High-dose Intravenous Immune Globulin Research Articles

Incidence of Myocarditis Associated with Diphtheria, Tetanus, and Pertussis Vaccine: A Rare Case Series

AbstractMyocarditis induced by diphtheria–tetanus–pertussis (DTP) vaccination is extremely rare, accounting for only two cases thus far. Hence, to supplement knowledge regarding its pathogenesis and treatment, we reported two cases of myocarditis associated with DTP vaccination in adults.Two patients (a 40-year-old female and a 43-year-old male) presented with mild symptoms and were hemodynamically stable. In both patients, the DTP vaccination was given 4 and 6 days before admission. Both patients had prolonged corrected QT interval (QTc), poor left ventricular function, and high troponin levels at admission. However, numerous ST segment depression was only noted in the first case. Bacteriology and virology study results were negative for any pathogen. No atherosclerotic lesions were observed by coronary angiography. Cardiac magnetic resonance imaging was only performed in the second case, which confirmed the diagnosis of myocarditis. Initial therapy was administered with a beta-blocker, angiotensin-converting enzyme inhibitor, and intravenous methylprednisolone. Nonetheless, in the first case, rapid clinical deterioration and sudden cardiac death occur within 3 days of hospitalization. Learn from the first case, a high-dose intravenous immunoglobulin (IVIG) treatment was initiated in the second case, which resulted in an improvement in left ventricular function and clinical symptoms, as well as a significant reduction in QTc interval and troponin levels.Rapid diagnostic testing and early recognition of the fulminant course is mandatory, allowing clinicians to aggressively treat the patient with high-dose intravenous immune globulin, thus obtaining a better outcome.

Treatment of vaccine-induced immune thrombotic thrombocytopenia (VITT)

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a novel prothrombotic disorder characterized by thrombosis, thrombocytopenia, and disseminated intravascular coagulation identified in hundreds of recipients of ChAdOx1 nCoV-19 (Oxford/AstraZeneca), an adenovirus vector coronavirus disease 2019 (COVID-19) vaccine. VITT resembles heparin-induced thrombocytopenia (HIT) in that patients have platelet-activating anti-platelet factor 4 antibodies; however, whereas heparin typically enhances platelet activation by HIT antibodies, VITT antibody-induced platelet activation is often inhibited in vitro by pharmacological concentrations of heparin. Further, the thrombotic complications in VITT feature much higher frequencies of atypical thrombosis, most notably cerebral vein thrombosis and splanchnic vein thrombosis, compared with HIT. In this review, we outline the treatments that have been used to manage this novel condition since its recognition in March 2021, including anticoagulation, high-dose intravenous immune globulin, therapeutic plasma exchange, corticosteroids, rituximab, and eculizumab. We discuss the controversial issue of whether heparin, which often inhibits VITT antibody-induced platelet activation, is harmful in the treatment of VITT. We also describe a case of “long VITT,” describing the treatment challenges resulting from platelet-activating anti-PF4 antibodies that persisted for more than 9 months.

Adjunct Immune Globulin for Vaccine-Induced Immune Thrombotic Thrombocytopenia

SummaryThe use of high-dose intravenous immune globulin (IVIG) plus anticoagulation is recommended for the treatment of vaccine-induced immune thrombotic thrombocytopenia (VITT), a rare side effect of adenoviral vector vaccines against coronavirus disease 2019 (Covid-19). We describe the response to IVIG therapy in three of the first patients in whom VITT was identified in Canada after the receipt of the ChAdOx1 nCoV-19 vaccine. The patients were between the ages of 63 and 72 years; one was female. At the time of this report, Canada had restricted the use of the ChAdOx1 nCoV-19 vaccine to persons who were 55 years of age or older on the basis of reports that VITT had occurred primarily in younger persons. Two of the patients in our study presented with limb-artery thrombosis; the third had cerebral venous and arterial thrombosis. Variable patterns of serum-induced platelet activation were observed in response to heparin and platelet factor 4 (PF4), indicating the heterogeneity of the manifestations of VITT in serum. After the initiation of IVIG, reduced antibody-induced platelet activation in serum was seen in all three patients. (Funded by the Canadian Institutes of Health Research.)

A prospective observational study of the incidence, natural history, and risk factors for intravenous immunoglobulin-mediated hemolysis.

