The longitudinal characterization of immune responses in COVID-19 patients reveals novel prognostic signatures for disease severity, patients' survival and long COVID.

Introduction: SARS-CoV-2 pandemic still poses a significant burden on global health and economy, especially for symptoms persisting beyond the acute disease. COVID-19 manifests with various degrees of severity and the identification of early biomarkers capable of stratifying patient based on risk of progression could allow tailored treatments. Methods: We longitudinally analyzed 67 patients, classified according to a WHO ordinal scale as having Mild, Moderate, or Severe COVID-19. Peripheral blood samples were prospectively collected at hospital admission and during a 6-month follow-up after discharge. Several subsets and markers of the innate and adaptive immunity were monitored as putative factors associated with COVID-19 symptoms. Results: More than 50 immunological parameters were associated with disease severity. A decision tree including the main clinical, laboratory, and biological variables at admission identified low NK-cell precursors and CD14+CD91+ monocytes, and high CD8+ Effector Memory T cell frequencies as the most robust immunological correlates of COVID-19 severity and reduced survival. Moreover, low regulatory B-cell frequency at one month was associated with the susceptibility to develop long COVID at six months, likely due to their immunomodulatory ability. Discussion: These results highlight the profound perturbation of the immune response during COVID-19. The evaluation of specific innate and adaptive immune-cell subsets allows to distinguish between different acute and persistent COVID-19 symptoms.

Inflammatory Markers Predict Blood Neurofilament Light Chain Levels in Acute COVID-19 Patients.

Acute coronavirus disease 2019 (COVID-19) is paralleled by a rise in the peripheral levels of neurofilament light chain (NfL), suggesting early nervous system damage. In a cohort of 103 COVID-19 patients, we studied the relationship between the NfL and peripheral inflammatory markers. We found that the NfL levels are significantly predicted by a panel of circulating cytokines/chemokines, including CRP, IL-4, IL-8, IL-9, Eotaxin, and MIP-1ß, which are highly up-regulated during COVID-19 and are associated with clinical outcomes. Our findings show that peripheral cytokines influence the plasma levels of the NfL, suggesting a potential role of the NfL as a marker of neuronal damage associated with COVID-19 inflammation.

Sarcopenic obesity and pre-sarcopenia contribute to frailty in community-dwelling Italian older people: data from the FRASNET study.

BACKGROUND: The ageing process is characterized by a change of body composition with an increase of fat mass and a reduction of muscle mass. Above a certain threshold these alterations configure a condition named sarcopenic obesity (SO). SO is associated with physical frailty in Asian and Brazilian populations. SO impacts on physical frailty in other ethnic groups but its influence on general frailty which is multidimensional and includes cognitive, social and physical factors, remain insufficiently explored in the Italian population. METHODS: Frailty was measured in community dwelling Italian older adults enrolled in the FRASNET study with the frailty index (FI). The FI quantifies frailty as the ratio of the number of present health deficits to the total number of health deficits considered. Regression analyses were performed to assess the association between body composition categories and frailty. Classification and regression tree models were run to evaluate the frailty predictors. RESULTS: One Thousand One Hundred Fourteen participants of the FRASNET study were included in the present analysis. The sample was composed for the 60.5% by females and its median age was 72 years. The median FI score was 0.11 (IQR 0.07-0.20); 234 individuals (21%) were frail (FI ≥ 0.25). SO (B 0.074, 95% C.I. 0.05-0.1, p < 0.001) and pre-sarcopenia (without obesity B 0.03, 95% C.I, 0.007-0.044, p < 0.001, with obesity B 0.11, 95% C.I. 0.05-0.16, p < 0.001) were associated with frailty. Fat mass percentage predicted frailty in people aged 65-70 years whereas, muscle strength predicted general frailty in people aged 70-81 years. CONCLUSION: Pre-sarcopenia and SO represent potentially treatable predictors of frailty.

Preferential and sustained platelet activation in COVID-19 survivors with mental disorders.

