John L. Perez

Protruding atheromas in the thoracic aorta and systemic embolization.

OBJECTIVE To determine whether protruding atheromas in the thoracic aorta are a risk factor for systemic embolization. DESIGN Case-control study. SETTING A referral hospital. PATIENTS A total of 122 patients with a history of stroke, transient ischemic attack, or peripheral emboli and an equal number of age- and sex-matched control patients. MEASUREMENTS Evaluation using transesophageal echocardiography was done in case patients to detect protruding atheromas in the thoracic aorta and in control patients for cardiac indications other than emboli. MAIN RESULTS Matched logistic regression showed that the presence of protruding atheromas was strongly related to the occurrence of embolic symptoms (odds ratio, 3.2; 95% Cl, 1.6 to 6.5; P less than 0.001). Furthermore, atheromas with mobile components were present only in case patients. When known risk factors for stroke (hypertension and diabetes) were added to the model, the presence of protruding atheromas remained an independent risk factor for embolic symptoms (odds ratio, 3.8). Hypertension was also independently associated with embolic symptoms (odds ratio, 2.7), but diabetes was not (odds ratio, 1.0). CONCLUSION Protruding atheromas in the thoracic aorta can be detected by transesophageal echocardiography and should be considered as a cause of strokes, transient ischemic attacks, and peripheral emboli.

High risk for vascular events in patients with protruding aortic atheromas: A prospective study

OBJECTIVES The purpose of this study was to prospectively evaluate the risk of vascular events in patients with protruding aortic atheromas. BACKGROUND Protruding atheromas of the thoracic aorta have been shown to be associated with embolic disease in previous retrospective studies. METHODS During a 1-year period, 521 patients had transesophageal echocardiography. Of these, 42 patients had protruding atheromas and no other source of emboli. They were followed up for up to 2 years (mean follow-up 14 months) and compared with a control group without atheromas, matched for age, gender and hypertension. RESULTS Of 42 patients with atheromas, 14 (33%) had 19 vascular events during follow-up (5 brain, 2 eye, 4 kidney, 1 bowel, 7 lower extremity). Of 42 control patients, 3 (7%) had vascular events (2 brain, 1 eye). Univariate analysis identified only protruding atheromas as significantly correlating with events (p = 0.003). There was no positive correlation of events with age, gender, hypertension, smoking, family history, atrial fibrillation, valve replacement, antithrombotic drug use, diabetes or coronary disease. Multivariate analysis showed that only protruding atheromas independently predicted events (p = 0.005, odds ratio 4.3, 95% confidence interval 1.2 to 15.0). Nine patients died in the atheroma group versus six in the control group, but this was not statistically significant (p = 0.39). CONCLUSIONS Protruding atheromas seen on transesophageal echocardiography predict future vascular events.

Safety, immunogenicity, and tolerability of meningococcal serogroup B bivalent recombinant lipoprotein 2086 vaccine in healthy adolescents: a randomised, single-blind, placebo-controlled, phase 2 trial

