Executive Summary from an NHLBI Working Group, November 28 - 29, 2012
The field of Apheresis Medicine incorporates multiple disease conditions, diverse medical specialties; multiple technology platforms, and multiple settings of care delivery. These specific circumstances have created the current situation where research in apheresis applications has been fragmented and insufficient to provide answers to basic scientific questions such as mechanism, relevance, appropriateness, efficacy and comparative value in comparison to other therapeutic modalities. The NHLBI sponsored Working Group for Therapeutic Apheresis formulated the following recommendations for consideration by NHLBI for implementation to expand our understanding of the role of apheresis in provision of the best care to patients.
Recommendation 1. There is a need to establish consortia for Apheresis Medicine to facilitate networking, information exchange and research collaboration among investigators, including junior investigators. These consortia would perform basic science and clinical research and investigate the best pathways to develop biorepositories and to establish data registries.
Justification: The creation of one or more Research Consortia devoted to research in Apheresis Medicine would allow for the establishment and support of a core group of investigators and institutions representing key specialty areas across the spectrum of Apheresis Medicine. An initial focus would be translational research priorities. In addition, we believe that a strong U.S. based consortium would facilitate participation of international investigators and societies, which would improve patient accrual on studies, especially those patients with rare disorders or who have rare indications for apheresis therapy. Such a group would significantly enhance the likelihood of completing high quality studies.
There is increasing national interest in developing new registries, bio-repositories and data-repositories. Very often such efforts do not include information regarding apheresis nor do they consider apheresis information as being important data points. A centralized, well organized and sustainable registry, either established and/or new for Apheresis Medicine, would be of great value to study the outcomes of therapeutic apheresis for different disease conditions. This need is particularly relevant for rare disorders and rare indications, for which a pilot effort is already being undertaken and sponsored by ASFA- the American Society for Apheresis. It is likely that formal or informal consortia could be formed as a result of Recommendation 1. Groups of established and junior investigators can coalesce around particular disease processes or particular therapeutic approaches to develop patient registries and, ideally, biorepositories. These data could then serve as source material for pilot projects, reviews, case series evaluation of practice patterns, guideline adherence, gap analyses and opportunities to formulate meritorious, prospective research projects with high clinical impact. A centralized therapeutic Apheresis Registry could also avoid costly unnecessary duplication of efforts in the field (e.g. with multiple registries for the same disease.
Recommendation 2. The discipline of Apheresis Medicine is complex, dealing with a wide range of diseases and organ systems. Currently there is no "home" for grant applications in Apheresis Medicine. There is a need to specifically charge an existing Study Section, or develop specific funding opportunities to include Apheresis Medicine as it integrates within different medical specialties, e.g., renal, neurology, dermatology, oncology and infectious diseases. Apheresis-oriented proposals should be encouraged and welcome. In the absence of being assigned to a standing Study Section, it would be important to establish ad hoc review panels for applications that address research in Apheresis Medicine or to review potential future Apheresis Medicine initiatives developed by one or more Institutes. There is also merit in the concept of establishing collaborative programs that span several Institutes (e.g. NEI, NCI, NIAID, NIBIB, NIDDK, NINDS, NINR, NHLBI, etc), because they are each, homes for the different disease entities treated by apheresis. Federal funding of Apheresis Medicine, would provide a strong stimulus for researchers and clinicians in other subspecialties, to collaborate with Apheresis Medicine specialists and in so doing, enhance the quality and depth of the translational research effort.
Justification: Current review mechanisms are insufficient to address the needs of the field of apheresis. The multi-disciplinary nature of Apheresis Medicine often excludes or discourages apheresis research within the funding opportunities for single disease entities. The diversity of experience and prerequisite knowledgebase required to evaluate proposals related to therapeutic apheresis is currently under-represented or not present on most NIH Study Sections.
Apheresis spans multiple fields of medicine and technology and successful collaboration with other institutes would be optimal. Proposals with multi-disciplinary approaches should be encouraged and these proposals should be reviewed by experts in the field for their significance, innovation, approach and scientific merit.
Recommendation 3. There is a need to promote Apheresis Medicine as a viable field of research for junior and established investigators. The influx of well-trained junior investigators committed to research in Apheresis Medicine is critical and training grants or mentorship grants that include Apheresis Medicine, should be investigated. Utilization of and integration with existing educational/training programs, such as T32 grants, K23/K24/K25 grants, institutional K12 awards and CTSA educational programs, should be explored.
Justification: It is well recognized that an influx of young investigators is paramount to the success of any field of research. In this case, appropriate support would promote the growth in research output in Apheresis Medicine, leading to entry of new investigators into the field. In addition, it is essential to have a cadre of appropriate mentors available for these junior investigators. These individuals should already have independent funding. It would be helpful to assemble a list of such potential mentors. Networking and trans-institutional initiatives in training or research should be encouraged to develop collaborative methods for funding, and for recruiting and retaining junior investigators in Apheresis Medicine. Considering the immunological impact (both positive and negative) of most apheresis treatments, it would be important to encourage young immunology investigators to perform independent or collaborative apheresis-related research.
Purpose and Background
The National Heart, Lung, and Blood Institute (NHLBI) sponsored the NIH State of the Science Symposium in Therapeutic Apheresis in Bethesda, Maryland, on November 28th and 29th, 2012.
Therapeutic apheresis is the process of transiently removing whole blood from the body, separating it into various components (e.g., cells, plasma, proteins, antibodies, antigen-antibody complexes, lipids, etc.), removing those components that contribute to disease, and then returning the remaining blood with possible addition of a blood component to the body. Several forms of therapeutic apheresis exist: therapeutic plasma exchange (plasma exchange; commonly known as TPE); white cell reduction (leukocytapheresis); platelet reduction (plateletapheresis); red cell exchange (erythrocytapheresis, or RBCX); low-density lipoprotein (LDL) apheresis; and extracorporeal photophoresis (ECP), which involves treating isolated leukocytes ex vivo with 8-methoxypsoralen and then exposing them to ultraviolet light before cells are returned to the patient.
