Successful treatment of cytomegalovirus-associated hemophagocytic syndrome by intravenous immunoglobulins

Virus-associated hemophagocytic syndrome (VAHS) is a rare complication in early cytomegalovirus (CMV) infection. There is no standard therapy for VAHS and the clinical course is variable. Data on the use of intravenous immunoglobulin (IVIG) in the treatment of CMV-associated VAHS are limited. We report a previously healthy, 32-year-old woman who presented with general malaise, fever, chills, and splenomegaly. Laboratory examination showed marked elevation of aminotransferase, leucopoenia, and thrombocytopenia. Acute CMV-infection was documented by the presence of immunoglobulin M anti-CMV and positive viremia in blood sample. Bone marrow examination revealed extensive hemophagocytosis. IVIG was administered after the diagnosis of CMV-associated VAHS. Her symptoms and laboratory abnormalities improved dramatically after the onset of the treatment and she did not require antiviral agent.     

Successful treatment of refractory systemic lupus erythematosus with intravenous immunoglobulins

Two cases of refractory systemic lupus erythematosus (SLE) were successfully treated with intravenous immunoglobulins (IVIg). In Case 1, the immediate recovery from severe pancytopenia and the improvement of proteinuria were observed, following IVIg therapy in high doses (450 mg/kg) for 5 consecutive days. In Case 2, 3 courses of IVIg therapy (100 mg/kg) for 6 to 8 days resulted in a significant reduction of massive proteinuria. In both cases, the improvement of immunological variables was also seen.     

Clinical uses of intravenous immunoglobulins

Immunoglobulins are an important component of host defense against infections. They also play a central role in immune regulation. A wide spectrum of human diseases is associated with decreased or abnormal regulation of immunoglobulin levels. Recently IV preparations of immunoglobulin have become available for clinical studies. There are already substantial data indicating a useful role for IV immunoglobulin in patients with primary hypogammaglobulinemia, neonates predisposed to group B streptococcal infections, individuals with ITP, children with Kawasaki disease, and bone marrow transplant patients predisposed to CMV infections. Promising data have been reported in burn patients and in individuals with CLL; these data require confirmation. Potential areas for future investigation include AIDS, autoimmune disorders, and viral disorders other than CMV.     

Functional mechanisms of intravenous immunoglobulins

Polyclonal immunoglobulins for intravenous use are increasingly used in clinical practice. The mechanisms involved in the treatment of patients with immunodeficiency diseases are not yet clear. In this article we review the most important of these mechanisms and we illustrate the use of immunoglobulins in different diseases. We discuss the interactions with the Fc-receptors, the interactions with the complement system, the influence on superantigens, idiotype-anti-idiotype interactions and the influence on B and T cell receptors. A better understanding of these mechanisms can lead to a better use of these expensive preparations.     

Clinical use of intravenous immunoglobulins

Prophylaxis and treatment with i.v. immunoglobulins must envisage preparations from normal or hyperimmunised human donors, animals (horses and rabbits) as well as monoclonal and genetically and proteomically engineered chimeric or recombinant antibodies. The latter group of antibody sources from the bioreactor source must be seen in the context of traditional antibody therapy, including passive immunization, general antibody substitution and provision of lost immune regulatory capacities such as downregulation of complement activation, attenuation of Fc receptor apparatus as well as anti-idiotypic potential. Beyond summarizing the present evidence based indications the present review is an outlook at the doorstep for future possibilities to improve precision of antibody dependent treatments and avoiding side effects which formerly compromised widespread use.     

Immunomodulatory effects of intravenous immunoglobulins

Intravenous immunoglobulin (IVIg) has been used for many years in the treatment of primary and secondary antibody deficiencies. IVIg was first demonstrated to be effective in auto-immune desorders twenty years ago in the treatment of idiopathic thrombocytopenic purpura. The beneficial effect of IVIg has since been established in the Guillain-Barré syndrome, chronic inflammatory demenilating polyneuropathy, myasthenia gravis, dermatomyositis, Kawasaki syndrome and graft versus host disease. The beneficial effect of IVIg has been suggested in a large number of other auto-immune and systemic inflammatory conditions. The mode of action of IVIg is complex, involving Fc receptor blockade, interference with complement activation and the cytokine network, provision of anti-idiotypic antibodies and modulation of T and B cell activation and differentiation. Such a broad range of activities reflects the function of normal circulating immunoglobulins in maintaining tolerance to self in healthy individuals.     

