Applications of Intravenous Immunoglobulin in Haematology

A. A. M. Todd, P. L. Yap SUMMA R Y. Intravenous immunoglobulin (IVIgG) has many potential applications in haematology both as antibody replacement therapy and as an immune-modulater in autoimmune disorders. Antibody replacement appears to be of value in the prophylaxis of infection in low-grade B-cell malignancies, in bone marrow transplant recipients and in children with AIDS, although optimal treatment strategies have not been assessed and determining which patients are likely to derive greatest benefit has been problematic. IVIgG appears to be effective in the prevention or amelioration of CMV-related pathology if given frequently and has also dramatically improved the survival of patients with established interstitial pneumonia when used in combination with ganciclovir. Intriguingly, IVIgG appears to moderate the severity of GVHD in adult transplant recipients. IVIgG has short term efficacy in most patients with ITP but, as long term remissions are uncommon, it has become necessary to be more selective in the use of IVIgG in this disorder. The response to IVIgG in other immune-mediated cytopenias is similar with generally transient improvement but also with occasional spectacular cures. The treatment of the acquired haemophilias with IVIgG has yielded in vivo and vitro evidence to support the idiotype-antiidiotype theory of IVIgG immune-modulation and has also demonstrated significant differences in the sensitivity of coagulation factor autoantibodies and alloantibodies to IVIgG therapy. IVIgG has several roles in pregnancy related disorders, including the management of both mother and fetus in ITP during pregnancy, the antenatal and postnatal management of platelet alloimmunisation and also in the management of severe rhesus isoimmunisation. IVIgG is safe and well tolerated. The expense of this therapy should be balanced against the likely gains and the overall costs of alternative approaches.

Intravenous immunoglobulin (IVIgG) has a wellestablished role in the replacement therapy of patients with primary immunodeficiencies such as X-linked agammaglobulinaemia (XLA) and common variable immunodeficiency (CVI) with undoubted efficacy in the prevention of infection and improvement in quality of life in these individuals. A. A. M. Todd MRCPatb, P. L. Yap, PbD, MRCPatb, Edinburgh and SE Scotland Blood Transfusion Service, Lauriston Building, 41 Lauriston Place, Edinburgh EH3 9HB, UK. Correspondence to A. A. M. Todd. Blood Reviews (1992) 6. 105-I 17 II’ 1992 Longman Group UK Ltd

The increased availability of a number of licenced IVIgG preparations and the recognition that IVIgG had potential as an immunomodulatory agent has led to an explosion of studies in secondary immunodeficiency states and conditions with an underlying autoimmune (or presumed autoimmune) aetiology. IVIgG therapy is popular with physicians and patients alike., beingY easv_ to administer and (relativelv).I innocuous. There is now an abundance of literature on the topic, much of it relating to poorly controlled or uncontrolled trials and anecdotal reports. This review

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will assess the evidence for the use of IVIgG in relation to haematological disorders and provide some guidance in the selection of dose and frequency of administration. Historical Background’ Antibody Therapy

Much progress has been made since the first Nobel prize winner, von Behring, developed the production of the diphtheria antitoxin in 1895. Subsequent studies established the efficacy of antitoxin in the prevention of scarlet fever, tetanus and measles and identified that the active ingredients were contained within the globulin fraction of serum. A massive effort initiated by Cohn following the outbreak of World War II established a fractionation method using lowered ionic strength with low concentrations of alcohol and temperature to produce large quantities of immunoglobulin from human plasma pools that were safe for intramuscular administration. A natural progression from the use of this intramuscular preparation for the prevention of specific infections came in 1952 when Bruton described the first patient with XLA and demonstrated the efficacy of replacement therapy. Increasing numbers of antibody deficient patients were identified and the need for an alternative to the intramuscular preparation was recognised as the large doses required were painful and unpopular with the patients. Unfortunately, intramuscular preparations caused anaphylactoid reactions when administered intravenously in almost all patients with XLA or common variable immunodeficiency (CVI). The Development of Intravenous Immunoglobulin (IVIgG)

As the reactions to standard immunoglobulin preparations were felt to be due to complement activation by IgG aggregates, initial steps in the preparation of an IVIgG product suitable for intravenous use concentrated on the removal of these aggregates by proteolytic digestion using pepsin or plasmin. Whilst this was successful in reducing the frequency of reactions the material was largely F(ab), fragments and lacked Fc function. Subsequently, pH reduction to pH 4 and the addition of trace amounts of pepsin (1 : 10 000) was found to yield largely ‘intact’ immunoglobulin with no loss of biological function and little anti-complementary activity. Other approaches to the production of safe and effective intravenous preparations have been successfully employed and a number of IVIgG preparations are now available (Table 1). Composition

and Pharmacokinetics

of IVIgG

IVIgG contains almost entirely IgG with less than 2% IgA and IgM. As yet, a definite role has not been

IN HAEMATOLOGY Table 1 Comparison of some commercially available IVIgG preparations* Product (manufacturer)

Preparation (stabiliser)

Endobulins (Immuno)

Immobilised trypsin PEG precipitation (glucose) pH4/trace pepsin (sucrose) pH4.25 (maltose) DEAE-Sephadex adsorption (glucose, PEG, albumin) PEG precipitation DEAE-Sephadex (mannitol, albumin)

Sandoglobulina (Sandoz) Gamimune-NR (Cutter) GammagardR (Baxter) VenoglobulinR (Alpha)

IgA mg/ml co.10

< 1.57 co.27 co.06 0.03 +0.008 (mean)

*Data in this table is derived from a number of sources and is not intended to imply therapeutic differences between products

established for the IgM enriched preparations which are currently available. The proportions of the IgG subclasses reflect those in the normal population although there are slight differences between the available preparations which reflect the sensitivity of the different subclasses to the particular manufacturing methods. In general the antibody profile reflects the serological responses to endemic pathogens and immunisation status of the donor population, with the use of plasma pools from around 10 000 donors resulting in minimal lot to lot variation in specific antibody titres. IVIgG as Antibody Replacement

Much experience has been gained in the treatment of primary immunodeficiency states with IVIgG which has yielded valuable information about the pharmacokinetics and effective dosage, and formed a basis for the management of secondary immune deficiency states in a variety of settings.2 While the clearance of IgG may be altered by the underlying disease state, the conclusions which can be drawn from the results of therapy in XLA and CVI provide a logical starting point for the management of secondary antibody deficiency states. Patients with primary hypogammaglobulinaemia present with a history of recurrent bacterial infections, particularly of the respiratory tract, with sinusitis, otitis media and chronic bronchial sepsis. Giardiasis and autoimmune disorders are common. Most viral and fungal infections are, however, not more common, due to the generally intact cell-mediated immune system. IgG levels in symptomatic patients are almost invariably very low (~2.0 g/l) with concomitant reduction in IgA and IgM.3 Commencement of regular IVIgG in a dose of around 200-400 mg/kg every 3-5 weeks brings the pre-infusion IgG level into the normal range in the majority of patients with a resulting marked reduction in the frequency of bacterial infections and improvement in general health.

