Apheresis of immune diseases and apheresis using immunological specificity.

It has been clearly shown that autoimmune diseases can be treated by apheresis by eliminating immune complexes, however, the effects of therapeutic apheresis are not limited to immune disorders. Almost all diseases are associated with immune systems. Immune systems can be regulated by advanced techniques of apheresis, including immunoadsorption and immunocytapheresis, removing immune effector molecules and various immune-associated cells selectively. Therefore, apheresis can be used as a nondrug treatment for many diseases. In addition, disease-associated proteins that cause disease or are produced in the course of diseases and accumulate in the body could be eliminated selectively by apheresis using the extremely powerful ability of the immune system to recognize polypeptide structures specifically and distinguish miniscale differences among molecules. In this article, we discuss the current status of treatment of immune diseases by apheresis and possible treatment approach of a variety of diseases by apheresis based on immune reactions.     

Immunoadsorption in neurological disorders

In recent years, immunoadsorption has been increasingly recognized as an alternative to therapeutic plasma exchange and used for the treatment of neurological disorders such as Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, neuromyelitis optica spectrum disorders, and multiple sclerosis, as well as autoimmune encephalitis. Unlike therapeutic plasma exchange, which requires fluid replacement with a blood solution such as fresh frozen plasma or albumin, immunoadsorption is a blood purification technique that enables the selective removal of humoral factors from separated plasma through a high-affinity adsorbent with tryptophan or phenylalanine. Although the mechanisms underlying the therapeutic effects of immunoadsorption treatment remain to be fully elucidated, they are based on the removal of pathogenic humoral factors from circulating blood, such as disease-specific autoantibodies, complement, and inflammatory cytokines. The American Society for Apheresis has published evidence-based guidelines on the use of therapeutic apheresis in clinical practice, with specific instructions on 16 neurological disorders. However, the modality recommended in the guidelines for most of these disorders is therapeutic plasma exchange. This part of our review focuses on the clinical aspects of immunoadsorption. We also describe the efficacy of immunoadsorption and the evidence obtained by previous studies of the treatment of neurological disorders. Immunoadsorption could greatly improve the treatment of patients with autoimmune neurological disorders but further evidence is needed to confirm the efficacy of immunoadsorption in clinical practice.     

Apheresis registry in Sweden: scope, techniques and indications for treatment. A report from the Swedish apheresis study group.

Registries of therapeutic apheresis can be used to evaluate changes in technology, clinical indications and applications over the years. This study reports data collected prospectively and voluntarily in Sweden during 1993-1999. A total number of 40 apheresis units have been performing therapeutic apheresis procedures: 16 blood centers, 20 dialysis units, two intensive care units, one hematology ward and one hemotherapy unit. The registry includes a median of 92%) of the centers for therapeutic apheresis in Sweden during the years and in 1999 there were 31 active units in 26 hospitals. The total numbers of procedures per year have remained fairly stable corresponding to a median of 46 treatments/ 100,000 inhabitants, and in 1999 4084 procedures were performed. The number of plasma exchanges has decreased, but LDL-apheresis and immunoadsorption procedures have increased over the years. 70% of the patients have been referred for 12 indications. A significant decline was found for patients with SLE and Guillain Barres syndrome. The use of extracorporeal photo-chemotherapy has increased over the years, and 3 indications include >75$ of the patients. There has been an adaptation to the experience learned by different studies. The number of collections of hematopoietic progenitor cells is about 9/100,000 inhabitants, and in 1999 821 collections were performed. The use of allogeneic donors is increasing. The extent of therapeutic apheresis in Sweden was compared to other countries on the basis of published data. In Sweden, the extent of therapy is two- to three-fold to that for Canada and France.     

Immunoadsorption for collagen and rheumatic diseases

The field of therapeutics has seen remarkable progress in the recent years, which has made mainstream drug treatment possible for collagen and rheumatic diseases. However, treatment of intractable cases where drug effectiveness is poor is a challenge. Furthermore, organ damage, concurrent illnesses or allergic reactions make adequate drug therapy impossible. For such cases, therapeutic apheresis is very significant, and it is important how this should be valued related to drug therapies. Therapeutic apheresis for collagen and rheumatic diseases involves the removal of factors that cause and exacerbate the disease; the aim of immunoadsorption, in particular, is to improve the clinical condition of patients with autoimmune disease by selectively removing pathogenic immune complexes and autoantibodies from their plasma.Immunoadsorption, in particular, unlike plasma exchange and DFPP, utilizes a high-affinity column that selectively removes autoantibodies and immune complexes, leaving other plasma components intact. There is no need to replenish fresh frozen plasma or blood products such as albumin and gamma globulin preparations. Immunoadsorption is thus superior in terms of safety, as the risk of infection or allergic reaction relating to these preparations can be avoided. We anticipate future investigations of application of synchronized therapy using drugs and therapeutic apheresis, most notably immunoadsorption, in combination to treat intractable clinical conditions such as collagen and rheumatic diseases.In this paper, our discussion includes the indications for immunoadsorption such as collagen and rheumatic diseases, the relevant conditions and types, as well as the latest understanding related to methods and clinical efficacy.     

