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Urticaria and angioedema are experienced by up to 1 in 5 people, usually the result of common allergen or medication triggers and infections. Similarly, the majority of recurrent angioedema has an exogenous trigger, for example, angiotensin converting enzyme inhibitors, or is hereditary (type 1 and 2 hereditary angioedema); chronic spontaneous urticaria are most often autoimmune or autoallergic in routine clinical practice. There are, however, several skin and systemic conditions that can imitate the clinical appearance of either angioedema or urticaria, whereas there are several uncommon conditions that have chronic urticaria and/or recurrent angioedema as part of their disease manifestations. Correct diagnosis is paramount to ensuring subsequent tailored therapy for many of these conditions, and in many instances, diagnostic delay can be several years with morbid consequence. In this grand rounds article, we present 2 illustrative clinical cases as the backdrop to discussing a practical diagnostic approach for clinicians to recognize copycat phenotypes and "red flags" that should prompt further investigation of several uncommon mimics. We highlight key diagnostic features, epidemiology, and management for mimics where treatment is distinct from the common phenotypes of recurrent angioedema and chronic urticarias.

Purpose Idiopathic Systemic Capillary Leak Syndrome (ISCLS) is a paroxysmal permeability disorder characterized by abrupt onset of shock and hemoconcentration due to massive shift of fluids and proteins from the intravascular to the interstitial compartment. We hypothesize that increased hemoglobin concentration has a pivotal role in the acid-base imbalance during life-threatening crises. Materials and methods Analysis of the acid-base balance fluctuations during six severe ISCLS flares admitted to ICU of a referral center for ISCLS. Results Acid-base equilibrium was assessed for plasma and the whole blood by single and multicompartmental models. The acute phase of ISCLS was characterized by shock, hypoalbuminemia, severe hemoconcentration, and acidosis. The physical-chemical approach for plasma found a remarkable component of unmeasured anions (SIG) during the acute phase. After correction of the physical-chemical model for the whole blood, the SIG variations disappeared because the buffer role of hemoglobin was relevant. Conclusion Hemoglobin has a remarkable role in buffering metabolic acidosis during the shock phase of ISCLS. In these circumstances, the assessment of acid-base equilibrium in plasma alone may overestimate unmeasured anions. On the contrary, the physical-chemical model corrected for whole blood better explains the metabolic component of acid-base imbalance when marked shift of hemoglobin concentration occurs.

Purpose Paroxysmal Permeability Disorders (PPDs) comprise a variety of diseases characterized by recurrent and transitory increase of endothelial permeability. Idiopathic Systemic Capillary Leak Syndrome (ISCLS) is a rare PPD that leads to an abrupt massive shift of fluids and proteins from the intravascular to the interstitial compartment. In some cases, tissue edema may involve the myocardium, but its role in the development of shock has not been elucidated so far. Materials and methods Assessment of cardiac involvement during ten life-threatening ISCLS episodes admitted to ICU. Results Transthoracic echocardiographic examination was performed in eight episodes, whereas a poor acoustic window prevented cardiac ultrasound assessment in two episodes. Myocardial edema was detected by echocardiography in eight episodes and marked pericardial effusion in one-episode. Cardiac magnetic resonance showed diffuse myocardial edema in another episode. In one case, myocardial edema caused fulminant left ventricular dysfunction, which required extracorporeal life support. The mean septum thickness was higher during the shock phase compared to the recovery phase [15.5 mm (13.1–21 mm) vs. 9.9 mm (9–11.3 mm), p = .0003]. Myocardial edema resolved within 72 h. Conclusions During early phases of ISCLS, myocardial edema commonly occurs and can induce transient myocardial dysfunction, potentially contributing to the pathogenesis of shock.

BackgroundIt remains elusive how the characteristics, the course of disease, the clinical management and the outcomes of critically ill COVID-19 patients admitted to intensive care units (ICU) worldwide have changed over the course of the pandemic.MethodsProspective, observational registry constituted by 90 ICUs across 22 countries worldwide including patients with a laboratory-confirmed, critical presentation of COVID-19 requiring advanced organ support. Hierarchical, generalized linear mixed-effect models accounting for hospital and country variability were employed to analyse the continuous evolution of the studied variables over the pandemic.ResultsFour thousand forty-one patients were included from March 2020 to September 2021. Over this period, the age of the admitted patients (62 [95% CI 60–63] years vs 64 [62–66] years,p p p p 2/FiO2at admission was lower (132 [123–141] mmHg vs 101 [91–113] mmHg,p p = 0.05). The number of patients treated with steroids and tocilizumab increased, while the use of therapeutic anticoagulation presented an inverse U-shaped behaviour over the course of the pandemic. The proportion of patients treated with high-flow oxygen (5 [4–7]% vs 20 [14–29],p p p p p ConclusionCharacteristics and disease course of critically ill COVID-19 patients have continuously evolved, concomitant to the clinical management, throughout the pandemic leading to a younger, less severely ill ICU population with distinctly different clinical, pulmonary and inflammatory presentations than at the onset of the pandemic.