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Secondary antibody deficiency occurs in a number of haematological conditions (Table 2) and the potential for replacement therapy in these disorders has been investigated (see below). IVIgG as an Immune Modulator

The immunomodulatory role of IVIgG was first recognised in the treatment of immune thrombocytopenic purpura (ITP, see below) and has subsequently been investigated in a number of other immunemediated cytopenias and coagulopathies (Table 2). The mechanism of action has often not been identified but IVIgG has been demonstrated to alter elements of the immune system in a variety of ways, any or all of which may be responsible for its’ efficacy 4,5 (Table 3). Reticuloendothelial Blockade

High doses of IgG may block the Fc receptors or alter Fc receptor expression either directly or by induction of antibody mediated haemolysis. It is likely that this mechanism plays a role in the early response in ITP, although it cannot account for late or long term responses.

Table 2 Potential haematology

roles for intravenous

immunoglobulin

in

Antibody replacement in: -Low-grade B cell malignancies -Bone marrow transplantation -HIV infection in children Immune modulation in: -Immune-mediated thrombocytopenias -Autoimmune neutropenia, red cell aplasia -Autoimmune haemolytic anaemia -Coagulation factor inhibitors -Graft-versus-host disease -Rhesus haemolytic disease Anti-viral effect in: -CMV prophylaxis/therapy in BMT -Parvovirus B19 associated aplasia -Virus-associated haemophagocytic syndrome

Table 3 Possible cytopenias

mechanisms

of action

of IVIgG

in immune

Immediate -Elimination of circulating immune complexes -Competitive (non-specific) inhibition of IgG or immune complex binding to cell surface -Competitive inhibition of Fc-receptor mediated binding of target cell to macrophage -Specific (antiidiotype) inhibition of autoantibody binding to cell surface antigen (eg platelet glycoprotein IIb/IIIa) Delayed -Reduction in autoantibody synthesis through: Reduced T-helper/inducer numbers/activity Increased T-suppressor numbers/activity Reduced B-cell proliferation/maturation Reduced immunoglobulin synthesis -Neutralisation of autoantibody by induction of antiidiotype production

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Antiidiotype Antibodies

Direct neutralisation of the antibody involved in the immunopathological process may be due to the presence of an antiidiotype antibody in the IVIgG. Evidence for this mechanism has been detected in the successful treatment of acquired haemophilias (see below).

Suppression

qf Antibody

Synthesis

This may be a result of non-specific inhibition of IgG production by the high plasma levels of IgG or by enhancement of T-suppressor function. Specific inhibition may also result from the idiotype-antiidiotype interaction. Clearance of a persistent infectious agent and blockade of specific antibody and immune complex binding are other proposed mechanisms with little supporting evidence.

Antibody Deficiency

in Low-grade B-Cell Malignancy

Chronic Lymphocytic Leukaemia (CLL) Hodgkins Lymphoma (NHL)

and Non-

Hypogammaglobulinaemia is common in patients with chronic lymphocytic leukaemia (CLL), increasing in frequency with stage and duration of the disease. Patients with CLL have a 5-fold increase in infection, predominantly bacterial, in comparison with age-matched controls6 and similar problems are seen in patients with hypogammaglobulinaemia secondary to low-grade non-Hodgkins Lymphoma (NHL). Results of a randomised multicentre trial of IVIgG in CLL were reported recently.7 8 1 patients with CLL were randomly assigned to receive either IVIgG (400 mg/kg) every 3 weeks or saline placebo on the basis of an increased susceptibility to infection (serum IgG level < 50% of the lower limit of normal or a history of one or more serious infections). There was a significant reduction in the incidence of bacterial infections in the treatment group (23 vs 47) while the incidence of viral and fungal infections remained unchanged. 18 of the 23 bacterial infections in the treatment group occurred at a time when the serum IgG level was below the normal range. A crossover study of 8 patients from the original group and four with NHL using the same IVIgG schedule confirmed the reduction in bacterial infection during the IVIgG therapy phase.* A recent analysis of the cost effectiveness9 of results from the multicentre trial in CLL7 suggested that prophylactic therapy with IVIgG might not result in improvement in duration or quality of life in treated patients, particularly when the inconvenience of the regular infusions is considered. The above trial in CLL patients7 has shown that there are no clear parameters on which to select a particularly vulnerable group of patients with CLL

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and, as yet, no comparisons of the efficacy of IVIgG and prophylactic antibiotics have been published. Myeloma

Patients with monoclonal gammopathies commonly have suppression of normal IgG production despite high total immunoglobulin levels and, historically, in patients with myeloma, bacterial infection was the immediate cause of death in up to 5O%.‘j In a randomised trial of 10 g IVIgG every 3-4 weeks in 94 patients with IgG or IgA myeloma there was a reduction in the number of patients experiencing symptomatic infection from 68% in the untreated group to 19.5% in the IVIgG group. This benefit was confirmed following cross-over of the two groups” and was obtained with a relatively modest dose of IVIgG despite the accelerated immunoglobulin catabolism which appears to pertain to this group of patients. Awareness of the risks of infection, particularly during the first 3 months of therapy, has increased and, as a result, the rates of infection and infection related mortality have decreased in comparison with historical data. A recent multicentre trial of IVIgG prophylaxis, run in conjunction with the MRC VI Myelomatosis trial was completed in 1991 and analysis of the results of this should help to clarify the role of IVIgG in the present management of myeloma patients. Therefore, despite the statistical evidence of benefit from IV/IgG prophylaxis in patients with CLL, lowgrade NHL and myeloma, this approach cannot generally be recommended as standard therapy for this group of patients. It may be that similar benefit can be obtained by the judicious use of prophylactic antibiotics.

