Hypersensitivity reactions to iodinate contrast media in Italy: a retrospective study. Characteristics of patients and risk factors.

SUMMARY: Objective. The purpose of the study was to describe the characteristics of patients experiencing hypersensitivity reactions (HRs) to iodinated contrast media (ICM) in a large Italian population and to investigate potential risks factors in order to obtain a risk stratification, helpful in the management of these patients. Methods. Data of 407 patients investigated in 9 Italian Allergy Centers for suspected HRs to ICM were analyzed and compared with a control group of 152 subjects that tolerated one or more ICM-enhanced examinations. The univariate and multivariate logistic regression model was used to evaluate associated factors. Results. The mean age of reactive patients was 61 years and 60% were female; 67% of patients reported immediate reactions and 35% experienced the reaction, more frequently with immediate onset, at the first examination in life. Iomeprol, iopromide and iodixanol were the most frequent culprit agents and 20% of patients showed a positive skin test result. Previous adverse reactions to ICM were reported by 15.6% of patients, whereas 35% of subjects experienced the reaction, more frequently immediate, after the first ICM-enhanced examination in their life. The multivariate analysis showed that male gender and age > 65 were associated with ICM reactions as protective factors [ORadja = 0.51; 95% CI: 0.33-0.77 and ORadja = 0.60; 95% CI: 0.39-0.92 respectively]. Cardio-vascular disease [ORadja = 2.06; 95% CI: 1.22-3.50)], respiratory allergy [ORadja = 2.30; 95% CI: 1.09-4.83)] and adverse drug reactions [ORadja = 1.99; 95% CI: 1.05-3.77)] were identified as risk factors for ICM reactions. Food allergy was not significantly associated with reactions [ORadja = 1.51; 5% CI: 0.41-5.56]. Conclusions. This is the largest study on Italian patients experiencing hypersensitivity reactions to ICM. Most results are in line with other studies, showing some association with factors that could influence the incidence of hypersensitivity reactions but not allowing an easy risk stratification.

The impact of COVID-19 pandemic on emergency services.

BACKGROUND: The SARS-Cov-2 pandemic has placed enormous strain on the global healthcare system. The strict containment measures have adversely affected population movements and mobility, daily activities, and the patterns of healthcare-seeking behavior. Although the Emergency and Admission Departments (EADS) activity has never been disrupted, the pandemic had a significant impact on the routine healthcare delivery. This study aims to assess the changes in healthcare delivery, with a focus on the elderly as a vulnerable component of the general population. DESIGN OF THE STUDY: Retrospective study. METHODS: All non-COVID visits to the EAD of the Local Health Unit (ASL1) in Abruzzo (Italy) from 9 March to 3 May 2020 were analyzed. These were compared to the hospital admissions recorded in the same period of the previous year. RESULTS: We found a 60.4% reduction in overall visits during the study period and an increase in the hospitalization rate from 30% to 39%. Emergency department visits have declined markedly for less acute medical conditions, while we have observed a statistically significant increase in the hospitalization rates for all age groups. Moreover, in 2020 we recorded a decrease in the ratio non-urgent/non-deferrable medical conditions for each age group; while the percentage of hospitalizations for each registered red code increased for each group, particularly for the 65-74 age group. CONCLUSIONS: The COVID-19 pandemic has significantly affected the care-seeking behavior of patients. During the COVID-19 epidemic, total hospital admissions have decreased, particularly for less severe illnesses, whereas the percentage of hospitalizations has increased. During 2020, hospital admissions for mild cases decreased, and patients presented to the EAD only in cases of acute medical condition, selecting those in need for more intensive care. However, several patients may have deferred necessary medical care even for potentially urgent conditions. Such reluctance to seek medical care may have caused delays in diagnosis. The impact of deferred care on patients' health is difficult to estimate at this time. This information will serve as a starting point for further research to improve healthcare management not only during emergency but also in non-emergency periods.

Thyroid hormones modulate irisin concentrations in patients with recently onset hypothyroidism following total thyroidectomy.