Background Autoptic pulmonary findings have been described in severe COVID-19 patients, but evidence regarding the correlation between clinical picture and lung histopathologic patterns is still weak. Methods This was a retrospective cohort observational study conducted at the referral center for infectious diseases in northern Italy. Full lung autoptic findings and clinical data of patients who died from COVID-19 were analyzed. Lung histopathologic patterns were scored according to the extent of tissue damage. To consider coexisting histopathologic patterns, hierarchical clustering of histopathologic findings was applied. Results Whole pulmonary examination was available in 75 out of 92 full autopsies. Forty-eight hospitalized patients (64%), 44 from ICU and four from the medical ward, had complete clinical data. The histopathologic patterns had a time-dependent distribution with considerable overlap among patterns. Duration of positive-pressure ventilation (p p = 0.007), worst serum albumin (p = 0.017), interleukin 6 (p = 0.047), and kidney SOFA (p = 0.001) differed among histopathologic clusters. The amount of PEEP for long-lasting ventilatory treatment was associated with the cluster showing the largest areas of early and late proliferative diffuse alveolar damage. No pharmacologic interventions or comorbidities affected the lung histopathology. Conclusions Our study draws a comprehensive link between the clinical and pulmonary histopathologic findings in a large cohort of COVID-19 patients. These results highlight that the positive end-expiratory pressures and the duration of the ventilatory treatment correlate with lung histopathologic patterns, providing new clues to the knowledge of the pathophysiology of severe SARS-CoV-2 pneumonia.

Introduction: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare yet still probably underdiagnosed clinical condition. Recurrent episodes of subcutaneous and sub-mucosal swelling may involve the skin, the gastrointestinal tract or even the upper airways, exposing the patients to the risk of death. With the aim of improving patients' quality of life, the therapeutic scenario has expanded over the years.Areas covered: The focus of the present review is lanadelumab, a fully human, κ-light-chain, monoclonal immunoglobulin G1 against plasma kallikrein, currently approved for long-term prophylaxis of C1-INH-HAE attacks in the USA and Canada and designated as an orphan drug by the European Medicines Agency.Expert opinion: Lanadelumab is able to inhibit plasma kallikrein with high selectivity and affinity. The subsequent phases of drug development and the ongoing open-label trial have proven its safety and efficacy. It overcomes some of the limitations of other drugs available for long-term prophylaxis, given the easy route of administration, the simple administration schedule and the possibility to tailor the treatment to each patient. Further studies are needed to test its efficacy also in other types of angioedema for which a central role of plasma kallikrein is envisaged.

Introduction Hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) is a rare disease with unpredictable, self-limiting and localized swelling episodes involving the cutaneous and subcutaneous tissues. In the last decade, the spectrum of the possibilities to control the disease has considerably changed with the development of biologic therapies making necessary a careful evaluation of the differences among current and emerging treatments to properly optimize the management of patients. Areas covered This review serves to summarize the literature regarding the use of biologics for the treatment of C1-INH-HAE. Medications already available on the market and new drugs in different phases of development are addressed. Expert opinion The advent of biologic therapies dramatically improved the lives of patients with C1-INH-HAE although further improvement is still needed. Whether this is cost/effective will be answered in the next years when we will see if these major advances will benefit the majority of the patients.

Introduction Among the multiple complex pathophysiological mechanisms underlying COVID‐19 pneumonia, immunothrombosis has been shown to play a key role. One of the most dangerous consequences of the prothrombotic imbalance is the increased incidence of micro‐ and macrothrombotic phenomena, especially deep vein thrombosis (DVT) and pulmonary embolism (PE). Methods We investigated the correlation between radiological and clinical–biochemical characteristics in a cohort of hospitalised COVID‐19 patients. Results PE was confirmed in 14/61 (23%) patients, five (35.7%) had DVT. The radiographic findings, quantified by Qanadli score calculated on CT angiography, correlated with the clinical score and biochemical markers. The ratio between the right and left ventricle diameter measured at CT angiography correlated with the length of hospital stay. Conclusion In our cohort radiological parameters showed a significant correlation with clinical prognostic indices and scores, thus suggesting that a multidisciplinary approach is advisable in the evaluation of PE in COVID‐19 patients.