Intravenous Immune Globulin (IVIG) is used to treat numerous immune-mediated and inflammatory conditions. There is growing awareness of hemolysis, occasionally severe, as a side-effect of this therapy. While most cases are associated with anti-A and/or anti-B isoagglutinins, the frequency and mechanism of hemolysis remain poorly characterized. A prospective observational study was conducted to determine incidence, natural history and risk factors for IVIG-mediated hemolysis. A total of 99 infusions of high-dose IVIG (2 g/kg or higher) administered to 78 non-group O patients were monitored and graded according to Canadian IVIG Hemolysis Pharmacovigilance Group. Serum ferritin and C3/C4 levels were monitored as indicators of macrophage activation and complement consumption, respectively. Supplementary investigations included assessment for ABO zygosity, Secretor status, FcR polymorphisms, eluate IgG subclass, monocyte monolayer assay, and a panel of cytokines. Hemolysis was observed in 32 of 99 (32%) of infusions, with 19 of 99 (19%) grade 2 or higher. Hemolysis was only apparent 5-10 days after a completed IVIG infusion in 84% of cases and was associated with increases in serum ferritin without complement-consumption. In univariate analysis, increased risk was observed in group AB patients, first-time IVIG recipients, those not taking immuosuppressive medications, or patients treated with a specific IVIG brand; however, in multivariate analysis, product association was no longer observed. No other patient- or practice-related risk factors were identified. IVIG-mediated hemolysis is common and frequently severe. Monitoring for 5-10 days following an infusion should be considered in non-O patients receiving high-dose IVIG with known risk factors.

Cytomegalovirus Induced Thrombocytopenia with No Platelets in an Immunocompetent Young Male

Introduction Immune thrombocytopenic purpura (ITP) is a common cause of acquired thrombocytopenia in an otherwise asymptomatic adult. It is generally believed to be caused by auto- antibodies against platelet antigens that destroy platelets peripherally and autoreactive cytotoxic T cells, as well as humoral and cellular autoimmunity directed at megakaryocytes, causing impaired platelet production. Cytomegalovirus (CMV) is a known cause of cause of morbidity and mortality in patients with immunosuppressed states, whereas in immunocompetent patients, it commonly manifest as asymptomatic or mononucleosis like syndrome. We are presenting a case of CMV induced thrombocytopenia with severe epistaxis and platelet count of 0 x10 9 in an otherwise healthy immunocompetent male who failed to improve after standard treatments with high dose steroids and intra venous immune globulin (IVIG). Case Description A 36-year-old Caucasian male without any past medical history presented to emergency room (ER) with flu like symptoms for five days associated with subjective fevers, anorexia, nausea, cough and weight loss of 15 lb. in two weeks. He also reported possible tick bite while working in the yard two days prior to admission. No dizziness, vomiting, diarrhea or any bleeding were reported. Denied any smoking, alcohol use or any illicit drug use. No significant family history was reported. On evaluation he was afebrile, normotensive with normal heart rate and respiratory rate. Physical examination was unremarkable. Initial laboratory data revealed hemoglobin of 11.2, platelet count 4 x109, white cell count of 13,100 with 4.5% atypical lymphocytes, aspartate aminotransferase of 41, alanine aminotransferase of 49, and creatinine of 1.4. He tested positive for Influenza A, CMV Immune globulin (Ig)M and IgG antibody. Serological tests for tick panel including anaplasma, babesia, Lyme disease and ehrlichia were negative. Epstein-Barr virus (EBV) antibody, parvo virus antibody, hepatitis screen, HIV screen, auto antibodies including anti-nuclear antibody and anti-double stranded DNA were negative. Coombs test was negative. Further work up includes ADAMTS13 activity was normal. No laboratory evidence of ADAMTS13 deficiency. After excluding all other causes, diagnosis of ITP was made. He was started on Tamiflu for Influenza A and high dose intra venous (IV) methyl prednisone for ITP. After platelet transfusion and two days of IV steroids platelet count improved 43 x 109 and he was discharged home with prolonged prednisone taper. Five days later, he presented to ER with severe epistaxis. Laboratory data revealed platelet count of 0 x109. Serum CMV-DNA was determined by PCR showed viral load of 8,790 copies/ml. Ultrasound abdomen showed mild splenomegaly. He received three doses of IVIG (1g/kg). Platelet count failed to improve after administration of IVIG. Bone marrow biopsy revealed hyper cellular marrow with trilineage hematopoiesis with no increase in CD 34 blasts. Per infectious disease and hematology recommendations, he was started on valganciclovir (900 mg PO BID). One month later, platelet count improved to 150 x 109 and CMV viral load dropped to 413 with subsequent resolution of patient's symptoms. Discussion Secondary ITP is an acquired thrombocytopenia caused by autoantibodies against platelets. Many patients with ITP are asymptomatic. For those who do have symptoms, initial presentations of ITP are petechiae, purpura and epistaxis, with a more severe progression to intracranial hemorrhage or gastrointestinal bleeding leading to a fatal outcome, if treatment is not started on a promptly manner. CMV induced thrombocytopenia in immunocompetent adults seems to be rare. we are presenting a case of CMV induced ITP which failed to improve after standard treatment with high dose steroids and IVIG but responded to anti-viral therapy with valganciclovir. In conclusion, it may be worthwhile to test for CMV infection in patients presenting with ITP. Further research is needed in order to establish treatment guidelines for CMV induced ITP in immunocompetent adults. Disclosures No relevant conflicts of interest to declare.