Apheresis Medicine is that discipline of medicine, engineering, and science concerned with the care and management of patients and donors involved in extracorporeal blood separation interventions used in the treatment of disease or in the collection of various blood constituents. Apheresis has an undeserved reputation as an "old" science; one that in recent years has been overtaken at times by newer medical treatments. Yet it still is the only and often life saving treatment for certain conditions. Apheresis remains the go-to procedure for treating many common and rare maladies alike, such as TTP, and new treatment indications are being added. Although many specialists like hematologists, neurologists, nephrologists see the evidence and benefits of therapeutic apheresis in their everyday work, the progress of Apheresis Medicine as a medical specialty has been generally slow. There is lack of good understanding pertaining to basic mechanisms of apheresis and optimal ways of applying apheresis to the improvement of underlying conditions as well as to the ability of apheresis to enhance other treatment modalities.
Thus, the purpose of the Symposium was multifaceted: (a) to discuss the current state of research in apheresis medicine; (b) to identify gaps in knowledge and scientific questions in apheresis medicine; (c) to explore ways of coordinating therapeutic apheresis with other medical disciplines and treatment modalities; (d) to identify and prioritize the most important research questions to be answered in apheresis medicine (within the next 5-10 years); and (e) to offer NHLBI representatives suggestions on how a structured research approach can be applied to the therapeutic apheresis research agenda in coming years. The following questions were raised for all participants to consider:
- What are the scientific opportunities in therapeutic apheresis?
- What are the challenges/barriers to increase therapeutic Apheresis research?
- Should/could consortia of Apheresis Medicine programs be formed under NHLBI auspices?
- How can we encourage more researchers to consider working in this area?
- What are the investigators' perspectives on applying for grants, review process, collaboration?
- Recommendations on key scientific priorities in Therapeutic Apheresis research
- Recommendations from the scientific community on how to develop an NHLBI Therapeutic Apheresis program
- Recommendations on how to enhance collaboration among different scientific communities with Therapeutic Apheresis specialists.
- Recommendations on strategies to successfully implement Therapeutic Apheresis research.
- Recommendations on benchmarks to measure progress.
The first day of the Symposium was devoted to presentations by medical specialists on specific, ongoing, and potential applications of apheresis. Each presentation was followed by a general discussion during which participants raised questions and thoughts for discussion. The second day consisted of an open forum to discuss research prioritization and implementation, which was followed by participants offering NHLBI representatives ideas for establishing a future path for therapeutic apheresis research on the basis of the presentations and discussions that had occurred throughout the Symposium.
State of the Science
An organizing committee of 12 individuals sought input from U.S. medical researchers, practitioners, and investigators to examine the scientific opportunities, challenges, and barriers to increasing therapeutic apheresis research; how more researchers might be encouraged to enter the science related to apheresis medicine; and the investigators' perspectives on collaboration, applying for National Institutes of Health grants, and the grant review process.
In seeking these inputs, the organizing committee established working groups around specific medical specialties and requested concept proposals from researchers and practitioners. The concept proposals were reviewed and ranked by the working groups; and those that received the highest scores and consideration were chosen for presentation and discussion at the Symposium. The remainder of the report consists of a summary of those proposals and associated discussions, which can be used to inform the future Apheresis Medicine research agenda.
A. General discussion
Throughout both days of the Symposium, all participants were invited to actively participate in an open discussion on research prioritization, funding mechanisms, implementation and steps to move forward. In addition, the presented concept proposals were ranked based on scientific quality and priority. Here is the summary of the key points and highlights:
- The organization committee as well as participants expressed their appreciation to the leadership and staff of NHLBI, for providing a home for transfusion medicine and cellular therapies research. The State of Science Symposium was intended to further elevate Therapeutic Apheresis as a specific medical and scientific discipline. A large number of Symposium participants were able to review the state of the science in Therapeutic Apheresis and to explore future research opportunities.
- There are numerous scientific opportunities for meritorious science as there have been limited systematic studies of: a) apheresis mechanisms of immunomodulation, b) apheresis for treatment of novel clinical conditions, c) standardization of apheresis protocols based on disease state, d) new treatment options
- Remaining challenges to apheresis research include:
- Lack of support for apheresis research. The success of obtaining funding for apheresis research is quite variable and may stem from the lack of apheresis expertise on existing review panels.
- Low incidence of some targeted diseases/conditions
- Cost of procedures
- Limited number of centers with ECP or other new technologies (while available outside of US)
- Limited animal models for apheresis
- Lack of infra-structure for apheresis research
- Specific support for Apheresis Medicine will be critical to further basic science and clinical studies in apheresis. Leveraging support from multiple sources will be important, for example, collaboration among different NIH institutes could be considered.
- Apheresis research proposals with innovative ideas, significance, and potential for new directions should be encouraged.
- There is a lack of research in the basic mechanisms of apheresis. Expansion of mechanistic studies is needed to understand how therapeutic apheresis works. More cause-effect types of studies other than correlation studies should be performed in order to understand the mechanisms of apheresis as a treatment modality. For example, it is very evident that there is a need to study ECP mechanisms in order to provide optimal patient care. Comparing apheresis to similar technology such as dialysis, discloses that the other technologies have multiple measurable biological parameters (toxin levels, etc) to guide therapy. However, there are, in general, no such measurements available or no established biomarkers that can be used to guide apheresis therapy. In many cases, this is due to an incomplete understanding of the disease and/or its relationship to, and the potential benefit from, apheresis treatment. As a somewhat “mature” specialty, there are still no answers to some of the basic questions, such as the impact of apheresis on the kinetics of IgG either therapeutic or pathological, or on coagulation factors. In addition, studies are rarely performed to evaluate the use of apheresis, comparing it to other treatment options such as IVIg or rituximab. The cost-effectiveness of apheresis is also under-studied.
