Gas exchange abnormalities in Long COVID are driven by the alteration of the vascular component.

BACKGROUND: There are uncertainties whether the impairment of lung diffusing capacity in COVID-19 is due to an alteration in the diffusive conductance of the alveolar membrane (Dm), or an alteration of the alveolar capillary volume (Vc), or a combination of both. The combined measurement DLNO and DLCO diffusion, owing to NO higher affinity and faster reaction rate with haemoglobin compared to CO, enables the simultaneous and rapid determination of both Vc and Dm. The aim of the present study was to better identify the precise cause of post-COVID-19 diffusion impairment. METHODS: Using the combined NO and CO gas transfer techniques (DLNO and DLCO), it is possible to better understand whether gas exchange abnormalities are due to membrane or alveolar capillary volume components. The present study was aimed at evaluating pulmonary gas exchange one year after severe COVID-19.  Results: The cohort included 33 survivors to severe COVID-19 (median age 67 years, 70% male) with no pre-existing lung disease, who underwent clinical, lung function and imaging assessments at 12 months due to persistence of respiratory symptoms or radiological impairment. The gas exchange abnormalities were mainly determined by the compromise of the vascular component as demonstrated by vascular pattern of gas exchange impairment (i.e., DLNO/DLCO≥110%, 76% of the sample), and by a reduction of the Vc (73%), while the Dm was reduced only in 9% of the entire sample. We did not find a correlation between the gas exchange impairment and the extent of the chest CT alterations (DLCO p = 0.059 and DLNO p = 0.054), which on average were found to be mild (11% of the parenchyma). CONCLUSION: In COVID-19 survivors who are still symptomatic or have minimal CT findings at one year, gas exchange abnormalities are determined by impairment of the vascular component, rather than the diffusive component of the alveolar membrane.

One-year mortality in COVID-19 is associated with patients' comorbidities rather than pneumonia severity.

BACKGROUND: In patients with pneumonia or acute respiratory distress syndrome who survived hospitalization, one-year mortality can affect up to one third of discharged patients. Therefore, significant long-term mortality after COVID-19 respiratory failure could be expected. The primary outcome of the present study was one-year all-cause mortality in hospitalized COVID-19 patients. METHODS: Observational study of COVID-19 patients hospitalized at Papa Giovanni XXIII Hospital (Bergamo, Italy), during the first pandemic wave. RESULTS: A total of 1326 COVID-19 patients were hospitalized. Overall one-year mortality was 33.6% (N 446/1326), with the majority of deaths occurring during hospitalization (N=412, 92.4%). Thirty-four patients amongst the 914 discharged (3.7%) subsequentely died within one year. A third of these patients died for advanced cancer, while death without a cause other than COVID-19 was uncommon (8.8% of the overall post-discharge mortality). In-hospital late mortality (i.e. after 28 days of admission) interested a population with a lower age, and fewer comorbidities, more frequentely admitted in ICU. Independent predictors of post-discharge mortality were age over 65 years (HR 3.19; 95% CI 1.28-7.96, p-value=0.013), presence of chronic obstructive pulmonary disease (COPD) (HR 2.52; 95% CI 1.09-5.83, p-value=0.031) or proxy of cardiovascular disease (HR 4.93; 95% CI 1.45-16.75, p-value=0.010), and presence of active cancer (HR 3.64; 95% CI 1.50-8.84, p-value=0.004), but not pneumonia severity. CONCLUSIONS: One-year post-discharge mortality depends on underlying patients' comorbidities rather than COVID-19 pneumonia severity per se. Awareness among physicians of predictors of post-discharge mortality might be helpful in structuring a follow-up program for discharged patients.

