Assessing Humoral Immuno-Inflammatory Pathways Associated with Respiratory Failure in COVID-19 Patients.

All severe cases of SARS-CoV-2 infections are characterized by a high risk of disease progression towards ARDS, leading to a bad outcome. Respiratory symptoms in COVID-19 patients often do not correspond to disease's worsening. In our sample, median age was 74 years (72-75) and 54% were men. The median period of hospitalization was 9 days. Firstly, we observed a significant asynchronous trend of neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) in 764 selected among 963 patients, who were consecutively recruited in two hospitals (Cannizzaro, S. Marco) in Catania, Italy. NLR values in deceased patients showed an increase from baseline over time. By contrast, CRP tended to fall from baseline to median day of hospitalization in all three subgroups, but steeply increased at the end of hospitalization only in ICU-admitted patients. Then, we evaluated the relationships between NLR and CRP as continuous variables with PaO2/FiO2 ratio (P/F). NLR was an independent predictor of mortality (HR: 1.77, p < 0.0001), while ICU admission was more significantly associated with CRP (HR: 1.70, p < 0.0001). Finally, age, neutrophils, CRP, and lymphocytes are significantly and directly linked to P/F, while the influence of inflammation on P/F, reflected by CRP, was also mediated by neutrophils.

Sclerosing cholangitis may mimic radiological pattern of cholangiocarcinoma: Differential diagnosis and review of literature.

IgG4 related sclerosing cholangitis (IgG4-SC) is a chronic cholestatic autoimmune liver disease, characterized by obstruction of the biliary tract due to IgG4-positive plasma cell infiltrations associated with fibrosis, phlebitis and presence of eosinophils. The diagnosis of the disease is supported by elevation in serum IgG4, radiological imaging and histology. In most of the cases IgG4-SC is associated with a wide spectrum of symptoms and manifestations summarized by the definition of IgG4-related disease (IgG4-RD). When the IgG4-SC causes an interruption of the biliary tract, differential diagnosis with cholangiocarcinoma may become challenging, due to the anatomical difficulty to get an appropriate histological pattern of the disease. Here we are describing a case of a male patient admitted to our hospital for jaundice. The stenosis of biliary ducts shown by radiologic imaging suggested Cholangiocarcinoma but, in the patient, IgG4-SC was definitely diagnosed.

Neutrophil-to-Lymphocyte Ratio (NLR) Is a Promising Predictor of Mortality and Admission to Intensive Care Unit of COVID-19 Patients.

The neutrophil-to-lymphocyte ratio (NLR) is an inflammatory marker predicting the prognosis of several diseases. We aimed to assess its role as a predictor of mortality or admission to the intensive care unit in COVID-19 patients. We retrospectively evaluated a cohort of 411 patients with COVID-19 infection. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP) of patients with COVID-19 were compared. The median age of our sample was 72 years (interquartile range: 70−75); 237 were males. Hypertension, diabetes and ischemic heart disease were the most common comorbidities. The study population was subdivided into three groups according to NLR tertiles. Third-tertile patients were older, showing significantly higher levels of inflammatory markers; 133 patients (32%) died during hospitalization, 81 of whom belonged to the third tertile; 79 patients (19%) were admitted to ICU. NLR showed the largest area under the curve (0.772), with the highest specificity (71.9%) and sensitivity (72.9%), whereas CRP showed lower sensitivity (60.2%) but slightly higher specificity (72.3%). Comparisons between NLR and CRP ROC curves were significantly different (p = 0.0173). Cox regression models showed that the association between NLR and death was not weakened after adjustment for confounders. Comparisons of ROC curves showed no significant differences between NLR, PLR, and CRP. Cox regression analysis showed that NLR predicted the risk of admission to ICU independently of demographic characteristics and comorbidities (HR: 3.9597, p < 0.0001). These findings provide evidence that NLR is an independent predictor of mortality and a worse outcome in COVID-19 patients and may help identify high-risk individuals with COVID-19 infection at admission.

Neutrophil to Lymphocyte Ratio: An Emerging Marker of the Relationships between the Immune System and Diseases.

