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.

An in-silico analysis reveals further evidence of an aggressive subset of lung carcinoids sharing molecular features of high-grade neuroendocrine neoplasms.

Little is known as to whether there may be any pathogenetic link between pulmonary carcinoids and neuroendocrine carcinomas (NECs). A gene signature we previously found to cluster pulmonary carcinoids, large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC), and which encompassed MEN1, MYC, MYCL1, RICTOR, RB1, SDHA, SRC and TP53 mutations or copy number variations (CNVs), was used to reclassify an independent cohort of 54 neuroendocrine neoplasms (NENs) [31 typical carcinoids (TC), 11 atypical carcinoids (AC) and 12 SCLC], by means of transcriptome and mutation data. Unsupervised clustering analysis identified two histology-independent clusters, namely CL1 and CL2, where 17/42 (40.5%) carcinoids and all the SCLC samples fell into the latter. CL2 carcinoids affected survival adversely, were enriched in T to G transversions or T > C/C > T transitions in the context of specific mutational signatures, presented with at least 1.5-fold change (FC) increase of gene mutations including TSC2, SMARCA2, SMARCA4, ERBB4 and PTPRZ1, differed for gene expression and showed epigenetic changes in charge of MYC and MTORC1 pathways, cellular senescence, inflammation, high-plasticity cell state and immune system exhaustion. Similar results were also found in two other independent validation sets comprising 101 lung NENs (24 carcinoids, 21 SCLC and 56 LCNEC) and 30 carcinoids, respectively. We herein confirmed an unexpected sharing of molecular traits along the spectrum of lung NENs, with a subset of genomically distinct aggressive carcinoids sharing molecular features of high-grade neuroendocrine neoplasms.

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.

Presumed Takotsubo syndrome is associated with high in-hospital mortality in very elderly frail females: a case series.

Given the aging of general population, very elderly females with Takotsubo syndrome (TTS) are not rarely encountered in clinical practice. Although coronary angiography with left ventriculography is the gold standard diagnostic tool to exclude or confirm TTS, currently, this invasive procedure is less frequently performed in older patients with several comorbidities, such as renal failure, anemia, infections, neurological disorders, malignancy, and severe frailty. In these patients, a "presumed" TTS is diagnosed on the basis of clinical presentation, electrocardiogram, cardiac biomarkers, and echocardiographic findings without coronary angiography. While, in younger patients, TTS is generally a benign condition, in very elderly females, it is associated with higher in-hospital mortality and poor prognosis. Herein, we present four cases of ultra-octogenarian females diagnosed with "presumed TTS", who did not undergo coronary angiography due to severe frailty and multiple comorbidities and who exhibited poor outcome. This could arise the question if an early more aggressive approach could have changed final results. Probably, the solution could only be a personalized decision deriving from a profound and detailed discussion of each case through a multidisciplinary team approach.

Post-recovery impact of the second and third SARS-CoV-2 infection waves on healthcare resource utilization in Lombardy, Italy.

The administrative claims database of the Italian region Lombardy, the first in Europe to be hit by the SARS-CoV-2 pandemic, was employed to evaluate the impact on healthcare resource utilization following recovery from the second (mainly alpha-related variant) and third (delta-related) infection waves. 317,164 individuals recovered from the infection and became negative after the second wave, 271,180 after the third. Of them, 1571 (0.5%) and 1575 (0.6%) died in the first 6 post-negativization months. In the remaining cases (315,593 after the second wave and 269,605 after the third), hospitalizations, attendances to emergency rooms and outpatient visits were compared with those recorded in the same pre-pandemic time periods in 2019. Dispensation of drugs as well as of imaging, and functional and biochemical diagnostic tests were also compared as additional proxies of the healthcare impact of the SARS-CoV-2 infection waves. Following both waves, hospitalizations, attendances at emergency rooms, and outpatient visits were similar in number and rates to the pre-pandemic periods. However, there was an increased dispensation a number of drugs and diagnostic tests, particularly those addressing the cardiorespiratory and blood systems. In a large region such as Lombardy taken as a relevant model because early and severely hit by the SARS-CoV-2 pandemic, the post-COVID burden on healthcare facilities was mildly relevant in cases who recovered from the second and third infection waves regarding such pivotal events as deaths, hospitalizations, and need for emergency room and outpatient visits, but was high regarding the dispensation of some drug classes and types of diagnostic tests.

