Description:
Plasma exchange (PE) is a procedure in which the plasma is isolated, then discarded and replaced with a fluid such as albumin. PE is a nonspecific therapy, because the entire plasma is discarded. PE has been used in a wide variety of acute and chronic conditions, as well as in the setting of solid organ transplantation.

Data from published studies clinical input and/or guidelines from the American Society for Apheresis support the use of PE for selected autoimmune, hematologic, neurologic, renal, and transplantation conditions.   

Background 
TERMINOLOGY
The terms therapeutic apheresis, plasmapheresis, and plasma exchange (PE) are often used interchangeably, but when properly used denote different procedures. The American Society for Apheresis definitions for these procedures are as follows:

Apheresis is a procedure in which blood of the patient or donor is passed through a medical device that separates out one or more components of blood and returns remainder with or without extracorporeal treatment or replacement of the separated component. 

Plasmapheresis is a procedure in which blood of a patient or the donor is passed through a medical device that separates plasma from the other components of blood and the plasma is removed (i.e., < 15% of total plasma volume) without the use of replacement solution.

Plasma exchange is a therapeutic procedure in which blood of the patient is passed through a medical device that separates plasma from other components of blood, the plasma is removed, and it is replaced with a replacement solution such as colloid solution (e.g., albumin and/ or plasma) or a combination of crystalloid/colloid solution.

This evidence review addresses only PE as a therapeutic apheresis procedure.

PLASMA EXCHANGE
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. PE is a symptomatic therapy, because it does not remove the source of the pathogenic factors. Therefore the success of PE depends on whether the pathogenic substances are accessible through the circulation and whether their rate of production and transfer to the plasma component can be adequately addressed by PE. For example, PE can rapidly reduce levels of serum autoantibodies; however, through a feedback mechanism, this rapid reduction may lead to a rebound overproduction of the same antibodies. This rebound production of antibodies is thought to render the replicating pathogenic clone of lymphocytes more vulnerable to cytotoxic drugs; therefore, PE is sometimes used in conjunction with cyclophosphamide.

Applications
Applications of PE can be broadly subdivided into 2 general categories: (1) Acute self-limited diseases, in which PE is used to acutely lower the circulating pathogenic substance; and (2) chronic diseases, in which there is ongoing production of pathogenic autoantibodies. Because PE does not address underlying pathology, and, because of the phenomenon of rebound antibody production, its use in chronic diseases has been more controversial than in acute self-limited diseases.

Also, plasmapheresis has been used in the setting of solid organ transplantation. It has been used as a technique to desensitize high-risk patients before transplant and also as a treatment of antibody-mediated rejection reaction occurring after transplant. Before transplant, plasmapheresis has been most commonly used to desensitize patients receiving an ABO mismatched kidney, often in combination with a splenectomy. As a treatment of antibody-mediated rejection, plasmapheresis is often used in combination with intravenous immunoglobulin or anti-CD20 therapy (i.e., rituximab).  

Regulatory Status 
FDA has a compliance program to ensure that source plasma, source leukocytes and therapeutic exchange plasma for further manufacture into products for human use are safe, pure, potent and appropriately labeled. The compliance program covers products intended for use both in injectable drug products (e.g., immune globulin, albumin) and noninjectable products (e.g., in vitro devices such as blood bank reagents). 

Compliance Program Guidance Manual Chapter 42-Blood and Blood Products 2011.¹ Product Code for Therapeutic Exchange Plasma (TEP): 57DI-65 

Related Policies
80105 Immune Globulin Therapy
80204 Low-Density Lipid Apheresis

Policy:
Plasma exchange is considered MEDICALLY NECESSARY for the conditions listed below:

Autoimmune

• Severe multiple manifestations of mixed cryoglobulinemia (MC) such as cryoglobulinemic nephropathy, skin ulcers, sensory motor neuropathy and widespread vasculitis in combination with immunosuppressive treatment
• Catastrophic antiphospholipid syndrome

Hematologic

• ABO incompatible hematopoietic progenitor cell transplantation
• Hyperviscosity syndromes associated with multiple myeloma or Waldenstrom’s macroglobulinemia
• Idiopathic thrombocytopenic purpura in emergency situations
• Thrombotic thrombocytopenic purpura (TTP)
• Atypical hemolytic-uremic syndrome
• Post-transfusion purpura
• HELLP syndrome of pregnancy (a severe form of pre-eclampsia, characterized by hemolysis [H], elevated liver enzymes [EL] and low platelet [LP] counts)
• Myeloma with acute renal failure

Neurological

• Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome [GBS]; severity grade 1 – 2 within two weeks of onset; severity grade 3 – 5 within four weeks of onset; and children younger than 10 years old with severe GBS)
• Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
• Multiple sclerosis (MS); acute fulminant central nervous system (CNS) demyelination
• Myasthenia gravis in crisis or as part of preoperative preparation
• Paraproteinemic polyneuropathy: IgA, IgG

• N-methyl-D-aspartate receptor antibody encephalitis

• Progressive multifocal leukoencephalopathy associated with natalizumab

Renal

• Anti-glomerular basement membrane disease (Goodpasture’s syndrome)
• ANCA [antineutrophil cytoplasmic antibody]-associated vasculitis [e.g., Wegener’s granulomatosis [also known as granulomatosis with polyangitis (GPA)] with associated renal failure
• Dense deposit disease with factor H deficiency and/or elevated C3 Nephritic factor.

Transplantation

• ABO incompatible solid organ transplantation;
  • Kidney
  • Heart (infants)
• Renal transplantation: antibody mediated rejection; HLA [human leukocyte antigen] desensitization
• Focal segmental glomulerulosclerosis after renal transplant

Plasmaexchange is considered INVESTIGATIONALin all other conditions, including, but not limited, to the following:

• ABO-incompatible solid organ transplant; liver
• Acute disseminated encephalomyelitis
• Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome) in children younger than 10 years old with mild or moderate forms
• Acute liver failure
• Amyotrophic lateral sclerosis
• ANCA [antineutrophil cytoplasmic antibody]-associated rapidly progressive glomerulonephritis (Wegener’s granulomatosis or GPA without renal failure)
• Aplastic anemia
• Asthma
• Autoimmune hemolytic anemia; warm autoimmune hemolytic anemia; cold agglutinin disease
• Chronic fatigue syndrome
• Coagulation factor inhibitors
• Cryoglobulinemia; except for severe mixed cryoglobulinemia, as noted above
• Dermatomyositis and polymyositis
• Focal segmental glomerulosclerosis (other than after renal transplant)
• Heart transplant rejection treatment
• Hemolytic uremic syndrome (HUS); typical (diarrheal-related)
• Idiopathic thrombocytopenic purpura; refractory or non-refractory
• Inclusion body myositis
• Lambert-Eaton myasthenic syndrome
• Multiple sclerosis; chronic progressive or relapsing remitting
• Mushroom poisoning
• Myasthenia gravis with anti-MuSK antibodies
• Neuromyelitis optica (NMO)
• Overdose and poisoning (other than mushroom poisoning)
• Paraneoplastic syndromes
• Paraproteinemia polyneuropathy; IgM
• Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)
• Pemphigus vulgaris
• Phytanic acid storage disease (Refsum’s disease)
• POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes)
• Psoriasis
• Red blood cell alloimmunization in pregnancy
• Rrheumatoid arthritis
• Sepsis
• Scleroderma (systemic sclerosis)
• Stiff person syndrome
• Sydenham’s chorea (SC)
• Systemic lupus erythematosus (including SLE [systemic lupus erythematosus] nephritis)
• Thyrotoxicosis
• Hyperviscosity syndromes with renal failure (other than associated with multiple myeloma or Waldenstrom’s macroglobulinemia) 

Policy Guidelines
Patients receiving PE as a treatment of CIDP should meet the diagnostic criteria for CIDP, which are included in an appendix to this policy.

The use of PE in patients with acute, life-threatening complications of chronic autoimmune diseases, such as rheumatoid arthritis and SLE, may need to be considered on an individual basis. An example of such a situation would be the development of a severe vasculitis, in which it is hoped that the use of PE can acutely lower the level of serum autoantibodies until an alternate long-term treatment strategy can be implemented. However, in these situations, the treatment goals and duration of treatment with PE need to be clearly established before its initiation; without such treatment goals, the use of an acute short-term course of PE may insidiously evolve to a chronic use of PE with uncertain benefit.

In 2003, CPT introduced a variety of CPT codes that describe different types of apheresis procedures. CPT codes 36514 specifically describe “therapeutic apheresis, for plasma pheresis.”

