Methacholine Challenges: comparison of different tidal breathing challenge methods

Tidal breathing methacholine challenges are now recommended by guidelines, to avoid the bronchoprotective effects of deep inhalation. This study compared different tidal breathing methacholine challenge methods, assessed the agreement between tidal dosimetric and continuous output challenges, and challenge repeatability with different methods. 15 asthma patients performed dosimetric challenges and a continuous output breath actuated challenge, all at least 3 days apart. All subjects had a pre-bronchodilator forced expired volume in 1 s (FEV1) ≥65% predicted, and PD20 <1.2 mg. Of the dosimetric challenges, one method increased methacholine concentration (standard dosimetric challenge), and one adjusted nebuliser output time to increase dose (adjusted dosimetric challenge). The adjusted dosimetric and continuous output challenges were performed twice on separate days to assess for repeatability. All challenges were matched for dose at each dose step. The mean PD20 ratio of the standard dosimetric challenge to the adjusted dosimetric challenge was 0.90 (CI: 0.66–1.23; p=0.49), and intraclass correlation coefficient (ICC)=0.82. Repeated adjusted dosimetric challenges had an ICC=0.62 for PD20. Repeated continuous output challenges had an ICC =0.74 for PD20. The adjusted dosimetric and continuous output challenges correlated (r=0.69, p=0.0043; ICC: 0.65), but PD20 was higher for the adjusted dosimetric challenge (mean PD20 ratio=2.31; CI: 1.57–3.40; p=0.0004). Tidal dosimetric methacholine challenge using adjustment of nebuliser output produces results with good repeatability. The results of this adjusted dosimetric method differed from the continuous output method, underscoring that the results of different methacholine challenge methodologies may not be directly comparable.

Outcomes from an inpatient beta-lactam allergy guideline across a large US health system

Objective:To assess the safety of, and subsequent allergy documentation associated with, an antimicrobial stewardship intervention consisting of test-dose challenge procedures prompted by an electronic guideline for hospitalized patients with reported β-lactam allergies.Design:Retrospective cohort study.Setting:Large healthcare system consisting of 2 academic and 3 community acute-care hospitals between April 2016 and December 2017.Methods:We evaluated β-lactam antibiotic test-dose outcomes, including adverse drug reactions (ADRs), hypersensitivity reactions (HSRs), and electronic health record (EHR) allergy record updates. HSR predictors were examined using a multivariable logistic regression model. Modification of the EHR allergy record after test doses considered relevant allergy entries added, deleted, and/or specified.Results:We identified 1,046 test-doses: 809 (77%) to cephalosporins, 148 (14%) to penicillins, and 89 (9%) to carbapenems. Overall, 78 patients (7.5%; 95% confidence interval [CI], 5.9%–9.2%) had signs or symptoms of an ADR, and 40 (3.8%; 95% CI, 2.8%–5.2%) had confirmed HSRs. Most HSRs occurred at the second (ie, full-dose) step (68%) and required no treatment beyond drug discontinuation (58%); 3 HSR patients were treated with intramuscular epinephrine. Reported cephalosporin allergy history was associated with an increased odds of HSR (odds ratio [OR], 2.96; 95% CI, 1.34–6.58). Allergies were updated for 474 patients (45%), with records specified (82%), deleted (16%), and added (8%).Conclusion:This antimicrobial stewardship intervention using β-lactam test-dose procedures was safe. Overall, 3.8% of patients with β-lactam allergy histories had an HSR; cephalosporin allergy histories conferred a 3-fold increased risk. Encouraging EHR documentation might improve this safe, effective, and practical acute-care antibiotic stewardship tool.

New European urticaria guideline. What’s new?

Urticaria is a disease which symptoms are caused by the activation and degranulation of the mast cells (MC). Urticaria and angioedema persisting for more than 6 weeks is concerning to be the chronic form of the disease (CU). Chronic spontaneous urticaria (CSU) is the most common subtype of CU and has a great negative impact on all aspects of the patient’s life, causing a decreasing a quality of life, as a burden for a health system and society as a whole. In the present version of the conciliatory document diagnostic approaches in CSU have three goals: to make a differential diagnosis; to evaluate an activity of the disease, its control and the impact on the patient’s life; to identify the triggers of exacerbation or, if possible, the causes of a disease. A basic assessment of disease activity (UAS, AAS), quality of life (CU-Q2oL, AE-QoL) and disease activity control (UCT) are necessary for decisionmaking in the treatment of patients with CSU, better understanding of the disease burden, and documentation improvement and standardization. The aim of a treatment of patients with CSU is the complete control of the symptoms. A therapy should be performed by steps. On the first step a 2nd generation of Hj-antihistamines in standard doses has to be applied. In case of unresponsiveness a dose step-up up to 4 times is recommended, at the third step omalizumab is advised, at the fourth step (inefficiency of omalizumab) - cyclosporine. At any step, it is possible to use a short term course of glucocorticosteroids to set back an exacerbation.

