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DESCRIPTIONPlasma exchange (PE) is a procedure in which the plasma is isolated, then discarded and replaced with a substitution fluid such as albumin. Plasma exchange is a nonspecific therapy, since the entire plasma is discarded. PE has been used in a wide variety of conditions including the treatment of neurological disease (e.g., Guillain-Barre) and hematological disorders (e.g., thrombotic thrombocytopenic purpura [TTP]).
The terms therapeutic apheresis, plasmapheresis, and plasma exchange (PE) are often used interchangeably, but when properly used donate 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.
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 combination of crystalloid/colloid solution.
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. Plasma exchange 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 the rate of production and transfer to the plasma component can be adequately addressed by the 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 (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, due to the phenomenon of rebound antibody production, its use in chronic diseases has been more controversial than in acute self-limited diseases.
Acute Self-Limited Conditions
Conditions associated with hyperviscosity
Serum hyperviscosity is most commonly related to overproduction of immunoglobulins and thus is seen in association with B-cell lymphocyte neoplasms such as multiple myeloma and Waldenstrom’s macroglobulinemia. Symptoms of hyperviscosity include bleeding disorders, retinopathy, and neurologic disorders including stroke. Treatment is principally directed at the underlying disorder, but PE may be used to acutely lower the serum viscosity.
Acute exacerbations of myasthenia gravis
Myasthenia gravis is an autoimmune disease with autoantibodies directed against the postsynaptic membrane of the muscle end-plate. Clinically, the disease is characterized by fatigable weakness of voluntary muscles. Initial treatment focuses on the use of cholinesterase inhibitors to overcome the postsynaptic blockade. Immunosuppressant drugs including corticosteroids and azathioprine are also effective. PE has been used as a short-term therapy in patients with acute exacerbations associated with severe weakness.
Guillian-Barré syndrome is an acute demyelinating neuropathy whose severity is graded on a scale of 1-5. The beneficial effect of plasma exchange has been observed regardless of severity of illness. PE is reserved for those patients with grades 3–5 disease who do not initially respond to prednisone.
Rapidly progressive glomerulonephritis (RPGN) including Goodpasture’s syndrome
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. RPGN may also be idiopathic. Because many cases of RPGN represent an immune-mediated disease of acute onset, RPGN was an early focus of PE research.
Thrombotic thrombocytopenic purpura (TTP)—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. The classic signs and symptoms include fever, thrombocytopenia, microangiopathic hemolytic anemia, neurologic abnormalities, and renal involvement. TTP-HUS may be seen in association with other conditions, such as pregnancy or HIV infection. PE has become the primary treatment for TTP-HUS, although a rationale for its effectiveness is unknown. PE is performed daily until a response is noted; the length of treatment averages about once a month, with increasing intervals between PE treatments.
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. PE does not appear to have a role in chronic ITP.
HELLP syndrome of pregnancy
The HELLP 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.
Post-transfusion purpura is a rare disorder characterized by an acute severe thrombocytopenia occurring about 1 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.
Acute fulminant CNS demyelination
Multiple sclerosis and other idiopathic inflammatory demyelinating diseases may present with an acute fulminant onset, which may proceed to severe cognitive dysfunction, hemiplegia, paraplegia, or quadraplegia.
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). The current hypothesis for the pathology of PANDAS is that a streptococcal infection occurring in a vulnerable host causes antibody production and these antibodies cross-react with the cellular components of the basal ganglia. SC is the neurological 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. At present, there has been no clearly effective immunomodulatory treatment (i.e., IVIg, plasma exchange), for PANDAS or SC.
Chronic inflammatory demyelinating polyneuropathy (CIDP)
CIDP is a symmetric polyneuropathy associated with both motor and sensory deficits. The disease course may present as either a relapsing/fluctuating or slowly progressive disease. PE is reserved for those patients who do not respond to treatment with prednisone. PE may be required on a chronic basis, its frequency titrated according to the durability of the patient’s response. Some of the symptoms of CIDP may overlap with those of chronic fatigue syndrome. However, the American Academy of Neurology has established diagnostic guidelines for CIDP.
A monoclonal immunoglobulin (paraprotein) is found in the serum or urine of approximately 10% of patients with idiopathic polyneuropathy, typically occurring in the context of a monoclonal gammopathy of undetermined significance (MGUS). In addition, approximately 25% of patients with CIDP may have a monoclonal gammopathy. The gammopathy is typically an IgM (in which it is often directed against myelin-associated proteins or the ganglioside GM-1) or less commonly IgG or IgA.
