Intravenous immunoglobulin increases plasma viscosity without parallel rise in blood pressure

What is known and Objective: Intravenous immunoglobulin (IVIg) is a commonly used therapy for autoimmune disease, but may cause chronic hypertension and thrombosis. We determined whether: (i) IVIg systematically affects blood pressure in the short term; (ii) acute changes in plasma viscosity because of IVIg correlate with blood pressure effects; (iii) effects of IVIg on acute blood pressure are related to baseline blood pressure or hypertension status and (iv) IVIg influences plasma markers of inflammation, anticardiolipin antibodies and homocysteine as additional putative prothrombotic risk factors. Methods: Twenty adults with autoimmune neurological disease who received a course of IVIg were evaluated immediately before and after each infusion, on every day of the course. Blood pressure, pulse and the following haematological parameters were determined: plasma viscosity, erythrocyte sedimentation rate (ESR), C‐reactive protein (CRP), haematocrit, fibrinogen, interleukin‐6 (IL‐6), homocysteine and anticardiolipin positivity. Results: Intravenous immunoglobulin caused both acute and cumulative rises in plasma viscosity across a treatment course, but no concordant changes in blood pressure. There was also no correlation between individual blood pressure changes and viscosity, baseline blood pressure or hypertension status. Levels of IL‐6 rose across the course of therapy, but the acute‐phase reactants CRP and fibrinogen did not. One patient developed anticardiolipin antibodies during therapy. What is new and Conclusion: Individual courses of IVIg do not systematically raise blood pressure. Where IVIg is found to cause hypertension, this does not appear to be due to a direct effect of IVIg on plasma viscosity.     

免疫调节疗法治疗重症肌无力临床观察

目的观察应用静脉注射用免疫球蛋白（IVIg）或血浆置换治疗全身型重症肌无力（MG）的临床疗效和安全性。方法对56例病情恶化需IVIg或血浆置换治疗的全身型重症肌无力患者分两组，27例应用IVIg治疗，29例应用血浆置换治疗。在接受治疗后14天、1个月、3个月分别进行疗效评估。结果两组患者治疗前后评分差异均有统计学意义，并且都能很好地耐受，在治疗初期两种方案疗效相差不大，有效率分别为77．8％（21／27）、75．9％（22／29）。好转后都可维持较长时间，但IVIg维持时间稍长于血浆置换。结论重症肌无力患者中IVIg的治疗效果可与血浆置换匹敌。IVIg在3个月后的评估中疗效优于血浆置换。但在病情恶化初期，患者可根据所在医院的医疗条件选择任一种方案。     

Treatment of the adult Guillain-Barré syndrome: indications for plasma exchange

The Guillain-Barré syndrome is the most common cause of acute flaccid paralysis. Currently, 5% of patients die and 10% are left with severe motor sequelae at one year. Multidisciplinary teams, trained to specific treatments, are required to manage these patients. Oral and intravenous steroid treatment of GBS has been disappointing. Two large randomized clinical trials comparing plasma exchange (PE) to standard supportive treatment have shown a short-term and a one-year benefit of PE. Appropriate number of exchanges and indications of PE are now more precisely known. Patients with mild forms of the disease (able to walk) should receive two PEs, while a further two exchanges should be done in case of deterioration or in advanced forms (loss of walking ability, mechanical ventilation). A greater number of exchanges does not appeared beneficial. More recently, two randomized trials produced some evidence that intravenous immune globulin (IVIg, 0.4 g/kg daily for five days) and PE had equivalent efficiency in advanced forms. The combination of PE with IVIg did not yield a significant advantage, but did increase cost and risk. In advanced forms, the choice between PE and IVIg depends on the contraindications of each treatment.     

Thrombotic thrombocytopenic purpura: 24 years of experience at the American University of Beirut Medical Center

Thrombotic thrombocytopenic purpura (TTP) is a hematological syndrome defined by the presence of thrombocytopenia and microangiopathic hemolytic anemia without a clinically apparent etiology. Patients may also suffer from fever in addition to neurological and renal impairment. Treatment should be initiated as soon as possible, otherwise this rare disease can be fatal. The main treatment options include therapeutic plasma exchange, fresh frozen plasma infusion, and adjuvant agents such as steroids and antiplatelet drugs. A search of patient records was carried out at the American University of Beirut Medical Center looking for patients who developed TTP over a 24-year period extending from 1980 to 2003. Relevant information was collected and analyzed. A total of 47 records were found. All presented with anemia and thrombocytopenia, 83% had neurological symptoms, 61.7% had fever and 34% had renal impairment. All patients were treated with a multimodality regimen including therapeutic plasma exchange, FFP infusion, steroids, antiplatelet agents, vincristine and others. 38 (81%) cases achieved complete remission. Out of these, 12 (31.6%) relapsed and responded to treatment. Patients who did not receive plasma exchange were more likely to relapse (P = 0.032). A second relapse was observed in 6 cases. The overall mortality rate from TTP over 24 years was 21.3%. TTP remains a fatal disease. A high index of suspicion should, therefore, always be present. Treatment options should be further developed and patients should directly be referred to tertiary care centers.     

