Italian good practice recommendations on management of persons with Long-COVID.

A significant number of people, following acute SARS-CoV-2 infection, report persistent symptoms or new symptoms that are sustained over time, often affecting different body systems. This condition, commonly referred to as Long-COVID, requires a complex clinical management. In Italy new health facilities specifically dedicated to the diagnosis and care of Long-COVID were implemented. However, the activity of these clinical centers is highly heterogeneous, with wide variation in the type of services provided, specialistic expertise and, ultimately, in the clinical care provided. Recommendations for a uniform management of Long-COVID were therefore needed. Professionals from different disciplines (including general practitioners, specialists in respiratory diseases, infectious diseases, internal medicine, geriatrics, cardiology, neurology, pediatrics, and odontostomatology) were invited to participate, together with a patient representative, in a multidisciplinary Panel appointed to draft Good Practices on clinical management of Long-COVID. The Panel, after extensive literature review, issued recommendations on 3 thematic areas: access to Long-COVID services, clinical evaluation, and organization of the services. The Panel highlighted the importance of providing integrated multidisciplinary care in the management of patients after SARS-CoV-2 infection, and agreed that a multidisciplinary service, one-stop clinic approach could avoid multiple referrals and reduce the number of appointments. In areas where multidisciplinary services are not available, services may be provided through integrated and coordinated primary, community, rehabilitation and mental health services. Management should be adapted according to the patient's needs and should promptly address possible life-threatening complications. The present recommendations could provide guidance and support in standardizing the care provided to Long-COVID patients.

Home monitoring of lung mechanics by oscillometry before, during and after severe COVID-19 disease: a case study.

A patient regularly self-performing home oscillometry developed severe COVID-19 pneumonia and continued testing during and after the disease. COVID-19 suddenly worsened oscillatory reactance, which took almost 1 year to recover to pre-COVID-19 values. https://bit.ly/3WCpWC0.

Successful Lung Transplantation From a Donor With Previous Severe COVID-19 Pneumonia.

Lungs from donors with previous COVID-19 could become a precious resource if proved safe. So far, only 3 successful lung transplantations from donors with previous mild COVID-19 have been reported. We describe a successful bilateral sequential lung transplantation from a donor who, 10 months before, had developed severe COVID-19 acute respiratory distress syndrome. No donor-derived viral transmission occurred, and 12 months after transplantation, the recipient's lung function is normal. In the presence of normal results of bronchoalveolar lavage and adequate functional and morphologic parameters, even a history of severe COVID-19 acute respiratory distress syndrome might not be considered a contraindication to lung donation.

Home monitoring of lung mechanics by oscillometry before, during and after severe COVID-19 disease: a case study

In November 2020, Europe faced the second Covid-19 pandemic wave. The need to manage patients while reducing potential exposure and healthcare system overload led to renewed interest in home-monitoring of respiratory variables. Together with variables related to COVID-19 infection [1], home-based lung imaging [2] and lung mechanics [3, 4] were used to monitor COVID-19 and chronic respiratory patients during limited access to traditional care. Home monitoring respiratory-specific variables may provide important information about patient health status and clinical course.

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 1,316 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.

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.

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.

Characterization of compliance phenotypes in COVID-19 acute respiratory distress syndrome.

BACKGROUND: Coronavirus disease 2019-associated acute respiratory distress syndrome (COVID-19 ARDS) seems to differ from the "classic ARDS", showing initial significant hypoxemia in the face of relatively preserved compliance and evolving later in a scenario of poorly compliant lungs. We tested the hypothesis that in patients with COVID-19 ARDS, the initial value of static compliance of respiratory system (Crs) (1) depends on the previous duration of the disease (i.e., the fewer days of illness, the higher the Crs and vice versa) and (2) identifies different lung patterns of time evolution and response to prone positioning. METHODS: This was a single-center prospective observational study. We enrolled consecutive mechanically ventilated patients with a diagnosis of COVID-19 who met ARDS criteria, admitted to intensive care unit (ICU). Patients were divided in four groups based on quartiles of initial Crs. Relationship between Crs and the previous duration of the disease was evaluated. Respiratory parameters collected once a day and during prone positioning were compared between groups. RESULTS: We evaluated 110 mechanically ventilated patients with a diagnosis of COVID-19 who met ARDS criteria admitted to our ICUs. Patients were divided in groups based on quartiles of initial Crs. The median initial Crs was 41 (32-47) ml/cmH2O. No association was found between the previous duration of the disease and the initial Crs. The Crs did not change significantly over time within each quartile. Positive end-expiratory pressure (PEEP) and driving pressure were respectively lower and greater in patients with lower Crs. Prone positioning significantly improved PaO2/FiO2 in the 4 groups, however it increased the Crs significantly only in patients in lower quartile of Crs. CONCLUSIONS: In our cohort, the initial Crs is not dependent on the previous duration of COVID-19 disease. Prone positioning improves oxygenation irrespective to initial Crs, but it ameliorates respiratory mechanics only in patients with lower Crs.

