High-dose Intravenous Immunoglobulin Infusions Research Articles

Comparative effectiveness of two intravenous immunoglobulin products in children with Kawasaki disease, a nationwide cohort study

Kawasaki Disease (KD) is the most common acquired pediatric heart disease in the developed world. Rapid infusion of high-dose intravenous immunoglobulin is the standard therapy. Different manufacturing processes of IVIG may influence their efficacy. This study aims to conduct a head to head comparison of two IVIGs, TBSF and Privigen, from a nationwide perspective. The main data source was the National Health Insurance Research Database (NHIRD) of Taiwan. A total of 3368 KD cases involving children under 2 years of age were enrolled from January 2015 to November 2020. The primary endpoint was IVIG resistance, which we defined as the total amount exceeding 26 g in one admission. The secondary endpoints encompassed two distinct criteria: coronary involvement, which was defined as the prolonged use of aspirin or anti-coagulation agents between 180 and 360 days after the index date, and recurrence, which was defined as readmission for IVIG therapy occurring more than 30 days after previous KD index day and continuing until the end of the follow-up period. Privigen demonstrated a lower IVIG resistance rate at 9.4% in comparison to TBSF, which exhibited a rate of 9.7% (odds ratio 0.72, 95% CI 0.52–0.99). Privigen had a lower odds of coronary involvement (odds ratio 0.38, 95% CI 0.18–0.82). There is no difference in recurrence rate (odds ratio 0.60, 95% CI 0.22–1.68). Privigen might have a lower rate of IVIG resistance and reduced coronary artery involvement. The discrepancy may be due to the concentration, the stabilizers, or the source of plasma. Further investigation is needed to compare the effectiveness of different IVIGs in the large randomized controlled clinical trial.

Cold autoimmune hemolytic anemia complicated with relapsed myelodysplastic syndrome after allogeneic hematopoietic cell transplantation

Myelodysplastic syndrome (MDS) is known to often be complicated by a range of autoimmune diseases. We herein present a case with MDS complicated by cold autoimmune hemolytic anemia (cold AIHA). The patient was a 51-year-old woman. She was diagnosed with MDS (refractory cytopenia with multilineage dysplasia) in May 2009. In January 2010, she underwent unrelated allogeneic bone marrow transplantation but was re-admitted in October 2010 for treatment of relapsed MDS. Despite daily transfusions of red blood cells, her anemia failed to improve. Her laboratory examinations showed a low haptoglobin level and elevation of indirect bilirubin and LDH. The direct Coombs test was positive at a low and at room temperature and cold agglutinin was negative. After confirming the diagnosis of cold AIHA, all transfusion fluids were warmed but her anemia still failed to improve. In addition to the warmed transfusion fluids, we administered corticosteroids, immunosuppressive agents and high-dose intravenous immunoglobulin infusions. This management strategy ameliorated the patient's hemolytic anemia. To our knowledge, MDS cases complicated by cold AIHA are rare. Our patient thus provides a valuable contribution to medical knowledge.

Elevation of Serum Acid Sphingomyelinase Activity in Acute Kawasaki Disease.

Kawasaki disease (KD) is an acute systemic vasculitis that affects both small and medium-sized vessels including the coronary arteries in infants and children. Acid sphingomyelinase (ASM) is a lysosomal glycoprotein that hydrolyzes sphingomyelin to ceramide, a lipid, that functions as a second messenger in the regulation of cell functions. ASM activation has been implicated in numerous cellular stress responses and is associated with cellular ASM secretion, either through alternative trafficking of the ASM precursor protein or by means of an unidentified mechanism. Elevation of serum ASM activity has been described in several human diseases, suggesting that patients with diseases involving vascular endothelial cells may exhibit a preferential elevation of serum ASM activity. As acute KD is characterized by systemic vasculitis that could affect vascular endothelial cells, the elevation of serum ASM activity should be considered in these patients. In the present study, serum ASM activity in the sera of 15 patients with acute KD was determined both before and after treatment with infusion of high-dose intravenous immunoglobulin (IVIG), a first-line treatment for acute KD. Serum ASM activity before IVIG was significantly elevated in KD patients when compared to the control group (3.85 ± 1.46 nmol/0.1 ml/6 h vs. 1.15 ± 0.10 nmol/0.1 ml/6 h, p < 0.001), suggesting that ASM activation may be involved in the pathophysiology of this condition. Serum ASM activity before IVIG was significantly correlated with levels of C-reactive protein (p < 0.05). These results suggest the involvement of sphingolipid metabolism in the pathophysiology of KD.