Benefit Application
BlueCard/National Account Issues
Because plasmapheresis frequently involves long-term chronic therapy, Plans may want to consider requiring precertification to ensure appropriate utilization.

State or federal mandates (e.g, FEP) may dictate that all devices, drugs, biologics and imaging approved by the U.S. Food and Drug Administration may not be considered investigational and, thus, may be assessed only on the basis of their medical necessity. 

Rationale
This evidence review was created in December 1995 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through July 21, 2017.

Assessment of efficacy for therapeutic intervention involves a determination of whether an intervention improves health outcomes. The optimal study design for this purpose is a randomized controlled trial (RCT) that includes clinically relevant measures of health outcomes. Intermediate outcome measures, also known as surrogate outcome measures, may also be adequate if there is an established link between the intermediate outcome and true health outcomes. Nonrandomized comparative studies and uncontrolled studies can sometimes provide useful information on health outcomes, but are prone to biases such as noncomparability of treatment groups, placebo effect, and variable natural history of the condition. The following is a summary of the key literature to date.

AUTOIMMUNE DISEASES
One potential type of evidence in support of the clinical effectiveness of plasma exchange (PE) in treating autoimmune diseases is the identification of a pathogenic component of plasma that is reliably eliminated by plasmapheresis.² 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 unknown to what extent plasma levels parallel clinical disease. For example, in many of the controlled trials discussed next, 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 here.

Systemic Lupus Erythematosus
A 2016 systematic review by Kronbichler et al. found that the interpretation of studies evaluating PE for treating systemic lupus erythematosus is limited due to factors such as the available study designs, small numbers of patients, and variability in PE dosing and protocols.³ Reviewers did not identify any recent controlled trials evaluating the impact of PE on health outcomes in patients with systemic lupus.

Reporting on the results of an RCT, Lewis et al. (1992) concluded that PE had no benefit in patients with systemic lupus and glomerulonephritis compared with a standard therapy regimen of prednisone and cyclophosphamide.⁴ Plasmapheresis has also been investigated as a technique to improve the effectiveness of cyclophosphamide therapy. For example, it is hypothesized that the acute lowering of pathogenic autoantibodies with plasmapheresis might result in their rebound production and that the pathogenic lymphocytes would be more sensitive to cyclophosphamide at this point. Danieli et al. (2002) reported on a prospective case series of 28 patients with proliferative lupus nephritis; 12 underwent synchronized plasmapheresis and pulse cyclophosphamide therapy, while the remaining 16 underwent cyclophosphamide alone.⁵ Although plasmapheresis was associated with a decreased time to remission of renal disease, at the end of the 4-year follow-up, there was no difference in outcomes.

Multiple Sclerosis
Several RCTs of PE in patients with multiple sclerosis (MS) have reported inconclusive results. Khatri et al. (1985) studied 54 patients with chronic progressive MS randomized to sham or true PE.⁶ The degree of improvement in the PE group was greater than that in the control group. Weiner et al. (1989) reported on a study that randomized patients with acute MS to PE or sham treatments; there was no statistical difference in improvement rates between groups, although patients receiving PE did have a faster recovery rate from acute attacks.⁷ A 1991 Canadian trial randomized 168 patients with progressive MS to PE or immunosuppressive therapy.⁸ There were no significant differences in the rates of treatment failures between groups.

Lambert-Eaton Myasthenic Syndrome and Other Paraneoplastic Syndromes
Paraneoplastic neuromuscular syndromes are characterized by the production of tumor antibodies that cross-react with the patient’s nervous system tissues. Lambert-Eaton myasthenic syndrome (LEMS), characterized by proximal muscle weakness of the lower extremities and associated most frequently with small-cell lung cancer, is the most common paraneoplastic syndrome. The presumed autoimmune nature of LEMS and other paraneoplastic syndromes led to the use of a variety of immunomodulatory therapies, including PE. However, there are minimal data in the published literature and no controlled trials. The largest case series assessing LEMS was reported by Tim et al. (2000) and included 73 patients with LEMS, 31 of whom were found to have lung cancer.⁹ Although detailed treatment strategies were not provided, 19 underwent plasmapheresis, with 27% reporting a moderate to marked response. However, the improvement after plasmapheresis was only transient, even when marked. Patients also received other therapies (e.g., various chemotherapy regimens for the underlying lung cancer). Also, 53 (73%) of the 73 patients received 3,4 diaminopyridine, with 79% reporting marked or moderate responses. In the same year, a small RCT of 3,4 diaminopyridine also reported positive results, confirming other anecdotal reports.¹⁰ Anderson et al. (1988) 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 2 (17%) patients showed a minor improvement in neurologic symptoms.¹¹

Rheumatoid Arthritis
In 1983, Dwosh et al. reported on 26 patients with chronic rheumatoid arthritis randomized in a crossover design to true or sham PE. The authors concluded that PE had no clinical benefit, despite impressive laboratory changes.¹²

Polymyositis and Dermatomyositis
Miller et al. (1992) conducted a randomized trial of PE in the treatment of 39 patients with polymyositis and dermatomyositis and found that PE was no more effective than sham pheresis.¹³

Pemphigus
Pemphigus is an autoimmune blistering skin disease that is characterized by serum antibodies that bind to squamous epithelia. Steroids or other immunosuppressants are the most common forms of treatment, but high doses of steroids can produce significant adverse effects. Guillaume et al. (1988) reported on a study of 40 patients with pemphigus randomized to prednisone alone or prednisone plus plasmapheresis.¹⁴ This trial sought to determine whether plasmapheresis can reduce the required dose of steroids, thus limiting its toxicity. Unfortunately, disease control in the 2 groups was the same, and the authors concluded that plasmapheresis in conjunction with low-dose steroids was ineffective in treating pemphigus.

Stiff Man (or Stiff Person) Syndrome
Stiff man syndrome is an autoimmune disorder characterized by involuntary stiffness of axial muscles and intermittent painful muscle spasm. Stiff man syndrome may be idiopathic in nature or seen in association with thymoma, Hodgkin disease, as well as small-cell lung, colon, or breast cancer. The mainstay of treatment of stiff man syndrome is diazepam. The published literature on plasmapheresis consists of small case series and anecdotal reports.^15,16,17 Most of these studies were published in the late 1980s or early 1990s. A small case series of 9 patients was published in 2014,¹⁸ and a smaller case report of 2 patients was published in 2016.¹⁹

Cryoglobulinemia
There are several types of cryoglobulinemia. Type I is associated with hematologic disorders. Types II and III are considered mixed cryoglobulinemias. Mixed cryoglobulinemia is a consequence of immune-complex mediated vasculitis and may be associated with infectious and systemic disorders (e.g., hepatitis C virus). In 2010, Rockx and Clark published a review of studies evaluating PE for treating cryoglobulinemia that included at least 5 patients.²⁰ They identified 11 studies (total N = 156 patients). Reviewers concluded: "The quality and variability of the evidence precludes a meta-analysis or even a systematic analysis. However, these studies weakly support the use of plasma exchange largely on a mechanistic basis."

HEMATOLOGIC CONDITIONS
Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome
Once considered distinct syndromes, thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are now considered different manifestations of the same disease process (i.e., thrombotic microangiopathy). In 2009, a systematic review evaluated the benefits and harms of different interventions for HUS and TTP (separately).²¹ Interventions were compared with placebo or supportive therapy or a comparison of two or more interventions. Interventions examined included heparin, aspirin/dipyridamole, prostanoids, ticlopidine, vincristine, fresh frozen plasma (FFP) infusion, plasmapheresis with FFP, systemic corticosteroids, Shiga toxin-binding agents, or immunosuppressive agents. For TTP, 6 RCTs (n = 331 patients) were identified evaluating PE with FFP as the control.  

Interventions tested included antiplatelet therapy plus PE with FFP, FFP transfusion, and PE with cryosupernatant plasma. Two studies compared plasma infusion with PE plus FFP and showed a significant increase in failure of remission at 2 weeks (relative risk [RR], 1.48) and all-cause mortality (RR = 1.91) in the plasma infusion group. Reviewers concluded that PE plus FFP is the most effective treatment available for TTP. Seven RCTs included children with HUS. None of the assessed interventions were superior to supportive therapy alone for all-cause mortality, neurologic/extrarenal events, renal biopsy changes, proteinuria, or hypertension at the last follow-up visit. The incidence of bleeding was significantly greater in those receiving anticoagulation therapy compared with supportive therapy alone (risk difference, 0.35). For patients with HUS, supportive therapy including dialysis was the most effective treatment. No RCTs evaluated the effectiveness of any interventions on patients with atypical HUS who have a more chronic and relapsing course. A 2009 review article by Noris and Remuzzi described data supporting use of PE in the atypical form of this disease, with results showing remission in up to 60% of patients.²²

All studies in HUS have been conducted with patients with the diarrheal (typical) form of the disease. Because the available evidence for patients with typical HUS shows supportive therapy, including dialysis, to be the most effective treatment, evidence for the use of PE for the treatment of typical HUS is inadequate to draw clinical conclusions. PE for HUS was considered medically necessary in previous updates. PE remains medically necessary for atypical HUS.

