BlueCross and BlueShield of Montana Medical Policy/Codes
Plasmapheresis (PP) / Therapeutic Plasma Exchange (TPE)
Chapter: Medicine: Treatments
Current Effective Date: November 26, 2013
Original Effective Date: May 09, 2008
Publish Date: November 26, 2013
Revised Dates: June 01, 2011; July 19, 2012; October 25, 2013
Description

Therapeutic plasma exchange (TPE) is a procedure in which the plasma is isolated, then discarded and replaced with a substitution fluid such as albumin.  Plasma exchange (PE) is a nonspecific therapy, since 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.

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

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

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

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

This policy addresses TPE and PP as therapeutic apheresis procedures, and does not differentiate between the two for medical policy coverage.  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 essentially a symptomatic therapy, since it does not remove the source of the pathogenic factors.  Therefore the success of PE will depend 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 of PE can be broadly subdivided into two 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, due to the phenomenon of rebound antibody production, its use in chronic diseases has been more controversial than in acute self-limited diseases.

In addition, plasmapheresis has been used in the setting of solid organ transplantation.  It has been used as a technique to desensitize high-risk patients prior to transplant and also as a treatment of antibody-mediated rejection reaction (AMR) occurring after transplant.  Prior to 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 AMR, plasmapheresis is often used in combination with intravenous immunoglobulin (IVIg) or anti-CD20 therapy (i.e., Rituxan).

The use of PE in patients with acute, life-threatening complications of chronic autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus (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 prior to 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.

Diagnostic Criteria for CIDP

The following criteria are adapted from the Task Force Report of the Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force found in Neurology (1991) 41:617-18.  The report included mandatory, supportive, and exclusionary diagnostic criteria.  Only the mandatory criteria are excerpted here.  The criteria are based on a combination of clinical observations, physiologic studies, pathologic features (i.e., nerve biopsy), and studies of the cerebrospinal fluid (CSF).

I.   Clinical criteria include the following mandatory requirements:

  • Progressive or relapsing motor and sensory (rarely only motor or sensory) dysfunction of more than one limb of a peripheral nerve nature, developing over at least two months;
  • Areflexia (absence of reflexes) which will usually involve all four limbs.

II.   Physiologic Studies include:  Mandatory - Nerve conduction studies including studies of proximal nerve segments in which the predominant process is demyelination.  Must have three of four of the following:

1.  Reduction in conduction velocity (CV) in two or more motor nerves:

  • <80% of lower limit of normal (LLN) is amplitude >80% of LLN
  • <70% of LLN is amplitude <80% of LLN.

2.  Partial conduction block or abnormal temporal dispersion in one or more motor nerves: either peroneal nerve between ankle and below fibular head, median nerve between wrist and elbow, or ulnar nerve between wrist and below elbow.

Criteria suggestive of partial conduction block: <15% change in duration between proximal and distal sites and >20% drop in negative peak (p) area or peak to peak (p-p) amplitude between proximal and distal sites.

Criteria for abnormal temporal dispersion and possible conduction block:

  • >15% change in duration between proximal and distal sites; and
  • >20% drop in p area or p-p amplitude between proximal and distal sites; and
  • >20% drop in p or p-p amplitude between proximal and distal sites.

These criteria are only suggestive of partial conduction block as they are derived from studies of normal individuals.  Additional studies, such as stimulation across short segments or recording of individual motor unit potentials, are required for confirmation.

3.  Prolonged distal latencies in two or more nerves:

  • >125% of upper limit of normal (ULN) if amplitude >80% of lower limit of normal (LLN)
  • >150% of ULN if amplitude <80% of LLN.

4.  Absent F waves or prolonged minimum:

  • >120% of ULN if amplitude >80% of LLN
  • >150% of ULN if amplitude <80% of LLN.

III.   Pathologic features are tested using the following mandatory study:  Nerve biopsy showing unequivocal evidence of demyelination and remyelination and demyelination by either electron microscopy (>5 fibers) or teased fiber studies >12% of 50 fibers, minimum of four internodes each, demonstrating demyelination/remyelination.

IV.   Cerebrospinal fluid (CSF) studies include the following mandatory tests:

  • Cell count <10/mm-3 if human immunodeficiency virus (HIV)-seronegative or <50/mm-3 if HIV seropositive, and
  • Negative Venereal Disease Research Laboratory (VDRL).
Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions.  Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coverage

Coverage of plasmapheresis (PP) / therapeutic plasma exchange (TPE) is described in the following table (the terms “plasmapheresis” and “therapeutic plasma exchange” are used interchangeably):

DISEASE

COVERAGE

Acute disseminated encephalomyelitis, severe

 

Therapeutic plasma exchange may be considered medically necessary as second-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment) for patients who respond poorly to steroid treatment or for whom steroids treatment is contraindicated.

Acute inflammatory demyelinating polyneuropathy (Guillain Barré´ Syndrome)

Therapeutic plasma exchange may be considered medically necessary as first-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment).

ANCA (Anti-Neutrophil Cytoplasmic Antibody)-associated rapidly progressive glomerulonephritis (Wegener’s granulomatosis)

 

Dialysis dependent:

Therapeutic plasma exchange may be considered medically necessary as first-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment). 

Diffuse alveolar hemorrhage (DAH):

Therapeutic plasma exchange may be considered medically necessary as first-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment). 

Dialysis independent:

Therapeutic plasma exchange is considered experimental, investigational and unproven.

Anti-glomerular basement membrane disease (Goodpasture’s syndrome)

Therapeutic plasma exchange may be considered medically necessary as first-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment).

Aplastic anemia,

Pure red cell aplasia

 

Aplastic anemia:

Therapeutic plasma exchange is considered experimental, investigational and unproven. 