Recent advances of therapeutic apheresis in Guillain-Barré syndrome.

Acute idiopathic demyelinating polyneuritis (AIDP), commonly known as the Guillain-Barré syndrome (GBS), is an immune-mediated demyelinating disease of the peripheral nerve and nerve roots. A number of immunological mechanisms were described, but the exact pathomechanism has not been explained fully. Presumably, a variety of immunological processes lead to a relatively uniform clinical phenotype. Two large multicenter studies showed that plasma exchange (PE) was significantly superior to supportive treatment only. Selective adsorption (SA) also was employed as a method of therapeutic apheresis, and various smaller studies established that both PE and SA are equally effective treatments for GBS. Recently, it was demonstrated that the number of apheresis treatments should be adapted to the severity of disease. A large multicenter controlled study established equal efficacy of PE and intravenous immunoglobulin treatment (IVIg) as well as the combination of PE and IVIg. Since that time, the use of apheresis for the treatment of GBS declined in many countries due to the easier application of IVIg. The number of patients treated in larger hospitals with long-standing experience in the treatment of GBS also has declined.     

Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity

Intravenous immunoglobulin (IVIg) is a potential alternative treatment for anti-neutrophil cytoplasm antibody (ANCA)-associated systemic vasculitis (AASV) with less toxicity than conventional immunosuppressive agents. This randomized, placebo-controlled trial aimed to investigate the efficacy of a single course of IVIg (total dose 2 g/kg) in previously-treated AASV with persistent disease activity in whom there was an intention to escalate therapy. Vasculitic activity was monitored by the Birmingham vasculitis activity score (BVAS), C-reactive protein (CRP) and ANCA levels. Treatment response was defined as a reduction in BVAS of more than 50% after 3 months, and there was an intention to keep doses of concurrent immunosuppressive drugs unchanged during this period; follow-up continued to 12 months. Seventeen patients were randomized to receive IVIg and 17 to receive placebo. Treatment responses were found in 14/17 and 6/17 of the IVIg and placebo groups, respectively (p=0.015, OR 8.56, 95%CI 1.74-42.2). Following infusion of trial medication, greater falls in CRP were seen at 2 weeks (p=0.02) and 1 month (p=0.04) in the IVIg group. No differences were observed between ANCA levels or cumulative exposure to immunosuppressive drugs, and after 3 months there were no differences in CRP levels or disease activity between the IVIg and placebo groups. Seventeen adverse effects occurred after IVIg and six after placebo: they were mostly mild, although reversible rises in serum creatinine occurred in four from the IVIg group. A single course of IVIg reduced disease activity in persistent AASV, but this effect was not maintained beyond 3 months; mild, reversible side-effects following IVIg were frequent. IVIg is an alternative treatment for AASV with persistent disease activity after standard therapy.     

Staphylococcus aureus bacteremia as a cause of early relapse of thrombotic thrombocytopenic purpura

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a multisystem disease characterized by the sudden onset of hemolytic anemia, thrombocytopenia, fever, renal failure, and neurologic dysfunction, occurring in various combinations. The most effective treatment of TTP is plasma exchange and the administration of corticosteroids, which reduces mortality from the 90 percent seen in untreated patients to 10 percent. CASE REPORTS: Two patients responded favorably to plasma exchange and corticosteroid therapy, but their TTP relapsed during treatment. In both cases, the early relapse of TTP was associated with Staphylococcus aureus bacteremia secondary to central line infection. Treatment of the infection and intensification of the plasma exchange regimen resulted in a sustained remission. CONCLUSION: Infection should be actively sought and treated in TTP patients who are refractory to treatment or in whom an exacerbation of the disease occurs while they are undergoing plasma exchange.     

Plasma exchange versus intravenous immunoglobulin for Guillain-Barré syndrome.

