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.

Donors risk assessment in transplantation: From the guidelines to their real-world application.

Transplantation of an organ from a donor carries an unavoidable risk of tumor transmission. The need to extend the donor pool increases the use of organs from donors with malignancies and potential disease transmission is a constant tension influencing donor suitability decisions. Current classification systems for the assessment of donor malignancy transmission risk have evolved from reports of potential transmission events in recipients to national donation and transplant surveillance agencies. Although the risk of malignancy transmission is very low in the general transplant setting it must constantly be balanced with the transplant benefits. Guidelines are mainly based on large registries and sparse case reports of transmission, so they cannot cover all the possible situations. For this reason, in 2004 in Italy, the National Transplant Center gave rise to the Second Opinion Service, charged by the Ministry of Health, by structuring expertise in diagnostic oncology and risk transmission and making it available to the Italian Transplant Centers. In this paper the registry of the Italian Oncological Second Opinion was reviewed, from 2016 to 2018, to detail the most frequent and problematic neoplastic topics addressed, those are separately reported and discussed. Furthermore, a review of the most recent strategies and risk stratification is provided, according to the most recent literature evidence and to the European Guidelines.

The Effect of Positive Pressure Ventilation on Acute Kidney Injury in COVID-19 Patients with Acute Respiratory Distress Syndrome: An Observational Study.

INTRODUCTION: Acute kidney injury (AKI) is frequent in critically ill COVID-19 patients and is associated with a higher mortality risk. By increasing intrathoracic pressure, positive pressure ventilation (PPV) may reduce renal perfusion pressure by reducing venous return to the heart or by increasing renal venous congestion. This study's aim was to evaluate the association between AKI and haemodynamic and ventilatory parameters in COVID-19 patients with ARDS. METHODS: This is a single-centre retrospective observational study. Consecutive patients diagnosed with COVID-19 who met ARDS criteria and required invasive mechanical ventilation were enrolled. The relationship between respiratory and haemodynamic parameters influenced by PPV and AKI development was evaluated. AKI was defined according to KDIGO criteria. AKI recovery was evaluated a month after ICU admission and patients were classified as "recovered," if serum creatinine (sCr) value returned to baseline, or as having "acute kidney disease" (AKD), if criteria for AKI stage 1 or greater persisted. The 6-month all-cause mortality was collected. RESULTS: A total of 144 patients were included in the analysis. AKI occurred in 69 (48%) patients and 26 (18%) required renal replacement therapy. In a multivariate logistic regression analysis, sex, hypertension, cumulative dose of furosemide, fluid balance, and plateau pressure were independently associated with AKI. Mortality at 6 months was 50% in the AKI group and 32% in the non-AKI group (p = 0.03). Among 36 patients who developed AKI and were discharged alive from the hospital, 56% had a full renal recovery after a month, while 14%, 6%, and 14% were classified as having an AKD of stage 0, 2, and 3, respectively. CONCLUSIONS: In our cohort, AKI was independently associated with multiple variables, including high plateau pressure, suggesting a possible role of PPV on AKI development. Further studies are needed to clarify the role of mechanical ventilation on renal function.

Second Opinion in the Italian Organ Procurement Transplantation: The Pathologist Is In.

Second opinion consultation is a well-established practice in different clinical settings of diagnostic medicine. However, little is known about second opinion consultation activity in transplantation, and even less is known about it concerning donor assessment. The consultations provided by the second opinion service led to the safer and homogeneous management of donors with a history of malignancy or ongoing neoplasm by transplant centers. Indeed, two of the most important aspects are the reduction of semantic differences in cancer reporting and the standardization of procedures, which are mainly due to the different settings and logistics of different pathology services. This article aims to discuss the role and the future of the second opinion in Italy during organ procurement, highlighting the critical issues and areas for improvement.

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.

Added prognostic value of molecular imaging parameters over proliferation index in typical lung carcinoid: an [18F]FDG PET/CT and SSTR imaging study.