Pure red cell aplasia:

Therapeutic plasma exchange may be considered medically necessary as second-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment) after at least one other treatment has been tried and failed (examples include, but are not limited to corticosteroids; identification and treatment of triggering etiologies; discontinuation of offending drugs; etc.).

Autoimmune hemolytic anemia

 

Warm autoimmune hemolytic anemia:

Therapeutic plasma exchange is considered experimental, investigational and unproven.

Cold agglutinin disease (CAD) that is life threatening:

Therapeutic plasma exchange may be considered medically necessary as second-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment) after at least one other treatment has been tried and failed (treatment of CAD is often not necessary, but if indicated by more severe hemolysis/anemia, primary treatment is avoidance of exposure to cold).

Catastrophic antiphospholipid syndrome

 

Therapeutic plasma exchange may be considered medically necessary as second-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment) after at least one other treatment has been tried and failed (examples include, but are not limited to, treatment of precipitating factors; prevention and control of thrombosis; suppression of excessive cytokine production; anticoagulants; and corticosteroids, etc.).

Chronic focal encephalitis (Rasmussen’s encephalitis)

 

Therapeutic plasma exchange may be considered medically necessary to delay surgery in cases that are refractory to treatment with anticonvulsant drugs, corticosteroids, immunosuppressants, etc.

Chronic inflammatory demyelinating polyradiculopathy (CIPD)

 

Therapeutic plasma exchange may be considered medically necessary as first-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment).

Patients should meet the diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP), which are included in the Description section below.

Cryoglobulinemia, severe, symptomatic

 

Therapeutic plasma exchange may be considered medically necessary as first-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment).

Familial hypercholesterolemia in homozygotes with small blood volume

(also see Medical Policy THE802.003 Low Density Lipid Apheresis)

Preferred method of treatment is selective removal systems.  Therapeutic plasma exchange may be considered medically necessary in small children where the extracorporeal volume of available selective removal systems is too large.

 

Focal segmental glomerulosclerosis, recurrent

 

Therapeutic plasma exchange may be considered medically necessary as first-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment).

HELLP syndrome of pregnancy (a severe form of preeclampsia, characterized by hemolysis (H), elevated liver enzymes (EL), and low platelet count (LP).

Therapeutic plasma exchange may be considered medically necessary as first-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment).

Hemolytic uremic syndrome (HUS)

 

Atypical:

Therapeutic plasma exchange may be considered medically necessary as first-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment). 

Typical (Diarrhea-associated):

Therapeutic plasma exchange is considered experimental, investigational and unproven.

Hyperviscosity in monoclonal gammopathies (i.e.,  associated with multiple myeloma, Waldenström’s macroglobulinemia), including:

  • Treatment of symptoms
  • Prophylaxis for Rituximab

Therapeutic plasma exchange may be considered medically necessary as first-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment).

Lambert-Eaton myasthenic syndrome (LEMS)

Therapeutic plasma exchange may be considered medically necessary as second-line therapy as an adjunctive treatment for severe or rapidly progressing neurological deficit, or for patients who cannot tolerate or are too uncomfortable to wait for immunosuppressive or aminopyridine drugs to take effect.

Multiple sclerosis (MS); Acute fulminant central nervous system (CNS) demyelination

Acute CNS inflammatory demyelinating disease 

Therapeutic plasma exchange may be considered medically necessary as second-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment) for disease that is unresponsive to steroids. 

Chronic progressive MS:

Therapeutic plasma exchange is considered experimental, investigational and unproven.

Myasthenia gravis:

  • Moderate-severe
  • Pre-thymectomy

Therapeutic plasma exchange may be considered medically necessary as first-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment).

Myeloma cast nephropathy

 

Therapeutic plasma exchange may be considered medically necessary as second-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment) after at least one other treatment has been tried and failed (examples include, but are not limited to, diuresis, anti-myeloma chemotherapy, immune modulation, proteosome inhibition, dialysis, etc.).

Neuromyelitis optica (Devic’s syndrome)

 

Therapeutic plasma exchange may be considered medically necessary as second-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment) after at least one other treatment has been tried and failed (examples include, but are not limited to, high-dose intravenous steroids, immunosuppressive medications, immunomodulation, etc.).

Overdose, venoms, poisoning

Mushroom poisoning:

Therapeutic plasma exchange may be considered medically necessary as second-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment) after at least one other treatment has been tried and failed (examples include, but are not limited to, induced emesis, gastric lavage, oral administration of activated charcoal, toxin-specific antidotes, etc.).  Plasmapheresis is most successful for protein-bound toxins (e.g., amanita poisoning).  

Other:

Therapeutic plasma exchange is considered experimental, investigational and unproven for all other poisonings, venom, overdose, etc.

Paraproteinemic polyneuropathies

 

IgG / IgA:

Therapeutic plasma exchange may be considered medically necessary as first-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment).

IgM:

Therapeutic plasma exchange may be considered medically necessary as first-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment).

Multiple myeloma with polyneuropathy:

Therapeutic plasma exchange is considered experimental, investigational and unproven.

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and Sydenham’s chorea

 

PANDAS (exacerbation):

Therapeutic plasma exchange may be considered medically necessary as first-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment).

Sydenham’s chorea

Therapeutic plasma exchange may be considered medically necessary as first-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment).

Phytanic acid storage (Refsum’s disease)

 

Therapeutic plasma exchange may be considered medically necessary as second-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment) for acute attacks or exacerbations of the disease to reduce phytanic acid levels.  Treatment usually consists of limiting intake of phytanic acid by dietary restrictions. 

Post transfusion purpura

Therapeutic plasma exchange may be considered medically necessary as first-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment).