Introduction: Hereditary angioedema (HAE) with C1 esterase inhibitor deficiency (C1-INH-HAE) is a rare disease that manifests with cutaneous and/or submucosal swellings due to uncontrolled activation of the contact/kinin system. Attacks recur with unpredictable frequency and severity, laryngeal edema is potentially lethal, and the disease burden may severely disrupt patients' lives.Areas covered: This review provides an overview of lanadelumab, a human monoclonal antibody targeted against plasma kallikrein that was recently approved for prevention of symptoms in C1-INH-HAE.Expert opinion: The phase III HELP Study demonstrated the efficacy of lanadelumab in reducing HAE attacks. These positive results are being further confirmed in the open-label extension study. This agent addresses some of the limitations of existing prophylactic options as tolerability issues, the need for intravenous administration and frequent dosing. Therefore, lanadelumab can profoundly improve the quality of life of patients with C1-INH-HAE.

Despite the efficacy of the on-demand treatment for the control of acute attacks of Hereditary Angioedema due to C1-Inhibitor Deficiency (C1-INH-HAE), the number and severity of attacks and the impairment in the quality of life of the affected patients have led to the development of a new monoclonal antibody, lanadelumab, directly addressed to the blockage of bradykinin, the principal mediator of vasodilation during angioedema attacks. It is indicated for the prophylactic treatment, it is easy to administer, highly effective and with known limited side effects. The current review summarizes the development of the drug, its clinical background and its perspectives.

Objective The term Idiopathic Systemic Capillary Leak Syndrome (ISCLS) refers to an uncommon condition of severe distributive shock, resulting from an abrupt shift of fluids and proteins from the intravascular to the interstitial compartment. We hypothesise that the autonomic nervous system (ANS) fails in regulating the response to hypovolemia in acute ISCLS and that ANS variables characterise the progression to the recovery. Design Prospective cohort study of patients admitted to ICU for severe ISCLS flares. Setting Single, referral center in Italy for ISCLS. Patients Analysis of cardiovascular signals recorded during seven severe ISCLS attacks and one prodromal period in five patients. Interventions ANS was studied non-invasively by means of heart rate variability (HRV) and blood pressure variability analysis, as an estimation of vagal and sympathetic modulation directed to the heart and vessels. Heart rate and systolic arterial pressure (SAP) variability were also used to assess baroreflex sensitivity. ANS variables were measured during the subsequent phases which characterise ISCLS flares, namely the acute phase, the post-acute phase, and the recovery phase. Measurements and main results HRV was severely depressed during the acute phase accounting for the loss of ANS modulation during massive capillary extravasation. This phase was characterised by shock and impaired baroreflex control, which allowed SAP to oscillate driven by respiratory activity. Impending shock and transition from shock to a post-acute phase were marked by change of baroreflex spectral variables. The baroreflex control was fully restored during recovery. Conclusions ANS modulation and baroreflex control are severely impaired during the acute haemodynamic instability which characterises ISCLS crises and their progressive restoration may be a clue of improvement. ANS indices during ISCLS flares might serve as useful biomarkers, able to timely announce the transition from one phase to the subsequent one, thus helping to adapt therapy accordingly.

Hypovolemia and intermittent positive pressure ventilation are conditions that frequently characterize the state of critical illness, but their interaction and resulting cardioventilatory coupling is poorly understood even in healthy humans. We explored heart rate variability, baroreflex activity, and their interaction in an experimental protocol involving twelve mildly hypovolemic healthy subjects during spontaneous breathing and noninvasive positive-pressure ventilation. In seven subjects, an echocardiographic assessment was also performed. Correction of hypovolemia, raising cardiac preload, produced an increase in high-frequency spectral power density of heart rate, left low-frequency spectral power density unchanged but enhanced baroreflex sensitivity. Cardioventilatory coupling was affected by both central blood volume and ventilatory mode and was mainly entrained by the respiratory oscillation. In conclusion, the autonomic nervous system and baroreflex have a significant role in compensating the hemodynamic perturbation due to changes of volemia and ventilatory-induced fluctuations of venous return. They exert an integrative function on the adaptive pattern of cardioventilatory coupling.

Marginal zone lymphoma represents about 10% of all non-Hodgkin lymphomas (NHLs). 33% of patients with acquired angioedema (AAE) due to acquired C1-inhibitor (C1-INH) deficiency (C1-INH-AAE) have or will develop NHLs. C1-INH-AAE is a rare condition. We report the follow-up of 72 C1-INH-AAE patients, followed for a median of 15 years (range 1-24). Median age was 71 (range 64-79) years; median age at onset of angioedema symptoms was 57·5 (range 50-66) years and it was 63 [range 45-80) years at diagnosis]. Twenty patients were diagnosed with low-grade non-follicular B-cell lymphomas (75% were splenic MZL), one with follicular and three with high-grade lymphomas (two diffuse large B-cell lymphomas and one mantle cell lymphoma). Fifteen NHLs were diagnosed at onset of AAE or thereafter (3 months to 7 years), eight had already been diagnosed at onset of angioedema. Two of 24 patients remain on watchful wait. Thirthen of 24 received chemotherapy, two received rituximab. Three underwent splenectomy. All 18 patients receiving therapy for NHL experienced post-treatment reduction in AAE symptoms. Our study suggests that clonal B-cell proliferation is the pathology underlying AAE leading to production of C1-INH-neutralizing autoantibodies and to NHLs. The post-germinal centre origin of NHL suggests that immune stimulation may contribute to lymphomagenesis.