Immunoglobulin G Fc N-glycosylation in Guillain-Barré syndrome treated with intravenous immunoglobulin.

Immunoglobulin G Fc N-glycosylation in Guillain-Barré syndrome treated with intravenous immunoglobulin.

Infusion of High-Dose Intravenous Immunoglobulin Fails to Lower the Strength of Human Leukocyte Antigen Antibodies in Highly Sensitized Patients

Human leukocyte antigen (HLA) sensitization presents a major obstacle for patients awaiting renal transplantation. HLA antibody reduction and favorable transplantation rates have been reported after treatment with high-dose intravenous immunoglobulin (IVIg). We enrolled 27 patients whose median flow cytometric calculated panel reactive antibody (CPRA) was 100% and mean wait-list time exceeded 4 years in a protocol whereby high-dose IVIg was administered, HLA antibody profiles of sera obtained before and after treatment were characterized, and cross-match tests were performed with all blood group identical kidney offers. Whereas 12.8% of a similarly sensitized historic control cohort underwent transplantation in the course of a year, 41% of the IVIg-treated group underwent transplantation during the study period. Surprisingly, HLA antibody profiles, measured by CPRA, showed no significant change in response to IVIg treatment. In fact, retrospective cross-match testing using pretreatment sera of those receiving deceased-donor allografts showed that all patients would have been eligible for transplantation with their respective donors before IVIg infusions. This study does not corroborate previous reports of CPRA reduction leading to increased deceased-donor transplantation rates in broadly sensitized patients undergoing desensitization with high-dose IVIg. The increased rate of transplantation relative to historic controls is not related to improved cross-match eligibility and likely resulted from frequent crossmatching using a cytotoxic strength threshold, improved medical readiness for transplantation, and newly recognized options for live-donor transplantation, all of which could have been achieved without IVIg treatment.

Safety of high-dose intravenous immunoglobulin in systemic autoimmune diseases

It is reported that the usage of high-dose intravenous immunoglobulin (HD-IVIG) in systemic autoimmune diseases is associated with various adverse events in a wide range of severity. We aimed to investigate the frequency and profile of adverse events in a group of patients with diffuse connective tissue diseases and Wegener's granulomatosis (WG) who were administrated HD-IVIG for different indications. We recorded the data of 38 patients (25 females and 13 males) aged 38 +/- 15 (12-75) years who were followed up with the diagnosis of systemic autoimmune diseases between 1994 and 2006 according to a predefined protocol. Patients with active disease were treated with HD-IVIG and standard immunosuppressives concomitantly. We evaluated the occurrence of allergy, acute renal failure, thromboembolic events, neutropenia, hemolytic anemia, aseptic meningitis, and vasculitis during infusion therapy of HD-IVIG and in the following 3 weeks. We commenced a total of 130 infusions of HD-IVIG. Patients were administrated 1-12 (3.4 +/- 2.6) infusions of HD-IVIG as needed. Indications for HD-IVIG were unresponsiveness or partial response to standard treatment, severe infections along with disease activity, and severe thrombocytopenia in the preoperative period in 97, 23, and 5% of patients, respectively. Minor adverse events were seen in two patients during HD-IVIG infusions. One patient with WG developed rapidly progressive renal failure during severe disease flare between HD-IVIG infusions. Another patient with WG developed recurrence of deep-vein thrombosis during severe disease flare 3 months after HD-IVIG. Both events were attributed to severe disease activity. Adverse events like allergy, acute renal failure, thromboembolic events, hematological problems, aseptic meningitis, and vasculitis are reported in different frequencies (1-81%) in patients who were administered HD-IVIG for systemic autoimmune diseases. HD-IVIG is considered a safe treatment in selected patients assuring adequate infusion precautions.