Idiopathic Thrombocytopenic Purpura
Idiopathic thrombocytopenic purpura is an acquired disease of adults or children characterized by the development of autoantibodies to platelets. Management of acute bleeding due to thrombocytopenia typically involves immediate platelet transfusion, occasionally in conjunction with a single infusion of intravenous immunoglobulin (IVIg). PE has been occasionally used in emergency situations.

Post-Transfusion Purpura
Post-transfusion purpura is a rare disorder characterized by an acute severe thrombocytopenia occurring approximately 1 week after a blood transfusion in association with a high titer of antiplatelet alloantibodies. Because of its rapid effect, PE is considered the initial treatment of choice.

HELLP Syndrome of Pregnancy
The HELLP syndrome of pregnancy (characterized by hemolysis, elevated liver enzymes, and low platelet counts) is a severe form of pre-eclampsia. The principal form of treatment is the delivery of the fetus. However, for patients with severe thrombocytopenia, PE may be indicated if the fetus cannot safely be delivered, or if the maternal thrombocytopenia persists into the postnatal period.

Myeloma With Acute Renal Failure
In 2015, Yu et al. published a meta-analysis of RCTs on the treatment of acute renal failure associated with multiple myeloma using chemotherapy alone vs chemotherapy and PE.²³ Four RCTs were identified; three had full text availability and were included in the data synthesis. None of the RCTs were double-blinded. The trials included 63 patients receiving chemotherapy only and 84 patients receiving chemotherapy and PE. A variety of chemotherapy agents and PE protocols were used. In a pooled analysis, there was no statistically significant difference in 6-month survival outcomes between the 2 groups (RR = 0.92; 95% confidence interval [CI], 0.76 to 1.11; p = 0.39). However, the dialysis dependent rate among survivors at 6 months was significantly lower in the chemotherapy plus PE group than in the group receiving chemotherapy alone (RR = 2.02; 95% CI, 1.03 to 3.96; p = 0.04).

NEUROLOGIC CONDITIONS
Guillain-Barré Syndrome
Guillain-Barré syndrome (GBS) is an acute demyelinating neuropathy whose severity is graded on a scale of 1 to 5. In 2017, The Cochrane Collaboration published an updated systematic review of the evidence concerning the efficacy of PE for treating GBS.²⁴ Reviewers included RCTs evaluating PE alone in children and/or adults with disease of any severity. Eight eligible trials were identified. The primary Interventions tested included antiplatelet therapy plus PE with FFP, FFP transfusion, and PE with cryosupernatant plasma. Two studies compared plasma infusion with PE plus FFP and showed a significant increase in failure of remission at 2 weeks (relative risk [RR], 1.48) and all-cause mortality (RR = 1.91) in the plasma infusion group. Reviewers concluded that PE plus FFP is the most effective treatment available for TTP. Seven RCTs included children with HUS. None of the assessed interventions were superior to supportive therapy alone for all-cause mortality, neurologic/extrarenal events, renal biopsy changes, proteinuria, or hypertension at the last follow-up visit. The incidence of bleeding was significantly greater in those receiving anticoagulation therapy compared with supportive therapy alone (risk difference, 0.35). For patients with HUS, supportive therapy including dialysis was the most effective treatment. No RCTs evaluated the effectiveness of any interventions on patients with atypical HUS who have a more chronic and relapsing course. A 2009 review article by Noris and Remuzzi described data supporting use of PE in the atypical form of this disease, with results showing remission in up to 60% of patients.²²

All studies in HUS have been conducted with patients with the diarrheal (typical) form of the disease. Because the available evidence for patients with typical HUS shows supportive therapy, including dialysis, to be the most effective treatment, evidence for the use of PE for the treatment of typical HUS is inadequate to draw clinical conclusions. PE for HUS was considered medically necessary in previous updates. PE remains medically necessary for atypical HUS.

Idiopathic Thrombocytopenic Purpura
Idiopathic thrombocytopenic purpura is an acquired disease of adults or children characterized by the development of autoantibodies to platelets. Management of acute bleeding due to thrombocytopenia typically involves immediate platelet transfusion, occasionally in conjunction with a single infusion of intravenous immunoglobulin (IVIg). PE has been occasionally used in emergency situations.

Post-Transfusion Purpura
Post-transfusion purpura is a rare disorder characterized by an acute severe thrombocytopenia occurring approximately 1 week after a blood transfusion in association with a high titer of antiplatelet alloantibodies. Because of its rapid effect, PE is considered the initial treatment of choice.

HELLP Syndrome of Pregnancy
The HELLP syndrome of pregnancy (characterized by hemolysis, elevated liver enzymes, and low platelet counts) is a severe form of pre-eclampsia. The principal form of treatment is the delivery of the fetus. However, for patients with severe thrombocytopenia, PE may be indicated if the fetus cannot safely be delivered, or if the maternal thrombocytopenia persists into the postnatal period.

Myeloma With Acute Renal Failure
In 2015, Yu et al. published a meta-analysis of RCTs on the treatment of acute renal failure associated with multiple myeloma using chemotherapy alone vs chemotherapy and PE.²³ Four RCTs were identified; three had full text availability and were included in the data synthesis. None of the RCTs were double-blinded. The trials included 63 patients receiving chemotherapy only and 84 patients receiving chemotherapy and PE. A variety of chemotherapy agents and PE protocols were used. In a pooled analysis, there was no statistically significant difference in 6-month survival outcomes between the 2 groups (RR = 0.92; 95% confidence interval [CI], 0.76 to 1.11; p = 0.39). However, the dialysis dependent rate among survivors at 6 months was significantly lower in the chemotherapy plus PE group than in the group receiving chemotherapy alone (RR = 2.02; 95% CI, 1.03 to 3.96; p = 0.04).

NEUROLOGIC CONDITIONS
Guillain-Barré Syndrome
Guillain-Barré syndrome (GBS) is an acute demyelinating neuropathy whose severity is graded on a scale of 1 to 5. In 2017, The Cochrane Collaboration published an updated systematic review of the evidence concerning the efficacy of PE for treating GBS.²⁴ Reviewers included RCTs evaluating PE alone in children and/or adults with disease of any severity. Eight eligible trials were identified. The primary outcome measure of the review was the time to recover walking with aid. However, reviewers noted that the outcome change in disability grade was the primary end point of many of the trials and this was included as a secondary outcome of the Cochrane review. Not enough trials reported the primary outcome of interest. However, 3 trials reported the proportion of patients who recovered walking with assistance after 4 weeks; in a pooled analysis, a significantly greater proportion of patients recovered after PE than after the control intervention (RR = 1.60; 95% CI, 119 to 2.15; I² = 34%). In a pooled analysis of 5 trials comparing improvement in walking by at least 1 grade after 4 weeks (a secondary outcome), PE was significantly more effective than sham or supportive treatment (RR = 1.64; 95% CI, 1.37 to 1.96; I2 = 0%). There were also significantly fewer patients on a ventilator at 4 weeks with PE vs control (RR = 0.53; 95% CI, 0.39 to 0.74; I2 = 43%). None of the studies in this review included patients younger than 10 years old.

A 2011 RCT from Iran evaluated PE for treating young children with severe GBS.²⁵ The trial included 41 children with GBS who required mechanical ventilation and had muscle weakness for no more than 14 days. Patients were randomized to PE (n = 21) or IVIg (n = 20). The mean (standard deviation [SD]) patient age was 96 months in the PE group and 106 months in the IVIg group. The mean duration of ventilation (the primary outcome) was 11 (1.5) days in the PE group and 13 (2.1) days in the IVIg group (p = 0.037). Duration of stay in the intensive care unit (a secondary outcome) was 15.0 (2.6) days in the PE group and 16.5 (2.1) days in the IVIg group (p = 0.94).

Chronic Inflammatory Demyelinating Polyradiculoneuropathy
A 2015 Cochrane review by Mehnidiratta et al. identified 2 randomized trials on PE for chronic inflammatory demyelinating polyradiculoneuropathy.²⁶ Both trials were considered to be of high quality, but had small sample sizes. One trial with 29 patients used a parallel design and compared PE with sham treatment. The other study included 18 patients and used a crossover design to compare PE with sham treatment. A pooled analysis of trial data found a statistically significantly greater reduction in impairment after 4 weeks with PE vs sham (mean difference in Neuropathy Impairment Score, 31 points; 95% CI, 16 to 45 points). This scale ranges from 0 (normative) to 280 (maximally affected). Data on other outcomes were not suitable for pooled analysis.