Aim Reflex alterations of cardiac autonomic modulation have been described after acute myocardial infarction (AMI). The non-homogeneous autonomic innervation of the heart gives reason of different patterns of autonomic modulation depending upon the site of AMI. Conflicting data are available on cardiac autonomic modifications after primary percutaneous coronary intervention (pPCI). We evaluated cardiac autonomic changes in patients with ST-elevation myocardial infarction (STEMI) after pPCI, either within 24 h after revascularization (T0) and at clinical stability (T1, 6 ± 2 days), taking into account the site of infarction. Methods and results We enrolled 33 consecutive patients with STEMI treated with pPCI (25 males, mean age 61 ± 12.1 yr); 15 had an anterior wall STEMI (ANT) and 18 had an inferior wall STEMI (INF). ECG and respiration were recorded at T0 and at T1. Cardiac autonomic modulation was evaluated by means of symbolic analysis of heart rate variability. At T0, At T0, 0V% (marker of sympathetic modulation) was higher in INF compared to ANT [31% (18–43) vs 18% (7–32), p = 0.014]. Moreover, ANT had a higher 2LV%, index of vagal modulation, compared to INF [8% (7–15) vs 5% (2–8), p = 0.006]. Conclusion After pPCI, these preliminary results suggest that patients with INF were characterized by a sympathetic predominance, while ANT by a predominant vagal modulation. Our data suggest that pPCI can be associated with specific autonomic patterns, which are different for ANT and INF STEMI, according to the different autonomic innervation. Future ad hoc studies are needed to confirm these preliminary observations.

Hereditary angioedema (HAE) usually results from C1 inhibitor (C1-INH) deficiency or dysfunction. It is a rare autosomal dominant disorder characterized by localized, non-pitting edema of the skin and submucosal tissues of the upper respiratory and gastrointestinal tracts, without significant wheals or pruritus, due to a temporary increase in vascular permeability. Other forms of HAE have been described, but therapies are approved only for HAE with C1-INH deficiency: hence, this review focuses on C1-INH-HAE.The aim of this review article is to present current available therapies for treatment of acute attacks as well as for short- and long-term prophylaxis of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE). The Authors highlight also critical issues on the management of C1-INH-HAE, which is continuously evolving thanks to evidence from clinical trials, post-marketing experience and ongoing studies.In the last decade, the quality of life of C1-INH-HAE patients has significantly improved due to increased knowledge and awareness of the disease, improved patient support and major progress in pharmacotherapy. Ongoing research will probably provide patients with other new effective therapeutic agents in the near future.

The information carried by heart period (HP) given systolic arterial pressure (SAP) changes was assessed to characterize spontaneous baroreflex (i.e. the relation linking SAP variability to HP variability): the larger the information carried by HP given SAP changes, the greater the unpredictability of HP given SAP variations, the smaller the strength of the causal coupling from SAP series to HP series. It was typified according to two parameters: i) the information carried by HP given SAP changes within the same heart cycle (i.e. 0-step-ahead information) describing immediate effects of SAP variations on HP; ii) the rate of increase of the information carried by HP given SAP changes as a function of the temporal distance, k, between the conditioning SAP pattern and future HP value (i.e. the rate of increase of k-step-ahead information with k) describing short-term effects of SAP modifications on HP. Both parameters were found under vagal control. Indeed, i) 0-step-ahead information suggested that HP and SAP variabilities were significantly coupled from SAP to HP at baseline and after the reduction of the inhibitory effect of sympathetic control on vagal influences performed through the administration of propranolol or clonidine; and ii) during vagal blockade induced by atropine or combined vagal and sympathetic blockade induced by the administration of propranolol after atropine k-step-ahead information reached a level incompatible with coupled HP and SAP dynamics regardless of k. In addition, it was found that the 0-step-ahead information at baseline and after propranolol and the rate of increase of k-step-ahead information with k at baseline could be exclusively explained in terms of linear HP–SAP interactions. Conversely, the same parameters after clonidine suggested the raise of nonlinear mechanisms probably unveiled by the central sympathetic blockade. Comparison with more traditional parameters describing the HP–SAP variability relation such as baroreflex sensitivity and squared HP–SAP coherence confirmed the complementary value of the proposed information domain analysis.

