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.

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.

Ejection fraction at hospital admission stratifies mortality risk in HFmrEF patients aged ≥ 70 years: a retrospective analysis from a tertiary university institution.

BACKGROUND: During the last few years, increasing focus has been placed on heart failure with mildly reduced ejection fraction (HFmrEF), an intermediate phenotype from preserved to reduced ejection fraction (EF). However, clinical features and outcome of HFmrEF in elderly patients aged ≥ 70 yrs have been poorly investigated. METHODS: The present study retrospectively included all consecutive patients aged ≥ 70 yrs discharged from our Institution with a first diagnosis of HFmrEF, between January 2020 and November 2020. All patients underwent transthoracic echocardiography. The primary outcome was all-cause mortality, while the secondary one was the composite of all-cause mortality + rehospitalization for all causes over a mid-term follow-up. RESULTS: The study included 107 HFmrEF patients (84.3 ± 7.4 yrs, 61.7% females). Patients were classified as "old" (70-84 yrs, n = 55) and "oldest-old" (≥ 85 yrs, n = 52) and separately analyzed. As compared to the "oldest-old" patients, the "old" ones were more commonly males (58.2% vs 17.3%, p < 0.001), with history of coronary artery disease (CAD) (54.5% vs 15.4%, p < 0.001) and significantly lower EF (43.5 ± 2.7% vs 47.3 ± 3.6%, p < 0.001) at hospital admission. Mean follow-up was 1.8 ± 1.1 yrs. During follow-up, 29 patients died and 45 were re-hospitalized. Male sex (HR 6.71, 95% CI 1.59-28.4), history of CAD (HR 5.37, 95% CI 2.04-14.1) and EF (HR 0.48, 95% CI 0.34-0.68) were independently associated with all-cause mortality in the whole study population. EF also predicted the composite of all-cause mortality + rehospitalization for all causes. EF < 45% was the best cut-off value to predict both outcomes. CONCLUSIONS: EF at hospital admission is independently associated with all-cause mortality and rehospitalization for all causes in elderly HFmrEF patients over a mid-term follow-up.

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.

The role of chest CT in deciphering interstitial lung involvement: systemic sclerosis versus COVID-19.

OBJECTIVE: The aim of this study was to identify the main CT features that may help in distinguishing a progression of interstitial lung disease (ILD) secondary to SSc from COVID-19 pneumonia. METHODS: This multicentric study included 22 international readers grouped into a radiologist group (RADs) and a non-radiologist group (nRADs). A total of 99 patients, 52 with COVID-19 and 47 with SSc-ILD, were included in the study. RESULTS: Fibrosis inside focal ground-glass opacities (GGOs) in the upper lobes; fibrosis in the lower lobe GGOs; reticulations in lower lobes (especially if bilateral and symmetrical or associated with signs of fibrosis) were the CT features most frequently associated with SSc-ILD. The CT features most frequently associated with COVID- 19 pneumonia were: consolidation (CONS) in the lower lobes, CONS with peripheral (both central/peripheral or patchy distributions), anterior and posterior CONS and rounded-shaped GGOs in the lower lobes. After multivariate analysis, the presence of CONs in the lower lobes (P < 0.0001) and signs of fibrosis in GGOs in the lower lobes (P < 0.0001) remained independently associated with COVID-19 pneumonia and SSc-ILD, respectively. A predictive score was created that was positively associated with COVID-19 diagnosis (96.1% sensitivity and 83.3% specificity). CONCLUSION: CT diagnosis differentiating between COVID-19 pneumonia and SSc-ILD is possible through a combination of the proposed score and radiologic expertise. The presence of consolidation in the lower lobes may suggest COVID-19 pneumonia, while the presence of fibrosis inside GGOs may indicate SSc-ILD.

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.

One-year pulmonary impairment after severe COVID-19: a prospective, multicenter follow-up study.