Observational, Multicenter Study on the Efficacy, Tolerability, and Safety of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis Older than 80 Years.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) primarily affects old patients. Old age is a predictor of mortality. Nintedanib, the only antifibrotic drug approved in Italy for patients aged >80 years, can slow the progression of IPF by reducing the rate of decline in forced vital capacity (FVC) and the risk of exacerbations. OBJECTIVES: The primary aim of the study was to compare the decline of FVC after 12 months of nintedanib in patients aged >80 years versus younger patients. Differences related to other functional data, safety, tolerability, hospitalizations, exacerbations, and mortality were evaluated. METHODS: An observational, retrospective, multicenter study was carried out in Italy. RESULTS: 159 (122 [76.7%] males) patients were recruited: 106 (66.7%) aged ≤80 years and 53 (33.3%) aged >80 years. FVC decline after 12 months of therapy was not significantly different (-45 mL [-170; 75] vs. -20 mL [-138; 110] mL; p: 0.51). No differences were found for other functional data. Diarrhea was the most frequent adverse event (AE). Rate and type of any AEs, permanent/temporary dose reduction, or drug discontinuation were not significantly different between patients aged ≤80 vs. >80 years. Furthermore, acute exacerbations, hospitalization, and mortality were not significantly different. CONCLUSIONS: Nintedanib is effective and safe in patients with IPF aged >80 years, and no significant differences were found when clinical outcomes were compared with those of younger patients. Thus, older age should not be a barrier for the early prescription of antifibrotic treatment in IPF patients.

Structural and Functional Pulmonary Assessment in Severe COVID-19 Survivors at 12 Months after Discharge.

Long-term pulmonary sequelae in COVID-19 patients are currently under investigation worldwide. Potential relationships between blood sampling and functional and radiological findings are crucial to guide the follow-up. In this study, we collected and evaluated clinical status, namely symptoms and patients' reported outcome, pulmonary function tests (PFT), laboratory tests, and radiological findings at 3- and 12-months post-discharge in patients admitted between 25 February and 2 May 2020, and who survived severe COVID-19 pneumonia. A history of chronic pulmonary disease or COVID-19-unrelated complications were used as exclusion criteria. Unenhanced CTs were analyzed quantitatively (compromising lung volume %) and qualitatively, with main patterns of: ground-glass opacity (GGO), consolidation, and reticular configuration. Patients were subsequently divided into groups based on their radiological trends and according to the evolution in the percentage of compromised lung volume. At 12 months post-discharge, seventy-one patients showed significantly improved laboratory tests and PFT. Among them, 63 patients also underwent CT examination: all patients with negative CT findings at three months (n = 14) had negative CT also at 12 months; among the 49/63 patients presenting CT alterations at three months, 1/49 (2%) normalized, 40/49 (82%) improved, 7/49 (14%) remained stably abnormal, and 1/49 (2%) worsened. D-dimer values were low in patients with normal CT and higher in cases with improved or stably abnormal CT (median values 213 vs. 329 vs. 1000 ng/mL, respectively). The overall compromised lung volume was reduced compared with three months post-discharge (12.3 vs. 14.4%, p < 0.001). In stably abnormal CT, the main pulmonary pattern changed, showing a reduction in GGO and an increase in reticular configuration. To summarize, PFT are normal in most COVID-19 survivors 12 months post-discharge, but CT structural abnormalities persist (although sensibly improved over time) and are associated with higher D-dimer values.

Frequency, characteristics, and outcome of patients with COVID-19 pneumonia and "silent hypoxemia" at admission: a severity-matched analysis.

BACKGROUND: An aspect of COVID-19 baffling physicians is the presentation of patients with acute respiratory failure, but normal mental faculties and no perception of dyspnea (i.e. "silent hypoxemia"). The aim of this study was to investigate the frequency, characteristics, and outcome of COVID-19 patients with silent hypoxemic status and comparing them with a symptomatic severity-matched group. METHODS: This is a retrospective monocentric observational study involving all patients with PCR confirmed SARS-CoV-2 pneumonia, admitted at Papa Giovanni XXIII Hospital, Bergamo (Italy) from Emergency Department due to acute respiratory failure, during the first Italian pandemic peak (February-April 2020). RESULTS: Overall 28-day mortality in 1316 patients was 26.9%. Patients who did not report dyspnea at admission (N 469, 35.6%) had a lower 28-day mortality (22.6 vs. 29.3%, P=0.009). The severity matching analysis (i.e. PaO2/FiO2 and imaging) led to the identification of two groups of 254 patients that did not differ for sex prevalence, age, BMI, smoking history, comorbidities, and PaCO2 at admission. The use of CPAP during the first 24 hours, such as the need of endotracheal intubation (ETI) during the overall admission were significantly lower in matched patients with silent hypoxemia, whereas 28-day mortality resulted similar (P=0.21). CONCLUSIONS: Lack of dyspnea is common in patients suffering from severe COVID-19 pneumonia leading to respiratory failure, since up to a third of them could be asymptomatic on admission. Dyspnea per se correlates with pneumonia severity, and prognosis. However, dyspnea loses its predictive relevance once other findings to evaluate pneumonia severity are available such as PaO2/FiO2 and imaging. Silent hypoxemic patients are less likely to receive CPAP during the first 24 hours and ETI during the hospitalization, in spite of a comparable mortality to the dyspneic ones.