Previous randomized controlled trials in the U.S.A. and France have provided strong evidence that plasma exchange (PE) hastens recovery from Guillain-Barré syndrome (GBS). A Dutch trial compared intravenous immunoglobulin (IVIg) with PE in an open study and showed that recovery was as fast or slightly faster in the group treated with IVIg. This report was followed by accounts of a small series of patients who had seemed to progress or relapse after treatment with IVIg. To resolve this controversy, the Plasma Exchange Sandoglobulin GBS Trial Group (PS GBS Trial Group) selected 383 patients randomly to receive PE, IVIg, or PE followed by IVIg. After 4 weeks, the outcome was similar in each of the 3 groups. These 3 regimens also had similar outcomes during 48 weeks of follow-up.     

Apheresis therapy in Guillain-Barré syndrome

Based on previous randomized controlled-trials (RCTs), plasma exchange (PE) has been established as an effective treatment for Guillain-Barré syndrome (GBS). Double filtration plasmapheresis (DFPP) and immunoadsorption plasmapheresis (IAPP) may be effective for GBS, however their effectiveness have not been established because any RCTs have not been available so far. Intravenous immunoglobulin (IVIG) has also been established to be effective for GBS according to several RCTs, however complications have been more frequent in PE than IVIG. Therefore IVIg treatment should be considered as the first choice for GBS, and PE treatment remains as the second-line if IVIg treatment is contraindicated.     

Myocardial injury in HIV‐associated thrombotic thrombocytopenic purpura (TTP)

Thrombotic thrombocytopenic purpura (TTP) has been associated with human immunodeficiency virus (HIV) infection. With the high prevalence of HIV in sub‐Saharan Africa, HIV‐associated TTP is the most common form of this disease seen in the South African population. Several case reports describe myocardial infarction in HIV‐negative TTP patients. The case of the first HIV‐positive patient who presented with clinical signs and symptoms of TTP and myocardial injury is reported in this study. A patient with fragmentation haemolysis and thrombocytopenia presented with angina. Risk factors for ischaemic heart disease were absent. An electrocardiogram (EKG) revealed ST‐segment elevation and a significantly raised Troponin T level. The patient's HIV test was positive and a diagnosis of myocardial injury with HIV‐associated TTP was made. The patient was treated with plasma infusion and steroid therapy. Due to poor response, the therapy was changed to plasma exchange. The patient recovered fully and subsequent coronary angiography revealed normal coronary vessels. Treatment of myocardial infarction in TTP is controversial, but the treatment cornerstone should remain plasma infusion or plasma exchange. As patients are often young and do not have the classical risk factors of ischaemic heart disease, a high level of suspicion and routine exclusion of myocardial ischaemia in these patients are advised.     

RhIg for the prevention Rh immunization and IVIg for the treatment of affected neonates

Rhesus D (RhD) negative pregnant women carrying an RhD positive fetus are at risk of developing anti-D during or after pregnancy. Anti-d-immunoglobulin (RhIg), which is mainly produced from special plasma donated in a few countries for the whole world, is able to prevent an anti-D alloimmunization. Through the introduction of ante- and postnatal anti-d-prophylaxis into clinical routine, the frequency of hemolytic disease of fetus and newborn decreased considerably. Postnatal prophylaxis from the beginning in the 1960s has been applied only to women who delivered an RhD positive newborn. Because the fetal RhD status can be determined with high sensitivity and accuracy from the mother’s peripheral blood, targeted antenatal anti-d-prophylaxis is becoming a new standard procedure in more and more countries. Phototherapy and exchange transfusion are still the main pillars for the treatment of RhD hemolytic disease of the newborn. The efficacy of IVIg in the management of these neonates is not conclusive and cannot be recommended until a larger randomized, double-blind, placebo-controlled study is performed.     

Efficacy and limitation of apheresis therapy in critical care.

Apheresis therapy such as plasma exchange and plasma adsorption has become therapeutic tools in critical care. The indications for apheresis therapy in ICU patients include fulminant hepatic failure, thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), autoimmune disease, and sepsis. During the past 11 years, 150 patients with various kinds of critical illnesses were treated with apheresis therapy in our ICU, and the overall survival rate was 50%. Apheresis therapy is especially useful in the treatment of a patient with fulminant hepatic failure because liver transplantation is seldom performed in Japan; therefore, the patient should be treated with artificial liver support. When plasma exchange is performed on the critically ill, continuous hemodiafiltration should be performed simultaneously to overcome the adverse effects of plasma exchange such as hypernatremia, metabolic alkalosis, and abrupt changes in colloid osmotic pressure and to enhance the removal rate of the causative middle molecular weight substances of hepatic failure or hepatic coma.     