- There are a very limited number of animal models available for apheresis research, and studies of the mechanism(s) of action of apheresis have been very limited as well as difficult and expensive to perform. However understanding pathological mechanisms and its relationship to apheresis is critical for optimization and advancement of patient care. High priority should be given to mechanistic studies that will advance our understanding of apheresis and its applicability for treating pathological processes.
- It is challenging to perform high quality clinical outcome studies related to apheresis. Such studies can be expensive, and are often confounded by having competing treatment modalities. However, high quality data providing good evidence of the beneficial effect of apheresis can lead to successful use of apheresis and the potential discovery of new treatment options. For example, take the successful use of plasma exchange in TTP. Forty years after the initial clinical use of plasma exchange as a life saving treatment for TTP, at the time without clear etiology or rational, provided a major scientific breakthrough that not only provided a life saving road to recovery for afflicted patients, but also led to new treatment regimens. With the failing of many available single therapies (drug) and incomplete understanding of many pathological processes, apheresis as a general empirical clinical approach, may offer multiple positive effects and provide for beneficial treatment outcomes. Clinical Apheresis outcome research followed by studies of the mechanisms in these scenarios can lead to better understanding of disease processes and better treatments.
- Establishment of animal models in apheresis should be highly encouraged.
- There is a need to develop standardized treatment regimens based on well designed clinical trials and to investigate applications in novel clinical conditions and optimize apheresis technology. Development and standardization of measurable outcomes is critical for the success of clinical studies in apheresis.
- There is a need to form a research forum and/or consortia in apheresis to engage further discussion and collaboration among practitioners and researchers. Establishment of research infrastructure and multi-level collaboration is critical for the success of apheresis studies. Infrastructure such as multi-center clinical consortia and discussion groups can help with information exchange, better design of study protocols, and importantly patient study accrual.
- Outreach with a multi-discipline approach is critical for the future of Apheresis Medicine. The participation and collaboration among apheresis specialists and non-apheresis specialists as well as among clinical specialists, industry experts, and basic scientists are considered critical for the success of future apheresis clinical trials and/or comparative effectiveness research and apheresis scientific advancement. The impact of such an approach on international collaboration is also an important point to consider. All of these collaborations will be essential to design of good clinical studies with measurable outcomes. This will bring in different views/perspectives from all specialties, and help ensure robust recruitment and the best possible patient care.
- It is critical to engage industry partners in Apheresis technology invention as well as to bring in available technology that is available outside of the US.
- There is a need to establish a National Apheresis Data Registry (currently existing in many other countries) and a National Biorepository. This will facilitate research planning, tracking of adverse apheresis events as well as helping to evaluate therapeutic efficacy, and generate future research ideas.
- Benchmarks may include
- Discovery of new mechanism (s) of action
- Adoption of standardized treatment protocols
- Improved patient outcome
- Expansion of approved clinical indications
- Optimization of technology based on comprehensive understanding of disease and apheresis
- Success in securing grant funding
- Academic professional organizations (AABB, ASFA, CAP, etc.) should also have a role to play in these efforts.
B. Specific area presentation and discussion
I. Cardiovascular Diseases
Acute Myocarditis. Despite an incidence of 36 per 100,000 annually, heart failure from nonischemic dilated cardiomyopathy often resulting from acute myocarditis is responsible for 50% of heart transplants. There is ample evidence that immune mediated pathology, both antibody and cell mediated are important in the pathology of myocarditis heart dilated congestive failure. Several small studies predominately done outside the United States in patients on therapy for at least six months prior to immunoadsoprtion therapy, demonstrated some benefit. Immunoadsorption in acute myocarditis remains untested. Protein A immunoadsorption nonspecifically removes multiple effector proteins including IgG subtypes and cytokines that can mediate cardiac inflammation and impair cardiac contractility. Studies were proposed to dissect the immunological pathways responsible for persistent left ventricular dysfunction using a prospective case control design in patients treated with protein A immunoasdoption therapy.
Peripheral Vascular Disease (PVD). Approximately 8 million Americans have PVD, with the prevalence increasing to about 20% in the elderly. Current therapy for PVD is vascular surgical intervention for limb ischemia combined with medical therapy and antiplatelet agents. LDL is associated with increased risk for development and progression of PVD. Removal of LDL via apheresis in combination with statin therapy in 28 patients with PVD and diabetes resulted in improvement of their Ankle brachial artery pressure index, decreased claudication and foot ulcers, and increased walking distance. Thus, strategies to limit atherosclerotic plaque, and to maintain or improve vascular flow, which might prevent ischemia, have the potential to decrease morbidity, including the loss of limbs, and costs. Studies to assess the addition of LDL apheresis to current conventional therapy are expected to decrease morbidity in patients with PVD and diabetes over conventional therapy alone, and would help determine how long the benefit can be sustained.
II. Hematological and Oncological Diseases
Heparin-induced Thrombocytopenia (HIT). Heparin remains the anticoagulant of choice for many patients undergoing cardiopulmonary bypass or percutaneous coronary surgery. HIT can result in recurrent thrombosis with significant morbidity and mortality. HIT develops in 1-3% of patients treated with unfractionated heparin for 5-10 days. Clinical manifestations of HIT generally result from antibodies that recognize a complex of heparin and platelet factor 4 (PF4) tetramers. Despite treatment with low-molecular-weight heparins and fondaparinux, many patients have few options but to be exposed to heparin, thus HIT continues to be a significant medical problem. TPE shows potential for benefit in some patients with HIT. Studies that determine whether reducing anti-PF4/heparin antibodies in patients undergoing cardiac surgery results in lower morbidity or mortality would be expected to lead to significant improvements in the care of patients with HIT.
Sickle Cell Disease (SCD). SCD occurs in ~1 in every 500 African American births, and results in ~75,000 hospitalizations per year. Pain is the most frequent cause for individuals to seek medical attention and is believed to occur due to ischemia secondary to sickled erythrocyte-mediated small vessel vaso-occlusion. Pain is managed with optimal hydration and aggressive pain relief using opiates and other analgesics. Reports that chronic RBCX therapy can decrease the frequency of pain in patients with recurrent, debilitating, painful crises are generally anecdotal, thus larger and more definitive studies would help determine whether RBCX has a role in the management of pain in patients with SCD.