Red cell alloimmunization in pregnancy, before intrauterine transfusion (IUT) availability

 

Therapeutic plasma exchange may be considered medically necessary as second-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment) after at least one other treatment has been tried and failed.  (Examples include, but are not limited to, assess father’s phenotype; perform maternal antibody titers; depending on titer levels, evaluate fetus per ultrasound and/or amniocentesis.  Typically, IUT can be performed after 20 weeks gestation).

Systemic lupus erythematosus

Severe (e.g., cerebritis, diffuse alveolar hemorrhage):

Therapeutic plasma exchange may be considered medically necessary as second-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment) after at least one other treatment has been tried and failed (examples include, but are not limited, to immunosuppressive agents). 

Nephritis:

Therapeutic plasma exchange is considered experimental, investigational and unproven.

Thrombotic microangiopathy, drug-associated

Ticlopidine/Clopidogrel:

Therapeutic plasma exchange may be considered medically necessary as first-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment).

 

Other, including Cyclosporine/Tacrolimus, Gemcitabine, or Quinine:

Therapeutic plasma exchange is considered experimental, investigational and unproven.

Thrombotic microangiopathy, hematopoietic stem cell transplant-associated

Therapeutic plasma exchange is considered experimental, investigational and unproven.

 

Thrombocytopenia purpura, idiopathic

Refractory or non-refractory:

Therapeutic plasma exchange is considered experimental, investigational and unproven.

 

Emergency situations:

Therapeutic plasma exchange may be considered medically necessary as second-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment) after at least one other treatment has been tried and failed (examples include, but are not limited to management of acute bleeding, platelet transfusion, single infusion of IVIg, etc.

Thrombocytopenia, thrombotic

Therapeutic plasma exchange may be considered medically necessary as first-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment).

Transplantation: ABO incompatible hematopoietic stem cell (HPC) transplantation, marrow

 

Therapeutic plasma exchange may be considered medically necessary as second-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment) after at least one other treatment has been tried and failed (examples include, but are not limited to high-dose erythropoietin, immunoadsorption, donor leukocyte infusions, rituximab, discontinuation of cyclosporine, antithymocyte globulin, etc.).

Transplantation, solid organ, ABO incompatibility

Heart (before 40 months of age), Kidney:

Therapeutic plasma exchange may be considered medically necessary as second-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment) after at least one other treatment has been tried and failed (examples include, but are not limited to immunosuppressive treatment with drugs, antithymocyte globulins (ATG), etc.).

 

Liver: 

Therapeutic plasma exchange is considered experimental, investigational and unproven.

Transplantation: Renal (kidney)

Antibody mediated rejection:

Therapeutic plasma exchange may be considered medically necessary as first-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment).

 

Desensitization, living donor, positive crossmatch due to specific HLA (human leukocyte antigens) antibody:

Therapeutic plasma exchange (in combination with immunosuppressive drugs) may be considered medically necessary pre- and post-transplant in select individuals to remove HLA antibodies.

 

High PRA (positive panel reactive antibody); or cadaveric donor:

Therapeutic plasma exchange is considered experimental, investigational and unproven.

Wilson’s disease (fulminant hepatic failure with hemolysis)

Fulminant hepatic failure with hemolysis:

Therapeutic plasma exchange may be considered medically necessary as first-line therapy (either as a primary standalone treatment or in conjunction with other modes of treatment).

In addition to the table above, plasmapheresis (PP) / therapeutic plasma exchange (TPE) are considered experimental, investigational and unproven for all other indications, including but not limited to:

  • Acute liver failure;
  • Age-related macular degeneration (dry ARMD);
  • Amyloidosis, systemic;
  • Amyotrophic lateral sclerosis;
  • Asthma;
  • Chronic fatigue syndrome;
  • Coagulation factor inhibitors;
  • Dilated cardiomyopathy;
  • Hypertriglyceridemic pancreatitis;
  • Inclusion body myositis;
  • Nephrogenic systemic fibrosis;
  • Paraneoplastic syndromes;
  • Pemphigus;
  • Polymyositis and dermatomyositis;
  • Psoriasis;
  • Regional enteritis (Crohn’s disease);
  • Rheumatoid arthritis;
  • Schizophrenia;
  • Scleroderma (systemic sclerosis);
  • Stiff man syndrome;
  • Thyroid storm.

Rationale

ABO Incompatibility: Hematopoietic Stem Cell Transplantation; Solid Organ Transplant

Plasmapheresis has been extensively used in the solid organ transplant 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.

Acute Inflammatory Demyelinating Polyneuropathy (Guillain-Barré Syndrome [GBS])

Guillain-Barré syndrome (GBS) is an acute demyelinating neuropathy whose severity is graded on a scale of 1–5 (the disability scale is summarized in the Description section of this policy).  In 2002, The Cochrane Collaboration published “Plasma Exchange for Guillain-Barré Syndrome”, a systematic review of the evidence concerning the efficacy of PE (plasma exchange) for treating GBS.  Six eligible trials (n=649) were identified, comparing PE versus supportive treatment alone.  Primary outcome measures included time to recover walking with aid and time to onset of motor recovery in mildly affected patients.  Secondary outcome measures included improvement in disability grade at four weeks.  A subgroup analysis showed PE was beneficial in patients with mild, moderate, and severe (needing ventilation) GBS.  The authors concluded that PE has been proven to be superior to supportive treatment alone in GBS.  Consequently, PE should be regarded as the treatment against which new treatments, such as intravenous IVIg, should be judged.  This review noted that the value of PE in children younger than 12 years-old is not known. 

