Journal of Internal Medicine

IntroductionMicrovascular abnormalities and impaired gas transfer have been observed in patients with COVID-19. The progression of pathophysiological pulmonary changes during the post-acute period in these patients remains unclear. MethodsPatients who were hospitalised due to COVID-19 pneumonia underwent a pulmonary 1H and 129Xe MRI protocol at 6, 12, 25 and 51 weeks after hospital admission. The imaging protocol included: ultra-short echo time, dynamic contrast enhanced lung perfusion, 129Xe lung ventilation, 129Xe diffusion weighted and 129Xe 3D spectroscopic imaging of gas exchange. Results9 patients were recruited and underwent MRI at 6 (n=9), 12 (n=9), 25 (n=6) and 51 (n=8) weeks after hospital admission. Patients with signs of interstitial lung damage at 3 months were excluded from this study. At 6 weeks after hospital admission, patients demonstrated impaired 129Xe gas transfer (RBC:M) but normal lung microstructure (ADC, LmD). Minor ventilation abnormalities present in four patients were largely resolved in the 6-25 week period. At 12 week follow up, all patients with lung perfusion data available (n=6) showed an increase in both pulmonary blood volume and flow when compared to 6 weeks, though this was not statistically significant. At 12 week follow up, significant improvements in 129Xe gas transfer were observed compared to 6-week examinations, however 129Xe gas transfer remained abnormally low at weeks 12, 25 and 51. Changes in 129Xe gas transfer correlated significantly with changes in pulmonary blood volume and TLCO Z-score. ConclusionsThis study demonstrates that multinuclear MRI is sensitive to functional pulmonary changes in the follow up of patients who were hospitalised with COVID-19. Impairment of xenon transfer may indicate damage to the pulmonary microcirculation.

BackgroundCOVID-19 induces progressive hypoxemic respiratory failure and acute respiratory distress syndrome, mostly due to a dysregulated inflammatory response. Since the first observations of COVID-19 patients, significant hypoalbuminemia was detected. This study aimed to investigate the hypothesis that hypoalbuminemia in COVID-19 patients is due to pulmonary capillary leakage and to test its correlation with indicators of respiratory function. Methods174 COVID-19 patients, 92 admitted to the Intermediate Medicine ward (IMW), and 82 to the Intensive Care Unit (ICU) at Luigi Sacco Hospital in Milan were included in this study. FindingsSerum albumin concentration was decreased in the whole cohort, with ICU patients displaying lower values than IMW patients [20 (18-23) vs 28 (24-33) g{middle dot}|-1, p<0.001], Lower albumin values were found in patients belonging to a more compromised group (lower PaO2 to FiO2 ratio and worst chest X-ray findings). In a subset of 26 patients, analysis of bronchoalveolar lavage fluid (BALF) highlighted high protein concentrations, which were correlated to Interleukin-8 and Interleukin-10 BALF concentration. The length of hospitalisation [20 (15-29) vs 8 (5-14) days, p<0.0001] and death rate (52.4% vs 21.7%, p<0.0001) were higher in ICU than in IMW patients, while a strict relation between hypoalbuminemia and 30 day-survival was detected in the whole cohort. Electron microscopy examinations of eight out of ten autopsy lung tissues showed diffuse loosening of interendothelial junctional complex. InterpretationThe degree of hypoalbuminemia can be considered as a useful severity marker in hospitalised COVID-19 patients. Pulmonary capillary leak syndrome secondary to the hyperinflammatory state plays a key role in the pathogenesis of COVID-19 respiratory dysfunction and should be regarded as a therapeutic target.

