Immunoglobulins

Uses

Preparations of human immunoglobulins given by intramuscular/subcutaneous administration are also given to prevent or treat specific diseases, such as rhesus disease (anti-D) or certain viral infections, for example measles, hepatitis A, hepatitis B, rabies, and cytomegalovirus. Polyclonal antilymphocyte preparations (for example antilymphocyte globulin and antithymocyte globulin) have been developed because of evidence that T cells are primarily responsible for rejection of transplants. Indications for treatment with, for example, horse antilymphocyte globulin and/or antithymocyte globulin are very much the same as the indications for the mouse monoclonal anti-CD3 (muromonab), namely acute rejection of transplants, and aplastic anemia [ , ].

Intravenous immunoglobulins are used in selected immunodeficiency and autoimmune diseases [ , ] and are licensed for a number of indications, such as various skin disorders [ , ], including pemphigus vulgaris and bullous pemphigoid unresponsive to conventional immunosuppressive drugs [ , ]; immune thrombocytopenia [ ]; various neurological disorders, including Guillain–Barré syndrome [ , ], chronic demyelinating polyneuropathy [ , ], myasthenia gravis [ ], multiple sclerosis, and multifocal motor neuropathy [ ]; membranous and membranoproliferative lupus nephritis [ ]; Kawasaki disease [ ]; and for allogeneic bone marrow transplantation [ ].

Higher dosages of intravenous immunoglobulin are used for autoimmune indications (400–2000 mg/kg) than in immunodeficiency diseases (100–400 mg/kg).

Current data suggest that high-dose intravenous immunoglobulin has a beneficial effect on the reduction of anti-HLA antibodies with subsequent improvement in renal transplantation in highly HLA-sensitized patients and is effective in the treatment of antibody-mediated rejection episodes. Intravenous immunoglobulin causes minor adverse reactions in these patients, such as headaches, associated with the infusion rate [ ]. It might also be a potential component of remission induction therapy for patients with myeloperoxidase–antineutrophil cytoplasmic antibody-associated rapidly progressive glomerulonephritis. Only one out of 12 patients had transient hypertension and edema of the limbs during intravenous immunoglobulin infusion, which abated after lowering the infusion rate [ ].

Anti-D immunoglobulin is used as an alternative to intravenous immunoglobulin to treat immune thrombocytopenia (idiopathic thrombocytopenic purpura, ITP). In 24 patients who were treated with an anti-D immunoglobulin product (WinRho®) there were more adverse drug reactions, particularly chills and rigors, despite pre-treatment with paracetamol and diphenhydramine. Two patients under treatment with this product needed treatment for severe anemia and one had severe hemoglobulinuria [ ]. Pretreatment with glucocorticoids or subcutaneous administration of anti-D immunoglobulin may reduce transfusion-related adverse drug reactions. However, the manufacturer of WinRho® withdrew its licensing applications in Europe over concerns with regard to the benefit to harm profile for the treatment of ITP.

Mechanisms of action

The mechanisms of action of intravenous immunoglobulin depend on the dose and the pathogenesis of the underlying disease [ ]. The effect of immunoglobulin therapy is either protection against micro-organisms (antibody substitution, passive immunization), or immunomodulation, or both. The mechanism of the response in non-infectious diseases is still not clear, but in immune thrombocytopenia an early fall in platelet-associated IgG and IgM may be a primary event, owing to interference with antibody binding by platelets [ ]. Several other mechanisms of action of intravenous immunoglobulin in autoimmune diseases have been suggested, such as enhanced suppressor activity, Fc receptor blockade on neutrophils and macrophages [ ], inhibition of complement activation and modulation of anti-idiotype responses [ ], cytokine modification, neutralization of superantigens, and regulation of T cells and the idiotypic network [ , ]. Suppression of polyclonal immunoglobulin biosynthesis induced by high-dose immunoglobulin infusions has also been suggested as a possible mechanism [ ].