Usefulness of CURB-65, pneumonia severity index and MuLBSTA in predicting COVID-19 mortality.

The aim of our study is to evaluate the accuracy of CURB-65 and Pneumonia Severity Index (PSI), the most widely used scores for community acquired pneumonia, and MuLBSTA, a viral pneumonia score, in predicting 28-day mortality in Coronavirus Disease 2019 (COVID-19) pneumonia.We retrospectively collected clinical data of consecutive patients with laboratory-confirmed COVID-19 pneumonia admitted at Papa Giovanni XXIII Hospital from February 23rd to March 14th, 2020. We calculated at Emergency Department (ED) presentation CURB-65, PSI and MuLBSTA and we compared their performances in discriminating between survivors and non-survivors at 28 days. Among 431 hospitalized patients, the majority presented with hypoxic respiratory failure: median (interquartile range, IQR) PaO2/FiO2 ratio at admission was 228.6 (142.0-278.1). In the first 24 hours, 111 (27%) patients were administered low-flow oxygen cannula, 50 (12%) Venturi Mask, 95 (23%) non-rebreather mask, 106 (26%) non-invasive ventilation, 12 (3%) mechanical ventilation and 41 (9%) were not administered oxygen therapy. Mortality rate at 28-day was 35% (150/431). Between survivors and non-survivors, median (IQR) scores were, respectively, 1.0 (1.0-2.0) and 2.0 (2.0-3.0) for CURB-65 (p<0.001); 90.5 (76.0-105.5) and 115.0 (100.0-129.0) for PSI (p<0.001); 7.0 (5.0-10.0) and 11.0 (9.0-13.0) for MuLBSTA (p<0.001). Areas under the receiver operating characteristic curve (AUCs) for each score were, respectively, 0.725 (0.662-0.787), 0.776 (0.693-0.859) and 0.743 (0.680-0.806) (p>0,05). PSI and MuLBSTA did not show a better performance when compared to CURB-65. Although CURB-65, PSI and MuLBSTA scores are useful tools to discriminate between survivors and non-survivors in COVID-19 pneumonia, their diagnostic accuracy in discriminating 28-day mortality in COVID-19 pneumonia is moderate, as confirmed by AUCs <0.80, and there is a potential underestimation of disease severity in the low-risk classes. For this reason, they should not be recommended in ED to decide between inpatient and outpatient management in patients affected by COVID-19 pneumonia.

A 57-year-old man with rapidly progressive pulmonary hypertension.

Pulmonary Tumor Thrombotic Microangiopathy (PTTM) is a rare condition associated with neoplastic disorders, predominantly gastric cancer, leading to pre-capillary Pulmonary Hypertension (PH). The pathologic mechanism involved is a fibrocellular intimal proliferation of small pulmonary vessels sustained by nests of carcinomatous cells lodged in pulmonary vasculature. Clinical presentation is nonspecific, including progressive dyspnea and dry cough. Diagnosis of PTTM is extremely challenging ante-mortem and prognosis is poor. Here we describe the case of a middle-aged man, without known previous cancer history. The clinical course was rapidly unfavorable, with progressive dyspnea and PH associated with hemodynamic instability, eventually culminating in patient's death. PTTM diagnosis was made post-mortem. PTTM should be considered in any patient presenting with unexplained PH, especially if it is rapidly progressive, poorly responsive to standard approaches or there is suspected history of malignancy. A prompt diagnosis of PTTM could help in bringing light into this still under-recognized condition.

