|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/5:2013
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Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.
Plasma 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 acute and chronic conditions, as well as in the setting of solid organ transplantation.
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 (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 a combination of crystalloid/colloid solution.
This policy addresses only plasma exchange as a therapeutic apheresis procedure.
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-CD-20 therapy (i.e., Rituxan).
Plasma exchange is considered medically necessary for the conditions listed below:
- 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 (CAPS).
- 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 preeclampsia, characterized by hemolysis [H], elevated liver enzymes [EL], and low platelet [LP] counts);
- myeloma with acute renal failure.
- acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome [GBS]; severity grade 1–2 within 2 weeks of onset; severity grade 3–5 within 4 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;
- paraproteinemia polyneuropathy; IgA, IgG.
- 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.
- ABO incompatible solid organ transplantation;
- Heart (infants);
- renal transplantation: antibody mediated rejection; HLA [human leukocyte antigen] desensitization;
- focal segmental glomulerulosclerosis after renal transplant.
Plasma exchange is considered investigational in 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;
- 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;
- 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);
- red blood cell alloimmunization in pregnancy;
- rheumatoid arthritis;
- scleroderma (systemic sclerosis);
- stiff person syndrome;
- Sydenham’s chorea (SC);
- systemic lupus erythematosus (including SLE [systemic lupus erythematosus] nephritis); and
- hyperviscosity syndromes with renal failure (other than associated with multiple myeloma or Waldenstrom’s macroglobulinemia).
Patients receiving plasma exchange (PE) as a treatment of CIDP should meet the diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (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 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.
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.”
BlueCard/National Account Issues
Since plasmapheresis frequently involves long-term chronic therapy, Plans may want to consider requiring precertification to ensure appropriate utilization.
State of federal mandates (e.g., FEP) may dictate that all FDA_approved devices, drugs, biologics and imaging may not be considered investigational and thus may be assessed only on the basis of their medical necessity.
This policy was originally created in 1995 and was updated regularly with searches of the MEDLINE database. The most recent literature search was performed for the period April 15, 2012 through March 21, 2013. Following is a summary of the key literature to date:
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. (1) Although many laboratory abnormalities are associated with autoimmune connective tissue diseases, it is unclear which, if any, cause the clinical manifestations of the disease. Furthermore, it is not known to what extent plasma levels parallel clinical disease. For example, in many of the controlled trials discussed as follows, 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
Reporting on the results of a randomized controlled trial (RCT), Lewis and colleagues concluded that PE had no benefit in patients with systemic lupus and glomerulonephritis compared to a standard therapy regimen of prednisone and cyclophosphamide. (2) 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. (3) While 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 outcome.
Multiple Sclerosis (MS)
There have been several RCTs of PE in patients with MS that have reported inconclusive results. Khatri and colleagues studied 54 patients with chronic progressive MS randomized to receive sham or true PE. (4) 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. (5) A Canadian trial randomized 168 patients with progressive MS to receive either PE or immunosuppressive therapy. (6) There were no significant differences in the rates of treatment failures between groups.
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. (7) 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. (8) Anderson and colleagues reported on a case series of 12 patients with paraneoplastic cerebellar degeneration. Although plasmapheresis was associated with an acute drop in the autoantibody titer, only 2 patients showed a minor improvement in neurologic symptoms. (9)
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. (10)
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. (11)
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. (12) 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. (13-15)
There are several types of cryoglobulinemia. Type I is associated with hematologic disorders. Types II and III are considered mixed cryoglobulins. Mixed cryoglobulin 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 5 patients. (16) 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.”
Thrombotic Thrombocytopenic Purpura (TTP) and Haemolytic Uraemic 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). (17) Interventions 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 fresh frozen plasma, systemic corticosteroids, Shiga toxin-binding agents, or immunosuppressive agents. For TTP, 6 RCTs (n=331 participants) 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 (PI) to PE with FFP and showed a significant increase in failure of remission at 2 weeks (risk ratio [RR]: 1.48) and all-cause mortality (RR: 1.91) in the PI group. The authors concluded that PE with fresh frozen plasma 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. (18)
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.
