Renin-angiotensin system modulation and outcomes in patients hospitalized for interstitial SARS-CoV2 pneumonia: a cohort study.

AIM: The role of cardiovascular (CV) pharmacotherapies in patients with severe COVID-19 pneumonia remains controversial. This study aims to assess the impact of renin-angiotensin system modulation (RASi) (either angiotensin-converting enzymes (ACEIs) or angiotensin-receptor blockers (ARBs)) on COVID-19 outcome. METHODS: We performed a cohort study on consecutive patients admitted for COVID-19 pneumonia at the Internal Medicine Unit of Sant'Orsola-Malpighi Hospital in Bologna, Italy. Patients with a possible alternative cause of respiratory failure other than COVID-19 were excluded. Clinical, pharmacological and laboratory data at admission and during the hospitalization were collected. Patients were treated with intravenous dexamethasone, low molecular weight heparin and nasal flow or Venturi mask oxygen. Subjects were followed until discharge, Intensive Care Unit (ICU) admission or death. Severe cases were defined by acute respiratory distress syndrome (arterial oxygen partial pressure and the fraction of inhaled oxygen ratio (P/F) ≤ 100 mmHg/%, or P/F ≤ 150 mmHg/% and respiratory rate ≥ 26/min). Patients with chronic use of RAS modulation were compared with those without for the composite outcome of in-hospital mortality or ICU admission. Hazard ratios (HR) were obtained by Cox regression, adjusted for several clinical factors. RESULTS: Of the 268 patients enrolled in the study, 93 (35%, mean age 68 ± 13 years, 67% males) were treated with RASi (58% ACEIs and 42% ARBs). There were no meaningful differences between the RASI and no RASI group regarding clinical and laboratory parameters at admission. As expected, patients in the RASi group had a higher prevalence of hypertension, diabetes mellitus, atrial fibrillation, and ischemic heart disease. One hundred eight patients (40%) were admitted to ICU during hospitalization due to severe respiratory failure, and 24 (9%) died. The risk of in-hospital death or ICU admission was lower in the RASI group than in the non-RASI group (age and sex-adjusted HR 0.57, 95% CI 0.37-0.8), even after adjustment for several comorbidities (fully adjusted HR 0.44, 95% CI 0.26-0.74). Seven (7.5%) patients died in the RASi group vs 17 (9.7%) in the non-RASi group, leading to a non-statistically significant mortality risk reduction (fully adjusted HR 0.69, 95% CI 0.18-1.90). The lower risk in the RASi group was primarily related to ARBs use compared to ACEIs (HR 0.5, 95% CI 0.28-0.92 and HR 0.82, 95% CI 0.51-1.32, respectively). CONCLUSIONS: Our study showed an inverse association between the chronic use of RASi and COVID-19 pneumonia severity (either ICU admissions or in-hospital death), even when significant comorbidities are considered.

Heart Team for Left Atrial Appendage Occlusion: A Patient-Tailored Approach.

BACKGROUND AND PURPOSE: Left atrial appendage occlusion (LAAO) is an accepted therapeutic option for stroke prevention; however, the ideal technique and device have not yet been identified. In this study we evaluate the potential role of a heart team approach for patients contraindicated for oral anticoagulants and indicated for left atrial appendage closure, to minimize risk and optimize benefit in a patient-centered decision-making process. METHODS: Forty patients were evaluated by the heart team for appendage occlusion. Variables considered were CHA2DS2VASc, HASBLED, documented blood transfusions, comorbidities, event forcing anticoagulant interruption, past medical history, anatomy of the left atrial appendage, and patient quality of life. Twenty patients had their appendage occluded percutaneously (65% male, mean age 72.3 ± 7.5, mean CHA2DS2VASc 4.2 ± 1.5, mean HASBLED 3.5 ± 1.1). The other twenty underwent thoracoscopic occlusion (65% male, mean age of 74.9 ± 8, mean CHA2DS2VASc 6.0 ± 1.5, HASBLED mean 5.4 ± 1.4). Percutaneous patients were on dual antiplatelet therapy for the first three months and aspirin thereafter, whereas the others received no anticoagulant/antiplatelet therapy from the day of surgery. Follow up included TEE, CT scan, and periodical clinical evaluation. RESULTS: Mean duration of procedures and hospital stay were comparable. All patients had complete exclusion of the appendage; at a mean follow up of 33.1 ± 14.1 months, no neurological or hemorrhagic events were reported. CONCLUSIONS: A heart team approach may improve the decision-making process for stroke and hemorrhage prevention, where LAAO is a therapeutic option. Percutaneous and thoracoscopic appendage occlusion seem to be comparably safe and effective. An epicardial LAAO could be advisable in patients for whom the risk of bleeding is estimated as being too high for post-procedural antiplatelet therapy.

