Specialist Advice Support for Management of Severe Hereditary Angioedema Attacks: A Multicenter Cluster-Randomized Controlled Trial.

STUDY OBJECTIVE: Hereditary angioedema is a rare disease associated with unpredictable, recurrent attacks of potentially life-threatening edema. Management of severe attacks is currently suboptimal because emergency medical teams are often unaware of new specific treatments. The objective of this trial is to test whether a dedicated national telephone care-management strategy would reduce resource use during severe hereditary angioedema attacks. METHODS: We conducted a cluster-randomized multicenter prospective trial of patients with a documented diagnosis of hereditary angioedema (type I, II or FXII hereditary angioedema). Participants were enrolled between March 2013 and June 2014 at 8 participating reference centers. The randomized units were the reference centers (clusters). Patients in the intervention arm were given a national free telephone number to call in the event of a severe attack. Emergency physicians in the SOS-hereditary angiœdema (SOS-HAE) call center were trained to advise or prescribe specific treatments. The primary outcome was number of admissions for angioedema attacks. Economic evaluation was also performed. RESULTS: We included 100 patients in the SOS-HAE group and 100 in the control group. During the 2 years, there were 2,368 hereditary angioedema attacks among 169 patients (85%). Mean number of hospital admissions per patient in the 2-year period was significantly greater in the usual-practice group (mean 0.16 [range 0 to 2] versus 0.03 [range 0 to 1]); patient risk difference was significant: -0.13 (95% confidence interval -0.22 to -0.04; P=.02). Probabilistic sensitivity graphic analysis indicated a trend toward increased quality-adjusted life-years in the SOS-HAE group. CONCLUSION: A national dedicated call center for management of severe hereditary angioedema attacks is associated with a decrease in hospital admissions and may be cost-effective if facilities and staff are available to deliver the intervention alongside existing services.

Dedicated call center (SOS-HAE) for hereditary angioedema attacks: study protocol for a randomised controlled trial.

BACKGROUND: Despite the availability of guidelines for the specific treatment of hereditary angioedema (HAE) attacks, HAE morbidity and mortality rates remain substantial. HAE attacks are a major medical issue requiring specific treatment as well as a considerable socio-economic burden. We report a protocol designed to test whether a dedicated call centre is more effective than usual practice in the management of patients experiencing an HAE attack. METHODS/DESIGN: This prospective, cluster-randomised, single-blind, parallel-group, multicentre trial evaluates the morbidity and consequent socio-economic costs of the management of patients experiencing an HAE attack by a dedicated call centre as compared to usual practice. The trial aims to recruit 200 patients. Patients in the intervention arm are provided with an SOS-HAE card with the call centre's freephone number that they can access in the case of an attack. The centre's mission is to provide recommended expert advice on early home treatment. The centre can route the call to a local emergency medical service with competency in HAE management or even arrange for the drugs needed for the specific treatment of an HAE attack to be sent to the emergency department of the local hospital. The primary outcome measure is the number of hospital admissions for an HAE attack. Each patient will be followed up every 2 months for 2 years. The study has been approved by the ethics committee (Comité de Protection des Personnes d'Ile de France 10; registration number: 2012-A00044-39; date of approval: 19 January 2012). DISCUSSION: The SOS-HAE protocol has been designed to address the handling of attacks experienced by patients with HAE in the home. The proposed trial will determine whether the setting up of a dedicated call centre is more effective than usual practice in terms of reducing morbidity as given by the numbers of hospital admissions. The results are also anticipated to have important implications in terms of socio-economic costs for both healthcare services and patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01679912 .

Observational Study of a French and Belgian Multicenter Cohort of 23 Patients Diagnosed in Adulthood With Mevalonate Kinase Deficiency.

