Therapeutic apheresis, including plasmapheresis/plasma exchange, involves the selective removal of abnormal cells or substances in the blood that may be associated with disease states. Therapeutic apheresis may also be used to administer treatment, such as plasma constituents present in subtherapeutic concentrations. Plasma exchange is a nonspecific therapy because the entire plasma is discarded. It is also a symptomatic therapy, because it does not remove the source of the pathologic factors. Plasma exchange has been used in a wide variety of acute and chronic conditions, as well as in the setting of solid organ transplantation.
I. Initial Review
Plasma exchange may be considered MEDICALLY NECESSARY AND APPROPRIATE for the following indications, when performed by or in consultation with a specialist:
II. Renewal Review
Plasma exchange may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:
III. Experimental/Investigative Uses
Plasma exchange is considered EXPERIMENTAL/INVESTIGATIVE for all other indications, including but not limited to the following conditions, due to the lack of clinical evidence demonstrating an impact on improved health outcomes:
No additional statements.
Summary of Evidence
Wilson disease is an inherited disorder of copper metabolism characterized by a pathological accumulation of copper. Treatment for Wilson disease is aimed at treating the release of large amounts of copper into the circulation. Plasma pheresis can be beneficial to removing significant amounts of copper (an average of 20 mg per treatment). In the case of liver transplantation, apheresis can be used to desensitize in the setting of ABO incompatible transplantation, prevent/treat biopsy-proven, rejection, and substitute for traditional immune suppression.
Rationale
Minnesota Statute 62A.3097: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) and Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) Treatment: Coverage, requires health plans to provide coverage for treatment of PANDAS and PANS. Treatments that must be covered under this section must be recommended by the insured’s licensed health care professional and include but are not limited to antibiotics, medication and behavioral therapies to manage neuropsychiatric symptoms, plasma exchange, and immunoglobulin. This mandate is effective January 1, 2020 and applies to health plans offered, sold, issued, or renewed on or after that date to Minnesota residents.
AUTOIMMUNE DISEASES
One potential type of evidence in support of the clinical effectiveness of plasma exchange in treating autoimmune diseases is the identification of a pathologic component of plasma that is reliably eliminated by plasmapheresis. Although many laboratory abnormalities are associated with autoimmune connective tissue diseases, it is unclear which, if any, cause the clinical manifestations of the disease. Furthermore, it is unknown to what extent plasma levels parallel clinical disease. For example, in many of the controlled trials discussed next, plasma exchange 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 controlled trials (RCTs) of plasma exchange have been conducted and, in general, have shown a lack of effectiveness as treatment of chronic autoimmune diseases. Clinical results of RCTs and systematic reviews of plasmapheresis for specific chronic autoimmune diseases are discussed here.
Systemic Lupus Erythematosus (SLE)
A systematic review by Kronbichler et al. (2016) reported that the interpretation of studies evaluating plasma exchange for treating systemic lupus erythematosus (SLE) is limited due to factors such as the available study designs, small numbers of patients, and variability in plasma exchange dosing and protocols. Reviewers did not identify any recent controlled trials evaluating the impact of plasma exchange on health outcomes in patients with SLE.
Reporting on the results of an RCT, Lewis et al. (1992) concluded that plasma exchange had no benefit in patients with SLE and glomerulonephritis compared with a 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 hypothesized that the acute lowering of pathogenic autoantibodies with plasmapheresis might result in their rebound production and that the pathogenic lymphocytes would be more sensitive to cyclophosphamide at this point. Danieli et al. (2002) reported on a prospective case series of 28 patients with proliferative lupus nephritis; 12 underwent synchronized plasmapheresis and pulse cyclophosphamide therapy, while the remaining 16 underwent cyclophosphamide alone. Although plasmapheresis was associated with a decreased time to remission of renal disease, at the end of the 4-year follow-up, there was no difference in outcomes.
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. 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 plasma exchange. However, there are minimal data in the published literature and no controlled trials. The largest case series assessing LEMS was reported by Tim et al. (2000) and included 73 patients with LEMS, 31 of whom were found to have lung cancer. (6) Although detailed treatment strategies were not provided, 19 underwent plasmapheresis, with 27% reporting a moderate to marked response. However, the improvement after plasmapheresis was only transient, even when marked. Patients also received other therapies (e.g., various chemotherapy regimens for the underlying lung cancer). In addition, 53 (73%) of the 73 patients received 3,4-diaminopyridine, with 79% reporting marked or moderate responses. In the same year, a small RCT of 3,4-diaminopyridine also reported positive results, confirming other anecdotal reports. Anderson et al. (1988) reported on a case series of 12 patients with paraneoplastic cerebellar degeneration. Although plasmapheresis was associated with an acute drop in the autoantibody titer, only 2 (17%) patients showed a minor improvement in neurologic symptoms.
Rheumatoid Arthritis
Dwosh et al. (1983) reported on 26 patients with chronic rheumatoid arthritis randomized in a crossover design to true or sham plasma exchange. The authors concluded that plasma exchange had no clinical benefit, despite impressive laboratory changes.
