Choroid plexus and perivascular space enlargement in neuropsychiatric systemic lupus erythematosus.

Choroid plexus (CP) enlargement is proposed as a marker of neuroinflammation in immune-mediated conditions. CP involvement has also been hypothesized in the immunopathology of systemic lupus erythematosus (SLE). We investigated whether CP enlargement occurs in SLE patients and its association with neuropsychiatric involvement. Additionally, we explored abnormalities along the glymphatic system in SLE patients through enlarged perivascular space (PVS) quantification. Clinical assessment and 3 Tesla brain dual-echo and T1-weighted MRI scans were obtained from 32 SLE patients and 32 sex and age-matched healthy controls (HC). CPs were manually segmented on 3D T1-weighted sequence and enlarged PVS (ePVS) were assessed through Potter's score. Compared to HC, SLE patients showed higher normalized CP volume (nCPV) (p = 0.023), with higher CP enlargement in neuropsychiatric SLE (NPSLE) (n = 12) vs. non-NPSLE (p = 0.027) patients. SLE patients with antiphospholipid antibodies (APA) positivity (n = 18) had higher nCPV compared to HC (p = 0.012), while APA negative ones did not. SLE patients also had higher Potter's score than HC (p < 0.001), with a tendency towards a higher number of basal ganglia ePVS in NPSLE vs. non-NPSLE patients. Using a random forest analysis, nCPV emerged as a significant predictor of NPSLE, together with T2-hyperintense white matter (WM) lesion volume (LV) and APA positivity (out-of-bag AUC 0.81). Our findings support the hypothesis of a role exerted by the CP in SLE physiopathology, especially in patients with neuropsychiatric involvement. The higher prevalence of ePVS in SLE patients, compared to HC, suggests the presence of glymphatic system impairment in this population.

Higher Seasonal Variation of Systemic Inflammation in Bipolar Disorder.

Seasonal rhythms affect the immune system. Evidence supports the involvement of immuno-inflammatory mechanisms in bipolar disorder (BD), with the neutrophil to lymphocyte ratio (NLR), and the systemic immune-inflammatory index (SII; platelets × neutrophils/lymphocytes) consistently reported to be higher in patients with BD than in HC, but seasonal rhythms of innate and adaptive immunity have never been studied. We retrospectively studied NLR and SII in 824 participants divided into three groups: 321 consecutively admitted inpatients affected by a major depressive episode in course of BD, and 255 consecutively admitted inpatients affected by obsessive-compulsive disorder (OCD; positive psychiatric control), and 248 healthy controls (HC). Patients with BD showed markedly higher markers of systemic inflammation in autumn and winter, but not in spring and summer, in respect to both HC and patients with OCD, thus suggesting a specific effect of season on inflammatory markers in BD, independent of a shared hospital setting and drug treatment. Given that systemic inflammation is emerging as a new marker and as target for treatment in depressive disorders, we suggest that seasonal rhythms should be considered for tailoring antidepressant immuno-modulatory treatments in a precision medicine approach.

COVID-19 Immunity in the Cohort of IRCCS San Raffaele Hospital Employees after BNT162b2 Vaccination: A Retrospective Observational Study.

Introduction: The COVID-19 pandemic represents the most severe health and socioeconomic crisis of our century. It began with the first reports in China, in the Wuhan region in December 2019, and quickly spread worldwide, causing a new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Among the population most at risk of infection and developing severe forms of the disease are the elderly and healthcare workers, who are more exposed to infected individuals. On December 11, 2020, the Food and Drug Administration approved the emergency use of the BNT162b2 vaccine, the first mRNA vaccine in history. Since then, the total number of vaccine doses administered has exceeded 12 billion. Italy was the first European country to be affected by the pandemic, recording the highest number of total COVID-19 cases (25,695,311) and, after the first 70 days, had the highest crude mortality rate (141.0 per 100,000). In this study, we analyze the rate of SARS-CoV-2 infection among healthcare workers at the San Raffaele Scientific Institute in Milan before and after receiving the BNT162b2 vaccine. Study design: Retrospective observational cohort study. Methods: The study analyzed the immunization status of 858 employees of the San Raffaele Scientific Institute in Milan, including doctors, healthcare workers, and administrative staff. The analysis is based on previous studies on the same cohort and is integrated with extrapolation and additional analysis of data from the Preventive Medicine Service's Biobank dataset of the same hospital to estimate the infection rate, duration of the disease, and antibody levels recorded in the personnel before and after receiving the double BNT162b2 vaccination. Results: The analysis confirms the positive impact achieved by the introduction of mRNA vaccination in reducing the SARS-CoV-2 infection rate and increasing antibody levels in healthcare workers. Although the BNT162b2 vaccination may not provide complete protection against SARS-CoV-2, it appears to be able to reduce the number of infections, particularly the more severe and symptomatic forms often detected in individuals with various risk factors and comorbidities, making them more vulnerable. Healthcare workers, who have extensive contact with patients and record the greatest decrease in the infection rates, represent the population that receives the most benefit from vaccination. Conclusions: The evidence suggests that vaccinations are essential in protecting high-risk groups, such as healthcare workers, from SARS-CoV-2 infection. Providing adequate vaccination coverage to healthcare workers limits the spread of infections and decreases the severity of disease manifestations, while also reducing their duration.