BackgroundCOVID-19 patients may experience long-lasting complications, particularly impairment of lung function. The persistence of inflammation may lead to tissue remodeling, but the impact on the lungs in these patients remains unclear. Research QuestionIs there evidence of neutrophil-mediated inflammation, tissue remodeling, and altered lung perfusion in individuals with long COVID-19 experiencing dyspnea and reduced diffusion capacity? Additionally, can the PET imaging findings be correlated with proteomic data reflecting inflammatory status and clinical information? Study Design and MethodsPatient experiencing persistent dyspnea and reduced diffusion capacity for carbon monoxide 20 to 30 months after severe COVID-19 illness were recruited and underwent sequential PET scans using [15O]water, [68Ga]Ga-FAPI-46, and [11C]NES. Clinical lung function and 6-minute walking tests were performed before the scans. Blood samples were collected for plasma analysis using proximity extension analysis, which enabled the measurement of 96 inflammation-related biomarkers. ResultsSix male patients were recruited (age 64 {+/-} 7 [median {+/-} range] years). Patients with known impaired lung function prior to COVID-19 illness were excluded. [15O]water did not show a clear reduction in areas with signs of inflammation or tissue remodeling. However, all patients showed uptake of [68Ga]Ga-FAPI-46 and [11C]NES in the lungs, especially in areas associated with inflammation and remodeling. Patients were categorized into two groups based on tracer uptake: a low-uptake group and a high-uptake group. While the plasma inflammatory profiles differed between long-COVID-19 patients and healthy individuals, there was no clear correlation between the lung uptake of [68Ga]Ga-FAPI-46 and [11C]NES in long-COVID-19 patients. Similar observations were made regarding clinical parameters. InterpretationSequential PET scans using [15O]water, [68Ga]Ga-FAPI-46, and [11C]NES, allowed observation of signs of neutrophil-mediated inflammation and tissue remodeling in patients with long-COVID-19. However, no association with lung perfusion was demonstrated. Additionally, the results from the PET scans could not be clearly associated with clinical parameters or inflammatory proteomics.

BackgroundMounting evidence supports the role of pulmonary hemodynamic alternations in the pathogenesis of COVID-19. Previous studies have demonstrated that changes in pulmonary blood volumes measured on CT are associated with histopathological markers of pulmonary vascular pruning, suggesting that quantitative HRCT analysis may eventually be useful in the assessment pulmonary vascular dysfunction more broadly. MethodsBuilding upon previous work, automated HRCT measures of small blood vessel volume and pulmonary vascular density were developed. Scans from 103 COVID-19 patients and 108 healthy volunteers were analyzed and their results compared, with comparisons made both on lobar and global levels. ResultsCompared to healthy volunteers, COVID-19 patients showed significant reduction in BV5 (pulmonary blood volume contained in blood vessels of <5 mm2) expressed as BV5/(Total pulmonary blood volume) (p<0.0001), and significant increases in BV5_10 and BV 10 (pulmonary blood volumes contained in vessels between 5 and 10 mm2 and above 10 mm2, respectively) (p<0.0001). These changes were consistent across lobes. ConclusionsCOVID-19 patients display striking anomalies in the distribution of blood volume within the pulmonary vascular tree, consistent with increased pulmonary vasculature resistance in the pulmonary vessels below the resolution of HRCT.

ObjectivesThe dynamic tissue distribution of the clinically available intravenous iron substitution agent ferric carboxymaltose (FCM) is largely unknown. We aimed to evaluate and quantify the dynamic tissue distribution of FCM using cardiovascular magnetic resonance (CMR). Materials and methodsT1 mapping was prospectively performed to determine T1 and the partition coefficient (lambda) in myocardium, liver, spleen and skeletal muscle up to 60 minutes after onset of a 15-minute-long infusion of 20 ml (50 mg iron/ml) FCM in healthy male volunteers. For comparison, myocardial lambda for gadobutrol (0.2 mmol/kg) was measured in a separate group of age-matched healthy male volunteers. The t-test was used for group comparisons. ResultsA total of 25 healthy males (mean{+/-}SD age 27{+/-}3 years) underwent CMR with intravenous FCM (n=8) or gadobutrol (n=17). T1 values decreased in myocardium, blood, liver, spleen and skeletal muscle following FCM infusion (p < 0.001 for all). Lambda for FCM in myocardium and spleen remained constant over time after injection of FCM (mean{+/-}SEM 64{+/-}8% and 81{+/-}20%, respectively, at 30 minutes), while liver and skeletal muscle lambda increased. Myocardial lambda for FCM was higher than myocardial lambda for gadobutrol (64{+/-}8 vs 45{+/-}1%, p=0.003). ConclusionsT1 mapping can detect and quantify the dynamic tissue distribution of iron from FCM in the myocardium, liver, spleen, and skeletal muscle. Higher myocardial lambda for FCM compared to gadobutrol, indicating that FCM distributes to a greater extent into the myocardium than extracellular contrast agents, most likely due to additional distribution into the intracellular space. Key pointsO_LIUnderstanding iron physiology in heart failure is crucial, as intravenous iron therapy by ferric carboxymaltose (FCM) improves cardiac function. C_LIO_LIT1 mapping effectively measures FCM in myocardium, showing higher myocardial distribution than gadobutrol, likely due to additional intracellular distribution. C_LIO_LIThis technique offers new insights into myocardial iron physiology in both healthy and diseased hearts. C_LI

