SARS-CoV-2 infection risk is higher in vaccinated patients with inflammatory autoimmune diseases or liver transplantation treated with mycophenolate due to an impaired antiviral immune response: results of the extended follow up of the RIVALSA prospective cohort.

Background: A relevant proportion of immunocompromised patients did not reach a detectable seroconversion after a full primary vaccination cycle against SARS-CoV-2. The effect of different immunosuppressants and the potential risks for SARS-CoV-2 infection in these subjects is largely unknown. Methods: Patients from the Rivalsa prospective, observational cohort study with planned anti SARS-CoV-2 third dose mRNA vaccination between October and December 2021 were asked to participate to this follow-up study. Patients were asked about eventual confirmed positivity to SARS-CoV-2 infection within 6 months from the third dose and to undergo a blood draw to evaluate seroconversion status after the additional vaccine shot. Results: 19 out of 114 patients taking part in the survey developed a confirmed SARS-CoV-2 infection; we identified mycophenolate treatment as an independent predictor of an increased risk of infection even after the third vaccine dose (OR: 5.20, 95% CI: 1.70-20.00, p=0.0053). This result is in agreement with the in vitro evidence that MMF impairs both B and T lymphocytes driven immune responses (reduction both in memory B cells producing anti-spike antibodies and in proliferating CD4+ and CD8+ T cells). Conclusions: Immunocompromised patients need an additional vaccine administration to reach a detectable seroconversion, thus fostering a more personalized approach to their clinical management. Moreover, patients undergoing mycophenolate treatment show a specific increased infection risk, with respect to other immunosuppressants thus supporting a closer monitoring of their health status.

Effect of Lactoferrin on Clinical Outcomes of Hospitalized Patients with COVID-19: The LAC Randomized Clinical Trial.

As lactoferrin is a nutritional supplement with proven antiviral and immunomodulatory abilities, it may be used to improve the clinical course of COVID-19. The clinical efficacy and safety of bovine lactoferrin were evaluated in the LAC randomized double-blind placebo-controlled trial. A total of 218 hospitalized adult patients with moderate-to-severe COVID-19 were randomized to receive 800 mg/die oral bovine lactoferrin (n = 113) or placebo (n = 105), both given in combination with standard COVID-19 therapy. No differences in lactoferrin vs. placebo were observed in the primary outcomes: the proportion of death or intensive care unit admission (risk ratio of 1.06 (95% CI 0.63-1.79)) or proportion of discharge or National Early Warning Score 2 (NEWS2) ≤ 2 within 14 days from enrollment (RR of 0.85 (95% CI 0.70-1.04)). Lactoferrin showed an excellent safety and tolerability profile. Even though bovine lactoferrin is safe and tolerable, our results do not support its use in hospitalized patients with moderate-to-severe COVID-19.

Baseline Plasma Osteopontin Protein Elevation Predicts Adverse Outcomes in Hospitalized COVID-19 Patients.

More than three years have passed since the first case, and COVID-19 is still a health concern, with several open issues such as the lack of reliable predictors of a patient's outcome. Osteopontin (OPN) is involved in inflammatory response to infection and in thrombosis driven by chronic inflammation, thus being a potential biomarker for COVID-19. The aim of the study was to evaluate OPN for predicting negative (death or need of ICU admission) or positive (discharge and/or clinical resolution within the first 14 days of hospitalization) outcome. We enrolled 133 hospitalized, moderate-to-severe COVID-19 patients in a prospective observational study between January and May 2021. Circulating OPN levels were measured by ELISA at admission and at day 7. The results showed a significant correlation between higher plasma concentrations of OPN at hospital admission and a worsening clinical condition. At multivariate analysis, after correction for demographic (age and gender) and variables of disease severity (NEWS2 and PiO2/FiO2), OPN measured at baseline predicted an adverse prognosis with an odds ratio of 1.01 (C.I. 1.0-1.01). At ROC curve analysis, baseline OPN levels higher than 437 ng/mL predicted a severe disease evolution with 53% sensitivity and 83% specificity (area under the curve 0.649, p = 0.011, likelihood ratio of 1.76, (95% confidence interval (CI): 1.35-2.28)). Our data show that OPN levels determined at the admission to hospital wards might represent a promising biomarker for early stratification of patients' COVID-19 severity. Taken together, these results highlight the involvement of OPN in COVID-19 evolution, especially in dysregulated immune response conditions, and the possible use of OPN measurements as a prognostic tool in COVID-19.

CGRP Plasma Levels Correlate with the Clinical Evolution and Prognosis of Hospitalized Acute COVID-19 Patients.

