Trends in Therapeutic Plasma Exchange: A Single-Center Evaluation

Abstract

Purpose

The quality of evidence supporting the use of therapeutic plasma exchange (TPE) in the treatment of individual diseases and disorders is often limited. Since we have experienced a growing variety of indications in our center we decided to make an inventory of our TPE population.

Methods

Single-center retrospective inventory of adult TPE-patients during a 7-year period to determine the evolution of indications for TPE, the response to treatment, and the existing evidence supporting TPE in specified settings.

Results

During a period of 84 months, 72 patients underwent 638 sessions of TPE in 91 episodes. There was no shift in frequency of TPE or level of indication. Our population consisted of 69 patients. A level I indication was seen in 41 patients (59.4%), while 14 (20.3%) had a level II indication, 8 (11.6%) had a level III indication, one had a level IV indication (1.4%) and 5 patients suffered from a condition not mentioned in the guidelines (7.2%). The response rate was inversely correlated with the level of evidence after exclusion of these 5 patients (category I 97.6%, category II 71.4%, category III 50%, category IV 0% response, p<0.01).

Conclusions

There was no shift in frequency of TPE or level of indication in our center. Controversial indications should be carefully evaluated on an individual basis and a trial of TPE cannot be solely ruled out because of lack of evidence.

Keywords

Plasma exchange Therapeutic use Plasmapheresis Epidemiology Indications Autoimmune diseases

Introduction

The quality of evidence supporting the use of therapeutic plasma exchange (TPE) in the treatment of individual diseases and disorders is often limited. Since many of the conditions are rare, it is unlikely that randomized controlled trials (RCT) will ever be performed (1). As we experienced a growing variety of indications in our center we decided to make an inventory of our TPE population, to determine the types of disorders for which TPE was performed and to compare the results of treatment with the level of evidence supporting TPE.

Materials and Methods

We report a single center retrospective inventory of all adult TPE patients during a 7-year period (March 2005 to February 2012). The Antwerp University Hospital is a regional tertiary referral hospital. TPE is performed at the dialysis unit of the department of Nephrology-Hypertension and/or the department of Intensive Care Medicine (ICU). Apheresis is performed for therapeutic indications such as leukapheresis in acute leukemia, and hematopoietic stem cell apheresis for transplantation as well as in the setting of a clinical trial (apheresis of monocytes in cancer vaccines). Retrospectively available data on patient characteristics, their indication for TPE, the level of evidence for every indication, additional treatment, result of treatment and survival were obtained from our central patient data system. Partial response to treatment was defined as amelioration of clinical and/or laboratory measures. Complete response was defined as complete recovery of clinical and relevant laboratory measures. We also documented the number of TPE sessions and the number of episodes of TPE (defined as a new series of sessions at least one month after the last session). Indications and level of evidence were determined according to the definitions and guidelines on the use of therapeutic apheresis published by the American Society for Apheresis (ASFA) in 2010 (2). Indication categories are reported in Table I and grading recommendations in Table II. Approval of the Institutional Review Board (IRB) was not required for this study. Data were analyzed using SPSS 20. Continuous data were expressed as mean and standard deviation. Possible differences in response and outcome were studied using chi-squared test (x²).

Table I

Indication Categories^*

Category	Description
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.
	(Example: plasma exchange in Guillain-Barre syndrome as first-line standalone therapy; plasma exchange in myasthenia gravis as first-line therapy in conjunction with immunosuppression and cholinesterase inhibition.)
II	Disorders for which apheresis is accepted as second-line therapy, either as a standalone treatment or in conjunction with other modes of treatment.
	(Example: plasma exchange as standalone secondary treatment for acute disseminated encephalomyelitis after high-dose IV corticosteroid failure.)
III	Optimum role of apheresis therapy is not established. Decision-making should be individualized. (Example: plasma exchange in patients with sepsis and multiorgan failure.)
IV	Disorders in which published evidence demonstrates or suggests apheresis to be ineffective or harmful. IRB approval is desirable if apheresis treatment is undertaken in these circumstances. (Example: plasma exchange for active rheumatoid arthritis.)

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;25:83-177.

