Novel Predictive Scoring System for Intravenous Immunoglobulin Resistance Helps Timely Intervention in Kawasaki Disease: The Chinese Experience.

Background: Approximately 10%-20% of patients with Kawasaki disease (KD) are nonresponsive to intravenous immunoglobulin (IVIG) treatment, placing them at higher risk of developing coronary heart lesions. Early detection of nonresponsiveness is crucial to curtail this risk; however, the applicability of existing predictive scoring systems is limited to the Japanese population. Our study aimed to identify a predictive scoring system for IVIG resistance in KD specific to the Chinese population. We aimed to assess the utility of three commonly used risk-scoring systems in predicting IVIG resistance and compare them to the newly developed predictive scoring system. Methods: A total of 895 patients with KD were enrolled in this retrospective review and divided into two groups: IVIG responders and nonresponders. Clinical and laboratory variables were compared between the two groups. Multivariable logistic regression models were used to construct a new scoring system. The utility of the existing and new scoring systems was assessed and compared using the area under the receiver operating characteristic curve. Results: Albumin levels, percentage of neutrophils, and hemoglobin were independent predictors of resistance by logistic regression analysis. The new predictive scoring system was derived with improved sensitivity (60.5%) and specificity (87.8%). The area under the receiver operating characteristic curve was 0.818. Conclusion: This study developed a novel risk-scoring system for predicting resistance to IVIG treatment in KD specific to the Chinese population. Although this new model requires further validation, it may be useful for improving prognostic outcomes and reducing the risk of complications associated with KD.

Intravenous immunoglobulins in dermatology. Part 1: biological mechanisms and methods of administration.

Intravenous immunoglobulin (IVIg) is a solution of human IgG, salt, sugars and solvents, which is used to treat a multitude of diseases. Although IVIg has been known to treat many diseases safely and successfully, there are relatively few supporting randomized controlled trials. In this article, we review the biological mechanisms of IVIg in dermatological disorders and the practicalities of its use, including its mechanism of action, dosing, availability, costs and adverse effects.

Assessment of Antibody-based Drugs Effects on Murine Bone Marrow and Peritoneal Macrophage Activation.

Macrophages are phagocytic innate immune cells, which initiate immune responses to pathogens and contribute to healing and tissue restitution. Macrophages are equally important in turning off inflammatory responses. We have shown that macrophages stimulated with intravenous immunoglobulin (IVIg) can produce high amounts of the anti-inflammatory cytokine, interleukin 10 (IL-10), and low levels of pro-inflammatory cytokines in response to bacterial lipopolysaccharides (LPS). IVIg is a polyvalent antibody, primarily immunoglobulin Gs (IgGs), pooled from the plasma of more than 1,000 blood donors. It is used to supplement antibodies in patients with immune deficiencies or to suppress immune responses in patients with autoimmune or inflammatory conditions. Infliximab, a therapeutic anti-tumor necrosis factor alpha (TNFα) antibody, has also been shown to activate macrophages to produce IL-10 in response to inflammatory stimuli. IVIg and other antibody-based biologics can be tested to determine their effects on macrophage activation. This paper describes methods for derivation, stimulation, and assessment of murine bone marrow macrophages activated by antibodies in vitro and murine peritoneal macrophages activated with antibodies in vivo. Finally, we demonstrate the use of western blotting to determine the contribution of specific cell signaling pathways to anti-inflammatory macrophage activity. These protocols can be used with genetically modified mice, to determine the effect of a specific protein(s) on anti-inflammatory macrophage activation. These techniques can also be used to assess whether specific biologics may act by changing macrophages to an IL-10-producing anti-inflammatory activation state that reduces inflammatory responses in vivo. This can provide information on the role of macrophage activation in the efficacy of biologics during disease models in mice, and provide insight into a potential new mechanism of action in people. Conversely, this may caution against the use of specific antibody-based biologics to treat infectious disease, particularly if macrophages play an important role in host defense against that infection.

Therapeutic advances in the treatment of vasculitis.