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.

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.

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.

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.

Preparing for future waves and pandemics: a global hospital survey on infection control measures and infection rates in COVID-19.

A survey of hospitals on three continents was performed to assess their infection control preparedness and measures, and their infection rate in hospital health care workers during the COVID-19 pandemic. All surveyed hospitals used similar PPE but differences in preparedness, PPE shortages, and infection rates were reported.

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.

Severity does not impact on exercise capacity in COVID-19 survivors.

BACKGROUND: current data on the impact of acute illness severity on exercise capacity and ventilatory efficiency of COVID-19 survivors, evaluated at cardiopulmonary exercise test (CPET), are limited. METHODS: in this post-hoc analysis of our previous observational, prospective, cohort study on mechanisms of exercise intolerance in COVID-19 survivors, we aimed at evaluating the impact of acute COVID-19 severity on exercise capacity, pulmonary function testing (PFT) and chest computed tomography (CT) outcomes. RESULTS: we enrolled 75 patients (18 with mild-to-moderate disease, 18 with severe disease, and 39 with critical disease). Mean (standard deviation - SD) follow-up time was 97 (26) days. Groups showed a similar PFT and CT residual involvement, featuring a mildly reduced exercise capacity with comparable mean (SD) values of peak oxygen consumption as percentage of predicted (83 (17) vs 82 (16) vs 84 (15), p = 0.895) among groups, as well as the median (interquartile range - IQR) alveolar-arterial gradient for O2 in mmHg at exercise peak (20 (15-28) vs 27 (18-31) vs 26 (21-21), p = 0.154), which was in the limit of normal. In addition, these patients featured a preserved mean ventilatory efficiency evaluated through the slope of the relation between ventilation and carbon dioxide output during exercise (27.1 (2.6) vs 29.8 (3.9) vs 28.3 (2.6), p = 0.028), without a clinically relevant difference. CONCLUSIONS: Disease severity does not impact on exercise capacity in COVID-19 survivors at 3 months after discharge, including a ventilatory response still in the limit of normal.

Clinical Management of Adult Patients with COVID-19 Outside Intensive Care Units: Guidelines from the Italian Society of Anti-Infective Therapy (SITA) and the Italian Society of Pulmonology (SIP).

INTRODUCTION: The Italian Society of Anti-Infective Therapy (SITA) and the Italian Society of Pulmonology (SIP) constituted an expert panel for developing evidence-based guidance for the clinical management of adult patients with coronavirus disease 2019 (COVID-19) outside intensive care units. METHODS: Ten systematic literature searches were performed to answer ten different key questions. The retrieved evidence was graded according to the Grading of Recommendations Assessment, Development, and Evaluation methodology (GRADE). RESULTS AND CONCLUSION: The literature searches mostly assessed the available evidence on the management of COVID-19 patients in terms of antiviral, anticoagulant, anti-inflammatory, immunomodulatory, and continuous positive airway pressure (CPAP)/non-invasive ventilation (NIV) treatment. Most evidence was deemed as of low certainty, and in some cases, recommendations could not be developed according to the GRADE system (best practice recommendations were provided in similar situations). The use of neutralizing monoclonal antibodies may be considered for outpatients at risk of disease progression. For inpatients, favorable recommendations were provided for anticoagulant prophylaxis and systemic steroids administration, although with low certainty of evidence. Favorable recommendations, with very low/low certainty of evidence, were also provided for, in specific situations, remdesivir, alone or in combination with baricitinib, and tocilizumab. The presence of many best practice recommendations testified to the need for further investigations by means of randomized controlled trials, whenever possible, with some possible future research directions stemming from the results of the ten systematic reviews.