Pre-existing mental disorders are considered a risk factor for severe COVID-19 outcomes, possibly because of higher vascular burden. Moreover, an unconventional platelet activation characterizes COVID-19 and contributes to inflammatory and thrombotic manifestations. In the light of the inflammation theory of mental disorders, we hypothesized that patients with mental disorders could be sensitive to the SARS-CoV-2 elicited platelet activation. We investigated platelet activation in 141 COVID-19 survivors at one month after clearance of the virus, comparing subjects with or without an established pre-existing diagnosis of mental disorder according to the DSM-5. We found that platelets from patients with a positive history of psychiatric disorder underwent unconventional activation more frequently than conventional activation or no activation at all. Such preferential activation was not detected when platelets from patients without a previous psychiatric diagnosis were studied. When testing the effects of age, sex, and psychiatric history on the platelet activation, GLZM multivariate analysis confirmed the significant effect of diagnosis only. These findings suggest a preferential platelet activation during acute COVID-19 in patients with a pre-existing psychiatric disorder, mediated by mechanisms associated with thromboinflammation. This event could have contributed to the higher risk of severe outcome in the psychiatric 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.

Post-COVID Trajectory of Pentraxin 3 Plasma Levels Over 6 Months and Their Association with the Risk of Developing Post-Acute Depression and Anxiety.

BACKGROUND AND OBJECTIVES: Clinical manifestations of coronavirus disease 2019 (COVID-19) often persist after acute disease resolution. Underlying molecular mechanisms are unclear. The objective of this original article was to longitudinally measure plasma levels of markers of the innate immune response to investigate whether they associate with and predict post-COVID symptomatology. METHODS: Adult patients with previous severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection during the first pandemic wave who underwent the 6-month multidisciplinary follow-up were included. Plasma levels of pentraxin 3 (PTX3), the complement components C3a and C5a, and chitinase-3 like-protein-1 (CHI3L1) were measured at hospital admission during acute disease (baseline) and at 1 and 6 months after hospital discharge. Associations with post-COVID-19 sequelae at 6 months were investigated using descriptive statistic and multiple regression models. RESULTS: Ninety-four COVID-19 patients were included. Baseline PTX3, C5a, C3a, and CHI3L1 did not predict post-COVID-19 sequelae. The extent of the reduction of PTX3 over time (delta PTX3) was associated with lower depressive and anxiety symptoms at 6 months (both p < 0.05). When entering sex, age, need for intensive care unit or non-invasive ventilation during hospital stay, psychiatric history, and baseline PTX3 as nuisance covariates into a generalized linear model (GLM), the difference between baseline and 6-month PTX3 levels (delta PTX3) significantly predicted depression (χ2 = 4.66, p = 0.031) and anxiety (χ2 = 4.68, p = 0.031) at 6 months. No differences in PTX3 levels or PTX3 delta were found in patients with or without persistent or new-onset other COVID-19 symptoms or signs at 6 months. Plasma levels of C3a, C5a, and CHI3L1 did not correlate with PTX3 levels at either time point and failed to associate with residual or de novo respiratory or systemic clinical manifestations of the disease at 6 months. CONCLUSIONS: A lower reduction of plasma PTX3 after acute COVID-19 associates with the presence of depression and anxiety, suggesting an involvement of inflammation in post-COVID-19 psychopathology and a potential role of PTX3 as a biomarker.

Universal screening for early detection of chronic autoimmune, metabolic and cardiovascular diseases in the general population using capillary blood (UNISCREEN): low-risk interventional, single-centre, pilot study protocol.