PURPOSE: Irisin is a newly discovered adipo-myokine known for having significant effects on body metabolism. Currently, there is a discussion regarding the relation between thyroid function and irisin concentration. This study was designed to evaluate the influential role of levothyroxine replacement therapy on circulating levels of irisin in patients with recently onset hypothyroidism following total thyroidectomy. METHODS: Circulating levels of thyroid hormones, irisin and other metabolic parameters, were assessed in 40 recently thyroidectomized patients (34 females, mean age 50.1 ± 15.2 years) at baseline (5-7 day after surgery) and after 2 months under replacement therapy with levothyroxine. RESULTS: At baseline, circulating levels of thyroid hormones were indicative of hypothyroidism (TSH 12.7 ± 5.0 µU/mL, FT3 1.9 ± 0.7 pg/mL, FT4 8.7 ± 3.6 pg/mL). Mean serum irisin concentrations significantly increased after 2 months under replacement therapy with levothyroxine (from 2.2 ± 0.6 to 2.9 ± 0.6 µg/mL, p < 0.0001). Variations of circulating levels of irisin under levothyroxine replacement therapy were directly correlated with those of FT3 (Rho = 0.454, p = 0.0033) and FT4 (Rho = 0.451, p = 0.0035). Multivariate regression analysis revealed that changes in thyroid hormones concentrations explained up to 10% of the variations of serum irisin levels under levothyroxine replacement therapy (FT3 R2 = 0.098, FT4 R2 = 0.103). CONCLUSION: Our study suggests that levothyroxine replacement therapy mildly influences irisin metabolism in patients with recently onset hypothyroidism following total thyroidectomy.

Hyperuricemia and Risk of Cardiovascular Outcomes: The Experience of the URRAH (Uric Acid Right for Heart Health) Project.

The latest European Guidelines of Arterial Hypertension have officially introduced uric acid evaluation among the cardiovascular risk factors that should be evaluated in order to stratify patient's risk. In fact, it has been extensively evaluated and demonstrated to be an independent predictor not only of all-cause and cardiovascular mortality, but also of myocardial infraction, stroke and heart failure. Despite the large number of studies on this topic, an important open question that still need to be answered is the identification of a cardiovascular uric acid cut-off value. The actual hyperuricemia cut-off (> 6 mg/dL in women and 7 mg/dL in men) is principally based on the saturation point of uric acid but previous evidence suggests that the negative impact of cardiovascular system could occur also at lower levels. In this context, the Working Group on uric acid and CV risk of the Italian Society of Hypertension has designed the Uric acid Right for heArt Health project. The primary objective of this project is to define the level of uricemia above which the independent risk of CV disease may increase in a significantly manner. In this review we will summarize the first results obtained and describe the further planned analysis.

The cortisol burden in elderly subjects with metabolic syndrome and its association with low-grade inflammation.

BACKGROUND: Elderly people are exposed to an increased load of stressful events and neuro-hormonal stimulation is a key finding in metabolic syndrome and its related disorders. AIMS: To determine the role of cortisol in elderly subjects, with or without metabolic syndrome (MetS), by means of a national multicentre observational study, AGICO (AGIng and Cortisol). METHODS: From 2012 to 2017, the AGICO study enrolled n.339 subjects (aged > 65), after obtaining their informed consent. The investigators assessed a cardio-metabolic panel (including electrocardiogram, carotid ultrasonography and echocardiography), the presence of MetS (on Adult Treatment Panel III criteria), a neurological examination (including brain imaging), and cortisol activity (using a consecutive collection of diurnal and nocturnal urine). RESULTS: In the patients presenting with MetS, the standardized diurnal and nocturnal cortisol excretion rates were 210.7 ± 145.5 and 173.7 ± 118.1 (mean ± standard deviation) µg/g creatinine/12 h; in those without MetS, the standardized diurnal and nocturnal cortisol excretion rates were 188.7 ± 92.7 and 144.1 ± 82.3 µg/g creatinine/12 h, respectively (nocturnal urinary cortisol in patients with MetS versus those without MetS p = 0.05, female patients with MetS vs female patients without MetS, p < 0.025). A significant positive correlation was found between the CRP levels and both the diurnal and nocturnal urinary cortisol levels with r = 0.187 (p < 0.025) and r = 0.411 (p < 0.00000001), respectively. DISCUSSION: The elderly patients with MetS showed a trend towards increased standardized nocturnal cortisol excretions, with particular regard to the female subjects. CONCLUSION: The positive correlation between cortisol excretion and low-grade inflammation suggests a common mechanism driving both hormonal and inflammatory changes.

