Including Intravenous Immunoglobulin Research Articles

Intravenous Immunoglobulin for the Treatment of Clostridium difficile Infection: A Review

Clostridium difficile infection (CDI) has increased sharply in incidence, mortality rate, and burden on the healthcare system over the past decade. Therefore, novel treatment modalities have been developed, including intravenous immunoglobulin (IVIG). The level of immune response to Clostridium difficile colonization is the major determinant of the magnitude and duration of clinical manifestations. This effect is mediated predominantly by serum IgG anti-toxin A antibodies. Based on this finding, anti-toxin A and B antibodies were successfully used in multiple in vitro and in vivo experimental settings to passively immunize hamsters in CDI models. In humans, IVIG was used as the source of those antibodies. Fifteen small, mostly retrospective and non-randomized reports documented IVIG's success in the treatment of protracted, recurrent, or severe CDI. Diarrhea resolution rates were higher in the former patient group, but the recurrence rates were similar. IVIG mechanism of action is neutralization of mainly toxin A through IgG anti-toxin A antibodies. Purified anti-toxin A and B antibodies were successfully used to decrease CDI recurrence rates among patients with no or one previous CDI episodes. In conclusion, the efficacy of IVIG for CDI treatment in animal models has been convincingly demonstrated. However, only few small non-randomized, mostly uncontrolled reports have been published on human subjects. A phase II trial results support the use of purified anti-toxin A and B antibodies to decrease CDI recurrence rates. Therefore, IVIG should currently only be used as adjunct therapy until results from large, randomized controlled trials are available.

Thymoma-Associated Paraneoplastic Polymyositis

We read with interest the recent commentary by Inoue et al describing the first reported case of thymic carcinoma–associated paraneoplastic polymyositis. We agree with Inoue et al that this is an extremely difficult complication to manage in this rare histological subtype of thymic malignanices. The authors report that only 23 cases of polymyositis associated with thymoma have previously been described. We have recently encountered a similar constellation of symptoms in a 24-year-old white woman, and wish to summarize her case briefly. She was originally diagnosed with a grade B2 stage IVA malignant thymoma in 2003 with coexistent autoimmune myasthenia gravis and diabetes mellitus. Before attending our clinic in November 2008, she had received extensive prior therapy including three separate debulking surgeries followed by adjuvant radiation on two occasions. Previous chemotherapeutic regimens included six cycles of cisplatin, adriamycin, vincristine, and cyclophoshamide, and three cycles of carboplatin/paclitaxel. In November 2008, she was enrolled on a phase I clinical trial of the histone deacetylase inhibitor belinostat 1,000 mg/m days 1 to 5 every 3 weeks. She attained stable disease on belinostat for 10 months until September 2009, when she presented with an urticarial rash, recurrence of myasthenia gravis, and generalized myalgias predominantly in her shoulder and bilateral thigh muscles. Computed tomography scan at that time revealed stable disease; however, her creatinine kinase was markedly elevated at 2,020 U/L (range, 38 to 252 U/L). Magnetic resonance imaging of her thighs revealed an unusual pattern of edema for an inflammatory myopathy with a fascial distribution in the right vastus lateralis. A muscle biopsy of her anterior thigh confirmed myositis. Despite aggressive therapy, which included intravenous immunoglobulin (IVIG), plasmapharesis, pulsed steroids, and rituximab, she continued to deteriorate and developed progressive bulbar symptoms, finally requiring ventilator support for respiratory failure and a prolonged intensive care unit admission. While myasthenia gravis and other autoimmune phenomena tend to be more closely associated with thymomas, our patient demonstrated a range of autoimmune phenomena including myasthenia gravis, type I diabetes mellitus, and autoantibodies to interferon and interferon . Interestingly, patients with autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy caused by autosomal recessive mutations in the autoimmune regulator (AIRE) gene also have endocrinopathies and autoantibodies against type I interferons. AIRE is known to promote negative selection of autoreactive T cells and apoptosis of thymic medullary epithelial cells. The suggestion that AIRE expression may be altered in thymic tumors provides a fascinating link between autoimmunity and malignancy as demonstrated by our patient.