OBJECTIVE: This study was performed to evaluate the prognostic meaning of volumetric and semi-quantitative parameters measured using [18F]FDG PET/CT and somatostatin receptor (SSTR) imaging in patients with typical lung carcinoid (TC), and their relationship with proliferative index (Ki67). METHODS: We retrospectively reviewed 67 patients (38-94 years old, mean: 69.7) with diagnosis of TC who underwent [18F]FDG PET/CT and/or SSTR scintigraphy/SPECT with [111In]DTPA-Octreotide plus contrast-enhanced CT (CECT) at staging evaluation. All patients had Ki67 measured and a follow-up (FU) of at least 1 year. SSTR density (SSTRd) was calculated as the percentage difference of tumor/non-tumor ratio at 4 and 24 h post-injection. At PET/CT, metabolic activity was measured using SUVmax and SUVratio; volumetric parameters included MTV and TLG of the primary tumor, measured using the threshold SUV41%. ROC analysis, discriminant analysis and Kaplan-Meier curves (KM) were performed. RESULTS: 11 patients died during FU. Disease stage (localized versus advanced), SUVratio, SUVmax, Ki67, MTV and TLG were significantly higher in non-survivors than in survivors. ROC curves resulted statistically significant for Ki67, SUVratio, SUVmax, MTV and TLG. On multivariate analysis, stage of disease and TLG were significant independent predictors of overall survival (OS). In KM curves, the combination of disease stage and TLG identified four groups with significantly different outcomes (p < 0.005). Metabolic activity (SUVmax and SUVratio) was confirmed as significant independent prognostic factor for OS also in patients with advanced disease, with the best AUC using SUVmax. In patients with advanced and localized disease, SSTRd proved to be the best imaging prognostic factor for progression and for disease-free survival (DFS), respectively. In localized disease, SSTRd 31.5% identified two subgroups of patients with significant different DFS distribution and in advanced disease, a high cutoff value (58.5%) was a significant predictor of adverse prognosis. CONCLUSION: Volumetric and semi-quantitative parameters measured using [18F]FDG PET/CT and SSTR imaging combined with Ki67 may provide a reference for prognosis evaluation of patients with TC, to better stratify risk groups with the goal of developing individualized therapeutic strategies.

Transthyretin Cardiac Amyloidosis: A Cardio-Orthopedic Disease.

Orthopaedic manifestations of wild-type transthyretin amyloidosis are frequent and characteristic, including idiopathic bilateral carpal tunnel syndrome, idiopathic lumbar canal stenosis, atraumatic rupture of the brachial biceps tendon, and, more rarely, finger disease and rotator cuff. These manifestations often coexisting in the same patient, frequently male and aged, steadily precede cardiac involvement inducing a rapidly progressive heart failure with preserved ejection fraction. Although transthyretin cardiac amyloidosis remains a cardiac relevant disease, these extracardiac localisation may increase diagnostic suspicion and allow for early diagnosis assuming the role of useful diagnostic red flags, especially in light of new therapeutic opportunities that can slow or stop the progression of the disease. For the cardiologist, the recognition of these extracardiac red flags is of considerable importance to reinforce an otherwise less emerging diagnostic suspicion. For orthopedists and rheumatologists, the presence in an old patient with or without clinical manifestations of cardiovascular disease, of an unexpected and inexplicable constellation of musculoskeletal symptoms, can represent a fundamental moment for an early diagnosis and treatment is improving a patient's outcome.

Validation of portable tablets for transplant pathology diagnosis according to the College of American Pathologists Guidelines.

Despite increased use of digital pathology, its application in the transplantation setting remains limited. One of the restraints is related to concerns that this technology is inadequate for supporting diagnostic work. In this study, we sought to establish non inferiority of whole slide imaging (WSI) to light microscopy (LM) for intraoperative transplantation diagnosis using inexpensive portable devices. A validation study was conducted according to updated guidelines from the College of American Pathologists (CAP) utilizing 80 intraoperative transplantation cases. Two pathologists reviewed glass slides with LM and digital slides on two different tablets after a washout period of 4 weeks. Diagnostic concordance and intra-observer agreement were recorded. A total of 45 (56%) cases were suitable for rendering transplant diagnoses and 35 (44%) for assessing cancer risk. Intra-observer agreement was 95.1% for organ suitability and 100% for cancer risk. There were no major discordances that could affect patient transplant management. Digital evaluation of intraoperative transplant specimens using tablets to view whole slide images was non-inferior to LM for primary diagnosis. This suggests that after validating WSI these digital tools can be safely used for remote intraoperative transplantation diagnostic work.

Extent and Distribution of Parenchymal Abnormalities in Baseline CT-Scans Do Not Predict Awake Prone Positioning Response in COVID-19 Related ARDS.