Therapeutic apheresis in multiple sclerosis

Therapeutic apheresis is divided in cytapheresis and plasmapheresis. And plasmapheresis(PP) is divided into three treatments, plasma exchange(PE), double filtration plasmapheresis(DFPP) and immunoadsorption plasmapheresis(IAPP). PE has been applied in the neuroimmunological disorders and the effectiveness of PP has been well established in some neuroimmunological disorders. In this article, PP treatment of multiple sclerosis(MS) was reviewed. PP is an effective means of removing the pathogenic immune-mediated factors, such as inflammatory cytokines, autoantibodies, immune complexes, and complements. PP may affect not only humoral immune responses but also cellular immune responses. Previous clinical reports suggested that PE might be effective in treating acute attacks of MS, but be no effective in patients with chronic progressive MS. IAPP may be superior to PE in the treatment of MS.     

National survey of apheresis activity in Italy (2000).

Data collection on apheresis in Italy throughout 2000, including techniques, machines, clinical indications and adverse effects, has been performed by means of a standardized questionnaire. These data provided from 102 Apheresis Units from 19 Italian regions, albeit rough, are sufficiently informative. In 2000 a total number of 164,943 apheresis procedures has been carried out, with a clear-cut prevalence of productive apheresis (90.8%), that has been performed by all Apheresis Units. Lombardy, Venetia and Liguria have been the most active regions for therapeutic apheresis (54.0% of the total activity). Adverse events, predominantly mild ones (i.e., paresthesia due to citrate-induced hypocalcemia) have occurred in 0.59% of productive and in 6.75% of therapeutic apheresis sessions, particularly in the course of peripheral blood stem cell collection (13.0%).     

Acquired immunodeficiency syndrome (AIDS)--apheresis and operative risks

The removal of immune complexes, autoantibodies and suppressor factors from the circulation of patients with AIDS and AIDS related conditions by plasmapheresis and selective immunoadsorption may play a role as a therapeutic modality in these disorders. Lymphocytapheresis may also be of potential use in AIDS related conditions with presumed autoimmune basis. Perfusion of plasma over immobilized protein A columns is being evaluated as a possible immunomodulatory and antitumor therapy in patients with AIDS related Kaposi's sarcoma. Although apheresis procedures as a therapeutic modality in AIDS related conditions are still at the experimental stage, preliminary results are encouraging. The possible transmission of the disease by blood products presents a health hazard to health workers involved in the field of apheresis. Since the mode of transmission of the disease appears to be similar to hepatitis B, strict hepatitis B precautions should be enforced in every case in which AIDS suspected blood is being processed.     

The indication of steroid pulse therapy and apheresis therapy for multiple sclerosis

We discuss steroid pulse therapy and apheresis therapy indicated for the treatment of multiple sclerosis (MS). In the basic treatment course for MS, steroid pulse therapy is a first-line treatment for relapsing-remitting multiple sclerosis (RR-MS) in the course of the exacerbation, and apheresis therapy is performed in refractory cases. Treatment strategies for chronic progressive MS are not to be established. Steroid pulse therapy has been established as a treatment for MS in the active phase through randomized controlled trials (RCT). Apheresis therapy includes plasmapheresis and cytapheresis, and plasmapheresis includes plasma exchange (PE) and immunoadsorption plasmapheresis (IAPP). PE and IAPP are performed for MS treatment. PE has been established as a useful treatment for active phase MS. The efficacy of IAPP has been frequently reported, but no reports have been based on RCT. We also summarize the indications, methods, and adverse reactions of steroid pulse therapy and apheresis therapy.     

Therapeutic apheresis in Sweden: update of epidemiology and adverse events.