Leukoaraiosis is an independent predictor of intracranial hemorrhage in patients with atrial fibrillation.

We evaluated the predictive value of several clinical, radiological and laboratory parameters on the risk of predict intracranial hemorrhage (ICH) in patients with atrial fibrillation (AF). We conducted a case-control study on a consecutive hospital based series of patients with AF and ICH. A random sample of subjects with AF without ischemic or hemorrhagic stroke was selected from the same hospital in the same period to perform as the control group, with a ratio of two controls per case. All patients underwent the same evaluation protocol. Patients without neuroimaging exams were excluded. During the study period we identified 37 subjects with AF and ICH. 74 subjects without stroke events were randomly chosen among subjects with AF. Among cases 56.8% were female; mean age was 83.1 years. Patients with ICH were more often on anticoagulant therapy (75.7%), compared with controls (45.9%; p = 0.0002). On CT scans, cases had a greater severity of leukoaraiosis at the Blennow scale (p < 0.0001) and a higher frequency of lacunar infarcts (p = 0.006). No significant association was found between MRI parameters or the HAS-BLED score and the occurrence of ICH. CT scan is more useful than MRI and HAS-BLED score to predict ICH in patients with AF on antithrombotic therapy.

Association Between the Serum Uric Acid Levels and Lacunar Infarcts in the Elderly.

Increasing evidence suggests that uric acid (UA) is a relevant risk factor for arteriolosclerosis and recent studies have demonstrated the positive relationship between UA concentrations and the severity of leukoaraiosis. However, the association between lacunar infarcts (LI) and UA levels has seldom been reported in the literature. The aim of our study was to assess whether serum UA levels may be related to the presence of LI. We recruited 242 patients (113 males and 129 females, aged 82.83 ± 6.49 years) from our Geriatric Department for whom CAT scans (CT) were available. Clinical and laboratory data was collected. Patients CT images were examined to identify the presence, the size, the number, and the location of LI. LI without neurological symptoms were considered silent LI. Serum UA levels were found to be positively associated with the presence (p = 0.0001), the number (p = 0.001), the size (p = 0.001), and the location of LI in the basal ganglia (p = 0.0038), the deep white matter (DWM) (p < 0.0001), and the pons (p = 0.0156). A significant association was also found between UA and silent LI (p = 0.0002). The prevalence of LI increased starting from UA levels of 5.7 mg/dl. Stepwise multiple regression analysis confirmed that UA was independently related with the presence, the number, the size, LI in the basal ganglia, the DWM, the pons, and with silent LI. Our study suggests a positive association between UA levels and LI, which is independent of traditional cardiovascular risk factors. This data suggests that UA plays an influential role on the physiopathology of LI and could represent a potential target to prevent cerebral microinfarcts.

Hypertriglyceridemia and omega-3 fatty acids: Their often overlooked role in cardiovascular disease prevention.

AIMS: This review aims to describe the pathogenic role of triglycerides in cardiometabolic risk, and the potential role of omega-3 fatty acids in the management of hypertriglyceridemia and cardiovascular disease. DATA SYNTHESIS: In epidemiological studies, hypertriglyceridemia correlates with an increased risk of cardiovascular disease, even after adjustment for low density lipoprotein cholesterol (LDL-C) levels. This has been further supported by Mendelian randomization studies where triglyceride-raising common single nucleotide polymorphisms confer an increased risk of developing cardiovascular disease. Although guidelines vary in their definition of hypertriglyceridemia, they consistently define a normal triglyceride level as <150 mg/dL (or <1.7 mmol/L). For patients with moderately elevated triglyceride levels, LDL-C remains the primary target for treatment in both European and US guidelines. However, since any triglyceride level in excess of normal increases the risk of cardiovascular disease, even in patients with optimally managed LDL-C levels, triglycerides are an important secondary target in both assessment and treatment. Dietary changes are a key element of first-line lifestyle intervention, but pharmacological treatment including omega-3 fatty acids may be indicated in people with persistently high triglyceride levels. Moreover, in patients with pre-existing cardiovascular disease, omega-3 supplements significantly reduce the risk of sudden death, cardiac death and myocardial infarction and are generally well tolerated. CONCLUSIONS: Targeting resistant hypertriglyceridemia should be considered as a part of clinical management of cardiovascular risk. Omega-3 fatty acids may represent a valuable resource to this aim.