Acute Fulminant Central Nervous System Demyelination
Plasmapheresis may be considered medically necessary in patients with acute fulminant central nervous system demyelination; this conclusion is based on the results of a 1999 randomized, double-blinded trial, in which 22 patients with MS or other acute idiopathic inflammatory demyelinating diseases of the central nervous system were enrolled a minimum of 14 days after having failed to respond to at least 5 days of high-dose corticosteroids.²⁷ Patients were randomized to 7 real or sham PE procedures over a 14-day period. The primary outcome was a targeted neurologic deficit (i.e., aphasia, cognitive dysfunction). Overall, moderate to marked improvement of the targeted outcome was obtained in 42% of the treatment group compared with only 6% in the placebo group.

Myasthenia Gravis
Several RCTs have evaluated use of PE in the treatment of myasthenia gravis. A 2011 trial from Germany included patients with myasthenic crisis.²⁸ Patients were randomized to treatment with PE (n = 10) or immunoadsorption (IA; n = 9). In both groups, 3 apheresis treatments were performed within 7 days; patients could have additional treatments if needed. A total of 16 (84%) of 19 of patients, 8 in each group, completed the study and were included in the efficacy analysis. The mean number of treatments was 3.5 in the PE group and 3.4 in the IA group (p > 0.05). The primary outcome was change in the modified clinical score (maximum of 3 points) on day 14 after the last treatment. The baseline modified clinical score was 2.6 in the PE group and 2.5 in the IA group. At day 14, score improvement was 1.6 points in the PE group and 1.4 points in the IA group (p > 0.05). Within 180 days after treatment, 1 patient in the PE group and 3 patients in the IA group experienced another myasthenic crisis; the number of events was too small for meaningful statistical analysis for this outcome.

 2017 RCT by Alipour-Faz et al. in Iran randomized 24 adults with myasthenia gravis to presurgical treatment with PE (n = 12) or IVIG (n = 12).²⁹ Treatments were given 10 to 30 days before thymectomy. All patients completed the trial. Study outcomes were duration of hospitalization, length of postsurgical intensive care unit stay, duration of intubation, duration of surgery, and dose of steroids. Most outcomes were similar in the 2 groups. One outcome, length of intubation period, differed significantly between groups. The median length of intubation was 0 hours in the IVIG group and 13 hours in the PE group (p = 0.01).

Paraproteinemic Polyneuropathies
A 1991 randomized, double-blinded trial compared PE with sham treatment in 39 patients who had monoclonal gammopathy of undetermined significance‒associated polyneuropathy.³⁰ After twice weekly PE for 3 weeks, the treatment group reported improvements in neurologic function in the immunoglobulin (Ig) G and IgA groups but not the IgM monoclonal gammopathy of undetermined significance groups. Those from the sham group who later crossed over to the PE group also reported improvement.

Neuromyelitis Optica
Neuromyelitis optica (NMO) is a rare inflammatory disorder of the central nervous system that predominantly affects the optic nerves and spinal cord. No RCTs evaluating PE for treatment of patients with NMO were identified. Several retrospective nonrandomized studies have evaluated PE as add-on therapy to intravenous (IV) corticosteroids.

In 2016, Abboud et al. reviewed 83 admissions for acute relapse of NMO at a single center in the United States.³¹ Relapses could involve the spinal cord, optic nerve, and/or the brain. Patients were initially treated with IV corticosteroids alone for 5 days and, if they did not respond, they were then treated with 5 to 7 sessions of PE in their second week of hospitalization. Eighteen relapses (16 patients) were treated with IV corticosteroid therapy alone, and 65 relapses (43 patients) were treated with IV corticosteroid plus PE. Patients were assessed using the Expanded Disability Status Score (EDSS), which has a range of 1 to 10, with higher numbers indicating more disability. The primary end point was a return to baseline EDSS (before admission) on discharge. The EDSS scores at baseline and discharge were calculated retrospectively based on available records and without blinding to treatment group.

In the relapses treated with IV corticosteroids only, the median baseline EDSS was 2.5, which increased to 4.5 at presentation and decreased to a median of 4 at discharge. In comparison, among the relapses also treated with PE, the median baseline EDSS was 5.75, which increased to 7.75 at presentation and decreased to a median of 6.5 at discharge. At discharge, 3 relapses (17%) in the IV corticosteroid-only group improved to baseline EDSS or lower at discharge, compared with 31 relapses in the IV corticosteroid plus PE group (p = 0.016). Follow-up data at approximately 1 year (range, 6 – 18 months) were available on 50 (77%) of 65 relapses. At this longer term follow-up point, 6 relapses in the intravenous methylprednisolone (IVMP) only group and 33 in the IVMP group improved to an EDSS equal or below their baseline EDSS (p = 0.039).

The study did not directly compare the efficacy of IV corticosteroid treatment alone with IV corticosteroids plus PE because the treatments were applied sequentially. Moreover, the patient populations differed; patients who received PE as add-on treatment were older and more disabled at baseline. The finding that a greater proportion of the more severely ill population had a resolution of acute relapses suggests that combination IV corticosteroid and PE therapy may be more beneficial than IV corticosteroids alone. However, to draw definitive conclusions, findings would need to be confirmed in randomized trials. Another study limitation was a lack of patient-level analyses and lack of other outcome measures at 1 year measuring disease progression.

Two other studies were conducted at a facility in Martinique, and both compared outcomes in patients treated before and after PE was introduced as a treatment. A 2009 study by Bonnan et al focused on spinal attacks associated with NMO.³² The study reported on 43 patients with NMO, 18 of whom received PE as add-on therapy for at least 1 spinal attack. The study period was 1982 to 2008; PE was introduced at the facility in 1999. The patients experienced a total of 96 spinal attacks; PE was used in 29 attacks. The PE-treated and corticosteroid-only groups had similar EDSS scores before the spinal attacks, and there was a greater reduction in EDSSs following treatment with PE. In the PE group, the mean acute EDSS (SD) was 7.9 (1.3), and the mean EDSS after therapy was 5.1 (2.4), for a mean decrease of 2.8 points. In comparison, the mean acute EDSS in the corticosteroid-only group was 8.0 (1.4), and the mean EDSS after treatment was 6.8 (1.9), for a mean decrease of 1.2 points. The analysis was done on a per-attack basis rather than a per-patient basis.

The 2012 study by Merle et al. evaluated the impact of PE as an add-on therapy on optic outcomes in 32 patients treated for acute optic neuritis between 1996 and 2010.³³ In 2006, PE was added to the treatment protocol, and 16 of the 32 patients also received 5 daily consecutive PEs in the intensive care unit. Study outcomes were obtained from an eye examination performed at least 6 months after optic neuritis treatment. At the final follow-up visit, visual acuity was significantly better in the PE group than in the corticosteroid-only group (20/400 vs 20/50, respectively, p = 0.04). Visual acuity gain was 20/200 in the corticosteroid group and 20/30 in the PE group (p = 0.01). Outcomes could be impacted by confounding factors. For example, longer disease duration was associated with poorer outcomes in univariate analysis and, at baseline, disease duration was significantly longer in the corticosteroid group than in the PE group (mean, 10.8 and 5.8 years, respectively, p < 0.001).

Limitations of the Bonnan and the Merle studies include possible patients overlap between studies, and lack of randomization, which might have led to baseline between-group differences in factors that affected outcomes. Also, both studies were subject to bias due to use of historical controls, i.e., patients in the latter period received PE and care could also have improved over time in other ways that led to improved outcomes.

A retrospective review of registry data was published by Kleiter et al. in 2016.³⁴ The investigators identified 185 patients NMO added to the registry since 2008; collectively, the patients experienced 871 acute attacks. Various first-line treatments of NMO attacks were used, most commonly high-dose IV steroids (70.3% of treatment courses). PE was the first-line treatment in 27 (15%) of 185 patients. The investigators did not report on the efficacy of PE as second-line or add-on treatment.

The available nonrandomized retrospective studies have methodologic limitations (e.g., lack of randomization, use of historical control groups), and findings need to be confirmed in well-designed and conducted randomized trials.

