying the mortality risk in both atrial fibrillation (AF) and non-AF patients. However, no previous study considered this score as a prognostic indicator in non-AF patients with mild-to-moderate idiopathic pulmonary fibrosis (IPF). All consecutive non-AF patients with mild-to-moderate IPF, diagnosed between January 2016 and December 2018 at our Institution, entered this study. All patients underwent physical examination, blood tests, spirometry, high-resolution computed tomography and transthoracic echocardiography. CHA2DS2-VASc score, Gender-Age-Physiology (GAP) index and Charlson Comorbidity Index (CCI) were determined in all patients. Primary endpoint was all-cause mortality, while the secondary endpoint was the composite of all-cause mortality and rehospitalizations for all causes over mid-term follow-up. 103 consecutive IPF patients (70.7 ± 7.3 yrs, 79.6% males) were retrospectively analyzed. At the basal evaluation, CHA2DS2-VASc score, GAP index and CCI were 3.7 ± 1.6, 3.6 ± 1.2 and 5.5 ± 2.3, respectively. Mean follow-up was 3.5 ± 1.3 yrs. During the follow-up period, 29 patients died and 43 were re-hospitalized (44.2% due to cardiopulmonary causes). On multivariate Cox regression analysis, CHA2DS2-VASc score (HR 2.15, 95% CI 1.59-2.91) and left ventricular ejection fraction (LVEF) (HR 0.91, 95% CI 0.86-0.97) were independently associated with all-cause mortality in IPF patients. CHA2DS2-VASc score (HR 1.66, 95% CI 1.39-1.99) and LVEF (HR 0.94, 95% CI 0.90-0.98) also predicted the secondary endpoint in the same study group. CHA2DS2-VASc score > 4 was the optimal cut-off for predicting both outcomes. At mid-term follow-up, a CHA2DS2-VASc score > 4 predicts an increased risk of all-cause mortality and rehospitalizations for all causes in non-AF patients with mild-to-moderate IPF.

Recent advances in the management of pulmonary hypertension with interstitial lung disease.

Pulmonary hypertension (PH) is known to complicate various forms of interstitial lung disease (ILD), including idiopathic pulmonary fibrosis, the interstitial pneumonias and chronic hypersensitivity pneumonitis. Pathogenesis of PH-ILD remains incompletely understood, and probably has overlap with other forms of pre-capillary pulmonary hypertension. PH-ILD carries a poor prognosis, and is associated with increased oxygen requirements, and a decline in functional capacity and exercise tolerance. Despite most patients having mild-moderate pulmonary hypertension, more severe pulmonary hypertension and signs of right heart failure are observed in a subset of cases. Clinical suspicion and findings on pulmonary function, computed tomography and echocardiography are often the initial steps towards diagnosis. Definitive diagnosis is obtained by right heart catheterisation demonstrating pre-capillary pulmonary hypertension. Drugs approved for pulmonary arterial hypertension have been investigated in several randomised controlled trials in PH-ILD patients, leading to discouraging results until the recent INCREASE study. This review provides an overview of the current understanding, approach to diagnosis and recent advances in treatment.

Coronary artery calcium score is a prognostic factor for mortality in idiopathic pulmonary fibrosis.

BACKGROUND: Cardiovascular diseases are frequent in idiopathic pulmonary fibrosis (IPF) and impact on survival. We investigated the association of coronary artery calcium (CAC) score at IPF diagnosis and during mid-term follow-up, with adverse cardiovascular events and all-cause mortality. METHODS: Consecutive patients with IPF were retrospectively analyzed. Demographic data, smoking history, comorbidities and pulmonary function tests (PFTs) were recorded. All patients had at least two chest high resolution computed tomography (HRCT) performed 2 years apart. The total CAC score and visual fibrotic score were calculated and all clinically significant cardiovascular events and deaths were reported. RESULTS: The population consisted of 79 patients (57 male, mean age 74.4 ± 7.6 years); 67% of patients had a history of smoking, 48% of hypertension, 37% of dyslipidemia and 22.8% of diabetes. The visual score was 21.28 ± 7.99% at T0 and 26.54 ± 9.34% at T1, respectively (T1-T0 5.26 ± 6.13%, p< 0.001). CAC score at T0 and at T1 was 537.93 ± 839.94 and 759.98 ± 1027.6, respectively (T1-T0 224.66 ± 406.87, p< 0.001). Mean follow-up time was 2.47±1.1 years. On multivariate analysis, male sex (HR 3.58, 95% CI 1.14-11.2) and CAC score at T0 (HR 1.04, 95% CI 1.01-1.07) correlated with mortality and cardiovascular events. CAC score at T0 ≥405 showed 82% sensitivity and 100% specificity for predicting mortality and adverse cardiovascular events. CONCLUSIONS: IPF patients with a CAC score at diagnosis ≥405 have a poor prognosis over a midterm follow-up. A higher CAC score is associated with mortality and cardiovascular events.