The aim of this study was to describe the clinical and biological features of Mevalonate kinase deficiency (MKD) in patients diagnosed in adulthood. This is a French and Belgian observational retrospective study from 2000 to 2014. To constitute the cohort, we cross-check the genetic and biochemical databases. The clinical, enzymatic, and genetic data were gathered from medical records. Twenty-three patients were analyzed. The mean age at diagnosis was 40 years, with a mean age at onset of symptoms of 3 years. All symptomatic patients had fever. Febrile attacks were mostly associated with arthralgia (90.9%); lymphadenopathy, abdominal pain, and skin lesions (86.4%); pharyngitis (63.6%); cough (59.1%); diarrhea, and hepatosplenomegaly (50.0%). Seven patients had psychiatric symptoms (31.8%). One patient developed recurrent seizures. Three patients experienced renal involvement (13.6%). Two patients had angiomyolipoma (9.1%). All but one tested patients had elevated serum immunoglobulin (Ig) D level. Twenty-one patients had genetic diagnosis; most of them were compound heterozygote (76.2%). p.Val377Ile was the most prevalent mutation. Structural articular damages and systemic AA amyloidosis were the 2 most serious complications. More than 65% of patients displayed decrease in severity and frequency of attacks with increasing age, but only 35% achieved remission. MKD diagnosed in adulthood shared clinical and genetic features with classical pediatric disease. An elevated IgD concentration is a good marker for MKD in adults. Despite a decrease of severity and frequency of attacks with age, only one-third of patients achieved spontaneous remission.

Bradykinin-mediated angioedema: factors associated with admission to an intensive care unit, a multicenter study.

OBJECTIVE: Bradykinin-mediated angioedema is characterized by transient attacks of localized edema of subcutaneous or submucosal tissues and can be life-threatening when involving the upper airways. The aim of this study was to determine the features of acute attacks that might be associated with admission to an ICU. PATIENTS AND METHODS: We carried out a retrospective, multicenter, observational study in consecutive patients attending one of six reference centers in France for acute bradykinin-mediated angioedema attacks. Patients had been hospitalized for an acute episode at least once previously. Acute attacks requiring ICU admission were compared with acute attacks that had not required ICU admission. RESULTS: Overall, 118 acute attacks in 31 patients were analyzed (10 patients with hereditary angioedema, 19 patients with angiotensin-converting enzyme inhibitor-induced angioedema, and two patients with acquired C1-inhibitor deficiency angioedema). In multivariate analysis, upper airway involvement, corticosteroid, and C1-inhibitor concentrate administration were associated with ICU admission. Seven episodes (18%) needed airway protection. The evolution was favorable in 38 of 39 attacks warranting ICU admission: patients were able to get out of the service (mean ICU stay 4±5 days). One death was observed by asphyxiation because of laryngeal swelling. CONCLUSION: Upper airway involvement is an independent risk factor for ICU admission. Corticosteroid use, which is an ineffective treatment, and C1-inhibitor concentrate use are factors for ICU admission. The presence of upper airway involvement should be a warning signal that the attack may be severe.

Detection of hospital outbreaks of influenza-like illness based on excess of incidence rates compared to the community.

The risk of nosocomial influenza-like illness (noso-ILI) compared with that of community-acquired ILI was calculated during 3 influenza seasons (2004-2007) at a 1100-bed university hospital with a total of 21,519 hospitalized patients. Outbreaks of noso-ILI occurred in each season, although a protective effect against noso-ILI was also identified for other wards.

An evidence-based review of the potential role of icatibant in the treatment of acute attacks in hereditary angioedema type I and II.

INTRODUCTION: Icatibant, a first-in-class B2 bradykinin receptor antagonist, appears to have a favorable efficacy and safety profile for the treatment of acute attacks of hereditary angioedema in adults. AIMS: To update the evidence and provide an overview of the available data on icatibant. EVIDENCE REVIEW: Peer reviewed articles published and listed in Medline Search and published updated guidelines for the treatment of acute attacks in hereditary angioedema type I and II in adults were reviewed. The validity and quality of evidence were evaluated. PLACE IN THERAPY: Clinical evidence for the treatment of acute hereditary angioedema attacks with icatibant is strong. Approximately 10% of the patients require a second dose. No serious adverse reactions have been reported. The only significant side effects consistently registered by 90% of patients are transient local pain, swelling, and erythema at the local injection site. CONCLUSION: Subcutaneously administered 30 mg icatibant has been shown to be a safe and efficacious treatment in clinical trials. It is the only specific treatment authorized for self-administration by the subcutaneous route offering increased patient independence.