N-methyl-D-aspartate Receptor Antibody Encephalitis
A 2017 review by the American Society for Apheresis has stated that, if left untreated, N-methyl-D-aspartate receptor antibody encephalitis can lead to decline in the autonomic function and, ultimately, to death.³⁵ The review indicated that approximately 50% of patients respond to one of several first-line immunotherapies, which includes PE. There is little published evidence. A 2015 retrospective evaluation of 14 patients with anti-N-methyl-D-aspartate receptor antibody encephalitis found improvement in the modified Rankin Scale score in 7 of 10 patients treated with PE, compared with 3 of 10 patients treated with corticosteroids.³⁶

Progressive Multifocal Leukoencephalopathy Associated With Natalizumab
As noted in the 2017 American Society for Apheresis review (discussed above) progressive multifocal leukoencephalopathy is a potentially fatal side effect of natalizumab, a treatment option for relapsing MS.³⁵ If progressive multifocal leukoencephalopathy is suspected, natalizumab should be stopped immediately. Also, PE, which was shown in a small 2009 study of 12 patients to reduce serum natalizumab concentration by 92% in a week,³⁷ can be used to quickly remove natalizumab from the bloodstream and reduce the consequences of progressive multifocal leukoencephalopathy.

RENAL DISEASES
Rapidly Progressive Glomerulonephritis
Rapidly progressive glomerulonephritis (RPGN) is a general term describing the rapid loss of renal function in conjunction with the finding of glomerular crescents on renal biopsy specimens. There are multiple etiologies of RPGN including vasculitis, the deposition of antiglomerular basement membrane antibodies, as seen in Goodpasture syndrome, or the deposition of immune complexes, as seen in various infectious diseases or connective tissue diseases. PE has long been considered a treatment alternative in immune-mediated RPGN. However, few controlled clinical trials have been 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.³⁸ Aside from cases of Goodpasture disease, the rationale for PE in idiopathic RPGN is not strong, because of the lack of an identifiable immune component. Studies of PE in this population have not demonstrated a significant improvement in outcome compared with the use of pulse steroid therapy.³⁹

Antineutrophil Cytoplasmic Antibody‒Associated Vasculitis
In 2011, Walsh et al. published a meta-analysis of studies on PE in adults diagnosed with idiopathic renal vasculitis or RPGN.⁴⁰ A total of 9 trials including 387 patients were identified. Clinical populations in the studies were somewhat ill-defined, but most patients appeared to have antineutrophil cytoplasmic antibody (ANCA)‒associated vasculitis. In a pooled analysis, the risk of end-stage renal disease was significantly lower in patients treated with adjunctive PE compared with standard care alone (RR = 0.64; 95% CI, 0.47 to 0.88). The risk of death did not differ statistically between the 2 groups (RR = 1.01; 95% CI, 0.71 to 1.40).

In 2007, Jayne et al. published a relatively large RCT,⁴¹ included in the previously mentioned meta-analysis. This multicenter RCT was conducted on behalf of the European Vasculitis Study Group. The trial investigated whether the addition of PE was more effective than the addition of IVMP. Patients (N = 137) with a new diagnosis of ANCA-associated systemic vasculitis confirmed by renal biopsy and serum creatinine greater than 5.8 mg/dL were randomized to 7 PEs (n = 70) or 3000 mg of IVMP (n = 67). Both groups received oral cyclophosphamide and oral prednisolone. The primary end point was dialysis independence at 3 months. Secondary end points included renal and patient survival at 1 year and severe adverse event rates. At 3 months, 33 (49%) of 67 were alive and independent of dialysis after IVMP, compared with 48 (69%) of 70 after PE. Compared with IVMP, PE was associated with a reduction in risk for progression to end-stage renal disease (24% at 12 months). At 1 year, patient survival was 51 (76%) of 67 in the IVMP group and 51 (73%) of 70 in the PE group, and severe adverse events occurred in 48% of the IVMP group and 50% of the PE group. Compared with IVMP, PE increased the rate of renal recovery in patients with ANCA-associated systemic vasculitis who presented with renal failure. Patient survival and severe adverse event rates were similar in both groups. Long-term outcomes of patients in this trial were published in 2013.⁴² The median follow-up was 3.95 years. A total of 70 of 136 patients had died, 35 (51%) in the PE group and 35 (51%) in the IVMP group (p = 0.75). Similarly, the difference between groups in the proportion of patients with end-stage renal disease (33% in the PE group vs 49% in the IVMP group, p = 0.08) was not statistically significant. According to trial results, PE appears to have a short-term benefit on preserving renal function in this population, but long-term efficacy remains uncertain.

TRANSPLANTATION
Solid Organ Transplant
Plasmapheresis has been extensively used in solid organ transplantation, 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-CD20 (i.e., rituximab). Plasmapheresis is more commonly used in patients receiving a living kidney transplant from an ABO mismatched donor.⁴³ A variety of protocols have also been developed for the treatment of AMR, often in combination with other therapies, such as IVIg or anti-CD20.^44-47 Most 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.

MISCELLANEOUS POTENTIAL APPLICATIONS
Acute Liver Failure
One controlled study, an unblinded RCT published in 2016 by Larsen, evaluated high-volume PE in patients with acute liver failure.⁴⁸ Patients with a diagnosis of acute liver failure and at least grade 2 encephalopathy were randomized to standard care only (n = 90) or standard care plus high-volume PE (n = 92). Entry into the study occurred within 24 hours of grade 2 encephalopathy onset. The high-volume PE procedure consisted of exchanging 15% of ideal body weight (8 – 12 liters per day per procedure). Patients’ plasma was removed at the rate of 1 to 2 liters per hour and was replaced with an equivalent amount of fresh frozen plasma. Patients underwent PE on 3 consecutive days. The primary endpoint was transplant-free survival at the time of hospital discharge. The mean length of hospital stay was 21.9 days in the PE group and 41.8 days in the standard care group. The number of patients surviving to hospital discharge was 54 (58.7%) in the PE group and 43 (47.8%) in the group receiving standard care only; the difference between groups was statistically significant. Survival of patients who had a liver transplant (24 [26%] in the PE group vs 32 [36%] in the standard care group) was not significantly impacted by the addition of PE. However, the rate of survival to hospital discharge was significantly higher with PE in the subset of patients who were not listed for transplantation due to contraindications such as medical comorbidities (28 [30%] in the PE group vs 36 [40%] in the standard care group, p = 0.03). Limitations of the study included its lack of blinding and measurement of the survival outcome only at hospital discharge, a period of several weeks, and longer term outcomes were not reported. Also, the PE protocol and transplantation criteria in Denmark, where the study was conducted, may differ from those in the United States.  

Asthma
Some researchers have assessed the use of plasmapheresis in patients with severe, steroid-dependent asthma. However, 1 small crossover trial (N = 4), published in 2001, did not suggest treatment effectiveness.⁴⁹ No subsequent controlled studies have been published.  

Sepsis
In 2014, Rimmer et al. published a systematic review and meta-analysis of the literature on PE for treatment of sepsis and septic shock.⁵⁰ Reviewers identified 4 RCTs comparing PE with usual care (total N = 194 patients). All trials were rated as unclear or high risk of bias. In a pooled analysis of data from the 4 trials, PE was not significantly associated with a reduction in mortality risk (RR = 0.83; 95% CI, 0.45 to 1.52). Data were insufficient for pooled analyses of other outcomes. The evidence identified in this systematic review was insufficient for drawing conclusions about the impact of PE for treating sepsis on the net health outcome.  

Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections and Sydenham Chorea
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is defined as rapid, episodic onset of obsessive-compulsive disorder and/or tic disorder symptoms after a group A beta-hemolytic streptococcal infection (GABHS). Sydenham chorea (SC) is the neurologic manifestation of acute rheumatic fever. The choreatic symptoms of SC are characterized by involuntary rapid and jerky movements that affect the extremities, trunk, and face. SC is a self-limited disorder with symptoms resolving in weeks to months. Perlmutter et al. (1999) conducted an RCT to evaluate the effectiveness of PE and IVIg in reducing the severity of neuropsychiatric symptoms in children diagnosed in the PANDAS subgroup.⁵¹ Children (N = 30) with clear evidence of a strep infection as the trigger of their obsessive-compulsive disorder and tics were randomized to PE (n = 10; 5 – 6 procedures over 2 weeks), IVIg (n = 10; 2 g/kg over 2 days), or placebo (n = 10; mimic IVIg). All were severely ill at the time of treatment. At 1 month, both active treatment groups demonstrated symptom improvement, but those in the placebo group were unchanged. The treatment effect was still apparent after 1 year. However, 50% of children were on the same or higher doses of their baseline medications; thus it is not entirely clear that IVIg or PE had a beneficial effect. This study needs to be replicated with a larger number of patients. The authors noted that children in the placebo group (IVIg control group) subsequently received PE in an open trial and showed only minor improvements.