Kawasaki syndrome: immunomodulatory benefit and potential toxin neutralization by intravenous immune globulin

Kawasaki Syndrome (KS) is an acute multi-system vasculitis of infancy and early childhood associated with the development of coronary artery abnormalities. The prevalence of cardiovascular abnormalities can be significantly reduced by treating patients during the first 10 days of illness with high-dose intravenous immune globulin (IVIG). Despite the widely held belief that KS is caused by an infectious agent, the aetiology of this illness remains controversial. Recent immunological and microbiological studies suggest a potential role for staphylococcal and streptococcal toxins (superantigens) in the pathogenesis of KS. Confirmation of these findings could result in more effective diagnostic and therapeutic approaches for the treatment of this common cause of acquired heart disease in children.

Intravenous immune globulin therapy of lupus nephritis: use of pathogenic anti-DNA-reactive IgG

The authors have recently shown that antibodies with anti-idiotype (Id) specificity to pathogenic Ids of lupus nephritis may occasionally occur in several intravenous immune globulin (IVIG) preparations because they are present in healthy donors and the healthy relatives of SLE patients. In the present study, the authors purified these anti-Ids and treated two SLE patients with nephritis in parallel with conventional high-dose IVIG management with a commercial preparation (IVIG 6) in three controls for two months. Because pathogenic Ids of anti-DNA molecules, such as both 8.12 and F4 Ids, show a cationic mobility in isoelectric focusing, a commercial preparation of IVIG (11) was absorbed on a Sepharose column coupled with DC-305-39 myeloma protein, namely an 8.12+ and F4+ cationic IgG. Infusion of the eluate (EL-11) induced a prompt resolution of proteinuria levels and an evident decrease of serum levels of anti-DNA antibodies in both patients, whereas in the three controls, proteinuria and anti-DNA antibodies were scarcely reduced. In addition, plasma levels of interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha were also significantly influenced by both treatments. The mean values of both cytokines increased significantly after 1 h and then progressively declined over the next 48 h. It was of interest, however, that the increased TNF-alpha in the two EL-11-treated patients was significantly lower than in the three controls. The data suggest that reduction of active lupus nephritis by enriched specific anti-Id molecules is the result of two (or perhaps more) mechanisms: suppression of pathogenic idiotypes at the cellular level and improvement in the mesangium of the secretion of anti-inflammatory cytokines, such as IL-6, whose defective function is related to the autoimmune disorder.

Development and Evaluation of a Physiologically Based Pharmacokinetic Model for Predicting the Effects of Anti-FcRn Therapy on the Disposition of Endogenous IgG in Humans

This work scaled up a previously developed physiologically based pharmacokinetic model to predict the effects of anti-FcRn agents on the disposition of endogenous IgG in human subjects. Simulations were performed with the scaled model to predict the effects of single- and multiple-dose administration of anti-FcRn monoclonal antibodies (1-256 mg/kg) and high-dose intravenous immune globulin (0.4-2 g/kg). The model was evaluated for prediction accuracy through comparison to the effects of rozanolixizumab, an anti-FcRn monoclonal antibodies under current clinical evaluation, on the disposition of endogenous IgG in healthy human subjects. The model provided reasonably accurate predictions of the effects of rozanolixizumab. Prediction errors for the maximum reduction in endogenous IgG concentrations were −8.50% (90% model prediction interval: −14.0% to 1.44%), 3.33% (90% model prediction interval: −13.9% to 21.2%), and 6.85% (90% model prediction interval: −35.2% to 10.5%) for rozanolixizumab doses of 1, 4, and 7 mg/kg, respectively. Model simulations predict that anti-FcRn therapies will exhibit greater dose potency in healthy volunteers than in patients with elevated IgG production rates (e.g., as typically found in autoimmune disease). The model appears to have potential for use in assessing and predicting novel dosing strategies for anti-FcRn therapies.