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 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.
HELLP Syndrome of Pregnancy
The HELLP syndrome of pregnancy (characterized by hemolysis [H], elevated liver enzymes [EL], and low platelet [LP] counts) is a severe form of preeclampsia, characterized by hemolysis, elevated liver enzymes, and low platelet 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.
Guillain-Barré Syndrome (GBS)
Guillain-Barré syndrome is an acute demyelinating neuropathy whose severity is graded on a scale of 1–5 (the disability scale is summarized in the Appendix to this policy). In 2012, The Cochrane Collaboration published an updated systematic review of the evidence concerning the efficacy of PE for treating GBS. (19) Six eligible trials (n=649) were identified comparing PE versus supportive treatment alone. No additional trials were published since the 2002 review. The primary outcome measures of the review included time to recover walking with aid and time to onset of motor recovery in mildly affected patients. A pooled analysis of data from 3 trials found that PE significantly increased the proportion of patients who recovered the ability to walk with assistance after 4 weeks (RR: 1.60, 95% confidence interval [CI]: 1.19 to 2.15). Data on time to onset of motor recovery were not pooled. Pooled analyses found that PE led to significant improvement in secondary outcomes including reduced time to recover walking without aid, increased likelihood of full muscle strength recovery and reduced likelihood of severe motor sequelae. However, there was a significantly higher risk of relapse in the group that received PE compared to supportive treatment alone (RR: 2.89, 95% CI: 1.05 to 7.93, 6 trials).
A 2007 systematic review evaluated the available randomized trials of immunotherapy to treat GBS. (20) In 4 trials with severely affected adult participants (n=585), those treated with plasma exchange (PE) improved significantly more on the disability scale 4 weeks after randomization than those who were not (weighted mean difference [WMD]: -0.89; range: -1.14 to -0.63). In 5 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 1 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 2 sessions of PE in 3 days or supportive care. The number of patients with one or more grades of improvement at 1 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 1 trial (n=148), following PE with IVIg, did not produce significant extra benefit. Limited evidence from 3 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. (21) The following are the key findings: 1) treatment with PE or IVIg hastens recovery from Guillain-Barré syndrome; 2) combining the 2 treatments is not beneficial; and 3) steroid treatment given alone is not beneficial. The AAN’s recommendations are: 1) PE is recommended for nonambulant adult patients with GBS who seek treatment within 4 weeks of the onset of neuropathic symptoms (PE should also be considered for ambulant patients examined within 2 weeks of the onset of neuropathic symptoms); 2) IVIg is recommended for nonambulant adult patients with GBS within 2 or possibly 4 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.
A 2011 RCT from Iran addresses PE for treating young children with severe GBS. (22) The study included 41 children with GBS who required mechanical ventilation and had muscle weakness for no more than 14 days. Patients were randomized to receive PE (n=21) or intravenous immunoglobulin (IVIg) (n=20). Mean age of the patients was 96 months in the PE group and 106 months in the IVIg group. Duration of ventilation, the primary outcome, was a mean of 11 days (standard deviation [SD]=1.5) in the PE group and 13 days (SD=2.1) in the IVIg group, p=0.037. Duration of stay in the intensive care unit, a secondary outcome, was 15.0 days (SD=2.6 days) in the PE group and 16.5 days (SD=2.1 days) in the IVIg group; p=0.94.
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 limited published data, as well as extrapolated data from studies in adults and clinical input, PE may be considered as a treatment option for children younger than 10 years-old with severe GBS.
Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)
A 2012 Cochrane review by Mehnidiratta and Hughes identified 2 randomized trials on PE for CIDP. (23) Both trials were considered to be of high quality, but both had small sample sizes. One trial with 29 patients used a parallel design and compared PE to sham treatment. The other study included 15 patients and used a cross-over design to compare PE and sham treatment. A pooled analysis of data from the 2 trials found a statistically significantly greater improvement in impairment after 4 weeks with PE versus sham (mean difference 31 points on the Neuropathy Impairment Score, 95% CI: 16 to 45 points). The scale ranges from 0 (normal) to 280 (maximally affected). Data on other outcomes were not suitable for pooled analysis.