Over the last 10 years, the evaluation of the neutrophil-to-lymphocyte ratio (NLR) as an emerging marker of diseases has become a compelling field of bio-medical research. Although a precise and unique cut-off value has not been yet found, its role as a flag of immune system homeostasis is well established. NLR has a well-known prognostic value and independently correlates with mortality in the general population and in several specific subsets of disease (sepsis, pneumonia, COVID-19, cancer, etc.). Moreover, NLR was recently considered as part of the decision-making processes concerning the admission/recovery of patients with COVID-19 pneumonia. This review aims to provide an overview of the main use of this biomarker, focusing on the pathophysiology and the molecular basis underlying its central role as a reliable mirror of inflammatory status and adaptive immunity.

Stroke and Hypertension: An Appraisal from Pathophysiology to Clinical Practice.

Stroke as a cause of long-term disability is a growing public health burden. Therefore, focusing on prevention is important. The most prominent aim of this strategy is to treat modifiable risk factors, such as arterial hypertension, the leading modifiable contributor to stroke. Thus, efforts to adequately reduce Blood Pressure (BP) among hypertensives are mandatory. In this respect, although safety and benefits of BP control related to long-term outcome have been largely demonstrated, there are open questions that remain to be addressed, such as optimal timing to initiate BP reduction and BP goals to be targeted. Moreover, evidence on antihypertensive treatment during the acute phase of stroke or BP management in specific categories (i.e. patients with carotid stenosis and post-acute stroke) remain controversial. This review provides a critical update on the current knowledge concerning BP management and stroke pathophysiology in patients who are either at risk for stroke or who experienced stroke.

Management of hypertension in the elderly: Looking for a trade-off between cardiovascular prevention and serious adverse events.

Despite the effectiveness of anti-hypertensive therapy is well recognized, the most adequate target to achieve in the management of hypertension in the elderly is still under debate. Indeed, looking at the balance between benefits and risks, accumulating evidence has recently specifically addressed this issue, focusing on controversies. Evidence surrounding a more aggressive treatment may lead to a turnaround in the clinical care of older adult hypertensives, but a balanced trade-off between benefits and risks needs to be programmed and achieved, particularly in this clinical setting. We argue whether and how the results from recent trials could influence the management of hypertension in older people.

Neutrophil-To-Lymphocyte Ratio: An Emerging Marker Predicting Prognosis in Elderly Adults with Community-Acquired Pneumonia.

OBJECTIVES: To explore the performance of the neutrophil-to-lymphocyte ratio (NLR), an index of systemic inflammation that predicts prognosis of several diseases, in a cohort of elderly adults with community-acquired pneumonia (CAP). DESIGN: Prospective clinical study from January 2014 to July 2016. SETTING: Unit of Internal Medicine, University of Catania, Catania, Italy. PARTICIPANTS: Elderly adults admitted for CAP (N = 195). MEASUREMENTS: Clinical diagnosis of CAP was defined as the presence of a new infiltrate on plain chest radiography or chest computed tomography associated with one or more suggestive clinical features such as dyspnea, hypo- or hyperthermia, cough, sputum production, tachypnea (respiration rate >20 breaths per minute), altered breath sounds on physical examination, hypoxemia (partial pressure of oxygen <60 mmHg), leukocytosis (white blood cell count >10,000/µL). Clinical examination, traditional tests such as Pneumonia Severity Index (PSI); Confusion, Urea, Respiratory rate, Blood pressure, aged 65 and older (CURB-65), and NLR were evaluated at admission. The accuracy and predictive value for 30-day mortality of traditional scores and NLR were compared. RESULTS: NLR predicted 30-day mortality (P < .001) and performed better than PSI (P < .05), CURB-65, C-reactive protein, and white blood cell count (P < .001) to predict prognosis. No deaths occurred in participants with a NLR of less than 11.12. Thirty-day mortality was 30% in those with a NLR between 11.12% and 13.4% and 50% in those with a NLR between 13.4 and 28.3. All participants with a NLR greater than 28.3 died within 30 days. CONCLUSIONS: These results would encourage early discharge of individuals with a NLR of less than 11.12, short-term in-hospital care for those with a NLR between 11.12 and 13.4, middle-term hospitalization for those with a NLR between 13.4 and 28.3, and admission to a respiratory intensive care unit for those with a NLR greater than 28.3.

Endocrine Tumors Causing Arterial Hypertension: Pathophysiological Mechanisms and Clinical Implications.