Post-discharge chest CT findings and pulmonary function tests in severe COVID-19 patients.

PURPOSE: To evaluate chest computed tomography (CT) and pulmonary function test (PFT) findings in severe COVID-19 patients after discharge and correlate CT pulmonary involvement with PFT results. METHODS: COVID-19 patients admitted to our hospital between February 25 and May 2, 2020, were retrospectively included according to the following criteria: (a) COVID-19 defined as severe based on the WHO interim guidance (i.e., clinical signs of pneumonia plus respiratory rate > 30 breaths/min, severe respiratory distress, and/or SpO2 < 90 % on room air); (b) chest radiograph in the acute setting; (c) post-discharge unenhanced chest CT; and (d) post-discharge comprehensive PFT. Imaging findings were retrospectively evaluated in consensus by two readers, and volume of abnormal lung was measured on CT using 3D Slicer software. Differences between demographics, comorbidities, acute radiographic findings, PFT, and post-discharge clinical and laboratory data of patients with normal and abnormal CT findings were assessed by Mann-Whitney or Fisher tests, and the compromised lung volume-PFT association by Pearson correlation after removing possible outliers. RESULTS: At a median of 105 days from symptom onset, 74/91 (81 %) patients had CT abnormalities. The most common CT pattern was combined ground-glass opacity and reticular pattern (46/74, 62 %) along with architectural distortion (68/74, 92 %) and bronchial dilatation (66/74, 89 %). Compromised lung volume had a median value of 15 % [11-23], was higher in dyspneic patients, and negatively correlated with the percentage of predicted DLCO, VA, and FVC values (r = -0.39, -0.5, and -0.42, respectively). These PFT parameters were significantly lower in patients with CT abnormalities. Impairment of DLCO and KCO was found in 12 (13 %) cases, possibly implying an underlying pulmonary vasculopathy in this subgroup of patients. CONCLUSIONS: Most severe COVID-19 survivors still had physiologically relevant CT abnormalities about three months after the disease onset, with an impairment of diffusion capacity on PFT. A pulmonary vasculopathy was suggested in a minor proportion of patients.

Surviving COVID-19 in Bergamo province: a post-acute outpatient re-evaluation.

Bergamo province was badly hit by the coronavirus disease 2019 (COVID-19) epidemic. We organised a public-funded, multidisciplinary follow-up programme for COVID-19 patients discharged from the emergency department or from the inpatient wards of 'Papa Giovanni XXIII' Hospital, the largest public hospital in the area. As of 31 July, the first 767 patients had completed the first post-discharge multidisciplinary assessment. Patients entered our programme at a median time of 81 days after discharge. Among them, 51.4% still complained of symptoms, most commonly fatigue and exertional dyspnoea, and 30.5% were still experiencing post-traumatic psychological consequences. Impaired lung diffusion was found in 19%. Seventeen per cent had D-dimer values two times above the threshold for diagnosis of pulmonary embolism (two unexpected and clinically silent pulmonary thrombosis were discovered by investigating striking D-dimer elevation). Survivors of COVID-19 exhibit a complex array of symptoms, whose common underlying pathology, if any, has still to be elucidated: a multidisciplinary approach is fundamental, to address the different problems and to look for effective solutions.

At the peak of COVID-19 age and disease severity but not comorbidities are predictors of mortality: COVID-19 burden in Bergamo, Italy.