Successful treatment of thymoma-associated pure red cell aplasia with intravenous immunoglobulins

Repeated cycles of intravenous immunoglobulins (IVIG) have been reported to be successful in a few patients with idiopathic pure red cell aplasia (PRCA) or associated with another pathology. The efficacy of this treatment for PRCA with thymoma has not been reported previously. We describe here the case of a 75-yr-old man who presented with PRCA associated with a benign thymoma. After failure of thymectomy, corticosteroids and octreotide, a complete durable remission was obtained after a single 5-d cycle of IVIG.     

Measles-virus-neutralizing antibodies in intravenous immunoglobulins

Measles infection induces lifelong immunity; however, wild-type infection stimulates higher levels of measles-virus-neutralizing antibodies (mnAbs) than does vaccination. Because the proportion of the donor population with vaccine-induced measles immunity is increasing, this study was conducted to determine whether this shift in demographic characteristics affects mnAb levels in contemporary lots of Immune Globulin Intravenous (Human) (IGIV). When 166 lots of 7 IGIV products manufactured between 1998 and 2003 were assayed by plaque-reduction neutralization test, there was a progressive decrease in geometric mean titers in lots manufactured between 1999 and 2002. IGIV products manufactured from recovered plasma had significantly higher titers than did those manufactured from Source Plasma, which could reflect a change in donor demographic characteristics, because Source Plasma donors tend to be much younger. A reduction in mnAbs also correlated with the loss of either IgG1 and IgG3, possibly because of certain manufacturing procedures, or bivalent antibodies (i.e., intact IgG and F(ab')2), because of fragmentation.     

The use of polyclonal intravenous immunoglobulins in the prevention and treatment of infectious diseases

In this review we discuss the prevention and treatment of infectious diseases with intravenous immunoglobulins (IVIG). IVIG can be used to prevent infections in primary as well as in certain secondary immunodeficiencies. We also discuss the use of IVIG in the prevention of CMV-disease after organ or bone marrow transplantation. Besides their use in prevention, IVIG can also be used as an additional therapy in sepsis in neonates, in streptococcal toxic shock syndrome and in CMV-disease after bone marrow or solid organ transplantation. We briefly discuss the different preparations of IVIG that are available in Belgium.     

Therapeutic use of intravenous immunoglobulins in the antiphospholipid syndrome

Although experience remains limited and uncontrolled, intravenous immunoglobulin (IVIg) therapy probably has a place in the management of selected patients with the antiphospholipid syndrome. It seems effective for the prevention of recurrent pregnancy losses when conventional strategies using subcutaneous heparin and low-dose aspirin have failed. IVIg are currently investigated in the treatment of recurrent in vitro fertilization failure associated with antiphospholipid antibodies. In patients with severe thrombocytopenia, IVIg usually induce a prompt but transient remission. Finally, IVIg associated with steroids and heparin might improve survival in the rare but life-threatening catastrophic antiphospholipid syndrome.     

High-dose intravenous immunoglobulin in the management of myasthenia gravis

Intravenous immunoglobulin, 400 mg/kg, was administered daily for five days to 12 patients with exacerbation of generalized myasthenia gravis. Degree of weakness, duration of illness, use of prednisone, and history of thymectomy or thymoma did not affect the response to intravenous immunoglobulin. Eleven patients improved, beginning 3.6 +/- 2.7 (mean +/- SD) days after the start of treatment and becoming maximal in 8.6 +/- 4.6 days, with sustained improvement lasting 52 +/- 37 days. Vital capacity increased from 1748 +/- 510 to 2700 +/- 614 mL at peak effect. Decreases in strength occurred in four patients beginning on day 3.2 +/- 2.5, lasted 1.5 +/- 0.6 days, and were mild in three patients. Other effects were minimal. There was no significant change in acetylcholine receptor antibody titers, which were elevated in all patients. Immunoglobulin seemed to produce a more rapid improvement than corticosteroids and is recommended as an adjunct in the management of myasthenia gravis exacerbations.     

Lupus refractory pleural effusion: transient response to intravenous immunoglobulins.

A patient with systemic lupus erythematosus complicated by refractory bilateral pleural effusions is described. High dose corticosteroids with azathioprine, as well as intrapleural instillation of corticosteroids, proved ineffective in management. As our patient remained severely symptomatic and required repeated thoracocentesis, a therapeutic trial of intravenous immunoglobulins (IVIG) was attempted. IVIG had a beneficial effect, although of a transient and partial nature. Despite the results achieved, it seems that IVIG has limited value in treating lupus pleural effusion.     

The prolonged administration of intravenous immunoglobulins as a treatment for refractory fistulous Crohn's diseases

Fistulating Crohn's disease is present in 17-35% of non-surgically treated patients and in up to 45% of surgically treated ones. Among the several therapeutic alternatives for this disease is intravenous immunoglobulin administration. We present a 28-year-old woman with refractory fistulating Crohn's disease who improved after prolonged immunoglobulin administration (32 months).