Acute Myeloid Leukemia (AML). Leukostasis, or symptomatic hyperleukocytosis (white cells >50 000/µL), is a medical emergency in patients with AML. Leukocytapheresis enables rapid reduction of the intravascular leukemic cellular burden and improves patient lives, but it is labor - and cost-intensive, logistically demanding, not universally available, and potentially risky for patients. The pathophysiology of leukostasis is not clear, but there is a clear association between the expression of potential markers (CD56, NCAM, CD11a) and leukostasis development and outcome in certain patients with hyperleukocytic AML Thus, studies were proposed to determine whether early leukapheresis can prevent irreversible leukostasis and reduce mortality, validate the Novotny grading score, and determine whether the CD56 and CD11a adhesion molecules can predict AML in patients at risk for progressive leukostasis and thereby provide markers for future management and therapeutic targets.
III. Extracorporeal Photopheresis
Extracorporeal Photopheresis of Selected Cell Populations to Improve Clinical Responses. ECP is used to suppress the immune response in diseases such as graft versus host disease (GVHD), solid organ transplant rejection, and potentially in autoimmune diseases such as Crohn’s Disease. Interestingly, ECP does not seem to cause general immunosuppression as it is not associated with increased risk of infection. While ECP successfully suppresses the immune disease in many patients, it has no to little benefit in a substantial proportion of patients treated for autoimmune diseases. With increased understanding of the mechanisms underlying ECP, which appears to shift an effector immune response to a regulatory one, therapy could be delivered more appropriately to patients. Targeting specific cell populations for ECP therapy, such as monocytes, pivotal in orchestrating the overall immune response, rather than all leukocytes could further our understanding of the variation in immune response seen in clinical practice. Using a currently available murine model of chronic GVHD, the importance of selected cell populations can be dissected and queried. Learning which cells or combination of cells are required for the beneficial response could potentially help expand the therapy in treatment of immune mediated disorders.
Acute Graft Versus Host Disease (GVHD). Patients who develop acute GVHD undergo toxic therapy with high-dose corticosteroids, often for long durations, resulting in high morbidity and treatment related mortality. Alternatively, T cell depletion from the donor graft to reduce GVHD is associated with high rates of infection and relapse. Targeting other pathways of GVHD pathogenesis may preserve the beneficial immune reconstitution and graft-versus-tumor (GVT) effects while ameliorating the severity of GVHD. One such pathway involves regulatory T cells (Tregs), which inhibit T cell alloreactivity, and are correlated with the incidence and severity of GVHD without loss of GVT. Studies were proposed to examine whether early and intensified delivery of ECP to standard GVHD prophylaxis will decrease overall steroid exposure while preserving expected relapse rates in patients undergoing unrelated donor hematopoietic stem cell transplant.
Chronic GVHD. A major contributor to late transplant-related mortality, chronic GVHD occurs in approximately 30-50% of allogeneic transplant recipients. Appropriate initial therapy involves high dosages and prolonged use (i.e., 2-3.5 years) of corticosteroids, and patients often develop irreversible sclerotic manifestations of disease. Early intervention prior to disease onset may help prevent disease development or lessen disease severity, requiring less corticosteroid exposure. ECP has resulted in improved Treg levels, which are known to inhibit T cell alloreactivity, and may promote the development of immune tolerance. Prevention of chronic GVHD with ECP might help induce Treg development and promote tolerance at an earlier point after hematopoietic cell transplantation and would be a novel, more easily measured, and desirable end point for a clinical trial. Studies are proposed to determine whether preemptive treatment with ECP will prevent or lessen chronic GVHD severity.
Bronchiolitis Obliterans Syndrome (BOS). Chronic allograft rejection is a frequent complication of lung transplantation and often manifests as BOS. Retrospective studies indicate that ECP as an intervention for BOS is associated with more stable lung function and that patients with early stage BOS are the most likely to improve or to experience stability in lung function. Studies were proposed to examine whether prophylactic ECP reduces the risk of BOS development and BOS severity, and whether initiation of ECP for patients with early stage BOS is associated with improved lung function and patient survival.
Arteritis. Giant cell arteritis (GCA) and Takayasu’s arteritis (TA) are large-vessel, systemic T cell-mediated vasculitides. GCA is a chronic, systemic immune disorder driven by tissue dendritic cells with in situ CD4+ T cell activation and production of Th17 and Th1 T-cell populations. Th17 cells are highly sensitive to steroids and decrease rapidly following treatment. In contrast, γ-IFN-producing Th1 cells are relatively resistant to steroids and account for the majority of T cells in arterial biopsies. Fifty percent of patients with GCA remain steroid-dependent after 2-3 years, with relapse rates of 30-80% during attempts to taper steroid dosage. Adjuvant therapy to reduce steroid dependence in GCA has largely been unsuccessful. Thus, studies were proposed to determine whether ECP can lead to a decrease in glucocorticoid use, a decrease in the rate of relapse, and a decrease in Th1-mediated inflammation in humans and animal models.
Crohn’s Disease (CD) and Ulcerative Colitis. Most patients with CD have chronic but intermittent exacerbations of disease, but 13% of patients experience an unrelenting disease course. The underlying pathogenic mechanism of CD appears to be a consequence of dysregulated immune responses to gut bacteria. Intestinal dendritic cells interact with the microbial environment via pattern recognition receptors (i.e., Toll-like receptors). Granulocytes and monocytes also may contribute to the pathogenesis. Only 50-65% of patients with CD respond to conventional immunosuppressive therapy (e.g., azathioprine, steroids, infliximab) and the regimens are associated with many adverse effects. Two pilot studies have demonstrated safe and effective outcomes using ECP in patients with refractory CD. Granulocyte/monocyte apheresis using the Adacolumn system has shown promising efficacy in open-label, uncontrolled studies of patients with CD and is used widely in Japan, where postmarketing surveillance has shown no serious side effects and high response rates. Thus, studies were proposed to determine whether ECP can promote tolerance and down-regulate inflammatory responses in patients with CD through the generation of tolerogenic dendritic cells and T regulatory cells; whether ECP can be a safe and effective alternative therapy for treating patients with steroid-dependent/intolerant or refractory CD, and whether adsorptive apheresis with the Adacolumn can be an alternative to the use of immunomodulators.