Considerable therapeutic advances for the treatment of vasculitis of the young have been made in the past 10 years, including the development of outcome measures that facilitate clinical trial design. Notably, these include: a recognition that some patients with Kawasaki Disease require corticosteroids as primary treatment combined with IVIG; implementation of rare disease trial design for polyarteritis nodosa to deliver the first randomised controlled trial for children; first clinical trials involving children for anti-neutrophil cytoplasmic antibody (ANCA) vasculitis; and identification of monogenic forms of vasculitis that provide an understanding of pathogenesis, thus facilitating more targeted treatment. Robust randomised controlled trials for Henoch Schönlein Purpura nephritis and Takayasu arteritis are needed; there is also an over-arching need for trials examining new agents that facilitate corticosteroid sparing, of particular importance in the paediatric population since glucocorticoid toxicity is a major concern.

Relative EBV antibody concentrations and cost of standard IVIG and CMV-IVIG for PTLD prophylaxis in solid organ transplant patients.

Some centers prefer CMV-IVIG over IVIG for the prophylaxis of EBV-related PTLD in solid organ transplant patients. Our objective was to compare the relative dose-related EBV ELISA antibody concentrations and cost of standard IVIG and CMV-IVIG. The concentration of EBV IgG to VCA was analyzed via ELISA in four lots of IVIG and four lots of CMV-IVIG. Relative EBV ELISA antibody concentrations and cost were compared assuming an IVIG dose of 0.5 gm/kg and CMV-IVIG dose of 0.15 gm/kg in a 50-kg patient. The price of IVIG was $70/gm and CMV-IVIG $430/gm. IVIG contains the same EBV antibody concentrations (20 790 ELISA antibody units/mL) than CMV-IVIG (17 430 ELISA antibody units/mL, p > 0.2) in the four lots of each product sampled. When factoring in the dosing scheme for a 50-kg patient, IVIG contains two times more EBV antibody than CMV-IVIG. Yet, CMV-IVIG is 1.8 times more expensive than IVIG ($3225 vs. $1750). In the four lots of each product sampled, IVIG contains more EBV antibodies and costs less than CMV-IVIG when factoring in the dosing scheme. Studies are needed to determine whether there is clinical efficacy of immunoglobulin products for EBV-related PTLD prophylaxis.

Use of intravenous immunoglobulin in the treatment of immune-mediated demyelinating diseases of the nervous system.

Intravenous immunoglobulins (IVIg) are used in treatment of a broad spectrum of diseases. Immunoglobulin replacement therapy is the standard treatment for immunodeficiencies with compromised humoural immunity. Use of this method as an immunomodulating therapy ranges from transplantation and treatment of autoimmune-haematological diseases to treatment of various neuroimmunological clinical entities. Limited quantitative availability due to dependence on human donors as a source of IVIg, coupled with high treatment costs, make necessary a highly responsible and evidence-based approach with these agents. Discussion of the indications and currently valid recommendations on use of IVIg in treatment of immunomediated demyelinating diseases of the nervous system is based on existing clinical studies. We describe further neurological indications for use of IVIg as well as mechanisms of action and adverse effects of its use.

The use of intravenous immunoglobulin for treatment of dermatological conditions in Australia: A review.

Intravenous immunoglobulin has been used in the treatment of various dermatological conditions, including toxic epidermal necrolysis, bullous pemphigoid and pemphigus vulgaris. From March 2008, the National Blood Authority has implemented the 'Criteria for the clinical use of intravenous immunoglobulins in Australia'. The new criteria have formalized the eligibility requirements for several dermatological conditions. This may increase access to intravenous immunoglobulin for treatment for these conditions. However, there remain stringent eligibility criteria with which dermatologists need to be acquainted. In some conditions, dermatology review is mandated by these criteria while in other conditions with skin manifestations, referral to other specialists is required. The following article provides a summary of the salient points in relation to the clinical use of intravenous immunoglobulin in dermatology, as well as its production and supply in Australia.

Intravenous immunoglobulin: properties, mode of action and practical use in dermatology.

Since they were first administered to patients with antibody deficiency disorders over 50 years ago, human intravenous immunoglobulin preparations have been used successfully to treat a rapidly increasing number of autoimmune and inflammatory disorders, among which are a series of cutaneous autoimmune and inflammatory diseases. These include dermatomyositis, Kawasaki's disease, a number of autoimmune bullous diseases, severe adverse drug reactions, and other autoimmune and/or allergic conditions, such as atopic dermatitis. Although only a minority of these indications (dermatomyositis, Kawasaki's disease) are officially registered or based on double-blind, placebo-controlled clinical studies, the observed efficacy and safety profile of currently available intravenous immunoglobulin sometimes makes this a treatment of choice for initiation of therapy or for replacement of more toxic alternatives, such as systemic immunosuppressive medications. The increasing use of intravenous immunoglobulin has been associated with further understanding of its mechanism(s) of action, clinical manipulation and associated side-effects, as well as the introduction of improved or new types of intravenous immunoglobulin. This paper reviews the current knowledge of the mode of action of intravenous immunoglobulin, its reported therapeutic effects in cutaneous disease, its mode of administration and safety profile, and compares the currently available intravenous immunoglobulin preparations.