Table II

Grading Recommendations^*

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

Szczepiorkowski ZM, Winters JL, Bandarenko N, Kim HC, Linenberger ML, Marques MB, Sarode R, Schwartz J, Weinstein R, Shaz BH. 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;25:83-177.

Results

Patient characteristics

During the 84-month study period, 72 patients underwent a total of 638 sessions of TPE in 91 episodes. Three patients were excluded. One patient was excluded because an initial diagnosis of hemolytic uremic syndrome (HUS) was afterwards changed to malignant hypertension associated thrombotic microangiopathy (TMA); another patient was excluded because of inconsistencies in the diagnosis and one patient because the initial diagnosis of chronic inflammatory demyelinating polyradiculopathy was later changed to a hereditary neuropathy.

In our population 36 patients (52.2%) were male and the mean age at the first session was 51.8 (∓18.0) years. The majority of patients (N = 50, 72.5%) were treated in the dialysis department, whereas 19 patients (27.5%) were treated in the intensive care unit. Mean number of treatment episodes was 1.3 (range 1-7, median 1) and mean number of TPE sessions was 9.0 (range 1-140, median 5). Diagnoses and their frequencies are reported in Table III together with the level of evidence considering the indication for TPE. In 41 patients (59.4%) TPE was performed based on a level I indication, in 14 (20.3%) there was a level II indication, in 8 (11.6%) a level III indication, whereas 1 patient had a level IV indication (1.4%) and 5 patients suffered from a condition that was not included in the guidelines (7.2%).

Table III

Diagnosis and Level of Evidence

Diagnosis	Underlying		Level of evidence
Diagnosis	cause of disease	Frequency	Category	Grade
Acute disseminated encephalomyelitis (ADEM)	Neurologic	2	II	2c
Cryoglobulinemia secondary to Hepatitis C virus	Nephrologic	1	II	2b
Anti-glomerular basement membrane disease with diffuse alveolar hemorrhage	Nephrologic	1	I	1b
Anti-glomerular basement membrane disease, dialysis independence	Nephrologic	1	I	1a
Acute inflammatory demyelinating polyneuropathy (Guillain Barré syndrome)	Neurologic	1	I	1a
Cardiac allograft rejection, antibody mediated	Other	3	III	2c
Renal transplantation, antibody mediated rejection	Nephrologic	8	I	1b
Hemolytic uremic syndrome (HUS) due to antibody to factor H	Nephrologic	1	I	2c
Atypical HUS	Nephrologic	6	II	2c
Autoimmune limbic encephalitis	Neurologic	1	–	–
Myasthenia gravis moderate-severe	Neurologic	27	I	1a
Multifocal motor neuropathy	Neurologic	1	–	–
Transverse myelitis	Neurologic	1	2	1c
Neuromyeltis optica	Neurologic	1	2	1c
Opsoclonus and gait ataxia	Neurologic	1	–	–
Polyarteritis nodosa	Nephrologic	1	–	–
Paraneoplastic neurologic syndrome	Neurologic	3	III	2c
Neuromyotonia (Isaacs’ syndrome)	Neurologic	1	–	–
Systemic lupus erythematosus-severe	Nephrologic	3	II	2c
Thyroid storm	Other	1	III	2c
Phytanic acid storage disease (Refsum's disease)	Neurologic	1	II	2c

Outcomes

We found no trend in number of treatments per year or distribution or category of indication (Tab. IV). A complete response was observed in 17 patients (24.6%). A partial response was seen in 42 patients (60.9%) and 10 patients (14.5%) experienced no response. During a follow-up period of 4 to 89 months, 18 patients (26.1%) died. The characteristics are reported in Table V. We tried to evaluate the role of TPE in the cause of death (see Tab. V). There was no difference in response or survival between sexes (p = 0.22 and p = 0.83, respectively). Patients treated at the dialysis unit had a better rate of survival (71.1% vs. 47.4%, p<0.05) when compared to patients treated in the ICU, consistent with a less severe state of illness. In patients with a (partial or complete) response we observed a better survival rate compared to non-responders (84.7% vs. 10.0%, p<0.01).