Extracorporeal Photopheresis (ECP) as Therapy for Immunomodulation and Tolerance Induction in a Mouse Model of Cardiac Transplantation. Patients undergoing solid organ transplantation face long term complications from immune suppression required for graft maintenance. These include increased risk of infections, secondary malignancy, repeated episodes of acute graft rejection and developing chronic graft injuries such as fibrosis or allograft vasculopathy in the setting of cardiac transplantation. ECP has been shown to modulate immune activity by decreasing cell mediate effector activities (Th1) and promoting tolerance by increasing T reg cells. In animal models of transplantation, allograft survival can be prolonged by treating donor splenocytes and infusing these cells at the time of transplantation. The exact mechanism of ECP modulation of these splenocytes and ability to prolong graft survival is not clear. The animal studies proposed would provide valuable information about how ECP promotes tolerance in transplantation, offering another avenue of possible pre-transplant conditioning where feasible.
IV. Multiorgan Failure, Infections, and Other Conditions
Malignant Pertussis. Pertussis is the leading cause of infectious death in children under the age of 2 months. The most notable laboratory finding is lymphocytosis, which is caused by the pertussis toxin, although hyperleukocytosis is an independent risk factor for death. Occlusion by leukocytes may be a key to the development of the refractory pulmonary hypertension. Studies were proposed to determine whether apheresis or exchange transfusion might dramatically improve patient survival, and whether double-volume exchange transfusion might be as effective as leukoreduction.
Chronic Idiopathic Urticaria (CIU). A common dermatological disorder of varying severity and unknown etiology, CIU has no identifiable cause for illness in a great majority of patients, although some patients exhibit an autoimmune component to their condition and some have elevated levels of total IgE. Initial therapy typically involves antihistamine drugs with other therapeutic agents such as corticosteroids, and immunomodulatory drugs as second-line therapy. Thus, studies were proposed to determine whether TPE might lower levels of total IgE and antibodies directed toward it on mast cells, and whether TPE used intermittently or as a “bridge modality” might reduce patient morbidity and allow the use of immunomodulatory drugs at lower dosing levels, which would lead to better patient safety and cost savings.
Thrombocytopenia-associated Multisystem Organ Failure. Current management of sepsis includes antimicrobial agents and control of the source of the infection, hemodynamic support including volume and pressors, and oxygenation and ventilatory support. Additional treatments have included administration of corticosteroids, monoclonal antibodies to tumor necrosis factor (TNF), soluble TNF receptor, antithrombin, activated protein C, and tissue factor pathway inhibitor. These therapies have sought to interrupt the cascade of inflammation and anti-inflammatory response by interfering with discreet steps in the cascade. Attempts to block or remove single mediators of sepsis have either failed or have had limited success. Plasma exchange to remove toxic mediators (e.g., TNF, IL-1, IL-2, IL-6, IL-8, leukotrienes, prostaglandins, endotoxin, and TGF-β) involved in perpetuating the syndrome may therefore be more effective than blocking single components of the process. Empiric data from its use in animal models in controlled trials have suggested efficacy. Such studies might have tremendous human significance because sepsis via thrombocytopenia-associated multiple organ failure represent the tenth most common cause of death in the United States.
Babesiosis is a worldwide emerging infectious disease caused by intraerythrocytic protozoal parasites that are transmitted primarily by ticks but also via transfusion of blood products. Tissue inflammation and organ dysfunction are most likely associated with elevated levels of systemic proinflammatory cytokines (i.e., TNF-α, IL-1β, IL-8) in patients experiencing severe babesiosis. Fatality rates vary from 6% to 9% in patients who require hospital admission, but can reach about 20% in immunocompromised hosts and in patients who contracted the disease through blood transfusion. Treatment of severe cases typically consists of antibiotics and apheresis. Apheresis is currently recommended when parasitemia is high, anemia is severe, or specific organ dysfunction is noted. Apheresis can quickly reduce parasitemia, correct anemia, and remove inflammatory mediators. Thus, studies that include proteomics, genomics, and animal models were proposed to identify biomarkers and other targets that would help optimize apheresis treatment. The body of knowledge that would result from these studies could also be relevant for other blood-borne infections such as malaria, anaplasmosis, and ehrlichiosis.
V. Renal Diseases
End-stage Renal Disease (ESRD). In most patients with ESRD, the treatment of choice is kidney transplantation, but more than 30% of American patients are denied access to transplantation or face significant delays in finding acceptable cadaveric donor kidneys due to HLA mismatches/anti-HLA antibodies. In live-donor renal transplantation, a high-dose intravenous IgG-based protocol with or without rituximab, and plasma exchange plus low-dose (100 mg/kg) intravenous IgG protocol is used to overcome the high immunologic risk. Unfortunately, the high dose has the disadvantage of higher antibody-mediated rejection and is subject to higher immunosuppressive therapy, especially if rituximab is being administered. In contrast, plasma exchange plus low-dose intravenous IgG, although less immunosuppressive, has the disadvantage of daily or near-daily plasma exchange, which cannot be easily accommodated in cadaveric renal transplantation. Initiating weekly plasma exchange might decrease panel reactive antibody/donor-specific antibody in sensitized patients with ESRD and might allow earlier time to transplantation, higher transplantation rates, and better patient outcomes.
