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Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, non-malignant hematologic disease characterized by complement-mediated hemolysis (with or without hemoglobinuria), fatigue, increased susceptibility to thrombosis, and bone marrow dysfunction. The development of complement inhibitors has transformed outcomes for patients with PNH, but patients may still experience pharmacodynamic breakthrough hemolysis (BTH), which can be caused by exposure to a complement amplifying condition (CAC), such as vaccination, infection, or surgery.Materials and methods: A 13-member expert panel used a validated methodology (a RAND/UCLA modified Delphi panel) to develop consensus on how to classify pharmacodynamic BTH in patients with complement-inhibitor treated PNH. Physicians reviewed literature, rated the appropriateness of over 400 scenarios, and discussed the ratings at an in-person meeting.Results: After the meeting, the panel agreed on 77% of scenarios. Here, we present the group’s agreed-upon recommendations on how to manage BTH caused by a CAC, as well as provide a severity classification system for BTH and strategies to mitigate risk of BTH in special circumstances (e.g. vaccination, planned or unplanned surgery, and pregnancy).Discussion: In general, as severity of BTH increased, experts agreed more interventions to manage the BTH were appropriate. These recommendations are based on clinical experience and opinion. Without clear data from randomized trials to guide the management of BTH, expert opinion can be useful to support patient care.

Abstract Background Thrombopoietin receptor agonists (TPO‐RAs) are used to treat primary immune thrombocytopenia (ITP). Some patients have discontinued treatment while maintaining a hemostatic platelet count. Objectives To develop expert consensus on when it is appropriate to consider tapering TPO‐RAs in ITP, how to taper patients off therapy, how to monitor patients after discontinuation, and how to restart therapy. Methods We used a RAND/UCLA modified Delphi panel method. Ratings were completed independently by each expert before and after a meeting. Second‐round ratings were used to develop the panel’s guidance. The panel was double‐blinded: The sponsor and nonchair experts did not know each other’s identities. Results Guidance on when it is appropriate to taper TPO‐RAs in children and adults was developed based on patient platelet count, history of bleeding, intensification of treatment, trauma risk, and use of anticoagulants/platelet inhibitors. For example, it is appropriate to taper TPO‐RAs in patients who have normal/above‐normal platelet counts, have no history of major bleeding, and have not required an intensification of treatment in the past 6 months; it is inappropriate to taper TPO‐RAs in patients with low platelet counts. Duration of ITP, months on TPO‐RA, or timing of platelet response to TPO‐RA did not have an impact on the panel’s guidance on appropriateness to taper. Guidance on how to taper patients off therapy, how to monitor patients after discontinuation, and how to restart therapy is also provided. Conclusion This guidance could support clinical decision making and the development of clinical trials that prospectively test the safety of tapering TPO‐RAs.

Abstract Study Objective Patients with sickle cell disease (SCD) have many emergency department visits because of painful vaso‐occlusive episodes (VOE). Guidelines recommend treatment within 30 minutes of triage, but this is rarely achieved in clinical practice. Our goal was to develop an order set that is being implemented in the ED to facilitate and standardize emergency care for SCD patients in acute pain from VOEs presenting to the emergency department (ED) in New York City (NYC). Methods Using a RAND/University of California, Los Angeles modified Delphi panel, we convened a multidisciplinary panel and reviewed evidence on how to best manage SCD pain in the ED. Panelists collaboratively developed then rated 202 items that could be included in an ED order set. Results A consensus order set, a practical how‐to guide for managing SCD pain in the ED, was developed based on items that received high median ratings. Conclusions The management of acute pain experienced during VOEs is critical to patients with SCD; ED order sets, such as this one, can help standardize pain management, including at triage, evaluation, discharge, and follow‐up care. After implementation in NYC EDs, studies to examine changes in quality care metrics (eg, wait times, readmissions) are planned.

Polysaccharide capsules are important virulence factors for many microbial pathogens including the opportunistic fungus Cryptococcus neoformans. In the present study, we demonstrate an unusual role for a secreted lactonohydrolase of C. neoformans, LHC1 in capsular higher order structure. Analysis of extracted capsular polysaccharide from wild-type and lhc1Δ strains by dynamic and static light scattering suggested a role for the LHC1 locus in altering the capsular polysaccharide, both reducing dimensions and altering its branching, density and solvation. These changes in the capsular structure resulted in LHC1-dependent alterations of antibody binding patterns, reductions in human and mouse complement binding and phagocytosis by the macrophage-like cell line J774, as well as increased virulence in mice. These findings identify a unique molecular mechanism for tertiary structural changes in a microbial capsule, facilitating immune evasion and virulence of a fungal pathogen.

Aim: To review literature on efficacy and safety of octreotide-long-acting repeatable (LAR) used at doses higher than the Food and Drug Administration (FDA)-approved 30 mg/mo for treatment of neuroendocrine tumors (NETs)., Methods: We searched PubMed and Cochrane Library from 1998-2012, 5 conferences (American Society of Clinical Oncology, Endocrine Society, European Neuroendocrine Tumor Society, European Society for Medical Oncology, North American Neuroendocrine Tumor Society) from 2000-2013 using MeSH and keyterms including neuroendocrine tumors, carcinoid tumor, carcinoma, neuroendocrine, and octreotide. Bibliographies of accepted articles were also searched. Two reviewers reviewed titles, abstracts, and full-length articles. Studies that reported data on efficacy and safety of ≥ 30 mg/mo octreotide-LAR for NETs in human subjects, published in any language were included in the review., Results: The search identified 1086 publications, of which 238 underwent full-text review (20 were translated into English); 17 were included in the review. Studies varied in designs, subjects, octreotide-LAR regimens, and definition of outcomes. Eleven studies reported use of higher doses to control symptoms and tumor progression, although symptom severity and formal quality-of-life analysis were not quantitatively measured. Ten studies reported efficacy, describing 260 subjects with doses ranging from 40 mg/mo or 30 mg/3 wk up to 120 mg/mo. Eight studies reported expert clinical opinion that supported dose escalation of octreotide-LAR up to 60 mg/mo for symptom control and suggested increased doses may be effective at preventing tumor progression. Eight studies reported safety; there was no evidence of increased toxicity associated with doses of octreotide-LAR > 30 mg/mo., Conclusion: As reported in this review, octreotide-LAR at doses > 30 mg/mo is being prescribed for symptom and tumor control in NET patients. Furthermore, expert clinical opinion provided support for escalation of somatostatin analogs for refractory hormonal symptoms.