The indications of apheresis have changed over time due to results from various studies as well as the innovation of new techniques and ideas. To get an overview of the indications used for apheresis by colleagues elsewhere, data from registries are valuable. In addition, registries can be used for detection of severe adverse events as well as extent of adverse events in various types of treatment. To have a basis for statistical calculations, apheresis units need to be very large or centralisation of data needs to be performed. Data from more than 20000 procedures show that in about 4.3% of occasions adverse events and other problems will develop. Interruption of the procedure was done in 1%, most frequently a plasma exchange. Technical problems can be expected more frequent when performing LDL apheresis and immunoadsorption. Severe adverse events needing medication or interruption of the treatment, such as hypotension and arrhythmia, will develop in about 1% of the procedures. Such an episode occurs more often in patients with TTP/HUS and Guillain-Barré syndrome than in hypercholesterolemia, hyperviscosity syndrome or septic shock/MODS. The non-severe adverse events have increased over time. The results will provide focus in analyses for the reduction of such adverse events.     

The use of therapeutic apheresis in cardiovascular disease

In the last few years, therapeutic apheresis (TA) has emerged as a valuable treatment option for certain life‐threatening cardiovascular diseases (CVDs) and for all the cardiac dysfunctions caused by autoimmune or metabolic disorders. Besides the well‐established indications for apheresis treatment, such as familial hypercholesterolaemia, hyperviscosity syndrome and thrombotic thrombocytopenic purpura (TTP), we discuss the novel approaches in the therapy of dilated cardiomyopathy, cardiac failure and some specific syndromes of severe dysfunction occurring after heart transplantation. The rationale for using apheresis in such patients is the contribution in immune modulation that this procedure can undoubtedly provide. The clinical course of TTP has dramatically changed, thanks to the introduction of therapeutic plasma exchange. Low‐density lipoprotein apheresis has been extremely efficacious, safe and suitable for lowering cholesterol levels and can be used even for long‐term treatment. In Waldenström macroglobulinaemia and other hyperviscosity syndromes, plasma exchange has demonstrated to be an efficient tool for reducing blood viscosity and the risk of a consequent cardiac dysfunction. However, TA may induce oxidative injury to erythrocytes, making these cells more prone to haemolysis and causing a significant reduction in their half‐life. Ascorbate administration can be useful to lower the levels of hydrogen peroxide and proinflammatory mediators in patients undergoing apheresis. Further data are needed to support this benefit and to test other potential antioxidant therapies. Many of these therapeutic indications need further studies to be definitively approved, but preliminary data are encouraging.     

Immunoadsorption in systemic connective tissue diseases and primary vasculitis.

Immunoadsorption offers some advantages over plasmapheresis; until recently the primary advantage has been avoidance of substitution fluids. In collagen vascular disorders, immunoadsorption is performed for the same indications as plasma exchange; most often adsorbers with binding capacities for IgG and circulating immune complexes are used. Tested ligands are protein A, anti-IgG antibodies, Clq, phenylalanine, and tryptophan. Human IgG was utilized to adsorb rheumatoid factor and dextran sulfate, DNA, or specific anti-idiotypes for anti-DNA antibodies in systemic lupus erythematous (SLE). Most applications have used immunoadsorbent columns in pretransplantation treatment of patients with high panel reactivity and in patients with idiopathic thrombocytopenic purpura (ITP). For these indications, as for systemic connective tissue diseases, randomized trials have yet to be conducted. SLE controlled trials have been completed for IMPH-350 and Ig-Therasorb. Results indicated excellent biocompatibility and good clinical responses. Using protein A in primary systemic vasculitis, histologically proven inactivation of renal involvement was demonstrated, but the patients were also treated with immunosuppressive drugs. Randomized controlled trials are mandatory to provide continued support to the therapeutical opportunities offered only by immunoadsorption.     

The Italian Registry for Therapeutic Apheresis. A report from the Apheresis Study Group of the Italian Society of Nephrology

Many clinical indications and different technical issues have been reported on therapeutic apheresis: much criticism has also been recorded in several instances, mainly due to the lack of large clinical trials to validate collected data. A Registry where all the available data can be organized and analyzed therefore becomes a priority for all the professionals involved in apheresis. The purpose of this report is to describe the data submitted from 1994 to 2004 from 15,285 treatments on 1,477 patients from 44 Centers, including mainly, but not exclusively, Nephrological Units, collected by the Apheresis Study Group of the Italian Society of Nephrology in 15 Italian regions. Plasma exchange accounted for 56.2% of the procedures, and of these 50.4% were performed by filtration. Plasma treatment was used in 40.1% of procedures, namely with Protein A immunoadsorption (14.6%), LDL-Cholesterol dextran sulfate adsorption (9.7%), and semiselective cascade or double filtration (12.6%). Cell apheresis, limited to photopheresis, was used in 0.85% of cases, and whole blood treatment (direct adsorption lipoprotein, and molecular adsorption recirculating system) in 2.7%. The procedures analyzed here account for less than 20% of estimated therapeutic apheresis performed in Italy, according to the national survey of activity performed for year 2000 by the Italian Apheresis Society. Notwithstanding that the data are largely incomplete, they are sufficiently informative for a definite trend: plasma treatment with filtration on fractionation filters and adsorption must be used as often as possible, instead of plasma exchange, thus obtaining the most selective removals.     