Atypical Hemolytic Uremic Syndrome (aHUS). The typical form of HUS follows a diarrheal prodrome and is associated with O157:H7 Escherichia coli infections. A diagnosis of atypical HUS relies on lack of associated disease, no criteria for Shiga-toxin HUS, and no criteria for thrombotic thrombocytopenic purpura. During the first year of HUS infection, 65% of all patients die, require dialysis, or have permanent kidney damage. New insights indicate that atypical HUS is caused by uncontrolled activation of the alternative complement system. A growing list of genetic mutations and polymorphisms are now known to increase susceptibility to atypical HUS, primarily involving complement regulatory proteins and leading to complement-mediated endothelial injury. Treatment guidelines currently recommend TPE and plasma therapy to remove mutated circulating complement regulatory components such as CFH, CFI, CFB, and C3 or autoantibodies while replacing absent or deficient complement factors with fresh, frozen plasma. Research to define the role of TPE in the context of eculizumab therapy would be expected to lead to better patient outcomes and earlier discontinuation of eculizumab alone for treatment of sustained atypical HUS.
Antibody-mediated Rejection (AMR). Plasmapheresis has efficacy in decreasing donor-specific antibodies (DSAs), but specific immunoglobulins cannot be selectively removed. Plasmapheresis has the disadvantage of decreasing desired plasma proteins including coagulation factors if albumin is used as replacement fluid, but if plasma is used as replacement solution, there may be increased donor exposure and transfusion risks. Adsorption columns may be useful in treating sensitized renal transplant recipients or patients with AMR via two hypothesized mechanisms. One involves the specific removal of C1q binding antibodies using a developed but discontinued C1q-ligand adsorption column; the other is the removal of specific types of human leukocyte antigen (HLA) antibodies, which shows potential for better safety and efficacy compared with standard plasmapheresis. Such columns have not yet been developed, thus research was proposed to create custom columns capable of removing specific HLA antibodies for eventual use in renal transplantation in patients with DSAs. Such research would also be expected to lead to a personalized apheresis protocol for transplant recipients with clinically significant DSAs.
Focal Segmental Glomerosclerosis (FSGS). The disease is characterized by focal areas of sclerosis of some glomeruli adjacent to intact glomeruli. Most disease is idiopathic and believed to arise from the development of a poorly characterized “permeability factor.” Renal failure is expected in most patients within 3 to 7 years, making transplantation a desirable option to avoid lifelong dialysis. Plasma exchange is considered to be first-line therapy for recurrent FSGS after transplant, but studies supporting its use consist mostly of case reports. Studies were proposed to identify useful biomarkers of podocyte function to monitor FSGS, develop laboratory assessment tools to determine the efficacy of plasma exchange, and to better understand the evolution of the disease after renal transplantation.
Treating donor-derived leukocytes to induce donor-specific tolerance in kidney transplant. In a preliminary study, a single infusion of ECP-treated donor splenocytes 7 days before heterotopic cardiac transplant significantly prolonged graft survival in a mouse model. This suggests that donor splenocytes play an important role in modulating recipient immune response toward donor antigens, and may present a promising strategy in donor-specific tolerance induction. Objectives of proposed studies are thus to determine whether infusion of ECP-treated donor cells can prevent rejection of the transplanted kidney by inducing tolerance, and if so, by which mechanisms. ECP-treated donor splenocytes are expected to facilitate donor-specific tolerance induction through modulating T cell priming and differentiation, thereby negatively regulating antigen-specific T cell responses following allogeneic kidney transplantation.
VI. Neurological Diseases
Most neurological disorders treated with TPE are mediated by humoral immune responses, and the beneficial effect of TPE is believed to occur through removal of the offending inflammatory mediators (e.g., autoantibodies, cytokines, complement constituents). The efficacy of TPE in the treatment of neurologic diseases remains less clear. Although TPE is used in some neurologic diseases, confirmatory studies and trials are lacking. Many questions remain about the ability of TPE to affect central nervous systems and the ideal timing in accessing the blood-brain barrier.
Relapsing Remitting Multiple Sclerosis (RRMS). MS is the most common disease of the central nervous system in young adults. Although its pathogenesis is not fully understood, evidence suggests that MS is an autoimmune disease mediated by autoreactive T cells. Accordingly, MS treatments are based on immunomodulating or immunosuppressive drugs, which are more effective in the reduction of the relapse rate than in the reduction of the disability load accumulation. ECP promotes tolerance and down-regulation of inflammatory responses in patients with MS through the generation of tolerogenic dendritic cells and T regulatory cells. Studies were thus proposed to determine whether initiation of ECP for patients with RRMS not responsive to or not eligible for traditional immunomodulating or immunosuppressive treatments is associated with decreased relapses and stabilization of Expanded Disability Status Scale.
Neuromelitis Optica (NMO). An inflammatory demyelinating disease of the central nervous system in which 85% of patients have associated antibody to aquaporin-4 and a relapsing course with poor prognosis. Growing evidence suggest patients with acute attacks may respond well to TPE. Prophylaxis to prevent further acute attacks includes immunosuppressive medications and immunomodulation such as rituximab, methotrexate, interferon, azathioprine, cyclophosphamide, prednisone, intravenous IgG, mitoxantrone, interferon, and mycophenolate mafetil. Some studies suggest that maintenance TPE may be beneficial in preventing further acute attacks. The primary purpose of using apheresis to study NMO would be to determine whether patients in an acute crisis improve to a greater degree when apheresis is initiated on day 1 of an attack in addition to steroid use versus steroid use alone.
Myasthenia Gravis (MG). Growing evidence suggest patients with muscle-specific kinase (MuSK) MG may respond differently to treatments than those with acetylcholine receptor-associated MG, thus treatment protocols were proposed to determine whether patients with anti-MuSK MG respond better to plasma exchange versus intravenous IgG administration during rapid deterioration.