BACKGROUND Neisseria meningitidis serogroup B is a major cause of invasive meningococcal disease, but a broadly protective vaccine is not currently licensed. A bivalent recombinant factor H-binding protein vaccine (recombinant lipoprotein 2086) has been developed to provide broad coverage against diverse invasive meningococcus serogroup B strains. Our aim was to test the immune response of this vaccine. METHODS This randomised, placebo-controlled trial enrolled healthy adolescents from 25 sites in Australia, Poland, and Spain. Exclusion criteria were previous invasive meningococcal disease or serogroup B vaccination, previous adverse reaction or known hypersensitivity to the vaccine, any significant comorbidities, and immunosuppressive therapy or receipt of blood products in the past 6 months. Participants were randomly assigned with a computerised block randomisation scheme to receive ascending doses of vaccine (60, 120, or 200 μg) or placebo at 0, 2, and 6 months. Principal investigators, participants and their guardians, and laboratory personnel were masked to the allocation; dispensing staff were not. Immunogenicity was measured by serum bactericidal assays using human complement (hSBA) against eight diverse meningococcus serogroup B strains. The co-primary endpoints were seroconversion for the two indicator strains (PMB1745 and PMB17) analysed by the Clopper-Pearson method. Local and systemic reactions and adverse events were recorded. The study is registered at ClinicalTrials.gov, number NCT00808028. FINDINGS 539 participants were enrolled and 511 received all three study vaccinations--116 in the placebo group, 21 in the 60 μg group, 191 in the 120 μg group, and 183 in the 200 μg group. The proportion of participants responding with an hSBA titre equal to or greater than the lower limit of quantitation of the hSBA assays (reciprcocal titres of 7 to 18, depending on test strain) was similar for the two largest doses and ranged from 75·6 to 100·0% for the 120 μg dose and 67·9 to 99·0% for the 200 μg dose. Seroconversion for the PMB1745 reference strain was 17 of 19 (89·5%) participants for the 60 μg dose, 103 of 111 (92·8%) participants for the 120 μg dose, 94 of 100 (94·0%) participants for the 200 μg dose, and four of 73 (5·5%) participants for placebo. For the PMB17 reference strain seroconversion was 17 of 21 (81·0%) participants for the 60 μg dose, 97 of 112 (86·6%) participants for the 120 μg dose, 89 of 105 (84·8%) participants for the 200 μg dose, and one of 79 (1·3%) participants for placebo. The hSBA response was robust as shown by the high proportion of responders at hSBA titres up to 16. Mild-to-moderate injection site pain was the most common local reaction (50 occurrences with the 60 μg dose, 437 with the 120 μg dose, 464 with the 200 μg dose, and 54 with placebo). Systemic events, including fatigue and headache, were generally mild to moderate. Overall, adverse events were reported by 18 participants (81·8%) in the 60 μg group, 77 (38·9%) in the 120 μg group, 92 (47·2%) in the 200 μg group, and 54 (44·6%) in the placebo group. Fevers were rare and generally mild (one in the 60 μg group, 24 in the 120 μg group, 35 in the 200 μg group, and five in the placebo group; range, 0-6·3% after each dose). Incidence and severity of fever did not increase with subsequent vaccine dose within groups. One related serious adverse event that resolved without sequelae occurred after the third dose (200 μg). INTERPRETATION The bivalent recombinant lipoprotein 2086 vaccine is immunogenic and induces robust hSBA activity against diverse invasive meningococcus serogroup B disease strains and the vaccine is well tolerated. Recombinant lipoprotein 2086 vaccine is a promising candidate for broad protection against invasive meningococcus serogroup B disease. FUNDING Wyeth, Pfizer.

Valve strands are strongly associated with systemic embolization: A transesophageal echocardiographic study

OBJECTIVES We attempted to determine the prevalence of strands on native and prosthetic valves, as detected by transesophageal echocardiography, and to assess the relative risk for systemic emboli associated with these strands. BACKGROUND Fine threadlike strands, seen on native and prosthetic valves by transesophageal echocardiography, have been implicated in systemic embolization. METHODS During a 2-year period, 1,559 patients underwent transesophageal echocardiography at our center. Of these, 41 patients had strands and no other identifiable source of systemic emboli. They were matched for age, gender, history of hypertension and history of smoking with a control group of 41 patients without strands who also had no identifiable source of emboli. The risk of embolization in the two groups was compared. RESULTS Of 1,559 patients studied by transesophageal echocardiography, 86 (5.5%) had strands. Strands were far more common on mitral valves than on aortic valves. Of the patients with strands, 38% had had an event consistent with a systemic embolus, whereas 62% had not. Of 597 patients with an embolic event, 63 (10.6%) had strands, whereas only 23 (2.3%) of 962 patients without emboli had strands. In the case-control study, 33 (83%) of the 41 patients with strands without another source of embolism had emboli compared with only 12 (29%) of the 41 control patients without another source (odds ratio 10.0, 95% confidence interval 3.6 to 27.8, p = 0.00001). CONCLUSIONS Valvular strands visualized by transesophageal echocardiography are associated with systemic embolization.