Prone positioning is frequently used for non-intubated hypoxemic patients with COVID-19, although conclusive evidence is still lacking. The aim of the present study was to investigate whether baseline CT-scans could predict the improvement in oxygenation in COVID-19 related Acute respira-tory syndrome (ARDS) patients when pronated. METHODS: A retrospective study of COVID-19 patients who underwent non-invasive ventilation (NIV) and prone positioning was conducted. RESULTS: Forty-five patients were included. On average, 50% of the overall lung volume was affected by the disease, as observed in the CT-scans, with ground glass opacities (GGOs) and consolidations accounting for 44% and 4%, respectively. The abnormalities were mainly posterior, as demonstrated by posterior/anterior distribution ratios of 1.5 and 4.4 for GGO and consolidation, respectively. The median PaO2/FiO2 ratio during NIV in a supine position (SP1) was 140 [IQR 108-169], which improved by 67% (+98) during prone positioning, on average. Once supine positioning was resumed (SP2), the improvement in oxygenation was maintained in 28 patients (62% of the overall population, categorized as "responders"). We found no significant differences between responders and non-responders in terms of the extent (p = 0.92) and the distribution of parenchymal abnormalities seen in the baseline CT (p = 0.526). CONCLUSION: Despite the lack of a priori estimation of the sample size, considering the absence of any trends in the differences and correlations, we can reasonably conclude that the baseline chest CT-scan does not predict a gas-exchange response in awake prone-positioned patients with COVID-19 related ARDS. Physicians dealing with this category of patients should not rely on the imaging at presentation when evaluating whether to pronate patients.

An Experimental Apparatus for E-Nose Breath Analysis in Respiratory Failure Patients.

Background: Non-invasive, bedside diagnostic tools are extremely important for tailo ring the management of respiratory failure patients. The use of electronic noses (ENs) for exhaled breath analysis has the potential to provide useful information for phenotyping different respiratory disorders and improving diagnosis, but their application in respiratory failure patients remains a challenge. We developed a novel measurement apparatus for analysing exhaled breath in such patients. Methods: The breath sampling apparatus uses hospital medical air and oxygen pipeline systems to control the fraction of inspired oxygen and prevent contamination of exhaled gas from ambient Volatile Organic Compounds (VOCs) It is designed to minimise the dead space and respiratory load imposed on patients. Breath odour fingerprints were assessed using a commercial EN with custom MOX sensors. We carried out a feasibility study on 33 SARS-CoV-2 patients (25 with respiratory failure and 8 asymptomatic) and 22 controls to gather data on tolerability and for a preliminary assessment of sensitivity and specificity. The most significant features for the discrimination between breath-odour fingerprints from respiratory failure patients and controls were identified using the Boruta algorithm and then implemented in the development of a support vector machine (SVM) classification model. Results: The novel sampling system was well-tolerated by all patients. The SVM differentiated between respiratory failure patients and controls with an accuracy of 0.81 (area under the ROC curve) and a sensitivity and specificity of 0.920 and 0.682, respectively. The selected features were significantly different in SARS-CoV-2 patients with respiratory failure versus controls and asymptomatic SARS-CoV-2 patients (p < 0.001 and 0.046, respectively). Conclusions: the developed system is suitable for the collection of exhaled breath samples from respiratory failure patients. Our preliminary results suggest that breath-odour fingerprints may be sensitive markers of lung disease severity and aetiology.

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.

Antecedent use of renin-angiotensin system inhibitors is associated with reduced mortality in elderly hypertensive Covid-19 patients.

OBJECTIVES: The effect of renin-angiotensin system inhibitors (RASIs) on mortality in patients with coronavirus disease (Covid-19) is debated. From a cohort of 1352 consecutive patients admitted with Covid-19 to Papa Giovanni XXIII Hospital in Bergamo, Italy, between February and April 2020, we selected and studied hypertensive patients to assess whether antecedent (prior to hospitalization) use of RASIs might affect mortality from Covid-19 according to age. METHODS AND RESULTS: Arterial hypertension was present in 688 patients. Overall mortality (in-hospital or shortly after discharge) was 35% (N = 240). After adjusting for 26 medical history variables via propensity score matching, antecedent use of RASIs (N = 459, 67%) was associated with a lower mortality in older hypertensive patients (age above the median of 68 years in the whole series), whereas no evidence of a significant effect was found in the younger group of the same population (P interaction = 0.001). In an analysis of the subgroup of 432 hypertensive patients older than 68 years, we considered two RASI drug subclasses, angiotensin-converting enzyme inhibitors (ACEIs, N = 156) and angiotensin receptor blockers (ARBs, N = 140), and assessed their respective effects by taking no-antecedent-use of RASIs as reference. This analysis showed that both antecedent use of ACEIs and antecedent use of ARBs were associated with a lower Covid-19 mortality (odds ratioACEI = 0.57, 95% confidence interval 0.36--0.91, P = 0.018) (odds ratioARB = 0.49, 95% confidence interval 0.29--0.82, P = 0.006). CONCLUSION: In the population of over-68 hypertensive Covid-19 patients, antecedent use of ACEIs or ARBs was associated with a lower all-cause mortality, whether in-hospital or shortly after discharge, compared with no-antecedent-use of RASIs.