Immunomodulatory effects of intravenous immunoglobulins as a treatment for autoimmune diseases, cancer, and recurrent pregnancy loss.

Intravenous immunoglobulin (IVIG) is a safe preparation, made of human plasma of thousands of healthy donors. The fascinating history of gamma globulin therapy begins in 1930 when Finland treated pneumococcal pneumonia patients with equine serum, which prolonged their survival from pneumonia. Since then, significant breakthroughs were achieved by Cohn, Bruton, Imbach, and others, whose clinical contribution to the world of medicine was of great importance. Originally IVIG was used to treat immunodeficiencies. Later on the use of IVIG extended to autoimmune diseases as well. The efficacy of IVIG has been established only in several autoimmune diseases; clinical reports of trials, series, and case reports indicate significant improvement in many more autoimmune diseases. IVIG have also showed antimetastatic effects in a variety of cancer cell lines, as well as in a few case reports. The efficiency of IVIG has also been observed in recurrent pregnancy loss (RPL), either as a result of an autoimmune disease or spontaneous. Several attempts were made to discover the immunomodulatory effects of IVIG, but it is still not fully understood. Clearly IVIG has multiple mechanisms of actions, which are thought to cooperate synergistically. One of the main mechanisms of actions of IVIG is its ability to neutralize pathogenic autoantibodies via anti-idiotypic antibodies within IVIG preparation. The ability of IVIG to neutralize pathogenic autoantibodies is of great importance in many autoimmune diseases, as well as in RPL. In cancer cell lines, IVIG modulates the immune system in a few ways, including the induction of IL-12 secretion, which consequently activates natural killer cells, and the induction of expression of proapoptotic genes only in cancer cells. Side effects from IVIG are rare and mostly mild and transient. More importantly adverse effects can be minimized by administration to a selective patient population in a proper way: slow infusion rate of 0.4 g/Kg body weight IVIG for 5 consecutive days, given in monthly cycles. The only downside of IVIG therapy is its high price. Therefore, clinicians should balance efficiency versus cost in deciding whether or not to treat certain conditions with IVIG.

Opsonic activity assessment of human intravenous immunoglobulin preparations against drug-resistant bacteria.

We have used the ability of opsonized bacteria to stimulate luminol-enhanced chemiluminescence (CL) of human polymorphonuclear leukocytes (PMN) to examine the opsonic capabilities of commercially available human intravenous immunoglobulin (i.v.Ig) preparations. The method was tested against 14 strains of drug-resistant gram-positive bacteria (including methicillin-resistant Staphylococcus aureus, hetero-vancomycin-resistant S. aureus, vancomycin-resistant enterococci, penicillin-resistant Streptococcus pneumoniae), and 23 strains of gram-negative bacteria (including extended-spectrum beta-lactamase-producing bacteria, metallo-beta-lactamase-producing bacteria, beta-lactamase-negative ampicillin-resistant Haemophilus influenzae). An Fc-intact i.v.Ig preparation treated with polyethylene glycol (PEG) was evaluated for opsonization effectiveness against these bacteria in vitro. The opsonization of these organisms was enhanced by an Fc-intact i.v.Ig, and the opsonic activity was dose dependent. A pepsin-treated i.v.Ig preparation exhibited poor opsonic activity for all bacteria tested. These results suggest that Fc-intact i.v.Ig, which augments opsonic activity against various drug-resistant bacteria, will be a useful addition to the treatment of severe bacterial infections in immunocompromised patients with impaired serum opsonic capacity.

The use of intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: evidence-based indications and safety profile.