Protruding atheromas of the aortic arch in symptomatic patients with carotid artery disease

Protruding aortic arch atheromas are associated with otherwise unexplained strokes and transient ischemic attacks. Therefore aortic atheromas also may be important in patients with carotid artery disease. Forty-five patients with > or = 50% carotid stenosis and stroke or transient ischemic attack within 6 weeks underwent transesophageal echocardiographic examination (TEE). They were matched for age, sex, and hypertension with 45 control subjects who had also had a recent cerebral event but in whom significant carotid stenosis was absent. Protruding aortic arch atheromas were present in 17 (38%) of 45 patients with carotid disease and only 7 (16%) of 45 of control subjects (p = 0.02). Mobile atheromas (with the greatest embolic potential) were present almost exclusively in case patients, 6 (13%) of 45, versus 1 (2%) of 45 control subjects (p = 0.05). Case patients with mobile atheromas had the most severe carotid stenosis ( > or = 80%). Cerebral symptoms were discordant with the side of the carotid stenosis in 10 case patients, and 4 had atheromas. In conclusion, protruding atheromas of the aortic arch are present in significant numbers of symptomatic patients with carotid artery disease. These atheromas may represent an additional cause of symptoms in patients with carotid stenosis. TEE to look for protruding aortic atheromas may be considered in patients with neurologic events despite the presence of significant carotid stenosis, especially if the symptoms are discordant with the side of carotid stenosis.

Safety and immunogenicity of a meningococcal B bivalent rLP2086 vaccine in healthy toddlers aged 18-36 Months: a phase 1 randomized-controlled clinical trial

Background: A bivalent, recombinant, factor H–binding protein (rLP2086) vaccine was developed to protect against invasive Neisseria meningitidis serogroup B (MnB) in children and adolescents. Methods: Healthy toddlers (N = 99) were enrolled to 3 ascending dose-level cohorts (20, 60 or 200 &mgr;g). Within each cohort (n = 33), subjects were randomized to receive an initial formulation of the bivalent rLP2086 vaccine at 0, 1 and 6 months or hepatitis A vaccine/placebo control (2:1 ratio). Reactogenicity was assessed by parental reporting of local and systemic reactions using electronic diaries and reports of unsolicited adverse events. Immunogenicity was assessed by serum bactericidal activity assay using human complement and rLP2086-specific IgG binding. Results: The vaccine was considered to be well tolerated. Tenderness was the most frequently reported local reaction. Upper respiratory tract infection was the most commonly reported adverse event and occurred more frequently in the control group. Three cases (200 &mgr;g dose) of severe erythema that did not interfere with limb movement were reported. Four toddlers developed fever >40.0°C, 3 in the 200 &mgr;g group and 1 in the 60 &mgr;g group. Postdose 3, seroconversion (serum bactericidal activity assay using human complement ≥4-fold rise from baseline) was observed in 61.1–88.9% of participants against MnB strains expressing LP2086 variants homologous or nearly homologous to vaccine antigens and 11.1–44.4% against MnB strains expressing heterologous LP2086 variants. Seroconversion was observed in 77.8–100% of participants against additional, exploratory MnB strains expressing vaccine-homologous or heterologous LP2086 variants. Conclusions: This study shows that the bivalent rLP2086 vaccine is well tolerated and immunogenic in toddlers.

A phase 2 open-label safety and immunogenicity study of a meningococcal B bivalent rLP2086 vaccine in healthy adults

BACKGROUND Neisseria meningitidis serogroup B (MnB) is a leading cause of bacterial meningitis and septicemia in adolescents and young adults. No currently licensed and available vaccine has been shown to provide broad protection against endemic MnB disease. A bivalent rLP2086 vaccine based on two factor H-binding proteins (fHBPs) has been developed to provide broad protection against MnB disease-causing strains. METHODS This study assessed the safety and immunogenicity of the final formulation of a bivalent rLP2086 vaccine in 60 healthy adults (18-40 years of age) receiving 120 μg doses at 0, 1, and 6 months. Safety was assessed by collecting solicited reactogenicity data and participant-reporting of adverse events. Immunogenicity was evaluated by human serum bactericidal assay (hSBA) against 5 MnB strains expressing distinct fHBP variants and fHBP-specific immunoglobulin G titre. RESULTS After each immunisation, local reactions such as pain at the injection site and erythema were generally mild or moderate. The most common vaccine-related adverse event was upper respiratory tract infection, which was reported by two participants. Seroprotection (hSBA titres ≥ 1:4) was achieved in 94.3% of participants against a MnB strain expressing the vaccine-homologous fHBP variant A05 and 70.0%-94.7% against MnB strains expressing the heterologous fHBP variants B02, A22, B44, and B24. Seroconversion rates (≥ 4-fold rise in hSBA titres) ranged from 70.0% to 94.7% across the five MnB test strains following the 3-dose vaccination regimen. Immunogenicity responses tended to increase upon subsequent vaccine doses. CONCLUSIONS Bivalent rLP2086 is a promising vaccine candidate for broad protection against MnB disease-causing strains.