Acute Fulminant Central Nervous System (CNS) Demyelination
The policy statement, which suggests that plasmapheresis may be considered medically necessary in patients with acute fulminant CNS demyelination, is based on the results of a randomized, double-blinded trial, in which 22 patients with 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 5 days of high-dose corticosteroids. (24) Patients were randomized to receive either 7 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.
A randomized, double-blinded trial compared PE to sham treatment in 39 patients with monoclonal gammopathy of undetermined significance (MGUS)-associated polyneuropathy. (25) After twice weekly PE for 3 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.
A randomized trial from China was published in 2009. (26) Liu and colleagues assigned 40 patients with late-onset myasthenia gravis to treatment with double-filtration plasmapheresis (n=15), immunoadsorption (IA) (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.
A 2011 RCT from Germany randomized patients with myasthenic crisis to treatment with PE (n=10) or immunoadsorption (IA) (n=9). (27) In both groups, 3 apheresis treatments were performed within 7 days; patients could have additional treatments if needed. A total of 16/19 (84%) 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 the 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. There were no statistically significant differences in outcomes in this study, but the sample was very small and the study was probably underpowered.
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. (28) 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. (29)
Antineutrophil Cytoplasmic Antibody (ANCA)-associated Vasculitis
In 2011, Walsh and colleagues published a meta-analysis of studies on plasma exchange in adults with the diagnosis of either idiopathic renal vasculitis or rapidly progressive glomerulonephritis. (30) A total of 9 trials including 387 patients were identified. The clinical populations in the studies were somewhat ill-defined, but most patients appeared to have ANCA-associated vasculitis. In a pooled analysis of study findings, there was a significantly lower risk of end-stage renal disease in patients treated with adjunctive PE compared to standard care alone (RR 0.64, 95% CI: 0.47 to 0.88). The risk of death did not differ significantly in the 2 groups (RR:1.01, 95% CI: 0.71-1.40).
A relatively large RCT, included in the Walsh et al. meta-analysis, was published in 2007 by Jayne and colleagues. (31) This was a multicenter trial conducted on behalf of the European Vasculitis Study Group. The study investigated whether the addition of PE was more effective than intravenous methylprednisolone. Patients (n=137) with a new diagnosis of ANCA-associated systemic vasculitis confirmed by renal biopsy and serum creatinine greater than 500 micromol/L (5.8 mg/dL) were randomly assigned to receive 7 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 3 months. Secondary endpoints 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 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. At 1 year, the patient survival rate was 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.
Solid Organ Transplant
Prior to 2006, plasmapheresis in the setting of solid organ transplant was not addressed by this policy. However, plasmapheresis has been extensively used in this setting, both as pretransplant prophylaxis (i.e., desensitization) for highly sensitized patients at high risk of antibody-mediated rejection (AMR), and as a treatment of AMR after transplant. Desensitization protocols vary among transplant centers; two commonly used protocols are referred to as the Cedars-Sinai protocol and the Johns Hopkins protocol. The Cedars-Sinai protocol consists of high-dose IVIg (2 g/kg) and is offered to patients awaiting either a deceased or live donor. The Johns Hopkins protocol consists of low-dose IVIg (100 mg/kg) in combination with plasmapheresis with or without treatment with anti-CD-20 (i.e., Rituxan). Plasmapheresis is more commonly used in patients receiving a living kidney transplant from an ABO mismatched donor. (32) 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. e.g. (33-35) 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.
Other conditions or applications
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. (36)
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 and colleagues 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. (37) 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 to 6 procedures over 2 weeks), IVIg (n=9; 2 gm/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 the 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 had only minor improvements.