Pulmonary Langerhans Cell Histiocytosis and Lymphangioleiomyomatosis Have Circulating Cells With Loss of Heterozygosity of the TSC2 Gene.

BACKGROUND: Lymphangioleiomyomatosis (LAM) and pulmonary Langerhans cell histiocytosis (PLCH) are cystic lung diseases in which a neoplastic cell is thought to be responsible for disease pathogenesis. The neoplastic LAM cell has mutations in the TSC genes, TSC1 or TSC2, whereas the neoplastic PLCH cell may have mutations in several genes (eg, BRAF, NRAS, MAP2K1). These mutations are not specific for PLCH and have been described in multiple cancers. TSC1 or TSC2 mutations and loss of heterozygosity (LOH) have also been described in cancers. RESEARCH QUESTION: Is TSC2 LOH specific to LAM or is it also found in PLCH? STUDY DESIGN AND METHODS: We recruited patients with LAM (n = 53) and healthy volunteers (n = 22) and compared the presence of cells with TSC2 LOH with patients with PLCH (n = 12). Blood and urine samples were collected for analysis. Fluorescence-activated cell sorting (FACS) was used to identify subpopulations of cells from blood and urine samples. We isolated CD45-CD235a-, CD45-CD235a+, and CD45+CD235a- cells from blood after density gradient separation. Cells were screened for TSC2 LOH at five microsatellites markers (ie, kg8, D16S3395, D16S3024, D16S521, D16S291). We obtained four cell subpopulations from urine (ie, CD44v6+CD9+, CD44v6+CD9-, CD44v6-CD9+, CD44v6-CD9-). RESULTS: Using FACS, cells were isolated from blood and urine from patients with PLCH that showed TSC2 LOH. Healthy volunteers did not have cells with TSC2 LOH. As a control, cells isolated from blood and urine from patients with LAM gave results similar to those reported previously. These data show that TSC2 LOH is found in patients with cystic lung diseases with potential neoplastic characteristics, and in patients with cancer. INTERPRETATION: The presence of TSC2 LOH in circulating cells is not specific for LAM. The data suggest that chromosomal abnormalities affecting the TSC2 gene are found in other diseases associated with cells having cancer-like neoplastic cells.

Improving Survival in Lymphangioleio-myomatosis: A 16-Year Observational Study in a Large Cohort of Patients.

BACKGROUND: Over the last 2 decades, great progress has been made in the understanding of the clinical aspects and pathogenesis of lymphangioleiomyomatosis (LAM), leading to publication of guidelines and approval of an effective therapy. OBJECTIVES: Aim of our study was to describe how the management and the natural history of this rare disease have changed after the publication of the ERS and American Thoracic Society/Japanese Respiratory Society guidelines and the introduction of sirolimus. METHODS: We examined 162 LAM patients followed at our center between 2001 and 2017, reporting clinical characteristics and diagnostic approach. Response to sirolimus in patients undergoing long-term treatment and mortality risk, estimated in terms of cumulative incidence taking into account organ transplantation as a competing cause of the event, were evaluated. The difference in the cumulative incidence between the patients admitted to the observation before 2011 and after 2011, year of the publication of the MILES trial for the efficacy of sirolimus, has also been estimated. RESULTS: Sixty-one patients had a histological diagnosis (22 from 2010 onward). 101 patients received a radiological diagnosis according to the guidelines criteria. Pulmonary function tests remained stable over a 3-year treatment period in patients who received sirolimus for over 12 months. The cumulative incidence of mortality after 10 years in the whole population was 25.5%. The cumulative incidence of mortality after 5 years was significantly lower in patients who entered the study since 2011 (after publication of the MILES trial) than in patients who entered the study before. CONCLUSIONS: We provide the data supporting the long-term efficacy of sirolimus therapy in a large cohort of patients with functional impairment and other manifestations of the disease. Our results also suggest that the advent of sirolimus and the publication of international guidelines changed the natural history of the disease lowering the mortality and reducing the need of invasive diagnostic techniques.

Ultra-rare cystic disease.