IVIgG in Bone Marrow Transplantation Immunodejiciency Post-BMT

Following bone marrow transplantation, a cellular and humoral immunodeficiency state exists which is particularly profound for the first 4-5 months after transplantation. Full recovery may be delayed for 2 years or even longer’l in patients with chronic graftversus-host disease (GVHD). Low serum levels of all immunoglobulin classes are found in the first 3 months and IgA deficiency may persist. IgG subclass deficiency (commonly IgG2 and IgG4) occurs in long term survivors which may predispose them to recurrent bacterial infections,” particularly with pneumococcus and haemophilus. Functional asplenia has been noted in patients with chronic GVHDi3 and qualitative immunoglobulin defects may exist, leading to an inability to mount specific antibody responses. Infections complicate every phase of the transplant procedure and cause, or contribute to, mortality in 20-40% of cases. IVIgG may have several potential

IN HAEMATOLOGY

roles in BMT: (1) prophylaxis and treatment of cytomegalovirus (CMV) infection; (2) prophylaxis of early and late bacterial infections, and (3) prophylaxis or modification of acute GVHD.

IVIgG in Post-BMT CMV Infection Epidemiologyt4

CMV infection in the post-transplant period may arise as a result of primary infection, reactivation of latent CMV or possibly reinfection with variant CMV strains. It is particularly common in CMV seropositive recipients (approximately 70%) and is a cause of severe post-transplant morbidity and mortality, particularly due to interstitial pneumonia and haemorrhagic enteritis. Although the incidence of CMV infection in patients who are seronegative at the time of transplantation is about 40% in those receiving unscreened blood products, provision of blood products exclusively from CMV-seronegative donors or the use of leucodepleted blood products15 reduces the incidence of infection to approximately 3%.16 Nevertheless, the majority of BMT recipients are CMV-seropositive and/or have a seropositive donor, and in these patients the use of CMV-seronegative blood products does not appear to reduce the incidence of CMV infection. Passive immunoprophylaxis against primary CMV infection using high-titre CMV immunoglobulin or standard IVIgG has been extensively studied, but with such a variety of doses, dosage frequency and patient groups that the efficacy of such an approach remains debatable. CMV antibody titres differ markedly between the available products, between lots of a single product and depending on the method of estimation. Doses used in prophylaxis have ranged from 200 mg/kg for three doses at 25 day intervals to 1000 mg/kg weekly for 17 weeks.i7 As the halflife of CMV antibody is approximately 5 days,l* it is likely that these differences will have a significant effect on the outcome of the trials. The successful reduction in incidence of CMV infection in trials utilising weekly therapy may bear this out. While IVIgG may not prevent CMV reactivation there is evidence that the severity of the infection may be reduced with a lower incidence of interstitial pneumonia. l9 An in vitro comparison of five available IVIgG products showed superiority of two standard IVIgG preparations in neutralising clinical isolates of CMV compared to the two hyperimmune products but in vivo comparisons are not available.20 Acyclovir prophylaxis in BMT led to a significant reduction in the development of CMV infection and invasive cytomegalovirus disease in the treated of this approach with group. 21 A combination prophylactic IVIgG may be more effective than either

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therapy in isolation, particularly for those at greatest risk.22 The use of IVIgG alone in the therapy of CMV related interstitial pneumonia has been ineffective, as has the use of a variety of antiviral drugs, whether used singly or in combination. However, recent trials of a combination of ganciclovir (9-[ 1,3-dihydroxy-Zpropoxymethyl] guanine) and IVIgG have shown convincing efficacy in the treatment of CMV pneumonia with an increase in survival compared with historical controls (up to 70% cf < 15%).23

IVIgG in the Prevention of Bacterial Sepsis Following BMT

IVIgG has also been shown to have an impact on the incidence of post-BMT septicaemia. In a randomised trial of IVIgG (500 mg/kg weekly to day 90, then monthly to day 360 after transplantation), the Seattle group found a significantly reduced incidence of gram-negative septicaemia and local infection.” Similar results have been shown in children.24 As a result of the combined immune defects described above, susceptibility to recurrent bacterial infection may persist beyond the immediate posttransplant period. There may be a role for long term prophylactic IVIgG therapy in certain patients, particularly when prophylactic antibiotic therapy is ineffective.i2

Efect

of IVIgG

on GVHD

and Platelet

Requirements

The incidence and severity of acute GVHD appears to be reduced in adult patients receiving IVIgG in the post transplant period” although this does not appear to be the case in children.24 Platelet transfusion requirements are also reduced.” It is not clear if these manifestations are a direct result of the immunomodulatory effect of IVIgG or if they are secondary to the reduced incidence of infection.

igM enriched Products Pentaglobin is an intravenous IgG preparation enriched with IgM (12%) and IgA (12%). A recent study of 10 patients with moderate-moderately severe acute GVHD suggested that Pentaglobin might have a slight effect in reducing the severity of this complication.25 In addition, a recent randomised, controlled trial using this preparation prophylactically in BMT candidates showed significant protection against infection related mortality and a reduction in posttransplantation hepatic damage, perhaps due to a reduction in endotoxaemia in the immunoglobulin recipients.26

Immune Thrombocytopenic

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Purpura (ITP)