Sleep loss is associated with increased cardiovascular morbidity and mortality. It is known that chronic sleep restriction affects autonomic cardiovascular control and inflammatory response. However, scanty data are available on the effects of acute sleep deprivation (ASD) due to night shifts on the cardiovascular system and its capability to respond to stressor stimuli. The aim of our study was to investigate whether a real life model of ASD, such as "one night on-call", might alter the autonomic dynamic response to orthostatic challenge and modify the immune response in young physicians.Fifteen healthy residents in Internal Medicine were studied before and after one night on-call at Rest and during a gravitational stimulus (head up-tilt test, HUT). Heart rate variability (HRV), blood pressure variability (BPV) and baroreflex sensitivity (BRS) were analyzed during Rest and HUT before and after ASD. Plasmatic hormones (epinephrine, norepinephrine, cortisol, renin, aldosterone, ACTH) and tissue inflammatory cytokines were measured at baseline and after ASD.HRV analysis revealed a predominant sympathetic modulation and a parasympathetic withdrawal after ASD. During HUT, the sympathovagal balance shifted towards a sympathetic predominance before and after ASD. However, the magnitude of the autonomic response was lower after ASD. BPV and BRS remained unchanged before and after ASD as the hormone levels, while IFN-γ increased after ASD compared to baseline.In summary, one night of sleep deprivation, at least in this real-life model, seems to affect cardiovascular autonomic response and immune modulation, independently by the activation of the hypothalamic-pituitary axis.

The definition of angioedema is an edema of subcutaneous and submucosal tissues due to increased vascular permeability and fluid extravasation. It can affect different areas, including extremities, genitals, upper airways and intestinal mucosa. The symptoms are disabling and this condition can be fatal if it involves the larynx. We can distinguish different forms of angioedema (hereditary and acquired) with different pathogenetic mechanisms, therefore responding to different treatments. Bradykinin-mediated angioedema (such as hereditary angioedema due to C1-inhibitor deficiency) does not respond to the standard therapy used for histamine-mediated angioedema. These forms should be immediately recognized and specific treatment should be used. In addition, when a patient manifests hypotension not responding to fluid replacement and associated with diffuse edema, hypoalbuminemia and hemoconcentration, we should consider the diagnosis of idiopathic systemic capillary leak syndrome, a very rare but fatal condition.

Background Attacks of Hereditary Angioedema due to C1-inhibitor deficiency (C1-INH-HAE)are often triggered by stressful events/hormonal changes. Objective Our study evaluates the relationship between autonomic nervous system (ANS) and contact/complement system activation. Methods Twenty-three HAE patients (6 males, mean age 47.5±11.4 years) during remission and 24 healthy controls (8 males, mean age 45.3±10.6 years) were studied. ECG, beat-by-beat blood pressure, respiratory activity were continuously recorded during rest (10') and 75-degrees-head-up tilt (10'). C1-INH, C4, cleaved high molecular weight kininogen (cHK) were assessed; in 16 patients and 11 controls plasma catecholamines were also evaluated. Spectral analysis of heart rate variability allowed extraction of low-(LF) and high-(HF) frequency components, markers of sympathetic and vagal modulation respectively. Results HAE patients showed higher mean systolic arterial pressure (SAP) than controls during both rest and tilt. Tilt induced a significant increase in SAP and its variability only in controls. Although sympathetic modulation (LFnu) increased significantly with tilt in both groups, LF/HF ratio, index of sympathovagal balance, increased significantly only in controls. At rest HAE patients showed higher noradrenaline values (301.4±132.9 pg/ml vs 210.5±89.6pg/ml, p = 0.05). Moreover, in patients tilt was associated with a significant increase in cHK, marker of contact system activation (49.5 ± 7.5% after T vs 47.1 ± 7.8% at R, p = 0.01). Conclusions Our data are consistent with altered ANS modulation in HAE patients, i.e. increased sympathetic activation at rest and blunted response to orthostatic challenge. Tilt test-induced increased HK cleavage suggests a link between stress and bradykinin production.

Background Acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE) is a rare disease with no prevalence data or approved therapies. Objective To report data on patients with C1-INH-AAE followed at Angioedema Center, Milan (from 1976 to 2015). Methods Diagnostic criteria included history of recurrent angioedema without wheals; decreased C1-INH antigen levels and/or functional activity of C1-INH and C4 antigen less than 50% of normal; late symptom onset (>40 years); no family history of angioedema and C1-INH deficiency. Results In total, 77 patients (58% females; median age, 70 years) were diagnosed with C1-INH-AAE and 675 patients with hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) (1 patient with C1-INH-AAE/8.8 patients with C1-INH-HAE). Median age at diagnosis was 64 years. Median time between symptom onset and diagnosis was 2 years. Sixteen patients (21%) died since diagnosis, including 1 because of laryngeal edema. Angioedema of the face was most common (N = 63 [82%]), followed by abdomen (N = 51 [66%]), peripheries (N = 50 [65%]), and oral mucosa and/or glottis (N = 42 [55%]). Forty-eight of 71 patients (68%) had autoantibodies to C1-INH. In total, 56 patients (70%) used on-demand treatment for angioedema including intravenous pdC1-INH 2000 U (Berinert, CSL Behring, Marburg, Germany) (N = 49) and/or subcutaneous icatibant 30 mg (Firazyr, Shire; Milano, Italy) (N = 27). Eventually, 8 of 49 patients receiving pdC1-INH became nonresponsive; all had autoantibodies. Thirty-four patients received long-term prophylaxis with tranexamic acid (effective in 29) and 20 with androgens (effective in 8). Conclusions The incidence of C1-INH-AAE was 1 for every 8.8 patients with C1-INH-HAE. Thirty percent of the deaths were related to the disease. Treatments approved for C1-INH-HAE are effective in C1-INH-AAE, although with minimal differences.