Garvey et al. (2005) conducted an RCT designed to determine whether IVIg or PE was superior to prednisone in decreasing the severity of chorea.⁵² Children with SC (N = 18) were randomized to treatment with PE (n = 8; 5 – 6 procedures over 1 – 2 weeks), IVIg (n = 4; 2 g/kg over 2 days), or prednisone (n = 6; 1 mg/kg/d for 10 days followed by taper over next 10 days). The primary outcome was chorea severity at 1 month. The secondary outcome variable was chorea severity at 1 year after treatment. There was no significant difference between the baseline chorea severity scores by treatment group. Chorea severity was assessed at baseline and at 1, 2, 3, 6 and 12 months after treatment. The Chorea Rating Scale scores range from 0 (no chorea) to 18 (severe or paralytic chorea). A score of 9 or higher was required for study entry. Baseline medications to control choreatic symptoms were discontinued 1 week before baseline assessment and each follow-up evaluation. The mean chorea severity for the entire group was lower at the 1-month follow-up evaluation (overall 48% improvement). Between-group differences were not statistically significant. Larger studies are needed to confirm these clinical observations.

SUMMARY OF EVIDENCE
Data from published studies clinical input and/or guidelines from the American Society for Apheresis support the use of PE for selected autoimmune, hematologic, neurologic, renal, and transplantation conditions. 

CLINICAL INPUT FROM PHYSICIAN SPECIALTY SOCIETIES AND ACADEMIC MEDICAL CENTERS
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received through 2 physician specialty societies and 3 academic medical centers while this policy was under review in 2012. There was consensus or near-consensus that plasma exchange (PE) for dense deposit disease with factor H deficiency and/or elevated C3 nephritis factor, catastrophic antiphospholipid syndrome, focal segmental glomerulosclerosis after renal transplant, and myeloma with acute renal failure may be considered medically necessary. Input was mixed on the medical necessity of hyperviscosity syndromes with renal failure (other than associated with multiple myeloma or Waldenström macroglobulinemia). Also, there was no consensus about an optimal creatinine threshold for instituting PE in patients with renal failure associated with antineutrophil cytoplasmic antibody-associated vasculitis or other diagnoses.

PRACTICE GUIDELINES AND POSITION STATEMENTS
National Comprehensive Cancer Network
In the current National Comprehensive Cancer Network guidelines on multiple myeloma (v.2.2018), use of plasmapheresis to improve renal function is a category 2B recommendation.⁵³ Plasmapheresis should also be used as adjunctive therapy for hyperviscosity.  

American Academy of Neurology
In 2011, the American Academy of Neurology issued evidence-based guidelines on plasmapheresis for the treatment of neurologic disorders.⁵⁴ The primary conclusions, based on the evidence review, are provided in Table 1.  

Table 1. Guidelines on Use Plasmapheresis to Treat Neurologic Disorders

Recommendation	Conclusion
Acute inflammatory demyelinating polyneuropathy/Guillain-Barré syndrome	Established effective
Chronic inflammatory demyelinating polyneuropathy, short-term treatment	Established effective
Relapses in multiple sclerosis	Probably effective
Fulminant demyelinating central nervous system disease	Probably effective
Chronic or secondary progressive multiple sclerosis	Established ineffective
Myasthenia gravis	Insufficient evidence
Sydenham chorea	Insufficient evidence
Acute obsessive-compulsive disorder and tics in PANDAS	Insufficient evidence

PANDAS: pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. 

In 2003, the American Academy of Neurology published a practice parameter on Guillain-Barré syndrome (GBS).⁵⁵ The following are the key findings: (1) Treatment with plasma exchange (PE) or intravenous immunoglobulin hastens recovery from GBS; (2) combining the 2 treatments is not beneficial; and (3) steroid treatment given alone is not beneficial. The American Academy of Neurology’s recommendations are:

• PE is recommended for adults with GBS who are nonambulant and who seek treatment within 4 weeks of the onset of neuropathic symptoms.
• PE should be considered for ambulant patients examined within 2 weeks of the onset of neuropathic symptoms).
• PE is a treatment option for children with severe GBS.

American Society for Apheresis
In 2016, the American Society for Apheresis updated its guidelines on the use of therapeutic apheresis (Seventh Special Issue).⁵⁶ Previously, the guidelines had been updated in 2013 (Sixth Special Issue).57 The following is a description of the Society categories (see Table 2), 2013 recommendations (see Table 3), and new indications added in 2016 (see Table 4).  

Table 2. American Society for Apheresis Categories

Category	Description
I	Category I includes diseases for which TA (therapeutic apheresis) is accepted as first-line treatment, either as a primary standalone treatment or in conjunction with other treatments. Note that this designation need not imply that TA is mandatory in all cases.
II	Category II denotes diseases for which TA is accepted as second-line treatment, either as a stand-alone treatment or in conjunction with other treatments.
III	Category III diseases are those for which the optimum role of TA is not established and treatment decisions on an individual basis are recommended.
IV	Category IV indicates disorders for which published evidence suggests or demonstrates that TA is ineffective or harmful.

TA: therapeutic apheresis.

Table 3. American Society for Apheresis Recommendations

Disease Group/Name/Condition	2013
Autoimmune
Catastrophic antiphospholipid syndrome	II
Cryoglobulinemia	I
Pemphigus vulgaris	III
Systemic lupus erythematosus
Manifestations other than nephritis	NC
Severe	II
Nephritis	IV
Hematologic
ABO-incompatible hematopoietic progenitor cell transplantation	II
Aplastic anemia	III
Pure red blood cell aplasia	III
Autoimmune hemolytic anemia:
Warm autoimmune hemolytic anemia	III
Cold agglutinin disease	II
Coagulation factor inhibitors	IV
Hyperviscosity in monoclonal gammopathies	I
Idiopathic thrombocytopenic purpura	NC
Refractory immunoadsorption	NC
Refractory or nonrefractory	NC
Myeloma and acute renal failure (in 2010 and 2013 myeloma cast nephropathy)
Posttransfusion purpura	III
Red blood cell alloimmunization in pregnancy	III
Thrombotic thrombocytopenic purpura	I
Metabolic
Acute liver failure	III
Sepsis	III
Thyrotoxicosis	III
Neurological
Acute disseminated encephalomyelitis	II
AIDP (Guillain-Barré syndrome)	I
AIDP, post IVIg	III
Chronic inflammatory demyelinating polyradiculoneuropathy	I
Lambert-Eaton myasthenic syndrome	II
Multiple sclerosis
Acute CNS inflammatory demyelinating disease	II
Devic syndrome	NC
Chronic progressive	III
Myasthenia gravis
In 2013, moderate-severe	I
In 2013, pre-thymectomy	I
Paraneoplastic neurologic syndromes	III
Paraproteinemic polyneuropathies
IgG/IgA	I
IgM	I
Multiple myeloma	III
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections; SC
PANDAS (2007, severe)	I
SC (2007, severe)	I
Rasmussen’s encephalitis	III
Stiff-person syndrome	III
Renal
ANCA-associated rapidly progressive glomerulonephritis (Wegener granulomatosis)
Dialysis dependence	I
Dialysis independence	III
Antiglomerular basement membrane disease (Goodpasture syndrome)
DAH	I
Dialysis dependence and no DAH	111
Dialysis independence	I
Focal segmental glomerulosclerosis
Primary	NC
Secondary	NC
Recurrent	I
HUS; thrombotic microangiopathy; transplant-associated microangiopathy
Idiopathic HUS	NC
Transplant-associated microangiopathy	NC
Diarrhea-associated pediatric	NC
Atypical HUS due to complement factor H	I
Diarrhea associated HUS or typical HUS
In 2013, Shiga toxin-associated	IV
Streptococcus pneumoniae associated	III
Renal transplantation: antibody mediated rejection; HLA desensitization
Antibody mediated rejection	I
HLA desensitization	II
Desensitization, living donor, positive cross-match due to donor-specific HLA antibody	I
High PRA: cadaveric donor	III
Rheumatic
Scleroderma (progressive systemic sclerosis)	III
Transplantation
ABO-incompatible solid organ transplantation
Kidney
In 2013, desensitization, living-donor	I
Humeral rejection	II
Heart (infants)	NC
Liver (2010 perioperative)
In 2013, desensitization living-donor	I
Desensitization, deceased-donor	II
Humeral rejection	III
Heart transplant rejection
Treatment	NC

ABO: A, B, and O blood types; AIDP: acute inflammatory demyelinating polyneuropathy; ANCA: antineutrophil cytoplasmic antibody; CNS: central nervous system; DAH: diffuse alveolar hemorrhage; HLA: human leukocyte antigen; HUS: hemolytic uremic syndrome; Ig: immunoglobulin; IVIg: intravenous immunoglobulin; NC: not categorized; PANDAS: pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection; PRA: Panel Reactive Antibody; SC: Sydenham chorea. 