Garvey and colleagues conducted an RCT designed to determine if IVIg or PE would be superior to prednisone in decreasing the severity of chorea. (38) Children with Syndenham’s chorea (n=18) were randomized to treatment with PE (n= 8; 5 to 6 procedures over 1 to 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 1 month. The secondary outcome variable was chorea severity at 1 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 1-month follow-up evaluation (overall 48% improvement). The between-group differences were not statistically significant. Larger studies are needed to confirm these clinical observations.
Clinical Input Received through Physician Specialty Societies and Academic Medical Centers
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. 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. There was consensus or near-consensus that plasma exchange 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. Clinical input was mixed on the medical necessity of hyperviscosity syndromes with renal failure (other than associated with multiple myeloma or Waldenstrom’s macroglobulinemia). In addition, there was no consensus about an optimal creatinine threshold for instituting plasma exchange in patients with renal failure associated with ANCA-associated vasculitis or other diagnoses.
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 investigational.
Practice Guidelines and Position Statements
In 2011, the American Academy of Neurology (Therapeutics and Technology Assessment Subcommittee) issued an evidence-based guideline on plasmapheresis in the treatment of neurological disorders. (39) The primary conclusions based on their evidence review are as follows:
- Established effective
- Acute inflammatory demyelinating polyneuropathy/ Guillain-Barre syndrome
- Chronic inflammatory demyelinating polyneuropathy, short-term treatment
- Probably effective
- Relapses in multiple sclerosis
- Possibly effective
- Fulminant demyelinating CNS disease
- Established ineffective
- Chronic or secondary progressive multiple sclerosis
- Insufficient evidence
- Myasthenia gravis
- Sydenham’s chorea
- Acute obsessive-compulsive disorder and tics in PANDAS
In 2010, the American Society for Apheresis (ASFA) released updated guidelines on the use of therapeutic apheresis. (40) The guidelines modified and simplified the categories introduced in 2007; for example, the following is a detailed description of the ASFA categories.
|I||Category I includes diseases for which TA is standard and acceptable, either as a primary therapy or a valuable first-line adjunct therapy. (The perception of efficacy in these disorders is usually based on well-designed randomized controlled trials or on a broad and non-controversial base of published experience.) Note that this designation need not imply that TA is mandatory in all cases.|
|II||Category II denotes diseases for which TA is generally accepted but considered to be supportive or adjunctive to other, more definitive treatments, rather than a primary first-line therapy. (Randomized controlled studies are available for some of these disorders, but in others the literature contains only small series or informative case studies.)|
|III||Category III diseases are those in which there is a suggestion of benefit for which existing evidence is insufficient, either to establish the efficacy of TA or to clarify the risk/benefit (or sometimes the cost/benefit) ratio associated with TA. Included are disorders in which controlled trials have produced conflicting results or for which anecdotal reports are too few or too variable to support an adequate consensus. Therapeutic apheresis may reasonably be used in such patients when conventional therapies do not produce an adequate response or as part of an IRB-approved research protocol.|
|IV||Category IV indicates disorders for which controlled trials have not shown benefit or anecdotal reports have been discouraging. TA for these disorders is discouraged and should be carried only in the context of an IRB [independent review board]-approved research protocol.|
|P||Category P (pending) includes diseases which can be treated by therapeutic apheresis using devices that are not available in the United States and/or do not have FDA clearance. This category is generally assigned to those diseases in which the devices are being studied in Phase III trials in the United States.|
Below are the indications for therapeutic plasma exchange followed by the ASFA category recommendations for 2007 and 2010.