Collection of hematopoietic stem cells and immune effector cells in small children

Apheresis procedures are standard of care for a wide range of indications in children, collection of hematopoietic stem cells being the most frequent one. With increasing numbers of hematopoietic stem cell transplants, advances in graft manipulation techniques and the development of innovative therapies using immune effector cells and gene therapy, apheresis within the pediatric population is growing in demand. While young children have higher circulating white blood cell counts and robustly mobilize hematopoietic stem cells, apheresis machines were designed for use within the adult population and apheresis procedures in children, particularly small children, can be more challenging as vascular access, collection techniques and impact of extracorporeal volumes increase the rate of adverse events. In this article we review topics of particular relevance to hematopoietic stem cell and immune effector cell collections in small children.     

The Italian registry of pediatric therapeutic apheresis: A report on activity during 2005

The results of the 2005 Survey of the Italian Society for Apheresis and Cell Manipulation (SIdEM) reporting on the pediatric procedures carried out in 18 Italian Apheresis Units are presented here. Utilizing a standardized questionnaire, the survey collected data on techniques, types of blood separators, clinical indications, and adverse events. A total of 1,693 apheresis procedures were carried out in 355 pediatric patients: 219 plasma‐exchange, 291 peripheral blood stem cell collections, 791 extracorporeal photochemotherapy (ECP), 265 LDL‐apheresis, 71 erythro‐exchange, 9 cytoreductive apheresis, 47 immunoadsorption sessions. Adverse events were registered in 94 procedures (5.6%), most of which of mild entity, e.g., insufficient flow rate (50.0%) and symptomatic hypocalcemia (24.4%). Our data indicate that all types of apheresis procedures can be safely carried out in children. ECP, utilized primarily for the treatment of graft versus host disease (GvHD) and rejection of solid organ transplantation, are burgeoning procedures in pediatric patients, whereas plasma exchange, which is a common treatment in adults, is infrequently utilized in pediatric medicine. J. Clin. Apheresis, 2009. © 2008 Wiley‐Liss, Inc.     

The current status of extracorporeal immunomodulation

A course of extracorporeal immunomodulation is defined as a treatment which intervenes and consequently modulates or, in other words, activates and/or suppresses the immune mechanisms utilizing an extracorporeal procedure. Such treatment has traditionally depended on administration of drugs, typically steroids and/or immunosuppressants. Most of the apheresis techniques currently available belong to or are very similar to those used for blood purification and involve the removal of the pathogenic substances such as antibody(ies) and/or immune complex(es). The cellular components are also treated in extracorporeal immunomodulation. As some of the extracorporeal immunomodulation techniques have already demonstrated clinical effectiveness that cannot be achieved by conventional therapies, it is appropriate to propose a new therapeutic approach to the immunological disorders.     

The mechanisms of rejection in solid organ transplantation

Organ transplantation represents the preferred treatment option for many patients in terminal organ failure. The half-life of transplanted organs, however, is still far from being satisfactory with the vast majority of the organs failing within the first two decades following transplantation. At this stage, it has become apparent that rejection (prevalently mediated by humoral events) remains the primary cause of graft loss after the first year. In this light, studies are underway to better comprehend the immune events underlying graft rejection and novel immunosuppressive strategies are being explored. In this context, therapeutic apheresis techniques, that include therapeutic plasma exchange (TPE), immunoadsorption (IA) and extracorporeal photochemotherapy (ECP), represent an important adjunct in the current immunosuppressive armamentarium. This article briefly reviews our current understanding of the immune process underlying rejection of a solid organ transplant and describes the principal areas of application of therapeutic apheresis techniques in transplantation.     

Ig-Therasorb immunoadsorption for selective removal of human immunoglobulins in diseases associated with pathogenic antibodies of all classes and IgG subclasses, immune complexes, and fragments of immunoglobulins.