High-dose intravenous immunoglobulin infusion as treatment for diffuse scleroderma

High-dose intravenous immunoglobulin infusion as treatment for diffuse scleroderma

High-dose intravenous immunoglobulin infusion in polyarteritis nodosa

We describe a 58-year-old Japanese female who developed polyarteritis nodosa (PN). Her skin disease and systemic symptoms were resistant to dapsone (1.5 mg kg(-1) day(-1)), high-dose oral prednisone (1 mg kg(-1) day(-1)) and azathioprine (2 mg kg(-1) day(-1)), and intravenous cyclophosphamide pulse therapy (10 mg kg(-1) day(-1)). She was ultimately treated with infusion of high-dose intravenous immunoglobulin (IVIG) at a dose of 0.1 g kg(-1) daily for five consecutive days weekly for a period of 12 weeks, resulting in remission of his cutaneous and systemic symptoms and successful tapering of his prednisone and azathioprine dose. However, 12 months later, relapsing fever and polyarthritis recurred, and eventually, 24 months later, indurated erythema and punched-out ulcers appeared on the lower legs. These symptoms were reduced after increasing the dose of oral prednisone (1 mg kg(-1) day(-1)). Our case indicates that the high-dose IVIG infusion therapy may be useful for controlling PN in certain periods since the long-term observation revealed deterioration of symptoms. We review related articles and discuss its effectiveness in PN.

Cytomegalovirus-induced thrombocytopenia in an immunocompetent adult effectively treated with intravenous immunoglobulin: A case report and review

The authors report the case of an 80-year-old male patient who presented with colitis and severe thrombocytopenia. The work-up revealed concurrent cytomegalovirus infection. After failure of prednisone, a single infusion of high-dose intravenous immunoglobulin produced a rapid and sustained response. Seventeen cases from the world literature are reviewed. Corticosteroids seem effective in about one third of cases. In those who do not respond, splenectomy is relatively ineffective and more specific anti-CMV treatment with ganciclovir is of unproven efficacy and toxic, in view of the relatively favourable long term outcome the authors recommend intravenous immunoglobulin in cases of severe bleeding or when the platelet level is under 10×109 /l.

Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases.

To evaluate the effect of high-dose intravenous immunoglobulin (IVIG) in toxic epidermal necrolysis (TEN), parameters that may affect response to treatment, and the effect of different IVIG batches on Fas-mediated cell death. Multicenter retrospective analysis of 48 consecutive TEN patients treated with IVIG. Fourteen university hospital dermatology centers in Europe and the United States. Forty-eight patients with TEN (skin detachment >10% of their body surface [mean, 44.8%; range, 10%-95%]). Infusion of IVIG in all patients (range, 0.8-5.8 g/kg), and analysis of the ability of different IVIG batches to inhibit Fas-mediated cell death. Objective response to IVIG treatment, final outcome at day 45, parameters that may affect response to IVIG treatment, and tolerance. Infusion of IVIG (mean total dose, 2.7 g/kg [range, 0.65-5.8 g/kg]; mean consecutive days, 4 [range, 1-5 days]) was associated with a rapid cessation (mean, 2.3 days [range, 1-6 days]) of skin and mucosal detachment in 43 patients (90%) and survival in 42 (88%). Patients who responded to IVIG had received treatment earlier in the course of disease and, on average, higher doses of IVIG. Furthermore, analysis of 35 IVIG batches revealed significant batch-to-batch variations in the capacity of IVIG to inhibit Fas-mediated cell death in vitro. Early infusion of high-dose IVIG is safe, well tolerated, and likely to be effective in improving the survival of patients with TEN. We recommend early treatment with IVIG at a total dose of 3 g/kg over 3 consecutive days (1 g/kg per day for 3 days).

