FABRY'S DISEASE is an X-linked recessive disorder resulting from deficient activity of the lysosomal hydrolase α-galactosidase A.1-3 The enzymatic defect leads to the progressive accumulation of neutral glycosphingolipids with terminal α-galactosyl moieties (particularly globotriaosylceramide) in the lysosomes of vascular endothelial and smooth-muscle cells throughout the body. In classically affected males, who have no detectable α-galactosidase A activity, the onset of disease manifestations occurs in childhood or adolescence and is characterized by severe acroparesthesias, angiokeratoma, corneal opacities, and hypohidrosis. The cardiac manifestations result from the accumulation of globotriaosylceramide in the myocytes, leading to myocardial failure; in coronary endothelial cells, resulting . . .
The presence of heterophilic antibodies in the serum of a small subpopulation of individuals continues to cause false results for modern-day immunoassays. In order to determine the frequency of heterophilic antibody (HA)-related false positives within our population of positive cardiac troponin I (cTnI) patients, we assayed 200 samples using the original in-house cTnI assay (Abbott AxSYM) and the Bayer ACS:180 cTnI, which we had previously observed to be more effective at blocking HA interference. Four samples were identified as false positives based on discordant results between the two assays, as well as the correction of the false positives by treatment of the samples with heterophilic antibody blocking reagent (HBR). An 'enhanced' version of the AxSYM cTnI reagent was designed to greatly reduce or eliminate HA interference, and has now replaced the original reagents. The present study shows that the enhanced reagent significantly reduced or eliminated much of the HA interference. Comparative studies between the enhanced cTnI reagent and the original Abbott AxSYM cTnI reagent showed excellent correlation and equivalent diagnostic concordance, when HA samples were excluded from the analysis.
The effects on immunoassays of heterophilic antibodies (HAs) in the plasma and serum have been well documented (1)(2)(3)(4)(5). The use of monoclonal mouse antibodies for radioimaging of tumors as well as in the treatment of some cancers often gives rise to human anti-mouse antibodies. HAs can also arise as a result of incidental or occupational exposure to foreign proteins, as in the case of veterinarians, farm workers, and food preparers, or by the presence of domestic animals in the home environment. The prevalence of HAs in the general population has been estimated to be as high as 40% (1). Typically, these antibodies are of the IgG class and recognize epitopes on the Fc portion of the foreign immunoglobulin, although instances where the epitope is located in the Fab region have been reported (6)(7). Additionally, the binding of these antibodies is not always species-specific, making it possible that antigens from two different species can be cross-linked. Although usually not clinically significant, the presence of high titers of these antibodies can lead to analytical errors in commonly used “sandwich” immunoassays by cross-linking the capture and label antibodies in the absence of specific analyte. Such cross-linking by HAs has been shown to lead to falsely increased CK-MB and CA125 (6)(7)(8).
Most modern immunoassays contain nonspecific, “blocker” immunoglobulins originating from the same species as the analyte-specific antibodies in an attempt to limit the effect of HAs; however, the problem persists. We report here a 69-year-old man whose plasma and serum cardiac troponin I (cTnI) concentrations were falsely increased when measured using the Abbott AxSYM® cTnI assay. We demonstrate that HAs accounted for the falsely increased cTnI, and we suggest how to resolve such situations.
A 69-year-old Caucasian man …
Background: Azithromycin 500mg three times a week has been shown to reduce exacerbation rates in severe asthma[Gibson, P.G. et al. ERJ Open Res 2019; 5: 00056-2019]. Aim: To explore the real-world efficacy of azithromycin in a severe asthma cohort. Method: We performed a retrospective review of exacerbations one-year pre and post starting azithromycin in 100 severe asthma patients. Results: After 1 year of treatment an overall reduction of 35% (5.8 to 3.7, p=0.0001) in exacerbations and an improvement in % predicted FEV1 (66.7 v 68.8, p=0.022) was seen (see table 1). The reduction in exacerbations was not affected by radiological presence of bronchiectasis, positive sputum culture or peripheral eosinophilia. In patients with peripheral eosinophilia an average reduction in exacerbations of 23% was seen compared to 40% (2.91 v 4.02, p=0.105) in those without. 60% of our cohort were prescribed azithromycin at 250mg three times a week. Conclusion: Our single centre real world evaluation confirms that azithromycin led to a significant reduction in exacerbations in our severe asthma cohort. 60% took azithromycin at half the dose used in the AMAZES trial, suggesting lower dosing may be possible.
TPS4689 Background: Ipilimumab (Ipi), a fully human monoclonal antibody which blocks CTLA-4, augments antitumor immune responses. Ipi has shown antitumor effects in prostate cancer model systems and clinical activity (via prostate-specific antigen [PSA] declines and RECIST response) in Phase 1/2 investigations in CRPC, with a side effect profile reflective of its mechanism of action. Preclinical data suggest that RT given prior to CTLA-4 blockade may increase antitumor activity. Methods: In this study, pts with CRPC who have progressed during or after D are randomized 1:1 to receive either a single dose of bone-directed RT followed by Ipi 10mg/kg, or RT followed by placebo. Within 2 days of RT administration (up to 5 lesions at 8 Gy on a single day) patients receive their initial dose of Ipi/placebo; Ipi/placebo is then given every 3 weeks for a total of 4 doses. Eligible pts may continue to receive blinded study drug every 12 weeks until they meet treatment stopping criteria, withdraw consent, are lost to follow-up, or study closure. The primary endpoint is overall survival (OS). Secondary endpoints include progression-free survival, pain response, and safety. The study is designed to detect a 3.8 month difference (HR=0.76) in median OS with 90% power and 0.05 2-sided type one error. The enrollment goal is 800 randomized patients, with a single interim analysis for superiority of OS planned at 435 events at approximately 33 months from first patient first visit (ClinicalTrials.gov identifier: NCT00861614). [Table: see text] [Table: see text]
Background: BTS long-term macrolide guidelines [Smith D, et al. Thorax 2020;0:1–35] recommends people with asthma to be prescribed 500mg of azithromycin three times a week; This is found to be effective in reducing exacerbations in the AMAZES trial [Gibson P, et al. ERJ Open Res 2019 5: 00056-2019]. Aim: Our aim was to explore the efficacy of azithromycin in reducing exacerbation frequency in a real life population of severe asthma patients at doses of 750mg per week compared to more than 750mg per week. Method: We performed a retrospective review of patients on azithromycin in our severe asthma clinic looking at their dosage and exacerbation rates 1-year pre- and post-starting the medication. Wilcoxon signed rank test was used to evaluate for reduction in each cohort, and the comparison of both cohorts was evaluated with Mann-Whitney U test. Results: Demographics are shown in Table 1. Over a 12 month period, group A had an average reduction of 1.4 exacerbations (6.1 to 4.4, p=0.0007) compared to group B’s 2.6 exacerbations (5.4 to 2.8, p=<0.00001). There was no significant difference in the reduction of exacerbations between the cohorts (1.4 vs 2.6). Conclusion: Azithromycin is well tolerated and at a dose of 250mg three times per week is effective in reducing number of exacerbations in patients with severe asthma.
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