Toxic epidermal necrolysis: retrospective analysis of 21 consecutive cases managed at a tertiary centre

Toxic epidermal necrolysis (TEN) is a rare, severe blistering disease. Outcome data in British patients is limited to case reports or small series. To characterize the aetiology, clinical features, complications and outcome in TEN, and to evaluate the effect of treatments including intravenous immunoglobulin (IVIg). This was a retrospective study of 21 consecutive patients with histologically confirmed TEN presenting between 1995 and 2007 to a tertiary referral unit for TEN in a university hospital in the UK. The mean age of the patients was 53.5 years. The mean surface area of denuded skin was 44% (range 30-90%). An adverse drug reaction was implicated in all patients, with mean time of TEN onset being 17 days (range 2-41 days) after initial drug exposure. The SCORTEN index was calculated in 19 patients (median SCORTEN 3, range 2-5). The SCORTEN predicted 7.3 deaths in this cohort, and 7 deaths were seen in the group of patients for whom SCORTEN was calculated. The overall mortality was 8/21 (38%). Ten patients received corticosteroids before transfer to our centre. In the steroid-treated group 4/10 patients (40%) died, and 4/11 patients (36%) who were not treated with steroids also died. Between 1995 and 2000, patients were treated with cyclophosphamide 1.5 mg/kg/day (n=2; both died) and subsequently with ciclosporin 2.5-4 mg/kg/day (n=3; 2 deaths). From 2000, patients were treated with IVIg 0.4-1 g/kg/day (n=14; 3 deaths); the SCORTEN-predicted mortality in this group was 5 deaths. Complications included sepsis (n=18), and organisms included Enterococcus, Acinetobacter, Staphylococcus aureus and methicillin-resistant S. aureus strains). Other complications included anaemia (n=17), lymphopenia (n=11) and neutrophilia (n=9). The presence of neutropenia (n=6; 4 deaths), renal impairment (n=5; 4 deaths) and disseminated intravascular coagulation (n=4; all died) were strong risk factors for mortality. Of 12 patients with ocular involvement, 6 (50%) developed symblepharon and/or visual impairment. This study confirmed the validity of SCORTEN in our series. In the subgroup treated with IVIg, there were three deaths, compared with the SCORTEN predicted mortality of five deaths. Corticosteroids did not seem to be beneficial.

Intravenous immunoglobulin for the treatment of severe Clostridium difficile colitis: An observational study and review of the literature

Clostridium difficile colitis (CDC) is the most common cause of hospital-acquired diarrhea. The increase in the incidence and fatality rate of CDC over the past decade has stimulated a search for new therapies, including intravenous immunoglobulin (IVIG). We report our experience with IVIG for the treatment of 21 patients with severe CDC. Retrospective review of patients with severe CDC who received IVIG between July 2002 and April 2006 at a teaching hospital. The existing literature on IVIG infusion for severe CDC was also reviewed. Twenty-one of 1230 patients with CDC were treated with IVIG. The mean age was 68 (range, 35-98) years, with mean hospital stay of 23 (range, 9-64) days. Conventional treatment was used for an average of 8 (range, 1-25) days before IVIG infusion. All patients had evidence of pancolitis (radiologically) or ileus (clinically). The mean Acute Physiological Assessment and Chronic Health Evaluation (APACHE II) score was 25 (range, 6-39) at day 1 of IVIG infusion. Nine patients (43%) survived their hospitalization with colitis resolution while 12 (57%) died. One patient developed pulmonary edema after IVIG infusion. Symptoms resolved after an average of 10 (range, 2-20) days for survivors. Two patients underwent urgent colectomy. This is the largest case series describing IVIG use for patients with severe CDC and the one with the highest mortality rate to date. The use of IVIG in this setting does not seem to benefit all patients. Benefit appears to depend on the extent of systemic involvement. Further studies are needed before adopting IVIG as routine treatment for severe CDC.

Use of Rituximab in Patients with Congenital Bleeding Disorders and High Titre Inhibitors.