Some tumors are a relatively rare and amendable cause of hypertension, often associated with a higher cardiovascular morbidity and mortality, as compared with that of both general population and patients with essential hypertension. This worse prognosis is not entirely related to blood pressure increase, because the release of substances from the tumor can directly influence blood pressure behavior. Diagnostic approach is challenging and needs a deep knowledge of the different neuro-hormonal and genetic mechanisms determining blood pressure increase. Surgical tumor removal can, but not always, cause blood pressure normalization, depending on how early was tumor detection, since a long-standing history of hypertension is often associated with a much weaker effect on blood pressure. Moreover, target organ damage can be affected by the substances themselves released by the tumors as well as by tumor removal. In this review we consider the phenotype and genetic features of patients with tumor-induced hypertension and focus on their diagnostic work-up.

Mean Transaortic Gradient is an Emerging Predictor of Chronic Kidney Disease in Elderly Patients.

Arterial hypertension (AH) is a major risk factor for chronic kidney disease (CKD). However, whether AH maintains this role in the development of CKD in elderly patients with aortic stenosis (AS) or whether transaortic gradient influences CKD remains unclear. Consecutive hospitalized patients were prospectively recruited to evaluate the relationship between AS and CKD. In all patients, transthoracic 2-dimensional echocardiography was performed to evaluate AS; renal function was evaluated using the Chronic Kidney Disease Epidemiology Collaboration formula. A total of 346 patients were included in the study (mean age: 79.5 ± 7.4 years): 104 had diabetes mellitus (DM), 298 had AH, and 59 (moderate: 52; severe: 7) showed AS. After multivariate analysis, age ( P <.01), DM ( P = .02), and mean transaortic gradient ( P = .03), but not AH, were independent predictors of CKD. Both in the presence (n = 59) or absence (n = 287) of AS, the estimated glomerular filtration rate did not differ in patients with (51 ± 24 mL/min/1.73 m2 and 59 ± 25 mL/min/1.73 m2, respectively) and those without AH (50 ± 21 mL/min/1.73 m2 and 65 ± 24 mL/min/1.73 m2, respectively). In the whole population, for each mm Hg of mean transaortic gradient, the risk of CKD increased by 2.5 times.

Impact of left ventricular remodeling and renal function on 24h-ECG recordings and cardiovascular outcome in elderly hypertensive patients.

BACKGROUND: The prognostic role of left ventricular remodeling and renal function in elderly hypertensive patients has been so far scarcely investigated. AIMS: We assessed the impact of left ventricular geometry and renal function on 24h-Holter electrocardiogram (ECG) recordings and outcome in elderly hypertensive patients. METHODS: We enrolled 251 asymptomatic hypertensive elderly patients (>65year-old). Left ventricular remodeling was evaluated by 2-D echocardiogram. Lown's class, mean QTc and standard deviation of all normal R-R intervals (SDNN) were assessed by 24-h Holter-ECG recordings. Data on all-cause and cardiovascular mortality were collected for 2years. RESULTS: Mean age was 76.2±11.4years. High Lown's classes were more frequently observed in the presence of left ventricular hypertrophy (LVH) (57.3% vs. 23.7%; p<0.001). Mean QTc was 444.8±34.8ms and resulted directly correlated with indexed left ventricular mass (r=0.228; p=0.001). Patients with Chronic Kidney Disease (CKD) showed lower SDNN as compared with those with preserved renal function (92.02±36.11ms vs. 103.84±33.96ms, respectively; p=0.017). At 2years, all-cause and cardiovascular mortality rates were 38.0% and 21.1%, respectively. Diabetes mellitus (HR: 2.40; 95% C.I.1.16 to 4.99; p=0.019), CKD (HR: 2.22; 95% C.I.1.10 to 4.52; p=0.028), prolonged QTc (HR: 2.18; 95% C.I.1.07 to 4.41; p=0.030) and SDNN<96ms (HR: 1.98; 95% C.I.1.03 to 4.13; p=0.048) were independent predictors of cardiovascular death at 2year follow-up. CONCLUSIONS: CKD and left ventricular remodeling predicted altered ventricular batmotropism. Diabetes, CKD, heart rate variability and QTc are important predictors of cardiovascular death in elderly hypertensive patients.

Testing Clinical Scores to Diagnose Incident Deep Vein Thrombosis in Patients Hospitalized in a Department of Medicine: Can Biomarkers Improve Accuracy?