BACKGROUND: Long-term pulmonary sequelae following hospitalization for SARS-CoV-2 pneumonia is largely unclear. The aim of this study was to identify and characterise pulmonary sequelae caused by SARS-CoV-2 pneumonia at 12-month from discharge. METHODS: In this multicentre, prospective, observational study, patients hospitalised for SARS-CoV-2 pneumonia and without prior diagnosis of structural lung diseases were stratified by maximum ventilatory support ("oxygen only", "continuous positive airway pressure (CPAP)" and "invasive mechanical ventilation (IMV)") and followed up at 12 months from discharge. Pulmonary function tests and diffusion capacity for carbon monoxide (DLCO), 6 min walking test, high resolution CT (HRCT) scan, and modified Medical Research Council (mMRC) dyspnea scale were collected. RESULTS: Out of 287 patients hospitalized with SARS-CoV-2 pneumonia and followed up at 1 year, DLCO impairment, mainly of mild entity and improved with respect to the 6-month follow-up, was observed more frequently in the "oxygen only" and "IMV" group (53% and 49% of patients, respectively), compared to 29% in the "CPAP" group. Abnormalities at chest HRCT were found in 46%, 65% and 80% of cases in the "oxygen only", "CPAP" and "IMV" group, respectively. Non-fibrotic interstitial lung abnormalities, in particular reticulations and ground-glass attenuation, were the main finding, while honeycombing was found only in 1% of cases. Older patients and those requiring IMV were at higher risk of developing radiological pulmonary sequelae. Dyspnea evaluated through mMRC scale was reported by 35% of patients with no differences between groups, compared to 29% at 6-month follow-up. CONCLUSION: DLCO alteration and non-fibrotic interstitial lung abnormalities are common after 1 year from hospitalization due to SARS-CoV-2 pneumonia, particularly in older patients requiring higher ventilatory support. Studies with longer follow-ups are needed.

Nintedanib in IPF: Post hoc Analysis of the Italian FIBRONET Observational Study.

BACKGROUND: The FIBRONET study was an observational study of patients with idiopathic pulmonary fibrosis (IPF) in Italy. OBJECTIVES: In this post hoc descriptive analysis, we describe changes in lung function, anxiety/depression, coughing, exacerbations, and adverse events (AEs) in patients receiving nintedanib treatment. METHODS: Patients with IPF from 20 centers in Italy, aged ≥40 years who received nintedanib for ≥7 months, were followed up for 12 months from study enrollment, attending clinic visits every 3 months. Outcomes included change in forced vital capacity (FVC)% predicted from baseline to 12 months, anxiety/depression measured by the Hospital Anxiety and Depression Scale (HADS), and the proportion of patients with cough, AEs, and exacerbations. RESULTS: In total, 52 patients received nintedanib (mean duration of 11.6 months). Ten patients had dose reductions from 150 mg to 100 mg twice daily, due to AEs. FVC% predicted was unchanged in the overall nintedanib population (78.7% at baseline; 79.8% at 12 months) and those with a reduced dose (77.7% at baseline; 81.0% at 12 months). HADS score was low at baseline and throughout the study. The proportion of patients with cough decreased from 50.0% to 21.2% over 12 months. Two patients experienced exacerbations, 2 patients discontinued treatment, and 27 (51.9%) reported AEs. The most common AE was diarrhea (34.6%). CONCLUSIONS: In patients with IPF who received nintedanib in the FIBRONET study, FVC% predicted was stable over 12 months, and the proportion of patients with cough decreased. The safety profile was consistent with the known safety profile for nintedanib in IPF.

Prevalence and clinical outcome of main echocardiographic and hemodynamic heart failure phenotypes in a population of hospitalized patients 70 years old and older.

BACKGROUND: Heart failure (HF) echocardiographic and hemodynamic categories are poorly characterized in the elderly. We aimed to evaluate the prevalence and clinical outcomes of echocardiographic and hemodynamic HF phenotypes in a consecutive series of hospitalized patients aged ≥ 70 years. METHODS: All consecutive patients ≥ 70 years old discharged from the Internal Medicine Unit of our Hospital with a diagnosis of HF, between January and November 2020, entered this retrospective study. All patients underwent physical examination, complete blood tests, chest X-ray and transthoracic echocardiography. At 1-year follow-up, we evaluated the occurrence of the composite outcome of all-cause mortality and re-hospitalization. RESULTS: Two hundred and sixty-one patients (86.3 ± 6.4 years, 60.9% women) were retrospectively analyzed. From the study group, 106 "old" (70-84 years) and 155 "oldest-old" (≥ 85 years) patients were separately analyzed. A total of 169 (64.7%) patients reported the composite outcome during follow-up: 41 (15.7%) died and 128 (49.0%) were re-hospitalized. At 1-year follow-up, survival analysis did not show any statistically significant difference between age groups (p = 0.31) and between HF echocardiographic categories (p = 0.34), whereas HF patients with "cold-dry" phenotype had significantly poorer survival compared to the other hemodynamic subtypes (p < 0.001). Male sex (HR 1.44, 95% CI 1.04-1.98), "cold-dry" phenotype (HR 3.90, 95% CI 1.73-8.77), high sodium level (HR 1.03, 95% CI 1.01-1.04) and low estimated glomerular filtration rate (eGFR) (HR 0.98, 95% CI 0.97-0.99) were independently associated with the outcome occurrence. CONCLUSIONS: Male sex, "cold-dry" phenotype, high sodium level and low eGFR are the main adverse prognostic indicators over a mid-term follow-up in hospitalized patients aged ≥ 70 years.