Table 4. American Society for Apheresis New Indications in 2016

Disease Group/Name/Condition	2016 Category
Atopic (neuro-) dermatitis (atopic eczema), recalcitrant	III
Cardiac neonatal lupus	III
Complex regional pain syndrome	III
Erythropoietic porphyria, liver disease	III
Hashimoto encephalopathy: steroid-responsive encephalopathy associated with autoimmune thyroiditis	II
HELLP syndromea
Postpartum	III
Antepartum	IV
Hematopoietic cell transplantation, human leukocyte antigen desensitization	III
Hemophagocytic lymphohistiocytosis; hemophagocytic syndrome; macrophage activating syndrome	III
N-methyl-D-aspartate receptor antibody encephalitis	I
Prevention of Rhesus D alloimmunization after red blood cell exposure	III
Progressive multifocal leukoencephalopathy associated with natalizumab	I
Pruritus due to hepatobiliary diseases	III
Thrombotic microangiopathy, coagulation mediated	III
Vasculitis
HBV-PAN	II
Idiopathic PAN	IV
EGPA	III
Behçet disease	III

EGPA: eosinophilic granulomatosis with polyangiitis; HBV: hepatitis B virus; PAN: polyarteritis nodosa.
^a  A severe form of preeclampsia, characterized by hemolysis, elevated liver enzymes, and low platelet counts.

U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
Not applicable. 

ONGOING AND UNPUBLISHED CLINICAL TRIALS
Some currently unpublished trials that might influence this review are listed in Table 5. 

Table 5. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT01442233	Plasma Exchanges in Multiple Sclerosis (MS) Relapses (PLASMASEP)	80	Dec 2017
NCT02622854	Plasma Exchange vs Conservative Management in Non-severe Acute Hypertriglyceridemic Pancreatitis	20	Dec 2018
NCT02647255	Trial of Plasma Exchange for Severe Crescentic IgA Nephropathy (RESCUE)	150	Dec 2019

NCT: national clinical trial.

References

1. Food and Drug Administration (FDA). Compliance Program Guidance Manual; Chapter 42- Blood and Blood Products. 2011; https://www.fda.gov/downloads/Enforcement/UCM247371.pdf. Accessed August 4, 2017.
2. Shumak KH, Rock GA. Therapeutic plasma exchange. N Engl J Med. Mar 22 1984;310(12):762-771. PMID 6199669
3. Kronbichler A, Brezina B, Quintana LF, et al. Efficacy of plasma exchange and immunoadsorption in systemic lupus erythematosus and antiphospholipid syndrome: A systematic review. Autoimmun Rev. Jan 2016;15(1):38-49. PMID 26318215
4. 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. May 21 1992;326(21):1373-1379. PMID 1569973
5. Danieli MG, Palmieri C, Salvi A, et al. Synchronised therapy and high-dose cyclophosphamide in proliferative lupus nephritis. J Clin Apher. 2002;17(2):72-77. PMID 12210709   
6. Khatri BO, McQuillen MP, Harrington GJ, et al. Chronic progressive multiple sclerosis: double-blind controlled study of plasmapheresis in patients taking immunosuppressive drugs. Neurology. Mar 1985;35(3):312-319. PMID 3974889
7. Weiner HL, Dau PC, Khatri BO, et al. Double-blind study of true vs. sham plasma exchange in patients treated with immunosuppression for acute attacks of multiple sclerosis. Neurology. Sep 1989;39(9):1143-1149. PMID 2549450
8. Canadian Cooperative Multiple Sclerosis Study Group. The Canadian cooperative trial of cyclophosphamide and plasma exchange in progressive multiple sclerosis. The Canadian Cooperative Multiple Sclerosis Study Group. Lancet. Feb 23 1991;337(8739):441-446. PMID 1671468
9. Tim RW, Massey JM, Sanders DB. Lambert-Eaton myasthenic syndrome: electrodiagnostic findings and response to treatment. Neurology. Jun 13 2000;54(11):2176-2178. PMID 10851390
10. Sanders DB, Massey JM, Sanders LL, et al. A randomized trial of 3,4-diaminopyridine in Lambert-Eaton myasthenic syndrome. Neurology. Feb 08 2000;54(3):603-607. PMID 10680790
11. Anderson NE, Rosenblum MK, Posner JB. Paraneoplastic cerebellar degeneration: clinical-immunological correlations. Ann Neurol. Oct 1988;24(4):559-567. PMID 3239956
12. Dwosh IL, Giles AR, Ford PM, et al. Plasmapheresis therapy in rheumatoid arthritis. A controlled, double-blind, crossover trial. N Engl J Med. May 12 1983;308(19):1124-1129. PMID 6339939
13. Miller FW, Leitman SF, Cronin ME, et al. Controlled trial of plasma exchange and leukapheresis in polymyositis and dermatomyositis. N Engl J Med. May 21 1992;326(21):1380-1384. PMID 1472183
14. Guillaume JC, Roujeau JC, Morel P, et al. Controlled study of plasma exchange in pemphigus. Arch Dermatol. Nov 1988;124(11):1659-1663. PMID 3178248
15. Vicari AM, Folli F, Pozza G, et al. Plasmapheresis in the treatment of stiff-man syndrome. N Engl J Med. Jun 01 1989;320(22):1499. PMID 2716805
16. Brashear HR, Phillips LH, 2nd. Autoantibodies to GABAergic neurons and response to plasmapheresis in stiff-man syndrome. Neurology. Oct 1991;41(10):1588-1592. PMID 1922799
17. Harding AE, Thompson PD, Kocen RS, et al. Plasma exchange and immunosuppression in the stiff man syndrome. Lancet. Oct 14 1989;2(8668):915. PMID 2571826
18. Pagano MB, Murinson BB, Tobian AA, et al. Efficacy of therapeutic plasma exchange for treatment of stiff-person syndrome. Transfusion. Jul 2014;54(7):1851-1856. PMID 24527774
19. Pham HP, Williams LA, 3rd. Therapeutic plasma exchange in two patients with stiff-person syndrome. J Clin Apher. Oct 2016;31(5):493-494. PMID 26407506
20. Rockx MA, Clark WF. Plasma exchange for treating cryoglobulinemia: a descriptive analysis. Transfus Apher Sci. Jun 2010;42(3):247-251. PMID 20382569
21. Michael M, Elliott EJ, Craig JC, et al. Interventions for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: a systematic review of randomized controlled trials. Am J Kidney Dis. Feb 2009;53(2):259-272. PMID 18950913
22. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. Oct 22 2009;361(17):1676-1687. PMID 19846853
23. Yu X, Gan L, Wang Z, et al. Chemotherapy with or without plasmapheresis in acute renal failure due to multiple myeloma: a meta-analysis. Int J Clin Pharmacol Ther. May 2015;53(5):391-397. PMID 25816886
24. Chevret S, Hughes RA, Annane D. Plasma exchange for Guillain-Barre syndrome. Cochrane Database Syst Rev. Feb 27 2017;2:Cd001798. PMID 28241090
25. El-Bayoumi MA, El-Refaey AM, Abdelkader AM, et al. Comparison of intravenous immunoglobulin and plasma exchange in treatment of mechanically ventilated children with Guillain Barre syndrome: a randomized study. Crit Care. Jul 11 2011;15(4):R164. PMID 21745374
26. Mehndiratta MM, Hughes RA, Pritchard J. Plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev. Aug 25 2015;8(8):CD003906. PMID 26305459
27. Weinshenker BG, O'Brien PC, Petterson TM, et al. A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol. Dec 1999;46(6):878-886. PMID 10589540
28. Kohler W, Bucka C, Klingel R. A randomized and controlled study comparing immunoadsorption and plasma exchange in myasthenic crisis. J Clin Apher. Dec 2011;26(6):347-355. PMID 22095647
29. Alipour-Faz A, Shojaei M, Peyvandi H. A comparison between IVIG and plasma exchange as preparations before thymectomy in myasthenia gravis patients. Mar 2017;117(1):245-249. PMID 27530310
30. Dyck PJ, Low PA, Windebank AJ, et al. Plasma exchange in polyneuropathy associated with monoclonal gammopathy of undetermined significance. N Engl J Med. Nov 21 1991;325(21):1482-1486. PMID 1658648
31. Abboud H, Petrak A, Mealy M, et al. Treatment of acute relapses in neuromyelitis optica: Steroids alone versus steroids plus plasma exchange. Mult Scler. Feb 2016;22(2):185-192. PMID 25921047
32. Bonnan M, Valentino R, Olindo S, et al. Plasma exchange in severe spinal attacks associated with neuromyelitis optica spectrum disorder. Mult Scler. Apr 2009;15(4):487-492. PMID 19324982   
33. Merle H, Olindo S, Jeannin S, et al. Treatment of optic neuritis by plasma exchange (add-on) in neuromyelitis optica. Arch Ophthalmol. Jul 2012;130(7):858-862. PMID 22776923
34. Kleiter I, Gahlen A, Borisow N, et al. Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses. Ann Neurol. Feb 2016;79(2):206-216. PMID 26537743
35. Ipe TS, Pham HP, Williams LA, 3rd. Critical updates in the 7th edition of the American Society for Apheresis guidelines. J Clin Apher. Jun 27 2017. PMID 28653762
36. DeSena AD, Noland DK, Matevosyan K, et al. Intravenous methylprednisolone versus therapeutic plasma exchange for treatment of anti-N-methyl-D-aspartate receptor antibody encephalitis: A retrospective review. J Clin Apher. Aug 2015;30(4):212-216. PMID 25664728
37.  Khatri BO, Man S, Giovannoni G, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology. Feb 03 2009;72(5):402-409. PMID 19188571
38. Couser WG. Rapidly progressive glomerulonephritis: classification, pathogenetic mechanisms, and therapy. Am J Kidney Dis. Jun 1988;11(6):449-464. PMID 3287904
39. Cole E, Cattran D, Magil A, et al. A prospective randomized trial of plasma exchange as additive therapy in idiopathic crescentic glomerulonephritis. The Canadian Apheresis Study Group. Am J Kidney Dis. Sep 1992;20(3):261-269. PMID 1519607
40. Walsh M, Catapano F, Szpirt W, et al. Plasma exchange for renal vasculitis and idiopathic rapidly progressive glomerulonephritis: a meta-analysis. Am J Kidney Dis. Apr 2011;57(4):566-574. PMID 21194817
41. Jayne DR, Gaskin G, Rasmussen N, et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol. Jul 2007;18(7):2180-2188. PMID 17582159
42. Walsh M, Casian A, Flossmann O, et al. Long-term follow-up of patients with severe ANCA-associated vasculitis comparing plasma exchange to intravenous methylprednisolone treatment is unclear. Kidney Int. Aug 2013;84(2):397-402. PMID 23615499
43. Montgomery RA, Zachary AA. Transplanting patients with a positive donor-specific crossmatch: a single center's perspective. Pediatr Transplant. Dec 2004;8(6):535-542. PMID 15598320
44. Jordan SC, Vo AA, Tyan D, et al. Current approaches to treatment of antibody-mediated rejection. Pediatr Transplant. Jun 2005;9(3):408-415. PMID 15910400 
45. Lehrich RW, Rocha PN, Reinsmoen N, et al. Intravenous immunoglobulin and plasmapheresis in acute humoral rejection: experience in renal allograft transplantation. Hum Immunol. Apr 2005;66(4):350-358. PMID 15866697
46. Ibernon M, Gil-Vernet S, Carrera M, et al. Therapy with plasmapheresis and intravenous immunoglobulin for acute humoral rejection in kidney transplantation. Transplant Proc. Nov 2005;37(9):3743-3745. PMID 16386524
47. Gubensek J, Buturovic-Ponikvar J, Kandus A, et al. Plasma exchange and intravenous immunoglobulin in the treatment of antibody-mediated rejection after kidney transplantation: a single-center historic cohort study. Transplant Proc. May 2013;45(4):1524-1527. PMID 23726611
48. Larsen FS, Schmidt LE, Bernsmeier C, et al. High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial. J Hepatol. Jan 2016;64(1):69-78. PMID 26325537
49. Ellingsen I, Florvaag E, Andreassen AH, et al. Plasmapheresis in the treatment of steroid-dependent bronchial asthma. Allergy. Dec 2001;56(12):1202-1205. PMID 11736751
50. Rimmer E, Houston BL, Kumar A, et al. The efficacy and safety of plasma exchange in patients with sepsis and septic shock: a systematic review and meta-analysis. Crit Care. Dec 20 2014;18(6):699. PMID 25527094
51. Perlmutter SJ, Leitman SF, Garvey MA, et al. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet. Oct 02 1999;354(9185):1153-1158. PMID 10513708
52. Garvey MA, Snider LA, Leitman SF, et al. Treatment of Sydenham's chorea with intravenous immunoglobulin, plasma exchange, or prednisone. J Child Neurol. May 2005;20(5):424-429. PMID 15968928
53. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma. Version 2.2018. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed September 29, 2017.
54. Cortese I, Chaudhry V, So YT, et al. Evidence-based guideline update: Plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. Jan 18 2011;76(3):294-300. PMID 21242498
55. Hughes RA, Wijdicks EF, Barohn R, et al. Practice parameter: immunotherapy for Guillain-Barre syndrome: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. Sep 23 2003;61(6):736-740. PMID 14504313
56. Schwartz J, Padmanabhan A, Aqui N, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: The Seventh Special Issue. J Clin Apher. Jun 2016;31(3):149-162. PMID 27322218
57. Schwartz J, Winters JL, Padmanabhan A, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: the sixth special issue. J Clin Apher. Jul 2013;28(3):145-284. PMID 23868759
58. Centers for Medicare & Medicaid Services (CMS). National Coverage Determination (NCD) for Apheresis (therapeutic pheresis) (110.14). 1992; https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?ncdid=82&ver=1. Accessed August 4, 2017.