Due to marked heterogeneity of clinical presentations, comprehensive knowledge of angioedema phenotypes is crucial for correct diagnosis and choosing the appropriate therapeutic approach. One of the ways to a meaningful clinical distinction can be made between forms of angioedema occurring “with or without wheals.” Angioedema with wheals (rash) is a hallmark of urticaria, either acute or chronic, spontaneous or inducible. Angioedema without wheals may still be manifested in about 10 % of patients with urticaria, but it may also occur as a separate entity. Several classifications of angioedema as part of urticaria were published over time, while a latest one, released in 2014 (HAWK group consensus, see below), provided a classification of all forms of “angioedema without wheals” distinct from urticaria, which will be the focus of the present review. At this time, the HAWK consensus classification is the best in terms of covering the pathophysiology, mediators involved, angioedema triggers, and clinical expression. According to this classification, three types of hereditary angioedema (genetic C1-INH deficiency, normal C1-INH with factor XII mutations, and unknown origin) and four types of acquired angioedema (C1-INH deficiency, related to ACE inhibitors intake, idiopathic histaminergic, and idiopathic non-histaminergic) are presented. We will review the distinctive clinical features of each phenotype in details.

Angioedema is a localized and self-limiting edema of the subcutaneous and submucosal tissue. Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is the best characterized form of hereditary angioedema. In C1-INH-HAE, the reduced plasma levels of C1-INH cause instability of the contact system with release of bradykinin, the key mediator of angioedema. C1-INH-HAE is characterized by recurrent skin swelling, abdominal pain, and potentially life-threatening upper airways obstruction. Knowledge of the molecular mechanisms leading from C1-INH deficiency to angioedema allowed the development of several therapies.The aim of this review article is to discuss the safety of currently available treatments of C1-INH-HAE. The authors give an insight on the mechanism of action and safety profile of drugs for treatment of acute attacks and for short- and long-term prophylaxis. Evidence from systematic reviews, clinical trials, retrospective studies, and case reports is summarized in this review.C1-INH-HAE is a disabling, life-threatening condition that lasts life-long. Different therapeutic approaches with different drugs provide significant benefit to patients. Safety profiles of these therapies are critical for optimal therapeutic decision and need to be known by C1-INH-HAE treating physicians for appropriate risk/benefit evaluation.

Several clinical and biological features of lymphoproliferative diseases have been associated with an increased risk of developing autoimmune manifestations. Acquired deficiency of C1-inhibitor (C1-INH) (AAE) is a rare syndrome clinically similar to hereditary angioedema (HAE) characterized by local increase in vascular permeability (angioedema) of the skin and the gastrointestinal and oro-pharyngo-laryngeal mucosa. Bradykinin, a potent vasoactive peptide, released from high molecular weight kininogen when it is cleaved by plasma kallikrein (a serine protease controlled by C1-INH), is the mediator of symptoms. In total 46% of AAE patients carry an underlying hematological disorder including monoclonal gammopathy of uncertain significance (MGUS) or B cell malignancies. However, 74% of AAE patients have anti-C1-INH autoantibodies without hematological, clinical or instrumental evidence of lymphoproliferative disease. Unlike HAE patients, AAE patients usually have late-onset symptoms, do not have a family history of angioedema and present variable response to treatment due to the hypercatabolism of C1-INH. Experiments show that C1-INH and/or the classical complement pathway were consumed by the neoplastic lymphatic tissues and/or anti-C1-INH neutralizing autoantibodies. Therapy of AAE follows two directions: 1) prevention/reversal of the symptoms of angioedema; and 2) treatment of the associated disease. Different forms of B cell disorders coexist and/or evolve into each other in AAE and seem to be dominated by an altered control of B cell proliferation, thus AAE represents an example of the strict link between autoimmunity and lymphoproliferation.