Coronavirus disease 2019 (COVID-19) mortality is associated with hypoxaemia, multiorgan failure, and thromboinflammation. However severity of disease varies considerably and understanding physiological changes that may link to poor outcomes is important. Although increased serum ferritin has been observed in COVID-19 patients consistent with inflammation, other iron parameters have not been examined to our knowledge. Because iron is required for immunity and oxygen utilisation, and dysregulated iron homeostasis has been observed in COPD, we investigated serum iron concentrations in 30 patients with COVID-19 requiring ICU admission. All patients had low serum iron but patients with severe hypoxemic respiratory failure had more profound hypoferraemia. The area under the curve for receiver operating characteristic curves for serum iron to identify severe hypoxemia was 0{middle dot}95; the optimal Youden Index for distinguishing between severe and non-severe hypoxemia was a serum iron concentration of 2{middle dot}9 mol/L. By linear regression, serum iron was associated with lymphocyte count and PaO2/FiO2. In conclusion, profound hypoferraemia identifies COVID-19 patients with severe hypoxaemia. Serum iron is a simple biomarker that could be usefully employed to stratify patients and monitor disease. Severe hypoferraemia may plausibly impair critical iron-dependent processes such as lymphocyte responses and hypoxia sensing, contributing to pathology, and is potentially treatable.

OBJECTIVENearly 5 % of the patients with COVID-19 develop an acute respiratory distress syndrome (ARDS). Extravascular lung water index (EVLWI) is a marker of pulmonary oedema which is associated with mortality in ARDS. In this study we evaluate whether EVLWI is higher in patients with COVID-19 associated ARDS as compared to controls and whether EVLWI has the potential to monitor disease progression. METHODSFrom the day of intubation, EVLWI, cardiac function were monitored by transpulmonary thermodilution in n=25 patients with COVID-19 and compared to a control group of 49 non-COVID-19 ARDS-patients. RESULTSEVLWI in COVID-19-patients was noticeably elevated and significantly higher than in the control group (17 (11-38) vs. 11 (6-26) mL/kg; p<0.001). High pulmonary vascular permeability index values (2.9 (1.0-5.2) versus 1.9 (1.0-5.2); p=0.003) suggest inflammatory oedema. By contrast, the cardiac parameters SVI, GEF and GEDVI were comparable. High EVLWI values were associated with viral persistence, prolonged intensive care treatment and mortality (23.2{+/-}6.7% vs. 30.3{+/-}6.0%, p=0.025). CONCLUSIONSCompared to the control group, COVID-19 results in markedly elevated EVLWI-values in patients with ARDS. EVLWI reflects a non-cardiogenic pulmonary oedema in COVID-19 associated ARDS and could serve as parameter to monitor ARDS progression.

INTRODUCTIONDuring the unprecedented health crisis of the COVID-19 pandemic it was suggested that obesity might aggravate severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Therefore, this study aims to investigate the association between Compute Tomography (CT)-based measurements of visceral and subcutaneous fat as measures of obesity and COVID-19 severity. METHODS30 patients with laboratory-confirmed COVID-19 and a mean age of 65.59 {+/-} 13.06 years from a level one medical center in Berlin, Germany, were retrospectively analyzed and included in the present analysis. SARS-CoV-2 was confirmed by polymerase chain reaction from throat swaps or deep nasal swabs on the day of admission. Severe clinical courses of COVID-19 were defined by hospitalization in intensive care unit (ICU) and invasive mechanical ventilation. All patients received low-dose chest CT-based fat measurements at the level of the first lumbar vertebra. RESULTSAn increase in visceral fat area (VFA) by one square decimeter was associated with a 22.53-fold increased risk for ICU treatment and a 16.11-fold increased risk for mechanical ventilation (adjusted for age and sex). For upper abdominal circumference, each additional centimeter of circumference showed a 1.13-fold increased risk for ICU treatment and a 1.25-fold increased risk for mechanical ventilation. There was no significant correlation of area (SFA) or body mass index (BMI) with severe clinical courses of COVID-19. CONCLUSIONSOur results suggest that visceral adipose tissue and upper abdominal circumference specifically increasing the risk of COVID-19 severity. CT-based quantification of visceral adipose tissue and upper abdominal circumference in routinely acquired chest CTs may therefore be a simple tool for risk assessment in SARS-CoV-2-patients.