There is no doubt that IVIgG can lead to a temporary increase in the platelet count in the majority of children and adults with ITP, whether primary or secondary to an underlying disease such as CLL, connective tissue disorders or HIV infection. Nevertheless, the paucity of long term responses, particularly in adults, has tempered initial enthusiasm and has prompted a more critical evaluation of the appropriate role of IVIgG in ITP.27 In childhood acute ITP, rapid spontaneous remissions are seen in the majority of cases. The incidence of intracranial haemorrhage (ICH), the most feared complication in this condition, is so rare as to make trials of any prophylactic therapy impossible to perform. In addition, anecdotal reports suggest that ICH may occur despite active therapy. Therapy with steroids or IVIgG in the acute phase does not appear to increase the proportion of cases achieve rapid remission, but, in a randomised trial of steroids or IVIgG in 108 children with acute ITP, those who entered remission more slowly or who required a further course of therapy were more likely to achieve sustained remission if they had received IVIgG.28 It is possible, therefore, that IVIgG alters the natural history of the disease. Similarly, adults who receive a course of IVIgG within 6 months of diagnosis may be more likely to achieve a sustained remission compared to those treated in chronic phase.29 Most adults and children in chronic phase treated with IVIgG will have a rise in platelet count lasting at least a few days which may be useful to cover surgical procedures. The benefit of IVIgG therapy prior to splenectomy is controversial as few haemostatic problems are experienced even in the absence of this therapy. However, there is recent evidence suggesting that pre-splenectomy infusion of IVIgG may increase the post-splenectomy remission rate and it would seem appropriate to administer IVIgG with this aim in mind.30 Regular infusions of IVIgG have been used in childhood ITP to avoid or postpone splenectomy and two thirds of children treated in this way may eventually stabilise off IVIgG therapy.31 It should be remembered, however, that spontaneous remissions in childhood ITP may be seen many years after presentation. Chronic ITP is a common manifestation of HIV infection with a frequency of j-30% depending on stage of disease. These patients respond at least as well as non-HIV related cases to standard therapies including steroids, IVIgG and splenectomy. IVIgG has the advantage of being less immunosuppressive than many of the alternative approaches but, again, sustained remissions are uncommon. 32 AZT raises the platelet count to haemostatic levels in the majority of HIV-infected patients and it is likely that the role of IVIgG in these patients will be

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mainly limited to providing cover for surgical procedures or managing acute haemorrhage. Dosage Initial trials of IVIgG in ITP employed doses of l-2 g/kg over 2-5 days. It is now clear that many patients will respond to rather lower doses of around 0.8-1.0 g/kg31*34 given as 1 or 2 infusions, thereby considerably reducing the cost of therapy and enabling treatment to be given on an outpatient basis. Patients requiring regular maintenance therapy may respond to a dose of 0.5 g/kg and there is no evidence that those who respond to this dose are likely to have more prolonged remissions with higher doses. Anti-D

Therapy

in ITP

It has been postulated that low levels of red cell antibodies in IVIgG may be responsible for some of the responses seen in IVIgG therapy of ITP by the substitution of antibody coated red cells for antibody coated platelets on the Fc receptors of the reticuloendothelial system. Intravenous anti-rhesus (D) immunoglobulin has now been shown to be effective in the majority of Rh(D) positive patients with ITP, including those with HIV-related ITP, although there is disagreement about whether it is ever effective in Rh(D) negative patients, perhaps acting through a different mechanism. A variety of studies have used a wide range of doses and some authors have reported a doseresponse effect.35-40 Understandable concern has been expressed about the potential of depleting supplies of anti-D intended for prophylaxis of rhesus-isoimmunisation through the increasing use of this product in large doses for patients with ITP. The eventual availability of monoclonal anti-Rh(D) suitable for clinical use may resolve this problem. For the present, anti-Rh(D) therapy cannot be recommended for routine use in ITP but should be considered for patients refractory to alternative therapy (including standard IVIgG, immunosuppressive agents, danazol and interferon) or for whom these alternatives are unsuitable and who are having significant haemorrhagic problems. Refractoriness to Platelet Transfusions

The development of HLA antibodies can lead to refractoriness to random donor platelet transfusions and this complication can be difficult to manage, even with HLA compatible platelets. There are a number of reports from anecdotal or non-randomised studies in the literature suggesting that IVIgG is effective in a significant minority. 41,42 However, this has not been confirmed in a randomised study which showed a minimal improvement in the 1 h platelet increment in a group of patients randomised to receive IVIgG in comparison with controls.43 It may be that the

IN HAEMATOLOGY

occasional reports of successful therapy are related to the concomitant production of platelet autoantibodies by some of these patients with a response analogous to that seen in ITP. IVIgG therapy cannot, therefore, be recommended in this disorder. Post-transfusion

Purpura (PTP)

PTP is an immune mediated thrombocytopenia which occurs 2-10 days after blood transfusion. Most cases have occurred in multiparous women following their first blood transfusion but exceptions to this are not uncommon.44 Serological investigation has demonstrated one or more platelet reactive alloantibodies in the serum of affected patients and in 90% of cases this has been specific for the platelet antigen PlA’ (or Zw”). Invariably, the platelets of the affected individual lack the offending antigen and there has been much speculation as to the mechanism of platelet destruction.45 There is some evidence that there is transient autoantibody formation in addition to the alloantibody and that it is this autoimmune response which is responsible for the thrombocytopenia. Alternatively, passive adsorption of free PlA’ antigen or immune complexes onto the surface of the recipients platelets may render them susceptible to destruction by alloantibody binding. Whilst PTP is a self-limiting disease with return of the platelet count to normal within 1 to 6 weeks, it cannot be considered a benign disorder as severe thrombocytopenia and mortality due to intracranial haemorrhage is not uncommon.46 Therapy with steroids and plasma exchange resulted in occasional successes but IVIgG has transformed the management of this disorder and is now clearly the treatment of choice. There are few failures and the response to doses of l-2 g/kg over 2-5 days is seen within 24 h. Occasional patients may require a second course of IVIgG to sustain the platelet count until natural resolution occurs. Neonatal Platelet Alloimmunisation

Fetal thrombocytopenia secondary to plateletalloimmunisation is associated with a high incidence of fetal morbidity and mortality secondary to intracranial haemorrhage, often occuring in utero.47 The majority of cases are due to the production of PlA’ antibodies in the PIA’ negative mother and may occur during the first pregnancy. Active management of the affected pregnancy is difficult, as determination of the fetal platelet count and intrauterine intravascular PIA’ transfusions are technically difficult and available at only specialised centres. Steroids are not effective antenatally but recently it has been shown that IVIgG given antenatally to the mother (1 g/kg/week from week 20) and postnatally to the affected infant can improve the expected outcome in these pregnancies.47 Never-