Abstract 3501Poster Board III-438The development of high titre inhibitors remains a serious complication of treatment in patients with congenital bleeding disorders. We describe a single centre experience of the use of Rituximab (monoclonal anti-CD20 antibody) in 10 patients with congenital bleeding disorders and high titre inhibitors. Nine of the patients have severe haemophilia A (Factor VIII <1%) and 1 patient has type 3 von Willebrand disease (VWD). Six patients had received previous immune tolerance therapy with various regimens prior to receiving Rituximab. Four patients with risk factors predictive of poor response to tolerisation received Rituximab as part of their initial therapy. Three of these four patients received additional immunosuppression (including intravenous immunoglobulin (IVIG) & prednisone (n=2), and IVIG, prednisone and vincristine (n=1)). Patients received cycles of weekly doses of 375 mg/m2 over 2 – 4 weeks. Four patients responded after one cycle of Rituximab therapy. The remaining 6 patients received repeated cycles of Rituximab with the frequency of cycles being between three and 12 months. These patients have to date received between 2 and 13 cycles of Rituximab over a period of up to 6 years. All patients have responded with a fall in their inhibitor titre and improvement in factor recovery. Five patients had a complete response so that they can be managed with second daily factor prophylaxis. One of these patients (the type 3 VWD patient) had a relapse 12 months after his initial response to Rituximab. He has responded to a second course of 4 doses of Rituximab. Three of the remaining five patients remain on immune tolerance induction (ITI) between 8 months and 6 years after starting Rituximab therapy. All of these patients have improved factor VIII recovery with marked reduction in bleeding frequency. Of the other two patients, 1 patient moved interstate and was no longer treated with Rituximab and the other had ITI stopped after 15 months because of poor compliance with daily factor therapy. At this time his inhibitor was undetectable and he had improved factor recovery and survival. The Rituximab was well tolerated in all patients. Four patients developed hypogammaglobulinaemia, 1 patient developed transient neutropenia, three patients had port infections, though the frequency of infection was no greater than before Rituximab therapy. This single centre of experience shows that repeated doses of Rituximab are well tolerated and has a role in the tolerisation of patients with poor response to more traditional methods of ITI. Disclosures:Off Label Use: Rituximab is a monoclonal antibody against CD20 that is being used for its immunomodulatory properties.

Rituximab Treatment in Childhood Chronic Immune Thrombocytopenic Purpura (ITP).

Abstract 4461 BackgroundImmune thrombocytopenic purpura (ITP) is characterized by mucocutaneous purpura and thrombocytopenia caused by circulating anti-platelet auto-antibodies. ITP is usually self-limited in children, but around 20% of patients will develop chronic ITP. The conventional treatments for children chronic ITP include intravenous immunoglobulin (IVIG), corticosteroid therapy, anti-D immune globulin, or splenectomy. Some children with chronic ITP are refractory to these treatments and nowadays begun to try new treatment agents such as rituximab. Rituximab as a monoclonal antibody to CD-20, has shown promising reports to these patients with refractory chronic ITP in adults groups and a few children groups. We investigated this study to evaluate the efficacy of rituximab for childhood chronic ITP in Korea. MethodsWe reviewed the questionnaires and medical records about the clinical progresses and results in thirteen children from eight clinical institutes, retrospectively. Complete response (CR) was considered if the platelet count was > 100,000/uL. ResultsThirteen patients with chronic thrombocytopenia who had been treated with rituximab were investigated. Two patients were lost to follow-up after rituximab. Finally eleven patients were evaluated including one patient with Evans syndrome. Median age was 6.5 year (range, 0.5 ∼ 15.4). Median platelet count at baseline was 13,700/uL (3,000∼46,000). All patients had been treated with conventional therapy including IVIG and steroids. One had done splenectomy. Median follow-up duration was 2.8 years (1.1-5.9). Among 11 patients, CR was achieved in 3 patients (27%). Their platelet count prior to rituximab were < 10,000/uL. They were treated as the regimen of 375 mg/m2/dose weekly for 4 doses. Time from the first rituximab dose to achievement of complete response was 3.9, 4.9 and 5.7 weeks respectively. One patient who was relapsed 6months after the first course of rituximab was received second course of rituximab using the same regimen and achieved a new CR at 9.3 weeks after. There were no reports about severe complication or interruption of medication. ConclusionsTherefore, we suggest that rituximab is effective treatment choice in childhood refractory chronic ITP and well tolerated. Disclosures:No relevant conflicts of interest to declare.

Treatment of Neonatal Hemochromatosis with Exchange Transfusion and Intravenous Immunoglobulin

To determine if immunomodulatory treatment including intravenous immunoglobulin (IVIG) can favorably affect survival in neontatal hemochromatosis (NH) diagnosed postnatally because it can effectively prevent occurrence of NH when applied during gestations at risk. We treated 16 newborn infants with liver failure due to NH with high-dose IVIG, in combination with exchange transfusion in 13 (ET/IVIG), and compared the outcome with 131 historical controls treated conventionally. The severity of liver disease as estimated by prothrombin time was similar in the subjects receiving ET/IVIG and the historical controls, and the medical therapy was equivalent with the exception of the ET/IVIG therapy. Twelve subjects (75%) had good outcome, defined as survival without liver transplantation, whereas good outcome was achieved in only 17% (23/131) of historical control patients (P < .001). Four subjects died, 2 without and 2 after liver transplant. Survivors were discharged 6 to 90 days after receiving ET/IVIG therapy, and those followed for more than 1 year are within normal measures for growth, development, and liver function. Immune therapy with ET/IVIG appears to improve the outcome and reduce the need for liver transplantation in patients with NH.