BackgroundThere is an ongoing critical need to improve therapeutic strategies for COVID-19 pneumonia, particularly in the most severely affected patients. Adult mesenchymal stem cell (MSC) infusions have the potential to benefit critically ill patients with acute respiratory syndrome SARS-COV-2 infection, but clinical data supporting efficacy are lacking. MethodsWe conducted a case-control study of critically ill patients with laboratory-confirmed COVID-19, severe acute respiratory distress syndrome (ARDS). To evaluate clinical responsiveness in the most critically ill patient we examined outcomes in a sub-group of those requiring extracorporeal membrane oxygenation (ECMO) support. Patients (n=9) were administered with up to 3 infusions of intravenous (IV) MSCs and compared to a local ECMO control group (n=31). The primary outcome was safety, and the secondary outcomes were all-cause mortality (or rate of hospital discharge), cytokine levels, and viral clearance. FindingsMSC infusions (12 patients) were well tolerated and no side effects occurred. Of ECMO patients receiving MSC infusions, 2 out of 9 died (22.2%; 95%CI: 2.8%, 60.0%) compared with a mortality of 15 of 31 (48.4%; 95%CI: 30.2%, 66.9%; p = 0.25) in the ECMO control group. Isolated plasma exosomes containing the SARS-COV-2 Spike protein decreased after MSC infusions between day 14 or 21 after administration (p=0.003 and p=0.005, respectively) and was associated with a decrease in COVID-19 IgG Spike protein titer at same time points (p = 0.006 and p=0.007, respectively). Control ECMO patients receiving convalescent plasma did not clear COVID-19 IgG over the same time frame. InterpretationTogether these findings suggest that MSC IV infusion is well tolerated in patients with a broad range of severity including the most severe COVID-19 ARDS requiring ECMO. These data also raise the possibility that MSCs, in addition to exerting an immunomodulatory effect, contribute to viral clearance and strongly support the conduct of randomized placebo-controlled trial.

BackgroundAcute Respiratory Distress Syndrome (ARDS) results in significant hypoxia, and ARDS is the central pathology of COVID-19. Inhaled prostacyclin has been proposed as a therapy for ARDS, but data regarding its role in this syndrome are unavailable. Therefore, we investigated whether inhaled prostacyclin would affect the oxygenation and survival of patients suffering from ARDS. MethodsWe performed a prospective randomized controlled single-blind multicenter trial across Germany. The trial was conducted from March 2019 with final follow-up on 12th of August 2021. Patients with moderate to severe ARDS were included and randomized to receive either inhaled prostacyclin (3 times/day for 5 days) or sodium chloride. The primary outcome was the oxygenation index in the intervention and control groups on Day 5 of therapy. Secondary outcomes were mortality, secondary organ failure, disease severity and adverse events. FindingsOf 707 patients approached 150 patients were randomized to receive inhaled prostacyclin (n=73) or sodium chloride (n=77). Data from 144 patients were analyzed. The baseline oxygenation index did not differ between groups. The primary analysis of the study was negative, and prostacyclin improved oxygenation by 20 mmHg more than NaCl (p=0{middle dot}17). Oxygenation was significantly improved in patients with ARDS who were COVID-19-positive (34 mmHg, p=0{middle dot}04). Mortality did not differ between groups. Secondary organ failure and adverse events were similar in the intervention and control groups. InterpretationAlthough the primary result of our study was negative, our data suggest that inhaled prostacyclin might be a more beneficial treatment than standard care for patients with ARDS.