Diffuse cystic lung diseases include a group of heterogeneous disorders characterised by the presence of cysts within the lung parenchyma, sometimes showing a characteristic computed tomography scan pattern that allows diagnosis. The pathogenetic mechanisms underlying cyst formation in the lung are still not clear and a number of hypotheses have been postulated according to the different aetiologies: ball-valve effect, ischaemic dilatation of small airways and alveoli related to infiltration and obstruction of small vessels and capillaries that supply the terminal bronchioles and connective tissue degradation by matrix metalloproteases. A wide number of lung cyst diseases have been classified into six diagnostic groups according to the aetiology: neoplastic, congenital/genetic, lymphoproliferative, infective, associated with interstitial lung diseases, and other causes. This article focuses on lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis and Erdheim-Chester disease, Birt-Hogg-Dubé, follicular bronchiolitis and lymphocytic interstitial pneumonia, light-chain deposition disease and amyloidosis, congenital lung disease associated with aberrant lung development and growth, and cystic lung disease associated with neoplastic lesion. These cystic diseases are epidemiologically considered as ultra-rare conditions as they affect fewer than one individual per 50 000 or fewer than 20 individuals per million. Despite the rarity of this group of disorders, the increasing use of high-resolution computed tomography has improved the diagnostic yield, even in asymptomatic patients allowing prompt and correct therapy and management without the need for a biopsy.

Comorbidities in idiopathic pulmonary fibrosis: an underestimated issue.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fibrosing lung disease with a poor prognosis. Between 60% and 70% of IPF patients die of IPF; the remaining causes of death may be due to comorbidities occurring in this ageing population. Interest in the role played by comorbidities in IPF has increased in the past few years. The optimal clinical management of IPF is multifaceted and not only involves antifibrotic treatment, but also vaccinations, oxygen supplementation, evaluation of nutritional status as well as psychological support and patient education. Symptom management, pulmonary rehabilitation, palliative care and treatment of comorbidities represent further areas of clinical intervention. This review analyses the major comorbidities observed in IPF, focusing on those that have the greatest impact on mortality and quality of life (QoL). The identification and treatment of comorbidities may help to improve patients' health-related QoL (i.e. sleep apnoea and depression), while some comorbidities (i.e. lung cancer, cardiovascular diseases and pulmonary hypertension) influence survival. It has been outlined that gathering comorbidities data improves the prediction of survival beyond the clinical and physiological parameters of IPF.

Pulmonary hypertension and chronic lung disease: where are we headed?

Pulmonary hypertension related to chronic lung disease, mainly represented by COPD and idiopathic pulmonary fibrosis, is associated with a worse outcome when compared with patients only affected by parenchymal lung disease. At present, no therapies are available to reverse or slow down the pathological process of this condition and most of the clinical trials conducted to date have had no clinically significant impact. Nevertheless, the importance of chronic lung diseases is always more widely recognised and, along with its increasing incidence, associated pulmonary hypertension is also expected to be growing in frequency and as a health burden worldwide. Therefore, it is desirable to develop useful and reliable tools to obtain an early diagnosis and to monitor and follow-up this condition, while new insights in the therapeutic approach are explored.

Hemodynamic Mechanisms of Exercise-Induced Pulmonary Hypertension in Patients with Lymphangioleiomyomatosis: The Role of Exercise Stress Echocardiography.

BACKGROUND: The pathogenesis of pulmonary hypertension (PH) in lymphangioleiomyomatosis (LAM) has not yet been completely clarified. The aim of this study was to conduct a noninvasive evaluation of the main hemodynamic mechanisms of exercise-induced PH in patients with LAM, assessed using exercise stress echocardiography. METHODS: Fifteen patients with LAM (mean age, 47 ± 13 years; all women) without resting PH were enrolled in a prospective single-center study and compared with 15 healthy female control subjects (mean age, 45.2 ± 8 years; P = .65). A complete echocardiographic study with Doppler tissue imaging was performed at baseline and during semisupine symptom-limited exercise testing to evaluate (1) left ventricular systolic and diastolic function, (2) right ventricular contractile function, (3) estimated pulmonary capillary wedge pressure, (4) estimated systolic and mean pulmonary artery pressure, and (5) estimated pulmonary vascular resistance. RESULTS: Compared with healthy control subjects, patients with LAM during exercise showed echocardiographic signs of right ventricular overload and right ventricular systolic dysfunction and significant increases in mean pulmonary artery pressure (14.4 ± 6.5 vs 4.2 ± 3.1 mm Hg, P < .0001), pulmonary vascular resistance (+68.3 ± 42.1 vs -0.1 ± 18.3 dyne-sec/cm5, P < .0001), and, unexpectedly, pulmonary capillary wedge pressure (+8.3 ± 5.3 vs -0.5 ± 1.3 mm Hg, P < .0001). CONCLUSIONS: Exercise-induced PH in patients with LAM could be related not only to hypoxic pulmonary vascular vasoconstriction during exercise (precapillary PH) but also to a significant exercise-induced increase in estimated pulmonary capillary wedge pressure, probably secondary to diastolic dysfunction (postcapillary PH).