SARS-CoV-2 is the etiological agent of COVID-19, an extremely heterogenous disease that can cause severe respiratory failure and critical illness. To date, reliable biomarkers allowing for early patient stratification according to disease severity are still lacking. Calcitonin gene-related peptide (CGRP) is a vasoactive neuropeptide involved in lung pathophysiology and immune modulation and is poorly investigated in the COVID-19 context. In this observational, prospective cohort study, we investigated the correlation between CGRP and clinical disease evolution in hospitalized moderate to severe COVID-19 patients. Between January and May 2021 (Italian third pandemic wave), 135 consecutive SARS-CoV-2 patients were diagnosed as being eligible for the study. Plasma CGRP level evaluation and routine laboratory tests were performed on blood samples collected at baseline and after 7 days of hospitalization. At baseline, the majority our patients had a moderate to severe clinical presentation, and higher plasma CGRP levels predicted a higher risk of in-hospital negative evolution (odds-ratio OR 2.84 [IQR 1.07-7.51]) and were correlated with pulmonary intravascular coagulopathy (OR 2.92 [IQR 1.19-7.17]). Finally, plasma CGRP levels were also correlated with plasma IP10 levels. Our data support a possible crosstalk between the lung and the neuroimmune axis, highlighting a crucial role for plasma CGRP in sustaining COVID-19-related hyperinflammation.

Ongoing Mycophenolate Treatment Impairs Anti-SARS-CoV-2 Vaccination Response in Patients Affected by Chronic Inflammatory Autoimmune Diseases or Liver Transplantation Recipients: Results of the RIVALSA Prospective Cohort.

Vaccines are the most effective means to prevent the potentially deadly effects of SARS-CoV-2 infection, but not all vaccinated individuals gain the same degree of protection. Patients undergoing chronic immunosuppressive therapy due to autoimmune diseases or liver transplants, for example, may show impaired anti-SARS-CoV-2 antibody response after vaccination. We performed a prospective observational study with parallel arms, aiming to (a) evaluate seroconversion after anti-SARS-CoV-2 mRNA vaccine administration in different subgroups of patients receiving immunosuppressive treatment for rheumatological or autoimmune diseases or to prevent organ rejection after liver transplantation and (b) identify negative predictors of IgG anti-SARS-CoV-2 development. Out of 437 eligible patients, 183 individuals were enrolled at the Rheumatology and Hepatology Tertiary Units of "Maggiore della Carità" University Hospital in Novara: of those, 52 were healthy subjects, while among the remaining 131 patients, 30 had a diagnosis of spondyloarthritis, 25 had autoimmune hepatitis, 10 were liver transplantation recipients, 23 suffered from connective tissue diseases (including 10 cases that overlapped with other diseases), 40 were treated for rheumatoid arthritis, and 5 had vasculitis. Moreover, all patients were receiving chronic immunosuppressive therapy. The immunogenicity of mRNA COVID-19 vaccines was evaluated by measuring IgG anti-SARS-CoV-2 antibody titers before vaccination and after 10, 30, and 90 days since the first dose administration. Of the selected cohort of patients, 24.0% did not develop any detectable anti-SARS-CoV-2 IgG after a complete mRNA-based two doses primary vaccination cycle. At univariate analysis, independent predictors of an absent antibody response to vaccine were a history of liver transplantation (OR 11.5, 95% CI 2.5−53.7, p = 0.0018), the presence of a comorbid active neoplasia (OR 26.4, 95% CI 2.8−252.4, p = 0.0045), and an ongoing immunosuppressive treatment with mycophenolate (MMF) (OR 14.0, 95% CI 3.6−54.9, p = 0.0002) or with calcineurin inhibitors (OR 17.5, 95% CI 3.1−99.0, p = 0.0012). At multivariate analysis, only treatment with MMF (OR 24.8, 95% CI 5.9−103.2, p < 0.0001) and active neoplasia (OR 33.2, 95% CI 5.4−204.1, p = 0.0002) were independent predictors of seroconversion failure. These findings suggest that MMF dose reduction or suspension may be required to optimize vaccine response in these patients.

Baseline plasma SARS-CoV-2 RNA detection predicts an adverse COVID-19 evolution in moderate to severe hospitalized patients.