Interstitial lung diseases (ILDs) encompass a large number of conditions that affect the lungs, characterized by varying degrees of inflammation and fibrosis. Accurate diagnosis and monitoring of ILDs remain challenging due to the complex nature of ILDs and the limitations of conventional diagnostic methods such as high-resolution computed tomography and pulmonary function tests. MethodsFourteen patients with different ILDs and four healthy controls underwent positron emission tomography (PET) imaging using [11C]NES followed by [68Ga]Ga-FAPI-46, to visualize and quantify neutrophil elastase and fibroblast activated protein in the lungs, respectively. On the same day of the PET examination, blood samples were collected from the participant to measure various immune biomarkers in order to compare between PET results, serum biomarker levels, and clinical observations. ResultsUptake of both radiotracers were higher in the lungs of ILD patients compared to healthy controls, with particularly strong uptake in regions showing CT features of fibrosis. [68Ga]Ga-FAPI-46 generally exhibited higher uptake than [11C]NES in these fibrotic areas. Despite the elevation of several immune biomarkers compared to healthy controls, no clear correlation was found between these biomarkers and PET imaging results. ConclusionThese preliminary results support the potential of [11C]NES and [68Ga]Ga-FAPI-46 PET/CT imaging as promising non-invasive methods for assessing neutrophil-mediated inflammation and tissue remodeling activity in the lungs of ILD patients.

IntroductionCerebral cavernous malformations (CCMs) are abnormal clusters of capillaries in the nervous system. This pilot study analyzed the cardiometabolic health status of individuals with familial CCMs caused by a rare mutation in the CCM1 gene (fCCM1). The aim was to compare plasma water T2 values from individuals with fCCM1 with values from metabolically unhealthy and healthy individuals with no known CCM mutations. DesignThis observational, cross-sectional study included 75 participants: 11 fCCM1 patients, 24 metabolically unhealthy and 40 metabolically healthy individuals. Plasma water T2, an early, global and practical marker of cardiometabolic health, was measured in the time domain using benchtop magnetic resonance relaxometry. The results were stratified by age ([&le;] 45 vs. >45 years). Group means were compared using Welchs one-way ANOVA and post hoc Tukey-Kramer tests. Multivariable linear regression, with T2 as the outcome variable, was used to explore associations with age, gender, Hispanic ethnicity and fCCM1 status. ResultsIn the younger age stratum, the fCCM1 group had a mean plasma water T2 value comparable to the metabolically healthy group (p=0.6388), but higher than the unhealthy group (p<0.0001). By contrast, in the older stratum, the mean plasma water T2 value for the fCCM1 group was comparable to the metabolically unhealthy group (p=0.7819) and lower than the healthy group (p=0.0005). Multivariable linear regression revealed that age and the interaction between age and fCCM1 status were significant predictors of T2, even after adjusting for gender and Hispanic ethnicity. ConclusionPlasma water T2 shows potential as a biomarker for assessing the health status of individuals with fCCM1. Further research is needed to validate these preliminary observations and elucidate the association between CCMs and cardiometabolic health.

IntroductionPlacenta accreta spectrum (PAS) occurs when the placenta is pathologically adherent to the myometrium. An intact retroplacental clear space (RPCS) is a marker of normal placentation, but visualization with conventional imaging techniques is a challenge. In this study, we investigate use of an FDA-approved iron oxide nanoparticle, ferumoxytol, for contrast-enhanced magnetic resonance imaging of the RPCS in mouse models of normal pregnancy and PAS. We then demonstrate the translational potential of this technique in human patients presenting with severe PAS (FIGO Grade 3C), moderate PAS (FIGO Grade 1), and no PAS. MethodsA T1-weighted gradient recalled echo (GRE) sequence was used to determine the optimal dose of ferumoxytol in pregnant mice. Pregnant Gab3-/- mice, which demonstrate placental invasion, were then imaged at day 16 of gestation alongside wild-type (WT) pregnant mice which do not demonstrate invasion. Signal-to-noise ratio (SNR) was computed for placenta and RPCS for all fetoplacental units (FPUs) with ferumoxytol-enhanced magnetic resonance imaging (Fe-MRI) and used for the determination of contrast-to-noise ratio (CNR). Fe-MRI was also performed in 3 pregnant subjects using standard T1 and T2 weighted sequences and a 3D magnetic resonance angiography (MRA) sequence. RPCS volume and relative signal were calculated in all three subjects. ResultsFerumoxytol administered at 5 mg/kg produced strong T1 shortening in blood and led to strong placental enhancement in Fe-MRI images. Gab3-/- mice demonstrated loss of hypointense region characteristic of the RPCS relative to WT mice in T1w Fe-MRI. CNR between RPCS and placenta was lower in FPUs of Gab3-/- mice compared to WT mice, indicating higher degrees of vascularization and interruptions throughout the space. In human patients, Fe-MRI at a dose of 5 mg/kg enabled high uteroplacental vasculature signal and quantification of the volume and signal profile in severe and moderate invasion of the placenta relative to a non-PAS case. DiscussionFerumoxytol, an FDA-approved iron oxide nanoparticle formulation, enabled visualization of abnormal vascularization and loss of uteroplacental interface in a murine model of PAS. The potential of this non-invasive visualization technique was then further demonstrated in human subjects. Diagnosis of placental invasion using Fe-MRI may provide a sensitive method for clinical detection of PAS.

