Plasmapheresis Printer-Friendly Version   

Medical Policy: 08.01.16 
Original Effective Date: February 2000 
Reviewed: November 2007 
Revised: September 2006 

This policy applies to all products unless specific contract limitations, exclusions or exceptions apply. Please refer to the member's coverage manual for benefit availability. Managed care guidelines related to referral authorization, and precertification of inpatient hospitalization, home health, home infusion and hospice services apply.

Description: 

The term plasmapheresis, therapeutic apheresis, and plasma exchange are often used interchangeably, however there are some differences. The following are the definitions:
Apheresis is a general term describing removal of blood from a subject; a portion of the blood is separated and retained while the rest is returned to the donor. 
Plasmapheresis, which describes the process whereby the plasma is separated and manipulated in a variety of ways, is probably the most common type of apheresis process. 
Plasma exchange (PE), the process in which plasma is isolated, then discarded and replaced with a substitute fluid such as albumin, is frequently done in conjunction with plasmapheresis.

The rationale for PE is based on the fact that circulating substances, such as toxins or autoantibodies can accumulate in the plasma. Also, it is hypothesized that removal of these factors can be therapeutic in certain situations. It is usually a symptomatic treatment since it does not deal with the source of the pathogenic factors. An intravenous catheter is placed into a vein, and the catheter is connected to a PE machine via tubing. The machine is able to take all parts of the blood, including cells, fluid, and natural chemicals, and separate them. The plasma is discarded, and the cells and other blood components are returned to the patient along with donated plasma or a plasma substitute.

Policy: 

Plasmapheresis and plasma exchange may be considered medically necessary for any of the conditions listed below: 

• Myasthenia gravis in crisis or as part of preoperative preparation
• Hyperviscosity syndrome associated with multiple myeloma, Waldenström’s macroglobulinemia or other conditions
• Thrombotic thrombocytopenic purpura (TTP) 
• Hemolytic uremic syndrome (HUS) 
• Idiopathic thrombocytopenic purpura in emergency situations 
• Guillain-Barré syndrome for severely ill patients who are diagnosed with grades 3-5 disease, which includes the ability to walk 5 meters with assistance, confinement to a bed or chair, or requiring assisted ventilation for at least part of the day or night 
• Chronic inflammatory demyelinating polyneuropathy for patients with severe or life threatening symptoms who have failed to respond to conventional therapy with prednisone or intravenous immunoglobulins (IVIG) 
• IgA or IgG paraproteinemia polyneuropathy
• HELLP syndrome of pregnancy 
• Post-transfusion purpura 
• Progressive renal failure due to anti-basement membrane antibodies (Goodpasture's syndrome) 
• Acute fulminant CNS demyelination associated with multiple sclerosis or other conditions, for example transverse myelitis.
• Prior to solid organ transplant, treatment of patients at high risk of antibody-mediated rejection, including highly sensitized patients, and those receiving an ABO incompatible organ.
• Following solid-organ transplant, treatment of antibody-mediated rejection. 

Investigational applications of plasma exchange include, but are not limited to the following conditions: 

• Rheumatoid arthritis 
• Scleroderma (systemic sclerosis) 
• Systemic lupus erythematosus (SLE) 
• Polymyositis and dermatomyositis
• Inclusion body myositis
• Pemphigus 
• Guillain-Barré syndrome, grades 1-2
• Chronic progressive or relapsing remitting multiple sclerosis
• Amyotrophic lateral sclerosis (ALS) 
• Paraneoplastic syndromes including Lambert-Eaton myasthenic syndrome
• Paraproteinemic polyneuropathy including monoclonal gammopathy of undetermined significance (MGUS)
• Chronic fatigue syndrome 
• Regional enteritis (Crohn's disease) 
• Rapidly progressive glomerulonephritides, excluding those related to anti-basement membrane immunoglobulins ( i.e. Goodpasture's syndrome)
• Asthma
• Stiff-man syndrome

Rationale:

Investigational Indications

Chronic Autoimmune Diseases

One potential type of evidence in support of the clinical effectiveness of PE in treating autoimmune diseases is the identification of a pathogenic component of plasma that is reliably eliminated by plasmapheresis.  Although many laboratory abnormalities are associated with autoimmune connective tissue diseases, it is unclear which, if any, cause the clinical manifestations of the disease. Furthermore, it is not known to what extent plasma levels parallel clinical disease. For example, in many of the controlled trials discussed below, PE reliably reduced circulating autoantibodies and immune complexes, but without demonstrable clinical benefit. It may be that the patient had already suffered irreversible damage, or that the pathogenesis of the disease was a local process unrelated to circulating factors. Over the past 10 years, randomized trials of PE have been conducted and, in general, have shown a lack of effectiveness as treatment of chronic autoimmune diseases. Clinical results of randomized trials of plasmapheresis for specific chronic autoimmune diseases are discussed below.