Coding Section

Codes	Number	Description
CPT	36514	Therapeutic apheresis; for plasma pheresis
ICD-9 Procedure	99.71	Therapeutic plasmapheresis
ICD-9 Diagnosis	273.2	Other paraproteinemias (Cryoglobulinemia)
	273.3	Macroglobulinemia (includes Waldenstrom's macroglobulinemia, and hyperviscosity syndrome NEC)
	282.8	Other specified hereditary hemolytic anemias (includes sclerothymic hyperviscosity syndrome)
	283.11	Hemolytic-uremic syndrome
	287.30	Primary thrombocytopenia (includes idiopathic thrombocytopenic purpura)
	287.4	Post-transfusion purpura
	289.0	Polycythemia, secondary (includes polycythemic hyperviscosity syndrome)
	340	Multiple sclerosis (coding does not distinguish between acute fulminant and chronic progressive/relapsing remitting)
	356.9	Unspecified hereditary and idiopathic peripheral neuropathy
	357.0	Acute infective polyneuritis (includes Guillain-Barré syndrome)
	357.81	Chronic inflammatory demyelinating polyneuritis
	358.00 – 358.01	Myasthenia gravis code range
	446.21	Goodpasture's syndrome
	446.4	Wegener's granulomatosis
	446.6	Thrombotic thrombocytopenia purpura
	642.5	HELLP syndrome
HCPCS	No code
ICD-10-CM (effective 10/01/15)	C88.0	Waldenstrom macroglobulinemia (includes macroglobulinemia)
	D58.0 – D58.9	Other hereditary hemolytic anemias code range
	D59.3	Hemolytic-uremic syndrome
	D69.3	Immune thrombocytopenic purpura (includes idiopathic thrombocytopenic purpura)
	D69.49	Other primary thrombocytopenia
	D69.5	Thrombocytopenia, unspecified
	D75.1	Secondary polycythemia
	D89.2	Hypergammaglobulinemia, unspecified
	G35	Multiple sclerosis
	G60.9	Hereditary and idiopathic neuropathy, unspecified
	G61.0	Guillain-Barre syndrome (includes acute infective polyneuritis)
	G61.81	Chronic inflammatory demyelinating polyneuritis
	G70.00 – G70.01	Myasthenia gravis, code range
	M31.0	Hypersensitivity angitis (includes thrombotic thrombocytopenic purpura)
	M31.1	Thrombotic microangiopathy (includes thrombotic thrombocytopenic purpura)
	M31.30 – M31.31	Wegener's granulomatosis code range
	O14.20 – O14.23	HELLP syndrome code range
ICD-10-PCS (effective 10/01/15)		ICD-10-PCS codes are only used for inpatient services.
	6A550Z3, 6A551Z3	Plasmapheresis, code single or multiple
Type of Service	Therapy
Place of Service	Outpaitent/Inpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

Index 
Apheresis, Therapeutic 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines. 

"Current Procedural Terminology^© American Medical Association. All Rights Reserved"