Indication Categories for Therapeutic Apheresis- Plasma Exchange
|Disease group / Name / Condition||ASFA 2007||ASFA 2010|
|Catastrophic antiphospholipid syndrome||III||II|
|Systemic lupus erythematosus|
|Manifestations other than nephritis||III||NC|
|ABO incompatible hematopoietic progenitor cell transplantation||II||II|
|Autoimmune hemolytic anemia:|
|warm autoimmune hemolytic anemia||III||III|
|cold agglutinin disease||III||II|
|Coagulation factor inhibitors||III||II|
|Hyperviscosity in monoclonal gammopathies||I||I|
|Idiopathic thrombocytopenic purpura||I|
|Refractory or non-refractory||IV||NC|
|Myeloma and acute renal failure||III||II|
|Red blood cell alloimmunization in pregnancy||II||II|
|Thrombotic thrombocytopenic purpura||I||I|
|Acute liver failure||III||III|
|Acute disseminated encephalomyelitis||III||II|
|Acute inflammatory demyelinating polyneuropathy (Guillain-Barre syndrome)||I||I|
|Chronic inflammatory demyelinating polyradiculoneuropathy||I||I|
|Lambert-Eaton myasthenic syndrome||II||II|
|Acute CNS inflammatory demyelinating disease||II||II|
|Paraneoplastic neurologic syndromes||III||III|
|Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections; Sydenham’s chorea|
|Severe PANDAS (2010 exacerbations)||I||I|
|ANCA-associated rapidly progressive|
|glomerulonephritis (Wegener’s granulomatosis)||II|
|Anti-glomerular basement membrane disease|
|Diffuse alveolar hemorrhage (DAH)||NC||I|
|Dialysis dependence and no DAH||NC||IV|
|Focal segmental glomerulosclerosis|
|Hemolytic uremic syndrome; thrombotic microangiopathy; transplant associated microangiopathy|
|Diarrhea associated pediatric||IV||NC|
|Atypical HUS due to complement factor gene mutations||NC||II|
|Atypical HUS due to autoantibody to factor H||NC||I|
|Diarrhea associated HUS or typical HUS||NC||IV|
|Rapidly progressive glomerulonephritis||III||NC|
|Renal transplantation: antibody mediated rejection; HLA desensitization|
|Antibody mediated rejection||II||I|
|Desensitization, ,living donor, positive||NC||II|
|crossmatch due to donor-specific HLA antibody|
|High PRA: cadaveric donor||NC||III|
|Scleroderma (progressive systemic sclerosis)||III||III|
|ABO incompatible solid organ transplantation|
|Liver (2010 perioperative)||III||III|
|Heart transplant rejection|
Abbreviations: NC – not-categorized
Medicare National Coverage
The Centers for Medicare and Medicaid Services, Medicare Coverage Database, National Coverage Determination (NCD) for apheresis (therapeutic pheresis) (41) states: “For purposes of Medicare coverage, apheresis is defined as an autologous procedure, i.e., blood is taken from the patient, processed, and returned to the patient as part of a continuous procedure (as distinguished from the procedure in which a patient donates blood preoperatively and is transfused with the donated blood at a later date). Apheresis is covered for the following indications: Plasma exchange for acquired myasthenia gravis; Leukapheresis in the treatment of leukemia; Plasmapheresis in the treatment of primary macroglobulinemia (Waldenstrom); Treatment of hyperglobulinemias, including (but not limited to) multiple myelomas, cryoglobulinemia and hyperviscosity syndromes; Plasmapheresis or plasma exchange as a last resort treatment of thrombotic thrombocytopenic purpura (TTP); Plasmapheresis or plasma exchange in the last resort treatment of life threatening rheumatoid vasculitis; Plasma perfusion of charcoal filters for treatment of pruritis of cholestatic liver disease; Plasma exchange in the treatment of Goodpasture's Syndrome; Plasma exchange in the treatment of glomerulonephritis associated with antiglomerular basement membrane antibodies and advancing renal failure or pulmonary hemorrhage; Treatment of chronic relapsing polyneuropathy for patients with severe or life threatening symptoms who have failed to respond to conventional therapy; Treatment of life threatening scleroderma and polymyositis when the patient is unresponsive to conventional therapy; Treatment of Guillain-Barre Syndrome; and Treatment of last resort for life threatening systemic lupus erythematosus (SLE) when conventional therapy has failed to prevent clinical deterioration.“
- Shumak KH, Rock GA. Therapeutic plasma exchange. N Engl J Med 1984; 310(12):762-71.