General adverse effects and adverse reactions

Common minor adverse reactions are headache, chills, dizziness, fever, flushing, nausea, backache, rash, arthralgia, myalgia, pruritus, hypotension, diarrhea, dyspnea, and chest pain [ ]. These reactions are sometimes related to the rate of infusion [ ] and can then be reduced or prevented by lowering the infusion rate. Pretreatment with NSAIDs, antihistamines, or glucocorticoids can prevent them [ ]. Acute renal insufficiency can occur [ , ] and has been associated with high osmolarity sucrose-containing intravenous immunoglobulin formulations, whereas aseptic meningitis seems to be more common in patients with a history of migraine. Severe reactions have included thromboembolism, acute encephalopathy, bleeding disorders, stroke, neutropenia, hyponatremia, non-infectious hepatitis, pleural effusion, aseptic meningitis, renal insufficiency (mostly transient), cryoglobulinemia and transient hyperviscosity syndrome, thromboembolic events including myocardial infarction and stroke, immune hemolysis, disseminated intravascular coagulation (DIC), acute respiratory distress syndrome (ARDS), and transfusion-related acute lung injury (TRALI) [ , ]. The postulated mechanisms are speculative, and remain to be confirmed. These serious adverse events occur particularly in older patients, partly reflecting the increased use of intravenous immunoglobulin in higher dosages (2 g/kg) for anti-inflammatory or immunomodulatory indications, partly because a large proportion of patients with these diseases are significantly older than patients with immune deficiencies (usual doses of 400–600 mg/kg).

Vasculitis occasionally develops in patients treated with intravenous immunoglobulin for rheumatic diseases, Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy, or dys/hypogammaglobulinemia. Autoimmune hemolytic anemia has been reported in several patients with Kawasaki disease and enhancement of the formation of cryoglobulins in individual patients with pre-existing cryoglobulinemia [ ].

In the case of an underlying infection, administration of immunoglobulins can lead to febrile reactions, probably due to the formation of immune complexes [ , ].

Additional antiviral steps are used in all formulations to prevent contamination of blood-borne agents, particularly with viruses. Viral transmission of hepatitis viruses and retroviruses has not been reported over the last years. Concern about transmission of variant Creutzfeldt–Jakob disease has not been justified by human-to-human transmission by intravenous immunoglobulin.

Specific immunoglobulins

When administering different lots of the same product of equine rabies immunoglobulin, significant differences in adverse reactions, reflecting differences in production or purification processes and protein content, have been observed [ ]. It has been concluded in the past that the incidence of reactions to antirabies immunoglobulin is particularly high, but any of these immunoglobulins can cause severe reactions. The WHO has recommended that animal immunoglobulins should be used only after tests to rule out hypersensitivity.

The discovery of antitoxins, the development of antibody formulations, and possible adverse reactions have been reviewed [ ].

Intramuscular immunoglobulin

Allerglobuline is a human gammaglobulin formulation, given intramuscularly, that has been reported to have a protective effect against type I allergic diseases and chronic infections of the upper respiratory tract in both adults and children. In 64 patients given allerglobuline, pain and inflammation at the injection site were the most common adverse effects [ ]. Fever, drowsiness, headache, nausea, back pain, and conjunctivitis occurred in only few patients. One patient had a rash and myalgia after the third injection; when the rash occurred again after the fourth injection, the patient was withdrawn.

Intravenous immunoglobulin

Adverse reactions to intravenous immunoglobulin are generally mild and self-limiting [ ]. Although more common during the first two infusions, reactions appear to be primarily related to the speed of infusion. When infusions are given over a 1–3-hour period, the incidence of reactions is less than 5% and they occur during the transfusion; when infusions are given rapidly, the reactions may appear soon after completing the infusion. In about 10% of cases they occur 30–60 minutes after the start of the infusion.