Two Cases of Kawasaki-Disease Who Showed Coronary Arterial Dilatation Even after Good Response to a Single High-dose Intravenous Immunoglobulin Infusion

It is now clear that a high-dose intravenous immunoglobulin therapy (IVIG) in patients with Kawasaki disease (KD) is effective for reducing the incidence of coronary arterial lesions (CAL). But both the total dose and the dose regimens of IVIG are still controversial.In this study, we report two cases with CAL in KD. These two cases were treated with aspirin (30mg/kg/day) and a single high-dose IVIG (1g/kg/day) on 5th day of illness. IVIG reduced their body temperature immediately to less than 37.5°C on 6th day of illness, so we did not add IVIG. Although they did not get high fever, and both the counts of white blood cells and the levels of C-reactive protein decreased after IVIG, their coronary arteries dilated gradually. In one case, the diameter of anterior descending branch of left coronary dilated to 4.0mm. In the other case, that of left main coronary artery dilated to 5.8mm. We confirmed these changes regressed to normal by either 2DE or selective coronary angiography after three months of onset. These cases suggest that a single high-dose IVIG (1g/kg/day) can not prevent CAL in KD, even after good response to IVIG.

Anticoagulant acquis antifacteur V : nosologie, risque hémorragique et prise en charge thérapeutique à propos de trois observations

Introduction. – Acquired factor V inhibitor is rare and clinical symptoms are quite variable. Bleeding is the leading symptom but some patients are asymptomatic. Several diseases or conditions are associated with factor V inhibitors. Various treatments have been attempted but randomized or prospective trials are not available. Exegesis. – Here we report three cases of acquired factor V inhibitor. These reports highlight the clinical variability of this disorder. Pathogenesis and therapy with reference to the literature are discussed. Conclusion. – Factor V inhibitors are rare and associated to several diseases or conditions. Pathogenesis is still unclear except in patients exposed to bovine thrombin. The majority of the cases developed after surgery. In a few cases there is an association to a malignant or autoimmune disease. Plasmapheresis and platelet transfusions might be the best treatment in case of severe bleeding. High-dose intravenous immunoglobulin infusions have been used successfully in some cases and we report here their efficacy in two cases.

The management of alloimmune neonatal thrombocytopenia

Neonatal alloimmune thrombocytopenia (NAITP), defined as thrombocytopenia (platelet count <150×109/l) due to transplacentally acquired maternal platelet alloantibodies, occurs in approximately 1 per 1200 live births in a Caucasian population. In such a population, the majority (>75 percent) of cases are due to fetomaternal incompatibility for the platelet specific alloantigen, HPA-1a (PlA1, Zwa). Incompatibility for the HPA-5b (Bra) alloantigen is the next most frequent cause of NAITP in Caucasians; much less common is NAITP due to incompatibility for HLA, blood group ABO or other platelet-specific antigens. In non-Caucasian populations (e.g. Orientals) HPA-1a incompatibility is a rare cause of NAITP and other alloantigens e.g. HPA-4b (Penb, Yuka) are implicated. The greatest clinical challange relates to the antenatal management of pregnant women alloimmunized to the HPA-1a (PlA1, Zwa) antigen, and particularly the subset of such women who have a history of a previously affected infant with severe thrombocytopenia and/or intracranial hemorrhage (ICH). The risk of antenatal ICH in the fetus of such women is high enough to merit intervention, either weekly infusion of high-dose intravenous immunoglobulin G (IVIG) with or without corticosteroids given to the mother (the preferred approach in North American centres), or repeated in-utero fetal platelet transfusions (the preferred treatment approach in some European centres). Post-natal management of severely affected infants centres on the rapid provision of compatible antigen-negative platelets harvested from the mother or a phenotyped donor. The value of antenatal screening programs to detect ‘at risk’ alloimmunized women during pregnancy continues to be debated.

X-linked agammaglobulinemia. A clinical and molecular analysis.