BACKGROUND: SARS-CoV-2 is a single-stranded RNA virus, known to be the causative agent of COVID-19. As the resulting disease shows a very heterogeneous range of clinical manifestations, the identification of early biomarkers allowing patients stratification according to the expected disease severity is still an unmet clinical need. METHODS: In this observational prospective cohort study, 137 consecutive patients, testing positive for SARS-CoV-2 infection by nasopharyngeal swab RT-PCR or antigenic test, were enrolled to evaluate their plasma viral load at the time of hospitalization. RESULTS: Even if all of them had a molecular diagnosis of COVID-19, only 29 patients showed a detectable plasma SARS-CoV-2 RNAemia. Such viremic patients also showed other clinical and laboratory finding alterations (increased troponin I, IL-6, RDW-CV, and creatinine levels along with decreased platelet count and glomerular filtration rate). A plasma detectable RNA viral load predicted in hospital death or ICU admission with an odds ratio of 3.53 (CI: 1.44-8.64, P=0.0058), while the lack of a detectable viral load was associated with a faster recovery, with an odds ratio of 4.06 (CI: 1.72-9.59, P=0.0014). These findings were confirmed in multivariate models including age, sex and baseline National Early Warning Score 2 and arterial oxygen tension over inspired oxygen fraction ratio. CONCLUSIONS: Our data thus suggest that plasma viral RNA load at the time of hospital admission could represent a useful independent biomarker allowing early patients' stratification according to the expected disease evolution, and driving clinical decisions tailored on the specific needs of the individual patient.

Baseline Plasma Gas6 Protein Elevation Predicts Adverse Outcomes in Hospitalized COVID-19 Patients.

Reliable biomarkers allowing early patients' stratification for the risk of adverse outcomes in COVID-19 are lacking. Gas6, together with its tyrosine kinase receptors named TAM, is involved in the regulation of immune homeostasis, fibrosis, and thrombosis. Our aim was to evaluate whether Gas6, sAxl, and sMerTK could represent early predictors of disease evolution either towards a negative (death or need of ICU admission) or a positive (discharge and/or clinical resolution within the first 14 days of hospitalization) outcome. To this purpose, between January and May 2021 (corresponding to third pandemic wave in Italy), 139 consecutive SARS-CoV-2 positive patients were enrolled in a prospective observational study. Plasma levels of these molecules were measured by ELISA at the time of hospitalization and after 7 and 14 days. We observed that higher plasma Gas6 concentrations at hospital admission were associated with a worsening in clinical conditions while lower sMerTK concentrations at baseline and after 7 days of hospitalization were associated with a more favorable outcome. At multivariate analysis, after correction for demographic and COVID-19 severity variables (NEWS2 and PiO2/FiO2), only Gas6 measured at baseline predicted an adverse prognosis with an odds ratio of 1.03 (C.I. 1.01-10.5). At ROC curve analysis, baseline Gas6 levels higher than 58.0 ng/ml predicted a severe disease evolution with 53.3% sensitivity and 77.6% specificity (area under the curve 0.653, p = 0.01, likelihood ratio of 2.38, IQR: 1.46-3.87). Taken together, these results support the hypothesis that a dysregulation in the Gas6/TAM axis could play a relevant role in modulating the course of COVID-19 and suggest that plasma Gas6 may represent a promising prognostic laboratory parameter for this condition.

Prognostic Markers in Hospitalized COVID-19 Patients: The Role of IP-10 and C-Reactive Protein.

BACKGROUND: SARS-CoV-2 is responsible for COVID-19, a clinically heterogeneous disease, ranging from being completely asymptomatic to life-threating manifestations. An unmet clinical need is the identification at disease onset or during its course of reliable biomarkers allowing patients' stratification according to disease severity. In this observational prospective cohort study, patients' immunologic and laboratory signatures were analyzed to identify independent predictors of unfavorable (either death or intensive care unit admission need) or favorable (discharge and/or clinical resolution within the first 14 days of hospitalization) outcome. METHODS: Between January and May 2021 (third wave of the pandemic), we enrolled 139 consecutive SARS-CoV-2 positive patients hospitalized in Northern Italy to study their immunological and laboratory signatures. Multiplex cytokine, chemokine, and growth factor analysis, along with routine laboratory tests, were performed at baseline and after 7 days of hospital stay. RESULTS: According to their baseline characteristics, the majority of our patients experienced a moderate to severe illness. At multivariate analysis, the only independent predictors of disease evolution were the serum concentrations of IP-10 (at baseline) and of C-reactive protein (CRP) after 7 days of hospitalization. Receiver-operating characteristic (ROC) curve analysis confirmed that baseline IP - 10 > 4271 pg/mL and CRP > 2.3 mg/dL at 7 days predict a worsening in clinical conditions (87% sensitivity, 66% specificity, area under the curve (AUC) 0.772, p < 0.001 and 83% sensitivity, 73% specificity, AUC 0.826, p < 0.001, respectively). CONCLUSIONS: According to our results, baseline IP-10 and CRP after 7 days of hospitalization could be useful in driving clinical decisions tailored to the expected disease trajectory in hospitalized COVID-19 patients.