Polymyositis and Dermatomyositis
Miller et al. (1992) conducted a randomized trial of plasma exchange in the treatment of 39 patients with polymyositis and dermatomyositis and found that plasma exchange 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 high doses of steroids can produce significant adverse effects. Guillaume et al. (1988) reported on a study of 40 patients with pemphigus randomized to prednisone alone or prednisone plus plasmapheresis. This trial sought to determine whether plasmapheresis can reduce the required dose of steroids, thus limiting its toxicity. Unfortunately, disease control in the 2 groups was the same, and the authors concluded that plasmapheresis in conjunction with low-dose steroids was ineffective in treating pemphigus.
Stiff Person Syndrome (SPS)
Stiff person syndrome (SPS) is an autoimmune disorder characterized by involuntary stiffness of axial muscles and intermittent painful muscle spasm. SPS may be idiopathic in nature or seen in association with thymoma, Hodgkin disease, as well as small-cell lung, colon, or breast cancer. The mainstay of treatment of SPS is diazepam. The published literature on plasmapheresis consists of small case series and anecdotal reports. Most of these studies were published in the late 1980s or early 1990s. A small case series of 9 patients was published in 2014, and a smaller case report of 2 patients was published in 2016.
Cryoglobulinemia
There are several types of cryoglobulinemia. Type I is associated with hematologic disorders. Types II and III are considered mixed cryoglobulinemias. Mixed cryoglobulinemia is a consequence of immune-complex mediated vasculitis and may be associated with infectious and systemic disorders (e.g., hepatitis C virus). In 2010, Rockx and Clark published a review of studies evaluating plasma exchange for treating cryoglobulinemia that included at least 5 patients. They identified 11 studies (total N=156 patients). Reviewers concluded: “The quality and variability of the evidence precludes a meta-analysis or even a systematic analysis. However, these studies weakly support the use of plasma exchange largely on a mechanistic basis.”
HEMATOLOGIC CONDITIONS
Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS)
Once considered distinct syndromes, thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are now considered different manifestations of the same disease process (i.e., thrombotic microangiopathy). In 2009, a systematic review evaluated the benefits and harms of different interventions for HUS and TTP separately. Interventions were compared with placebo or supportive therapy, or a comparison of 2 or more interventions. Interventions examined included heparin, aspirin/dipyridamole, prostanoids, ticlopidine, vincristine, fresh frozen plasma (FFP) infusion, plasmapheresis with FFP, systemic corticosteroids, Shiga toxin-binding agents, or immunosuppressive agents. For TTP, 6 RCTs (n=331 patients) were identified evaluating plasma exchange with FFP as the control. Interventions tested included antiplatelet therapy plus plasma exchange with FFP, FFP transfusion, and plasma exchange with cryosupernatant plasma. Two studies compared plasma infusion with plasma exchange plus FFP and showed a significant increase in failure of remission at 2 weeks (relative risk [RR], 1.48) and all-cause mortality (RR=1.91) in the plasma infusion group. Reviewers concluded that plasma exchange plus FFP is the most effective treatment available for TTP. Seven RCTs included children with HUS. None of the assessed interventions were superior to supportive therapy alone for all-cause mortality, neurologic/extrarenal events, renal biopsy changes, proteinuria, or hypertension at the last follow-up visit. The incidence of bleeding was significantly greater in those receiving anticoagulation therapy compared with supportive therapy alone (risk difference, 0.35). For patients with HUS, supportive therapy including dialysis was the most effective treatment. No RCTs evaluated the effectiveness of any interventions on patients with atypical HUS who have a more chronic and relapsing course. A 2009 review article by Noris and Remuzzi described data supporting use of plasma exchange in the atypical form of this disease, with results showing remission in up to 60% of patients.
HELLP Syndrome of Pregnancy
The HELLP syndrome of pregnancy (characterized by hemolysis, elevated liver enzymes, and low platelet counts) is a severe form of preeclampsia. The principal form of treatment is the delivery of the fetus. However, for patients with severe thrombocytopenia, plasma exchange may be indicated if the fetus cannot safely be delivered, or if the maternal thrombocytopenia persists into the postnatal period.
Myeloma With Acute Renal Failure
Yu et al. (2015) published a meta-analysis of RCTs on the treatment of acute renal failure associated with multiple myeloma using chemotherapy alone versus chemotherapy and plasma exchange. Four RCTs were identified; 3 had full text availability and were included in the data synthesis. None of the RCTs were double-blinded. The trials included 63 patients receiving chemotherapy only and 84 patients receiving chemotherapy and plasma exchange. A variety of chemotherapy agents and plasma exchange protocols were used. In a pooled analysis, there was no statistically significant difference in 6-month survival outcomes between the 2 groups (RR=0.92; 95% confidence interval [CI], 0.76 to 1.11; p=0.39). However, the dialysis dependent rate among survivors at 6 months was significantly lower in the chemotherapy plus plasma exchange group than in the group receiving chemotherapy alone (RR=2.02; 95% CI, 1.03 to 3.96; p=0.04).