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theless, this approach is not uniformly successful and close fetal monitoring with fetal platelet counts prior to the commencement of therapy and 5-6 weeks later to monitor response is advisable. At the time of blood sampling, a transfusion of compatible platelets can be administered and may maintain the fetal platelet count for several days. If the fetus is found to be severely thrombocytopenic despite maternal IgG therapy, early elective caesarean section can be planned with transfusion of compatible platelets in the postnatal period. Unfortunately, this disorder is commonly diagnosed following the delivery of a severely affected baby in the first pregnancy. In these infants the treatment of choice is the administration of compatible (e.g. washed, maternal) platelets. If these are not available or delay is anticipated, IV/IgG in a dose of l-2 g/kg may lead to a haemostatic platelet increment and improve the survival of random donor platelets. Recent in vitro studies have demonstrated that IVIgG reduces the transfer of anti-PlA’ across the placenta and it is possible that this mechanism is responsible for the successful outcome in some pregnancies4* In the future, direct administration of IVIgG to the fetus may improve the outcome in this condition. Thromhocytopenia

in Pregnancy

The pathogenesis of thrombocytopenia in pregnancy is complex and it may be difficult, in the individual patient, to be certain of the underlying aetiology, particularly in the absence of any significant history or abnormal clinical findings. Patients with a past history of ITP may well present with thrombocytopenia during pregnancy with the possibility of morbidity in both mother and fetus, due to transfer of platelet auto-antibodies across the placenta. Up to 50% of infants born to mothers with a history of ITP have reduced platelet counts, which resolves spontaneously as the antibody is cleared but with significant morbidity in occasional infants.47 A recent review of 162 women with a presumptive diagnosis of immune thrombocytopenia in pregnancy demonstrated that those without a past history of ITP. and those with a history of ITP but without circulating platelet antibodies gave birth to no infants with severe thrombocytopenia ( < 50 x lOg/l).4QThere was poor correlation between the maternal and neonatal platelet counts, regardless of maternal therapy. Steroids may raise the maternal platelet count but there is a theoretical risk of antibody dissociation and exacerbation of fetal thrombocytopenia if these are used near term. Refractory patients may respond to IVIgG infusions administered to maintain maternal haemostasis or withheld until the third trimester with the possibility of elevating both the maternal and fetal platelet counts. 5o Delivery by caesarean section may be desirable in pregnancies felt to be at particular risk because of a past history of neonatal morbidity

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or splenectomy (due to the high risk of neonatal thrombocytopenia) but there is no evidence that this removes the risk of intracranial haemorrhage. The advisability of assessing the fetal platelet count by scalp or umbilical vein sampling will depend on the local expertise and maternal risk factors as these procedures are associated with some morbidity. Autoimmune thrombocytopenia in the neonate generally responds well to IVIgG in a dose of l-2 g/kg. While asymptomatic moderate thrombocytopenia may require no therapy, infants with frank haemorrhage will probably derive maximum benefit from a combined regime of steroids and IVIgG.47

Other Cytopenia? Auto-immune Neutropenia

IVIgG therapy in children and adults with autoimmune neutropenia usually leads to a rapid but generally short lasting rise in the neutrophil count. As in ITP, this response appears to be due to a combination of Fc receptor blockade and reduction in antibody synthesis. Patients with auto-antibody mediated neutropenia appear to be more likely to respond to this therapy than those with immune complexmediated disease. The short term response may be of value in the management of acute sepsis but is unlikely to be of long term benefit. Autoimmune Haemolytic Anaemia (AIHA)

Patients with AIHA have a markedly expanded reticuloendothelial system (RES) and this may account, in part, for the lack of a clinically useful response to IVIgG therapy. While some studies claim to show clinical benefit, in general, the response to IVIgG in standard doses (2 g/kg) has been absent or very transient. Therapy with increased doses (5 g/kg) increases the response rate, particularly in patients who have undergone previous splenectomy, perhaps related to the reduction in their RES. Occasional long term responses are seen but, on the whole, IVIgG may have a more valuable role in the acute situation, reducing uncontrolled haemolysis until immunosuppression with steroids or cytotoxic agents can take effect. Exacerbation of haemolysis has been described, due to the presence of high titres of blood group antibodies in occasional batches of IVIgG but this appears to be an uncommon complication and is unlikely to be significant in most patients. Red Cell Aplasia and Pancytopenia52-54

Red cell aplasia is antibody mediated in about half of the adult patients but this mechanism is rare in children. Parvovirus B19 induced aplasia has been successfully treated with IVIgG (see below) and there are a number of reports documenting successful

112 APPLICATIONS OF INTRAVENOUS IMMUNOGLOBULIN responses to IVIgG in non-virally induced pure red cell aplasia and aplastic anaemia. A dose of 1.62.0 g/kg has been successful in inducing complete or partial remissions in a few patients, including those who had failed to respond to prior therapy with steroids, cyclophosphamide and anti-thymocyte globulin. These reports suggest that IVIgG has a role in these disorders and may be considerably less toxic than alternative treatment options. Thrombotic Thrombocytopenic Purpura/Haemolytic Uraemic Syndrome (TTP-HUS) Haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are heterogeneous conditions which are probably variable manifestations of one disease syndrome (TTP-HUS). The high mortality in adults with this syndrome has been dramatically reduced with the advent of plasma exchange and fresh frozen plasma (FFP) replacement with a mortality rate of 22% in adults treated in this way. 55 Nevertheless a significant number of patients fail to respond to first line therapy and there are now a number of anecdotal reports of response to IVIgG in adults with TTP-HUS.56 In addition there has been one preliminary report of IVIgG in the treatment of childhood TTP-HUS. In this study, which was not randomised, 8 consecutive patients with HUS received 2 g/kg of IVIgG over 5 days.57 Comparison with historical controls treated conservatively or with FFP showed improved outcome in terms of morbidity and mortality. While these reports suggest there may be a role for IVIgG in this syndrome, IVIgG should not be considered to be the therapy of choice without an initial trial of intensive plasma-exchange with FFP replacement. Coagulation Inhibitors The formation of antibodies to coagulation factors may arise in association with autoimmune disorders, malignancy, pregnancy or in the absence of any underlying disease in 50% of cases. The incidence of these autoantibodies is rare, however, in comparison with the more commonly seen alloantibody formation in patients with inherited coagulation factor deficiency. Acquired factor VIIIC (FVIIIC) deficiency is the commonest amongst the autoimmune coagulation inhibitor states. The FVIIIC autoantibodies react inefficiently with heterologous FVIIIC, and therapy with porcine FVIIIC may be effective in the acute management of the haemorrhagic state. Nevertheless, the eventual aim in patients with acquired haemophilia and with the inherited condition with alloantibody formation should be suppression of clinically relevant titres of the inhibitor. A recent symposium on the management of acquired Factor VIII inhibitors reviewed the results