INTRODUCTION: Chronic autoimmune (type 1 diabetes and coeliac disease) and metabolic/cardiovascular (type 2 diabetes, dyslipidaemia, hypertension) diseases are highly prevalent across all age ranges representing a major public health burden. Universal screening for prediction/early identification of these conditions is a potential tool for reducing their impact on the general population. The aim of this study is to assess whether universal screening using capillary blood sampling is feasible at a population-based level. METHODS AND ANALYSIS: This is a low-risk interventional, single-centre, pilot study for a population-based screening programme denominated UNISCREEN. Participants are volunteers aged 1-100 who reside in the town of Cantalupo (Milan, Italy) undergoing: (1) interview collecting demographics, anthropometrics and medical history; (2) capillary blood collection for measurement of type 1 diabetes and coeliac disease-specific autoantibodies and immediate measurement of glucose, glycated haemoglobin and lipid panel by point-of-care devices; (3) venous blood sampling to confirm autoantibody-positivity; (4) blood pressure measurement; (5) fulfilment of a feasibility and acceptability questionnaire. The outcomes are the assessment of feasibility and acceptability of capillary blood screening, the prevalence of presymptomatic type 1 diabetes and undiagnosed coeliac disease, distribution of glucose categories, lipid panel and estimate of cardiovascular risk in the study population. With approximately 3000 inhabitants, the screened population is expected to encompass at least half of its size, approaching nearly 1500 individuals. ETHICS AND DISSEMINATION: This protocol and the informed consent forms have been reviewed and approved by the San Raffaele Hospital Ethics Committee (approval number: 131/INT/2022). Written informed consent is obtained from all study participants or their parents if aged <18. Results will be published in scientific journals and presented at meetings. CONCLUSIONS: If proven feasible and acceptable, this universal screening model would pave the way for larger-scale programmes, providing an opportunity for the implementation of innovative public health programmes in the general population. TRIAL REGISTRATION NUMBER: NCT05841719.

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.

Micronized/ultramicronized palmitoylethanolamide improves depression and fatigue in coronavirus disease 2019 (COVID-19) survivors.

Coronavirus disease 2019 (COVID-19) may lead to neuropsychiatric sequelae. Palmitoylethanolamide (PEA) is an anti-inflammatory and neuroprotective amide used in depressive syndromes. Here we investigate whether micronized/ultramicronized (m/um) PEA improves neuropsychiatric sequelae in COVID-19 survivors. Patients evaluated at our post-COVID-19 outpatient clinic between February and August 2021 and presenting neuropsychiatric manifestations (n = 98) were offered treatment with m/umPEA 600 mg twice daily for 3 months. Those accepting m/umPEA therapy (n = 57) were compared with those who did not (n = 41), in terms of depression, fatigue, chronic pain and subjective well-being, through validated scales administered pre- and posttreatment. The two groups did not differ in terms of demographics, comorbidities, psychiatric history, antidepressant therapy, acute COVID-19 severity and baseline neuropsychiatric status. Patients receiving m/umPEA showed a greater improvement in depression and fatigue (both P < 0.05). Conversely, no association was found with changes in chronic pain or subjective well-being. At multivariable logistic regression, m/umPEA predicted neuropsychiatric improvement independently of age, sex and baseline neuropsychiatric status. Worse pretreatment fatigue and subjective well-being identified those who most likely benefited from treatment. In conclusion, despite its retrospective nature, our study suggests that m/umPEA may improve depression and fatigue in COVID-19 survivors, justifying future research in this setting.

Exploring the Association between Delirium and Malnutrition in COVID-19 Survivors: A Geriatric Perspective.

Older individuals face an elevated risk of developing geriatric syndromes when confronted with acute stressors like COVID-19. We assessed the connection between in-hospital delirium, malnutrition, and frailty in a cohort of COVID-19 survivors. Patients aged ≥65, hospitalized in a tertiary hospital in Milan for SARS-CoV-2 pneumonia, were enrolled and screened for in-hospital delirium with the 4 'A's Test (4AT) performed twice daily (morning and evening) during hospital stay. Malnutrition was assessed with the malnutrition universal screening tool (MUST) at hospital admission and with the mini-nutritional assessment short-form (MNA-SF) one month after hospital discharge. Frailty was computed with the frailty index one month after hospital discharge. Fifty patients (median age 78.5, 56% male) were enrolled. At hospital admission, 10% were malnourished. The 13 patients (26%) who developed delirium were frailer (7 vs. 4), experienced a higher in-hospital mortality (5 vs. 3), and were more malnourished one month after discharge (3 of the 4 patients with delirium vs. 6 of the 28 patients without delirium who presented at follow up). The 4AT scores correlated with the MNA-SF scores (r = -0.55, p = 0.006) and frailty (r = 0.35, p = 0.001). Frailty also correlated with MUST (r = 0.3, p = 0.04), MNA-SF (r = -0.42, p = 0.02), and hospitalization length (r = 0.44, p = 0.001). Delirium, malnutrition, and frailty are correlated in COVID-19 survivors. Screening for these geriatric syndromes should be incorporated in routine clinical practice.