A systematic review conducted in the United Kingdom (UK) evaluated the available randomized trials of immunotherapy to treat GBS.  In four trials with severely affected adult participants (n=585), those treated with PE improved significantly more on the disability scale four weeks after randomization than those who were not (weighted mean difference [WMD]: -0.89; range: -1.14 to -0.63).  In five trials (n=582), the improvement on the disability grade scale with IVIg was very similar to that with PE, WMD: -0.02 (range: -0.25 to 0.20).  There was also no significant difference between IVIg and PE for any of the other outcome measures.  There was one trial that included patients (n=91) with the mild form of GBS who were able to walk unaided at enrollment.  Patients were randomized to receive either two sessions of PE in three days or supportive care.  The number of patients with one or more grades of improvement at one month was significantly greater, 26/45 in the treated compared to the control group, 13/45.  Fewer patients in the PE-treated group had clinical deterioration (4%) as compared to the control group (39%) or required ventilation; PE group (2% ) versus the control group (13%).  In one trial (n=148), following PE with IVIg, did not produce significant extra benefit.  Limited evidence from three open trials in children suggested that IVIg hastens recovery compared with supportive care alone.  None of the treatments significantly reduced mortality.  The authors concluded that “since approximately 20% of patients die or have persistent disability despite immunotherapy, more research is needed to identify better treatment regimens and new therapeutic strategies.”

In 2003, a report of the Quality Standards Subcommittee of the American Academy of Neurology (AAN) “Practice Parameter: Immunotherapy for Guillain-Barré Syndrome” was published.  The following are the key findings: 1) treatment with PE or IVIg hastens recovery from Guillain-Barré syndrome; 2) combining the two treatments is not beneficial; and 3) steroid treatment given alone is not beneficial.  The AAN’s recommendations are: 1) PE is recommended for non-ambulant adult patients with GBS who seek treatment within four weeks of the onset of neuropathic symptoms (PE should also be considered for ambulant patients examined within two weeks of the onset of neuropathic symptoms); 2) IVIg is recommended for non-ambulant adult patients with GBS within two or possibly four weeks of the onset of neuropathic symptoms (the effects of PE and IVIg are equivalent); 3) corticosteroids are not recommended for the management of GBS; 4) sequential treatment with PE followed by IVIg, or immunoabsorption followed by IVIg is not recommended for patients with GBS; and 5) PE and IVIg are treatment options for children with severe GBS.

In conclusion, the available evidence is sufficient regarding PE for the treatment of patients with all severity grades of GBS.  This therapy has a beneficial impact on net health outcome for all severity grades.  The published studies are insufficient regarding PE for treatment of GBS in the pediatric population.  However, based on extrapolated evidence in adults and clinical input, PE may be considered as a treatment option for children younger than 10-years-old with severe GBS.

ANCA (Antineutrophil Cytoplasmic Antibody)-associated Vasculitis (e.g., Wegener’s Granulomatosis)

Jayne et al. conducted a multicenter, randomized trial on behalf of the European Vasculitis Study Group.  The study investigated whether the addition of PE was more effective than intravenous methylprednisolone in the achievement of renal recovery in those who presented with a serum creatinine >500 micromol/L (5.8 mg/dL).  Patients (n=137) with a new diagnosis of ANCA-associated systemic vasculitis confirmed by renal biopsy and serum creatinine >500 micromol/L (5.8 mg/dL) were randomly assigned to receive seven PEs (n=70) or 3,000 mg of intravenous methylprednisolone (n=67).  Both groups received oral cyclophosphamide and oral prednisolone.  The primary endpoint was dialysis independence at three months.  Secondary endpoints included renal and patient survival at one year and severe adverse event rates.  At three months, 33 (49%) of 67 were alive and independent of dialysis after intravenous methylprednisolone, as compared with 48 (69%) of 70 after PE.  As compared with intravenous methylprednisolone, PE was associated with a reduction in risk for progression to end-stage renal disease of 24% at 12 months.  Results at one year: Patient survival, 51 (76%) of 67 in the intravenous methylprednisolone group; 51 (73%) of 70 in the PE group; severe adverse event rates, 32 of 67 (48%) in the intravenous methylprednisolone group; 35 of (50%) 70 in the PE group.  PE increased the rate of renal recovery in ANCA-associated systemic vasculitis that presented with renal failure when compared with intravenous methylprednisolone.  Patient survival and severe adverse event rates were similar in both groups.  A recent review article summarized treatment of ANCA-associated vasculitis and supported the role of PE in severe renal vasculitis.  This article concluded that the role of PE in lung hemorrhage with ANCA-vasculitis is unproved.  In addition, a retrospective case series reported effective management of pulmonary hemorrhage in ANCA vasculitis.

Anti-Glomerular Basement Membrane Disease (Goodpasture’s Syndrome); Rapidly Progressive Glomerulonephritis (RPGN)

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 anti-glomerular basement membrane (GBM) antibodies as seen in Goodpasture’s 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, 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.

Acute Disseminated Encephalomyelitis; Acute Fulminant Central Nervous System (CNS) Demyelination; Multiple Sclerosis (MS)

The coverage statement, which suggests that PP 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 MS or other acute idiopathic inflammatory demyelinating diseases 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.

Keegan et al. reviewed 59 consecutive patients treated with PE for acute, severe attacks of CNS demyelination at Mayo Clinic from January 1984 through June 2000.  Most patients had relapsing-remitting MS (n = 22, 37.3%), neuromyelitis optica (NMO) (n = 10, 16.9%), and acute disseminated encephalomyelitis (n = 10, 16.9%).  PE was followed by moderate or marked functional improvement in 44.1% of treated patients.  Male sex (p = 0.021), preserved reflexes (p = 0.019), and early initiation of treatment (p = 0.009) were associated with moderate or marked improvement.  Successfully treated patients improved rapidly following PE, and improvement was sustained.