Immune deficiency derive a favorable response to IVIg in PANDAS

For two decades, pediatric autoimmune neuropsychiatric disorder associated with group a beta hemolytic streptococcal infection (PANDAS) has been treated with high-dose intravenous immune globulin (IVIg) therapy based upon the understanding that the disorder is partly due to post-infectious dysimmunity.

The role of inflammation in intravenous immune globulin-mediated hemolysis.

Intravenous immune globulin (IVIG) therapy has shown great success in a number of autoimmune and inflammatory conditions and its use continues to increase worldwide. There is growing awareness of significant side effects of high-dose IVIG: however, particularly severe hemolysis in patients that are non-group O. It has been proposed that IVIG-associated hemolysis may be heralded by an existing inflammatory condition. In the work presented herein, we have provided a review of the pathophysiology of inflammation, particularly as it applies in immune-mediated red blood cell hemolysis, and a summary of previous publications that suggest an association between IVIG-mediated hemolysis and a state of existing inflammation. In addition, preliminary results from a prospective study to address the mechanism of IVIG-associated hemolysis are provided. These preliminary data support the idea of an existing inflammatory condition preceding overt hemolysis after high-dose IVIG therapy that: 1) is restricted to non-group O patients, 2) is seen when using IVIG doses of more than 2 g/kg, 3) involves an activated mononuclear phagocyte system, 4) may be presaged by a significant increase in the anti-inflammatory cytokine interleukin-1 receptor agonist, and 5) is independent of secretor status.

A Case Of Refractory Autoimmune Hemolytic Anemia In a Patient With Digeorge Syndrome Treated Successfully With Plasma Exchange

Background warm auto-immune hemolytic anemia (AIHA) results from targeted antibodies towards the RBCs and can be secondary to certain diseases (auto-immune disease or malignancy), drugs, infections or may be idiopathic in nature. Patients with DiGeorge syndrome are vulnerable to auto-immune conditions secondary to thymic hypoplasia with an estimated incidence in one series of 8.5% (Tison, Nicholas et al. 2011). First line therapy of AIHA consists of corticosteroids with an anticipated response rate of 80% (Lechner and Jager 2010). Relapses are not uncommon and are treated with splenectomy or rituximab. Case we describe an unusual case of an 18 year old female with DiGeorge syndrome who presented with AIHA refractory to usual modes of therapy. In this case, she was diagnosed with immune thrombocytopenia purpura (ITP) at age 13 with multiple relapses following successful standard therapy. Eventually, she was managed with monthly IVIG (intravenous immune globulin) infusions and thrombopoietin analogue romiplostim, maintaining her platelet count between 50 - 100 x 10 9/L. At 18 years of age she presented with severe anemia (Hb 55 g/L), positive hemolytic markers and a positive direct Coombs (3+ IgG and negative C3). A diagnosis of AIHA was established, and patient was started on prednisone (1-1.5 mg/kg) with transfusion support. Due to lack of response, high dose IVIG was administered followed by weekly rituximab 375 mg/m2. Due to hemodynamic instability, Rituximab was interrupted after the second dose. The finding of ineffective erythropoiesis evident by inappropriately low reticulocytosis prompted a bone marrow aspirate and biopsy. Aside from erythroid hyperplasia (M:E ratio of 1:4) with a left shift, no other anomaly was noted. PNH and G6PD screen was negative. The refractory nature of her AIHA required that the patient undergo a splenectomy. Hemolytic markers transiently improved however, within a few days, her hemolytic picture worsened and patient remained transfusion dependent. Given deterioration of her clinical status, decision was made to proceed with plasma exchange (PE) daily for 5 sessions with fresh frozen plasma fluid replacement. 24 hours following her first exchange session, there was a steady improvement of her hemolytic markers and patient became transfusion independent (Fig 1). Hb normalized eight days following the last exchange session. Additionally, platelets normalized following the splenectomy and she no longer required romiplostim. At her last follow up, 280 days following her last session of PE, Her Hb is within normal limits and hemolytic markers continue to be negative. During her admission, she required 42 bags of PRBCs (Fig 2). Conclusion This is the first reported case of a DiGeorge syndrome presenting with refractory AIHA successfully treated with PE. We conclude in this case that the combination of splenectomy followed by PE successfully controlled her hemolysis. Thus, we hope this report will give an additional insight on the use of PE as a therapeutic modality in refractory cases. Disclosures: No relevant conflicts of interest to declare.