Idiopathic Thrombocytopenic Purpura (ITP)
Idiopathic thrombocytopenic purpura (ITP) is an acquired disease of adults or children characterized by the development of autoantibodies to platelets. Management of acute bleeding due to thrombocytopenia typically involves immediate platelet transfusion, occasionally in conjunction with a single infusion of IVIG. Plasma exchange has been occasionally used in emergency situations.
NEUROLOGIC CONDITIONS
Guillain-Barré Syndrome
Guillain-Barré syndrome (GBS) is an acute demyelinating neuropathy whose severity is graded on a scale of 1 to 5. In 2017, The Cochrane Collaboration published an updated systematic review of the evidence concerning the efficacy of plasma exchange for treating GBS. Reviewers included RCTs evaluating plasma exchange alone in children and/or adults with disease of any severity. Eight eligible trials were identified. The primary outcome measure of the review was the time to recover walking with aid. However, reviewers noted that the outcome change in disability grade was the primary endpoint of many of the trials and this was included as a secondary outcome of the Cochrane review. Not enough trials reported the primary outcome of interest. However, 3 trials reported the proportion of patients who recovered walking with assistance after 4 weeks; in a pooled analysis, a significantly greater proportion of patients recovered after plasma exchange than after the control intervention (RR=1.60; 95% CI, 119 to 2.15; I2=34%). In a pooled analysis of 5 trials comparing improvement in walking by at least 1 grade after 4 weeks (a secondary outcome), plasma exchange was significantly more effective than sham or supportive treatment (RR=1.64; 95% CI, 1.37 to 1.96; I2=0%). There were also significantly fewer patients on a ventilator at 4 weeks with plasma exchange versus control (RR=0.53; 95% CI, 0.39 to 0.74; I2=43%).
A 2011 RCT evaluated plasma exchange for treating young children with severe GBS. The trial included 41 children with GBS who required mechanical ventilation and had muscle weakness for no more than 14 days. Patients were randomized to plasma exchange (n=21) or IVIG (n=20). The mean (standard deviation [SD]) patient age was 96 months in the plasma exchange group and 106 months in the IVIG group. The mean duration of ventilation (the primary outcome) was 11 (1.5) days in the plasma exchange group and 13 (2.1) days in the IVIG group (p=0.037). Duration of stay in the intensive care unit (a secondary outcome) was 15.0 (2.6) days in the plasma exchange group and 16.5 (2.1) days in the IVIG group (p=0.94).
Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)
A 2015 Cochrane review by Mehnidiratta et al. identified 2 randomized trials on plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Both trials were considered high quality but had small sample sizes. One trial with 29 patients used a parallel design and compared plasma exchange with sham treatment. The other study included 18 patients and used a crossover design to compare plasma exchange with sham treatment. A pooled analysis of trial data found a statistically significantly greater reduction in impairment after 4 weeks with plasma exchange versus sham (mean difference in Neuropathy Impairment Score, 31 points; 95% CI, 16 to 45 points). This scale ranges from 0 (normative) to 280 (maximally affected). Data on other outcomes were not suitable for pooled analysis.
Multiple Sclerosis
Several RCTs of plasma exchange in patients with multiple sclerosis (MS) have reported inconclusive results. Khatri et al. (1985) studied 54 patients with chronic progressive MS randomized to sham or true plasma exchange. The degree of improvement in the plasma exchange group was greater than that in the control group. Weiner et al. (1989) reported on a study that randomized patients with acute MS to plasma exchange or sham treatments. There was no statistical difference in improvement rates between groups, although patients receiving plasma exchange did have a faster recovery rate from acute attacks. A 1991 Canadian trial randomized 168 patients with progressive MS to plasma exchange or immunosuppressive therapy. (26) There were no significant differences in the rates of treatment failures between groups.
Acute Fulminant Central Nervous System Demyelination
Plasmapheresis may be considered medically necessary in patients with acute fulminant central nervous system (CNS) demyelination; this conclusion is based on the results of a 1999 randomized, double-blinded trial, in which 22 patients with MS or other acute idiopathic inflammatory demyelinating diseases of the CNS were enrolled a minimum of 14 days after having failed to respond to at least 5 days of high-dose corticosteroids. Patients were randomized to 7 real or sham plasma exchange procedures over a 14-day period. The primary outcome was a targeted neurologic deficit (i.e., aphasia, cognitive dysfunction). Overall, moderate to marked improvement of the targeted outcome was obtained in 42% of the treatment group compared with only 6% in the placebo group.
Myasthenia Gravis
Several RCTs have evaluated use of plasma exchange in the treatment of myasthenia gravis. A 2011 trial from Germany included patients with myasthenic crisis. Patients were randomized to treatment with plasma exchange (n=10) or immunoadsorption (IA; n=9). In both groups, 3 apheresis treatments were performed within 7 days; patients could have additional treatments if needed. A total of 16 (84%) of 19 of patients, 8 in each group, completed the study and were included in the efficacy analysis. The mean number of treatments was 3.5 in the plasma exchange 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 plasma exchange group and 2.5 in the IA group. At day 14, score improvement was 1.6 points in the plasma exchange group and 1.4 points in the IA group (p>0.05). Within 180 days after treatment, 1 patient in the plasma exchange 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.