CHA2DS2-VASc score stratifies mortality risk in heart failure patients aged 75 years and older with and without atrial fibrillation.

BACKGROUND: During the last decade, the CHA2DS2-VASc score has been associated with adverse clinical outcomes in several cardiovascular (CV) and non-cardiovascular diseases beyond atrial fibrillation (AF). Whether the CHA2DS2-VASc score stratifies mortality risk in elderly patients with AF and without AF is not well established. METHODS: All consecutive patients aged ≥ 75 yrs hospitalized due to heart failure (HF), between January 2020 and November 2020, were retrospectively enrolled. All patients underwent physical examination, blood tests, electrocardiography and conventional transthoracic echocardiography. Primary endpoint was all-cause mortality, while secondary endpoint was the composite of all-cause mortality + rehospitalizations for all causes over mid-term follow-up. RESULTS: The study included 261 HF patients (86.3 ± 6.4 years, 60.5% females). 85 AF and 176 non-AF patients were separately analyzed. Compared to non-AF patients, those with AF had significantly higher CHA2DS2-VASc score (5.6 ± 1.4 vs 5.1 ± 1.4, p = 0.007) and lower ejection fraction (47.4 ± 16.5 vs 56.7 ± 15.1%, p < 0.001). Mean follow-up was 1.7 ± 0.5 yrs. During follow-up, 96 patients died (58.3% due to CV causes) and 79 were rehospitalized (58.2% due to CV causes). CHA2DS2-VASc score was independently associated with all-cause mortality in whole study population (HR 1.61, 95% CI 1.36-1.92) and in both AF (HR 1.41, 95% CI 1.09-1.82) and non-AF patients (HR 1.84, 95% CI 1.40-2.40). CHA2DS2-VASc score also predicted the secondary endpoint in the same study groups. CHA2DS2-VASc score ≥ 5 was the best cut-off value for predicting both outcomes. CONCLUSION: At mid-term follow-up, a CHA2DS2-VASc score ≥ 5 predicts increased risk of all-cause mortality and re-hospitalizations for all causes in elderly HF patients, regardless of AF.

Prevalence, management and impact of chronic obstructive pulmonary disease in atrial fibrillation: a systematic review and meta-analysis of 4,200,000 patients.

AIM: Prevalence of chronic obstructive pulmonary disease (COPD) in atrial fibrillation (AF) patients is unclear, and its association with adverse outcomes is often overlooked. Our aim was to estimate the prevalence of COPD, its impact on clinical management and outcomes in patients with AF, and the impact of beta-blockers (BBs) on outcomes in patients with COPD. METHODS AND RESULTS: A systematic review and meta-analysis was conducted according to international guidelines. All studies reporting the prevalence of COPD in AF patients were included. Data on comorbidities, BBs and oral anticoagulant prescription, and outcomes (all-cause death, cardiovascular (CV) death, ischaemic stroke, major bleeding) were compared according to COPD and BB status. Among 46 studies, pooled prevalence of COPD was 13% [95% confidence intervals (CI) 10-16%, 95% prediction interval 2-47%]. COPD was associated with higher prevalence of comorbidities, higher CHA2DS2-VASc score and lower BB prescription [odds ratio (OR) 0.77, 95% CI 0.61-0.98]. COPD was associated with higher risk of all-cause death (OR 2.22, 95% CI 1.93-2.55), CV death (OR 1.84, 95% CI 1.39-2.43), and major bleeding (OR 1.45, 95% CI 1.17-1.80); no significant differences in outcomes were observed according to BB use in AF patients with COPD. CONCLUSION: COPD is common in AF, being found in 13% of patients, and is associated with increased burden of comorbidities, differential management, and worse outcomes, with more than a two-fold higher risk of all-cause death and increased risk of CV death and major bleeding. Therapy with BBs does not increase the risk of adverse outcomes in patients with AF and COPD.

Lung transplantation for sarcoidosis: outcome and prognostic factors.