Romiplostim: A Bridge To Splenectomy In Three Patients With Refractory Immune Thrombocytopenia (ITP)

Background Ten to thirty percent of patients with immune thrombocytopenia (ITP) do not respond to initial therapy. Options for such patients include Rituximab, TPO-mimetic agents and splenectomy. We report on three patients with refractory ITP and significant thrombocytopenia who received romiplostim as a bridge to splenectomy. Methods Three patients with isolated ITP or Evans syndrome did not respond to steroids, intravenous immune-globulin (IVIG) or Rituximab. Romiplostim was given to increase the platelet count prior to laparoscopic splenectomy. Before surgery the bone marrow was evaluated and patients were vaccinated. We reviewed their baseline clinical characteristics, and clinical course. Results Patient 1: 51 y/o M presented with fatigue and melena. Laboratory data showed hemoglobin (Hgb) of 7.9 g/dl, platelet (plt) count of < 2,000/uL, LDH of 997 U/L, reticulocyte count of 7.5 % and positive direct Coombs test. Prednisone and IVIG were started with improvement in Hgb but plt count remained < 2000/uL. Rituximab was started on day 7 with no response in plt count after 4 doses. Weekly romiplostim was started on day 37 with no response after 3 doses and then pt was lost to follow up. He presented two months later with plt count of < 2,000/uL and was treated with IVIG with transient response and restarted on Romiplostim. Plt count reached to 93,000/uL with a dose of 6 mcg/kg of romiplostim. He was maintained on romiplostim for a total of 19 doses and then underwent laparoscopic splenectomy. Platelet counts pre-op were 294,000/uL, post-op rose to 1,261,000/uL but normalized afterwards and he has been off all treatment for more than two years (figure 1). Patient 2: 28 y/o F presented with bruising and plt count of 12,000/uL. She was treated with 5 days of dexamethasone with transient improvement in plt count to 50,000/uL which rapidly dropped to < 2,000/uL. Despite daily prednisone and IVIG, plt count continued to be < 2000/uL and weekly rituximab was started on day 7. On day 14, plt count continued to be <10,000/uL and weekly romiplostim was initiated at 1 mcg/kg and increased weekly for four weeks when the plt count reached 61,000/uL after receiving 4 mcg/kg. Patient then underwent laparoscopic splenectomy. Post-op platelet count increased to 1,053,000/uL which returned to normal afterwards and remained so off all treatment at nine months follow up after splenectomy. Patient 3: 66 y/o M with coronary artery disease and long standing ITP was on prednisone 10-20 mg/day with plt count of 10-20,000/uL. Because of side effects of steroids, he was treated with danazol and rituximab (6 weeks) with no response in plt count. Cardiac catheterization prior to splenectomy could not be done because of thrombocytopenia. Romiplostim was then started at dose of 1 mcg/kg and advanced weekly to 3 mcg/kg with improvement in counts to 60,000/uL with peak of 200,000/uL. Cardiac catheterization was normal and he underwent successful laparoscopic splenectomy. Plt count before splenectomy was 73,000/uL and increased to 513,000/uL post-op. The plt count decreased to 120,000/uL and has remained stable for more than two years without further treatment. Conclusions Rituximab and TPO-mimetic agents are increasingly used for treatment of relapsed, refractory ITP as an alternative to splenectomy. Rituximab has a significant relapse rate. TPO-mimetic agents are expensive, require lifelong use, and are associated with rebound thrombocytopenia in those who stop treatment. Long-term use has also been associated with reversible bone marrow fibrosis and thromboembolism. Laparoscopic splenectomy is a safe procedure that is ideally done after a platelet response to high dose steroids and/or IVIG to reduce bleeding risk. Two of our patients were refractory to Rituximab. One received Rituximab concurrently with Romiplostim. All 3 patients did not want long term treatment with a TPO agent and had low platelet counts that were an impediment to surgery. We found that a short course of Romiplostim increased the platelet counts enough to enable surgery. All 3 patients achieved sustained remissions requiring no further treatment. No rebound thrombocytopenia was observed after stopping Romiplostim and none of the patients had bleeding or thrombotic complications. This case series suggests that a short course of Romiplostim can be used safely and effectively as a bridge to splenectomy for patients with refractory ITP. Disclosures: No relevant conflicts of interest to declare.