Table IV

Epidemiology

Year	Indication category								Total
	Neurologic				Nephrologic
	I	II	III	NR	I	II	III	NR
2005 (10 months)	4					2			6
2006	2			1					3
2007	9					4			13
2008	1		1		2	1			5
2009	6	2	1		5	1		1	16
2010	4	2		1	3				10
2011	1	1	1	1	1	1			6
2012 (2 months)	1			1	1				3

Table V

Characteristics of Deceased Patients

Patient number	Age	Indication for TPE	Response	Cause of death	Timing of death	Direct relation with TPE
1	76	MG	Yes	Malignancy	2 years after TPE	no
10	56	MG	Yes	Septic shock, multiple organ failure	9 months after TPE	no
11	82	HUS	No	Respiratory failure, withdrawing of therapy	During TPE	no
12	69	Paraneoplastic neurologic syndrome	No	Progressive malignancy (ovarian cancer)	unknown	no
14	56	Thyroid storm	No	Cardiogenic shock	During TPE	no
15	20	Systemic lupus erythematosus-severe	No	Multiple organ failure	2 weeks after TPE	unknown
16	43	Cardiac allograft rejection, antibody mediated	No	Refractory cardiogenic and/or septic shock	1 week after TPA	possible
19	58	Paraneoplastic neurologic syndrome	Yes	Progressive malignancy (ovarian cancer)	At least 8 months after TPE	unknown
20	75	MG	Yes	Refractory cardiogenic shock, no revascularization possible	After second TPE-session	probable
21	81	MG	Yes	Multiple organ failure after gastro-intestinal bleeding	3 months after TPE	no
31	83	MG	Yes	Myastenic crisis, withholding of TPE	16 months after TPE	no
40	28	ADEM	No	Respiratory failure, persistent vegetative state	6 weeks after TPE	possible
42	79	MG	Yes	Acute respiratory failure after myasthenic crisis	2 months after TPE	no
48	72	Paraneoplastic neurologic syndrome	No	Progressive malignancy	unknown	unknown
53	62	Cardiac allograft rejection, antibody mediated	Yes	Combined septic and cardiogenic shock, possible relapse of rejection	6 weeks after TPE	possible
55	64	ADEM	No	Progressive disease	3 weeks after TPE	possible
59	61	MG	Yes	Septic shock	4 month after TPE	possible

When considering categories of indication we found no difference in response (100% no indication vs. 85.7% category I-III, p = 0.35), probably because of the small number of patients with conditions not rated in the guidelines. These 5 patients are further categorized in Table VI. When these 5 patients with a diagnosis not mentioned in the guidelines are excluded, the response rate is inversely correlated with the level of evidence (category I 97.6%, category II 71.4%, category III 50%, category IV 0% response, p<0.01).

Table VI

Characteristics of Patients with a Condition not Mentioned in the Guidelines

Sex	Age	Condition	Year	Symptoms	Additional treatment	Outcome	Additional episodes
Female	25	autoimmune limbic encephalitis GAD-antibodies +	2011	short-term memory loss, partial epileptic insults	high dose corticosteroids, levetiracetam	cessation of epileptic insults, subjective partial amelioration of memory	+
Male	75	polyarteritis nodosa	2009	intra-abdominal bleeding, biopsy proven arthritis	surgery, cyclophosphamide, high dose corticosteroids	favorable	–
Female	36	multifocal motor neuropathy	2006	blocks, paralysis left arm, paresis right arm	intravenous immunoglobulins	partial gain of function	–
Male	34	neuromyotonia (Isaac's syndrome)	2010	myalgias, fasciculations	carbamazepin	amelioration of complaints	–
Male	35	opsoclonus and gait ataxia	2012	chronic and progressive gait ataxia and opsoclonus. Nausea and vomiting	high dose corticosteroids	gain in gait stability, cessation of vomiting and nausea	+

Discussion

In our population we see no trend in change of frequency or class of indication over the years. Our distribution of indications is similar as reported in the studies by Lankford et al (3) and Yeo et al (4) (our population 79.7% category I and II, 7.2% not rated, population Lankford 75-88% category I and II and 3-9% not rated and population Yeo et al 77% category I and II, 9% not rated).