Acute Disseminated Encephalomyelitis (ADEM). ADEM typically presents as fever, headache, and meningeal signs followed by acute encephalopathy, seizures, and multifocal neurological deficits. The pathogenesis of ADEM is not completely clear, but a significant association with certain HLA alleles has been reported. Patients with severe ADEM and who have contraindications to steroids or are not responsive to steroids are usually treated with either TPE or intravenous IgG. The dose and timing of intravenous IgG remains unclear. The mechanism of action of either TPE or IgG administration in this disease is yet to be elucidated. Both treatments have different requirements, availability, convenience, costs, and unique side effect profiles. Therefore, studies were proposed to assess whether TPE or intravenous IgG administration alone or as an adjunct to steroid therapy in severe ADEM would be beneficial in reducing hospital stays, ventilation days, complications, and the need for long-term rehabilitation.
Anti-NMDAR Encephalitis. Encephalitis associated with antibodies against the N-methyl-d-aspartate receptor (NMDAR) is characterized by a prodrome of headache, fever, nausea, vomiting, diarrhea, or symptoms of upper respiratory tract infection followed over a 2-week course by short-term memory deficits, psychiatric symptoms, decreased consciousness, seizures, and hypoventilation. A significant proportion of patients require hospitalization to manage seizures, receive mechanical ventilation, and treat hemodynamic instability. Because the disease is caused by an autoantibody, both intravenous IgG administration and TPE are predicted to have efficacy. Therefore, studies to determine the optimal treatment regimen via TPE or intravenous IgG alone or as an adjunct to steroid therapy is expected to help develop diagnostic criteria, define meaningful response criteria, improve patient outcomes, and be cost-effective.
Idiopathic Sudden Senorineural Hearing Loss is considered a medical emergency. Definitive treatment and etiology are still unknown, although the disease has been attributed to pathology of cochlear microperfusion, viral infection, am immunopathologic process, or a combination of these. The currently accepted first-line therapy is oral corticosteroids. Several studies have shown a role for a single fibrinogen/LDL apheresis procedure as opposed to oral prednisone therapy especially in a subgroup of patients who present with elevated fibrinogen and LDL levels. These molecules are known to cause microvascular compromise in other organs. The practice has not been employed in the United States. Therefore, studies were proposed to assess the use of fibrinogen/LDL apheresis in a subset of patients who have risk factors for hyperviscosity, cardiovascular disease, and thrombophilia in the belief that they would respond better to a single fibrinogen/LDL apheresis procedure than to a 10- to 19-day tapering course of systemic corticosteroids.
Polymyositis is a rare disease that more commonly occurs with systemic autoimmune or connective tissue disease or known viral or bacterial infection, which often can make it difficult to diagnose. The fundamental immune process is mediated by CD8+ cytotoxic T cells, which invade non-necrotic muscle fibers that express the major histocompatibility class (MHC)-I antigen. Patients with polymyositis have overexpression of MHC-I on the surface of their muscle fibers. Treatment is predominately high-dose corticosteroids, with steroid-sparing therapy as second-line treatment. Intravenous IgG has also been shown to be an effective treatment. Further studies of the use of ECP in patients with polymyositis are expected to lead to a decrease in the dose of corticosteroids and faster patient improvement.
Rare Neurologic Diseases Registry and Biorepository. In the United States, a rare disease is defined as one with a prevalence of fewer than 200,000 affected individuals. Many rare neurological diseases are treated or potentially treated with apheresis, and each disease by itself may not have enough patients to perform feasible studies. A biorepository for rare neurologic diseases might advance the fields of genomics, proteomics, and metabolomics by providing a standardized format for the processing, collection, storage, and distribution of high-quality biological specimens linked to clinical data.
Other than this symposium report, summaries of the Symposium are expected to be published in several scientific journals.
- Jill Adamski, MD, PhD, University of Alabama, Birmingham
- Nicole A. Aqui, MD, University of Pennsylvania, Philadelphia
- Chester Andrzejewski, MD, PhD, Bay State Medical Center, Springfield, Massachuesetts
- Rasheed Abiodun Balogun, MD FACP, FASN, HP(ASCP), University of Virginia, Charlottesville
- Nick Bandarenko, MD, Duke University, Durham, North Carolina
- Joanne Becker, MD, Roswell Park Cancer Institute, Buffalo, New York
- Mark Elliott Brecher, MD, LabCorp, Burlington, North Carolina
- Wolfgang Boecker, MD, Fresenius Kabi Deutschland GmbH, Bod Homburg, Germany
- Kelley E. Capocelli, MD, Children's Hospital Colorado, Aurora
- Sally A. Campbell-Lee, MD, University of Illinois at Chicago
- Joseph A. Carcillo, MD, Children's Hospital of Pittsburgh-UPMC
- Cathy Conry-Cantilena, MD, Baltimore Typing Lab and Staff Physician, NIH/CC/DTM
- Laura Connely-Smith, MBBCh, DM, University of Washington, Seattle
- Leslie W. Cooper, MD, University of Utah, Park City
- Daniel R. Couriel, MD, University of Michigan, Ann Arbor
- Marie Csete, MD, PhD, AABB Center for Cellular Therapies, Bethesda, Maryland