Follicular helper T cell signature of replicative exhaustion, apoptosis, and senescence in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is the most frequent primary antibody deficiency whereby follicular helper T (Tfh) cells fail to establish productive responses with B cells in germinal centers. Here, we analyzed the frequency, phenotype, transcriptome, and function of circulating Tfh (cTfh) cells in CVID patients displaying autoimmunity as an additional phenotype. A group of patients showed a high frequency of cTfh1 cells and a prominent expression of PD-1 and ICOS as well as a cTfh mRNA signature consistent with highly activated, but exhausted, senescent, and apoptotic cells. Plasmatic CXCL13 levels were elevated in this group and positively correlated with cTfh1 cell frequency and PD-1 levels. Monoallelic variants in RTEL1, a telomere length- and DNA repair-related gene, were identified in four patients belonging to this group. Their blood lymphocytes showed shortened telomeres, while their cTfh were more prone to apoptosis. These data point toward a novel pathogenetic mechanism in CVID, whereby alterations in DNA repair and telomere elongation might predispose to antibody deficiency. A Th1, highly activated but exhausted and apoptotic cTfh phenotype was associated with this form of CVID.

Cognitive remediation therapy for post-acute persistent cognitive deficits in COVID-19 survivors: A proof-of-concept study.

Cognitive impairments figure prominently in COVID-19 survivors. Cognitive remediation therapy (CRT) improves functional outcomes reducing long-term cognitive deficits in several neurological and psychiatric conditions. Our case-control study investigates the efficacy of a CRT programme administered to COVID-19 survivors in the post-acute phase of the illness. Seventy-three COVID-19 survivors presenting cognitive impairments at one-month follow-up were enrolled. Among them, 15 patients were treated with a two-month CRT programme, and 30 non-treated patients were matched conditional to their baseline cognitive functioning. Cognitive functions were assessed before and after treatment. Depression and quality of life were also evaluated. Mixed model ANOVA revealed a significant effect over time of the CRT programme on global cognitive functioning (F = 4.56, p = 0.039), while no significant effect was observed in the untreated group. We observed a significant effect of the improvement in verbal fluency (χ2 = 7.20, p = 0.007) and executive functions (χ2 = 13.63, p < 0.001) on quality of life. A positive significant correlation was found between depressive symptomatology and verbal fluency (r = -0.35), working memory (r = -0.44), psychomotor coordination (r = -0.42), and executive functions (r = -0.33). Our results could pave the way to a plausible innovative treatment targeting cognitive impairments and ameliorating the quality of life of COVID-19 survivors.

Predictors and outcomes of delirium in the emergency department during the first wave of the COVID-19 pandemic in Milan.