- Lewis EJ, Hunsicker LG, Lan SPActoptisln et al. The Lupus Nephritis Collaborative Study Group. N Engl J Med 1992; 326(21):1373-9.
- Danieli MG, Palmieri C, Salvi A et al. Synchronised therapy and high-dose cyclophosphamide in proliferative lupus nephritis. J Clin Apheresis 2002; 17(2):72-7.
- Khatri BO, McQuillen MP, Harrington GJ et al. Chronic progressive multiple sclerosis: double-blind controlled study of plasmapheresis in patients taking immunosuppressive drugs. Neurology 1985; 35(3):312-9.
- Weiner HL, Dau PC, Khatri BOD-bsotv et al. sham plasma exchange in patients treated with immunosuppression for acute attacks of multiple sclerosis. Neurology 1989; 39(9):1143-9.
- Canadian CMSSG. The Canadian cooperative trial of cyclophosphamide and plasma exchange in progressive multiple sclerosis. Lancet 1991; 337(8739):441-6.
- Tim RW, Massey JM, Sanders DB. Lambert-Eaton myasthenic syndrome: electrodiagnostic findings and response to treatment. Neurology 2000; 54(11):2176-8.
- Sanders DB, Massey JM, Sanders LL et al. A randomized trial of 3,4-diaminopyridine in Lambert-Eaton myasthenic syndrome. Neurology 2000; 54(3-Jan):603-7.
- Anderson NE, Rosenblum MK, Posner JB. Paraneoplastic cerebellar degeneration: clinical-immunological correlations. Ann Neurol 1988; 24(4):559-67.
- Dwosh IL, Giles AR, Ford PMPtira et al. A controlled, double-blind, crossover trial. N Engl J Med 1983; 308(19):1124-9.
- Miller FW, Leitman SF, Cronin ME et al. Controlled trial of plasma exchange and leukapheresis in polymyositis and dermatomyositis. N Engl J Med 1992; 326(21):1380-4.
- Guillaume JC, Roujeau JC, Morel P et al. Controlled study of plasma exchange in pemphigus. Arch Dermatol 1988; 124(11):1659-63.
- Vicari AM, Folli F, Pozza G et al. Plasmapheresis in the treatment of stiff-man syndrome. N Engl J Med 1989; 320(22):1499.
- Brashear HR, Phillips LH. Autoantibodies to GABAergic neurons and response to plasmapheresis in stiff-man syndrome. Neurology 1991; 41(10):1588-92.
- Harding AE, Thompson PD, Kocen RS et al. Plasma exchange and immunosuppression in the stiff man syndrome. Lancet 1989; 2(8668):915.
- Rockx MA, Clark WF. Plasma exchange for treating cryoglobulinemia: a descriptive analysis. Transfus Apher Sci 2010; 42(3):247-51.
- 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.
- Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med 2009; 361(17):1676-87.
- Raphael JC, Chevret S, Hughes RA et al. Plasma exchange for Guillain-Barre syndrome. Cochrane Database Syst Rev 2012; 7:CD001798.
- Hughes RA, Swan AV, Raphaël JC et al. Immunotherapy for Guillain-Barré syndrome: a systematic review. Brain 2007; 130(pt 9):2245-57.
- Hughes RA, Wijdicks EF, Barohn RQSSotAAoN et al. Practice parameter: immunotherapy for Guillain-Barré syndrome: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2003; 61(6-Jan):736-40.
- 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 2011; 15(4):R164.
- Mehndiratta MM, Hughes RA. Plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 2012; 9:CD003906.
- 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 1999; 46(6):878-86.
- Dyck PJ, Low PA, Windebank AJ et al. Plasma exchange in polyneuropathy associated with monoclonal gammopathy of undetermined significance. N Engl J Med 1991; 325(21):1482-6.
- 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.