Reactions include flushing, myalgia, headache, fever, chills and shaking, low backache, nausea and vomiting, diarrhea, chest tightness and shortness of breath, wheezing, changes in blood pressure, tachycardia, and rashes [ , ]. Most of the adverse reactions are related to the rate of administration and can be attenuated by slowing the rate of the infusion [ ] or by prior administration of hydrocortisone and/or an antihistamine. When infusions are given over a 1–3-hour period, the incidence of reactions is less than 5% and they occur during the transfusion; when infusions are given rapidly the reactions may appear soon after completing the infusion. The current high dosage of 0.8–1.0 g/kg intravenous immunoglobulin for 1–2 days (instead of the original dosage regimen of 0.4 g/kg for 5 days) for patients with idiopathic thrombocytopenic purpura is probably associated with an increased risk of adverse effects [ ].

Of 37 patients with primary hypogammaglobulinemia who received 1235 immunoglobulin infusions, 10 had adverse reactions during 34 infusions (2.8% of all infusions), but only five reactions were moderately severe. The reactions are related to the rate of administration [ ]; a rate of 5 mg/kg/minute was well tolerated.

Of 56 patients with autoimmune diseases who received high dosages of intravenous immunoglobulin, 20 had at least one adverse effect after one or more courses of treatment [ ]. The most frequently reported adverse reactions were low-grade fever, headache, and chills. The authors concluded that the occurrence of adverse effects with intravenous immunoglobulin was not related to the clinical response to treatment. However, patients who developed adverse effects during the first course of treatment were more at risk of adverse effects during subsequent courses.

Patients with thrombocytopenia generally tolerate intravenous immunoglobulin well [ ]. In 16 young patients aged 9 months to 22 years with immune-mediated hemocytopenias (13 with childhood immune thrombocytopenic purpura), who received a total of 210 infusions, minimal adverse reactions (transient headaches) were experienced during only four infusions, and later infusions were problem-free in three of the four patients [ ].

Polyclonal antilymphocyte immunoglobulins

Short-term toxicity from polyclonal antilymphocyte immunoglobulins has been particularly marked in patients treated with combined antilymphocyte/antithymocyte globulin preparations from immunized horses [ ]. Immediate adverse effects and reactions include leukopenia and thrombocytopenia, fever, arthralgia, rash, urticaria, hepatotoxicity, hyperglycemia, hypertension, and diarrhea [ ]. A later adverse reaction is serum sickness. Many of the effects may be due to an increase in tumor necrosis factor [ ].

The longer-term effects of immunosuppression, and in particular the residual hematological and immunological abnormalities in patients with aplastic anemia treated with antilymphocyte globulin, have been documented: there is toxicity to hemopoietic cells, eventually leading to clonal marrow diseases years after treatment [ ]. Paroxysmal nocturnal hemoglobinuria, refractory sideroblastic anemia, chronic myelomonocytic leukemia, or acute leukemia can develop 4–10 years after treatment [ ].

Observational studies

Experience with monthly, high-dose intravenous immunoglobulin in patients with different connective tissue diseases who failed to respond to standard therapies or for whom immunosuppressive drugs were contraindicated, the success rate was 70 %, without serious adverse effects [ ].

In a retrospective review of 63 cases of intramuscular immunoglobulin in suppurative skin diseases, pain at the injection site was the most frequent complaint; three patients had hyperpigmentation, but this was not distinguishable from adjacent skin lesions [ ].

Placebo-controlled studies

In a multicenter, double-blind, placebo-controlled, dose-escalating study of the safety and efficacy of an experimental plasma-derived, donor-selected, polyclonal antistaphylococcal immunoglobulin with high titers of IgG directed against staphylococcal fibrinogen-binding proteins (INH-A21), 2 % of the 505 infants had 13 drug-associated adverse events, of which seven involved changes in vital signs (apnea, tachycardia, bradycardia, hypertension, and temperature changes) [ ].

In a multicenter, randomized, double-blind, placebo-controlled trial the clinical effect of intravenous immunoglobulin 90 g on 3 consecutive days, twice at 3-months intervals was analysed in patients with post-polio syndrome [ ]. There were no serious adverse drug reactions. Headache was the most frequent adverse effect. Infusion site reactions, gastrointestinal, nervous system, skin, and subcutaneous disorders were more frequent in those who were given intravenous immunoglobulin.