BACKGROUND: Respiratory infections can be complicated by acute brain failure. We assessed delirium prevalence, predictors and outcomes in COVID-19 ED patients. METHODS: This was a retrospective observational study conducted at the San Raffaele ED (Italy). Patients age >18 years attending the ED between 26 February 2020 and 30 May 2020 and who had a positive molecular nasopharyngeal swab for SARS-CoV-2 were included. The Chart-Based Delirium Identification Instrument (CHART-DEL) was used to retrospectively assess delirium. Univariable and multivariable logistic regression analyses were used to evaluate delirium predictors. Univariable binary logistic regression analyses, linear regression analyses and Cox regression analyses were used to assess the association between delirium and clinical outcomes. Age-adjusted and sex-adjusted models were then run for the significant predictors of the univariable models. RESULTS: Among the 826 included patients, 123 cases (14.9%) of delirium were retrospectively detected through the CHART-DEL method. Patients with delirium were older (76.9±13.15 vs 61.3±14.27 years, p<0.001) and more frequently living in a long-term health facility (32 (26%) vs 22 (3.1%), p<0.001). Age (OR 1.06, 95% CI 1.04 to 1.09, p<0.001), dementia (OR 17.5, 95% CI 7.27 to 42.16, p<0.001), epilepsy (OR 6.96, 95% CI 2.48 to 19.51, p<0.001) and the number of chronic medications (OR 1.09, 95% CI 1.01 to 1.17, p=0.03) were significant predictors of delirium in multivariable analyses. Delirium was associated with increased in-hospital mortality (adjusted HR 2.16, 95% CI 1.55 to 3.03, p<0.001) and with a reduced probability of being discharged home compared with being institutionalised (adjusted OR 0.39, 95% CI 0.25 to 0.61, p<0.001). CONCLUSIONS: Chart review frequently identified ED delirium in patients with COVID-19. Age, dementia, epilepsy and polypharmacy were significant predictors of ED delirium. Delirium was associated with an increased in-hospital mortality and with a reduced probability of being discharged home after hospitalisation. The findings of this single-centre retrospective study require validation in future studies.

Myocardial injury in patients with SARS-CoV-2 pneumonia: Pivotal role of inflammation in COVID-19.

AIMS: Infection by SARS-CoV-2 may result in a systemic disease and a proportion of patients ranging 15%-44% experienced cardiac injury (CI) diagnosed by abnormal troponin levels. The aim of the present study was to analyse the clinical characteristics of a large series of hospitalized patients for COVID-19 in order to identify predisposing and/or protective factors of CI and the outcome. METHODS AND RESULTS: This is an observational, retrospective study on patients hospitalized in two Italian centres (San Raffaele Hospital and Cremona Hospital) for COVID-19 and at least one high-sensitivity cardiac troponin (hs-cTnt) measurement during hospitalization. CI was defined if at least one hs-cTnt value was above the 99th percentile. The primary end-point was the occurrence of CI during hospitalization. We included 750 patients (median age 67, IQR 56-77 years; 69% males), of whom 46.9% had history of hypertension, 14.7% of chronic coronary disease and 22.3% of chronic kidney disease (CKD). Abnormal troponin levels (median troponin 74, IQR 34-147 ng/l) were detected in 390 patients (52%) during the hospitalization. At multivariable analysis age, CKD, cancer, C-reactive protein (CRP) levels were independently associated with CI. Independent predictors of very high troponin levels were chronic kidney disease and CRP levels. Patients with CI showed higher rate of all-cause mortality (40.0% vs. 9.1%, p = 0.001) compared to those without CI. CONCLUSION: This large, multicentre Italian study confirmed the high prevalence of CI and its prognostic role in hospitalized patients with COVID-19, highlighting the leading role of systemic inflammation for the occurrence of CI.

Resting state network functional connectivity abnormalities in systemic lupus erythematosus: correlations with neuropsychiatric impairment.

Neuropsychiatric manifestations are highly prevalent in systemic lupus erythematosus (SLE)-patients. We aimed to unravel the substrates of these manifestations by investigating abnormalities of resting state (RS) functional connectivity (FC) and their correlations with neuropsychiatric variables in SLE-patients. Thirty-two SLE-patients and 32 age- and sex-matched healthy controls (HC) underwent brain 3T RS fMRI. Neuropsychological assessment was performed for all SLE-patients. The main large-scale cognitive and psychiatric functional networks were derived and between-group comparisons and correlations with neuropsychological measures were performed. Compared to HC, SLE-patients exhibited increased RS FC in the right middle cingulate cortex and decreased RS FC in the left precuneus within default-mode network (DMN). They also showed increased RS FC in the left cerebellar crus I and left posterior cingulate cortex, and decreased RS FC in the left angular gyrus within working-memory networks (WMN). Compared to HC, SLE-patients exhibited increased RS FC in the left insular cortex and decreased RS FC in the right anterior cingulate cortex within salience network (SN), as well as decreased RS FC in the right middle frontal gyrus within executive-control network (ECN). Correlation analysis indicated a maladaptive role for left angular gyrus and cerebellar RS FC abnormalities in WMN, affecting memory and executive functions; and for precuneus and insular abnormalities in DMN and SN for psychiatric symptoms. Cingulate cortex modifications within DMN and SN correlated with better memory and global cognitive performance. Significant RS FC alterations in relevant cognitive and psychiatric networks occur in SLE-patients and participate in the pathophysiology of neuropsychiatric symptoms.