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.

Post-COVID condition: dispensation of drugs and diagnostic tests as proxies of healthcare impact.

With the goal to increase knowledge on the healthcare impact of the post-COVID-19 condition we exploited the administrative claims database of Lombardy, the largest Italian region and the first after China to be heavily hit by the SARS-CoV-2 pandemic in February-May 2020. We chose to employ the dispensation of drugs and diagnostic tests as proxies of the impact of the post-COVID condition in 46,574 cases who recovered from COVID-19 and were negative at PCR testing within June 20, 2020. Data were obtained throughout the 18-month post-negativization period until December 2021 and results on the use of drugs and diagnostic tests were compared with those accrued in the same cases during the pre-COVID period in July-December 2019. After an increase in the first semester after SARS-CoV-2 negativization (July-December 2020), trends in the dispensation of drugs according to the broad ATC classes and of diagnostic tests decreased or remained substantially stable. However, dispensation of drugs for acid related disorders (A02), diabetes (A10), heparins (B01AB), direct oral anticoagulants (B01AP), antipsychotics (N05A), antidepressants (N06A) and for obstructive airways diseases (R03) was still higher than in the pre-COVID period. These findings, based upon drug and diagnostic test dispensation as proxies of the healthcare impact of the post-COVID condition, show that in a substantial proportion of recovered cases the post-COVID condition is active and clinically relevant 18 months after the acute disease. The findings also provide indirect evidence of the body organs and systems more compromised in the post-COVID period.

Sarcopenia in idiopathic pulmonary fibrosis: a prospective study exploring prevalence, associated factors and diagnostic approach.

BACKGROUND: Sarcopenia gained importance in the evaluation of patients with chronic respiratory diseases, including idiopathic pulmonary fibrosis (IPF), since it may impact negatively on clinical outcomes. AIM: Aim of this study is to evaluate the prevalence and factors associated with sarcopenia, defined according to the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) 2019 definition, and to evaluate the prevalence of the single criteria that define the EWGSOP2 definition (muscle strength, muscle quantity and physical performance), in a cohort of consecutive patients with IPF prospectively followed up in 9 hospitals in Northern Italy between December 2018 and May 2021. METHODS: Enrolled patients underwent an extensive pulmonary and nutritional assessment, including bioelectrical impedance analysis, dynamometry and 4-m gait speed test, both at IPF diagnosis and at 6-month follow-up. RESULTS: Out of the 83 patients (81% males, mean age 72.5 years) with IPF at disease diagnosis enrolled in the study, 19 (22.9%) showed sarcopenia, including 2 (2.4%) with severe sarcopenia, 5 (6.0%) with confirmed sarcopenia and 12 (14.5%) with probable sarcopenia. Sarcopenia was associated with a significantly higher severity of the disease and sedentary lifestyle, while no differences were observed in regards to body mass index, history of weight loss and comorbidities between patients with and without sarcopenia. Out of the 64 patients without sarcopenia at baseline, 16 cases showed alteration of muscle quantity and/or physical performance. In the 51 patients with complete data at 6-month follow-up, there were no cases of severe sarcopenia, 1 case (2.0%) showed confirmed sarcopenia, while the prevalence of probable sarcopenia was 19.6% (10 cases). No differences in regards to antifibrotic treatment received and onset of gastrointestinal side effects were observed between patients with and without sarcopenia at follow-up. CONCLUSIONS: The prevalence of sarcopenia in patients with IPF both at diagnosis and at 6-month follow-up was low but not negligible and was associated with higher severity of the disease and sedentary lifestyle. In IPF patients, a comprehensive diagnostic work-up including all the criteria defining the EWGSOP2 definition might be more useful than a series testing for prompt recognition of nutritional and physical performance abnormalities.

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.

The Octopus Sign-A New HRCT Sign in Pulmonary Langerhans Cell Histiocytosis.