IN HAEMATOLOGY

of a variety of treatment options. Combination therapy with steroids, cyclophosphamide, vincristine and cyclosporin was successful in the majority of those treated (20/22) but there remain a few patients who are unsuitable for, or who fail to respond to this approach. 58 In 10 reported patients treated with intravenous immunoglobulin, 9 showed a reduction or even disappearance of inhibitor.sg The response was generally rapid, consistent with a direct neutralisation of inhibitor and, in several cases was sustained, suggesting that the IVIgG had also suppressed inhibitor synthesis. The rapidity of this response compared to that seen with cytotoxic therapy may be valuable in the acute haemorrhagic state, particularly in patients whose inhibitors prove to have significant cross-reactivity with porcine FVIIIC. The experience with IVIgG in the management of alloantibodies has been less impressive. However, a combined approach with IVIgG, cyclophosphamide, factor replacement and (when inhibitor titres are particularly high) Protein A adsorption has been successful in 13 of 15 haemophiliacs (11 A, 4B), including 1 patient who had shown an anamnestic response to similar therapy without the use of IVIgG.60 This condition has lent support to the idiotypeantiidiotype theory of IVIgG action. In vitro and in vivo studies have shown that the direct neutralisation of inhibitor F(ab’), fragments can be achieved with F(ab1)2 fragments from normal IVIgG, consistent with the presence of antiidiotype antibodies in IVIgG. 61 Evidence of neutralisation of inhibitor activity in vitro at optimal concentrations of IVIgG may be useful in predicting response in the individual patient. In summary, IVIgG given in doses of 2 g/kg divided over 2-5 days and repeated if necessary may be effective in suppressing inhibitor titres in patients with acquired haemophilia. In the inherited haemophilias, IVIgG used in similar doses is unlikely to be effective unless combined with immunosuppression and coagulation factor infusions. Recommendations for IVIgG dosage for the management of coagulation inhibitors and other autoimmune disorders are summarised in Table 4. IVIgG in HIV Infection IVIgG has several potential roles in HIV infection. As discussed above, high dose IVIgG appears to be at least as effective in HIV-related thrombocytopenia as it is in other forms of ITP. In addition, it may be indicated for the treatment of prolonged red cell aplasia secondary to parvovirus B19 infection (see below). CMV-related pathology including enteritis, interstitial pneumonia and retinitis does not respond as well to combined therapy with ganciclovir and immunoglobulin as do these disorders in posttransplant patients and this may be related to the difference in pathogenesis of CMV infections in those

BLOOD Table 4

Recommended

doses of immunoglobulin

for autoimmune

Condition

*Dosage

ITP (inc. neonatal)

1 g/kg single dose

Autoimmune neutropenias Red cell aplasia/ aplastic anaemia Autoimmune haemolytic anaemia Post-transfusion purpura Isoimmune thrombocytopenia -antenatal

0.5-1.0 g/kg 3-4 wkly l-2 g/kg over 1-5 days

Coagulation inhibitors -autoimmune -alloimmune

recommended

113

disorders Comments Repeat if poor increment by day 3 As maintenance therapy if indicated Sustained response unlikely

1-2 g/kg over 1-5 days 5 g/kg over 5 days l-2 g/kg over l-5 days

1 g/kg wkly from 20 weeks 1-2 g/kg over l-5 days

-neonate

*The maximum

and schedule

REVIEWS

l-2 g/kg over l-5 days t-2 g/kg over l-5 days

single daily dose is

Acute management ( + immunosuppression) May need to be repeated

Monitor fetal platelet count Consider steroids in addition

Combination therapy recommended (see text)

1g/kg

with AIDS, being more a feature of viral invasion rather than reactive inflammatory response. In contrast to adults with HIV infection, HIV infected children may have a profound deficiency of both humoral and cellular immunity and, as a consequence, have a marked susceptibility to serious bacterial infections. Previous studies of IVIgG prophylaxis in small numbers of HIV infected children. without adequate control groups, provided suggestive evidence of improved quality and duration of survival. A large multicentre trial has recently reported the results of a double-blind controlled trial of IVIgG in HIV-infected children showing convincing evidence of benefit. 62 372 children with HIV disease of CDC P2 (symptomatic) or PI B (asymptomatic but with abnormal immune function) were randomly allocated to receive either IVIgG (400 mg/kg) or placebo every 28 days. Children with CD4+ counts 20.2 x log/1 showed a significant increase in the time free from infection, reduction in the number of bacterial infections and fewer admissions for acute care. These benefits were not seen in the group with CD4 + counts of < 0.2 x log/l. It seems appropriate, therefore, to recommend that all HIV-infected children who become symptomatic or demonstrate major immunological abnormalities should be commenced on prophylactic IVIgG in a dose of 400 mg/kg every 4 weeks, although smaller doses may also be effective. In contrast, there is little evidence that adults with HIV-infection benefit from the prophylactic use of IVIgG. In addition, there is no evidence that IVIgG therapy alters the natural course of the HIV-infection. Appropriate IVIgG dosage and treatment schedules for paediatric HIV infection and other secondary immunodeficiency states are summarised in Table 5.