53-P

Aim The presence of antibodies against human leukocyte antigen (HLA) is a major challenge for successful kidney transplantation and results in prolonged waiting times. The aim of the study is to investigate the efficacy of high dose intravenous immune globulin (IVIG) on HLA antibody reduction and graft dysfunction in renal transplant recipients transplanted against DSA. Methods Between 07/2005 and 04/2012, 53 sensitized patients whose T and B flow crossmatches were under 200 median channel shift were transplanted with single or multiple dose of IVIG (2 g/kg). Levels of HLA antibodies were measured using single antigen Luminex assay, T/B cell crossmatches were performed by cytotoxicity and flow cytometry. Results All 53 patients displayed DSA to their donors pretransplant. Among them, 25/53 (47%) patients had a calculated PRA (cPRA) >90%. 26 patients had pretransplant DSA to HLA class I, 17 had DSA to class II and 10 had DSA to both class I and class II. 10 (18.8%) patients experienced antibody mediated rejection (AMR) posttransplant, and 5 (9.4%) patients were diagnosed with acute cellular rejection (ACR). 65% (17/26) of patients transplanted with pretransplant DSA to only class I antigens lost their DSA after transplant. However, for patients with pretransplant DSA to class II, only 5/17 (29%) patients showed no detectable DSA posttransplant (p = 0.02). For the 10 patients who had pretransplant DSA to both class I and class II, 4 patients no longer had detectable DSA posttransplant. Four patients had persistent class II DSA and 2 patients had persistent DSA to both class I and class II posttransplant. Conclusions IVIG seems to be more efficient in removing HLA class I antibodies than class II. Patients who had pretransplant DSA to HLA class II had higher risk of AMR compared to patients who had DSA to class I, with the highest risk in patients with DSA to both. Additional study should be performed to understand the differential mechanisms of IVIG on HLA class I and class II antibodies.

Epidemiology and Management of Kawasaki Disease

Kawasaki disease (KD) is an acute systemic vasculitis affecting young children and is rising in incidence worldwide. It is most common in children <5 years of age, males and those of Asian ethnicity. It is an important cause of acquired heart disease in children. Standard treatment with high-dose aspirin (acetylsalicylic acid; ASA) and intravenous immune globulin (IVIG) has been shown to decrease the rate of coronary artery aneurysm development. Anti-coagulation has an important place in the management of KD, although guidance based on evidence is lacking. Treatment of refractory KD is an area under intense study and may include IVIG, corticosteroids and/or tumour necrosis factor (TNF)-α inhibitors among immunosuppressive agents. Acute complications of KD include myocarditis/KD shock syndrome and macrophage activation syndrome, which necessitate appropriate awareness in order to initiate proper management.

Neuromuscular Manifestations of West Nile Virus Infection

The most common neuromuscular manifestation of West Nile virus (WNV) infection is a poliomyelitis syndrome with asymmetric paralysis variably involving one (monoparesis) to four limbs (quadriparesis), with or without brainstem involvement and respiratory failure. This syndrome of acute flaccid paralysis may occur without overt fever or meningoencephalitis. Although involvement of anterior horn cells in the spinal cord and motor neurons in the brainstem are the major sites of pathology responsible for neuromuscular signs, inflammation also may involve skeletal or cardiac muscle (myositis, myocarditis), motor axons (polyradiculitis), and peripheral nerves [Guillain–Barré syndrome (GBS), brachial plexopathy]. In addition, involvement of spinal sympathetic neurons and ganglia provides an explanation for autonomic instability seen in some patients. Many patients also experience prolonged subjective generalized weakness and disabling fatigue. Despite recent evidence that WNV may persist long-term in the central nervous system or periphery in animals, the evidence in humans is controversial. WNV persistence would be of great concern in immunosuppressed patients or in those with prolonged or recurrent symptoms. Support for the contention that WNV can lead to autoimmune disease arises from reports of patients presenting with various neuromuscular diseases that presumably involve autoimmune mechanisms (GBS, other demyelinating neuropathies, myasthenia gravis, brachial plexopathies, stiff-person syndrome, and delayed or recurrent symptoms). Although there is no specific treatment or vaccine currently approved in humans, and the standard remains supportive care, drugs that can alter the cascade of immunobiochemical events leading to neuronal death may be potentially useful (high-dose corticosteroids, interferon preparations, and intravenous immune globulin containing WNV-specific antibodies). Human experience with these agents seems promising based on anecdotal reports.