Therasorb immunoadsorption (IA), by selectively eliminating pathogenic substances from the circulation, allows for successful therapy of previously insufficiently treatable diseases. Molecules (specific polyclonal sheep antibodies) coupled to a matrix (Sepharose CL 4B) selectively bind plasma components in extracorporeal circulation. This procedure has been established in the treatment of various diseases. Examples are familial hypercholesterolemia (LDL-Therasorb) and selected autoimmune diseases (Ig-Therasorb). Ig-Therasorb IA has been performed in a variety of clinical indications, primarily in the treatment of autoimmune diseases. In most cases, Ig-Therasorb IA has been applied in patients who have failed to respond to conventional therapy with a high rate of clinical improvement. In defined groups of patients with autoimmune diseases and alloantibodies, immunoadsorption can now be considered an established therapeutic means. The fast and efficient removal of immunoglobulins obviously exceeds the efficiency of conventional plasma exchange by far. Autoimmune diseases could be induced by balanced and nonbalanced immunity. The importance of autoantibodies remains unclear, but the efficacy of Ig-Therasorb IA suggests a key role for them. In addition to the established indications for removal of immunoglobulins, there may be a number of promising new indications.     

Apheresis techniques and cellular immunomodulation.

Significant advances have been made in the capabilities to remove white blood cells (WBCs) from blood by both centrifugal and filtration techniques. New techniques have applications for both donor products (and their effects upon the recipients) and for selected disease therapeutics. The immunomodulatory effects of donor WBCs may be therapeutic, e.g., granulocytes harvested by apheresis may be used for the treatment of sepsis, or mononuclear cells collected by apheresis for peripheral blood progenitor (stem) cell transplantation or graft versus leukemia effect. In contrast, WBCs are removed from many transfusable components to decrease the immune effects in recipients. This has been accomplished primarily by the use of leukoreduction filters although newer adaptations of centrifugal equipment allow for the reduction of WBCs to target range of <1 x 10(6) WBCs/product. Therapeutic WBC removal by centrifuge has been used for treatment of the effects due to elevated levels of WBCs or platelets. More specific cellular immunotherapy has included lymphocytapheresis for the treatment of autoimmune diseases such as systemic lupus erythematosis (SLE). Various mononuclear cell fractions collected by apheresis have been used for lymphokine activated killer cells (LAK) and tumor infiltrating lymphocytes (TIL) cell therapy or autologous stem cell transplantation. The development of WBC adsorbent filters for therapeutic use has evolved as nonspecific filter materials have been demonstrated to show selective WBC removal, and filter columns permit therapeutic reductions in WBCs using online filtration therapy. Specific adsorption techniques, e.g., CD-34 selection, are in use in vitro and indicate directions for further developments in cellular immunotherapy.     

Therapeutic plasmapheresis and protein A immunoadsorption in malignancy: a brief review

Plasmapheresis is being used with considerable frequency in the management of malignant and non-malignant disorders. More recently, staphylococcal Protein A immunoadsorption has been employed in similar clinical situations. In patients with malignancy, plasmapheresis has been shown to produce alterations in plasma proteins, decrease circulating immune complexes, remove "specific" and "non-specific" blocking factors, change immune reactivity, and affect monocyte function. Partial responses have been reported in a small number of patients with carcinoma of lung, colon, and breast following plasmapheresis. In addition, there are reports of favorable responses in patients with melanoma, head and neck tumors, lymphomas, leukemias, and Kaposi's sarcoma in acquired immune deficiency. All these responses were partial and brief, and the treatment did not alter the course of the disease. Plasmapheresis has been useful in the management of hyperviscosity and occasionally of paraneoplastic syndromes. It may also have a role in the treatment of thrombotic thrombocytopenic purpura associated with mitomycin-C therapy. Protein A immunoadsorption, by which circulating immune complexes are selectively removed, can activate the complement system, increase blastogenic responses, and increase the natural killer cell activity. It has been shown to produce partial responses in breast and colon cancer, as well as Kaposi's sarcoma in acquired immune deficiency. It may have a useful role to play in the management of mitomycin-C-associated thrombotic thrombocytopenic purpura. Both plasmapheresis and Protein A immunoadsorption should be considered investigational interventions at this time. Toxicity of plasmapheresis, though uncommon, can be serious and may rarely be fatal. Toxicity of Protein A immunoadsorption is mild, consisting mainly of influenza-like symptoms and rash.     

Therapeutic apheresis in neurology critical care

Therapeutic apheresis has been widely accepted in the treatment of neurological disorders that are understood to be mediated by humoral and/or cellular immunity. The clinical presumption is that well-established and/or unknown insults cause damage to nerves or their myelin sheaths. The rationale for apheresis treatments for these neurological disorders relates to removal of offending immune (or other) mediators, thus blunting the attack and permitting recovery of nerve and/or myelin. This review will concentrate on the role of therapeutic apheresis, in particular therapeutic plasma exchange, in neurological disorders that may frequently be seen by intensivists.