Shifting the context from the emergency department to the department of medicine, we compared different scores to diagnose deep vein thrombosis (DVT) in patients with several comorbidities, hospitalized in a department of internal medicine. We prospectively recruited 178 consecutive hospitalized patients in whom clinical suspicion of DVT was assessed by Wells modified score for DVT, Hamilton, Kahn, and St Andrè Hospital scores. Deep vein thrombosis was confirmed in 85 (48%) patients by both echocolor Doppler and angiocomputed tomography scan. The use of risk scores based on symptoms and clinical signs was weakly useful (area under the curve [AUC]: 0.69, positive predictive value: 59%, and negative predictive value: 74%). Patients with DVT had significantly (P < .0001) lower serum albumin and protein S levels compared to those without DVT. Moreover, serum protein S (AUC: 0.82) and albumin in percentage (AUC: 0.80) showed a better accuracy than clinical scores (P < .001) in assessing the diagnosis of DVT. Therefore, serum albumin and protein S improved the accuracy of clinical scores for the diagnosis of incident DVT in patients hospitalized in a department of medicine.

Comparison of Wells and Revised Geneva Rule to Assess Pretest Probability of Pulmonary Embolism in High-Risk Hospitalized Elderly Adults.

OBJECTIVES: To assess and compare the diagnostic power for pulmonary embolism (PE) of Wells and revised Geneva scores in two independent cohorts (training and validation groups) of elderly adults hospitalized in a non-emergency department. DESIGN: Prospective clinical study, January 2011 to January 2013. SETTING: Unit of Internal Medicine inpatients, University of Catania, Italy. PARTICIPANTS: Elderly adults (mean age 76 ± 12), presenting with dyspnea or chest pain and with high clinical probability of PE or D-dimer values greater than 500 ng/mL (N = 203), were enrolled and consecutively assigned to a training (n = 101) or a validation (n = 102) group. The clinical probability of PE was assessed using Wells and revised Geneva scores. MEASUREMENTS: Clinical examination, D-dimer test, and multidetector computed angiotomography were performed in all participants. The accuracy of the scores was assessed using receiver operating characteristic analyses. RESULTS: PE was confirmed in 46 participants (23%) (24 training group, 22 validation group). In the training group, the area under the receiver operating characteristic curve was 0.91 (95% confidence interval (CI) = 0.85-0.98) for the Wells score and 0.69 (95% CI = 0.56-0.82) for the revised Geneva score (P < .001). These results were confirmed in the validation group (P < .05). The positive (LR+) and negative likelihood ratios (LR-) (two indices combining sensitivity and specificity) of the Wells score were superior to those of the revised Geneva score in the training (LR+, 7.90 vs 1.34; LR-, 0.23 vs 0.66) and validation (LR+, 13.5 vs 1.46; LR-, 0.47 vs 0.54) groups. CONCLUSION: In high-risk elderly hospitalized adults, the Wells score is more accurate than the revised Geneva score for diagnosing PE.

Norepinephrine, left ventricular disorders and volume excess in ESRD.

BACKGROUND: Sympathetic over-activity is a hallmark of end stage renal disease (ESRD). Left ventricular (LV) disorders and volume overload are pervasive in ESRD and sympathetic over-activity may be a relevant mediator of the cardiovascular (CV) risk by these alterations in this population. DESIGN: We investigated the relationship between a combined biomarker of LV disorders and volume excess, atrial natriuretic peptide (ANP), and the plasma concentration of nor-epinephrine (NE) in 227 ESRD patients without heart failure at baseline and modelled the risk for incident CV events by these biomarkers over a 3.5 years follow-up. RESULTS: Plasma NE was strongly and independently related to ANP (ß = 0.31, P < 0.001). In a multivariate Cox's regression analysis, ANP was an independent predictor of these events [HR (1-SD) 1.25, 95 % CI 1.01-1.54]. However, when NE was introduced into the multivariate model, HR by ANP reduced substantially (1.14, 95% CI 0.91-1.42) and was no longer significant (P = 0.25) while the CV risk signalled by NE was clinically relevant (HR 1.29, 95% CI 1.05-1.59) and statistically significant (P = 0.02). CONCLUSIONS: In ESRD patients without heart failure, NE is strongly and independently related to ANP. The predictive power of ANP for CV events is largely captured by NE in a statistical model including both biomarkers. These data suggest that sympathetic over-activity may be a relevant mediator of the high risk of CV events triggered by LV disorders and volume excess in this population. However, further mechanistic and intervention studies are needed to prove the nature (causal/non causal) of these findings.