Table 5 Reccomended doses of IVIgG in secondary immunodeficiency states Condition

Dosage

CLL/myeloma

400 mg/kg

Bone marrow transplant

500 mg/kg weekly (first 3 months)

HIV infection

and schedule 3-4 weekly

206400

mg/kg

3-4 weekly

200-400

mg/kg

4 weekly

Comment Trials of lower doses in progress CMV prophylaxis Prophylaxis of bacterial infection (?GVHD prophylaxis) Prophylaxis of pyogenic infection in susceptible patients (see text) Children only

Other Viral Infections

Viral infections occasionally come to the attention of the haematologist as a result of effects on the bone marrow or peripheral blood count, either as a primary phenomenon or complicating some pre-existing haematological disorder. Parvovirus B19

Parvovirus B19 infection is generally a mild or subclinical infection in childhood but, in the presence of immunodeficiency or preceding haemolytic state chronic red cell aplasia may occur, due to virus persistence in the erythroid progenitor cells. Very rarely, pancytopenia may occur and it has also been shown to be a cause of fetal hydrops. IVIgG has high titres of neutralising antibody to parvovirus B1963 and this therapy has been successful

114

APPLICATIONS OF INTRAVENOUS

IMMUNOGLOBULIN

IN HAEMATOLOGY

in the treatment of a child with hereditary spherocytosis and aplastic crisis secondary to parvovirus B 19 infection. IVIgG therapy has also cured a patient with a ten year history of aplastic anaemia due to defective antibody response to parvovirus B 19.64 Recently, parvovirus B19 infection has been recognised as a cause of chronic anaemia in HIV infection. 6 patients with HIV infection and red cell aplasia due to parvovirus B 19 infection responded to IVIgG in a dose of 0.4 g/kg for 5 or 10 days. Only those with CD4 counts greater than 0.3 x 109/1 had sustained remissions but further responses could be obtained in those who relapsed with further IVIgG.‘j5 Parvovirus B19 infection should be considered in all those presenting with aplasia, particularly those with predisposing conditions, as above. It is possible that some of the reported cases of pancytopenia or red cell aplasia responding to IVIgG have, in fact, been due to neutralisation of this virus.

and, in those with a history of previous fetal/neonatal death, fetal and neonatal outcome was better than predicted. IVIgG may act in part by reducing transplacental passage of antibody, but there also appears to be suppression of maternal antibody production, the mechanism of which is, as yet, unexplained. Although there have been no controlled trials of therapy, this approach would appear to merit further investigation as it may reduce the need for invasive therapy in the mother and fetus. Administration of IVIgG to neonates with Rh haemolytic disease has also been reported to reduce the bilirubin level and the need for exchange transfusion.70T7’ Only small numbers of infants have been treated in this way, in an uncontrolled manner, and further trials are necessary to establish which babies are likely to benefit. The observed changes in bilirubin may be due to blockade of Fc receptors with reduction in further haemolysis.

Virus Associated Haemophagocytic Syndrome (VAHS)

Other Autoimmune Conditions

This disorder is characterised by the development of benign histiocytic hyperplasia and haemophagocytosis associated with a systemic viral infection, generally CMV or Epstein-Barr virus. A recent report documents the response of severe thrombocytopenia in a child with CMV-related VAHS to therapy with IVIgG.@j An adult with apparent VAHS also showed a rise in his platelet count with IVIgG and subsequently achieved complete remission when acyclovir and cyclosporin were added to the regular IVIgG infusions (Parker A C, Todd A and Yap P L, unpublished observations, 1992). These reports are encouraging in a disease which otherwise has a high mortality. Rhesus Isoimmunisation in Pregnancy Severe rhesus (Rh) isoimmunisation results in high fetal mortality unless intensive support with intrauterine transfusions is undertaken. The practical difficulties of carrying out this therapy in the extremely immature fetus may preclude fetal salvage in the most severely affected pregnancies and may, indeed, boost the maternal antibody titre as a result of feto-maternal bleeding. Plasmapheresis has been used in an attempt to reduce the titre of maternal antibody but frequent, large volume exchanges may be necessary. There are now a number of reports of maternal IVIgG therapy, often in combination with plasma exchange in women with rhesus or Kell sensitisation. A recent study67 of 24 severely Rh-sensitised pregnant women given IVIgG in a dose of 1.6-2.0 g/kg over 4-5 days every 15-21 days confirmed the results of earlier smaller studies68p69 and showed particular benefit in those treated before 28 weeks gestation. IVIgG reduced maternal anti-D titres and intrauterine haemolysis

There is an extensive literature on the use of IVIgG in other autoimmune conditions which may come to the attention of the haematologist, perhaps because of haematological complications. These include Kawasaki’s disease, systemic lupus erythematosus (SLE), systemic vasculitis and immune mediated neurological disorders. Readers are referred to recent reviews of this topic for further information.4*5*27

Safety of IVIgG Therapy72 Immune Mediated Reactions

Reactions to the administration of intravenous immunoglobulin occur with approximately 5% of infusions and are more common in hypogammaglobulinaemic patients, particularly during initial IVIgG therapy. These may be due to the presence of aggregates with anti-complementary activity and contaminants such as kallikreins or endotoxins. Vasomotor disturbances, chest tightness, wheezing, headaches and muscle pains’are more common with rapid infusions and may be reduced by slowing the infusion rate. In addition, pre-medication with corticosteroids, paracetamol or non-steroidal antiinflammatory drugs may abolish or minimise these reactions in patients requiring regular therapy. Severe anaphylactic reactions are very rare and may be due to the presence of antibodies to IgA in IgA deficient patients. The significance of these antibodies in patients or in the normal population is unclear. However, when these are felt to be implicated in a severe reaction the use of an IgA deficient IVIgG preparation is recommended. There have been occasional reports of haemolysis (see AIHA, above) or a transiently positive antiglobulin test in recipients of IVIgG, relating to the presence of blood group antibodies in the preparation. This is

BLOOD

rarely of clinical significance. Thrombotic episodes have been reported in elderly patients with severe atherosclerotic disease receiving IVIgG for ITP though the mechanism of this is not clear and no further cases have been described following the original report. Deterioration of renal function following IVIgG therapy has been seen in patients with preexisting renal disease, particularly those with SLE. Animal studies show some evidence that IVIgG in high doses may be detrimental in the presence of sepsis, possibly as a result of reticuloendothelial blockade. Anecdotal reports of overwhelming candidiasis or bacterial sepsis lend some credence to this and suggest that high doses of IVIgG should be used with caution in infected patients and in those who have been immunocompromised by recent cytotoxic therapy. Transient marked neutropenia was noted in a patient with SLE treated with IVIgG on two separate occasions,73 possibly mediated by antileucocyte antibodies in the IVIgG. This appears to be an uncommon phenomenon, but this case emphasises the need for caution and careful monitoring of patients receiving high dose IVIgG therapy. Virus Transmission