Eculizumab in patients with severe coronavirus disease 2019 (COVID-19) requiring continuous positive airway pressure ventilator support: Retrospective cohort study.

BACKGROUND: Complement activation contributes to lung dysfunction in coronavirus disease 2019 (COVID-19). We assessed whether C5 blockade with eculizumab could improve disease outcome. METHODS: In this single-centre, academic, unblinded study two 900 mg eculizumab doses were added-on standard therapy in ten COVID-19 patients admitted from February 2020 to April 2020 and receiving Continuous-Positive-Airway-Pressure (CPAP) ventilator support from ≤24 hours. We compared their outcomes with those of 65 contemporary similar controls. Primary outcome was respiratory rate at one week of ventilator support. Secondary outcomes included the combined endpoint of mortality and discharge with chronic complications. RESULTS: Baseline characteristics of eculizumab-treated patients and controls were similar. At baseline, sC5b-9 levels, ex vivo C5b-9 and thrombi deposition were increased. Ex vivo tests normalised in eculizumab-treated patients, but not in controls. In eculizumab-treated patients respiratory rate decreased from 26.8±7.3 breaths/min at baseline to 20.3±3.8 and 18.0±4.8 breaths/min at one and two weeks, respectively (p<0.05 for both), but did not change in controls. Between-group changes differed significantly at both time-points (p<0.01). Changes in respiratory rate correlated with concomitant changes in ex vivo C5b-9 deposits at one (rs = 0.706, p = 0.010) and two (rs = 0.751, p = 0.032) weeks. Over a median (IQR) period of 47.0 (14.0-121.0) days, four eculizumab-treated patients died or had chronic complications versus 52 controls [HRCrude (95% CI): 0.26 (0.09-0.72), p = 0.010]. Between-group difference was significant even after adjustment for age, sex and baseline serum creatinine [HRAdjusted (95% CI): 0.30 (0.10-0.84), p = 0.023]. Six patients and 13 controls were discharged without complications [HRCrude (95% CI): 2.88 (1.08-7.70), p = 0.035]. Eculizumab was tolerated well. The main study limitations were the relatively small sample size and the non-randomised design. CONCLUSIONS: In patients with severe COVID-19, eculizumab safely improved respiratory dysfunction and decreased the combined endpoint of mortality and discharge with chronic complications. Findings need confirmation in randomised controlled trials.

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.

Worsening of gas exchange parameters at high FiO2 in COVID-19: misleading or informative?

BACKGROUND: In COVID-19, higher than expected level of intrapulmonary shunt has been described, in association with a discrepancy between the initial relatively preserved lung mechanics and the hypoxia severity. This study aim was to measure the shunt fraction and variations of PaO2/FiO2 ratio and oxygen alveolar-arterial gradient (A-a O2) at different FiO2. METHODS: Shunt was measured by a non-invasive system during spontaneous breathing in 12 patients hospitalized at COVID-19 Semi-Intensive Care Unit of Papa Giovanni XXIII Hospital, Bergamo, Italy, between October 22 and November 23, 2020. RESULTS: Nine patients were men, mean age (±SD) 62±15 years, mean BMI 27.5±4.8 Kg/m2. Systemic hypertension, diabetes type 2 and previous myocardial infarction were referred in 33%, 17%, and 7%, respectively. Mean PaO2/FiO2 ratio was 234±66 and 11 patients presented a bilateral chest X-ray involvement. Mean shunt was 21±6%. Mainly in patients with a more severe respiratory failure, we found a progressive decrease of PaO2/FiO2 ratio with higher FiO2. Considering (A-a O2), we found a uniform tendency to increase with FiO2 increasing. Even in this case, the more severe were the patients, the higher was the slope, suggesting FiO2 insensitiveness due to a shunt effect, as strengthened by our measurements. CONCLUSION: Relying on a single evaluation of PaO2/FiO2 ratio, especially at high FiO2, could be misleading in COVID-19. We propose a two steps evaluation, the first at low SpO2 value (e.g., 92-94%) and the second one at high FiO2 (i.e., >0.7), allowing to characterize both the amendable (ventilation/perfusion mismatch), and the fixed (shunt) contribution quote of respiratory impairment, respectively.