There have been several RCTs of PE in patients with MS that have reported inconclusive results. Khatri et al. 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 et al. 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.

Aplastic Anemia

Sawada et al. report that the major objective in the treatment of pure red cell aplasia is to induce a remission with the recovery of erythropoiesis.  Treatment usually focuses on the sequential use of various immunosuppressive therapies until a remission is obtained.  Remissions have been achieved by treatment with corticosteroids (CS), cyclophosphamide (CY), cyclosporine A (CsA), anti-thymocyte globulin (ATG), splenectomy, and plasmapheresis.

Autoimmune Hemolytic Anemia

Plasmapheresis can serve as a temporary measure.  Taft et al. reported on two patients with advanced lymphoma, chronic cold agglutinin disease refractory to conventional therapy and severe, progressive anemia who were treated with exchange plasma transfusion.  Both experienced significant reduction in titers.  Szczepiorkowski et al. states that anecdotal evidence of favorable results has been described in some cases of IgG hemolysis.  IgM is mostly intravascular and binds poorly to red blood cells at body temperature; therefore TPE may significantly reduce antibody titer in CAD.  However, improvement after TPE is usually temporary, thus TPE should be combined with concomitant immunosuppressive therapy.

Catastrophic Antiphospholipid Syndrome (CAPS)

Due to the rarity of the condition, the optimal treatment of CAPS is still debatable.  Therapeutic approach has three goals: 1) treat any precipitating factors, 2) prevent and control ongoing thrombosis, and 3) suppress excessive cytokine production.  Cervera et al. published outcomes of 280 patients enrolled in the CAPS Registry; they noted that most patients received multiple treatments and that the combination with the best outcomes was anticoagulants, corticosteroids, and TPE and/or IVIg.  Szczepiorkowski et al. notes the exact mechanism of TPE in CAPS is not known, but the removal of antiphospholipid antibodies as well as cytokines, tumor necrosis factor-α, and compliment is likely to play an important role. 

Chronic Focal Encephalitis (Rasmussen’s Encephalitis)

In their European Consensus Statement, Bien et al. recommend steroid boluses and TPE for periods of status epilepticus.  They also state that there is currently insufficient evidence to give specific guidelines regarding the choice of the initial kind of immunotreatment, and that steroids, IVIg, TPE or tacrolimus appear to be the most suitable.  Szczepiorkowski et al. state that despite the paucity of clinical reports, investigators in the field recommend a trial of immunotherapy, including TPE to control seizures, mitigate functional decline, and delay the need for hemispherectomy in patients with Rasmussen’s disease. 

Chronic Inflammatory Demyelinating Polyradiculopathy (CIPD)

In a 2004 Cochrane Systematic Review, Mehndiratta et al. concluded evidence from two small trials showed that plasma exchange provides significant short-term benefit in about two-thirds of patients with CIDP.

Cryoglobulinemia

There are several types of cryoglobulinemia.  Type I is associated with hematologic disorders.  Types II and III are considered mixed cryoglobulins (MC).  MC syndrome 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 five patients.  They identified 11 studies with a total of 156 patients.  The authors 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.”

Familial hypercholesterolemia

TPE was first used in 1975 to reduce cholesterol, but removal of beneficial substances prompted development of selective removal systems.  In the American Society for Apheresis (AFSA) Guidelines, Szczepiorkowski et al. state that, although TPE can be effective, the availability of the selective removal systems and their superior efficacy in cholesterol removal makes its use uncommon.  However, TPE may be the only option in small children where the extracorporeal volume of selective removal systems is too large.

Focal Segmental Glomerulosclerosis (FSGS), Recurrent

Szczepiorkowski et al. report that patients with primary focal segmental glomerulosclerosis with proteinuria >3 g/day do not benefit from TPE and should be treated with corticosteroids, which is the standard treatment; recurrent FSGS usually responds to a combination of TPE with cyclosporine A and/or an angiotensin II receptor antagonist or  angiotensin-converting enzyme inhibitor.  Several small studies of TPE in combination with other therapies have reported complete or partial remission (Garcia et al., Valdivia et al., Sener, et al., Moroni et al.).

HELLP Syndrome of Pregnancy

The HELLP syndrome of pregnancy is a severe form of preeclampsia, characterized by hemolysis (H), elevated liver enzymes (EL), and low platelet (LP) counts.  The principal form of treatment is 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.

Hyperviscosities in Monoclonal Gammopathies (e.g., Multiple Myeloma, Waldenström’s Macroglobulinemia)

Hyperviscosity syndrome occurs most typically in Waldenström’s macroglobulinemia, which is a lymphoplasmacytic lymphoma associated with elevated monoclonal IgM immunoglobulin (M-protein) in the plasma (≥3 g/dL).  As the M-protein rises, the effect on blood viscosity increases logarithmically.  At the symptomatic level, a modest removal of M-protein from the plasma by TPE will have a logarithmic viscosity-lowering effect; TPE is fast and efficient in lowering viscosity.  The addition of Rituximab in the treatment of Waldenström’s macroglobulinemia creates another rationale for TPE.  Half of patients receiving Rituximab will have a flare up of IgM.  Patients with IgM ≥5000 mg/dL at the initiation of Rituximab therapy are at risk for symptomatic hyperviscosity if the IgM “flare” occurs; prophylactic TPE is recommended for these patients (Szczepiorkowski et al.).

Lambert-Eaton Myasthenic Syndrome (LEMS) 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.  The 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 focusing on LEMS was reported by Tim and colleagues and included 73 patients with LEMS, 31 of whom 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 RCT 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.  Plasmapheresis was associated with an acute drop in the autoantibody titer.  Szczepiorkowski et al. state that TPE may be a useful adjunct to management of LEMS when neurological deficit is severe or rapidly developing, or when the patient is too uncomfortable to wait for immunosuppressive or aminopyridine drugs to take effect, or who cannot tolerate IVIg therapy. 