In view of the recognised risks of virus transmission by blood products attention has been focussed on the possibility of transmission of hepatitis B, non-A non-B (NANB) hepatitis and human immunodeficiency virus type 1 (HIV-l) by IVIgG. Although antibodies to HIV-l have been detected in commercial preparations of IVIgG the virus itself has not been found in any preparations and appears to be effectively excluded by the cold liquid ethanol fractionation process. No cases of IVIgG transmitted HIV have been reported. A few cases of NANB hepatitis have been identified following treatment with a small number of IVIgG preparations. Although the current consensus is that IVIgG preparations do not transmit NANB hepatitis the finding that only one lot in a total of 110 lots monitored had the potential to transmit NANB hepatitis74 suggests that surveillance of the recipients for possible NANB hepatitis should continue. However, this risk appears to be very low. Transmission of hepatitis B has not been detected following IVIgG and the virus has not been found following Cohn fractionation. In addition, hepatitis B antibody in the product may give passive protection against the virus. Conclusion

The efficacy of IVIgG in many haematological disorders remains speculative, supported by a few, often anecdotal, reports. The evidence of efficacy in a number of disorders is summarised in Table 6. The nature of responses in some disorders such as the acquired coagulation inhibitors and ITP offer exciting insights into the mechanisms of autoimmune dis-

Table 6

IVIgG

in haematological

REVIEWS

115

disorders

Good evidence for efficacy -Primary hypogammaglobulinaemias -1TP (acute and chronic) -Post transfusion purpura -Neonatal isoimmune and autoimmune thrombocytopenias -Prevention of secondary bacterial infection in HIVinfected children Limited evidence for efficacy -Prevention of infection in low-grade B-cell malignancies -Autoimmune haemolytic anaemias -Autoimmune neutropenias -Red cell aplasia/aplastic anaemia -Parvovirus B 19 induced aplasia -Coagulation factor auto/alloantibody formation -Maternal antenatal treatment of Rh haemolytic disease Anecdotal reports only -TTP/HUS -Virus-associated haemophagocytic syndrome -Neonatal treatment of Rh haemolytic disease

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a possible response to high-dose intravenous gamma globulin. Acta Haematologia 82: 201-204 Sheth K J, Gill J C, Leichter H E 1990 High-dose intravenous gammaglobulin infusions in Hemolytic-Uremic Syndrome: a preliminary report. American Journal of Diseases of Children 144: 268-270 Green D 1991 Cytotoxic suppression of acquired factor VIILC inhibitors. The American Journal of Medicine 91 (5A): 14S-19s Sultan Y, Kazatchkine M D, Nydegger U, Rossi F, Dietrich G, Algiman M 1991 Intravenous immunoglobulin in the treatment of spontaneously acquired factor VIII:C inhibitors. The American Journal of Medicine 91 (5A): 35%44s Nilsson I M, Berntorp E 1991 Induction of immune tolerance in hemophiliacs with inhibitors, by combined treatment with IVIG. cyclophosphamide and factor VIII or IX-the Malmo model. In: Imbach P (ed) Immunotherapy with intravenous immunoglobulins. London: Academic Press, 333-344 Rossi F, Sultan Y, Kazatchkine M D 1988 Antiidiotypes against autoantibodies and alloantibodies to VIILC (antihaemophilic factor) are present in therapeutic polyspecific normal immunoglobulins. Clinical and Experimental Immunology 74: 311-316 National Institute of Child Health and Human Development Intravenous Immunoglobulin Study Group 1991 Intravenous immune globulin for the prevention of bacterial infections in children with symptomatic human immunodeficiency virus infection. New England Journal of Medicine 325: 73-80 Takahashi T, Koike T, Moriyama Y, Shibata A 1991 Neutralizing activity of immunoglobulin preparation against erythopoietic suppression of human parvovirus. American Journal of Hematology 37: 68 Griffiths J K, Snydman D R 1992 The use of intravenous immunoglobulin in viral infections. In: Yan P L (Ed) Clinical Applications of Intravenous Immunoglobulin Therapy. Churchill Livingstone, Edinburgh, pages 167-201

I 17

65. Frickhofen N, Abkowitz J L, Safford M et al 1990 Persistent Bl9 Parvovirus Infection in Patients Infected with Human Immunodeficiency Virus Type 1 (HIV-l): A Treatable Cause of Anemia in AIDS. Annals of Internal Medicine 113: 926-933 66. Goulder P, Seward D, Hatton C 1990 Intravenous immunoglobulin in virus associated haemophagocytic syndrome. Archives of Disease in Childhood 65: 1275-1277 67. Margulies M, Voto L S, Mather E, Margulies M 1991 Highdose intravenous IgG for the treatment of severe rhesus alloimmunisation. VOXSanguinis 61: 181- I89 68. Besalduch J, Forteza A, Duran M A, Reyero J, Caso M 1991 Rh hemolytic disease of the newborn treated with high dose intravenous immunoglobulin and plasmapheresis. Transfusion 31: 380-381 69. de la Camara C, Arrieta R, Gonzalez A, Iglesias E, Omenaga F 1991 High-dose intravenous immunoglobulin as the sole prenatal treatment for severe Rh immunization. New England Journal of Medicine 318: 5 19-520 70. Sato K. Hara T. Kondo T. Iwao H. Honda S. Ueda K 1991 High-dose intravenous gammaglobulin therapy for neonatal immune haemolytic jaundice due to blood group incompatibility. Acta Paediatrica Scandinavica 80: 163- 166 71. Rtibo J, Wahn V 1990 Versuch einer hochdosierten Gammaglobulintherapie bei 3 kindern mit hyperbilirubinlmie bei rhesusinkompatibilitat. Monatsschrift Kinderheilkunde 138: 216-220 72. Yap P L, Williams P E 1992 The safety of IVIG preparations. In: Yap P L (ed) Clinical applications of intravenous immunoglobulin therapy. Edinburgh: Churchill Livingstone, 43-62 73. Ben-Chetrit E, Putterman C 1992 Transient neutropenia induced by intravenous immunoglobulin. New England Journal of Medicine 326: 270-271 74. Williams P E, Yap P L, Gillon J, Crawford R J, Urbaniak S J, Galea G 1989 Transmission of non-A, non-B hepatitis by pH4-treated intravenous immunoglobulin. VOXSanguinis 57: 15-18