PurposeFunctional status and chronic health status are important baseline characteristics of critically ill patients. The assessment of frailty on admission to the intensive care unit (ICU) may provide objective, prognostic information on baseline health. To determine the impact of frailty on the outcome of critically ill patients, we performed a systematic review and meta-analysis comparing clinical outcomes in frail and non-frail patients admitted to ICU.MethodsWe searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PubMed, CINAHL, and Clinicaltrials.gov. All study designs with the exception of narrative reviews, case reports, and editorials were included. Included studies assessed frailty in patients greater than 18 years of age admitted to an ICU and compared outcomes between fit and frail patients. Two reviewers independently applied eligibility criteria, assessed quality, and extracted data. The primary outcomes were hospital and long-term mortality. We also determined the prevalence of frailty, the impact on other patient-centered outcomes such as discharge disposition, and health service utilization such as length of stay.ResultsTen observational studies enrolling a total of 3030 patients (927 frail and 2103 fit patients) were included. The overall quality of studies was moderate. Frailty was associated with higher hospital mortality [relative risk (RR) 1.71; 95% CI 1.43, 2.05; p < 0.00001; I 2 = 32%] and long-term mortality (RR 1.53; 95% CI 1.40, 1.68; p < 0.00001; I 2 = 0%). The pooled prevalence of frailty was 30% (95% CI 29–32%). Frail patients were less likely to be discharged home than fit patients (RR 0.59; 95% CI 0.49, 0.71; p < 0.00001; I 2 = 12%).ConclusionsFrailty is common in patients admitted to ICU and is associated with worsened outcomes. Identification of this previously unrecognized and vulnerable ICU population should act as the impetus for investigating and implementing appropriate care plans for critically ill frail patients. Registration: PROSPERO (ID: CRD42016053910).Electronic supplementary materialThe online version of this article (doi:10.1007/s00134-017-4867-0) contains supplementary material, which is available to authorized users.

Summary. Successful factor (F) VIII replacement therapy in hemophilia A patients is confounded by the generation of inhibitory anti-FVIII antibodies (Ab) in 25-30% of treated patients. These antibodies, termed ÔinhibitorsÕ, significantly increase morbidity within the hemophilia population and lower the quality of life for these patients. For the past 30 years, immune tolerance induction (ITI) has been the standard therapy to elicit immunological tolerance to FVIII in the clinic. ITI works well in approximately 75% of patients, but it is expensive, can take years to show effect and is in many cases practically challenging. Therefore, new immunological tolerance induction strategies are now being designed and tested in hemophilia A animal models. This review attempts to provide a comprehensive description, at both the cellular and molecular levels, of these novel advances in tolerance induction and immunomodulation of FVIII. We begin by briefly reviewing why and how the immune system generates a protective response against exogenous FVIII. This leads to a discussion of the latest advances in FVIII tolerance/immunomodulation technology. These advances include interesting methodologies to induce B cell specific tolerance in FVIII primed humans and animals, as well as newer T cell-specific therapies that modify and/or block co-stimulation. We also discuss methods to manipulate FVIII loading of antigen-presenting cells.

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IntroductionHemophilia A is the most common severe inherited bleeding disorder. Patients with this disease are treated with recombinant or plasma-derived factor VIII (FVIII), which allows them to lead relatively normal lives. 1 In approximately 25% of treated patients, however, the development of anti-FVIII antibodies (FVIII inhibitors) severely complicates FVIII replacement therapy and significantly increases morbidity within the hemophilia population. [2][3][4][5] These antibodies neutralize the procoagulant cofactor activity of FVIII or enhance its clearance from plasma. 5 In economically developed countries, there are 2 approaches to the clinical management of FVIII inhibitors: the treatment or prevention of bleeding and long-term immune tolerance induction (ITI). Bleeding is controlled with variably effective and expensive FVIII-bypassing agents, such as recombinant (r) FVIIa and FEIBA (FVIII-inhibitor bypassing agent). In contrast, ITI is usually attempted through the administration of FVIII at a dose and frequency that depends on the ITI protocol. 6 This treatment approach is practically challenging, costly, and can take months to years to become effective. In light of the significant limitations of the current treatment options, the development of effective, rapid, and economical ITI strategies is a clinical priority.Currently, the most consistent model to study FVIII inhibitors is the hemophilia A mouse (FVIII Ϫ/Ϫ ). [7][8][9] Repeated intravenous infusion of human FVIII into hemophilia A mice results in high titer inhibitor formation. This is a CD4 ϩ T cell-dependent process that requires costimulation. [9][10][11][12] The dependence on CD4 ϩ T cells for inhibitor formation also occurs in humans. Evidence of this first came from hemophilia A patients with FVIII inhibitors who were also HIV ϩ : as patient CD4 ϩ levels declined, there was concomitant disappearance of FVIII inhibitors. 13 Therefore, therapies that blocked T-cell activation seemed to be promising candidates to prevent inhibitor formation.Indeed, Qian et al demonstrated that FVIII Ϫ/Ϫ B7.2 Ϫ/Ϫ doubleknockout mice will not develop anti-FVIII antibodies (Abs) after repeated immunization with FVIII, and that blocking the CD80-CD28 costimulatory interaction with soluble cytotoxic T lymphocyte antigen-4 (CTLA-4)-immunoglobulin (Ig) in FVIII Ϫ/Ϫ mice also prevented inhibitor formation. 10 Additional studies in FVIII Ϫ/Ϫ mice showed that blockade of the CD40-CD40L interaction with anti-CD40L monoclonal Ab (mAb) also protects against FVIII inhibitor formation. 11,12 However, costimulatory blockade must be applied with each FVIII administration to maintain tolerance, and once the blockade is removed, the protective effect is lost. As the potential health risks of long-term costimulatory blockade have not yet been determined and because many hemophilia A patients are treated frequently with FVIII and would most likely need to coadminister blockade with each infusion, this therapy is not a viable option.To reach the clinic, a therapy that induces tole...

This study shows that tolerogenic presentation of cFVIII to the immune system can significantly reduce immunogenicity of the protein.