Human Immunoglobulin Preparations

Description

Human immunoglobulins (Ig) are prepared from large pools of whole blood or apheresis-derived plasma. Ig preparations are concentrated (through Cohn fractionation), purified, filtered, and sterilized, making the risk of infectious disease transmission virtually zero ( Figure 39.1 ). Human Ig preparations consist mostly of IgG, with half-life of 21–28 days. Ig preparations can be made for intramuscular (IM), subcutaneous (SC), or intravenous (IV) administration and clinically are used to replenish IgG in patients with hypogammaglobulinemia or for their immunomodulatory properties. Many preparations are available in the United States and throughout the world.

$Figure 39.1, Cohn plasma fractionation process.$

Mechanism of Action

For patients with acquired or congenital Ig deficiency (hypo- or agammaglobulinemia), these products supplement or replace the missing humoral components of their immune system. Diversity of antibody specificities contained in Ig preparations protects patients from increased susceptibility to infection by classical elimination of opsonized infectious organisms via antibody-dependent cell-mediated cytotoxicity or by complement activation. These processes are followed by lysis and/or neutralization of soluble infectious proteins by immunocomplex formation and elimination through the reticuloendothelial system.

In treatment of autoimmune disorders or other diseases associated with antibodies, Ig preparations result in immunomodulation and may alleviate the symptoms of the disease. Mechanisms of Ig-induced immunomodulation are incompletely understood but may include the following:

Macrophage Fc receptor blockage by immune complexes formed between Ig and native antibodies
Modulation of complement
Inhibition of cell-mediated cytotoxicity
Reduction of apoptosis
Inhibition of leukocyte adhesion
Regulation and inhibition of B cells and T cells
Downregulation of dendritic cells and metalloproteinases
Suppression of antibody production
Suppression of inflammatory cytokines and chemokines
Antiidiotypic regulation of autoreactive B lymphocytes or antibodies

Indications and Dose

There are seven FDA-approved indications for human Ig preparations and an expanding list of off-label uses, many of which are considered first-line therapy. Some of the FDA-approved indications and non–FDA-approved indications are described below where data support clinical benefit ( Table 39.1 ). There are multiple different products, and not all products have been FDA-approved for each of the listed indications. Moreover, each disease indication has its own distinct recommended therapeutic dosages. Many clinicians use different products interchangeably, and doses are usually spread out over a period of days owing to slow infusion rates and to minimize adverse effects.

Table 39.1

Some Clinical Indications for Ig Administration

FDA-Approved Indications	Non–FDA-Approved Indications of Proven or Probable Benefit
B-cell chronic leukemia/lymphoma with infection Chronic inflammatory demyelinating polyradiculoneuropathy Immune thrombocytopenia Kawasaki disease Multifocal motor neuropathy Primary/secondary immune deficiency Passive immunity for certain viruses (e.g., Hep A)	Antibody-mediated kidney transplant rejection Aplastic anemia secondary to parvovirus Autoimmune hemolytic anemia Autoimmune uveitis Bullous pemphigoid Birdshot retinochoroidopathy CMV pneumonitis in solid organ transplants Dermatomyositis or polymyositis Graft-versus-host disease Graves ophthalmopathy Guillain–Barre syndrome Henoch–Shonlein purpura Hematopoietic stem cell transplantation Hemolytic disease of the fetus/newborn Hypogammaglobulinemia associated with multiple myeloma IgM antimyelin-associated glycoprotein Immune neutropenia Lambert–Eaton myasthenic syndrome Myasthenia gravis Necrotizing fasciitis Neonatal alloimmune thrombocytopenia Neonatal sepsis Paraprotein-associated peripheral neuropathy Pemphigus vulgaris and pemphigus foliaceus Postinfectious thrombocytopenic purpura Relapsing–remitting multiple sclerosis Stiff person syndrome Toxic epidermal necrolysis and Stevens–Johnson syndrome Viral enterocolitis/meningoencephalitis

FDA-Approved Indications

Non–FDA-Approved Indications of Proven or Probable Benefit

B-cell chronic leukemia/lymphoma with infection
Chronic inflammatory demyelinating polyradiculoneuropathy
Immune thrombocytopenia
Kawasaki disease
Multifocal motor neuropathy
Primary/secondary immune deficiency
Passive immunity for certain viruses (e.g., Hep A)

Antibody-mediated kidney transplant rejection
Aplastic anemia secondary to parvovirus
Autoimmune hemolytic anemia
Autoimmune uveitis
Bullous pemphigoid
Birdshot retinochoroidopathy
CMV pneumonitis in solid organ transplants
Dermatomyositis or polymyositis
Graft-versus-host disease
Graves ophthalmopathy
Guillain–Barre syndrome
Henoch–Shonlein purpura
Hematopoietic stem cell transplantation
Hemolytic disease of the fetus/newborn
Hypogammaglobulinemia associated with multiple myeloma
IgM antimyelin-associated glycoprotein
Immune neutropenia
Lambert–Eaton myasthenic syndrome
Myasthenia gravis
Necrotizing fasciitis
Neonatal alloimmune thrombocytopenia
Neonatal sepsis
Paraprotein-associated peripheral neuropathy
Pemphigus vulgaris and pemphigus foliaceus
Postinfectious thrombocytopenic purpura
Relapsing–remitting multiple sclerosis
Stiff person syndrome
Toxic epidermal necrolysis and Stevens–Johnson syndrome
Viral enterocolitis/meningoencephalitis