Multiple sclerosis (MS) is an inflammatory demyelinating disease, the etiology of which has remained frustratingly elusive; both environmental and genetic factors are thought to play a role. Laboratory abnormalities suggest that MS is an immune-mediated disease. PE has been used primarily as a technique to either shorten the duration of an acute attack or to reduce the number of acute attacks.
Paraneoplastic neuromuscular syndromes
Paraneoplastic neuromuscular syndromes are characterized by the production of tumor antibodies that cross-react with the patient’s nervous system tissues. In many cases, the paraneoplastic syndrome may be the initial manifestation of the tumor, and in other instances the symptoms of the syndrome are more disabling than the tumor itself. 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. Although presence of LEMS should prompt a search for a lung primary tumor, the syndrome may also occur idiopathically. Other syndromes include paraneoplastic sensory neuropathy, encephalomyelitis, cerebellar degeneration, or opsoclonus/myoclonus (related to the presence of anti-Hu antibody, or in the case of cerebellar degeneration, anti-Purkinje cell antibodies). Paraproteinemic immunoglobulin M can also be associated with a demyelinating polyneuropathy. Although treatment of the underlying primary tumor is the cornerstone of treatment, PE has also been investigated due to the presence of circulating autoantibodies.
Stiff Man Syndrome
Stiff man syndrome is an autoimmune disorder characterized by involuntary stiffness of axial muscles and intermittent painful muscle spasm. Symptoms are related to the autoantibodies directed against glutamic acid decarboxylase in the nervous system. 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.
Pemphigus is an autoimmune blistering skin disease that is characterized by serum antibodies that bind to squamous epithelia. Clinically, it is characterized by flaccid bullae that rupture and leave areas of denuded skin, creating serious problems of secondary infection and fluid balance. Steroids or other immunosuppressants are the most common forms of treatment, but the high doses of steroids can produce significant side effects. PE has been investigated in patients refractory or intolerant to steroids or other immunosuppressant therapies.
Autoimmune connective tissue diseases
This family of diseases includes systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (also referred to as scleroderma), polymyositis, and dermatomyositis. Inclusion body myositis is the most commonly acquired inflammatory myopathy in patients over age 50 years, characterized by weakness of the quadriceps, biceps, and triceps. When PE first became available during the 1970s and early 1980s, there was considerable interest and enthusiasm for the use of PP/PE for these autoimmune diseases. However since that time, successive randomized controlled trials have not validated the role of PE as a treatment of the chronic phase of these conditions.
There are several types of cryoglobulinemia. Type I is associated with hematological 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).
Plasmapheresis in the setting of solid organ transplantation
Acute rejection after transplant can be broadly divided into 2 categories, the more common acute cellular rejection (ACR) related to activation of T cells, and the less common antibody-mediated rejection reaction (AMR) related to the presence of anti-donor antibodies. While ACR typically responds to immunologic therapy directed at T cells, AMR does not, and, as such, has also been referred to as “steroid resistant rejection.” The risk of AMR is related to the presence of preformed allo-antibodies in the recipient due to prior blood transfusions, transplants, or pregnancies. The presence of allo-antibodies is assessed by using a panel reactive antibody (PRA) screen, which combines the recipient’s serum with samples of antigen containing cells taken from 60 individuals representative of the potential donor pool. The percentage PRA is the percentage of positive reactions. Those with a PRA >20% are referred to as “sensitized,” and these patients often have prolonged waiting times to identify a compatible donor. Living donor kidney transplants have also been performed using ABO mismatched donor organs. These recipients are also at risk of AMR. Plasmapheresis has been used as a technique to desensitize high-risk patients prior to transplant, and also as a treatment of AMR occurring after transplant. Prior to transplant, plasmapheresis has been most commonly used to desensitized 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 (see Immune Globulin Replacement Therapy policy) or anti-CD20 therapy (i.e., Rituxan).
Note: This policy addresses only plasma exchange as a therapeutic apheresis procedure.
POLICYPlasma exchange may be considered medically necessary for any of the conditions listed below:
Investigational applications of plasma exchange include, but are not limited to, the following conditions:
POLICY EXCEPTIONSFederal Employee Program (FEP) may dictate that all devices, drugs, biologics and imaging approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational and thus may be assessed only on the basis of their medical necessity.