Body composition (adiposity and muscle depots) is strongly associated with cardiometabolic risk. However, using body composition measures for future disease risk prediction is difficult as they may reflect total body size or typical aging rather than poor health. We used data from the UK Biobank (UKB) and the German National Cohort (NAKO) to calculate age-, sex-, and height-specific z-scores for body composition measures (subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), skeletal muscle (SM), SM fat fraction (SMFF), and intramuscular adipose tissue (IMAT)) and describe changes across the lifespan. Multivariable Cox regression assessed the prognostic value of z-score categories (low: z<-1; middle: z=-1 to 1; high: z>1) for incident diabetes, major adverse cardiovascular events (MACE), and all-cause mortality beyond traditional cardiometabolic risk factors in the UKB. Among 66,608 individuals (mean age: 57.7{+/-}12.9 y; mean BMI: 26.2{+/-}4.5 kg/m2, 48.3% female), SAT, VAT, SMFF, and IMAT were positively, and SM negatively associated with age. In multivariable-adjusted Cox regression, z-score risk categories had hazard ratios of up to 2.69 for incident diabetes (high VAT category), 1.41 for incident MACE (high IMAT), and 1.49 for all-cause mortality (low SM) compared to middle categories. Body composition shows distinct age-related changes across the lifespan. Z-scores of age-, sex-, and height-adjusted body composition measures identify individuals at risk and predict cardiometabolic outcomes and mortality beyond traditional risk factors. Our open-source tool facilitates the clinical translation of age-specific body composition assessments and supports future research. One Sentence SummaryAge-, sex-, and height-adjusted body composition z-scores predict cardiometabolic outcomes and enable clinical translation of body composition data.

ObjectivesCritically ill patients with COVID-19 may suffer from a cytokine release syndrome (CRS) characterized by remarkably high levels of interleukin 6 (IL-6). We assessed the effects of tocilizumab, an IL-6 receptor antagonist, on intra-hospital mortality and development of positive cultures in patients with COVID-19 admitted to the ICU. DesignPatients with COVID 19 admitted in the ICU who were treated with tocilizumab plus standard care were enrolled and compared to controls. SettingCOVID-19 severe disease PatientsPatients with severe COVID-19 disease admitted in the ICU. InterventionsTocilizumab 400 mg IV two doses. Standard and intensive medical care as per institutional clinical protocol. Measures and Main ResultsMain outcome: 1) intra-hospital mortality; Secondary Outcomes: 1) the need for renal replacement therapy, 2) use of antibiotics and positive culture, and 3) inflammatory and oxygenation markers. There was no difference in mortality, need for renal replacement therapy, use of antibiotics or positive cultures between the two groups. The use of corticosteroids was more frequent in the treatment group. Levels of C-reactive protein (CRP) and WBC (white blood cells) counts declined significantly faster in the treatment group. Oxygenation markers rose significantly higher in patients in the tocilizumab group as compared to controls. ConclusionTocilizumab was associated with rapid improvement in oxygenation and a faster decrease of CRP and WBC counts in patients with COVID-19 and should be evaluated as rescue therapy for patients with progressive disease