A 2017 RCT by Alipour-Faz et al. randomized 24 adults with myasthenia gravis to presurgical treatment with plasma exchange (n=12) or IVIG (n=12). Treatments were given 10 to 30 days before thymectomy. All patients completed the trial. Study outcomes were duration of hospitalization, length of postsurgical intensive care unit stay, duration of intubation, duration of surgery, and dose of steroids. Most outcomes were similar in the 2 groups. One outcome, length of intubation period, differed significantly between groups. The median length of intubation was 0 hours in the IVIG group and 13 hours in the plasma exchange group (p=0.01).
Paraproteinemic Polyneuropathies
A 1991 randomized, double-blinded trial compared plasma exchange with sham treatment in 39 patients who had monoclonal gammopathy of undetermined significance‒associated polyneuropathy. After twice weekly plasma exchange for 3 weeks, the treatment group reported improvements in neurologic function in the immunoglobulin (Ig) G and IgA groups but not the IgM monoclonal gammopathy of undetermined significance groups. Those from the sham group who later crossed over to the plasma exchange group also reported improvement.
Neuromyelitis Optica (NMO)
Neuromyelitis optica (NMO) is a rare inflammatory disorder of the CNS that predominantly affects the optic nerves and spinal cord. No RCTs evaluating plasma exchange for treatment of patients with NMO were identified. Several retrospective nonrandomized studies have evaluated plasma exchange as add-on therapy to intravenous (IV) corticosteroids.
In 2016, Abboud et al. reviewed 83 admissions for acute relapse of NMO at a single center in the United States. Relapses could involve the spinal cord, optic nerve, and/or the brain. Patients were initially treated with IV corticosteroids alone for 5 days and, if they did not respond, they were then treated with 5 to 7 sessions of plasma exchange in their second week of hospitalization. Eighteen relapses (16 patients) were treated with IV corticosteroid therapy alone, and 65 relapses (43 patients) were treated with IV corticosteroid plus plasma exchange. Patients were assessed using the Expanded Disability Status Score (EDSS), which has a range of 1 to 10, with higher numbers indicating more disability. The primary endpoint was a return to baseline EDSS (before admission) on discharge. In the relapses treated with IV corticosteroids only, the median baseline EDSS was 2.5, which increased to 4.5 at presentation and decreased to a median of 4 at discharge. In comparison, among the relapses also treated with plasma exchange, the median baseline EDSS was 5.75, which increased to 7.75 at presentation and decreased to a median of 6.5 at discharge. At discharge, 3 relapses (17%) in the IV corticosteroid-only group improved to baseline EDSS or lower at discharge, compared with 31 (51%) relapses in the IV corticosteroid plus plasma exchange group (p=0.016). Follow-up data at approximately 1 year (range, 6-18 months) were available on 50 (77%) of 65 relapses. At this longer-term follow-up point, 6 (35%) relapses in the intravenous methylprednisolone (IVMP) only group and 33 (65%) in the IVMP plus plasma exchange group improved to an EDSS equal or below their baseline EDSS (p=0.039).
Two other studies were conducted at a facility in Martinique, and both compared outcomes in patients treated before and after plasma exchange was introduced as a treatment. A 2009 study by Bonnan et al. focused on spinal attacks associated with NMO. The study reported on 43 patients with NMO, 18 of whom received plasma exchange as add-on therapy for at least 1 spinal attack. The study period was 1982 to 2008; plasma exchange was introduced at the facility in 1999. The patients experienced a total of 96 spinal attacks; plasma exchange was used in 29 attacks. The plasma exchange-treated and corticosteroid-only groups had similar EDSS scores before the spinal attacks, and there was a greater reduction in EDSSs following treatment with plasma exchange. In the plasma exchange group, the mean acute EDSS (SD) was 7.9 (1.3), and the mean EDSS after therapy was 5.1 (2.4), for a mean decrease of 2.8 points. In comparison, the mean acute EDSS in the corticosteroid-only group was 8.0 (1.4), and the mean EDSS after treatment was 6.8 (1.9), for a mean decrease of 1.2 points. The analysis was done on a per-attack basis rather than a per-patient basis.
The 2012 study by Merle et al. evaluated the impact of plasma exchange as an add-on therapy on optic outcomes in 32 patients treated for acute optic neuritis between 1996 and 2010. In 2006, plasma exchange was added to the treatment protocol, and 16 of the 32 patients also received 5 daily consecutive plasma exchanges in the intensive care unit. Study outcomes were obtained from an eye examination performed at least 6 months after optic neuritis treatment. At the final follow-up visit, visual acuity was significantly better in the plasma exchange group than in the corticosteroid-only group (20/400 vs 20/50, respectively, p=0.04). Visual acuity gain was 20/200 in the corticosteroid group and 20/30 in the plasma exchange group (p=0.01).