BACKGROUND: Findings from February 2020, indicate that the clinical spectrum of COVID-19 can be heterogeneous, probably due to the infectious dose and viral load of SARS-CoV-2 within the first weeks of the outbreak. The aim of this study was to investigate predictors of overall 28-day mortality at the peak of the Italian outbreak. METHODS: Retrospective observational study of all COVID-19 patients admitted to the main hospital of Bergamo, from February 23 to March 14, 2020. RESULTS: Five hundred and eight patients were hospitalized, predominantly male (72.4%), mean age of 66±15 years; 49.2% were older than 70 years. Most of patients presented with severe respiratory failure (median value [IQR] of PaO2/FiO2: 233 [149-281]). Mortality rate at 28 days resulted of 33.7% (N.=171). Thirty-nine percent of patients were treated with continuous positive airway pressure (CPAP), 9.5% with noninvasive ventilation (NIV) and 13.6% with endotracheal intubation. 9.5% were admitted to Semi-Intensive Respiratory Care Unit, and 18.9% to Intensive Care Unit. Risk factors independently associated with 28-day mortality were advanced age (≥78 years: odds ratio [OR], 95% confidence interval [CI]: 38.91 [10.67-141.93], P<0.001; 70-77 years: 17.30 [5.40-55.38], P<0.001; 60-69 years: 3.20 [1.00-10.20], P=0.049), PaO2/FiO2<200 at presentation (3.50 [1.70-7.20], P=0.001), need for CPAP/NIV in the first 24 hours (8.38 [3.63-19.35], P<0.001), and blood urea value at admission (1.01 [1.00-1.02], P=0.015). CONCLUSIONS: At the peak of the outbreak, with a probable high infectious dose and viral load, older age, the severity of respiratory failure and renal impairment at presentation, but not comorbidities, are predictors of 28-day mortality in COVID-19.

Interaction between the promoter MUC5B polymorphism and mucin expression: is there a difference according to ILD subtype?

The MUC5B promoter variant rs35705950 is associated with idiopathic pulmonary fibrosis (IPF). MUC5B glycoprotein is overexpressed in IPF lungs. We examined immunohistochemical expression of MUC5B in different interstitial lung disease patterns according to rs35705950 T-allele carriage. We observed increased expression of MUC5B in T-allele carriers in both distal airways and honeycomb cysts in patients with IPF (n=23), but no difference in MUC5B expression according to T-carrier status in the distal airways of patients with idiopathic non-specific interstitial pneumonitis (n=17), in scleroderma-associated non-specific interstitial pneumonitis (n=15) or in control lungs (n=20), suggesting that tissue overexpression in MUC5B rs35705950 T-carriers is specific to IPF.

[Echocardiographic indices related with acute coronary anatomy in acute phase of myocardial infarction: our experience]. / Indici ecocardiografici correlati con l'anatomia coronarica in fase acuta di infarto miocardico: la nostra esperienza.

UNLABELLED: Inferior acute myocardial infarction (IAMI) is often associated with right ventricle involvement (RVAMI). Echocardiogram (Echo) shows the ischemic involvement of the right ventricle with an initial dilatation (RVD) and segmental cinetic abnormalities (RVSCS). During RVAMI the normal convexity of the interatrial septum (IAS) toward right atrium is inverted (IASI). 53 patients with IAMI were studied with ECG, echo and hemodinamic monitoring by a Swan-Ganz catheter. Echo was early performed and patients were subdivided into three groups: 1. IAMI with RVSCS and/or RVD with IASI (12 patients); 2. IAMI with RVSCS and/or RVD without IASI (8 patients); 3. IAMI without VSCS, RVD IASI (33 patients). ECG showed RV involvement only in A and B groups (ST-T segment elevation more than 2 mm in V3 r - V5 r). Echo-Doppler showed no statistically differences between the two groups on RV protodiastolic pression; no hemodinamic differences between the two groups (p = n.s.); no statistically differences in central venous pressure, right ventricular pressure, cardiac output, wedge pressure. Complications (arrhytmias, heart failure, ipotension, pericarditis, 3rd A-V block) were so subdivided: group A: 6 patients (50%); group B: 2 patients (24%); group C: 4 patients (12%) with statistical significance (p<0.03) between all three groups. Coronarography showed that in group A significative lesions were localized in the proximal tract of the right coronary and/or in the proximal tract of the circumflex coronary; on the contrary in B and C groups the lesions were localized in medium and distal tract of the two vessels. Mortality at six months was 41 % in group A (5 patients); 20 % in group B (2 patients); 6 % in group C (2 patients), with p<0.01 between all three groups. Echo after six months showed IASI only in two patients of group A. Patients with IASI revealed complications (residual angina, ventricular ipercinetic arrytmias). IN CONCLUSION: IASI in patients with IAMI and RVAMI seems to identify a group with higher risk in developing complications and with a more adverse prognosis.