With respect to non-rated conditions, autoimmune limbic encephalitis is thought to be a channelopathy, and a potential reversible component to it has been suggested. Although several treatment algorithms implement TPE for this condition, there is no randomized controlled trial evidence supporting its effectiveness (5, 6). As with our patient who presented with this disease, evaluation of clinical evolution is partially based on subjective measures, which complicate the evaluation of treatment.

TPE is also performed in patients with severe polyarteritis nodosa (PAN) (7) but authors tend to be more restrictive by citing one published RCT that did not show any benefit (8). In our patient suffering from PAN, however, we did see a benefit of combined immunosuppressive therapy and TPE. As for multifocal motor neuropathy, the underlying pathological mechanisms are unclear, but IgM autoantibodies against the ganglioside GM1 may cause changes in nodal and perinodal structures that compromise nerve conduction. Prednisolone and plasmapheresis are ineffective in most patients and may even exacerbate symptoms and are therefore not recommended (9). Nevertheless, in our patient we did see an amelioration of complaints, however subjective this improvement may be.

Neuromyotonia is another autoimmune channelopathy and TPE has been described as a second line therapy after anticonvulsants (6).

As for the case of the patient with opsoclonus and gait ataxia no clear evidence was found.

All cases considered to be non-rated indications had a favorable outcome, which suggests that in individual cases and after careful evaluation of indication and possible risks, TPE can be of benefit even in the absence of good evidence. The main problem with these diseases is the fact that many complaints can only be measured subjectively and the treatment never consisted of TPE alone.

As compared to the report of Yeo et al (4), our all-cause death is relatively high: 26.1% (our study) versus 11% (Yeo). However, Yeo does not report the time of follow-up and he questions whether mortality should be attributed to the severity of disease, suggesting TPE as the direct cause of death. In our population, however, there was only one death that was associated with TPE with a high probability - in a patient suffering from cardiac ischemia and cardiogenic shock after TPE, possibly because of fluid shifts (Tab. V, patient 20). Another five deaths were possibly caused (among other reasons) by infectious complications; therefore, a role of TPE cannot be ruled out (Tab. V, patients 10, 15, 16, 53, and 59). In theory, by removing immunoglobulins and complement, TPE can lead to an immunosuppressed state. However, literature on this subject is sparse and controversial. In a randomized controlled trial Pohl at al found no differences in infectious complications between patients treated with a regimen with or without TPE for severe lupus nephritis (10). Data on complications such as allergic symptoms, hypocalcaemia, catheter-related infections or fluid overload were not adequately documented.

TPE is usually applied in combination with other therapies such as corticosteroids or cyclophosphamide. Recent studies also suggest a benefit for the combination of TPE and rituximab in for example refractory thrombotic thrombocytopenic purpura (TTP) (11); and, with less firm evidence, bortezomib and TPE in multiple myeloma with cast nephropathy (12).

Novel techniques are gaining interest and evidence is augmenting. Potential gain is a decrease in side effects by a more selective treatment. Immunoadsorption is promising in ABO-incompatible transplantation, for example (13). Novel monoclonal antibodies such Eculizumab, which prevents complement C5 activation, may also appear to be of great benefit (14).

Our data were reviewed using the ASFA guidelines and although recent and well documented when concerning scientific evidence, a possible flaw is that the committee behind these guidelines includes physicians with training in pathology, hematology, and pediatrics but not in nephrology or neurology. As such, nephrologists are regularly confronted with a dilemma when not making the primary diagnosis but still being responsible for performing the definitive therapy, with all its attendant risks (4).

Conclusions

Besides well-known indications for TPE with strong evidence, for many diseases the indication for TPE is controversial or even obscure. In our population the response rate is indeed inversely correlated with the level of evidence, but only after exclusion of the patients with a diagnosis not mentioned in the guidelines. We suggest that controversial indications be carefully evaluated on an individual base and that a trial of TPE cannot be solely ruled out because of lack of evidence. This means that in these settings a careful, multidisciplinary review of all determining factors is obligatory and treatment under a research protocol is preferred. Newer techniques such as immune-adsorption are promising but can not be considered standard of care yet.

Footnotes

Conflict of Interest: None.

Meeting Presentation: Data were presented at the Benelux Kidney Meeting organized by the Dutch and Belgian Society of Nephrology in Eindhoven on October 11, 2012.

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