Gastrointestinal (GI) symptoms of SARS-CoV2/COVID-19 in the form of anorexia, nausea, vomiting, abdominal pain and diarrhea are usually preceeded by respiratory manifestations and are associated with a poor prognosis. Hematochezia is an uncommon clinical presentation of COVID-19 disease and we hypothesize that older patients with significant comorbidites (obesity and cardiovascular) and prolonged hospitalization are suspectible to ischemic injury to the bowel. We reviewed the clinical course, key laboratory data including acute phase reactants, drug/medication history in two elderly male patients admitted for COVID-19 respiratory failure. Both patients had a complicated clinical course and suffered from hematochezia and acute blood loss anemia requiring blood transfusion around day 40 of their hospitalization. Colonoscopic impressions were correlated with the histopathological findings in the colonic biopies and changes compatible with ischemia to nonspecific acute inflammation, edema and increased eosinophils in the lamina propria were noted. Both patients were on anticoagulants, multiple antibiotics and antifungal agents due to respiratory infections at the time of lower GI bleeding. Hematochezia resolved spontaneously with supportive care. Both patients eventually recovered and were discharged. Elderly patients with significant comorbid conditions are uniquely at risk for ischemic injury to the bowel. Hypoxic conditions due to COVID-19 pneumonia and respiratory failure, compounded by preexisting cardiovascular complications, and/or cytokine storm orchestrated by the viral infection leading to alteration in coagulation profile and/or drug/medication injury can be difficult to distinguish in these critically ill patients. Presentation of hematochezia may further increase the mortality and morbidity of COVID-19 patients, and prompt consultation and management by gastroenterology is therefore warranted.

ObjectiveIn physiological conditions arterial blood lactate concentration is equal or lower than central venous. The aim of this study was to explore if the COVID-19 induced lung cells damage was mirrored by an arterial lactatemia higher than the central venous one; then if the administration of immunosuppressant drugs (i.e. canakinumab) could normalize such abnormal lactate a-cv difference. MethodsProspective cohort study started on March 25th 2020 for a duration of 10 days, enrolling 21 patients affected by severe COVID-19 pneumonia undergoing mechanical ventilation consecutively admitted to the ICU of the Rimini Hospital, Italy. Arterial and central venous blood samples were contemporary collected to calculate the difference between arterial and central venous lactate (Delta a-cv lactate) concentration within 24 h from tracheal intubation (T0), and 24 hours after canakinumab administration (T1). ResultsAt the T0 19/21 (90.5%) patients showed a pathologic Delta a-cv lactate (median 0.22 mmol/L; IQR 0.07-0.36), suggesting severe inflammation. In the 13 patients undergoing canakinumab administration, at the T1 Delta a-cv lactate decreased in 92.3% of cases, being the decrease statistically significant (T0: median 0.15, IQR 0.07-0.25 mmol/L; T1: median -0.01, IQR 0.09-0.04 mmol/L; p=0.002). ConclusionA reversed Delta a-cv lactate is likely to be one of the effects of COVID-19 related cytokine storm, that could reflect a derangement in the lung cells mitochondrial metabolism induced by inflammation or other uncoupling mediators. Delta a-cv lactate decrease may reflect the anti-inflammatory activity of canakinumab. Our preliminary findings need to be confirmed by larger outcome studies.

BackgroundCardiovascular complication in patients affected by novel Coronavirus respiratory disease (COVID-19) are increasingly recognized. However, although a cardiac tropism of SARS-CoV-2 for inflammatory cells in autopsy heart samples of COVID-19 patients has been reported, the presence of the virus in cardiomyocytes has not been documented yet. MethodsWe investigated for SARS-CoV-2 presence in heart tissue autopsies of 6 consecutive COVID-19 patients deceased for respiratory failure showing no signs of cardiac involvement and with no history of heart disease. Cardiac autopsy samples were analysed by digital PCR, Western blot, immunohistochemistry, immunofluorescence, RNAScope, and transmission electron microscopy assays. ResultsThe presence of SARS-CoV-2 into cardiomyocytes was invariably detected. A variable pattern of cardiomyocytes injury was observed, spanning from the absence of cell death and subcellular alterations hallmarks to the intracellular oedema and sarcomere ruptures. In addition, we found active viral transcription in cardiomyocytes, by detecting both sense and antisense SARS-CoV-2 spike RNA. ConclusionsIn this analysis of autopsy cases, the presence of SARS-CoV-2 into cardiomyocytes, determining variable patterns of intracellular involvement, has been documented. All these findings suggest the need of a cardiologic surveillance even in survived COVID-19 patients not displaying a cardiac phenotype, in order to monitor potential long-term cardiac sequelae.