Dipeptidyl peptidase 4/CD26 expression in human idiopathic inflammatory myopathies reveals skeletal muscle injury and vascular inflammation.

OBJECTIVES: We performed a retrospective and prospective observational study to investigate whether the T lymphocyte activation antigen dipeptidyl peptidase 4 (DPP4)/CD26 is expressed in the skeletal muscle of patients with idiopathic inflammatory myopathies (IIM) and whether its expression offers clues to understand the events taking place in the tissue. METHODS: CD26 expression in the muscle, evaluated by immunofluorescence, was assessed in 32 patients with IIM and 5 healthy controls and compared among patients with dermatomyositis (DM), immune-mediated necrotising myopathy (IMNM), inclusion body myositis (IBM), and polymyositis (PM). The relationship of CD26 expression and localization with clinical, serological and histological features was determined. RESULTS: CD26 is selectively expressed in the skeletal muscle of patients with IIM. The highest levels of CD26 are found in the skeletal muscle from patients with DM and in particular in those characterized by tissue necrosis and vascular inflammation. CD26 expression is associated with decreased muscle performance and independently predicts the number of treatments before reaching disease stabilization or improvement (odds ratio, OR=1.2, p<0.05). CONCLUSIONS: CD26 is expressed in the IIM skeletal muscle and may represent a target of molecular intervention for patients with treatment-refractory myositis.

Acute Kidney Injury at Hospital Admission for SARS-CoV-2 Infection as a Marker of Poor Prognosis: Clinical Implications for Triage Risk Stratification.

BACKGROUND/AIMS: The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a wide spectrum of effects, including acute kidney injury (AKI) in up to 40% of hospitalized patients. Given the established relationship between AKI and poor prognosis, whether AKI might be a prognostic indicator for patients admitted to the hospital for SARS-CoV-2 infection would allow for a straightforward risk stratification of these patients. METHODS: We analyzed data of 623 patients admitted to San Raffaele Hospital (Milan, IT) between February 25 and April 19, 2020, for laboratory-confirmed SARS-CoV-2 infection. Incidence of AKI at hospital admission was calculated, with AKI defined according to the KDIGO criteria. Multivariable Cox regression models assessed the association between AKI and overall mortality and admission to the intensive care unit (ICU). RESULTS: Overall, 108 (17%) patients had AKI at hospital admission for SARS-CoV-2 infection. After a median follow-up for survivors of 14 days (interquartile range: 8, 23), 123 patients died, while 84 patients were admitted to the ICU. After adjusting for confounders, patients who had AKI at hospital admission were at increased risk of overall mortality compared to those who did not have AKI (hazards ratio [HR]: 2.00; p = 0.0004), whereas we did not find evidence of an association between AKI and ICU admission (HR: 0.95; p = 0.9). CONCLUSIONS: These data suggest that AKI might be an indicator of poor prognosis for patients with SARS-CoV-2 infection, and as such, given its readily availability, it might be used to improve risk stratification at hospital admission.

Long-term consequences of COVID-19 on cognitive functioning up to 6 months after discharge: role of depression and impact on quality of life.