Myasthenia Gravis (MG)

A randomized trial from China was published in 2009; Liu and colleagues assigned 40 patients with late-onset myasthenia gravis to treatment with double-filtration plasmapheresis (n=15), immunoadsorption (n=10), or intravenous immune globulin (n=15).  Treatment was clinically effective, defined as at least a 50% improvement in the relative symptom score, in 12 of 15 (80%) of the plasmapheresis group, 7 of 10 (70%) in the immunoadsorption group, and 6 of 15 (40%) of the immune globulin group.  The clinical efficacy rate was significantly higher in both the plasmapheresis and immunoadsorption groups compared to the immune globulin group (p<0.05).  Findings were similar for other outcomes; the study was limited by the small sample size.

Myeloma Cast Nephropathy

Although chemotherapy and alkaline intravenous fluids are the primary therapy for myeloma cast nephropathy, TPE has been used to acutely decrease the delivery of light chains to the renal glomerulus for filtration (Szczepiorkowski et al.).  In addition, the Scientific Advisors of the International Myeloma Foundation endorses TPE for myeloma nephropathy. 

Neuromyelitis Optica (Devic’s Disease)

Neuromyelitis optica (Devic’s disease) is an inflammatory demyelinating disorder characterized by attacks within the spinal cord and optic nerve.  Acute attacks are managed by high-dose steroids, and if symptoms fail to resolve, TPE is added.  Szczepiorkowski et al. conclude that TPE removes pathologic antibodies, immune complexes, and inflammatory mediators, and TPE has a role in treatment neuromyelitis optica.

Overdose, Venoms, and Poisoning (Including Mushroom)

Agents known to be highly protein-bound or those with delayed metabolic effects are the best candidates for removal by TPE.  Amanita poisoning (mushroom) is the most frequent clinical diagnosis where TPE is used.  Large case series showed decreased mortality among patients, mostly children, who were treated with TPE, compared to historical controls (Szczepiorkowski et al.).

Paraproteinemic Polyneuropathies

A randomized, double-blinded trial compared PE to sham treatment in 39 patients with monoclonal gammopathy of undetermined significance (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.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS) and Sydenham’s chorea (SC)

PANDAS is defined as rapid, episodic onset of obsessive-compulsive disorder (OCD) and/or tic disorder symptoms after a group A β-hemolytic streptococcal infection (GABHS).  SC is the neurologic manifestation of acute rheumatic fever.  The choreatic symptoms of Sydenham’s chorea are characterized by involuntary rapid and jerky movements that affect the extremities, trunk, and face.  SC is generally a self-limited disorder with symptoms resolving in weeks to months.  Perlmutter et al. 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.  Children (n=30) with clear evidence of a strep infection as the trigger of their OCD and tics were randomized to receive PE (n=10; 5-6 procedures over two weeks), IVIg (n=9; 2 gm/kg over two days) or placebo (n=10; mimic IVIg).  All were severely ill at the time of treatment.  At one month, both active treatment groups demonstrated symptom improvement, but those in the placebo group were unchanged.  The treatment effect was still apparent after one year.

Garvey et al. conducted an RCT designed to determine if IVIg or PE would be superior to prednisone in decreasing the severity of chorea.  Children with SC (n=18) were randomized to treatment with PE (n= 8; 5-6 procedures over 1-2 weeks), IVIg (n=4; 2 gm/kg over 2 days), or prednisone (n=6; 1 mg/kg/day for 10 days followed by taper over next 10 days).  The primary outcome was chorea severity at one month.  The secondary outcome variable was chorea severity at one year following treatment.  There was no significant difference between the baseline chorea severity scores by the treatment group.  Chorea severity was assessed at baseline and at 1, 2, 3, 6, and 12 months following 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 prior to baseline assessment and each follow-up evaluation.  Mean chorea severity for the entire group was lower at the one-month follow-up evaluation (overall 48% improvement).  The between-group differences were not statistically significant.

Phytanic Acid Storage (Refsum’s disease)

Phytanic acid storage disease (Refsum’s disease) is an autosomal recessive disorder that causes significant defects in metabolism of phytanic acid (PA) due to deficiency in alpha-oxidase.  Limiting dietary intake of PA to 10 mg/day is the cornerstone of therapy.  PA is found in dairy, butter, cheese, meat and some fish.  The relative unpalatability of a low-PA diet limits compliance and thus effectiveness of dietary management.  Even with adequate dietary compliance, fall of PA levels may be delayed due to release from adipose tissue.  TPE rapidly reduces plasma PA in acute attacks or exacerbations, as well as maintenance.  Normal plasma PA is <33 µmole/L; symptomatic levels of PA in Refsum’s disease range from 700 to 8000 µmole/L.  A number of small case series and isolated reports have described clinical improvement in patient signs and symptoms with TPE in conjunction with dietary control.  TPE has been found to improve polyneuropathy, ichthyosis, ataxia, and cardiac disfunction in most, but not all patients treated (Szczepiorkowski et al.).

Red Cell Alloimmunization in Pregnancy

Hemolytic disease of the fetus and newborn (HDFN) occurs when the maternal plasma contains an alloantibody against a red blood cell (RBC) antigen carried by the fetus.  The maternal IgG crosses the placenta and causes hemolysis of the fetal RBCs.  This may be caused by a variety of RBC alloantibodies.  TPE removes the maternal RBC alloantibody that causes HDFN, which will potentially decrease the maternal antibody titer and, in turn, the amount of antibody transferred to the fetus, thereby protecting the fetus from HDFN.  Survival of the fetus in severe cases of HDFN with the use of TPE and/or IVIg prior to intrauterine transfusion (IUT) is about 70%.  Typically, IUT can be performed after the fetus reaches 20 weeks of gestation (Szczepiorkowski et al.).