Bortezomib-dexamethasone (bort-dex) is effective for relapsed/refractory (R/R) multiple myeloma, but few data are available for elderly patients. The aim of this study was to evaluate efficacy and toxicity of bort-dex in elderly R/R MM patients. We evaluated 81 R/R MM patients treated with bort-dex. Eight of them had light-chain disease. The median age of the patients was 73 years (range 65-89 years). All patients were R/R MM patients and had been treated with melphalan and prednisone with or without thalidomide or bortezomib in the first line or with lenalidomide and dexamethasone in the second line. The median number of previous lines was 2. Thirty-nine (48%) patients received bortezomib intravenously and 42 (52%) patients received bortezomib subcutaneously. The median number of bort-dex cycles was 6 (range 1-11). Fifty-three (65.4%) patients achieved at least a partial response, including eight (11%) patients with complete response and nine (12.5%) patients with very good partial responses. The median duration of response, time to next therapy and treatment-free intervals were 8, 11 and 5 months. Duration of response was significantly longer for patients achieving complete response/very good partial response than for those achieving partial response (7.3 vs. 3.8 months, P=0.03). After a median follow-up of 24 months, 78 patients showed disease progression and 70 died. The median time to progression, progression-free survival and overall survival were 8.9, 8.7 and 22 months, respectively. Peripheral neuropathy occurred in 38 (47%) patients. Our data highlight that bort-dex is effective and tolerable in fit elderly patients, thus justifying the efforts for deeper responses. However, awareness of short-lived responses to bort-dex should lead to a thorough evaluation of the need for maintenance. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Ischemic stroke is a significant cause of mortality and of serious long-term morbidity. It is estimated that cryptogenic stroke (stroke whose underlying causes remain unknown despite a complete work-up,) accounts for about 20–40 % of all ischemic events, one quarter of which tend to be recurrent [1]. Paroxysmal and persistent atrial fibrillation (AF) is a well-recognized cause of ischemic stroke, and the risk may be reduced with anticoagulation. However, only 5 % of patients are diagnosed to have AF after an ischemic stroke. Indeed the use of traditional monitoring techniques may not detect episodes of asymptomatic paroxysmal AF, which might underlie some apparently ‘‘cryptogenic’’ strokes. Therefore, the most effective duration of ECG monitoring has not been determined by current guidelines [2]. Nowadays, external and implanted loop recorders may allow identification of silent AF, thus increasing AF detection rate. However, the effectiveness of prolonged heart rhythm monitoring in patients with cryptogenic stroke is still unproved [3, 4].

Background The first classification of angioedema without wheals was recently reported and comprises different forms of the disease distinguished by aetiology, mediator of oedema and inheritance. Methods In total, 1725 consecutive patients with angioedema without wheals were examined at our centre between 1993 and 2012. We excluded from the analysis 667 patients because of incomplete data or because angioedema was related to a specific factor. Results According to the new classification of angioedema, the 1058 patients included in this analysis were diagnosed with hereditary (HAE; n = 377) or acquired angioedema (AAE; n = 681). The former group included HAE with C1-inhibitor (C1-INH) deficiency (C1-INH-HAE; n = 353) and HAE with normal C1-INH levels (n = 24), of which six had a factor XII mutation (FXII-HAE) and 18 had disease of unknown origin (U-HAE). The AAE group included disease with C1-INH deficiency (C1-INH-AAE; n = 49), AAE related to angiotensin-converting enzyme inhibitor treatment (n = 183), idiopathic histaminergic (IH-AAE; n = 379) and idiopathic nonhistaminergic angioedema (InH-AAE; n = 70). We compared hereditary and AAE with uncertain aetiopathogenesis: the FXII-HAE and U-HAE groups pooled (FXII/U-HAE) versus InH-AAE. The median age at onset of FXII/U-HAE and InH-AAE was 26 and 38 years, respectively. In addition, 56% of patients with FXII/U-HAE and 81% of those with InH-AAE reported more than five attacks per year (median duration of 48 h). The location of angioedema in patients with FXII/U-HAE versus those with InH-AAE was the following: face, 70% versus 86%; tongue, oral cavity or larynx, 55% versus 68%; limbs, 70% versus 56%; and gastrointestinal mucosa, 50% versus 20%. Prophylaxis with tranexamic acid was effective in all six patients with U-HAE and in 37 of 38 with InH-AAE who were started on this treatment. Conclusion Our findings in this cohort of patients with angioedema provide new information on the clinical characteristics, diagnosis and treatment of this disease.

Case presentation A 68-year-old man had been suffering from recurrent syncopal episodes for the previous 3 years. These episodes usually lasted about 1 or 2 min, were associated with diaphoresis, and sometimes with chest and epigastric discomfort; they were related to neither exertion nor orthostatic position, and they resolved with a rapid and spontaneous recovery. The frequency of these occurrences had progressively increased, from a few occurrences per year to monthly and sometimes even weekly presentations. The patient had several cardiovascular risk factors: a positive family history for coronary artery disease and stroke; hypercholesterolemia; previous smoking; BMI 29.6 kg/m 2 . His past medical history was remarkable for Helicobacter pylori positive gastroduodenitis, unresponsive to eradication therapy, and a recently diagnosed arterial hypertension. His only medication was simvastatin 20 mg OD.