New insights in lymphangioleiomyomatosis and pulmonary Langerhans cell histiocytosis.

Lymphangioleiomyomatosis (LAM) and pulmonary Langerhans cell histiocytosis (PLCH) are rare diseases that lead to progressive cystic destruction of the lungs. Despite their distinctive characteristics, these diseases share several features. Patients affected by LAM or PLCH have similar radiological cystic patterns, a similar age of onset, and the possibility of extrapulmonary involvement. In this review, the recent advances in the understanding of the molecular pathogenesis, as well as the current and most promising biomarkers and therapeutic approaches, are described.

Sirolimus Therapy for Patients With Lymphangioleiomyomatosis Leads to Loss of Chylous Ascites and Circulating LAM Cells.

A young woman received a diagnosis of abdominal, sporadic lymphangioleiomyomatosis (LAM) and multiple abdominal lymphangioleiomyomas and was referred for recurrent chylous ascites responding only to a fat-free diet. On admission, pulmonary function test (PFT) results showed a moderate reduction in the transfer factor for carbon monoxide with normal exercise performance. The serum vascular endothelial growth factor D (VEGF-D) level was 2,209 pg/mL. DNA sequences, amplified at loci kg8, D16S3395, D16S3024, D16S521, and D16S291 on chromosome 16p13.3, showed a loss of heterozygosity (LOH) only for kg8. Fat-free total parenteral nutrition in association with sirolimus (2 mg po daily) was initiated. Serum sirolimus levels were maintained at concentrations between 5 and 15 ng/mL. After 1 month, reintroduction of a low-fat oral feeding was achieved without recurrence of ascites. PFT results were stable. Interestingly, clinical improvement was associated with a reduction in the VEGF-D serum level (1,558 pg/mL). LOH at the kg8 biomarker in blood LAM cells was no longer detected.

Pulmonary hypertension in patients with chronic myeloproliferative disorders.

Pulmonary hypertension (PH) is a major complication of several haematological disorders. Chronic myeloproliferative diseases (CMPDs) associated with pulmonary hypertension have been included in group five of the clinical classification for pulmonary hypertension, corresponding to pulmonary hypertension for which the aetiology is unclear and/or multifactorial. The aim of this review is to discuss the epidemiology, pathogenic mechanism and treatment approaches of the more common forms of pulmonary hypertension in the context of CMPD's: chronic thromboembolic pulmonary hypertension, precapillary pulmonary hypertension and drug-induced PH.

Pulmonary Langerhans cell histiocytosis: a comprehensive analysis of 40 patients and literature review.

BACKGROUND: Pulmonary Langerhans cell histiocytosis (PLCH) is a rare interstitial disease affecting primarily young adult smokers. In order to highlight the clinical features of the disease, we conducted a retrospective analysis on clinical data of PLCH patients followed at our center; moreover, we reviewed the current literature on PLCH. METHOD AND RESULTS: Between January 2004 and July 2014, 40 patients with PLCH were evaluated at our Division. The average patients' age was 40 (± 14) years, and 22 of them were females. Diagnosis was based on search of CD1a+ cells in the bronchoalveolar lavage (10 patients), lung biopsy (8 patients), or cystic bone lesion's biopsy (2 patients); in 12 patients, diagnosis was achieved on the basis of the clinical-radiological data. The principal manifestation of PLCH was the presence of cysts involving upper lung zones with costophrenic sparing on chest CT scan (in 25 patients); micronodular pattern in the middle-upper zone and combination of the two radiological patterns were less frequently observed (in 9 and 6 patients, respectively). Pulmonary hypertension was found in 4 patients. Extra pulmonary manifestations were diabetes insipidus, bone lesions, and skin involvement (in 5, 7, and 1 patient, respectively). For 25 patients, smoking cessation was the only required therapy. Treatments with low dose of prednisolone, vinblastine and prednisolone, or 6-mercaptopurin were reserved for patients with major pulmonary or extra-pulmonary involvement (for 11, 4, and 5 patients, respectively). In conclusion, PLCH is a rare, multi-systemic disease; early diagnosis, accurate staging and smoking cessation are considered critical in PLCH management.