STUDY QUESTION: In patients with sarcoidosis, past and ongoing immunosuppressive regimens, recurrent disease in the transplant and extrapulmonary involvement may affect outcomes of lung transplantation. We asked whether sarcoidosis lung phenotypes can be differentiated and, if so, how they relate to outcomes in patients with pulmonary sarcoidosis treated by lung transplantation. PATIENTS AND METHODS: We retrospectively reviewed data from 112 patients who met international diagnostic criteria for sarcoidosis and underwent lung or heart-lung transplantation between 2006 and 2019 at 16 European centres. RESULTS: Patient survival was the main outcome measure. At transplantation, median (interaquartile range (IQR)) age was 52 (46-59) years; 71 (64%) were male. Lung phenotypes were individualised as follows: 1) extended fibrosis only; 2) airflow obstruction; 3) severe pulmonary hypertension (sPH) and airflow obstruction; 4) sPH, airflow obstruction and fibrosis; 5) sPH and fibrosis; 6) airflow obstruction and fibrosis; 7) sPH; and 8) none of these criteria, in 17%, 16%, 17%, 14%, 11%, 9%, 5% and 11% of patients, respectively. Post-transplant survival rates after 1, 3, and 5 years were 86%, 76% and 69%, respectively. During follow-up (median (IQR) 46 (16-89) months), 31% of patients developed chronic lung allograft dysfunction. Age and extended lung fibrosis were associated with increased mortality. Pulmonary fibrosis predominating peripherally was associated with short-term complications. ANSWER TO THE STUDY QUESTION: Post-transplant survival in patients with pulmonary sarcoidosis was similar to that in patients with other indications for lung transplantation. The main factors associated with worse survival were older age and extensive pre-operative lung fibrosis.

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.

Six-Month Pulmonary Impairment after Severe COVID-19: A Prospective, Multicentre Follow-Up Study.

BACKGROUND: Long-term pulmonary sequelae following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia are not yet confirmed; however, preliminary observations suggest a possible relevant clinical, functional, and radiological impairment. OBJECTIVES: The aim of this study was to identify and characterize pulmonary sequelae caused by SARS-CoV-2 pneumonia at 6-month follow-up. METHODS: In this multicentre, prospective, observational cohort study, patients hospitalized for SARS-CoV-2 pneumonia and without prior diagnosis of structural lung diseases were stratified by maximum ventilatory support ("oxygen only," "continuous positive airway pressure," and "invasive mechanical ventilation") and followed up at 6 months from discharge. Pulmonary function tests and diffusion capacity for carbon monoxide (DLCO), 6-min walking test, chest X-ray, physical examination, and modified Medical Research Council (mMRC) dyspnoea score were collected. RESULTS: Between March and June 2020, 312 patients were enrolled (83, 27% women; median interquartile range age 61.1 [53.4, 69.3] years). The parameters that showed the highest rate of impairment were DLCO and chest X-ray, in 46% and 25% of patients, respectively. However, only a minority of patients reported dyspnoea (31%), defined as mMRC ≥1, or showed restrictive ventilatory defects (9%). In the logistic regression model, having asthma as a comorbidity was associated with DLCO impairment at follow-up, while prophylactic heparin administration during hospitalization appeared as a protective factor. The need for invasive ventilatory support during hospitalization was associated with chest imaging abnormalities. CONCLUSIONS: DLCO and radiological assessment appear to be the most sensitive tools to monitor patients with the coronavirus disease 2019 (COVID-19) during follow-up. Future studies with longer follow-up are warranted to better understand pulmonary sequelae.

Recent advances and current controversies in lung neuroendocrine neoplasms✰.

In the lung, neuroendocrine tumors (NETs), namely typical and atypical carcinoids, and neuroendocrine carcinomas (NECs), grouping small cell carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC), make up for distinct tumor entities according to epidemiological, genetic, pathologic and clinical data. The proper classification is essential in clinical practice for diagnosis, prognosis and therapy purposes. Through an extensive literature survey, three perspectives on lung NENs have been revised: i) criteria and terminology on biopsy or cytology samples of primaries or metastases; ii) carcinoids with elevated mitotic counts and/or Ki-67 proliferation rates; iii) relevance of molecular landscape to identify new tumor entities and therapeutic targets. Furthermore, a dispute about lung NEN development has been raised according to emerging molecular models. We herein provide a pathology update on practical topics in the setting of lung NENs according to the current classification (recent advances). We have also reappraised the development of these tumors by modeling risk factors and natural history of disease (recent controversies). Combining recent advances and controversies may help clarify our biological understanding of lung NENs and give practical information for the clinical decision-making process.

Correlation Between Doppler Echocardiography and Right Heart Catheterisation-Derived Systolic and Mean Pulmonary Artery Pressures: Determinants of Discrepancies Between the Two Methods.