Myositis and myasthenia during nivolumab administration for advanced lung cancer: a case report and review of the literature.

The immunotherapy significantly improved survival of non-small cell lung cancer patients, but it may cause immune-related adverse events, which are severe in less than 10% of cases. We report the case of one patient who developed myositis and myasthenia during nivolumab treatment for metastatic lung squamous carcinoma. Moreover, we reviewed literature data in order to identify similar cases in cancer patients treated with immune-checkpoints inhibitors. A 65-year-old patient, who had previously received a first-line platinum-based therapy, developed diplopia and ptosis 4 weeks after the start of nivolumab. Although antibodies associated with myositis, myasthenia gravis and paraneoplastic syndromes were absent, immune-related myositis and myasthenia were diagnosed. Corticosteroids, immunoglobulin and pyridostigmine showed poor efficacy and the patient died 7 weeks after the appearance of the first symptoms. Fifteen similar cases were found in the literature. A close collaboration between different specialists is essential to rapidly identify and treat severe immune-related adverse events.

A model based on intensity of medical care may improve outcomes for internal medicine patients in Italy.

BACKGROUND: In medical wards, to guarantee safe, sustainable and effective treatments to heterogeneous and complex patients, care should be graduated into different levels of clinical intensity based on a standardised assessment of acute-illness severity. To support this assumption, we conducted a prospective observational study on all unselected admissions of 3,381 patients to a medium size internal Italian Medicine Unit by comparing Standard Medical Care model (SMC) to a new paradigm of patient admission based on Intensity of Medical Care (IMC). METHODS: The SMC operated during 2013, while an IMC organizational model started in 2014. In SMC, patient's admission was performed according to bed availability only. In IMC, after the stratification of clinical instability performed using the National Early Warning Score (NEWS) and clinical judgment, patients were allocated to three different ward areas (high, middle, and post-acute medical care). We compared clinical and organizational outcomes of IMC patients (2015) to SMC patients (2013), performing adjusted logistic regression model. RESULTS: We managed 1,609 and 1,772 patients using SMC and IMC, respectively. The IMC seemed to be associated to a lower risk of clinical worsening for patients. Comparing IMC to SMC, the odds ratio (aOR) for urgent transfers to intensive care units was 0.69 (p = 0.03), and for combination of urgent transfers and early deaths was 0.68 (p<0.01). CONCLUSIONS: Redesigning the configuration of internal medicine ward to support urgency and competency of the clinical response by applying IMC paradigm based on the NEWS, improved outcomes in patients with acute illness and enhanced ward performances.

Endothelial cells' activation and apoptosis induced by a subset of antibodies against human cytomegalovirus: relevance to the pathogenesis of atherosclerosis.

BACKGROUND: Human cytomegalovirus (hCMV) is involved in the pathogenesis of atherosclerosis. We have previously shown in patients with atherosclerosis that antibodies directed against the hCMV-derived proteins US28 and UL122 are able to induce endothelial cell damage and apoptosis of non-stressed endothelial cells through cross-rection with normally expressed surface molecules. Our aim was to dissect the molecular basis of such interaction and to investigate mechanisms linking innate immunity to atherosclerosis. METHODOLOGY/PRINCIPAL FINDINGS: We analysed the gene expression profiles in endothelial cells stimulated with antibodies affinity-purified against either the UL122 or the US28 peptides using the microarray technology. Microarray results were validated by quantitative PCR and by detection of proteins in the medium. Supernatant of endothelial cells incubated with antibodies was analysed also for the presence of Heat Shock Protein (HSP)60 and was used to assess stimulation of Toll-Like Receptor-4 (TLR4). Antibodies against UL122 and US28 induced the expression of genes encoding for adhesion molecules, chemokines, growth factors and molecules involved in the apoptotis process together with other genes known to be involved in the initiation and progression of the atherosclerotic process. HSP60 was released in the medium of cells incubated with anti-US28 antibodies and was able to engage TLR4. CONCLUSIONS/SIGNIFICANCE: Antibodies directed against hCMV modulate the expression of genes coding for molecules involved in activation and apoptosis of endothelial cells, processes known to play a pivotal role in the pathogenesis of atherosclerosis. Moreover, endothelial cells exposed to such antibodies express HSP60 on the cell surface and release HSP60 in the medium able to activate TLR4. These data confirm that antibodies directed against hCMV-derived proteins US28 and UL122 purified from patients with coronary artery disease induce endothelial cell damage and support the hypothesis that hCMV infection may play a crucial role in mediating the atherosclerotic process.