Influenza vaccination of healthcare workers in acute-care hospitals: a case-control study of its effect on hospital-acquired influenza among patients.

BACKGROUND: In acute-care hospitals, no evidence of a protective effect of healthcare worker (HCW) vaccination on hospital-acquired influenza (HAI) in patients has been documented. Our study objective was to ascertain the effectiveness of influenza vaccination of HCW on HAI among patients. METHODS: A nested case-control investigation was implemented in a prospective surveillance study of influenza-like illness (ILI) in a tertiary acute-care university hospital. Cases were patients with virologically-confirmed influenza occurring ≥ 72 h after admission, and controls were patients with ILI presenting during hospitalisation with negative influenza results after nasal swab testing. Four controls per case, matched per influenza season (2004-05, 2005-06 and 2006-07), were randomly selected. Univariate and multivariate conditional logistic regression models were fitted to assess factors associated with HAI among patients. RESULTS: In total, among 55 patients analysed, 11 (20%) had laboratory-confirmed HAI. The median HCW vaccination rate in the units was 36%. The median proportion of vaccinated HCW in these units was 11.5% for cases vs. 36.1% for the controls (P = 0.11); 2 (20%) cases and 21 (48%) controls were vaccinated against influenza in the current season (P = 0.16). The proportion of ≥ 35% vaccinated HCW in short-stay units appeared to protect against HAI among patients (odds ratio = 0.07; 95% confidence interval 0.005-0.98), independently of patient age, influenza season and potential influenza source in the units. CONCLUSIONS: Our observational study indicates a shielding effect of more than 35% of vaccinated HCW on HAI among patients in acute-care units. Investigations, such as controlled clinical trials, are needed to validate the benefits of HCW vaccination on HAI incidence in patients.

Safety and efficacy of rituximab treatment for vasculitis in hepatitis B virus-associated type II cryoglobulinemia: a case report.

INTRODUCTION: Systemic B-cell depletion and clinical remission of the systemic effects of cryoglobulins have already been achieved using rituximab in hepatitis C virus-positive immunocompetent patients. Conversely, to the best of our knowledge there are no reports in the literature regarding the use of rituximab in hepatitis B virus-associated cryoglobulinemia. CASE PRESENTATION: We report here the case of a 60-year-old Caucasian man who presented with hepatitis B virus-associated type II cryoglobulinemia with severe multisystem disease, including membranoproliferative glomerulonephritis with acute renal failure. The vasculitis was refractory to conventional and antiviral therapy but rituximab use led to a fall in cryoglobulin levels and disease control. The B-cell depletion was safe and efficient to induce a complete remission of the disease. CONCLUSION: Our case highlights the benefit and the efficacy of rituximab in association with antiviral therapy in small vessel vasculitis related to hepatitis B virus-associated mixed cryoglobulinemia.

Influenza vaccine effectiveness among adult patients in a University of Lyon hospital (2004-2009).

The aim of this study was to estimate influenza vaccine effectiveness (IVE) against laboratory-confirmed influenza among hospitalized patients. A case-control investigation was based on the prospective surveillance of influenza-like illness (ILI) during five flu seasons. We compared influenza-positive cases and influenza-negative controls. Unadjusted overall IVE was 62% (95% confidence interval 24% to 81%). We found that IVE was lower during the 2004-05 flu season (11%; 95% CI -232% to 76%) when the vaccine and circulating viruses were mismatched. Expansion of the study to other hospitals could provide IVE estimates earlier in the season, for different age groups and emerging virus strains.

Rituximab plus Peg-interferon-alpha/ribavirin compared with Peg-interferon-alpha/ribavirin in hepatitis C-related mixed cryoglobulinemia.