Longitudinal Changes in Physical Function and Their Impact on Health Outcomes in COVID-19 Patients.

BACKGROUND: Coronavirus disease (COVID-19) is correlated with a variety of long-term sequelae that affect different aspects of health, including physical function. This study investigated the longitudinal changes in handgrip strength (HGS) over six months post-hospital discharge in COVID-19 patients and explores the associations between HGS, health-related quality of life, dyspnoea, exercise capacity, and body mass index (BMI). METHODS: Adult COVID-19 patients were followed up at one, three, and six months after hospital discharge. HGS, BMI, exercise capacity, and health-related quality of life were assessed. Data from patients with HGS measurements at all three time points were analysed. RESULTS: Low HGS was prevalent one month post-discharge (35%). Participants with low HGS exhibited more severe disease (30.5% vs. 5.9% were admitted to the intensive care unit, p < 0.01), longer hospital stays (median [IQR] 21 [10.0; 40.5] vs. 12.0 [8.0; 20.0] days, p < 0.01), greater weight loss (-5.7 [-9.1; -0.6] vs. -3.2 [-5.7; -0.0] kg, p = 0.004), and reduced exercise capacity (6 min walking test [6 MWT], 95.7 [84.0; 102.0] vs. 100.0 [92.9; 105.0]% predicted, p = 0.007). Those with persistently low HGS (40% of the initial low HGS group) had worse exercise capacity (6-MWT 93.3 [78.3; 101.0] vs. 101.0 [95.0; 107.0]% predicted, p < 0.001), more dyspnoea (29.0% vs. 2.0% of participants, p < 0.001), poorer quality of life (visual analogue scale score, 75 [50; 75] vs. 85 [75; 95], p < 0.001), and higher rates of problems in various health dimensions. HGS at 1 month was the only significant predictor of HGS improvement from 1 month to 6 months (odds ratio [95% CI] 1.11 [1.03; 1.20], p = 0.008). CONCLUSIONS: This study highlights the prevalence of reduced physical function among COVID-19 survivors and emphasises the importance of early identification and intervention to optimise their long-term health. Monitoring HGS, a simple and reliable tool, can provide valuable insights into patients' overall physical function, aiding in tailored care and improved outcomes.

Biomarkers of aging in frailty and age-associated disorders: State of the art and future perspective.

According to the Geroscience concept that organismal aging and age-associated diseases share the same basic molecular mechanisms, the identification of biomarkers of age that can efficiently classify people as biologically older (or younger) than their chronological (i.e. calendar) age is becoming of paramount importance. These people will be in fact at higher (or lower) risk for many different age-associated diseases, including cardiovascular diseases, neurodegeneration, cancer, etc. In turn, patients suffering from these diseases are biologically older than healthy age-matched individuals. Many biomarkers that correlate with age have been described so far. The aim of the present review is to discuss the usefulness of some of these biomarkers (especially soluble, circulating ones) in order to identify frail patients, possibly before the appearance of clinical symptoms, as well as patients at risk for age-associated diseases. An overview of selected biomarkers will be discussed in this regard, in particular we will focus on biomarkers related to metabolic stress response, inflammation, and cell death (in particular in neurodegeneration), all phenomena connected to inflammaging (chronic, low-grade, age-associated inflammation). In the second part of the review, next-generation markers such as extracellular vesicles and their cargos, epigenetic markers and gut microbiota composition, will be discussed. Since recent progresses in omics techniques have allowed an exponential increase in the production of laboratory data also in the field of biomarkers of age, making it difficult to extract biological meaning from the huge mass of available data, Artificial Intelligence (AI) approaches will be discussed as an increasingly important strategy for extracting knowledge from raw data and providing practitioners with actionable information to treat patients.

Prognostic performance of blood neurofilament light chain protein in hospitalized COVID-19 patients without major central nervous system manifestations: an individual participant data meta-analysis.