Systemic Lupus

Reporting on the results of a randomized controlled trial, Lewis and colleagues concluded that PE had no benefit in patients with SLE and glomerulonephritis compared to standard therapy regimen of prednisone and cyclophosphamide.  Plasmapheresis has also been investigated as a technique to improve the effectiveness of cyclophosphamide therapy. For example, it is thought that the acute lowering of pathogenic autoantibodies with plasmapheresis may result in their rebound production. It is hoped that the pathogenic lymphocytes would be more sensitive to cyclophosphamide at this point. Danieli and colleagues reported on a prospective nonrandomized trial of 28 patients with proliferative lupus nephritis; 12 underwent synchronized plasmapheresis and pulse cyclophosphamide therapy, while the remaining 16 underwent cyclophosphamide alone. While plasmapheresis was associated with a decreased time to remission of renal disease, at the end of the four-year follow-up there was no difference in outcome.

Rheumatoid Arthritis

In 1983, Dwosh and colleagues reported on 26 patients with chronic rheumatoid arthritis randomized in a crossover design to either true or sham PE. The authors concluded that PE did not have any clinical benefit despite impressive laboratory changes.

Polymyositis/Dermatomyositis

Miller and colleagues conducted a randomized trial of PE in the treatment of 39 patients with polymyositis and dermatomyositis and found that it was no more effective than sham pheresis.

Pemphigus

Guillaume and colleagues reported on a study of 40 patients with pemphigus randomized to receive prednisone alone or prednisone plus plasmapheresis. The goal of the study was to determine whether plasmapheresis could reduce the required dose of steroids, thus limiting its toxicity. Unfortunately, disease control in the two groups was the same, and the authors concluded that plasmapheresis in conjunction with low-dose steroids is not effective in treating pemphigus.

Multiple Sclerosis (MS)

There have been several controlled, randomized trials of PE in patients with MS that have reported inconclusive results. Khatri studied 54 patients with chronic progressive MS randomized to receive sham or true PE. The degree of improvement in the PE group was greater than that in the control group. Weiner reported on a study that randomized patients with acute attacks of MS to receive either PE or sham treatments; there was no statistical difference in improvement between groups, although patients receiving PE did have a faster recovery rate from acute attacks. A Canadian trial randomized 168 patients with progressive MS to receive either PE or immunosuppressive therapy. There were no significant differences in the rates of treatment failures between groups.

Other Conditions

Rapidly Progressive Glomerulonephritis (RPGN)

PE has long been considered a treatment alternative in immune-mediated RPGN. However, there have been few controlled clinical trials published, and their interpretation is difficult due to the small number of patients, choice of intermediate outcomes (i.e., the reduction in antibody levels as opposed to more direct patient outcomes), and heterogeneity in patient groups. Aside from cases of Goodpasture’s disease, the rationale for PE in idiopathic RPGN is not as strong, due to the lack of an identifiable immune component. Studies of PE in this population have not demonstrated a significant improvement in outcome compared to the use of pulse steroid therapy.

Lambert-Eaton Myasthenic Syndrome (LEMS) and Other Paraneoplastic Syndromes

The presumed autoimmune nature of LEMS and other paraneoplastic syndromes led to the use of a variety of immunomodulatory therapies, including plasma exchange. However, there are minimal data in the published literature and no controlled trials. The largest case series focusing on LEMS was reported by Tim and colleagues and included 73 patients with LEMS, 31 of which were found to have lung cancer. Although detailed treatment strategies are not provided, 19 underwent plasmapheresis, with 27% reporting a moderate to marked response. However, the improvement after plasmapheresis, even when marked, was only transient. Patients also received other therapies, for example, various chemotherapy regimens for the underlying lung cancer. In addition, 53 of the 73 patients received 3,4 diaminopyridine, with 79% reporting marked or moderate responses. A small, randomized controlled trial of 3,4 diaminopyridine has also reported positive results, confirming other anecdotal reports. Anderson and colleagues reported on a case series of 12 patients with paraneoplastic cerebellar degeneration. Although plasmapheresis was associated with an acute drop in the autoantibody titer, only two patients showed a minor improvement in neurologic symptoms.

Stiff Man Syndrome

The mainstay of treatment of stiff man syndrome is diazepam. The published literature regarding plasmapheresis consists of small case series and anecdotal reports.

Asthma

There has been some research interest in the use of plasmapheresis in patients with severe, steroid-dependent asthma. However, preliminary results do not suggest treatment effectiveness.

Medically Necessary Indications

Acute Fulminant CNS Demyelination

The policy statement, which suggests that plasmapheresis may be considered medically necessary in patients with acute fulminant CNS demyelination, is based on the results of a randomized, double-blinded trial, in which 22 patients with multiple sclerosis or other acute idiopathic inflammatory demyelinating disease of the CNS were enrolled a minimum of 14 days after having failed to respond to at least five days of high-dose corticosteroids. Patients were randomized to receive either seven real or sham PE procedures over a 14-day period. The primary outcome was a targeted neurologic deficit (i.e., aphasia, cognitive dysfunction, etc.). Overall, moderate to marked improvement of the targeted outcome was obtained in 42% of the treatment group, compared to only 6% in the placebo group.