The potential beneficial effect of intravenous immunoglobulin treatment for recurrent spontaneous pregnancy loss has been assessed in five randomized, controlled trials in 250 patients [ ]. Intravenous immunoglobulin was not effective. Adverse events included transient rash and fever, but they were not frequent.

Cardiovascular

Intravenous immunoglobulin expands the plasma volume and increases blood viscosity, which can lead to volume overload in patients with cardiac insufficiency [ ]. Stroke, thromboembolic events, and myocardial infarction have been reported after high-dose treatment with intravenous immunoglobulin [ , ].

Thromboembolic events can complicate the administration of intravenous immunoglobulins [ ]., and include myocardial infarction, stroke, pulmonary embolism, and deep vein thrombosis [ ]. Risk factors are obesity, advanced age, immobilization, hypertension, diabetes mellitus, and a history of vascular disease or thrombosis [ ]. Stroke has been described in 16 patients, 15 of whom had recognized risk factors [ ]. These events appear to be related to hyperviscosity of the blood after intravenous immunoglobulin [ , , ]. This has been confirmed by analysis of blood viscosity after intravenous immunoglobulin infusion [ , ]. Patients with high plasma concentrations of albumin and fibrinogen are considered to be more susceptible to thrombotic complications after intravenous immunoglobulin infusion [ ].

• A 54-year-old woman developed an acute severe headache, nausea, and difficulty in speech 1 day after receiving intravenous immunoglobulin (21 g) for isolated IgG1 deficiency [ ]. She had a transverse sinus thrombosis, at first considered to be a complication of intravenous immunoglobulin. However, she also had primary thrombocythemia, which is also known to cause headache and is associated with a risk of lateral sinus thrombosis.

Diffuse venous thromboembolism was reported in a patient with streptococcal toxic syndrome after two courses of high-dose intravenous immunoglobulin (0.4 g/kg/day over 5 days and 8 days later 0.4 g/kg/day over 4 days) [ ].

• A 38-year-old woman with multiple sclerosis developed a deep vein thrombosis after a course of intravenous immunoglobulin 2 g over 2 days in combination with methylprednisolone [ ]. She was not immobilized by her multiple sclerosis.

The authors proposed that the combination of intravenous immunoglobulin and methylprednisolone might have been associated with the thrombotic event, because this patient had tolerated several courses of intravenous immunoglobulin without methylprednisolone. They discussed 27 previously reported cases of thrombotic events after intravenous immunoglobulin. In eight cases a glucocorticoid had also been used. In nine cases, there were no data on glucocorticoid usage, but the clinical conditions made it likely that a glucocorticoid had indeed been used.

Thrombosis in elderly patients with an increased risk of thrombosis, such as those with hypertension or previous episodes of infarction, has been described [ , ]. A few cases of thrombosis subsequent to intravenous immunoglobulin have been reported, including myocardial infarction in five patients, stroke in four cases, and spinal cord ischemia in one [ ]. It has been postulated that these events are induced by platelet activation and increased plasma viscosity [ ].

• A 75-year-old man with idiopathic thrombocytopenia purpura who was treated with intravenous immunoglobulin developed recurrent myocardial ischemia [ ].

• A 54-year-old woman with idiopathic thrombocytopenic purpura received intravenous immunoglobulin 1 g/kg/day for 2 days and had an ischemic stroke with hemiparesis; 3 days later she had a deep vein thrombosis [ ].

• A 33-year-old woman with Evans’ syndrome received intravenous immunoglobulin 400 mg/kg/day and developed a deep vein thrombosis after 1 week [ ]. She was treated with warfarin, and 6 months later received an additional course of intravenous immunoglobulin for recurrent hemolytic anemia; 1 day later she died of pulmonary thromboembolism.

• A 70-year-old woman with polycythemia rubra vera and Guillain–Barré syndrome, but no known risk factors for thrombosis, had a cerebral infarction 10 days after receiving intravenous immunoglobulin; the authors wondered whether there was a relation to the polycythemia vera [ ].