Complete remission of paraneoplastic sensorimotor neuropathy: a case associated with small-cell lung cancer responsive to chemotherapy, plasma exchange, and radiotherapy

A 61-year-old man was found to have small-cell lung cancer following a 1-year history of a progressive peripheral sensorimotor neuropathy. The neuropathy initially improved following chemotherapy, but subsequently progressed to the point of respiratory failure. Treatment with plasma exchange, additional chemotherapy, and radiotherapy resulted in a sustained complete tumor remission and neurologic recovery. The role of plasma exchange is unclear, but its use should be considered in cases of severe sensorimotor neuropathy unresponsive to antineoplastic treatment.     

Long-term treatment of chronic inflammatory demyelinating polyradiculoneuropathy with plasma exchange or intravenous immunoglobulin

To assess long-term treatment of chronic idiopathic demyelinatingpolyradiculoneuropathy (CIDP) with plasma exchange (PE) andintravenous immunoglobulin (IVIg), we studied 105 patients retrospectivelyby case-notes and follow-up. Thirty-three were treated withPE; 23 responded well. Twenty-two were treated with IVIg; 14responded well and one had a hypotensive reaction during thefirst infusion. For both treatments, responders were more likelyto be female and younger, and to have a shorter duration ofsymptoms. Most patients required only one course of treatment.Seven patients received repeated courses of PE for 8.1–59.7months; seven received repeated courses of IVIg for 6–51months. Transient complications occurred with PE: hypotensionin three, difficulty in gaining venous access in three, andhaematoma, bleeding diathesis, hypocalcaemia, and septicaemiain one patient each. Four patients transferred from long-termPE to IVIg, but the fifth responded to PE only. Two patientswho were transferred from PE to IVIg were eventually able tostop all treatments. Long-term use of IVIg was free of any significantcomplications. Both PE and IVIg are possible long-term treatmentsfor CIDP, but both are expensive, and PE had more side-effects.     

Effective concentration of intravenous immunoglobulin for neutralizing Panton-Valentine leukocidin in human blood

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infects healthy individuals, although the precise cause remains unclear. CA-MRSA produces Panton-Valentine leukocidin (PVL), which often causes severe invasive infection; however, antitoxin drugs against PVL are limited. Intravenous immunoglobulin (IVIg) possesses antitoxin activity, but unfortunately, the optimal dose is unknown. Here, we measured the PVL neutralizing antibody titer in the plasma of Japanese individuals and sera of American donors. Next, we compared the cytotoxic effects of PVL on neutrophils in phosphate buffered saline (PBS) or whole blood to determine the effect of the neutralizing antibody. Finally, we evaluated the effective concentration of IVIg required to neutralize PVL in PBS and whole blood. We observed that the titer of PVL neutralizing antibody in healthy individuals polarized as high and low/none group. Additionally, the PVL neutralizing antibody titer considerably affected the concentration at which IVIg elicited its effect. This suggests that PVL-producing CA-MRSA might be involved in determining the severity of infection in healthy individuals without neutralizing antibody against PVL. The neutralizing effect of IVIg was observed in both PBS and whole blood. However, the optimal concentration of IVIg required for neutralizing PVL varied between PBS and whole blood. In addition, since the PVL-neutralizing activity of IVIg also largely depends on blood composition, such as neutralizing antibody concentration, the optimal dosage of IVIg as an antitoxin drug should be decided in a timely manner after considering the patient's medical background.     

A multicenter retrospective analysis on therapeutic plasma exchange in immune thrombocytopenic purpura

Immune Thrombocytopenia (ITP) is an autoimmune disease characterized by thrombocytopenia and skin and mucosal bleeding. In patients with an indication for treatment, corticosteroids, intravenous immunoglobulin (IVIg) and anti-D are recommended as the first line, while splenectomy, thrombopoietin receptor agonists or rituximab are recommended second line options. Approximately 10 % of adult patients with ITP fall into the chronic refractory ITP group. Therapeutic plasma exchange (TPE) has generally been tested in patients with refractory ITP, who have failed to respond to conventional treatments, in case of bleeding or prior to surgical interventions. It has been stated that elimination of the antibodies that are held responsible in the pathogenesis of the disease has an effective role in the treatment. In this article, we present the results of 17 patients, who underwent TPE for refractory ITP, together with the literature data.     