Intravenous immunoglobulin (i.v.Ig) has multiple actions on the immunoregulatory network that operate in concert with each other. For each autoimmune neuromuscular disease, however, there is a predominant mechanism of action that relates to the underlying immunopathogenetic cause of the respective disorder. The best understood actions of i.v.Ig include the following: (a) modulation of pathogenic autoantibodies, an effect relevant in myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and stiff-person syndrome (SPS); (b) inhibition of complement activation and interception of membranolytic attack complex (MAC) formation, an action relevant to the complement-mediated mechanisms involved in GBS, CIDP, MG, and dermatomyositis (DM); (c) modulation of the inhibitory or activation Fc receptors on macrophages invading targeted tissues in nerve and muscle, as seen in CIDP, GBS, and inflammatory myopathies; (d) down-regulation of pathogenic cytokines and adhesion molecules; (e) suppression of T-cell functions; and (f) interference with antigen recognition. Controlled clinical trials have shown that i.v.Ig is effective as first-line therapy in patients with GBS, CIDP, and multifocal motor neuropathy (MMN), and as second-line therapy in DM, MG, LEMS, and SPS. In paraproteinemic IgM anti-MAG (myelin-associated glycoprotein) demyelinating polyneuropathies and inclusion body myositis (IBM), the benefit is variable, marginal, and not statistically significant. i.v.Ig has a remarkably good safety record for long-term administration, however, the following side effects have been observed: mild, infusion-rate-related reactions, such as headaches, myalgia, or fever; moderate but inconsequential events, such as aseptic meningitis and skin rash; and severe, but rare, complications, such as thromboembolic events and renal tubular necrosis. Future studies are needed to (a) find the appropriate dose and frequency of infusions that maintain a response; (b) address pharmacoeconomics, comparing the high cost of i.v.Ig to the cost of the other therapies, which, although less expensive, cause significantly more long-term side effects; (c) determine why some patients respond better than others; and (d) examine the merits of combining i.v.Ig with other immunosuppressive drugs.

Utility of intravenous immune globulin in kidney transplantation: efficacy, safety, and cost implications.

Intravenous immunoglobulin preparations (IVIG) are known to be effective in the treatment of various autoimmune and inflammatory disorders into their immunomodulatory, immunoregulatory, and anti-inflammatory properties. Recently, IVIG has been utilized in the management of highly sensitized patients awaiting renal transplantation. The mechanisms of suppression of panel reactive antibodies (PRA) in patients awaiting transplantation are currently under investigation and appear to be related to anti-idiotypic antibodies present in IVIG preparations. In this review, the various immunomodulatory mechanisms attributable to IVIG and their efficacy in reducing PRAs will be described. In addition, the use of IVIG in solid organ transplant recipients will be reviewed. The adverse events, safety considerations, and economic impact of IVIG protocols for patients awaiting solid organ transplantation will be discussed.

Properties of a new intravenous immunoglobulin (IGIV-C, 10%) produced by virus inactivation with caprylate and column chromatography.

BACKGROUND AND OBJECTIVES: Current manufacture of intravenous immunoglobulin (Gamimune N) uses four cold-ethanol precipitation steps and solvent-detergent treatment. Our objective was to design a new manufacturing process to maximize immunoglobulin G (IgG) purity, achieve robust viral safety, preserve all the biological activities of antibody and avoid unnecessary protein loss. MATERIALS AND METHODS: The new process combines multiple functions in single steps. Caprylate is added to precipitate non-IgG proteins and to inactivate enveloped viruses. Two successive anion-exchange columns are used to purify IgG and remove caprylate. The new product, IGIV-C (Gamunex, 10%) is formulated with glycine at 100 mg/ml IgG, pH 4.25. Vials are incubated for 21 days at 23-27 degrees C in a final virus-inactivation step. RESULTS: Compared with the process for production of Gamimune N, that for IGIV-C requires a shorter production time, achieves more robust virus inactivation, increases IGIV yield from plasma, improves physiological IgG subclass distribution (resulting in higher levels of IgG4), and improves purity, with lower levels of IgA (40 microg/ml), IgM (< 2 microg/ml) and albumin (< 20 microg/ml). Antibody binding, opsonization and protective activities are similar. CONCLUSIONS: Compared with the current commercial process, the new IGIV-C manufacturing process produces a more highly purified preparation that contains slightly higher levels of IgG4 and retains antibody activities required for clinical efficacy.

Intravenous immunoglobulin in neurological disease: a specialist review.