Genome-wide association study identifies CAMKID variants involved in blood pressure response to losartan: the SOPHIA study.

BACKGROUND: Essential hypertension arises from the combined effect of genetic and environmental factors. A pharmacogenomics approach could help to identify additional molecular mechanisms involved in its pathogenesis. AIM: The aim of SOPHIA study was to identify genetic polymorphisms regulating blood pressure response to the angiotensin II receptor blocker, losartan, with a whole-genome approach. MATERIALS & METHODS: We performed a genome-wide association study on blood pressure response in 372 hypertensives treated with losartan and we looked for replication in two independent samples. RESULTS: We identified a peak of association in CAMK1D gene (rs10752271, effect size -5.5 ± 0.94 mmHg, p = 1.2 × 10(-8)). CAMK1D encodes a protein that belongs to the regulatory pathway involved in aldosterone synthesis. We tested the specificity of rs10752271 for losartan in hypertensives treated with hydrochlorothiazide and we validated it in silico in the GENRES cohort. CONCLUSION: Using a genome-wide approach, we identified the CAMK1D gene as a novel locus associated with blood pressure response to losartan. CAMK1D gene characterization may represent a useful tool to personalize the treatment of essential hypertension.

[Hypertensive nephrosclerosis: an exhaustive diagnosis?]. / Nefroangiosclerosi: entita' clinica definita?

Hypertensive nephrosclerosis is a much overused clinical diagnosis, largely unsubstantiated by biopsy data. It is in fact a clinical-pathological diagnosis implying a causal role of hypertension in the associated chronic kidney disease. However, such a simple, linear causality is often not obvious or easy to demonstrate. Further factors like age, Afro-American descent, genetic and immunological factors as well as dysmetabolic syndrome may contribute to the development and progression of arterionephrosclerosis independently of hypertension.

Genomewide association study using a high-density single nucleotide polymorphism array and case-control design identifies a novel essential hypertension susceptibility locus in the promoter region of endothelial NO synthase.

Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37-1.73]; combined P=2.58 · 10(-13)). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25-1.44; P=1.032 · 10(-14)). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16-3.66) for systolic and 1.40 (95% CI: 0.25-2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.

Traditional and nontraditional risk factors as predictors of cerebrovascular events in patients with end stage renal disease.

OBJECTIVES AND METHODS: End stage renal disease (ESRD) patients exhibit a higher risk of cerebrovascular events as compared with the general population. In 283 ESRD patients followed up for 10 years, we investigated the long-term predictive value for stroke and transient ischemic attacks of traditional and nontraditional risk factors. Data analysis was performed by a modified Cox regression analysis for repeated events and by a competing risks analysis. RESULTS: During the follow-up, 61 cerebrovascular events occurred in 47 patients. On univariate Cox analysis, the risk of cerebrovascular outcomes was directly related to age, smoking, diabetes, BMI, systolic and pulse pressures, triglycerides, hemoglobin, history of stroke/transient ischemic attacks, arrhythmia and left ventricular mass index. Nontraditional risk factors in ESRD such as norepinephrine, homocysteine, interleukin-6 and asymmetric dimethylarginine failed to predict these events. In a multivariate Cox model for repeated events only smoking [hazard ratio: 2.45, 95% confidence interval (CI): 1.29-4.65], age (hazard ratio: 1.05, 95% CI: 1.01-1.08), hemoglobin (hazard ratio: 1.28, 95% CI 1.06-1.54), triglycerides (hazard ratio: 1.04, 95% CI 1.01-1.08), pulse pressure (hazard ratio: 1.53, 95% CI 1.01-2.23) and left ventricular mass index (hazard ratio: 1.02, 95% CI 1.01-1.04) maintained an independent relationship with cerebrovascular events. The direct link between hemoglobin and cerebrovascular events was significantly stronger (P < 0.05) than that of the same variable and death. CONCLUSION: The risk of stroke in ESRD depends mainly on traditional risk factors, high hemoglobin and left ventricular hypertrophy. Multiple interventions aimed to reduce arterial stiffness, left ventricular mass and smoking as well as to maintain hemoglobin within the recommended therapeutic range may have beneficial effects on the risk of cerebrovascular events in ESRD patients.