Replacement therapy with levothyroxine modulates platelet activation in recent-onset post-thyroidectomy subclinical hypothyroidism.

BACKGROUND AND AIM: Subclinical hypothyroidism has been linked to increased risk of atherosclerotic disease. Soluble CD40 ligand (sCD40L), mainly derived from activated platelets, and the lipid peroxidation product 8-iso-prostaglandin F2α (8-iso-PGF2α) are known to play a relevant pathophysiological role in atherogenesis. In this study, we analyzed the relationship between thyroid hormones and circulating levels of sCD40L and 8-iso-PGF2α in patient with recent-onset post-thyroidectomy subclinical hypothyroidism under replacement therapy. METHODS AND RESULTS: Circulating levels of thyroid hormones, sCD40L, and 8-iso-PGF2α were assessed in 40 recently thyroidectomized patients (33 females, mean age 52.0 ± 11.7 years) at baseline (5-7 day after surgery) and after 2 months under replacement therapy with levothyroxine (LT-4). At baseline, circulating levels of thyroid hormones were indicative of a subclinical hypothyroidism (TSH 7.7 ± 3.9 µU/mL, FT3 1.8 ± 0.6 pg/mL, and FT3 8.9 ± 3.0 pg/mL). Circulating levels of sCD40L and 8-iso-PGF2α were directly correlated with each other (r = 0.360, p = 0.023) and with TSH levels (r = 0.322, p = 0.043 and r = 0.329 p = 0.038, respectively). After 2 months under the replacement therapy with LT-4 circulating levels of TSH (from 7.7 ± 3.9 to 2.7 ± 2.8 µU/mL, p < 0.0001), sCD40L (from 6.11 ± 2.41 to 2.43 ± 2.00 ng/mL, p < 0.0001) and 8-iso-PGF2α (from 45.33 ± 6.94 to 40.36 ± 6.20, p < 0.0001) significantly decreased. Changes in circulating levels of sCD40L and 8-iso-PGF2α were directly correlated with each other (r = 0.349 p = 0.028) and with changes in TSH levels (r = 0.367 p = 0.020 and r = 0.339 p = 0.032, respectively). CONCLUSION: Our study suggests an influential role of TSH on proatherogenic activation of platelets, probably through enhanced lipid peroxidation. These findings could partially explain the increased susceptibility of patients with subclinical hypothyroidism to develop atherosclerotic disease.

Hyperuricemia is associated with increased hospitalization risk and healthcare costs: Evidence from an administrative database in Italy.

BACKGROUND AND AIM: Chronic hyperuricemia is responsible for a relevant burden of articular diseases and cardio-nephrometabolic disorders. We evaluated the effect of high serum uric acid (SUA) levels on hospitalization risk and mortality and on healthcare costs in a real-life setting. METHODS AND RESULTS: We conducted a retrospective analysis using a large administrative database and a clinical registry among 112,170 subjects from three Italian local health units. Individuals were divided into four groups according to their SUA levels: <6 mg/dL (66.5%), >6 mg/dL and ≤7 mg/dL (19.3%), >7 mg/dL and ≤8 mg/dL (8.7%), and >8 mg/dL (5.5%). Compared to those with SUA level of <6 mg/dL, the risk of hospitalization related to gout and/or nephrolithiasis was higher in the three groups of patients with higher SUA levels (1.51, P = 0.100; 2.21, P = 0.005; and 1.17, P = 0.703, respectively). A similar trend was also observed for hospitalization due to chronic kidney disease (CKD) (1.31, P < 0.001; 1.40, P < 0.001; and 2.18, P < 0.001, respectively) and cardiovascular disease (CVD) (1.08, P < 0.001; 1.23, P < 0.001; and 1.67, P < 0.001, respectively) and for all-cause mortality (0.97, P = 0.309; 1.21, P < 0.001; and 2.15, P < 0.001). The mean annual healthcare costs were higher in patients with higher SUA level (€2752, €2957, €3386, and €4607, respectively) mainly because of a progressive increase in hospitalization costs per patient (from € 1515 for SUA <6 mg/dL to € 3096 for SUA >8 mg/dL). CONCLUSIONS: Increased SUA levels are associated with an increased risk of hospitalizations related to hyperuricemia, CKD, and CVDs and total mortality, and consequently with higher total healthcare costs and hospitalization costs per patient.