Comparison of cardiac catheterization and Doppler echocardiography in the decision to operate in aortic and mitral valve disease

Clinical decisions utilizing either Doppler echocardiographic or cardiac catheterization data were compared in adult patients with isolated or combined aortic and mitral valve disease. A clinical decision to operate, not operate or remain uncertain was made by experienced cardiologists given either Doppler echocardiographic or cardiac catheterization data. A prospective evaluation was performed on 189 consecutive patients (mean age 67 years) with valvular heart disease who were being considered for surgical treatment on the basis of clinical information. All patients underwent cardiac catheterization and detailed Doppler echocardiographic examination. Three sets of two cardiologist decision makers who did not know patient identity were given clinical information in combination with either Doppler echocardiographic or cardiac catheterization data. The combination of Doppler echocardiographic and clinical data was considered inadequate for clinical decision making in 21% of patients with aortic and 5% of patients with mitral valve disease. The combination of cardiac catheterization and clinical data was considered inadequate in 2% of patients with aortic and 2% of patients with mitral valve disease. Among the remaining patients, the cardiologists using echocardiographic or angiographic data were in agreement on the decision to operate or not operate in 113 (76% overall). When the data were analyzed by specific valve lesion, decisions based on Doppler echocardiography or catheterization were in agreement in 92%, 90%, 83% and 69%, respectively, of patients with aortic regurgitation, mitral stenosis, aortic stenosis and mitral regurgitation. Differences in cardiac output determination, estimation of valvular regurgitation and information concerning coronary anatomy were the main reasons for different clinical management decisions. These results suggest that for most adult patients with aortic or mitral valve disease, alone or in combination, Doppler echocardiographic data enable the clinician to make the same decision reached with catheterization data.

A randomized, controlled, phase 1/2 trial of a Neisseria meningitidis serogroup B bivalent rLP2086 vaccine in healthy children and adolescents.

Background: Neisseria meningitidis serogroup B (MnB) is a significant cause of invasive meningococcal disease. Factor H binding protein (also known as LP2086) is a conserved outer membrane neisserial lipoprotein that has emerged as a strong candidate protein antigen for MnB vaccination. This study examined the safety, tolerability and immunogenicity of an initial formulation of a bivalent recombinant LP2086 (rLP2086) vaccine in healthy children and adolescents. Methods: In this randomized, observer-blinded, parallel-group, multicenter trial conducted at 6 centers in Australia, 127 healthy participants aged 8–14 years were assigned to receive 20, 60 or 200 µg of the bivalent rLP2086 vaccine (n = 16, 45 and 45, respectively) or active control (Twinrix, n = 21) at 0, 1 and 6 months. Immunogenicity was assessed before the first dose and 1 month after doses 2 and 3. Local reactions, systemic events and other adverse events were recorded. The primary immunogenicity endpoint was the rate of seroconversion (≥4-fold rise in human complement serum bactericidal assay titer) against MnB strains expressing the homologous A05 or heterologous B02 LP2086 variants. Results: The bivalent rLP2086 vaccine was generally well-tolerated, with mostly mild to moderate local reactions. The most common adverse events, headache and upper respiratory tract infection, occurred with similar frequency in each group. Post-dose 3 seroconversion rates against strains expressing B02 and A05 variants were 68.8–95.3% for rLP2086 recipients and 0% for Twinrix recipients. Conclusions: The bivalent rLP2086 vaccine was well-tolerated and immunogenic in healthy children and adolescents, supporting further evaluation as a broadly protective MnB vaccine.

The Discovery and Development of a Novel Vaccine to Protect against Neisseria meningitidis Serogroup B Disease

Vaccines have had a major impact on the reduction of many diseases globally. Vaccines targeted against invasive meningococcal disease (IMD) due to serogroups A, C, W, and Y are used to prevent these diseases. Until recently no vaccine had been identified that could confer broad protection against Neisseria meningitidis serogroup B (MnB). MnB causes IMD in the very young, adolescents and young adults and thus represents a significant unmet medical need. In this brief review, we describe the discovery and development of a vaccine that has the potential for broad protection against this devastating disease.