Use of Intravenous Immune Globulin and Rituximab for Desensitization of Highly HLA-Sensitized Patients Awaiting Kidney Transplantation

BACKGROUND.: We have shown that high-dose intravenous immune globulin (IVIG; 2 g/kg x2 doses)+rituximab (1 g x2 doses) was effective in lowering anti-human leukocyte antigen (HLA) antibodies and improving rates of transplantation. The aim of this report was to evaluate the efficacy of IVIG+rituximab on reduction of anti-HLA antibodies to a level that was permissive for living donor (LD) or deceased donor (DD) transplantation without incurring the risk of antibody-mediated rejection and immediate graft loss. METHODS.: From July 2006 to February 2009, 76 HLA-sensitized (HS) patients who met strict sensitization criteria received kidney transplants after desensitization using IVIG 2 g/kg (days 1 and 30)+rituximab (1 g, day 15). Parameters evaluated included rates of transplantation, previous transplants, panel reactive antibodies, donor specific antibody, crossmatches (CMXs), patient and graft survival, acute rejection, serum creatinines, and infections. RESULTS.: Seventy-six HS CMX treated patients (31 LD/45 DD) were transplanted. For LD and DD recipients, significant reductions were seen in T-cell flow cytometry CMXs from pretreatment (T cell 183.5+/-98.4 mean channel shifts (MCS) for LD and 162.8+/-41 MCS for DD) to time of transplant (T cell 68.2+/-58 MCS for LD [P<0.00006] and 125+/-49 for DD [P=0.05]), respectively. Time on wait list for DD recipients was reduced from 95+/-46 months to 4.2+/-4.5 months after treatment. Twenty-eight patients (37%) experienced acute rejection (29% C4d/8% C4d). Patient and graft survival up to 24 months was 95% and 84%, respectively. The mean serum creatinines, at 12 and 24 months were 1.5+/-1.1 and 1.3+/-0.3 mg/dL, respectively. Viral infections were seen in six patients. CONCLUSIONS.: IVIG and rituximab seems to offer significant benefits in reduction of anti-HLA antibodies allowing improved rates of transplantation for HS patients, especially those awaiting DD, with acceptable antibody-mediated rejection and survival rates at 24 months.

Efalizumab-Induced Autoimmune Hemolytic Anemia

Efalizumab (Raptiva; Genentech Inc.) is a humanized, recombinant, T-cell targeted monoclonal antibody, which binds to CD11a which combined with CD18 forms lymphocyte function-associated antigen 1 (LFA-1) and is approved for use in adults with moderate to severe plaque psoriasis. Previous publications have described autoimmune thrombocytopenia, hemolytic anemia as well as neutropenia with use up to 8 months after initiating treatment. We now report two patients who developed refractory autoimmune hemolytic anemia nine and twenty-six months after successful treatment of their psoriasis with efalizumab. The first patient is a 56 year old African-American man who presented with severe Coombs positive (IgG+, C3d −}anemia, with a hemoglobin of 4.1 g/dL, reticulocyte count of 25% after 26 months of treatment with efalizumab. Over the next two weeks the anemia was refractory to high dose prednisone, a total dose of 100 gms of intravenous immune globulin (IVIG), mycophenolate, danazol and 2 doses of rituximab and 10 units of blood, hemoglobin remained at 5.9 g/dLand .splenectomy was performed two weeks after presentation. Hemoglobin 2 weeks post splenectomy improved to 10.4 g/dL with near normalization one month later. The second patient a 61 year old woman, presented to an outside hospital with severe anemia. Upon transfer 1 week later, she was found to be Coombs positive, with a hemoglobin of 6.1 g/dL, reticulocytes of 1 %., and underwent a bone marrow aspirate and biopsy with noted erythroid hyperplasia, this after nine months of treatment with efalizumab. The patient underwent splenectomy three weeks after high dose prednisone, intravenous cyclophosphamide, cyclosporine, danazol, IVIG, rituximab and plasmapheresis failed to induce a remission. After splenectomy, the patient remained refractory to treatment and eventually succumbed to a combination of arterial and venous thrombi, bowel ischemia and bacterial sepsis six weeks after presentation. Little is known regarding the mechanism behind the immune mediated cytopenias following efalizumab therapy. In addition to lymphocytes, CD11a is expressed on several other cell lines, however, CD11a is not expressed on mature erythrocytes making a direct antibody mediated response against an efalizumab/LFA-1 complex less likely. The development of anti-efalizumab antibody occurs in 5% of patients but is not associated with autoimmune phenomena. More likely mechanisms may include dysregulation of autoreactive T cells from either defective T-cell function, loss of regulatory T cells or aberrant antigen presentation. These two cases highlight the difficulty and relative resistance to treatment in patients who develop autoimmune hemolytic anemia secondary to efalizumab and stress the importance of continued close monitoring of complete blood counts throughout the duration of active treatment.