Dermatomyositis complicated with Kaposi sarcoma: a case report.

We describe the case of a 75-year-old Italian woman affected by dermatomyositis (DM) treated with steroid, high-dose intravenous immunoglobulins (IVIgs) and cyclophosphamide (CPX), taken orally. After a few months, the patient presented multiple red vascular skin lesions diagnosed as Kaposi sarcoma (KS). Steroid was furtherly reduced, and CPX was stopped. We put the patient on chemotherapy with intravenous infusion of vinblastine and vincristine on alternate weeks obtaining the remission of KS. DM is well controlled by a low-dosage steroid and high-dose IVIgs.

Serologic and molecular detection of human Parvovirus B19 infection.

Following its identification by Yvonne Cossart in 1975, human Parvovirus B19 has been recognized as the causative agent of a wide range of diseases. In childhood, the most common disease is a typical exanthema called "fifth disease". In adults, viral infection may be responsible for fetal loss and for aplastic anaemia in immuno-compromised patients. Because persistent viral infection may induce an autoimmune response, Parvovirus B19 is emerging as an environmental factor linked to the pathogenesis of autoimmunity. As a result of its expanding disease spectrum, Parvovirus B19 is the subject of intense efforts to clarify the pathogenesis of virus-related disorders as well as improve diagnostic laboratory testing including standardization of serological and nucleic acid-based detection assays. Enzymatic immunoassays based on conformational antigens have proven to be the most important tools for accurate diagnosis in the majority of cases. In other selected clinical cases, the detection of Parvovirus B19 infection can be complemented by PCR and, more recently, by the real-time PCR.

Antibodies against human cytomegalovirus in the pathogenesis of systemic sclerosis: a gene array approach.

BACKGROUND: Systemic sclerosis is an autoimmune disease characterized by immunological abnormalities, vascular damage, and fibroblast proliferation. We have previously shown that a molecular mimicry mechanism links antibodies against the human-cytomegalovirus-derived protein UL94 to the pathogenesis of systemic sclerosis. The UL94 epitope shows homology with NAG-2, a surface molecule highly expressed on endothelial cells. Anti-UL94 peptide antibodies purified from patients' sera induce apoptosis of endothelial cells upon engagement of the NAG-2-integrin complex. METHODS AND FINDINGS: We show here that NAG-2 is expressed on dermal fibroblasts and that anti-UL94 antibodies bind to fibroblasts. We have used the gene array strategy (Affimetrix oligonucleotide microarrays) to analyze the transcriptional profile in response to a 4-h and an 8-h treatment with antibodies against the UL94 peptide in endothelial cells and dermal fibroblasts. Exposure of endothelial cells to anti-UL94 antibodies had a profound impact on gene expression, resulting in the upregulation of 1,645 transcripts. Several gene clusters were upregulated including genes encoding adhesion molecules, chemokines, colony-stimulating factors (CSFs), growth factors, and molecules involved in apoptosis. Following antibody stimulation, dermal fibroblasts showed an upregulation of 989 transcripts and acquired a "scleroderma-like" phenotype. Indeed, genes involved in extracellular matrix deposition, growth factors, chemokines, and cytokines were upregulated. We confirmed the microarray results by real-time quantitative polymerase chain reaction and by measuring some of the corresponding proteins with ELISA and Western blotting. CONCLUSION: Our results show that anti-human-cytomegalovirus antibodies may be linked to the pathogenesis of systemic sclerosis not only by inducing endothelial cell activation and apoptosis but also by causing activation of fibroblasts, one of the hallmarks of the disease.