BACKGROUND AND AIMS: To investigate the prognostic value of blood neurofilament light chain protein (NfL) levels in the acute phase of coronavirus disease 2019 (COVID-19). METHODS: We conducted an individual participant data (IPD) meta-analysis after screening on MEDLINE and Scopus to May 23rd 2022. We included studies with hospitalized adult COVID-19 patients without major COVID-19-associated central nervous system (CNS) manifestations and with a measurement of blood NfL in the acute phase as well as data regarding at least one clinical outcome including intensive care unit (ICU) admission, need of mechanical ventilation (MV) and death. We derived the age-adjusted measures NfL Z scores and conducted mixed-effects modelling to test associations between NfL Z scores and other variables, encompassing clinical outcomes. Summary receiver operating characteristic curves (SROCs) were used to calculate the area under the curve (AUC) for blood NfL. RESULTS: We identified 382 records, of which 7 studies were included with a total of 669 hospitalized COVID-19 cases (mean age 66.2 ± 15.0 years, 68.1% males). Median NfL Z score at admission was elevated compared to the age-corrected reference population (2.37, IQR: 1.13-3.06, referring to 99th percentile in healthy controls). NfL Z scores were significantly associated with disease duration and severity. Higher NfL Z scores were associated with a higher likelihood of ICU admission, need of MV, and death. SROCs revealed AUCs of 0.74, 0.80 and 0.71 for mortality, need of MV and ICU admission, respectively. CONCLUSIONS: Blood NfL levels were elevated in the acute phase of COVID-19 patients without major CNS manifestations and associated with clinical severity and poor outcome. The marker might ameliorate the performance of prognostic multivariable algorithms in COVID-19.

Profiling Covid-19 patients with respect to level of severity: an integrated statistical approach.

A full understanding of the characteristics of Covid-19 patients with a better chance of experiencing poor vital outcomes is critical for implementing accurate and precise treatments. In this paper, two different advanced data-driven statistical approaches along with standard statistical methods have been implemented to identify groups of patients most at-risk for death or severity of respiratory distress. First, the tree-based analysis allowed to identify profiles of patients with different risk of in-hospital death (by Survival Tree-ST analysis) and severity of respiratory distress (by Classification and Regression Tree-CART analysis), and to unravel the role on risk stratification of highly dependent covariates (i.e., demographic characteristics, admission values and comorbidities). The ST analysis identified as the most at-risk group for in-hospital death the patients with age > 65 years, creatinine [Formula: see text] 1.2 mg/dL, CRP [Formula: see text] 25 mg/L and anti-hypertensive treatment. Based on the CART analysis, the subgroups most at-risk of severity of respiratory distress were defined by patients with creatinine level [Formula: see text] 1.2 mg/dL. Furthermore, to investigate the multivariate dependence structure among the demographic characteristics, the admission values, the comorbidities and the severity of respiratory distress, the Bayesian Network analysis was applied. This analysis confirmed the influence of creatinine and CRP on the severity of respiratory distress.

A longitudinal analysis of humoral, T cellular response and influencing factors in a cohort of healthcare workers: Implications for personalized SARS-CoV-2 vaccination strategies.

Introduction: SARS-CoV-2 mRNA vaccinations elicit both virus-specific humoral and T-cell responses, but a complex interplay of different influencing factors, such as natural immunity, gender, and age, guarantees host protection. The present study aims to assess the immune dynamics of humoral, T-cell response, and influencing factors to stratify individual immunization status up to 10 months after Comirnaty-vaccine administration. Methods: To this aim, we longitudinally evaluated the magnitude and kinetics of both humoral and T-cell responses by serological tests and enzyme-linked immunospot assay at 5 time points. Furthermore, we compared the course over time of the two branches of adaptive immunity to establish an eventual correlation between adaptive responses. Lastly, we evaluated putative influencing factors collected by an anonymized survey administered to all participants through multiparametric analysis. Among 984 healthcare workers evaluated for humoral immunity, 107 individuals were further analyzed to describe SARS-CoV-2-specific T-cell responses. Participants were divided into 4 age groups: <40 and ≥40 years for men, <48 and ≥48 years for women. Furthermore, results were segregated according to SARS-CoV-2-specific serostatus at baseline. Results: The disaggregated evaluation of humoral responses highlighted antibody levels decreased in older subjects. The humoral responses were higher in females than in males (p=0.002) and previously virus-exposed subjects compared to naïve subjects (p<0.001). The vaccination induced a robust SARS-CoV-2 specific T-cell response at early time points in seronegative subjects compared to baseline levels (p<0.0001). However, a contraction was observed 6 months after vaccination in this group (p<0.01). On the other hand, the pre-existing specific T-cell response detected in natural seropositive individuals was longer-lasting than the response of the seronegative subjects, decreasing only 10 months after vaccination. Our data suggest that T-cell reactiveness is poorly impacted by sex and age. Of note, SARS-CoV-2-specific T-cell response was not correlated to the humoral response at any time point. Discussion: These findings suggest prospects for rescheduling vaccination strategies by considering individual immunization status, personal characteristics, and the appropriate laboratory tests to portray immunity against SARS-CoV-2 accurately. Deepening our knowledge about T and B cell dynamics might optimize the decision-making process in vaccination campaigns, tailoring it to each specific immune response.