In a randomized, controlled study in 56 patients with untreated autoimmune thrombocytopenic purpura, who were treated with intravenous immunoglobulin 0.7 g/kg/day for 3 days, one had a deep vein thrombosis complicated by pulmonary embolism [ ]. One of 10 children with toxic epidermal necrolysis, for which they were given intravenous immunoglobulin 0.5 g/kg/day, developed a deep vein thrombosis requiring heparin [ ]. Of the 10 children, this child was the only one who received intravenous immunoglobulin for 7 days instead of the standard 4-day course.

Several causes of immunoglobulin-mediated thrombosis have been postulated, including increased plasma and blood viscosity, platelet activation, cytokine-mediated vasospasm, and contamination with factor IX. In a retrospective study in seven patients with susceptibility factors who developed such reactions the authors suggested that the thromboembolic complications were caused by clotting factors and vasoactive cytokines within specific batches of intravenous immunoglobulin formulations [ ].

One report described an adolescent girl with idiopathic thrombocytopenic purpura who developed fatal bilateral jugular vein thrombosis after a single dose of intravenous immunoglobulin; she had multiple prothrombotic susceptibility factors [ ].

• Transient hypertension occurred in a patient with dermatomyositis during therapy with intravenous immunoglobulin [ ]. In the past, his diastolic blood pressure had been 104–106 mm Hg, but he was normotensive with antihypertensive drug medication.

Several mechanisms for this transient hypertension were postulated, for example stimulation of the vascular endothelium to secrete endothelin to inhibit nitric oxide synthesis.

It has been recommended that patients with cardiac diseases should be monitored during intravenous immunoglobulin therapy, because hypertension and cardiac failure have occurred, presumably as a result of fluid overload or electrolyte shifts [ ].

Hypotension after treatment with intravenous immunoglobulin is rare and is due to the presence of IgG dimers in some immunoglobulin formulations [ ].

Respiratory

Intravenous immunoglobulin can cause transfusion-related acute lung injury (TRALI) [ ].

• A 35-year-old woman with idiopathic thrombocytopenic purpura treated with high dosages of intravenous immunoglobulin developed a recurrent lymphocytic pleural effusion [ ].

• In a patient with Guillain–Barré syndrome, and a history of ischemic heart disease, intravenous immunoglobulin 400 mg/kg for 5 consecutive days caused severe bronchospasm and hypercapnia after a dose of 12.5 g had been given [ ]. The complaints disappeared after withdrawal of the intravenous immunoglobulin.

• Transfusion-related acute lung injury (TRALI) occurred 5 hours after treatment with intravenous anti-D immunoglobulin in a 14-year old girl with idiopathic thrombocytopenic purpura; there were no pulmonary sequelae [ ].

Nervous system

Headache occurred in 25% of all patients who received an infusion of intravenous immunoglobulin, probably related to larger volumes and fluid shifts, protein loads, and infusion rates [ ]. Intravenous immunoglobulin caused severe headache in 56% of patients without a history of migraine [ ]. The pathogenesis of this headache is unknown.

Severe headache has also been reported in children with idiopathic thrombocytopenic purpura using intravenous immunoglobulins [ ]. In a randomized, controlled study of patients with myasthenia gravis, two of six patients who received intravenous immunoglobulin developed severe headache after the initial dose of 2 g/kg [ ].

In 14 patients with primary immunodeficiency disease, progressive neurodegeneration occurred and a possible relation to immunoglobulin therapy could not be ruled out [ ].

A possible relation between intravenous immunoglobulin for chronic inflammatory demyelinating polyneuropathy and Guillain–Barré syndrome has been described in a single patient [ ]. There have been reports of chronic inflammatory demyelinating polyneuropathy that began like acute Guillain–Barré syndrome, but without typical subsequent deterioration. The authors speculated that the presence of soluble CD receptors and cytokines may have a pro-inflammatory effect, leading to polyneuroradiculitis.