Acute stroke with high-dose intravenous immune globulin

A case of acute stroke in a patient who was receiving high-dose intravenous immune globulin (IVIG) for dermatomyositis is reported. A 43-year-old woman presented with overwhelming proximal weakness and myalgias, swelling in her hands, facial and knee rash, generalized fatigue, numbness in her left arm, and lower-back pain. Physical examination revealed that she had symptoms consistent with dermatomyositis. The patient was initially treated with prednisone but developed a severe adverse drug reaction to the medication. The prednisone was discontinued, and the patient was admitted to the hospital for a first-time dose of IVIG therapy. During the infusion, the patient was found to have a facial droop, left-sided hemiplegia, and an increase in restlessness. A large, significant right internal carotid artery occlusion was discovered and initially treated mechanically and then with drugs in an attempt to establish revascularization. A subsequent computed tomography scan of the brain demonstrated a large right-middle cerebral distribution infarct with slight hemorrhage into the basal ganglia. IVIG is increasingly being used for many approved and non-approved indications. Although rare, stroke associated with thrombosis caused by the administration of IVIG has been reported in the literature. On the basis of the Naranjo probability scale, this adverse drug event was calculated as a probable reaction due to the administration of IVIG. A patient had an acute stroke after receiving a high dose of IVIG for dermatomyositis. Patients should be given a slower rate of infusion and smaller dosages of IVIG, and they should be closely monitored for potential stroke associated with thrombosis during IVIG therapy.

Steroids for Children with Kawasaki Disease

Despite receiving high-dose intravenous immune globulin (IVIG) within the first 10 days of illness, approximately 5% of children with Kawasaki disease

Clinical characteristics and progress of Kawasaki disease patients who had early treatment with intravenous immune globulin

Purpose : To determine the optimal time of high dose intravenous immune globulin (IVIG) treatment, we analysed the clinical characteristics and progress of a group of Kawasaki disease patients who had early treatment with IVIG. Method : A retrospective study was conducted of 188 patients with Kawasaki disease who were admitted to Yeungnam University Medical Center from January 2000 to December 2005. All patients were treated with a high dose IVIG and high dose aspirin for the initial acute phase treatment. The early treatment group consisted of 94 patients who received treatment before 5 days of fever, and the conventional group consisted of 94 patients who were treated on or after day 5. The patients' sex, age, laboratory findings, total duration of fever, duration of fever after initial IVIG, need for additional IVIG and coronary artery status were noted. Result : There were no significant differences between the two groups in sex ratio and age. No significant differences were noted in the level of WBC count, ESR, CRP, serum albumin, LDH, total duration of fever and coronary abnormality. But the value of ALT(151.8±17.3 vs. 81.9±13.4, P=0.002), duration of fever after initial IVIG (3.8±0.5 days vs. 2.1±0.2 days, P=0.003), and rate of additional IVIG (15.9% vs. 6.3%, P=0.037) were significantly higher in the early treatment group. There was no significant difference in initial dose of IVIG, but dosage of aspirin was lower in early treatment group (P=0.037). Conclusion : There is no evidence that early treatment of IVIG has greater efficacy in preventing cardiac sequelae than conventional treatment. In addition, early treatment is likely to result in a greater requirement for additional IVIG treatment.