N-methyl-D-aspartate (NMDA) Receptor Antibody Encephalitis
A 2017 review by the ASFA stated that, if left untreated, N-methyl-D-aspartate (NMDA) receptor antibody encephalitis can lead to decline in the autonomic function and, ultimately, to death. (34) The review indicated that approximately 50% of patients respond to one of several first-line immunotherapies, which includes plasma exchange. There is little published evidence. A 2015 retrospective evaluation of 14 patients with NMDA receptor antibody encephalitis found improvement in the modified Rankin Scale score in 7 of 10 patients treated with plasma exchange, compared with 3 of 10 patients treated with corticosteroids. (35)
Progressive Multifocal Leukoencephalopathy (PML) Associated With Natalizumab
As noted in the 2017 ASFA review, progressive multifocal leukoencephalopathy (PML) is a potentially fatal side effect of natalizumab, a treatment option for relapsing MS. If PML is suspected, natalizumab should be stopped immediately. Also, plasma exchange, which was shown in a small 2009 study of 12 patients to reduce serum natalizumab concentration by 92% in a week, can be used to quickly remove natalizumab from the bloodstream and reduce the consequences of PML.
Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections (PANDAS) and Sydenham Chorea
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is defined as rapid, episodic onset of obsessive-compulsive disorder (OCD) and/or tic disorder symptoms after a group A beta-hemolytic streptococcal infection (GABHS). Sydenham chorea is the neurologic manifestation of acute rheumatic fever. The choreatic symptoms of Sydenham chorea are characterized by involuntary rapid and jerky movements that affect the extremities, trunk, and face. Sydenham chorea is a self-limited disorder with symptoms resolving in weeks to months. Perlmutter et al. (1999) conducted an RCT to evaluate the effectiveness of plasma exchange 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 obsessive-compulsive disorder and tics were randomized to plasma exchange (n=10; 5-6 procedures over 2 weeks), IVIG (n=10; 2 g/kg over 2 days), or placebo (n=10; mimic IVIG). All were severely ill at the time of treatment. Investigators were not blinded with regard to treatment. Results of this study showed that at 1 month, patients treated with plasma exchange had improvement in OCD symptoms (58%, p<0.006), anxiety (47%, p<0.001), overall functioning (35%, p<0.0009), and tics (49%, p<0.005) compared to placebo, and these gains were maintained at 1 year post-treatment.
Garvey et al. (2005) conducted an RCT designed to determine whether IVIG or plasma exchange was superior to prednisone in decreasing the severity of chorea. Children with Sydenham chorea (N=18) were randomized to treatment with plasma exchange (n= 8; 5-6 procedures over 1-2 weeks), IVIG (n=4; 2 g/kg over 2 days), or prednisone (n=6; 1 mg/kg/d for 10 days followed by taper over next 10 days). The primary outcome was chorea severity at 1 month. The secondary outcome variable was chorea severity at 1 year after treatment. There was no significant difference between the baseline chorea severity scores by treatment group. Chorea severity was assessed at baseline and at 1, 2, 3, 6, and 12 months after treatment. The Chorea Rating Scale scores range from 0 (no chorea) to 18 (severe or paralytic chorea). A score of 9 or higher was required for study entry. Baseline medications to control choreatic symptoms were discontinued 1 week before baseline assessment and each follow-up evaluation. The mean chorea severity for the entire group was lower at the 1-month follow-up evaluation (overall 48% improvement). Between-group differences were not statistically significant. Larger studies are needed to confirm these clinical observations.
Alzheimer's Disease
Boada et al (2020) published the results of randomized, controlled clinical trial of plasma exchange with albumin replacement for Alzheimer’s disease (AMBAR study). In this study, 347 patients (of 496 screened) were randomized into 3 plasma exchange (PE) treatment arms with different doses of albumin and IV immunoglobulin replacement (a 6-week period of weekly conventional PE followed by a 12-month period of monthly low-volume PE), and placebo (sham). Results indicated that PE-treated patients performed significantly better than placebo for endpoints: change from baseline of Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL; P = .03; 52% less decline) with a trend for Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog; P = .06; 66% less decline) scores at month 14. Moderate-AD patients (baseline Mini-Mental State Examination [MMSE] 18-21) scored better on ADCS-ADL (P = .002) and ADAS-Cog (P = .05), 61% less decline both. There were no changes in mild-AD patients (MMSE 22-26). PE-treated patients scored better on the Clinical Dementia Rating Sum of Boxes (CDR-sb) (P = .002; 71% less decline) and Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) (P < .0001; 100% less decline) scales. Investigators concluded that while this trial suggests that plasma exchange with albumin replacement could slow cognitive and functional decline, further studies are warranted.
Cuberas-Borros et al published further results from the AMBAR study (2021) with the MRI analysis of neuroimaging of 198 patients. Selected subcortical structures showed fewer volume changes from baseline to final visit in the high albumin + IVIG treatment group (p < 0.05 in 3 structures vs. 4 to 9 in other groups). The high albumin + IVIG group showed no statistically significant reduction of right hippocampus. In 213 patients, SPM 18FDG-PET analyses showed worsening of metabolic activity in the specific areas affected in AD (posterior cingulate, precuneus, and parieto-temporal regions). The high-albumin + IVIG treatment group showed the greatest metabolic stability over the course of the study, i.e., the smallest percent decline in metabolism (MaskAD), and least progression of defect compared to placebo. Conclusion was that plasma exchange with albumin replacement was associated with fewer deleterious changes compared to typical progression of Alzheimer's disease.