- Meghan Delaney, DO, MPH, Puget Sound Blood Center, Seattle,
- Katharine A. Downes, MD, FCAP, University Hospitals Case Medical Center, Cleveland
- Deborah Ferrell, RN, MSN, HP (ASCP), University of Illinois Hospital and Health Sciences System, Chicago
- Debbie Fleming, Canadian Apheresis Group, Ottawa
- Brenda J. Grossman, MD, MPH, Washington University School of Medicine, St. Louis
- Howard Grossberg, MD, Consultant to Therakos, Newark, New Jersey
- Ayad Hamdan, MD, Beth Israel Deaconess Medical Center, Boston
- Jan Hoffmann, MD, Apheresis Care Group, San Francisco
- Cassandra Josephson, MD, Emory University, Atlanta
- Richard Kaufman, MD, Brigham and Women's Hospital, Boston
- Haewon C. Kim, MD, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
- Karen E. King, MD, Johns Hopkins Hospital, Baltimore
- Carrie Kitko, MD, University of Michigan, Ann Arbor
- Anna P. Koo, MD, Cleveland Clinic, Cleveland, Ohio
- Peter J. Krause, MD, Yale School of Public Health, New Haven, Connecticut
- Susan F. Leitman, MD, Department of Transfusion Medicine, National Institutes of Health, Bethesda, Maryland
- John E. Levine, MD, MS, University of Michigan Health System, Ann Arbor, Michigan
- Ileana Lopez-Plaza, MD, Henry Ford Health System, Detroit
- Robert Maitta, MD, PhD, University Hospitals Case Medical Center, Cleveland
- Jeffrey McCullough, MD, University of Minnesota, Minneapolis
- Erin Meyer, DO, MPH, Emory/CHOA, Atlanta
- Paul D. Mintz, MD, Food and Drug Administration, Rockville, Maryland
- Augustin Min, PhD, Fenwal Inc., Lake Zurich, Illinois
- Shanna Morgan, MD, University of Minnesota, Minneapolis
- Patrick M. Moriarty, MD, University of Kansas Medical Center, Kansas City
- Yara A. Park, MD, University of North Carolina at Chapel Hill
- Katerina Pavenski, MD, FRCPC, St. Michael's Hospital, Toronto
- Mark A. Popovsky, MD, Haemonetics Corporation, Braintree, Massachusetts
- Patricio E. Ray, Children’s National Medical Center and The George Washington University, Washington, DC
- Thomas J. Raife, MD, University of Iowa Hospitals and Clinics, Iowa City
- Nora Ratcliffe, MD, Veterans Affairs Medical Center, White River Junction, Vermont
- Gail Rock, MD, PhD, FRCP, Canadian Apheresis Group, Ottawa
- Jennifer Schneiderman, MD, MS, Ann & Robert H. Lurie Children’s Hospital of Chicago
- Steven Sloan, MD, Children’s Hospital Boston
- Beth Shaz, MD, New York Blood Center
- Steven Spitalnik, MD, Columbia University, New York
- Leslie Silberstein, MD, Harvard Medical School, Boston, Massachusetts
- Victor Turpaid, Terumo BCT, Inc., Lakewood, Colorado
- Edouard Vannier, PhD, Tufts Medical Center, Boston
- Volker Witt, MD, St. Anna Kinderspital, Vienna, Austria
- Gay Wehrli, MD, University of Virginia Health System, Charlottesville
- Robert Weinstein, MD, University of Massachusetts Memorial Medical Center, Worcester
- Mark E. Williams, MD, FACP, FASN, Harvard Medical School, Boston, Massachusetts
- Jeffrey L. Winters, MD, Mayo Clinic, Rochester, Minnesota
- Edward Wong, MD, Children’s National Medical Center, Washington, DC
- Chisa Yamada, MD, University of Michigan, Ann Arbor
- Nicole Dodge Zantek, MD, PhD, University of Minnesota, Minneapolis
- Abba C. Zubair, MD, PhD, Mayo Clinic, Jacksonville, Florida
- Laura Cooling, MD, University of Michigan Medical School, Ann Arbor
- Jerome Gottschall, MD, Blood Center of Wisconsin, Milwauke
- Joseph Kiss, MD, University of Pittsburgh
- Harvey G. Klein, MD, Chief, Department of Transfusion Medicine, National Institutes of Health Clinical Center, Bethesda, Maryland
- Michael Linenberger, MD, FACP, University of Washington School of Medicine, Seattle
- Paul Ness, MD, Johns Hopkins Center for Global Health, Baltimore, Maryland
- Anand Padmanabhan, MD, Blood Center of Wisconsin, Milwaukee
- Bruce Sachais, MD, PhD, University of Pennsylvania Health System, Philadelphia
- Joseph Schwartz, MD, Columbia University College of Physicians and Surgeons, New York
- Edward Snyder, MD, Yale University School of Medicine, New Haven, Connecticut
- Zbigniew M. Szczepiorkowski, MD, Dartmouth-Hitchcock Norris Cotton Cancer Center, Lebanon, New Hampshire
- Yanyun Wu, MD, PhD, Yale University School of Medicine, New Haven, Connecticut
- Paul Ness
- Edward Snyder
- Harvey Klein
- Jerry Gottschall
- Steven Spitalnik
- Zbigniew M. Szczepiorkowski
- YanYun Wu
- Phyllis Mitchell
- Simone Glynn
Sub-working group members
Nora Ratcliffe, Patrick Moriarty, Jeffrey L. Winters, Leslie Cooper, Yanyun Wu
Nora Ratcliffe, Nancy Dunbar, Brenda J. Grossman, Jill Adamski, Jennifer Schneiderman, Steven Sloan, John E. Levine, Daniel Couriel, Carrie Kitko, Michael Linenberger, Joseph Schwartz, , Beth Shaz, Nicole A. Aqui, Yanyun Wu, Zbigniew M. Szczepiorkowski, Barbara Jean Bryant, Anna Koo, Shanna M. Morgan, Laura Cooling
Anand Padmanabhan, Laura Connely-Smith, Brenda J. Grossman, John E. Levine, Jennifer Schneiderman, Joseph Schwartz, Bruce Sachais, Michael Linenberger
Peter Krause, Edouard Vannier, Yanyun Wu, Edward Snyder
Multi-organ failure, infections, and other conditions:
Steven Sloan, Nicole A. Aqui, Nancy Dunbar, Chester Andrzejewski, Joseph E. Kiss, Joseph Carcillo, Yara A Park, Yanyun Wu
Edward Wong, Balogun, Rasheed, Ray Patricio, Mark E Williams, Chisa Yamada, Bruce Sachais
Shanna M Morgan, Beth Shaz, Meghan Delaney, Erin Meyer, Katerina Pavenski, Zbigniew M
- W. Keith Hoots, MD, Director, Division of Blood Diseases and Resources, NHLBI
- Simone A. Glynn, Branch Chief, NHLBI Transfusion Medicine and Cellular Therapeutics
- Phyllis Mitchell, MSc, Program Director, Transfusion Medicine and Cellular Therapeutics