Systemic Lupus Erythematosus (SLE)

Reporting on the results of a randomized controlled trial (RCT), 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.

Szczepiorkowski et al. reported the following: 

Use of cyclosporine A and TPE to control symptomatic disease in a prospective trial of 28 patients with flares resulted in quicker resolution of symptoms and decreased doses of cytotoxic drugs.  Multiple well-documented case reports of beneficial effect of TPE in SLE-associated TTP, pulmonary hemorrhage, MG, hyperviscosity and cryoglobulinemia have been published.  A recent review of 26 patients with SLE and CNS involvement who were treated with TPE or combination TPE/cyclophosphamide revealed that 74% of patients improved, 13% stabilized, and 13% progressed.  These results highlighted a potential benefit for refractory or critically ill patients.  Addition of TPE to immunosuppressive therapy in SLE patients with diffuse alveolar hemorrhage has also been reported.  In a small non-controlled trial of patients (n=5) undergoing TPE in the setting of severe SLE, it has been reported that during the course of TPE (4-6 days) the peripheral level of CD4+CD25(high)FoxP3+ cells (T regulatory cells) significantly increased.  The increased number of T regulatory cells was accompanied by a decrease in SLEDAI (SLE disease activity index), possibly due to elimination of alpha and lymphocytic antibodies.

Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS)

Once considered distinct syndromes, TTP and 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). 

Included were trials that compared an intervention with placebo, an intervention with supportive therapy, or one or more different interventions for HUS or TTP.  Interventions examined included heparin, aspirin/dipyridamole, prostanoids, ticlopidine, vincristine, fresh frozen plasma (FFP) infusion, PE with FFP, systemic corticosteroids, Shiga toxin binding agents, or immunosuppressive agents.  For TTP, six RCTs (n=331 participants) were identified evaluating PE with FFP as the control.  Interventions tested included antiplatelet therapy (APT) plus PE with FFP, FFP transfusion, and PE with cryosupernatant plasma (CSP).  Two studies compared plasma infusion (PI) to PE with FFP and showed a significant increase in failure of remission at two weeks (risk ratio [RR]: 1.48) and all-cause mortality (RR: 1.91) in the PI group.  The authors concluded that PE with FFP is the most effective treatment available for TTP.  Seven RCTs included children with HUS.  None of the assessed interventions was superior to supportive therapy alone for all-cause mortality, neurological/extrarenal events, renal biopsy changes, proteinuria, or hypertension at the last follow-up visit.  Bleeding was significantly higher in those receiving anticoagulation therapy compared to supportive therapy alone (RR: 25.89).  For patients with HUS, supportive therapy including dialysis was the most effective treatment.  All studies in HUS have been conducted in the diarrheal form of the disease.  There were no RCTs evaluating the effectiveness of any interventions on patients with atypical HUS who have a more chronic and relapsing course.  A recent review article by Noris and Remuzzi describes the data supporting use of PE in the atypical form of this disease, with results showing remission in up to 60% of patients.  

Because the available evidence for patients with typical HUS shows supportive therapy, including dialysis, to be the most effective treatment, all studies in HUS have been conducted with patients with the diarrheal (typical) form of the disease; 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.

Thrombotic Microangiopathy, Drug-Associated

Ticlopidine/Clopirogrel:  Patients presenting two or more weeks after initial exposure had improved survival (84% vs. 38%, p<0.05) with TPE; when presenting <2 weeks after drug initiated, survival with TPE or without TPE was similar (77% vs. 78%).  The presence of severely deficient ADAMTS13 activity (<10%) with autoantibodies, which is similar to idiopathic TTP, may relate to the overall response of those patients with TPE (Szczepiorkowski et al.). 

Cyclosporine/Tacrolimus, Gemcitabine, or Quinine:  Response has been unpredictable and has not been proven to improve outcomes (Szczepiorkowski et al.).

Idiopathic Thrombocytopenic Purpura (ITP)

ITP is an acquired disease of either 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 about one week after a blood transfusion in association with a high titer of anti-platelet alloantibodies.  Due to its rapid effect, PE is considered the initial treatment of choice.

Wilson’s Disease

Wilson’s disease is an autosomal recessive genetic disorder of the ATP7B gene, a copper transporting P-type ATPase protein found in hepatocytes.  ATP7B protein deficiency impairs biliary copper excretion, resulting in copper accumulation in the liver, brain, cornea, and kidney.  Patients with Wilson’s disease may present with hepatic, neurologic and/or hematological manifestations.  Rarely, Wilson’s disease can present as fulminant hepatic failure with necrotic hepatocytes releasing free copper into the serum, which leads to severe DAT-negative hemolysis and acute renal failure.  This syndrome is associated with rapid clinical deterioration and is nearly always fatal without liver transplantation.  Since there is no alternative method to lower serum copper, TPE can be beneficial as it rapidly removes a significant amount of copper.  Decreased serum copper would decrease hemolysis, prevent progression of renal failure and provide clinical stabilization.  In most cases, TPE has been used as a bridge to transplant (Szczepiorkowski et al.).

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.  

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

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 the high doses of steroids can produce significant side effects.  Guillaume and colleagues reported on a study of 40 patients with pemphigus randomized to receive either 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.

Stiff Man (aka 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's disease, and small cell lung, colon, or breast cancer.  The mainstay of treatment of stiff man syndrome is diazepam.  The published literature regarding plasmapheresis consists of small case series and anecdotal reports.