Unified infusion rates for 10% intravenous immunoglobulin

Although manufacturers recommend varying infusion rates for differing intravenous immunoglobulin products (IVIg), there may be improved efficiency and reduced potential for error with the application of a single infusion policy for all IVIg products. During the transition from a 6% to a 10% IVIg, we prospectively evaluated patient reported adverse reactions to IVIg with the 10% product (Intragam 10) given at a rate faster than recommended by the manufacturer. While there was a significant increase in the rate of immediate infusion reactions when compared with the previous IVIg preparation (Intragam P), there was no increase in the rate of reactions post infusion. The rate of reactions was within previously reported expectations for other IVIg products. All reactions were minor, requiring no or minimal intervention and few impacted significantly on the quality of life. Despite an active haemovigilance program, minor adverse reactions were generally not reported. Our results suggest that a fast single rate of IVIg infusion is safe, and may minimise patient attendance and hospital resources with acceptable safety. In implementing a strategy to increase IVIg infusion rates an active process to monitor safety is preferred over standard haemovigiliance or pharmacovigilance processes.     

无骨折脱位型颈髓损伤18例分析

BACKGROUND: Traditionaly , operation should not be performed on patients suffered from cervical injury without fracture and dislocation during rehabilitation or patients with complete paralysis. Dang Gengting suggested that although external force resulting cervical injury is slight, fracture and dislocation are rare, spinal damage is severe. So, doctors should consider risk factors of vertebral canal affecting spinal cord. Acute nerve and spinal injury, for example, will progress into chronic spinal disease or nerve root disease if not properly managed. So, once diagnosis was confirmed, traction, mobilization should be carried out to prevent other injury. Treatment protocol should be determined according to type of injury. If object increasing pressure, operation should be done to remove pressure. Additionaly, stability of cervical cord must be ensured.     

Intravenous immunoglobulin in multiple sclerosis

Intravenous immunoglobulin(IVIg) is a immunomodulating therapy to administer a relatively high dose of human immunoglobulins to a number of autoimmune diseases. Clinical trials of IVIg for neurological disorders including autoimmune peripheral neuropathy were carried out since the later of 1980's, and the efficacy of IVIg for such diseases was proved. In recent years the effectiveness of IVIg for multiple sclerosis(MS) has been reported in several randomized controlled trials(RCTs). MS patients in the trials were given immunoglobulin or placebo every month or two months for more than half a year. IVIg in particular is beneficial in prevention a recurrence of relapsing remitting MS and in improvement of MRI findings in a part of RCTs. However, IVIg does not recognize the distinct effectiveness in progression of secondary progressive MS yet. Some problems, for example, optimal dose or dosage frequency are unsolved. Generally a adverse effect of IVIg in MS patient is slightness and the continuation treatment of IVIg is tolerate for most patients. Now, in Europe where a clinical trial goes ahead, IVIg might be considered the therapy for MS when a already established treatment for MS such as interferon--beta is not effective or not be able to use. On the other hand, unfortunately the effectiveness of IVIg for MS could not be recognized by RCT executed in Japan.     

Plasma exchange in endocrine ophthalmopathy

We studied the effects of intensive plasma exchange on endocrine ophthalmopathy in 12 patients with Graves' disease and one with Hashimoto's thyroiditis. All patients were euthyroid at the time of plasma exchange. All but five had concomitant treatment with azathioprine. Each patient had a treatment period consisting of six plasma exchanges performed in 2-3 weeks; two patients were treated in two periods. Each time a mean of 2.4 liters plasma was exchanged. There was a prompt reduction in the concentration of circulating immune complexes and/or thyrotropin receptor antibodies following plasma exchange. Six of the 13 patients improved their proptosis; their median duration of eye symptoms before treatment was less than 8 months. In patients suffering from eye symptoms for more than 1 year improvement was rare. Overall the Hertel values were 24.1 +/- 4.4 (SD) before and 22.8 +/- 3.4 after plasma exchange for the left eyes (P = 0.07) and 23.8 +/- 4.0 before and 23.0 +/- 3.8 after for the right eyes (P = 0.09). Nine patients altogether improved their ophthalmopathy index and periorbital oedema. In patients with disabling endocrine ophthalmopathy plasma exchange may sometimes be of value to induce a relief of the ophthalmopathy; when it is used it should be instituted before fibrotic changes occur. We suggest that concomitant immunosuppressive drugs should be given to prevent rebound phenomenon induced by plasma exchange. To establish the role of plasma exchange in the treatment of endocrine ophthalmopathy controlled studies should be performed.