RENAL DISEASES
Rapidly Progressive Glomerulonephritis
Rapidly progressive glomerulonephritis (RPGN) is a general term describing the rapid loss of renal function in conjunction with the finding of glomerular crescents on renal biopsy specimens. There are multiple etiologies of RPGN including vasculitis, the deposition of antiglomerular basement membrane antibodies, as seen in Goodpasture syndrome, or the deposition of immune complexes, as seen in various infectious diseases or connective tissue diseases. Plasma exchange has long been considered a treatment alternative in immune-mediated RPGN. However, few controlled clinical trials have been published, and their interpretation is difficult due to the small number of patients, choice of intermediate outcomes (i.e., the reduction in antibody levels as opposed to more direct patient outcomes), and heterogeneity in patient groups. (39) Aside from cases of Goodpasture disease, the rationale for plasma exchange in idiopathic RPGN is not strong, because of the lack of an identifiable immune component. Studies of plasma exchange in this population have not demonstrated a significant improvement in outcome compared with the use of pulse steroid therapy.
Antineutrophil Cytoplasmic Antibody (ANCA)‒Associated Vasculitis
In 2011, Walsh et al. published a meta-analysis of studies on plasma exchange in adults diagnosed with idiopathic renal vasculitis or RPGN. A total of 9 trials including 387 patients were identified. Clinical populations in the studies were somewhat ill-defined, but most patients appeared to have antineutrophil cytoplasmic antibody (ANCA)‒associated vasculitis. In a pooled analysis, the risk of end-stage renal disease was significantly lower in patients treated with adjunctive plasma exchange compared with standard care alone (RR=0.64; 95% CI, 0.47 to 0.88). The risk of death did not differ statistically between the 2 groups (RR=1.01; 95% CI, 0.71 to 1.40).
In 2007, Jayne et al. published a relatively large RCT, (42) included in the previously mentioned meta-analysis. This multicenter RCT was conducted on behalf of the European Vasculitis Study Group. The trial investigated whether the addition of plasma exchange was more effective than the addition of IVMP. Patients (N=137) with a new diagnosis of ANCA-associated systemic vasculitis confirmed by renal biopsy and serum creatinine greater than 5.8 mg/dL were randomized to 7 plasma exchanges (n=70) or 3000 mg of IVMP (n=67). Both groups received oral cyclophosphamide and oral prednisolone. The primary endpoint was dialysis independence at 3 months. Secondary end points included renal and patient survival at 1 year and severe adverse event rates. At 3 months, 33 (49%) of 67 were alive and independent of dialysis after IVMP, compared with 48 (69%) of 70 after plasma exchange. Compared with IVMP, plasma exchange was associated with a reduction in risk for progression to end-stage renal disease (24% at 12 months). At 1 year, patient survival was 51 (76%) of 67 in the IVMP group and 51 (73%) of 70 in the plasma exchange group, and severe adverse events occurred in 48% of the IVMP group and 50% of the plasma exchange group. Compared with IVMP, plasma exchange increased the rate of renal recovery in patients with ANCA-associated systemic vasculitis who presented with renal failure. Patient survival and severe adverse event rates were similar in both groups. Long-term outcomes of patients in this trial were published in 2013. (43) The median follow-up was 3.95 years. A total of 70 of 136 patients had died, 35 (51%) in the plasma exchange group and 35 (51%) in the IVMP group (p=0.75). Similarly, the difference between groups in the proportion of patients with end-stage renal disease (33% in the plasma exchange group vs 49% in the IVMP group, p=0.08) was not statistically significant. According to trial results, plasma exchange appears to have a short-term benefit on preserving renal function in this population, but long-term efficacy remains uncertain.
TRANSPLANTATION
Solid Organ Transplant
Plasmapheresis has been extensively used in solid organ transplantation, both as pretransplant prophylaxis (i.e., desensitization) for highly sensitized patients at high risk of antibody-mediated rejection (AMR), and as a treatment of AMR after transplant. Desensitization protocols vary among transplant centers; two commonly used protocols are referred to as the Cedars-Sinai protocol and the Johns Hopkins protocol. The Cedars-Sinai protocol consists of high-dose IVIG (2 g/kg) and is offered to patients awaiting either a deceased or live donor. The Johns Hopkins protocol consists of low-dose IVIG (100 mg/kg) in combination with plasmapheresis with or without treatment with anti-CD20 (i.e., rituximab). Plasmapheresis is more commonly used in patients receiving a living kidney transplant from an ABO mismatched donor. A variety of protocols have also been developed for the treatment of AMR, often in combination with other therapies, such as IVIG or anti-CD20. Most studies of plasmapheresis in the transplant setting are retrospective case series from single institutions. Therefore, it is not possible to compare immunomodulatory regimens to determine their relative efficacy. Nevertheless, in part based on the large volume of literature published on this subject, it appears that plasmapheresis is a component of the standard of care for the management of AMR.