BACKGROUND & AIMSEarly reports suggest that both fecal shedding and dysbiosis of the gut microbiome are associated to disease severity in COVID-19 patients. We investigated the gut microbiome as well as the prevalence of SARS-CoV-2 in stool samples from two French populations: exposed healthcare workers and elderly hospitalized COVID-19 patients. The predictive power of bacterial loss of diversity and detection of SARS-CoV-2 in stool was assessed at 4 weeks against clinical outcomes in the patient group. METHODS79 healthcare workers in contact with COVID-19 patients and 64 elderly patients hospitalised in a COVID-19 unit in France were included in the EDIFICE trial from April 2020 until May 2021. Stool samples were collected at inclusion. Loss of bacterial diversity was diagnosed based on 16S rRNA gene sequencing. Stool positivity to SARS-CoV-2 was determined by RT-PCR. Clinical outcomes were recorded at a 4 weeks follow up visit. In particular, these include whether the patient had been put under oxygen during the 4 weeks follow up, whether he had been discharged with or without aggravation from initial symptoms or whether the patient had died. The primary end point was to validate the hypothesis that hospitalized COVID-19 patients had more often lost their bacterial diversity than highly exposed active healthcare workers. RESULTSElderly hospitalised patients with COVID-19 had more frequently lost their bacterial diversity when compared to exposed healthcare workers (p-value = 0.005), their severe dysbiosis was characterized by enrichment of the family Erysipelotrichaceae and depletion of beneficial bacteria at the genus level such as butyrate producers (Butyrivibrio, Roseburia, Faecalibacterium) and Bifidobacterium. The virus was detected in 61% of hospitalized patients and in only one healthcare workers (2%) who had previously been diagnosed with COVID-19 (p-value<0.001). No significant difference in the gut microbiome composition at the genus level of patients that tested positive in stool versus patients that tested negative was observed. Neither bacterial loss of diversity nor positivity to SARS-CoV-2 were associated to clinical outcome at 4 weeks. CONCLUSIONSWe report findings of the first French trial investigating the clinical interest of stool based diagnosis of SARS-CoV-2 and loss of bacterial diversity in a population of elderly hospitalised COVID-19 patients and highly exposed healthcare workers. Our findings of reduced bacterial diversity and a strong gut dysbiosis in elderly hospitalized COVID-19 patients are highly consistent with previous reports mostly from Chinese populations. A major limitation is that observed differences in the gut microbiome between the two studied groups cannot be attributed to COVID-19 per se given the large number of confounding factors. SARS-CoV-2 was detected in the stool of the majority of hospitalized patients even several weeks after initial diagnosis by nasopharyngeal swabs. This high prevalence warrants further investigation by the scientific community into mechanism.

IntroductionAcute Respiratory Distress Syndrome (ARDS) is an acute inflammatory pulmonary process that leads to protein-rich, non-hydrostatic pulmonary edema, undesirable hypoxemia, and lung stiffness. Due to COVID-19, a significant proportion of people who will require hospitalization to treat COVID-19, between 15%-30%, will develop severe respiratory failure, ARDS, and an increased likelihood of intubation for mechanical respiratory support. AimTo investigate the pulmonary function in COVID-19-related ARDS survivors after hospitalization. MethodsA search was performed on the Greek and international literature, as well as at the online Databases PubMed, Cochrane, Embase, and Google Scholar. Exclusion and integration criteria were set for the studies found, and a flow chart was created for the studies included. ResultsThrough the search, 352 articles were found matching the subject under study, and after further evaluation, four articles were included. The majority of the articles highlight that after ARDS occurs due to COVID-19, patients face impaired pulmonary function in combination with other physical and psychological symptoms like weakness, anxiety, depression, and generalized functional disability. ConclusionsIt is a fact that COVID-19 disease, in severe form and following the need for hospitalization due to the development of ARDS, results in an increased likelihood of prolonged occurrence of some symptoms of impaired respiratory function. Impaired CO2 diffusion is observed in the majority of studies as well as impaired respiratory function regarding prolonged imaging findings and impaired physical function.