Therapeutic plasma exchange in patients with neurologic diseases: Retrospective multicenter study

Therapeutic plasma exchange (TPE) is commonly used in many neurological disorders where an immune etiology was known or suspected. We report our experience with TPE performed for neuroimmunologic disorders at four university hospitals. The study was a retrospective review of the medical records of neurological patients ( n = 57) consecutively treated with TPE between April 2006 and May 2007. TPE indications in neurological diseases included Guillain-Barrè Syndrome (GBS) ( n = 41), myasthenia gravis (MG) ( n = 11), acute disseminated encephalomyelitis (ADEM) ( n = 3), chronic inflammatory demyelinating polyneuropathy (CIDP) ( n = 1) and multiple sclerosis (MS) ( n = 1). Patient median age was 49; there was a predominance of males. Twenty-two patients had a history of other therapy including intravenous immunoglobulin (IVIG), steroid, azothioprin, and pridostigmine prior to TPE. Another 35 patients had not received any treatment prior to TPE. All patients were classified according to the Hughes functional grading scores pre- and first day post-TPE for early clinical evaluation of patients. The TPE was carried out 1–1.5 times at the predicted plasma volume every other day. Two hundred and ninety-four procedures were performed on 57 patients. The median number of TPE sessions per patient was five, and the median processed plasma volume was 3075 mL for each cycle. Although the pre-TPE median Hughes score of all patients was 4, it had decreased to grade 1 after TPE. While the pre-TPE median Hughes score for GBS and MG patients was 4, post-TPE scores were decreased to grade 1. Additionally, there was a statistically significant difference between post-TPE Hughes score for GBS patients with TPE as front line therapy and patients receiving IVIG as front line therapy (1 vs. 3.5; p = 0.034). Although there was no post-TPE improvement in Hughes scores in patients with ADEM and CIDP, patients with MS had an improved Hughes score from 4 to 1. Mild and manageable complications such as hypotension and hypocalcemia were also observed. TPE may be preferable for controlling symptoms of neuroimmunological disorders in early stage of the disease, especially with GBS.

Rituximab in chronic inflammtory demyelinating polyneuropathy associated with diabetes mellitus

Background: Some patients with diabetes mellitus (DM) develop a peripheral neuropathy indistinguishable from chronic demyelinating polyneuropathy (CIDP). Immune-mediated mechanisms are involved in the pathogenesis of demyelinating neuropathy in DM and in CIDP. Immunotherapy, including intravenous immunoglobulin (IVIg) is effective in idiopathic CIDP and CIDP-DM. Despite treatment with IVIg, CIDP may remain clinically active. It has been reported that CIDP may respond to Rituximab (RTX), a chimeric humanized monoclonal antibody against CD20+ antigen on B-lymphocytes. We reported a patient with CIDP associated with DM increasingly less responsive to IVIg who was treated with RTX.

Cholecystectomy and Acquired Factor VIII Inhibitor Coagulopathy

The purpose of this study was to describe the outcome of patients undergoing surgery with recognized and unrecognized factor VIII inhibitor. The setting was a tertiary care center with a community-based general surgery training program. Two patients with acquired factor VIII inhibitor coagulopathy required cholecystectomy. Interventions included intravenous immunoglobulin (IVIG) and factor VIII transfusions. An elderly patient undergoing urgent open cholecystectomy for acute cholecystitis exsanguinated despite postoperative recognition and treatment of factor VIII inhibitor. A second patient with known factor VIII inhibitor underwent laparoscopic cholecystectomy with perioperative transfusions of factor VIII and IVIG. No hemorrhage occurred, but cost to the patient exceeded 50,000 dollars. Acquired factor VIII inhibitor coagulopathy is rare and potentially lethal. Preoperative recognition and appropriate hematologic intervention is crucial to achieve a successful outcome.

Nonstandard and adjunctive medical therapies for systemic lupus erythematosus

Nonstandard and adjunctive medical therapies for systemic lupus erythematosus