The American Society for Apheresis states in its guideline that there are no controlled clinical trials using TPE in ABO incompatible (ABOi) liver transplantation. () However, given the significant risks of hyperacute/ acute antibody mediated rejection (AMR), TPE is used as a key therapeutic modality to reduce anti-A or anti-B isoagglutinin titers in the peri-transplant period. In ABOi deceased donor liver transplant (DDLT), TPE procedures are often utilized in the urgent/emergent setting after a deceased ABOi allograft has been identified, making a thorough analysis of TPE efficacy challenging.
GENETIC DISORDERS
Wilson Disease
The American Society for Apheresis has included Wilson disease in category I for therapeutic apheresis, disorders for which apheresis is accepted as first-line therapy, either as a primary stand-alone treatment or in conjunction with other modes of treatment, with a recommendation grade of 1C, strong recommendation, low-quality of very low-quality evidence. Pham et al (2016), reported on the American Society for Apheresis registry study on Wilson’s disease; specifically, the use of therapeutic plasma exchange for the removal of copper for a bridge to liver transplantation. () The multi-center registry involves both prospective and retrospective data. A total of 10 patients (3 males and 7 females) with Wilson's disease treated between 2005 and 2013 were included. All patients were in acute liver failure at admission. Median age of first diagnosis and first TPE were 16 and 17 years, respectively. Via central venous access, these patients underwent a total of 43 TPEs; the median number of TPE procedures per patient was 3.5. All of the TPEs used ACD-A as anticoagulation, 42/43 TPEs targeted 1–1.25 plasma volumes, and 41/43 TPEs were performed with 100% fluid balance. Post TPE procedures, 9 patients underwent liver transplantation; all 10 patients had at least a 6-month survival.
Pham et al (2016), reported on the American Society for Apheresis registry study on Wilson’s disease; specifically the use of therapeutic plasma exchange for the removal of copper for a bridge to liver transplantation. The multi-center registry involves both prospective and retrospective data. A total of 10 patients (3 males and 7 females) with Wilson's disease treated between 2005 and 2013 were included. All patients were in acute liver failure at admission. Median age of first diagnosis and first TPE were 16 and 17 years, respectively. Via central venous access, these patients underwent a total of 43 TPEs; the median number of TPE procedures per patient was 3.5. All of the TPEs used ACD-A as anticoagulation, 42/43 TPEs targeted 1–1.25 plasma volumes, and 41/43 TPEs were performed with 100% fluid balance. Post TPE procedures, 9 patients underwent liver transplantation; all 10 patients had at least a 6-month survival.
Pawaria et al (2021), reported on the results of high volume plasma exchange (HVPE) in Wilson disease presenting as acute liver failure. Of 43 cases of Wilson disease with acute liver failure, 37 were enrolled. Patients were divided into 2 groups: high volume plasma exchange (HVPE) group - who received HVPE + standard medical therapy (SMT), and SMT group- received only SMT. Outcome measure was transplant free survival (TFS) at 90 days post enrollment, change in biochemical, hemodynamic parameters & incidence of organ dysfunction in HVPE as compared to SMT group, and HVPE related complications. Findings included significantly improved biochemical parameters and prognostic indices, with the exception of blood ammonia and serum creatinine, 72 to 96 hours after enrollment in the HVPE group. Overall, TFS at 90 days was present in 9/19 (47.3%) in HVPE group vs 3/18 (16.6%) in the SMT group (OR 2.84, 95% CI 0.91-8.8, P = .049). Kaplan Meier survival analysis revealed that HVPE group had significantly higher cumulative survival as per the Log Rank test (P = .027); median days of survival was 38 days (IQR 12-63) in HVPE group vs 14 (IQR 5-22) days in SMT group. Investigators concluded that HPVE acts not only as bridging therapy to liver transplant, but may also improve proportion of cases with transplant free survival.
MISCELLANEOUS POTENTIAL APPLICATIONS
Acute Liver Failure
One controlled study, an unblinded RCT published in 2016 by Larsen, evaluated high-volume plasma exchange in patients with acute liver failure. Patients with a diagnosis of acute liver failure and at least grade 2 encephalopathy were randomized to standard care only (n=90) or standard care plus high-volume plasma exchange (n=92). Entry into the study occurred within 24 hours of grade 2 encephalopathy onset. The high-volume plasma exchange procedure consisted of exchanging 15% of ideal body weight (8-12 liters per day per procedure). Patients’ plasma was removed at the rate of 1 to 2 liters per hour and was replaced with an equivalent amount of fresh frozen plasma. Patients underwent plasma exchange on 3 consecutive days. The primary endpoint was transplant-free survival at the time of hospital discharge. The mean length of hospital stay was 21.9 days in the PE group and 41.8 days in the standard care group. The number of patients surviving to hospital discharge was 54 (58%) in the plasma exchange group and 43 (48%) in the group receiving standard care only; the difference between groups was statistically significant. Survival of patients who had a liver transplant (24 [26%] in the plasma exchange group versus 32 [36%] in the standard care group) was not significantly impacted by the addition of plasma exchange. However, the rate of survival to hospital discharge was significantly higher with plasma exchange in the subset of patients who were not listed for transplantation due to contraindications such as medical comorbidities (28 [30%] in the plasma exchange group versus 36 [40%] in the standard care group, p=0.03). Limitations of the study included its lack of blinding and measurement of the survival outcome only at hospital discharge, a period of several weeks, and longer term outcomes were not reported. Also, the plasma exchange protocol and transplantation criteria in Denmark, where the study was conducted, may differ from those in the United States.