Low-dose gonadotropin induction of ovulation in anovulatory women: still needed in the age of IVF

Low-dose, step-up gonadotropin is the treatment of choice for women with polycystic ovary syndrome (PCOS) who have not conceived after anti-oestrogen treatment and as an effective alternative to pulsatile GnRH in women with hypogonadotropic hypogonadism (HH). There has been, however, no large-scale, comparative study between the two groups using low-dose gonadotropins. Here, we performed a retrospective, comparative analysis, in a single clinic database, of efficacy and safety of induction of ovulation using low-dose gonadotropins in 364 women with PCOS and 80 women with HH. The rate of ovulation was high in both PCOS (83%) and HH (84%) but mono-follicular, ovulatory cycles were more prevalent in PCOS than in HH (77% vs 53%,P < 0.0001) and the proportion of cycles that were abandoned was higher in HH than in PCOS (25% vs 15%,P < 0.0001). The median threshold dose of gonadotropin required to induce ovulation was 75 IU/day in PCOS and 113 IU/day in HH (P < 0.001) and the range of doses was greater in HH women. Forty-nine percent of women with PCOS and 65% of those with HH conceived (more than 90% within 6 cycles of treatment) and had at least one pregnancy. Multiple pregnancies (all twins) occurred in only 4% of women with PCOS and 5% of those with HH. These findings emphasise the efficacy and safety of low-dose gonadotropin treatment for both clomiphene-resistant women with PCOS and those with HH. These results highlight the importance of choosing the more physiological approach of gonadotropin induction of ovulation in both groups as the most appropriate treatment, in preference to IVF.

Omalizumab Dose Step-Up and Treatment Response in Patients with Chronic Idiopathic/Spontaneous Urticaria (CIU/CSU): Results from the OPTIMA Study

not available. Disclosures: Study sponsored by Novartis. Copyright 2018 SKIN

Pathogenesis-Based Development of Potential Mitigation Strategies for Blinatumomab-Associated Neurologic Events (NEs)

Introduction: Blinatumomab (blin), a CD19/CD3 bispecific T-cell engager (BiTE®) antibody construct, has shown clinical efficacy in patients with both B-precursor acute lymphoblastic leukemia (ALL) and B-cell non-Hodgkin lymphoma (NHL). NEs are known blin-associated adverse drug reactions; most NEs occur early during the first treatment cycle and are transient and fully reversible. While NEs are manageable in ALL (favorable risk/benefit profile at a maximum target dose of 28 µg/day), NEs increase in frequency and were dose-limiting in low-grade NHL. The maximum tolerated dose in NHL was 112 µg/day. Here we present translational and single-patient data for potential mitigation strategies for blin-associated NEs. Methods: Pharmacokinetic and pharmacodynamic data from blin clinical studies in NHL and ALL were combined to develop a pathogenetic model for blin-associated NEs. The mitigation potential of substances with antiadhesive properties was studied in vitro in a flow chamber system mimicking blin-induced T-cell redistribution. Three patients with low-grade NHL who had a higher risk of developing NEs due to their low peripheral blood B/T-cell ratios received concomitant pentosan polysulfate (PPS) at infusion start and dose step. ClinicalTrials.gov NCT00274742, NCT00560794, NCT01209286, NCT01471782. Results: T-cell redistribution occurred at infusion start and dose step of blin irrespective of circulating B cells. Concurrently, T cells upregulated the activation marker CD69 and the T-cell adhesion molecule LFA-1 switched from its low to intermediate affinity isoform as shown by binding of soluble ICAM-1. Blood vessel endothelial cells were activated as indicated by release of angiopoietin-2 and clinical signs of peripheral edema. Monocyte and thrombocyte redistribution were also observed. Both B and T cells were detected in cerebrospinal fluid (CSF) of some patients with NEs, and quantifiable blin concentrations were measured in CSF of some patients independent of blood-CSF barrier integrity. A low B/T-cell ratio in peripheral blood (NHL) and/or bone marrow (ALL) has been identified as a potential risk factor for developing NEs. In flow chamber experiments, addition of blin mimicked T-cell redistribution as indicated by reduced T-cell rolling velocity and increased T-cell adhesion to brain microvascular endothelial cells and by upregulation of P-selectin and ICAM-1 adhesion molecules on endothelial cells. Substances potentially interfering with interactions between T cells and endothelial cells (eg, PPS, minocycline) reversed the above-described effects to levels seen without the addition of blin. T-cell kinetics of three patients receiving concomitant PPS at infusion start and dose step showed delayed T-cell redistribution (without circulating B cells) compared with patients without PPS coadministration. These altered T-cell kinetics correlated with less severe NEs; no treatment interruptions or discontinuations were necessary. Finite PPS coadministration had no apparent negative impact on clinical response as two patients achieved an objective response, including one patient who has been in ongoing remission for more than six years. Conclusion: We propose an evidence-based model for the development of blin-associated NEs: 1) First exposure to blin or dose steps increase endothelial adhesiveness of circulating T cells. 2) Adhering T cells activate the endothelium and start extravasating; activated endothelium attracts other circulating leukocytes. 3) At low B/T-cell ratios, extravasated T cells first encountering (rare) B cells in the brain are activated by blin in the perivascular space to locally secret cytokines and chemokines that induce transient neuroinflammation including transmigration of monocytes. 4) Attracted non-T cells and other released factors enhance transient neurotoxicity. Based on this model, T-cell adhesion to blood vessel endothelial cells is the first necessary (but not sufficient) step in the pathogenesis of blin-associated NEs. Coadministration of substances with antiadhesive properties at infusion start and dose steps may offer opportunities to mitigate blin-associated NEs to further improve the safety and efficacy of blin therapy. Disclosures Klinger: Amgen Research (Munich) GmbH: Employment, Equity Ownership, Patents & Royalties: Blinatumomab. Zugmaier:Amgen: Employment, Patents & Royalties. Naegele:Amgen Research (Munich) GmbH: Employment, Equity Ownership, Patents & Royalties. Goebeler:GEmoAb: Consultancy; Novartis: Consultancy; Roche: Consultancy. Brandl:Amgen: Employment. Kufer:AMGEN Research Munich: Employment, Equity Ownership, Patents & Royalties.