X-linked agammaglobulinemia (XLA), characterized by a profound deficiency of B lymphocytes due to an arrest in B lymphocyte development, is caused by mutations in the gene encoding Btk (Bruton tyrosine kinase). The BTK gene has been cloned and the genomic organization determined. BTK codes for 19 exons and is expressed in all hematopoietic cell lineages but is selectively down-regulated in T lymphocytes and plasma cells. The different Btk domains include PH, TH, SH3, SH2, and the kinase (SH1) domains. Btk, a cytoplasmic protein tyrosine kinase, is involved in cell signaling, although the precise pathway remains elusive. Mutation analysis has been performed in 236 families representing 282 patients. Mutations are scattered throughout the gene and consist of missense, nonsense, and splice site mutations as well as deletions and insertions. The major consequence of nonfunctional Btk appears to be a delay or block of the development of pro-B cells to pre-B cells and then to mature lymphocytes. Because IgG is actively transported across the placenta, affected newborns have normal levels of serum IgG at birth followed by gradually decreasing IgG levels and development of hypogammaglobulinemia and increased susceptibility to infections. Bacterial infections are the most common clinical manifestation. Resistance to viral infection is intact, except for an unusual susceptibility to infections with enteroviruses that may result in vaccine-related paralytic poliomyelitis or a dermatomyositis-meningoencephalitis syndrome. The diagnosis of XLA is based on the presence of lymphoid hypoplasia, markedly reduced serum levels of all 3 major classes of immunoglobulins, failure to make antibody to antigenic stimulation, and almost complete absence of B lymphocytes in the peripheral blood. Carrier detection and prenatal diagnosis are possible. The prophylactic infusion of high-dose intravenous immunoglobulin (IVIG) and the use of antibiotics have markedly improved the long-term prognosis of patients with XLA.

Effect of high-dose intravenous immunoglobulin on amyotrophic lateral sclerosis and multifocal motor neuropathy.

To determine if high-dose intravenous immunoglobulin therapy is effective in improving muscle strength or in arresting the pace of disease progression in patients with rapidly progressive amyotrophic lateral sclerosis. An open-label pilot study of intravenous infusions of high-dose immunoglobulin administered once a month for 3 months in nine patients with classic amyotrophic lateral sclerosis. Selected patients had a rapidly progressive course with signs of worsening noticeably evident every 6 weeks prior to therapy. A patient with multifocal motor neuropathy with conduction block that presented as a lower motor neuron syndrome was concurrently treated to document the efficacy of the same preparation of immunoglobulin in a potentially treatable disease that simulates lower motor neuron syndrome. The efficacy of high-dose intravenous immunoglobulin infusions was assessed by objective measurement of maximum voluntary isometric contraction in all muscle groups of two limbs before and after therapy. The Clinical Center of the National Institutes of Health, Bethesda, Md. All patients with amyotrophic lateral sclerosis worsened during the study. By the end of the third month, their mean total muscle scores (megascores) had declined by 71.2 points, from a mean of 369.7 (range, 200 to 605) to 298.5 (range, 130 to 552) points. The pace of progression did not change during the 4-month observation period. In contrast, the patient with multifocal motor neuropathy responded to intravenous immunoglobulin therapy and increased his megascores by 146 points after 3 months. The GM1 antibody titers were normal in all the patients. High-dose intravenous immunoglobulin, a prohibitively expensive drug, has no apparent therapeutic role in improving the symptoms or arresting the pace of progression in patients with amyotrophic lateral sclerosis. In contrast, multifocal motor neuropathy is an immunopathologically different disease that responds to intravenous immunoglobulin therapy.

Partial Neutralization of a Lupus Anticoagulant by Human Immunoglobulin

In a patient with a Lupus Anticoagulant (LA) and recurrent fetal loss, we observed a significant shortening of the APTT after high-dose intravenous immunoglobulin infusion (IVIg). The LA activity present in patient's serum and purified IgG was partially neutralized by IVIg in a dose-dependent way. In addition, IgG purified from IVIg and its F(ab')2 fragment neutralized LA activity of the patient's IgG. In both cases, the neutralization was dose-dependent and it was obtained with similar molar ratios. The "in vitro" neutralization of LA activity and the immediate shortening of the APTT after IVIg infusion, might be mediated through idiotype/antiidiotype interactions. On the other hand, the long-lasting effect of IVIg in this patient indicates that it may induce specific inhibition of autoantibody synthesis. We believe that IVIg should be considered as a therapeutic alternative for LA-related clinical disorders.

Mechanism of therapeutic effect of high-dose intravenous immunoglobulin. Attenuation of acute, complement-dependent immune damage in a guinea pig model.