Treatment of hepatitis C (HCV)-mixed cryoglobulinemia (MC) may target either the viral trigger (HCV) or the downstream B-cell clonal expansion. Prospective cohort study of 38 HCV-MC patients who received a combination of rituximab (375 mg/m(2)) once a week for 1 month followed by Peg-interferon-alpha (Peg-IFN-alpha; 2a, 180 microg or 2b, 1.5 microg/kg) weekly plus ribavirin (600-1200 mg) daily for 48 weeks were compared with 55 HCV-MC patients treated by Peg-IFN-alpha/ribavirin with the same modalities. In the whole population of HCV-MC patients (n = 93), a complete clinical response was achieved in 73.1% (68 of 93), cryoglobulin clearance in 52.7% (49 of 93), and a sustained virologic response in 59.1% (55 of 93). Compared with Peg-IFN-alpha/ribavirin, rituximab plus Peg-IFN-alpha/ribavirin-treated patients had a shorter time to clinical remission (5.4 +/- 4 vs 8.4 +/- 4.7 months, P = .004), better renal response rates (80.9% vs 40% of complete response, P = .040), and higher rates of cryoglobulin clearance (68.4% vs 43.6%, P = .001) and clonal VH1-69(+) B-cell suppression (P < .01). Treatment was well tolerated with 11% of discontinuation resulting from antiviral therapy and no worsening of HCV RNA under rituximab. Our findings indicate that rituximab combined with Peg-IFN-alpha/ribavirin is well tolerated and more effective than Peg-IFN-alpha/ribavirin in HCV-MC.

Reactive hemophagocytic syndrome in adult-onset Still disease: clinical features and long-term outcome: a case-control study of 8 patients.

Reactive hemophagocytic syndrome (RHS) is a rare, life-threatening, and little-known complication of rheumatic diseases. This disorder is characterized by fever, pancytopenia, liver failure, coagulopathy, and neurologic symptoms. RHS may develop in patents who have lymphoma, organ transplantation, serious infection, and rheumatic diseases, most notably systemic lupus erythematosus and adult-onset Still disease (AOSD). Observations of specific cases of RHS in AOSD remain rare, and the significance of this syndrome during the course of AOSD remains unknown. We retrospectively studied 16 episodes of AOSD-associated RHS in 8 patients. To determine whether RHS is associated with a particular phenotype of AOSD, we conducted a case-control study from the cohort of AOSD patients seen during the same period. The estimated frequency of RHS in AOSD patients from our cohort was 15.3% (8/52). The median age at RHS diagnosis was 44.5 years. We collected clinical and laboratory data. RHS was the first manifestation of AOSD in 7 cases. The main symptoms were fever (n = 8), salmon rash (n = 6), arthralgia (n = 7), lymphadenopathy (n = 6), and shock (n = 4). Serum ferritin concentration was consistently elevated (>1000 microg/L in 8 cases), and the level of glycosylated ferritin was low in all cases (<5% in 7 cases, 15% in 1 case). Six patients presented with coagulopathy; hypertriglyceridemia was found in 6 cases. Admission to the intensive care unit was required in 4 cases. Treatment included corticosteroids (n = 8) and intravenous immunoglobulin (n = 6), cyclophosphamide in 2 cases, infliximab in the same 2 cases, and cyclosporine in 1 case. With a follow-up ranging from 2 to 15 years, the patients were in remission with prednisone plus methotrexate (n = 4), prednisone plus infliximab (n = 2), and low-dose prednisone alone (n = 2). We compared the 8 patients included in this study with 44 control patients with AOSD without RHS. Low haptoglobin levels, very high ferritin levels (>10,000 microg/L), and a normal or low neutrophil count seem to be predictive factors of the occurrence of RHS in AOSD.

Efficacy and tolerability of rituximab with or without PEGylated interferon alfa-2b plus ribavirin in severe hepatitis C virus-related vasculitis: a long-term followup study of thirty-two patients.