Neurologic and psychiatric symptoms have been reported in the months following the infection with COVID-19. A low-grade inflammation has been associated both with depression and cognitive symptoms, suggesting a link between these disorders. The aim of the study is to investigate cognitive functioning 6 months following hospital discharge for COVID-19, the impact of depression, and the consequences on quality of life. Ninety-two COVID-19 survivors evaluated at 1-month follow-up, 122 evaluated at 3 months and 98 evaluated at 6 months performed neuropsychological and psychiatric evaluations and were compared with a healthy comparison group (HC) of 165 subjects and 165 patients with major depression (MDD). Cognitive performances were adjusted for age, sex, and education. Seventy-nine percent of COVID-19 survivors at 1 month and 75% at 3- and 6-month follow-up showed cognitive impairment in at least one cognitive function. No significant difference in cognitive performances was observed between 1-, 3-, and 6-months follow-up. COVID-19 patients performed worse than HC but better than MDD in psychomotor coordination and speed of information processing. No difference between COVID-19 survivors and MDD was observed for verbal fluency, and executive functions, which were lower than in HC. Finally, COVID-19 survivors performed the same as HC in working memory and verbal memory. The factor that most affected cognitive performance was depressive psychopathology which, in turn, interact with cognitive functions in determining quality of life. Our results confirm that COVID-19 sequelae include signs of cognitive impairment which persist up to 6 months after hospital discharge and affect quality of life.

Residual lung damage following ARDS in COVID-19 ICU survivors.

BACKGROUND: Coronavirus disease 2019 acute respiratory distress syndrome (COVID-19 ARDS) is a disease that often requires invasive ventilation. Little is known about COVID-19 ARDS sequelae. We assessed the mid-term lung status of COVID-19 survivors and investigated factors associated with pulmonary sequelae. METHODS: All adult COVID-19 patients admitted to the intensive care unit from 25th February to 27th April 2020 were included. Lung function was evaluated through chest CT scan and pulmonary function tests (PFT). Logistic regression was used to identify predictors of persisting lung alterations. RESULTS: Forty-nine patients (75%) completed lung assessment. Chest CT scan was performed after a median (interquartile range) time of 97 (89-105) days, whilst PFT after 142 (133-160) days. The median age was 58 (52-65) years and most patients were male (90%). The median duration of mechanical ventilation was 11 (6-16) days. Median tidal volume/ideal body weight (TV/IBW) was 6.8 (5.71-7.67) ml/Kg. 59% and 63% of patients showed radiological and functional lung sequelae, respectively. The diffusion capacity of carbon monoxide (DLCO ) was reduced by 59%, with a median per cent of predicted DLCO of 72.1 (57.9-93.9) %. Mean TV/IBW during invasive ventilation emerged as an independent predictor of persistent CT scan abnormalities, whilst the duration of mechanical ventilation was an independent predictor of both CT and PFT abnormalities. The extension of lung involvement at hospital admission (evaluated through Radiographic Assessment of Lung Edema, RALE score) independently predicted the risk of persistent alterations in PFTs. CONCLUSIONS: Both the extent of lung parenchymal involvement and mechanical ventilation protocols predict morphological and functional lung abnormalities months after COVID-19.

CXCL10 levels at hospital admission predict COVID-19 outcome: hierarchical assessment of 53 putative inflammatory biomarkers in an observational study.

BACKGROUND: Host inflammation contributes to determine whether SARS-CoV-2 infection causes mild or life-threatening disease. Tools are needed for early risk assessment. METHODS: We studied in 111 COVID-19 patients prospectively followed at a single reference Hospital fifty-three potential biomarkers including alarmins, cytokines, adipocytokines and growth factors, humoral innate immune and neuroendocrine molecules and regulators of iron metabolism. Biomarkers at hospital admission together with age, degree of hypoxia, neutrophil to lymphocyte ratio (NLR), lactate dehydrogenase (LDH), C-reactive protein (CRP) and creatinine were analysed within a data-driven approach to classify patients with respect to survival and ICU outcomes. Classification and regression tree (CART) models were used to identify prognostic biomarkers. RESULTS: Among the fifty-three potential biomarkers, the classification tree analysis selected CXCL10 at hospital admission, in combination with NLR and time from onset, as the best predictor of ICU transfer (AUC [95% CI] = 0.8374 [0.6233-0.8435]), while it was selected alone to predict death (AUC [95% CI] = 0.7334 [0.7547-0.9201]). CXCL10 concentration abated in COVID-19 survivors after healing and discharge from the hospital. CONCLUSIONS: CXCL10 results from a data-driven analysis, that accounts for presence of confounding factors, as the most robust predictive biomarker of patient outcome in COVID-19.

Weight trajectories and abdominal adiposity in COVID-19 survivors with overweight/obesity.