POLICY GUIDELINESInvestigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY6/1993: Therapeutic Apheresis approved by Medical Policy Advisory Committee (MPAC)
11/1993: Extracorporeal Immunoadsorption Using Protein A Columns approved by MPAC
5/1999: MPAC reviewed policies; updated, combined and renamed
12/1999: Interim revision; new FDA-approved indication added for some stages of rheumatoid arthritis
2/2000: Interim revisions approved by MPAC
4/11/2001: Photopheresis for human heart transplant recipients at high risk for fatal rejection
8/2001: Reviewed by MPAC
2/13/2002: Investigational definition added
5/2/2002: Type of Service and Place of Service deleted
10/4/2002: ICD-9 procedure code 99.76 added
3/5/2003: Code Reference section updated
7/2003: Reviewed by MPAC, policy aligned to be consistent with BCBSA, Sources updated
3/17/2004: Code Reference section updated, CPT code 36520, 36521 deleted, ICD-9 diagnosis code 203.0, 273.2, 282.8, 284.8, 356.3, 356.9, 358.00 (note 358.0 was covered), 391.1, 710.1, 710.4 deleted, HCPCS Q0068 deleted, ICD-9 diagnosis 642.5 fifth digit added
10/22/2004: Code Reference section updated, CPT 36511, 36512, 36513 deleted, ICD-9 diagnosis 202.20, 202.21, 202.22, 202.23, 202.24, 202.25, 202.26, 202.27, 202.28, 272.0, 272.2, 273.0, 273.3, 283.11, 287.3, 287.4, 289.0, 341.0, 341.1, 341.8, 341.9, 357.0, 357.81, 358.01, 446.21, 446.6, 583.81, 642.50, 642.51, 642.52, 642.53, 642.54, 714.0, 714.1, 714.2, 714.30, 714.31, 714.32, 714.33, 714.4, 714.81, 714.89, 714.9, 996.83, E878.0 note added, ICD-9 diagnosis 340 deleted, HCPCS S2120 added
11/7/2005: Code Reference section updated, 5th digit added to ICD9 diagnosis code 287.31
3/10/2006: Coding updated. CPT4/HCPCS 2006 revisions added to policy
7/27/2006: Policy updated. Updates approved per Medical Policy Advisory Committee (MPAC)
8/31/2006: Code Reference section updated. V42.0, V42.1,V42.6, V42.7, V42.81, V42.83 added to covered table
5/1/2008: Policy description updated with acute and chronic conditions; photopheresis, extracorporeal immunoadsorption, and lipid apheresis removed from policy. IgA or IgG paraproteinemia polyneuropathy added as a medically necessary indication. Inclusion body myositis and asthma added as investigational. Code reference section reviewed; CPT codes 36515, 36516, 36522, 86960 removed; ICD-9 procedure codes 99.76, 99.88 removed; ICD-9 diagnosis codes 202.20-202.28, 272.0-272.2, 714.0-714.9 removed; HCPCS S2120 removed. ICD-9 diagnosis codes 203.00, 203.01, 341.0, 341.20-341.22, 996.81, 996.82, 996.84-996.85 added
9/11/2008: Annual ICD-9 updates applied
06/23/2010: Policy Title changed, removed "Plasmapheresis." Policy Description section was revised for multiple reasons: definitions of apheresis, plasmapheresis and plasma exchange was added; addition applications of PE related to cryoglobulinemia, PANDAS and SC. Policy Statements (medically necessary and investigational) were revised to include conditions that may be considered medically necessary and conditions that are considered investigational. FEP verbiage was added to the Policy Exceptions section. ICD-9 Diagnosis codes: 282.8, 340 and 446.4 were added to the Covered Codes Table.
10/14/2010: Annual ICD-9 code update: 287.4 deleted/expanded to the fifth digit. Added 287.41 and 287.49 to the Covered Codes table.
04/20/2011: Policy reviewed; no changes.
07/12/2012: Policy statement revised as follows: Myeloma with acute renal failure and catastrophic antiphospholipid syndrome were changed from investigational 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 revised 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) was added as investigational. The serum creatinine threshold was removed from the policy statement on ANCA-associated vasculitis. Deleted outdated references from the Sources section. Added ICD-9 codes 289.81, 582.1, and 583.2 to the Covered Codes table.
08/14/2013: Policy reviewed; no changes.
06/14/2014: Policy reviewed; no changes.
07/10/2015: Neuromyelitis optica (NMO) added as an investigational application.
09/01/2015: Code Reference section updated for ICD-10. Removed deleted ICD-9 diagnosis code 287.4.
SOURCE(S)Blue Cross Blue Shield Association policy # 8.02.02
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.