OBJECTIVE: To report on the long-term followup of a cohort of patients with hepatitis C virus (HCV)-related vasculitis treated with rituximab with or without PEGylated interferon alfa-2b (PEG-IFN alfa-2b) plus ribavirin. METHODS: The study group comprised 32 HCV RNA-positive patients with HCV-related vasculitis: 20 patients were treated with rituximab and PEG-IFN alfa-2b (9 of whom had not previously received antiviral treatment and 11 of whom had experienced disease resistance to or relapse with antiviral treatment), and 12 antiviral-intolerant patients were treated with rituximab alone. RESULTS: Treatment with rituximab and PEG-IFN alfa-2b plus ribavirin induced a complete clinical response and a partial clinical response in 80% and 15% of patients, respectively, a complete immunologic response and a partial immunologic response in 67% and 33% of patients, respectively, and a sustained virologic response in 55% of patients. Treatment with rituximab alone induced a complete clinical response and a partial clinical response in 58% and 9% of patients, respectively, and a complete immunologic response and a partial immunologic response in 46% and 36% of patients, respectively. B cell depletion was achieved in 96% of patients, and B cell recovery began after a median delay of 12 months. After a mean+/-SD followup period of 23+/-12 months, 22% of patients experienced a clinical relapse, and 34% of patients experienced an immunologic relapse. All relapses were associated with the absence of virologic control, and 78% of relapses were associated with B cell recovery. Six patients were re-treated with rituximab. All 6 of these patients had a complete clinical response, 50% had a complete immunologic response, and 50% had a partial immunologic response. Rituximab was well tolerated overall. CONCLUSION: Rituximab is an effective treatment of severe and/or refractory HCV-related vasculitis. Relapses were consistently associated with the absence of virologic control. The clinical and immunologic efficacy of rituximab after repeated infusion appeared to be the same as that observed after induction therapy.

Successful treatment of cytomegalovirus-associated hemophagocytic syndrome by intravenous immunoglobulins.

Virus-associated hemophagocytic syndrome (VAHS) is a rare complication in early cytomegalovirus (CMV) infection. There is no standard therapy for VAHS and the clinical course is variable. Data on the use of intravenous immunoglobulin (IVIG) in the treatment of CMV-associated VAHS are limited. We report a previously healthy, 32-year-old woman who presented with general malaise, fever, chills, and splenomegaly. Laboratory examination showed marked elevation of aminotransferase, leucopoenia, and thrombocytopenia. Acute CMV-infection was documented by the presence of immunoglobulin M anti-CMV and positive viremia in blood sample. Bone marrow examination revealed extensive hemophagocytosis. IVIG was administered after the diagnosis of CMV-associated VAHS. Her symptoms and laboratory abnormalities improved dramatically after the onset of the treatment and she did not require antiviral agent.

Marked improvement of Churg-Strauss vasculitis with intravenous gamma globulins during pregnancy.

Churg-Strauss syndrome (CSS) is an extremely rare disease, and even less common in women of childbearing age. Patients with severe disease or those who are un-responsive to corticosteroids are usually treated with cytotoxic drugs, especially cyclophosphmide. Intravenous immunoglobulin (IVIg) has became a promising, but not completely accepted, form of treatment for systemic vasculitis that is un-responsive to standard therapy. We report a case of a woman who presented with a CSS flare during pregnancy. Because of mono-neuritis, treatment with IVIg was instituted with successful results. Our case not only supports the beneficial effect of IVIg in CSS, but it also illustrates its successful and safe use in a patient who was pregnant. We discuss the indication of IVIg during the course of anti-neutrophil cytoplasm antigen (ANCA) vasculitis during the pregnancy.

Spontaneous proximal deep vein thrombosis in a patient with severe haemophilia A.

Venous thrombosis is a very rare occurrence in patients with haemophilia A. The majority of these cases occurred during or after the administration of clotting factor concentrates. We report the case of a patient with severe haemophilia A, who spontaneously developed a deep venous thrombosis (DVT). The thrombosis occurred in the superficial femoral vein with an extension in the profunda femoris vein. Neither any local anatomic compression nor any predisposing thrombophilic risk factors were identified. Treatment with recombinant factor VIII at prophylactic doses associated with unfractionated heparin led to a successful resolution. This case illustrates the possibility for severe haemophilia patients to develop authentic spontaneous DVT without anti-haemophilic treatment and predisposing risk factors.