BACKGROUND: COVID-19 is associated with unintentional weight loss. Little is known on whether and how patients regain the lost weight. We assessed changes in weight and abdominal adiposity over a three-month follow-up after discharge in COVID-19 survivors. METHODS: In this sub-study of a large prospective observational investigation, we collected data from individuals who had been hospitalized for COVID-19 and re-evaluated at one (V1) and three (V2) months after discharge. Patient characteristics upon admission and anthropometrics, waist circumference and hunger levels assessed during follow-up were analyzed across BMI categories. RESULTS: One-hundred-eighty-five COVID-19 survivors (71% male, median age 62.1 [54.3; 72.1] years, 80% with overweight/obesity) were included. Median BMI did not change from admission to V1 in normal weight subjects (-0.5 [-1.2; 0.6] kg/m2, p = 0.08), but significantly decreased in subjects with overweight (-0.8 [-1.8; 0.3] kg/m2, p < 0.001) or obesity (-1.38 [-3.4; -0.3] kg/m2, p < 0.001; p < 0.05 vs. normal weight or obesity). Median BMI did not change from V1 to V2 in normal weight individuals (+0.26 [-0.34; 1.15] kg/m2, p = 0.12), but significantly increased in subjects with overweight (+0.4 [0.0; 1.0] kg/m2, p < 0.001) or obesity (+0.89 [0.0; 1.6] kg/m2, p < 0.001; p = 0.01 vs. normal weight). Waist circumference significantly increased from V1 to V2 in the whole group (p < 0.001), driven by the groups with overweight or obesity. At multivariable regression analyses, male sex, hunger at V1 and initial weight loss predicted weight gain at V2. CONCLUSIONS: Patients with overweight or obesity hospitalized for COVID-19 exhibit rapid, wide weight fluctuations that may worsen body composition (abdominal adiposity). CLINICALTRIALS. GOV REGISTRATION: NCT04318366.

Quantitative MRI adds to neuropsychiatric lupus diagnostics.

OBJECTIVE: Attributing neuropsychiatric manifestations to SLE is often challenging. Brain white matter lesions are frequent in SLE at MRI, but their diagnostic role is unclear. Here, we assessed whether white matter lesions count, volume and distribution measurement can help in the diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: Brain dual-echo and 3D T1-weighted sequences were acquired from 32 patients with SLE and 32 healthy controls with a 3 T-scanner and employed to derive T2-hyperintense lesion volume (T2LV), number (T2LN) and probability maps (LPM) using a semi-automatic local thresholding segmentation technique. NPSLE was classified as per the ACR nomenclature, the Italian Society for Rheumatology algorithm and by clinical impression. Clinical descriptors including the SLE International Collaborating Clinics/ACR damage index (SDI) were also recorded. RESULTS: Higher T2LV were observed in SLE vs healthy controls (P < 0.001) and in NPSLE vs other SLE (P =0.006). Patients with NPSLE also had higher T2LN (P =0.003) compared with other SLE. In SLE, T2LPM revealed a high prevalence of lesions in the splenium of the corpus callosum, right superior longitudinal fasciculus and right corona radiata. T2LV and T2LN correlated with SLE duration (rho = 0.606; P <0.001 and rho = 0.483; P =0.005, respectively) and age (rho = 0.478; P =0.006 and rho = 0.362; P = 0.042, respectively). T2LV also correlated with SDI (rho = 0.352; P =0.048). SLE patients with fatigue had lower T2LN (P =0.038) compared with patients without fatigue. Thresholds of T2LV ≥ 0.423 cm3 or of T2LN ≥ 12 were associated with definite NPSLE and improved the classification of patients with possible NPSLE per clinical impression. CONCLUSION: Brain white matter lesions (WML) quantitation adds to NPSLE diagnostics.

Persistent psychopathology and neurocognitive impairment in COVID-19 survivors: Effect of inflammatory biomarkers at three-month follow-up.

