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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.

S A T U R D A Y Mike Tankersley, MD, FAAAAI, Alan DeJarnatt, MD, Ross DeJarnatt; University of Tennessee Health Sciences Center, Allergy and Asthma Care. RATIONALE: Galactose-alpha-1,3-galactose hypersensitivity (alphagal) is a recently reported condition associated with the production of specific IgE to this oligosaccharide found in mammalian meat. A registry was maintained of alpha-gal patients to more fully understand this condition in our patient population. METHODS: A retrospective chart review of a single-site Allergy practice in Tennessee was conducted of the clinic’s alpha-gal registry of patients seen from 2010-2015. RESULTS: There were 38 patients diagnosed with alpha-gal hypersensitivity over a five-year period (2010-2015). Patient characteristics included: mean age at diagnosis 50.7 years (range 14-74 years), 44.7% were male (17/38), mean alpha-gal IgE 29.7 kU/L (range 1.1-97.3; two patients excluded from mean with levels >100). Four patients had followup alpha-gal levels which had all decreased: patient 1 (6.2 to 1.9 kU/L after 42 months), patient 2 (23.2 to 8.7 kU/L after 42 months), patient 3 (82.3 to 58.7 kU/L after 34 months) and patient 4 (95.2 to 1.3 kU/L after 48 months). Signs and symptoms included cutaneous pruritus, urticaria, angioedema, hoarseness, dyspnea, nausea, vomiting, diarrhea, lightheadedness, hypotension, and syncope. Culprit foods included beef, pork, venison, cow’smilk, and lamb. Time between onset of signs and symptoms to diagnosis was 1 month-15 years. Time between ingestion and signs/ symptoms was 1-6 hours. CONCLUSIONS: Alpha-gal hypersensitivity is not an uncommon food hypersensitivity as demonstrated by the 38 patients diagnosed in this single-site clinic in Tennessee over a 5-year period. All medical care providers should maintain a high index of suspicion of this condition in patients presenting with anaphylaxis in the absence of an immediate allergen association.

Background Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare disease characterized by recurrent episodes of cutaneous, abdominal and laryngeal edema. Bradykinin is the mediator of increased vascular permeability and edema formation. Treatment of HAE attacks in Italy is based on the administration of human C1 inhibitor or bradykin receptor antagonist. A recombinant human C1 inhibitor (rhC1INH) is marketed in Italy since 2012 for the treatment of HAE in adults. Safety and efficacy of rhC1INH were documented in several phase III trials. This analysis reports characteristics and treatment outcomes of HAE attacks treated with rhC1INH in a real-life setting.