Background: Fibrosis in pulmonary Langerhans cell histiocytosis (PLCH) histologically comprises a central scar with septal strands and associated airspace enlargement that produce an octopus-like appearance. The purpose of this study was to identify the octopus sign on high-resolution computed tomography (HRCT) images to determine its frequency and distribution across stages of the disease. Methods: Fifty-seven patients with confirmed PLCH were included. Two experienced chest radiologists assessed disease stages as early, intermediate, or late, as well as the lung parenchyma for nodular, cystic, or fibrotic changes and for the presence of the octopus sign. Statistical analysis included Cohen's kappa for interrater agreement and Fisher's exact test for the frequency of the octopus sign. Results: Interobserver agreement was substantial for the octopus sign (kappa = 0.747). Significant differences in distribution of the octopus sign between stages 2 and 3 were found with more frequent octopus signs in stage 2 and fewer in stage 3. In addition, we only found the octopus sign in cases of nodular und cystic lung disease. Conclusions: The octopus sign in PLCH can be identified not only on histological images, but also on HRCT images. Its radiological presence seems to depend on the stage of PLCH.

Impact of the post-COVID-19 condition on health care after the first disease wave in Lombardy.

BACKGROUND: Lombardy was affected in the early months of 2020 by the SARS-CoV-2 pandemic with very high morbidity and mortality. The post-COVID-19 condition and related public health burden are scarcely known. SETTING AND DESIGN: Using the regional population administrative database including all the 48,932 individuals who survived COVID-19 and became polymerase-chain-reaction negative for SARS-CoV-2 by 31 May 2020, incident mortality, rehospitalizations, attendances to hospital emergency room, and outpatient medical visits were evaluated over a mid-term period of 6 months in 20,521 individuals managed at home, 26,016 hospitalized in medical wards, and 1611 in intensive care units (ICUs). These data were also evaluated in the corresponding period of 2019, when the region was not yet affected by the pandemic. Other indicators and proxies of the health-care burden related to the post-COVID condition were also evaluated. MAIN RESULTS: In individuals previously admitted to the ICU and medical wards, rehospitalizations, attendances to hospital emergency rooms, and out-patient medical visits were much more frequent in the 6-month period after SARS-CoV-2 negativization than in the same prepandemic period. Performances of spirometry increased more than 50-fold, chest CT scans 32-fold in ICU-admitted cases and 5.5-fold in non-ICU cases, and electrocardiography 5.6-fold in ICU cases and twofold in non-ICU cases. Use of drugs and biochemical tests increased in all cases. CONCLUSIONS: These results provide a real-life picture of the post-COVID condition and of its effects on the increased consumption of health-care resources, considered proxies of comorbidities.

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.

Influence of chest wall conformation on spirometry parameters and outcome in mild-to-moderate idiopathic pulmonary fibrosis.

Extrinsic causes of restrictive lung syndrome in idiopathic pulmonary fibrosis (IPF) patients have been poorly investigated. We aimed to investigate the influence of the anterior chest wall deformity, noninvasively assessed by modified Haller index (MHI), on spirometry parameters and outcome in a consecutive population of patients with mild-to-moderate IPF. Sixty consecutive IPF patients (73.8 ± 6.6 years, 45 males) were included in this retrospective study. All patients underwent physical examination, spirometry, blood tests, conventional transthoracic echocardiography and MHI assessment (chest transverse diameter over the distance between sternum and spine) at basal evaluation. During follow-up, we evaluated the composite endpoint of (1) pulmonary or cardiovascular hospitalizations and (2) all-cause mortality. IPF patients with concave-shaped chest wall (MHI > 2.5) (36.7% of total) and those with normal chest shape (MHI ≤ 2.5) (63.3%) were separately analyzed. In comparison to IPF patients with MHI ≤ 2.5, those with MHI > 2.5: were less likely to be men and smokers; had a more severe restrictive pattern; had significantly smaller cardiac chamber dimensions and significantly higher systolic pulmonary artery pressure (51.9 ± 15.1 vs 42.4 ± 14.3 mmHg, p = 0.02). Mean follow-up time was 2.5 ± 1.4 years. During follow-up, 13 deaths and 16 pulmonary or cardiovascular hospitalizations were detected. At multivariate Cox regression analysis, concave-shaped chest wall (MHI > 2.5) (HR 4.55, 95% CI 1.02-20.4), increased C-reactive protein (HR 1.68, 95% CI 1.08-2.61) and absence of beta-blocker therapy (HR 0.13, 95% CI 0.01-0.26) were independently associated to the investigated outcome. MHI assessment and implementation may help the clinician to identify, among IPF patients, those with poorer prognosis over a medium-term follow-up.