The management of hyperuricemia with urate deposition.

Recent epidemiological data suggest a progressive increase of serum levels of uric acid worldwide. This rise in the prevalence of hyperuricemia may be related to the epidemic diffusion of overweight and obesity as well as the shifts in diet with increased consumption of foods rich in purines, alcoholic consumption, and soft drinks sweetened with fructose. The rise in serum uric acid levels worldwide may be regarded as leading an increased risk for gout and other systemic diseases, especially in the cardio-renal system. Therefore, careful management of hyperuricemia with urate deposition is crucial to prevent or even treat those systemic diseases. Despite this, hyperuricemia and gout often remain untreated. This paper reviews current evidence on the management of hyperuricemia with urate deposition, with a focus on its most controversial aspects. This review is based on a PubMed/Embase database search for articles on hyperuricemia and its impact on cardiovascular and renal function.

Is it time to revise the normal range of serum uric acid levels?

The actual reference range of serum uric acid has been assessed according to its variations among healthy individuals. i.e. those without clinical evidence of gout. By this approach, serum uric acid values between 3.5 and 7.2 mg/dL in adult males and postmenopausal women and between 2.6 and 6.0 mg/dL in premenopausal women have been identified as normal in many countries. However, this definition of normal range of serum uric acid in the general population is inevitably influenced by what we consider as "normal", since the absence of gout flares does not necessarily imply the absence of uric acid-related damage. Indeed, a growing body of evidence indicates that silent deposition of monosodium urate crystals as a result of hyperuricaemia may occur and lead to early destructive skeletal changes. In addition, a growing body of evidences demonstrates that uric acid might play a pathophysiological role in many "cardio-nephro-metabolic" disorders, which seems to be independent of the deposition of monosodium urate crystals, since it is evident also for serum uric acid concentrations below the saturation point for monosodium urate. Taken together, these findings strongly suggest to carefully reconsider the concept of "asymptomaticity" for chronic hyperuricemia and to consequently revise the normal range of serum uric acid levels also considering the progressive worldwide increase of circulating levels of uric acid, which could lead to a "shift to right" (i.e. toward higher values) of normal range. In the light of the new scientific knowledge on the pathophysiological role of uric acid in human disease, a threshold value < 6.0 mg/dL (< 360 µmol/L) seems to better identify true "healthy subjects" and should reasonably be considered for all subjects.

Italian Society of Rheumatology recommendations for the management of gout.

OBJECTIVE: Gout is the most common arthritis in adults. Despite the availability of valid therapeutic options, the management of patients with gout is still suboptimal. The Italian Society of Rheumatology (SIR) aimed to update, adapt to national contest and disseminate the 2006 EULAR recommendations for the management of gout. METHODS: The multidisciplinary group of experts included rheumatologists, general practitioners, internists, geriatricians, nephrologists, cardiologists and evidence-based medicine experts. To maintain consistency with EULAR recommendations, a similar methodology was utilized by the Italian group. The original propositions were translated in Italian and priority research queries were identified through a Delphi consensus approach. A systematic search was conducted for selected queries. Efficacy and safety data on drugs reported in RCTs were combined in a meta-analysis where feasible. The strength of recommendation was measured by utilising the EULAR ordinal and visual analogue scales. RESULTS: The original 12 propositions were translated and adapted to Italian context. Further evidences were collected about the role of diet in the non-pharmacological treatment of gout and the efficacy of oral corticosteroids and low-dose colchicine in the management of acute attacks. Statements concerning uricosuric treatments were withdrawn and replaced with a proposition focused on a new urate lowering agent, febuxostat. A research agenda was developed to identify topics still not adequately investigated concerning the management of gout. CONCLUSIONS: The SIR has developed updated recommendations for the management of gout adapted to the Italian healthcare system. Their implementation in clinical practice is expected to improve the management of patients with gout.