Studies were performed in in vitro and in vivo models to assess the effect of intravenous immunoglobulin (IVIG) on the development of acute complement-mediated tissue damage. IVIG significantly increased the duration of survival and frequently prevented the death of guinea pigs injected with anti-Forssman antiserum to cause lethal Forssman shock; no control animal treated with albumin and/or maltose vehicle survived. The most pronounced effect was achieve by delivering IVIG as one slow injection at 1,800 mg/kg 3 h before Forssman shock was elicited. Infusion of guinea pig IgG at the same dosage was similarly protective. A strong positive correlation was found between IgG plasma levels and survival time in guinea pigs treated with graded doses of IVIG. Therapy itself did not affect C3 and C4 levels nor the capacity to activate these components. In vitro studies showed almost complete inhibition of C3 uptake onto IgG-sensitized erythrocytes using serum from an IVIG-treated animal. We suggest that supraphysiologic levels of IVIG act in part by preventing active C3 fragments from binding to target cells. Infusion of high dose IVIG may be a rational approach to modulating acute, complement-dependent tissue damage in a variety of diseases in man.

Persistent remission of adult chronic autoimmune thrombocytopenic purpura after treatment with high‐dose intravenous immunoglobulin

Transient efficacy of high-dose intravenous immunoglobulin infusions (HDI) is widely demonstrated in autoimmune thrombocytopenic purpura (AITP). A trial involving repeated injections of HDI was conducted in two adult patients with chronic AITP in order to evaluate their long-term efficacy in refractory forms and their ability to obviate splenectomy. Both patients received 2 g/kg body weight of polyvalent intact intravenous immunoglobulin followed by seven and eight boosters (0.8 to 1.2 g/kg body weight) when the platelet count decreased. It was found that the injections could be spaced progressively. The platelet count remained normal 200 and 800 days after the end of the treatment. The demonstration of the possible long-term efficacy of repeated injections of intravenous immunoglobulin encourages us to recommend this safe therapy for patients with chronic AITP.

Intravenous immunoglobulin therapy for idiopathic thrombocytopenic purpura.

Twenty-two patients with idiopathic thrombocytopenic purpura were treated with high-dose intravenous immunoglobulin infusions using an intact intravenous immunoglobulin preparation and a product designed for intramuscular administration. Seventeen patients (77%) responded favourably (rise in platelet count to 100 X 10(9)/1 or above). Children responded better than the adults, and the acute cases better than the chronic. Splenectomy and the presence of detectable platelet antibody had no effect on the response rate. Both products induced identical responses.

Use of intravenous immunoglobulin in chronic lymphocytic leukemia

Five patients with clinical stage III and IV chronic lymphocytic leukemia were treated with a five-day infusion of high-dose intravenous immunoglobulin for either autoimmune hemolytic anemia or immune thrombocytopenic purpura or by a dose of intravenous immunoglobulin G every three to four weeks for prevention and control of infections associated with hypogammaglobulinemia. The hematocrlt level stabilized with a decrease in red blood cell destruction by intravenous immunoglobulin G in chronic lymphocytic leukemia patients with AIHA without altering red blood cell autoantibody titers, but severe hemolysis recurred after 21 days. A long-term remission was observed when intravenous immunoglobulin G was combined with steroids, chemotherapy, plasmapheresis, and splenectomy. The platelet count increased and platelet transfusion requirement was eliminated in a chronic lymphocytic leukemia patient with immune thrombocytopenic purpura by the intravenous immunoglobulin G, and chemotherapy was administered and a complete remission resulted. An interesting observation was the lymphocytopenic effects observed in the five patients during a daily infusion of intravenous immunoglobulin for five days. Furthermore, the maintenance intravenous immunoglobulin G given every three weeks controlled both infections and lymphocyte counts with the chemotherapy. Changing the schedule to every four weeks resulted in poor control of the lymphocyte counts with chemotherapy. These observations indicate a direct macrophage blocking effect in autoimmune hemolytic anemia and immune thrombocytopenic purpura, but the lymphocytopenic effect suggests immunomodulating effects of intravenous immunoglobulin G, which may alter the response of chronic lymphocytic leukemia cells to chemotherapy.