- Kohler W, Bucka C, Klingel R et al. A randomized and controlled study comparing immunoadsorption and plasma exchange in myasthenic crisis. J Clin Apher 2011; 26(6):347-55.
- Couser WG. Rapidly progressive glomerulonephritis: classification, pathogenetic mechanisms, and therapy. Am J Kidney Dis 1988; 11(6):449-64.
- Cole E, Cattran D, Magil AAprtopeaatiicg et al. The Canadian Apheresis Study Group. Am J Kidney Dis 1992; 20(3):261-9.
- 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 2011; 57(4):566-74.
- Jayne DR, Gaskin G, Rasmussen NEVSG et al. 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.
- Montgomery RA, Zachary AA. Transplanting patients with a positive donor-specific crossmatch: a single center’s perspective. Pediatr Transpl 2004; 8(6):535.42.
- Jordan SC, Vo AA, Tyan D et al. Current approaches to treatment of antibody-mediated rejection. Pediatr Transpl 2005; 9(3):408-15.
- Lehrich RW, Rocha PN, Reinsmoen N et al. Intravenous immunoglobulin and plasmapheresis in acute humoral rejection: experience in renal allograft transplantation. Hum Immunol 2005; 66(4):350-8.
- Ibernon M, Gil-Vernet S, Carrera M et al. Therapy with plasmapheresis and intravenous immunoglobulin for acute humoral rejection in kidney transplantation. Transplant Proc 2005; 37(9):3743-5.
- Ellingsen I, Florvaag E, Andreassen AH et al. Plasmapheresis in the treatment of steroid-dependent bronchial asthma. Allergy 2001; 56(12):1202-5.
- Perlmutter SJ, Leitman SF, Garvey MA et al. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet 1999; 354(9185):1153-8.
- Garvey MA, Snider LA, Leitman SF et al. Treatment of Sydenham's chorea with intravenous immunoglobulin, plasma exchange, or prednisone. J Child Neurol 2005; 20(5):424-9.
- Cortese I, Chaudhry V, So YT et al. Evidence-based guideline update: Plasmapheresis in neurologic disorders. Neurology 2011; 76(3):294-300.
- 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. J Clin Apher 2010; 25(3):83-177.
- Centers for Medicare and Medicaid Services (CMS). National Coverage determination (NCD) for apheresis (therapeutic pheresis) (110.14). Available online at: http://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=82&ncdver=1&CoverageSelection=National&KeyWord=apheresis&KeyWordLookUp=Title&KeyWordSearchType=And&ncd_id=110.14&ncd_version=1&basket=ncd%25253A110%25252E14%25253A1%25253AApheresis+%252528Therapeutic+Pheresis%252529&bc=gAAAABAAAAAAAA%3d%3d&. Last accessed March, 2013.
|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)|
|287.30||Primary thrombocytopenia (includes idiopathic thrombocytopenic purpura)|
|289.0||Polycythemia, secondary (includes polycythymic 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|
|446.6||Thrombotic thrombocytopenia purpura|
|ICD-10-CM (Effective 10/1/14)||C88.0||Waldenstrom macroglobulinemia (includes macroglobulinemia)|
|D58.0 – D58.9||Other hereditary hemolytic anemias code range|
|D69.3||Immune thrombocytopenic purpura (includes indiopathic thrombocytopenic purpura)|
|D69.49||Other primary thrombocytopenia|
|G60.9||Hereditary and idiopathic neuropathy, unspecified|
|G61.0||Guillain-Barre syndrome (includes acute infective polyneurtis)|
|G61.81||Chronic inflammatory demyelinating polyneuritis|
|G70.00 – G70.01||Myasthenia gravis, code range|
|M31.0||Hypersensitivity angitis (includes Goodpasture’s syndrome)|
|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 10/1/14)||ICD-10-PCS codes are only used for inpatient services.|
|6A550Z3, 6A551Z3||Plasmapheresis, code single or multiple|
|Type of Service||Therapy|
|Place of Service||Outpatient
|12/01/95||Add to Therapy section||New policy|
|11/01/98||Replace policy||Policy reviewed; new indications added|
|05/15/02||Replace policy||Policy reviewed; new indications added|
|12/18/02||Replace policy||Update CPT code only|
|12/17/03||Replace policy||Policy reviewed with literature search; references added. No change in policy statement|
|03/15/05||Replace policy||Policy updated with literature search; no change in policy statement. Reference number 22 updated, and comparison between ASA recommendations and policy statement included in the Rationale section|