Identification of tear lipocalin as a novel autoantigen target in Sjögren's syndrome.

Sjögren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration and tissue damage mainly confined to the salivary and lacrimal glands, resulting in dryness of mouth and eyes. Since different epithelial cells of exocrine and non-exocrine tissues are primarily affected, an autoimmune reaction against antigens commonly expressed in epithelial cells is believed to play a pathogenic role. To identify novel autoantigen targets associated with the systemic involvement in SS, we screened a random peptide library with pooled IgG immunoglobulins derived from patients with primary SS. Among the identified peptides, one was recognized by the majority of patients' sera, but not by sera of normal donors and of patients with other autoimmune diseases. The peptide showed homology with an Epstein-Barr Virus (EBV) derived protein and with tear lipocalin, a protein highly expressed in tears and saliva, and with alpha-fodrin, a cytoskeleton protein considered an important autoantigen target in SS. Anti-peptide antibodies affinity purified from patients' sera recognize the viral protein, tear lipocalin and alpha-fodrin. Our findings suggest that EBV infection may be linked to the pathogenesis of SS and that tear lipocalin can be considered a novel and yet unidentified autoantigen in SS.

[HLA-DRB1 alleles and rheumatoid arthritis in northern Italy: lack of correlation with disease severity and extra-articular manifestations]. / Alleli HLA-DRB1 e artrite reumatoide nel nord Italia: assenza di correlazione con la gravità della malattia e con manifestazioni extra-articolari.

We studied HLA-DRB1 alleles in 101 patients with rheumatoid arthritis (RA) and 229 normal subjects by polymerase chain reaction and sequence-specific oligonuclotide hybridization. We observed a statistically significant association between HLA-DR4 and RA (p = 0,0088). This association was not observed for the DR1 status. No particular DR4 suballeles were preferentially expressed in patients. Allele *0102 was more frequent in RA patients (p = 0.0084), while *0103 in controls (p = 0.000047). No difference was observed for the presence of early erosions and extra-articular features in patients with no, one or two RA associated alleles and among share epitope positive and negative patients.

Reactive arthritis following BCG immunotherapy for bladder carcinoma.

Intravesical instillation of bacillus Calmette-Guérin (BCG) is used in the treatment of patients with intermediate and high-risk superficial bladder carcinoma with efficacy and safety. The vast majority of patients do not present any side effects and only 5% of patients have mild and short-lived clinical manifestations such as malaise, low-grade fever, cystitis, and hematuria. Arthralgia and/or arthritis is one of the rare severe complications following intravesical BCG immunotherapy. We report here the case of a patient with reactive arthritis successfully treated with nonsteroidal anti-inflammatory drugs (NSAIDs) after the discontinuation of BCG immunotherapy.

The presence of parvovirus B19 VP and NS1 genes in the synovium is not correlated with rheumatoid arthritis.

OBJECTIVE: To amplify both NS1 and VP genes of Parvovirus B19 DNA in synovial membrane (SM) and serum obtained from patients with rheumatoid arthritis (RA) and to analyze whether the presence of viral DNA is correlated with synovitis. METHODS: DNA obtained from 30 SM and 24 serum samples from RA patients was analyzed using single round-polymerase chain reaction (PCR) and nested PCR for both VP and NS1 genes of parvovirus B19. Twenty-four SM and serum samples from sex and age matched subjects with osteoarthritis (OA) or joint trauma served as controls. RESULTS: The first round PCR was negative for NS1 in RA samples. After nested PCR, NS1 was detected in the SM of 6/30 patients and of 10/24 controls and in the serum of 4/24 patients and controls. Nested PCR for the VP gene detected viral DNA in the SM of 7/30 patients with RA and of 7/24 of the controls and in the serum of 5/24 patients and of 2/24 controls. Altogether parvovirus DNA was found in the SM of 11/30 (36.6%) patients and of 12/24 (50%) controls and in the serum of 8/24 (33.3%) patients with RA and of 5/24 (20.8%) controls. CONCLUSION: Our results suggest that the amplification by nested PCR of both NS1 and VP genes is necessary to define the presence of viral DNA in tissue samples and confirm that the presence of parvovirus B19 DNA is similar in RA and control SM, suggesting that simple detection of viral DNA is not sufficient to confirm a link between the virus and RA.