Paraproteinemic Polyneuropathies

A randomized, double-blinded trial compared PE to sham treatment in 39 patients with MGUS-associated polyneuropathy. After twice weekly PE for three weeks, the treatment group reported improvements in neurologic function in the IgG and IgA groups, but not the IgM MGUS groups. In addition, those from the sham group who were later crossed over to the PE group also reported improvement.

Plasmapheresis in the Setting of Solid Organ Transplant

Plasmapheresis has been extensively used in this setting, both as pretransplant prophylaxis (i.e., desensitization) for highly sensitized patients at high risk of antibody-mediated rejection (AMR), and as a treatment of AMR after transplant. Desensitization protocols vary among transplant centers; two commonly used protocols are referred to as the Cedars-Sinai protocol and the Johns Hopkins protocol. The Cedars-Sinai protocol consists of high-dose IVIg (2 g/kg) and is offered to patients awaiting either a deceased or live donor. The Johns Hopkins protocol consists of low-dose IVIg (100 mg/kg) in combination with plasmapheresis with or without treatment with anti CD-20 (i.e., Rituxan) Plasmapheresis is more commonly used in patients receiving a living kidney transplant from an ABO mismatched donor. A variety of protocols have also been developed for the treatment of AMR, often in combination with other therapies, such as IVIg or anti CD-20. The majority of studies of plasmapheresis in the transplant setting are retrospective case series from single institutions. Therefore, it is not possible to compare immunomodulatory regimens to determine their relative efficacy. Nevertheless, in part based on the large volume of literature published on this subject, it appears that plasmapheresis is a component of the standard of care for the management of AMR.

Top

Procedure Codes and Billing Guidelines: 

• To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or ICD-9 diagnostic codes. 
• CPT code 36514; Therapeutic apheresis; for plasmapheresis.
• ICD-9 Procedure code 99.71.

Top

Selected References: 

• The Medical Policy Reference Manual (MPRM) developed by the Blue Cross Blue Shield Association Health Management Systems, based on Technology Evaluation Center (TEC) criteria.
• A review of the medical literature and recommendations from the Medical Policy Advisory Council (MPAC), which assists Wellmark’s medical directors in the development of medical policies. MPAC is comprised of practicing physicians from Iowa and South Dakota.
• Brian G, et al.  A Randomized Trial of Plasma Exchange in Acute Central Nervous System Inflammatory Demyelinating Disease. The American Neurological Association Annals of Neurology 1999; 46(6):878-86.
• Shumak KH, Rock GA. Therapeutic plasma exchange. N Engl J Med 1984; 310(12):762-71.
• Lewis EJ, Hunsicker LG, Lan SP et al. A controlled trial of plasmapheresis therapy in severe lupus nephritis. The Lupus Nephritis Collaborative Study Group. N Engl J Med 1992; 326(21):1373-9.
• Canadian Cooperative Multiple Sclerosis Study Group. The Canadian cooperative trial of cyclophosphamide and plasma exchange in progressive multiple sclerosis. Lancet 1991; 337(8739):441-6.
• Brashear HR, Phillips LH. Autoantibodies to GABAergic neurons and response to plasmapheresis in stiff-man syndrome. Neurology 1991; 41(10):1588-92.
• Sanders DB, Massey JM, Sanders LL et al. A randomized trial of 3,4-diaminopyridine in Lambert-Eaton myasthenic syndrome. Neurology 2000; 54(3):603-7.
• Weinstein R. Therapeutic apheresis in neurological disorders. J Clin Apheresis 2000; 15(1-2):74-128.
• Weinshenker BG, O’Brien PC, Petterson TM et al. A randomized trail of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol 1999; 46(6):878-86.
• Dyck PJ, Low PA, Windebank AJ et al. Plasma exchange in polyneuropathy associated with monoclonal gammopathy of undetermined significance. N Engl J Med 1991; 325(21):1482-6.
• Kyriakidis AV, Karydakis P, Neofytou N et al. Plasmapheresis in the management of acute severe hyperlipidemic pancreatitis: report of 5 cases. Pancreatology. 2005;5(2-3):201-4. Epub 2005 Apr 22.
• TARGET [database online]. Plymouth Meeting (PA): ECRI; 2003 June; ABO-incompatible living-donor kidney transplantation for endstage kidney disease. Available: http://www.ecri.org.
• Jordan SC, Vo AA, et al. Use of high-dose human intravenous immunoglobulin therapy in sensitized patients awaiting transplantation: the Cedars-Sinai experience. Clin Transpl 2003:193-8.
• Ibernon M, Gil-Vernet S, et al. Therapy with plasmapheresis and intravenous immunoglobulin for acute humoral rejection in kidney transplantation. Transplant Proc 2005; 37(9):3743-5. 

Top

Wellmark Blue Cross and Blue Shield
Medical Policy Analyst
Station 304
636 Grand Ave.
Des Moines, IA 50309

*Current Procedural Terminology © 2008 American Medical Association. All Rights Reserved.

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.