FDA-Approved Indications

B-Cell Chronic Leukemia/Lymphoma With Infection

The most common cause of morbidity and mortality in individuals with chronic leukemia/lymphoma (CLL) is infection. As up to 96% of patients with CLL have hypogammaglobulinemia in at least one Ig isotype, administration of immunoglobulin preparations may replace the missing immunoglobulins needed for humoral immunity. A multicenter, double-blind clinical trial found that those who received intravenous immunoglobulin (IVIG) 400 mg/kg every 3 weeks for 1 year had significantly fewer bacterial infections and experienced longer time to first major infection than those who did not receive this therapy. However, given more recent advances in CLL treatment and management, IVIG use should be restricted to those with recurrent serious bacterial infections and serum IgG levels <500 despite immunization to diphtheria, tetanus, or pneumococcal infection (typical dose 300–500 mg/kg monthly to maintain nadir IgG levels of 500 mg/dL).

Chronic Inflammatory Demyelinating Polyradiculoneuropathy

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic autoimmune disorder resulting in antibody-mediated demyelination of peripheral nerves that result in weakness and sensory changes. Equivalent outcomes have been observed in the treatment of CIDP with IVIG (typical loading dose 2000 mg/kg, then 1000–2000 mg every three to 4 weeks, with dose divided over 2–5 infusion days) (SC administration under investigation), therapeutic plasma exchange (TPE), or steroids. Decision as to which treatment to use is made on an individual basis, as up to one-third of patients do not respond to IVIG. Balancing risks and benefits of each treatment modality is an important consideration for this disease.

Immune Thrombocytopenia

Immune thrombocytopenia (ITP) is a bleeding disorder characterized by immune-mediated platelet destruction and resultant thrombocytopenia (see Chapter 101, Chapter 102 ). The most effective pharmacologic therapies for acute ITP include corticosteroids, IVIG, and RhIg. RhIg and IVIG have rapid but temporary response. IVIG (typical dose 2000 mg/kg) is therefore indicated in acute bleeding episodes or before surgery, including splenectomy; in patients at high risk of intracranial hemorrhage; and in those in whose corticosteroids are contraindicated or ineffective. IVIG has also been used to treat ITP during pregnancy, postinfectious thrombocytopenia, ITP associated with HIV infection, and neonatal thrombocytopenia.

Kawasaki Disease

Kawasaki disease is an acute, self-limited childhood disorder manifested by fever, bilateral conjunctivitis, rash, and cervical lymphadenopathy. It is associated with systemic vasculitis, which results in coronary artery aneurysms in 15%–25% of untreated children. IVIG (typical dose 2000 mg/kg) given with aspirin and prednisolone (2 mg/kg) within 7 days of illness presentation reduces this risk from 23% to 4%.

Multifocal Motor Neuropathy

Multifocal motor neuropathy is a chronic progressive disorder resulting in primarily hand weakness. IVIG (SC administration under investigation), at a dose of 2000 mg/kg, is now considered a first-line treatment for this condition.

Primary or Secondary Immune Deficiencies

Patients with primary immunodeficiency syndromes have decreased levels of IgG and increased susceptibility to infections. Prophylactic administration of IVIG reduces number and duration of infections (typical maintenance dose for adults, 400–600 mg/kg every 3–4 weeks to maintain a trough IgG level of at least 500 mg/dL).

Patients with secondary immunodeficiency syndromes have acquired disorders of the immune system, which may be caused by multiple etiologies including hematologic malignancy (e.g., CLL, multiple myeloma, protein-losing enteropathy, nephrotic syndrome, or other severe illnesses). Criteria in support of IVIG use in these conditions include hypogammaglobulinemia (IgG < 200 or total Ig < 400 mg/dL), absent or low natural antibodies, absent or low response to antigenic challenge (i.e., vaccines), and lack of antibody response to the infecting organism.

Passive Immunity for Certain Viruses

Administration of specific formulations of Ig is approved to provide passive immunity for hepatitis A and measles (Rubeola) and can modify or prevent disease manifestations. Prophylactic value is greatest (80%–90% effective for hepatitis A) when given prophylactically before or soon after exposure (within 2 weeks for hepatitis A and within 6 days in unvaccinated person for measles). For hepatitis A, a dose of 0.02 mL/kg is recommended for recently exposed patients and those who will be in a hepatitis A endemic area for <3 months. For measles, a dose of 0.25 mL/kg is generally suggested.

Selected Off-Label Indications

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