The treatment and the long-term management of deep vein thrombosis and pulmonary embolism are a delicate challenging topic. A thoughtful evaluation is warranted to balance the possible risks and benefits of antithrombotic therapy. While there is evidence that anticoagulation can be discontinued after 3 months in most of the patients who experience thromboembolism provoked by precise risk factors [1], conclusive data are still lacking concerning the best treatment regimen for patients with unprovoked venous thromboembolism (VTE), which has a higher rate of recurrence [2]. Some trials address the issue of the possible use in these patients of new anticoagulants, which might be valid alternatives to warfarin due to similar efficacy and administration in fixed doses, without the need for laboratory monitoring. Apixaban is an oral factor Xa inhibitor, which has already been shown to be useful for the prevention of stroke in patients with atrial fibrillation (at a dose of 5 mg twice daily) [3] and for thromboprophylaxis after major orthopedic surgery (at a lower dose of 2.5 mg twice daily) [4]. Summary

BackgroundPeripheral intravenous catheterisation is the most commoninvasive procedure in hospitalized patients. In a significantpercentage of patients it can be associated with minorcomplications such as phlebitis and infiltration. Seriouscomplications such as catheter-related bloodstream infec-tions (CRBSI) are fortunately rare, occuring in about 0.1 %of intravenous catheters [1]. A regular removal andreplacement of peripheral intravenous catheters (IVC) hasbeen recommended by the US Centers for Disease Controland Prevention (CDC) to reduce the risks of such com-plications [2].However, such approach may lead to discomfort forpatients requiring additional needdlesticks and increasedworkload for clinical staff. Furthermore, it can be a sig-nificant contributor to health-care costs. For these reasons,IVC are already frequently left in place beyond the cur-rently recommended 72–96 h for appropriate reasons suchas a treatment soon to be completed, poor veins, or noavailable staff to cannulate [3].Small randomized clinical trials showed that IVCreplacement based on clinical indication is safe in terms ofdevelopment of phlebitis and other complications as com-pared to IVC routine replacement every 72–96 h [4, 5].Despite this evidence, the 2011 CDC guidelines designateclinically indicated replacement of IVC as an unresolvedissue, indicating that more research is needed [2].SummaryIn a multicentre, non blinded, randomized controlledequivalence trial Rickard and colleagues [6] investigate thesafety, effectiveness and possible benefits of clinicallyindicated replacement of IVC as compared to routinereplacement. Patients were considered eligible if they wereat least 18 years old and they were scheduled or expectedto have a peripheral IVC in situ for 4 days or more. Theexclusion criteria were current bacteraemia, plannedremoval of IVC within 24 h, IVC already in situ for morethan 72 h, IVC inserted in an emergency. 3,283 patientswere enrolled in three university-affiliated hospitals inAustralia and randomized either to IVC replacement everythird calendar day or to a replacement only after thedevelopment of phlebitis, infusion failure or completion oftherapy (clinically indicated IVC replacement). 1,593patients were assigned to the clinically indicated replace-ment group, 1,690 patients were randomized to the routinereplacement group.The primary endpoint was phlebitis during catheterisa-tion or within 48 h after removal; there were several sec-ondary outcomes, including bloodstream infection,infusion failure and mortality. The routine replacement andclinically indicated replacement of IVC were consideredequivalent if the limits of the two-sided 95 % confidenceinterval (CI) for the absolute risk difference were includedinside the predefined equivalence margin of 3 %.

During general anesthesia positive pressure mechanical ventilation (MV) profoundly affects intrathoracic pressure and venous return, thus soliciting cardiopulmonary reflexes and modifying stroke volume. As a consequence heart period, approximated as the temporal distance between two consecutive R peaks on the ECG (RR), and systolic arterial pressure (SAP) variability series are usually highly correlated at the MV frequency (MVF) and this significant correlation is commonly taken as an indication of an active baroreflex. In this study the involvement of baroreflex was tested according to a time-domain linear Granger causality approach accounting explicitly for MV in two experimental protocols. In the first protocol volatile (VA) or intravenous (IA) anesthetic was administered in humans during pressure controlled MV (PCMV). In the second protocol IA was administered in pigs during PCMV or pressure support MV (PSMV). Causality analysis was contrasted with RR-SAP squared coherence. Significant coherence values at MVF were always found in both protocols. On the contrary, a significant causal link from SAP to RR was less frequently found in humans independently of the anesthesiological strategy and in animals during PCMV. PSMV was superior to PCMV in animals because it was able to better preserve a link from SAP to RR. During general anesthesia the involvement of baroreflex in governing RR-SAP variability interactions is largely overestimated by RR-SAP squared coherence and causality analysis can be exploited to rank anesthesiological strategies and MV modes according to the ability of preserving a working baroreflex. © 2013 Elsevier B.V.