Respiratory and Psychophysical Sequelae Among Patients With COVID-19 Four Months After Hospital Discharge.

Importance: Although plenty of data exist regarding clinical manifestations, course, case fatality rate, and risk factors associated with mortality in severe coronavirus disease 2019 (COVID-19), long-term respiratory and functional sequelae in survivors of COVID-19 are unknown. Objective: To evaluate the prevalence of lung function anomalies, exercise function impairment, and psychological sequelae among patients hospitalized for COVID-19, 4 months after discharge. Design, Setting, and Participants: This prospective cohort study at an academic hospital in Northern Italy was conducted among a consecutive series of patients aged 18 years and older (or their caregivers) who had received a confirmed diagnosis of severe acute respiratory coronavirus 2 (SARS-CoV-2) infection severe enough to require hospital admission from March 1 to June 29, 2020. SARS-CoV-2 infection was confirmed via reverse transcription-polymerase chain reaction testing, bronchial swab, serological testing, or suggestive computed tomography results. Exposure: Severe COVID-19 requiring hospitalization. Main Outcomes and Measures: The primary outcome of the study was to describe the proportion of patients with a diffusing lung capacity for carbon monoxide (Dlco) less than 80% of expected value. Secondary outcomes included proportion of patients with severe lung function impairment (defined as Dlco <60% expected value); proportion of patients with posttraumatic stress symptoms (measured using the Impact of Event Scale-Revised total score); proportion of patients with functional impairment (assessed using the Short Physical Performance Battery [SPPB] score and 2-minute walking test); and identification of factors associated with Dlco reduction and psychological or functional sequelae. Results: Among 767 patients hospitalized for severe COVID-19, 494 (64.4%) refused to participate, and 35 (4.6%) died during follow-up. A total of 238 patients (31.0%) (median [interquartile range] age, 61 [50-71] years; 142 [59.7%] men; median [interquartile range] comorbidities, 2 [1-3]) consented to participate to the study. Of these, 219 patients were able to complete both pulmonary function tests and Dlco measurement. Dlco was reduced to less than 80% of the estimated value in 113 patients (51.6%) and less than 60% in 34 patients (15.5%). The SPPB score was suggested limited mobility (score <11) in 53 patients (22.3%). Patients with SPPB scores within reference range underwent a 2-minute walk test, which was outside reference ranges of expected performance for age and sex in 75 patients (40.5%); thus, a total of 128 patients (53.8%) had functional impairment. Posttraumatic stress symptoms were reported in a total of 41 patients (17.2%). Conclusions and Relevance: These findings suggest that at 4 months after discharge, respiratory, physical, and psychological sequelae were common among patients who had been hospitalized for COVID-19.

Radiotherapy in COVID-19 patient affected by multiple myeloma: a case report.

In COVID-19 pandemic, cancer patients may be vulnerable for their immunological status and need of immunosuppressive anti-neoplastic treatments. Choosing the best treatment option in COVID-19 positive cancer patients is still a challenging issue. We report the case of a 62-year-old woman diagnosed with multiple myeloma and affected by COVID-19. After the diagnosis of multiple myeloma in January 2019, the patient underwent first line therapy followed by bone marrow autologous stem cell transplantation, achieving a complete response in September 2019. In March 2020, the patient showed intrathoracic progression of the disease, resulting in a severe dysphagia and concomitant positivity to SARS-CoV-2 swab test, cough, fever, and dyspnea related to the involvement of the lung parenchyma as shown by CT-scan. After her admittance to a COVID-19 dedicated inward, she was administered oral hydroxychloroquine and darunavir-cobicistat for 7 days with stabilization of her general clinical conditions. For the worsening of dysphagia, after multidisciplinary discussion, it was decided to deliver radiotherapy to the mediastinal and paravertebral mass with 8 Gy single fraction. After 5 days, her clinical conditions improved, with reduction of dysphagia. The CT confirmed a partial response with reduction of the mass of about 50%. Viral clearance was confirmed by triple negative search for SARS-CoV-2 on nasopharyngeal swabs, one month after first documentation of positivity. Unfortunately, the patient died three months later due to a pulmonary mycotic infection causing respiratory failure. To our knowledge, this case report describes the first experience of mediastinal radiotherapy in a COVID-19 patient affected by myeloma reported in the literature. In case of clinical indication, even in presence of SARS-CoV-2 infection, radiotherapy can be safely delivered and might be considered a treatment option as shown by our experience in this challenging case of intrathoracic myeloma.