COVID-19 outbreak is associated with mental health implications during viral infection and at short-term follow-up. Data on psychiatric and cognitive sequelae at medium-term follow-up are still lacking. During an ongoing prospective cohort study, the psychopathological and cognitive status of 226 COVID-19 pneumonia survivors (149 male, mean age 58) were prospectively evaluated one and three months after hospital discharge. Psychiatric clinical interview, self-report questionnaires, and neuropsychological profiling of verbal memory, working memory, psychomotor coordination, executive functions, attention and information processing, and verbal fluency were performed. Three months after discharge from the hospital, 35.8% still self-rated symptoms in the clinical range in at least one psychopathological dimension. We observed persistent depressive symptomatology, while PTSD, anxiety, and insomnia decreased during follow-up. Sex, previous psychiatric history, and the presence of depression at one month affected the depressive symptomatology at three months. Regardless of clinical physical severity, 78% of the sample showed poor performances in at least one cognitive domain, with executive functions and psychomotor coordination being impaired in 50% and 57% of the sample. Baseline systemic immune-inflammation index (SII), which reflects the immune response and systemic inflammation based on peripheral lymphocyte, neutrophil, and platelet counts, predicted self-rated depressive symptomatology and cognitive impairment at three-months follow-up; and changes of SII predicted changes of depression during follow-up. Neurocognitive impairments associated with severity of depressive psychopathology, and processing speed, verbal memory and fluency, and psychomotor coordination were predicted by baseline SII. We hypothesize that COVID-19 could result in prolonged systemic inflammation that predisposes patients to persistent depression and associated neurocognitive dysfunction. The linkage between inflammation, depression, and neurocognition in patients with COVID-19 should be investigated in long-term longitudinal studies, to better personalize treatment options for COVID-19 survivors.

Initial chest radiographs and artificial intelligence (AI) predict clinical outcomes in COVID-19 patients: analysis of 697 Italian patients.

OBJECTIVE: To evaluate whether the initial chest X-ray (CXR) severity assessed by an AI system may have prognostic utility in patients with COVID-19. METHODS: This retrospective single-center study included adult patients presenting to the emergency department (ED) between February 25 and April 9, 2020, with SARS-CoV-2 infection confirmed on real-time reverse transcriptase polymerase chain reaction (RT-PCR). Initial CXRs obtained on ED presentation were evaluated by a deep learning artificial intelligence (AI) system and compared with the Radiographic Assessment of Lung Edema (RALE) score, calculated by two experienced radiologists. Death and critical COVID-19 (admission to intensive care unit (ICU) or deaths occurring before ICU admission) were identified as clinical outcomes. Independent predictors of adverse outcomes were evaluated by multivariate analyses. RESULTS: Six hundred ninety-seven 697 patients were included in the study: 465 males (66.7%), median age of 62 years (IQR 52-75). Multivariate analyses adjusting for demographics and comorbidities showed that an AI system-based score ≥ 30 on the initial CXR was an independent predictor both for mortality (HR 2.60 (95% CI 1.69 - 3.99; p < 0.001)) and critical COVID-19 (HR 3.40 (95% CI 2.35-4.94; p < 0.001)). Other independent predictors were RALE score, older age, male sex, coronary artery disease, COPD, and neurodegenerative disease. CONCLUSION: AI- and radiologist-assessed disease severity scores on CXRs obtained on ED presentation were independent and comparable predictors of adverse outcomes in patients with COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04318366 ( https://clinicaltrials.gov/ct2/show/NCT04318366 ). KEY POINTS: • AI system-based score ≥ 30 and a RALE score ≥ 12 at CXRs performed at ED presentation are independent and comparable predictors of death and/or ICU admission in COVID-19 patients. • Other independent predictors are older age, male sex, coronary artery disease, COPD, and neurodegenerative disease. • The comparable performance of the AI system in relation to a radiologist-assessed score in predicting adverse outcomes may represent a game-changer in resource-constrained settings.

Macrophages Guard Endothelial Lineage by Hindering Endothelial-to-Mesenchymal Transition: Implications for the Pathogenesis of Systemic Sclerosis.