|04/25/06||Replace policy||Policy revised with addition of policy statements and discussion of plasmapheresis in the setting of solid organ transplantation, considered medically necessary. Reference numbers 21–29 added and reference number 31 updated. Remainder of the policy is unchanged|
|02/11/10||Replace policy||Policy reviewed with literature search from April 2006 through May 2009. Clinical input reviewed. The policy statement has been modified to include: Guillain-Barré syndrome severity grades 1-2 as medically necessary; use in the pediatric population is investigational for mild and moderate forms of GBS and medically necessary for the severe form of GBS; the policy statement has been modified to include severe manifestations of mixed cryoglobulinemia (MC) as medically necessary when used in combination with immunosuppressive therapy; typical- hemolytic uremic syndrome is investigational (considered medically necessary in previous updates) and investigational for treatment of PANDAS, Sydenham Chorea, Refsum’s disease, cryoglobulinemia (except severe MC), myasthenia gravis with anti-MuSk antibodies; additional conditions were added as investigational based on American Society for Apheresis (ASFA) review. Title changed from “Plasma Exchange (Plasmapheresis) to “Plasma Exchange.” Reference numbers 32-41 added.|
|3/10/11||Replace policy||Policy reviewed with literature search from May 2009 through January 2011. No changes to policy statements. Rationale rewritten. References 16, 24, 31 and 41 added; other references renumbered or removed.|
|5/10/12||Replace policy||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.|
|5/09/13||Replace policy||Policy reviewed with literature search through March 21, 2013. Policy statements unchanged. References 19, 23 and 40 added.|
Diagnostic Criteria for Diagnosis of Chronic Inflammatory Demyelinating Polyneuropathy (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. (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).
- Progressive or relapsing motor and sensory, rarely only motor or sensory, dysfunction of more than 1 limb or a peripheral nerve nature, developing over at least 2 months.
- Hypo- or areflexia. This will usually involve all 4 limbs.
II. Physiologic Studies
Nerve conduction studies including studies of proximal nerve segments in which the predominant process is demyelination.
Must have 3 of 4:
1. Reduction in conduction velocity (CV) in 2 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 1 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 2 or more nerves:
- >125% of upper limit of normal (LEN) is amplitude >80% of LLN
- >150% of LEN 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
Nerve biopsy showing unequivocal evidence of demyelination and remyelination.
Demyelination by either electron microscopy (>5 fibers) or teased fiber studies >12% of 50 fibers, minimum of 4 internodes each, demonstrating demyelination/remyelination.
IV. CSF Studies
- Cell count <10/mm-3 if HIV-seronegative or <50/mm-3 is HIV seropositive
- Negative VDRL
Guillain-Barré Syndrome Disability Scale
The following is the disability scale as first described by Hughes et al. in Lancet 1978; 2(8093):750-3.
- Minor symptoms or signs of neuropathy but capable of manual work
- Able to walk without support of a stick but incapable of manual work
- Able to walk with a stick, appliance or support
- Confined to bed or chair bound
- Requiring assisted ventilation
The scale has been modified since 1978 and appears below as it did in the Hughes et al. 2007 systematic review published in Brain 2007; 130(9):2245-57.
- Minor symptoms or signs of neuropathy but capable of manual work/capable of running
- Able to walk without support of a stick (5 m across an open space) but incapable of manual work/running
- Able to walk with a stick, appliance or support (5 m across an open space)
- Confined to bed or chair bound
- Requiring assisted ventilation (for any part of the day or night)