Asthma
Some researchers have assessed the use of plasmapheresis in patients with severe, steroid-dependent asthma. However, 1 small crossover trial (N=4), published in 2001, did not suggest treatment effectiveness. No subsequent controlled studies have been published.
Sepsis
In 2014, Rimmer et al. published a systematic review and meta-analysis of the literature on plasma exchange for treatment of sepsis and septic shock. Reviewers identified 4 RCTs comparing plasma exchange with usual care (total N=194 patients). All trials were rated as unclear or high risk of bias. In a pooled analysis of data from the 4 trials, plasma exchange was not significantly associated with a reduction in mortality risk (RR=0.83; 95% CI, 0.45 to 1.52). Data were insufficient for pooled analyses of other outcomes. The evidence identified in this systematic review was insufficient for drawing conclusions about the impact of plasma exchange for treating sepsis on the net health outcome.
Practice Guidelines and Position Statements
American Society for Apheresis
In 2023, the American Society for Apheresis published updated guidelines on the use of therapeutic apheresis in clinical practice. The Special Issue Writing Committee “is charged with reviewing, updating, and categorizing indication for the evidence-based use of therapeutic apheresis in human disease.” Recommendations are based upon systematic review and evidence-based approaches in the grading of evidence (I – IV) and categorization (1A – 2C) of indications. Liver transplantation (desensitization, living donor) and Wilson disease are given an evidence grade of I (Disorders for which apheresis is accepted as first-line therapy, either as a primary standalone treatment or in conjunction with other modes of Treatment) and a category of IC (Strong recommendation, low-quality or very low-quality evidence).
Table 1. ASFA Category Definitions for Therapeutic Apheresis
Category |
Description |
I |
Disorders for which apheresis is accepted as first-line therapy, either as a primary stand-alone treatment or in conjunction with other modes of treatment. |
II |
Disorders for which apheresis is accepted as second-line therapy, either as a stand-alone treatment or in conjunction with other modes of treatment. |
III |
Optimum role of apheresis therapy is not established. Decision making should be individualized. |
IV |
Disorders in which published evidence demonstrates or suggests apheresis to be ineffective or harmful. IRB/Ethics Committee approval is desirable if apheresis treatment is undertaken in these circumstances. |
Table 2. ASFA Grading Recommendations for Therapeutic Apheresis
Recommendation |
Description |
Methodological quality of supporting evidence |
Implications |
Grade 1A |
Strong recommendation, high-quality evidence |
RCTs without important limitations or overwhelming evidence from observational studies |
Strong recommendation, can apply to most patients in most circumstances without reservation |
Grade 1B |
Strong recommendation, moderate quality evidence |
RCTs with important limitations (inconsistent results, methodological flaws, indirect, or imprecise) or exceptionally strong evidence from observational studies |
Strong recommendation, can apply to most patients in most circumstances without reservation |
Grade 1C |
Strong recommendation, low-quality or very low-quality evidence |
Observational studies or case series |
Strong recommendation but may change when higher quality evidence becomes available |
Grade 2A |
Weak recommendation, high-quality evidence |
RCTs without important limitations or overwhelming evidence from observational studies |
Weak recommendation, best action may differ depending on circumstances or patients’ or societal values |
Grade 2B |
Weak recommendation, moderate-quality evidence |
RCTs with important limitations (inconsistent results, methodological flaws, indirect, or imprecise) or exceptionally strong evidence from observational studies |
Weak recommendation, best action may differ depending on circumstances or patients’ or societal values |
Grade 2C |
Weak recommendation, low-quality or very low-quality evidence |
Observational studies or case series |
Very weak recommendations; other alternatives may be equally reasonable |
National Comprehensive Cancer Network (NCCN)
In National Comprehensive Cancer Network (NCCN) clinical practice guidelines on multiple myeloma (v.4.2024), plasmapheresis should be used as adjunctive therapy for symptomatic hyperviscosity.
American Academy of Neurology
In 2016, the AAN endorsed an international consensus guidance for management of myasthenia gravis. In this guidance, plasma exchange is recommended as short-term treatment in patients with myasthenia gravis with life-threatening signs such as respiratory insufficiency or dysphagia; in preparation for surgery in patients with significant bulbar dysfunctions; when a rapid response to treatment is needed; when other treatments are insufficiently effective; and prior to beginning corticosteroids if deemed necessary to prevent or minimize exacerbations. Plasma exchange is identified as a mainstay of management in myasthenic crisis.
Reference List
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Acknowledgements:
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