The signals that control endothelial plasticity in inflamed tissues have only been partially characterized. For example, it has been shown that inadequate vasculogenesis in systemic sclerosis (SSc) has been associated with an endothelial defect. We used a genetic lineage tracing model to investigate whether endothelial cells die or change phenotypically after fibrosis induction and whether signals released by cells of the innate immune system and in the blood of patients influence their commitment. We observed that in the lineage-tracing transgenic mice Cdh5-CreERT2::R26R-EYFP, endothelial-derived cells (EdCs) underwent fibrosis after treatment with bleomycin, and EdCs retrieved from the lung showed expression of endothelial-to-mesenchymal transition (EndoMT) markers. Liposome-encapsulated clodronate was used to assess macrophage impact on EdCs. Clodronate treatment affected the number of alternatively activated macrophages in the lung, with upregulated expression of EndoMT markers in lung EdCs. Endothelial fate and function were investigated in vitro upon challenge with serum signals from SSc patients or released by activated macrophages. Sera of SSc patients with anti-Scl70 Abs, at higher risk of visceral organ fibrosis, induced EndoMT and jeopardized endothelial function. In conclusion, EdCs in SSc might be defective because of commitment to a mesenchymal fate, which is sustained by soluble signals in the patient's blood. Macrophages contribute to preserve the endothelial identity of precursor cells. Altered macrophage-dependent plasticity of EdCs could contribute to link vasculopathy with fibrosis.

Epicardial adipose tissue characteristics, obesity and clinical outcomes in COVID-19: A post-hoc analysis of a prospective cohort study.

BACKGROUND AND AIMS: Obesity-related cardiometabolic risk factors associate with COVID-19 severity and outcomes. Epicardial adipose tissue (EAT) is associated with cardiometabolic disturbances, is a source of proinflammatory cytokines and a marker of visceral adiposity. We investigated the relation between EAT characteristics and outcomes in COVID-19 patients. METHODS AND RESULTS: This post-hoc analysis of a large prospective investigation included all adult patients (≥18 years) admitted to San Raffaele University Hospital in Milan, Italy, from February 25th to April 19th, 2020 with confirmed SARS-CoV-2 infection who underwent a chest computed tomography (CT) scan for COVID-19 pneumonia and had anthropometric data available for analyses. EAT volume and attenuation (EAT-At, a marker of EAT inflammation) were measured on CT scan. Primary outcome was critical illness, defined as admission to intensive care unit (ICU), invasive ventilation or death. Cox regression and regression tree analyses were used to assess the relationship between clinical variables, EAT characteristics and critical illness. One-hundred and ninety-two patients were included (median [25th-75th percentile] age 60 years [53-70], 76% men). Co-morbidities included overweight/obesity (70%), arterial hypertension (40%), and diabetes (16%). At multivariable Cox regression analysis, EAT-At (HR 1.12 [1.04-1.21]) independently predicted critical illness, while increasing PaO2/FiO2 was protective (HR 0.996 [95% CI 0.993; 1.00]). CRP, plasma glucose on admission, EAT-At and PaO2/FiO2 identified five risk groups that significantly differed with respect to time to death or admission to ICU (log-rank p < 0.0001). CONCLUSION: Increased EAT attenuation, a marker of EAT inflammation, but not obesity or EAT volume, predicts critical COVID-19. TRIAL REGISTRATION: NCT04318366.

Six-month respiratory outcomes and exercise capacity of COVID-19 acute respiratory failure patients treated with continuous positive airway pressure.

BACKGROUND: COVID-19 long-term sequelae are ill-defined since only a few studies have explored the long-term consequences of this disease so far. AIMS: To evaluate the 6-month respiratory outcome and exercise capacity of COVID-19 acute respiratory failure (ARF) patients treated with continuous positive airway pressure (CPAP) during the first wave of the ongoing COVID-19 pandemic. METHODS: A retrospective observational study included COVID-19 patients with ARF. Interventions included CPAP during hospitalisation and 6-month follow up. Frailty assessment was carried out through frailty index (FI), pO2 /FiO2 during hospitalisation and at follow up, respiratory parameters, 6-min walking test (6MWT) and the modified British Medical Research Council (mMRC) and Borg scale at follow up. RESULTS: More than half of the patients had no dyspnoea according to the mMRC scale. Lower in-hospital pO2 /FiO2 correlated with higher Borg scale levels after 6MWT (ρ 0.27; P 0.04) at the follow-up visit. FI was positively correlated with length of hospitalisation (ρ 0.3; P 0.03) and negatively with the 6MWT distance walked (ρ -0.36; P 0.004). CONCLUSIONS: Robust and frail patients with COVID-19 ARF treated with CPAP outside the intensive care unit setting had good respiratory parameters and exercise capacity at 6-month follow up, although more severe patients had slightly poorer respiratory performance compared with patients with higher PaO2 /FiO2 and lower FI.