Summary

In conclusion, due to data from published studies and/or clinical support, plasma exchange is considered medically necessary for selected conditions.  For conditions in which there is a lack of efficacy data and clinical support, plasma exchange is considered experimental, investigational and unproven.

Coding

Disclaimer for coding information on Medical Policies          

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.           

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers.  Only the written coverage position in a medical policy should be used for such determinations.           

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

99.71, 203.00, 203.01, 203.02, 272.0, 273.1, 273.2, 273.3, 275.1, 282.8, 283.0, 283.11, 283.9, 283.9, 284, 284.01, 284.09, 287.30, 287.31, 287.32, 287.33, 287.39, 287.41, 287.49, 287.5, 289.0, 289.81, 323.61, 323.81, 333.91, 335.2, 340, 341.0, 356.3, 356.9, 357.0, 357.81, 358.00, 358.01, 358.1, 358.30, 358.31, 358.39, 359.71, 446.21, 446.4, 446.6, 493.00-493.92, 570, 581.1, 583.81, 642.50, 642.51, 642.52, 642.53, 642.54, 694.4, 696, 710.0, 710.1, 710.3, 710.4, 714.0, 780.71, 961, 962, 963, 964, 965, 967, 968, 972, 975, 977, 996.8, 996.80, 996.81, 996.82, 996.83, 996.85, 996.88, 996.89, 999.60-999.69, E850, E851, E852, E855, E856, E860, E865, E950, V42.0, V42.1, E865.5

ICD-10 Codes

C88.0, D58.0-D58.9, D59.3, D69.3, D69.49, D69.5, D75.1, D89.2, G35, G60.9, G61.0, G61.81, G70.00-G70.01, M31.0, M31.30-M31.31, O14.20-O14.23, 6A550Z3, 6A551Z3

Procedural Codes: 36514
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  44. Hughes RA, Swan AV, Raphaël JC et al.  Immunotherapy for Guillain-Barré syndrome: a systematic review.  Brain 2007; 130(pt 9):2245-57.
  45. Jayne DR, Gaskin G, Rasmussen N et al.  European Vasculitis Study Group. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis.  J Am Soc Nephrol 2007; 18(7):2180-8.
  46. Shaz BH, Linenberger ML, Bandarenko N et al.  Category IV indications for therapeutic apheresis: ASFA fourth special issue.  J Clin Apher 2007; 22(3):176-80.
  47. Stussi G, Halter J Bucheli E, et al.  Prevention of pure red cell aplasia after major or bidirectional ABO blood group incompatible stem cell transplant by pretransplant reduction of host anti-donor isoagglutinins.  Haematologica 2008; 94:2 239-248.
  48. Sawada K, Fujishima N, et al.  Acquired pure red cell aplasia: updated review of treatment.  BJH 2008; 142, 505-514.
  49. Jayne D. Review article: progress of treatment in ANCA-associated vasculitis.  Nephrology 2009; 14(1):42-8.
  50. 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 2009; 53(2):259-72.
  51. Noris M, Remuzzi G.  Atypical hemolytic-uremic syndrome.  N Engl J Med 2009; 361(17):1676-87.
  52. Yuan X, Wang C, Gao W et al.  Kidney transplant in highly sensitized patients after desensitization with plasmapheresis and low-dose intravenous immunoglobulin.  Exp Clin Transplant 2010; 8(2):130-5.
  53. Liu J, Wang W, Zhao C et al.  Comparing the autoantibody levels and clinical efficacy of double filtration plasmapheresis, immunoadsorption and intravenous immunoglobulin for the treatment of late-onset myasthenia gravis.  Ther Apher Dial 2010; 14(2):153-60.
  54. Rockx MA, Clark WF.  Plasma exchange for treating cryoglobulinemia: a descriptive analysis.  Transfus Apher Sci 2010; 42(3):247-51.
  55. Szczepiorkowski ZM, Winters JL, Bandarenko N, et al.  Guidelines on the use of therapeutic apheresis in clinical practice—evidence-based approach from the apheresis applications committee of the American Society for Apheresis (5th edition, 2010) 25:3; 1-180.
  56. Cortese I, Chaudhry V, So YT et al.  Evidence-based guideline update: Plasmapheresis in neurologic disorders.  Neurology 2011; 76(3):294-300.
  57. Harper, JL.  Pediatric cold agglutinin disease.  2011 August.  Medscape Reference Available at www.emedicine.medscape.com (accessed 2012 January 31).
  58. Plasma Exchange.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2011 March) Therapy 8.02.02.
History
June 2011 Updated policy statement, rationale and references. Policy statement change from NMN to investigational
July 2012 Policy reviewed with literature search through April 15, 2012. Rationale rewritten. References 22, 26 and 29 added; other references renumbered or removed. Myeloma with acute renal failure and catastrophic antiphospholipid syndrome were changed to medically necessary. Dense deposit disease with Factor H deficiency and/or elevated C3 nephritis factor and focal segmental glomerulosclerosis after renal transplant were added as medically necessary. The investigational statement on focal segmental glomerulosclerosis was modified to indicate that it applied to situations other than after renal transplant. Hyperviscoscity syndromes with renal failure (other than associated with multiple myeloma or Waldenstrom’s macroglobulinermia) added as investigational. In addition, the serum creatinine threshold was removed from the policy statement on ANCA-associated vasculitis.
November 2013 Policy formatting and language revised.  Title changed from "Plasma Exchange (Plasmapheresis)" to "Plasmapheresis (PP) / Therapeutic Plasma Exchange (TPE)".  Removed CPT codes 36511, 36512, 36513, 36515, and 36516.  Coverage completely revised, with new indications, and all covered indications categorized as first-line therapy or second-line therapy in a table. 
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Plasmapheresis (PP) / Therapeutic Plasma Exchange (TPE)