Treatment of neurological disorders with intravenous immunoglobulin (IVIg) is an increasing feature of our practice for an expanding range of indications. For some there is evidence of benefit from randomised controlled trials, whereas for others evidence is anecdotal. The relative rarity of some of the disorders means that good randomised control trials will be difficult to deliver. Meanwhile, the treatment is costly and pressure to "do something" in often distressing disorders considerable. This review follows a 1 day meeting of the authors in November 2000 and examines current evidence for the use of IVIg in neurological conditions and comments on mechanisms of action, delivery, safety and tolerability, and health economic issues. Evidence of efficacy has been classified into levels for healthcare interventions (tables 1 and 2).

Criteria for the appropriate drug utilisation of immunoglobulin.

Intravenous immunoglobulins (IVIGs) are prepared from human plasma pools and further modified enzymatically or chemically. Despite careful selection of donors and inclusion of effective virus elimination steps in the production process, contamination with hepatitis C virus can still occur. IVIGs possess most of the characteristics of native immunoglobulins, such as antigen neutralisation and complement activation. The serum half-life of native immunoglobulin is about 21 days, and comparable half-lives have been reported for several IVIG preparations. IVIGs have received general approval for the treatment of primary immuno-deficiencies such as agammaglobulinaemia. Of the secondary immuno-deficiencies, only paediatric AIDS, chronic lymphocytic leukaemia and multiple myeloma, as well as allogeneic bone marrow transplantation, are accepted indications for IVIGs. Because of their immunomodulatory action, IVIGs are also recommended for the treatment of idiopathic thrombocytopenic purpura, Kawasaki disease (mucocutaneous lymph node syndrome) and, recently, Guillain Barre syndrome IVIGs have been investigated in a wide range of immunodeficient states (e.g. prematurity) and autoimmune diseases (e.g. multiple sclerosis), but conclusive results are not available. Since IVIGs are associated with a certain risk of transmission of viral infections and, secondly, because they are generally acknowledged as expensive drugs, their use requires careful consideration of risk, benefit and cost.

High dose intravenous immunoglobulins in systemic lupus erythematosus: clinical and serological results of a pilot study.

OBJECTIVE: To investigate the effect of high dose intravenous immunoglobulins (IVIG) in systemic lupus erythematosus (SLE). METHODS: Twelve patients with mildly to moderately active disease were given 30 g of sulfonated IVIG preparation on each of Days 1-4 and 21-24. RESULTS: Within 6 weeks the mean disease activity score, the Systemic Lupus Activity Measure (SLAM), declined from 7.33 (range 3-15) to 5.25 (range 0-10) (p < 0.01). In 9/12 patients the SLAM dropped by at least 2 points. In 3/12 patients the improvement lasted 5 to 12 months. Within 1 week after initiation of therapy most patients showed a decline in ds-DNA antibodies, whereas titers of antinuclear antibodies and complement proteins were not affected. The treatment was well tolerated, with the exception of transient hypotension in one patient. CONCLUSION: In this uncontrolled study, IVIG had temporary beneficial effects in mildly to moderately active SLE.

Opsonic activity of commercially available standard intravenous immunoglobulin preparations.

Several standard intravenous immunoglobulin G (IVIG) products are available in the United States and have been used with the intent to treat or prevent infections in neonates. We evaluated more than 100 lots of IVIG, from 6 products, to determine the amount of opsonic antibody against neonatal pathogens. Neutrophil-mediated opsonophagocytosis was used to determine opsonic activity in these preparations for Staphylococcus epidermidis; Haemophilus influenzae type b; Streptococcus pneumoniae serotypes 3, 14 and 19; Group B Streptococcus serotypes Ia, Ib, Ia/c, II and III; and Escherichia coli (K1). Pathogen-specific opsonic activity of the lots tested ranged from undetectable to 1:80 and was detectable in < 10% to > 90% of lots tested depending on the organism and manufacturer. Within an IVIG lot there was variable opsonic activity against different strains or serotypes of the same organism. Opsonic activity was significantly (P < or = 0.05) affected by the manufacturer's donor pool and less so by the manufacturing method. We conclude that the pathogen-specific opsonic antibody activity of an IVIG lot is: (1) highly variable for several common neonatal pathogens; (2) predominantly dependent on the donor pool and not the manufacturing method. Clinicians may more appropriately select therapy if the pathogen-specific antibody content of IVIG products by lot are known. In the future neonatal IVIG research should focus on using preparations with known pathogen-specific antibody activity.