Physical and psychological sequelae at three months after acute illness in COVID-19 survivors.

BACKGROUND: Coronavirus disease 2019 (COVID-19) may leave behind an altered health status early after recovery. We evaluated the clinical status of COVID-19 survivors at three months after hospital discharge. METHODS: In this prospective observational cohort study, hospitalized patients aged ≥18 years, evaluated at one (M1) and three (M3) months post-discharge were enrolled. 251 patients (71.3% males, median [IQR] age 61.8 [53.5-70.7] years) were included. Median (IQR) time from discharge to M3 was 89 (79.5-101) days. Primary outcome was residual respiratory dysfunction (RRD), defined by tachypnea, moderate to very severe dyspnea, or peripheral oxygen saturation ≤95% on room air at M3. RESULTS: RRD was found in 30.4% of patients, with no significant difference compared with M1. Chronic obstructive pulmonary disease and length of stay were independent predictors of RRD at multivariable logistic regression (OR [95% CI]: 4.13 [1.17-16.88], P=0.033; OR [95% CI]: 1.02 [1.00-1.04], P=0.047, respectively). Obesity and C-reactive protein levels upon admission were additional predictors at regression tree analysis. Impaired quality of life (QoL) was reported by 53.2% of patients. Anxiety and insomnia were each present in 25.5% of patients, and PTSD in 22.4%. No difference was found between M1 and M3 in QoL, anxiety or PTSD. Insomnia decreased at M3. Current major psychiatric disorder as well as anxiety, insomnia and PSTD at M1 independently predicted PTSD at M3. CONCLUSIONS: Clinical damage may persist at three months after discharge in COVID-19 survivors. Post-recovery follow-up is an essential component of patient management.

Treating unexplained recurrent pregnancy loss based on lessons learned from obstetric antiphospholipid syndrome and inherited thrombophilia: A propensity-score adjusted retrospective study.

The efficacy of low molecular weight heparin (LMWH) is well-established in patients with obstetric antiphospholipid syndrome (O-APS). Their role in women with unexplained recurrent pregnancy loss (U-RPL) and late obstetrical complications (intrauterine growth restriction, IUGR and preeclampsia) is controversial. Here we compared rates of miscarriage and late obstetrical complications in RPL patients diagnosed with O-APS (n = 57) or hereditary thrombophilia (n = 25) (both assuming LMWH from the beginning of pregnancy) and in patients with a history of U-RPL (n = 118), assuming or not LMWH, followed at the 'Pregnancy at risk' and 'Recurrent pregnancy loss' outpatient clinics at the San Raffaele Hospital from April 2010 to April 2020. Patients with systemic autoimmune diseases other than primary O-APS were excluded. We tested for bivariate or multivariate associations among adverse pregnancy outcomes, the presence of thrombophilia and LMWH use by using chi-square test, Anova, propensity score adjusted univariate logistic regression and multivariate analysis as appropriate. U-RPL patients assuming LMWH from the beginning of pregnancy (group A) had a significantly lower rate of miscarriage compared to U-RPL patients who were not treated with LMWH (group B) (13 % vs. 41 % respectively, p 0.001) and similar pregnancy rates compared to both O-APS patients with a history of RPL taking LMWH (group C, 18 %) and RPL patients with thrombophilia and treated with LMWH (group D, 16 %). Our data highlight a protective effect of LMWH on miscarriage in patients with a history of U-RPL. In these patients, LMWH seems as effective as in O-APS and hereditary thrombophilia in reducing RPL.