A 28-Year-Old Woman with Ascites and Multiple Focal Spleen Lesions.

Serous effusions complicating the course of lymphomas occur commonly in the pleural space but seldom in the peritoneum, where they most often present as chylous ascites with diagnostic cytology. Almost invariably, in these rare cases, the serum to ascites albumin gradient is low. We describe a 28-year-old woman with anasarca, ascites and a serum to ascites albumin gradient of 1.1 g/dl, consistent with portal hypertension. No tumour cells were detected in the ascitic fluid. However, a CT scan of the chest and abdomen disclosed liver and spleen enlargement and multiple enlarged retroperitoneal lymph nodes, suspicious for a lymphoproliferative disorder. Bone marrow aspiration and biopsy were not diagnostic, so a decision was made to proceed with a splenectomy despite the onset of low-grade disseminated intravascular coagulation. Surgery was uneventful. Diffuse large B cell lymphoma was diagnosed. A liver biopsy taken at the time of surgery demonstrated that the liver parenchyma was massively infiltrated by reactive T lymphocytes surrounding rare large CD20+ tumour cells. This infiltrate had likely led to increased portal pressure attended by ascites formation, which resolved completely after chemotherapy. The case emphasizes the rewards of pursuing a diagnosis supported by a high prior probability even in the presence of apparently discordant laboratory findings, as well as the importance of performing a diagnostic splenectomy in case of splenomegaly with unexplained focal lesions. LEARNING POINTS: Lymphomas may present with serous effusion, which is usually chylous and with positive cytology when represented by ascites accumulation; non-chylous effusions can be due to altered lymphatic drainage, extrinsic compression of the portal vein by enlarged lymph nodes as well as massive infiltration of the liver by lymphoma.If the cause of splenomegaly is unclear, diagnostic splenectomy remains a viable option.The diagnosis of lymphoma should always be pursued, even if it requires apparently unwise surgery, since this type of cancer can be treated effectively only if thoroughly characterized pathologically and molecularly.

First reported human case of meningitis by Staphylococcus condimenti.

Staphylococcus condimenti (S. condimenti) is a coagulase-negative bacterium, generally regarded as not pathogenic. Indeed, S. condimenti owes its name to having been isolated from starter cultures of fermented sausage, as well as from fish and soy sauces. To the best of our knowledge, only two cases of human infection caused by this bacterium have been reported. Here, we present a case of meningitis by S. condimenti in a 65-year-old woman who was brought to hospital after having been found unconscious at home. At her arrival, she had a Glasgow coma scale = 3, fever, and hypoxic-normocapnic respiratory failure. Examination of her cerebrospinal fluid showed a slightly increased white blood cell count, normal glucose and protein concentrations. Paired cultures on blood and liquor samples yielded S. condimenti. Targeted antibiotic treatment with ceftriaxone led to a complete recovery. This unique case expands our knowledge on S. condimenti as a pathogenic bacterium.

Defective interhemispheric inhibition in drug-treated focal epilepsies.

BACKGROUND: Focal epilepsies (FEs) arise from a lateralized network, while in generalized epilepsies (GEs) there is a bilateral involvement from the outset. Intuitively, the corpus callosum is the anatomical substrate for interhemispheric spread. OBJECTIVE: We used transcranial magnetic stimulation (TMS) to explore whether there are any physiological differences in the corpus callosum of drug-treated patients with FE and those with genetic GE (GGE), compared to healthy subjects (HS). METHODS: TMS was used to measure the interhemispheric inhibition (IHI) from right-to-left primary motor cortex (M1) and viceversa in 16 patients with FE, 17 patients with GGE and 17 HS. A conditioning stimulus (CS) was given to one M1 10 and 50 ms before a test stimulus delivered to the contralateral M1. Motor evoked potentials (MEPs) were analysed both as a function of the side of stimulation and of the epileptic focus (left-right). RESULTS: In HS, IHI was reproducible with suppression of MEPs at ISIs of 10 and 50 ms. Similar effects occurred in GGE patients. FE patients behaved differently, since IHI was significantly reduced bilaterally. When FE patients were stratified according to the side of their epileptic focus, the long-ISI IHI (=50 ms) appeared to be defective only when the CS was applied over the "focal" hemisphere. CONCLUSIONS: FE patients had a defective inhibitory response of contralateral M1 to inputs travelling from the "focal" hemisphere that was residual to the drug action. Whilst IHI changes would not be crucial for the GGE pathophysiology, they may represent one key factor for the contralateral spread of focal discharges, and seizure generalization.