Maddalena Alessandra Wu

Presentation, diagnosis and treatment of angioedema without wheals: a retrospective analysis of a cohort of 1058 patients

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.

Modulation of sympathetic activity and heart rate variability by ivabradine

AIMS Bradycardic agents are currently used in the treatment of angina and heart failure; direct information on their effects on cardiac sympathetic nerve activity (SNA) may be relevant to their chronic use. The present study evaluates the effect of pacemaker inhibition on SNA; direct nerve recordings and indirect autonomic indexes are compared. METHODS AND RESULTS Experiments were performed in 18 anaesthetized rats. SNA (direct nerve recording) and heart rate variability (HRV) indexes were evaluated in parallel. All parameters were recorded 10 min before to 60 min after administration of the If blocker ivabradine (IVA; 2 mg/kg, i.v.; n = 8) or vehicle (VEH; n = 5). IVA-induced RR interval (RR) prolongation (at 60 min +15.0 ± 7.1%, P < 0.01) was associated with decreased diastolic arterial pressure (DAP; -17.3 ± 8.4%, P < 0.05) and increased SNA (+51.1 ± 12.3%, P < 0.05). These effects were accompanied by increased RR variance (RRσ(2)), which showed strong positive correlation with RR. Frequency-domain HRV indexes (in normalized units) were unchanged by IVA. After baroreceptor reflexes had been eliminated by sino-aortic denervation (n = 5), similar IVA-induced RR prolongation (at 60 min +14.3 ± 5.9%, NS vs. intact) was associated with a larger DAP reduction (-30.9 ± 4.1%, P < 0.05 vs. intact), but failed to affect SNA. CONCLUSIONS (i) IVA-induced bradycardia was associated with increased SNA, resulting from baroreceptor unloading; if this applied to chronic IVA use in humans, it would be of relevance for therapeutic use of the drug. (ii) Whenever mean HR is concomitantly changed, time-domain HRV indexes should not be unequivocally interpreted in terms of autonomic balance.

High prevalence of splenic marginal zone lymphoma among patients with acquired C1 inhibtor deficiency.

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.

Coherence analysis overestimates the role of baroreflex in governing the interactions between heart period and systolic arterial pressure variabilities during general anesthesia

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.

The Janus faces of acquired angioedema: C1-inhibitor deficiency, lymphoproliferation and autoimmunity

Abstract 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.

Current treatment options for hereditary angioedema due to C1 inhibitor deficiency

Introduction: 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. Areas covered: 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. Expert opinion: 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.

Efficacy of on-demand treatment in reducing morbidity in patients with hereditary angioedema due to C1 inhibitor deficiency.

Angioedema due to hereditary deficiency of C1 inhibitor causes temporarily disability. Guidelines recommend early on‐demand treatment of attacks to reduce morbidity. In this prospective observational study, we evaluated the efficacy of on‐demand approach.

The safety of treatments for angioedema with hereditary C1 inhibitor deficiency.

Introduction: 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. Areas covered: 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. Expert opinion: 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.

Laboratory and clinical risk assessment to treat myelodysplatic syndromes.

Abstract Myelodisplastic syndromes (MDS) are heterogeneous myeloid disorders characterized by peripheral cytopenias and increased risk of transformation into acute myelogenous leukemia (AML). MDS are generally suspected in the presence of cytopenia on routine analysis and the evaluation of bone marrow cells morphology and cellularity leads to correct diagnosis of MDS. The incidence of MDS is approximately five cases per 100,000 people per year in the general population, but it increases up to 50 cases per 100,000 people per year after 60 years of age. Typically MDS affect the elderly, with a median age at diagnosis of 65–70 years. Here the current therapeutic approaches for MDS are evaluated by searching the PubMed database. Establishing the prognosis in MDS patients is a key element of therapy. In fact an accurate estimate of prognosis drives decisions about the choice and timing of the therapeutic options. Therapy is selected based on prognostic risk assessment, cytogenetic pattern, transfusion needs and biological characteristics of the disease, comorbidities and clinical condition of the patients. In lower-risk patients the goals of therapy are different from those in higher-risk patients. In lower-risk patients, the aim of therapy is to reduce transfusion needs and transformation to higher risk disease or AML, improving the quality of life and survival. In higher-risk patients, the main goal of therapy is to prolong survival and to reduce the risk of AML transformation. Current therapies include growth factor support, lenalidomide, immunomodulatory and hypomethylating agents, intensive chemotherapy, and allogenic stem cell transplantation. The challenge when dealing with MDS patients is to select the optimal treatment by balancing efficacy and toxicity.

Is clinically indicated replacement of peripheral catheters as safe as routine replacement in preventing phlebitis and other complications

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 %.