BACKGROUND: There is still controversy about whether transthoracic echocardiography (TTE) can provide reliable estimations of pulmonary artery pressures (PAP). The primary endpoint of this study was to evaluate the correlation between TTE and right heart catheterisation (RHC) in estimating systolic (SPAP) and mean (MPAP) pulmonary artery pressures. METHODS: Between January 2011 and December 2018, 141 consecutive patients (average age 63.6±11.5 years; 84 women) with suspected or confirmed pulmonary hypertension (PH) were enrolled into this retrospective observational monocentric study. All patients underwent TTE and, within 3 hours, RHC. The correlation between TTE and RHC in estimating both SPAP and MPAP was retrospectively determined. RESULTS: Seventeen (17) of the patients were excluded due to insufficient TTE signal quality. Of the remaining 124 patients, 18 had no PH. There was moderate correlation between both SPAP and MPAP estimated by TTE and those assessed by RHC (r=0.65 and r=0.60, respectively). Bland-Altman analysis revealed a bias of -11.9 mmHg (with the 95% limits of agreement ranging -45.4 to +21.5 mmHg) for SPAP estimation and -4.6 mmHg (with the 95% limits of agreement ranging -27.9 to +18.8 mmHg) for MPAP estimation, suggesting a general overestimation of PAP by TTE. The main factors responsible for discrepancies between TTE and RHC were: female gender, arrhythmic cardiac electrical activity, systemic arterial hypertension, and diuretic treatment. CONCLUSIONS: Transthoracic echocardiography frequently overestimated PAP in comparison with RHC, especially in hypertensive women with arrhythmias and under diuretic treatment.

Older Idiopathic Pulmonary Fibrosis Male Patients Are at a Higher Risk of Nintedanib Dose Reduction.

BACKGROUND: Two pharmaceutical agents have been approved for treatment of idiopathic pulmonary fibrosis (IPF): pirfenidone and nintedanib. OBJECTIVES: We investigated the need of dose reduction in consecutive patients treated with nintedanib in relation to gender and body max index, comparing the population over and under 80 years of age. METHODS: We retrospectively reviewed the data of all consecutive IPF patients treated with nintedanib for at least 3 months. Data on age, gender, body max index, side effects, and duration of therapy after enrolment were recorded. RESULTS: A total of 82 patients has been evaluated. All dose reductions were related to side effects and/or toxicities. The need for a dose reduction was significantly more frequent in patients aged 80 years or older (50 vs. 26.8%, p = 0.039), independently from their body mass index. A total of 52% of males >80 years and only 16% of males <80 years reduced the dose (p = 0.002). CONCLUSIONS: Male gender and not body mass index in IPF patients aged ≥80 years treated with nintedanib seems to influence dose reduction.

Progressive Fibrosing Interstitial Lung Diseases: Prevalence and Characterization in Two Italian Referral Centers.

BACKGROUND: The prevalence and natural history of progressive fibrosing interstitial lung diseases (PF-ILDs), and their response to commonly used treatments in real life are largely unknown. OBJECTIVES: The aim of the study was to describe the prevalence, clinical characteristics, management, and outcomes of PF-ILD patients attending 2 Italian referral centers (San Gerardo Hospital, Monza, and San Giuseppe Hospital, Milan) from January 1, 2011, to July 31, 2019. METHODS: From a cohort of non-idiopathic pulmonary fibrosis fibrosing ILD patients with at least 2-year follow-up, we selected only those with progressive disease, defined as per the INBUILD trial, collecting their demographical, clinical, and functional data. RESULTS: Out of the 245 fibrosing ILD patients, 75 (31%) were classified as PF-ILDs (median age 66 years, 60% males), most frequently idiopathic non-specific interstitial pneumonia (28%), followed by connective tissue disease-associated ILD (20%), chronic hypersensitivity pneumonitis, and sarcoidosis (17% each). Most patients (81%) were categorized as PF-ILDs because of forced vital capacity (FVC) decline ≥10%, while 19% experienced a marginal FVC decline (between 5 and 10%) associated with worsening respiratory symptoms or increasing extent of fibrotic changes on high-resolution computed tomography. Disease progression occurred after a median of 18 months from ILD diagnosis. The vast majority (93%) of PF-ILD patients received prednisolone, alone (40%) or associated with steroid-sparing agents (52%), and 35% of treated patients developed treatment-related adverse events. After ILD progression, the median survival was 3 (interquartile range (IQR) 2-5) years, with a 2- and 3-year mortality rate of 4 and 20%, respectively. CONCLUSIONS: In a real-life setting, approximately one-third of the fibrosing ILD patients showed a progressive course despite treatment. Studies aimed to better phenotype this subgroup of patients are needed.