How to manage patients with gout.

OBJECTIVES: Recently, after almost 50 years of dormancy, new therapeutic agents for the management of gout have entered the market or are in clinical development. In this article, the current guidelines for the diagnosis and management of gout are reviewed. METHODS: Key papers for inclusion were identified by a PubMed search, and articles were selected according to their relevance for the topic, according to the authors' judgment. RESULTS AND CONCLUSIONS: Although our therapeutic arsenal is strong, and effective gout management with urate lowering therapy improves many patient-reported outcomes in clinical trials, major gaps exist in patient understanding of disease and adherence to long-term therapy. Research is required to identify the optimal models of care for patients with gout. However, quality of care in gout can be enhanced through better gout-centered education. To properly manage gout, education of the gout patient is critical, since only the patient who understands their gout will stay with their medication long-term.

Cyclooxygenase and atherosclerosis: a smoking area.

Chronic smoking is associated with functional and structural vascular changes underlying inflammatory processes responsible for plaque formation and rupture. Cyclooxygenase (COX) is the key enzyme linking smoking action to inflammatory damages: it is responsible for the conversion of arachidonic acid to prostanoids, and lipid mediators involved in most of pathological processes. Two COX isoenzymes have been characterized, COX-1 and COX-2, that differ in terms of regulatory mechanisms of expression, tissue distribution, substrate specificity, and preferential coupling to upstream and downstream enzymes. The aim of this review is to highlight the pathogenetic role of chronic smoking in vasomotor dysfunction, inflammation, and modification of lipids underlying the initiation and the progression of atherosclerosis and to remark the hypothesis that plaque composition rather than plaque size is the real determinant of the plaque evolution toward rupture and the major responsible for acute ischemic syndromes. The concomitantly higher expression of EP4, COX-2, mPGES-1, MMP-2 and MMP-9 in unstable plaques is focused and the role of PGE(2) as pathophysiological link between smoking, COX-2 and MMP activity is stressed. Indeed, the intracellular pathways regulating COX-2 and the mechanisms suggested to clarify the role of COX-2 and downstream synthases in atherothrombosis are summarized.

Enhanced soluble CD40 ligand contributes to endothelial cell dysfunction in vitro and monocyte activation in patients with diabetes mellitus: effect of improved metabolic control.

AIMS/HYPOTHESIS: Inflammation plays a pathogenic role in the development of accelerated atherosclerosis in diabetes. Soluble CD40 ligand (sCD40L) is enhanced in diabetes; however, the molecular mechanisms linking sCD40L to accelerated atherosclerosis in diabetes are still unclear. We tested the hypothesis that sCD40L may be involved in the vascular complications in diabetes and exerts its effect by triggering inflammatory reactions on mononuclear and endothelial cells (ECs). METHODS: We studied 70 patients, 40 with type 2 and 30 with type 1 diabetes, with a history or physical examination negative for cardiovascular disease, and 40 non-diabetic and 30 healthy subjects, matched with the type 2 and type 1 diabetic patients, respectively. Plasma and serum sCD40L, and plasma soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, E-selectin and monocyte chemo-attractant protein-1 (MCP-1) were measured. Adhesion molecules and MCP-1 release, the ability to repair an injury in ECs, and O2- generation in monocytes were analysed in vitro after stimulation with serum from patients or controls. RESULTS: Type 2 and type 1 diabetic patients had significantly higher sCD40L levels than controls. Furthermore, high sCD40L was associated with in vitro adhesion molecules and MCP-1 release, impaired migration in ECs and enhanced O2- generation in monocytes. Improved metabolic control was associated with a reduction of plasma sCD40L by 37.5% in 12 type 1 diabetic patients. Furthermore, elevated sCD40L in diabetic patients was significantly correlated with HbA1c levels. CONCLUSIONS/INTERPRETATION: Upregulation of sCD40L as a consequence of persistent hyperglycaemia in diabetic patients results in EC activation and monocyte recruitment to the arterial wall, possibly contributing to accelerated atherosclerosis development in diabetes.