Page 1178 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Immunoglobulin Therapy:

Replacement and Immunomodulation

Mark C. Ballow

Over 70 years ago, a cold ethanol fraction of plasma that contained KEY CONCEPTS 1
an enriched fraction of gammaglobulin was used intramuscularly
as passive immunotherapy for the treatment and protection of Properties of Intravenous Immunoglobulin (IVIG)
infectious pathogens and subsequently as antibody replacement and Subcutaneous Immunoglobulin (SCIG)
therapy for patients with primary immune deficiency diseases • Plasma fractionation (first step) by cold ethanol / Cohn-Oncley modifica-
(PIDDs). This Cohn ethanol plasma fraction of immunoglobulin tion (fraction II)
G (IgG) remained the principal form of therapy until 1981 when • >98% IgG; >90% monomeric IgG
an intravenous (IV) preparation (i.e., intravenous immunoglobu- • Traces of other immunoglobulins (i.e., IgA and IgM) and serum
lin [IVIG]) became available. Subsequently, Imbach observed proteins
that thrombocytopenia resolved when patients with immune • Addition of sugar, and amino acids, stabilizes IgG from aggregation
deficiency were treated with IVIG. This observation led to the • Multiple viral inactivation/removal steps
• Cold ethanol fraction
use of IVIG in patients with autoimmune idiopathic thrombo- • Chromatography
cytopenic purpura, and an expansion on the use of IVIG as • Solvent/detergent treatment
immunomodulatory therapy in several FDA approved autoimmune • Caprylate fractionation
disorders (Table 84.1). Most IVIG preparations are derived from • Nanofiltration
plasma by the Cohn ethanol fractionation method or the Cohn- • Depth filtration
Oncley modification. IVIG products are modified to prevent the • Pasteurization
formation of IgG aggregates and to make IVIG suitable for the • Intact Fc receptor important for biological function
• Opsonization and phagocytosis
IV route. Excipients, such as sugars (maltose or D-sorbitol) or • Complement activation
amino acids (glycine or L-proline), stabilize the IgG molecules • Antibody dependent cytotoxicity
from aggregation. Cold ethanol fractionation as the first step in • Normal half-life comparable to serum IgG
plasma processing inactivates human immunodeficiency virus • Normal proportion of IgG subclasses
(HIV). Treatment with low pH, solvent and detergent, pasteuriza- • Broad spectrum of antibodies to bacterial and viral agents
tion or nanofiltration/depth filtration in combination, depending
on the Ig product, is used as further 5–7 steps for viral inactivation
and removal. Commercial lots of IVIG are derived from ≈15 000
donors (not to exceed 60 000 donors according to the U.S. Food and a comparison of low-dose with high-dose IVIG therapy.
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and Drug Administration [FDA] and the Plasma Protein Thera- Quartier et al. performed a retrospective study of the clinical
peutics Association). Each lot must contain adequate levels of features and outcomes of 31 patients with X-linked agamma-
antibody to measles. These products may vary slightly among globulinemia receiving replacement IVIG therapy between 1982
manufacturers and from lot to lot, but they are generally com- and 1997. Although early treatment with IVIG and achieving a
parable with regard to clinical efficacy, but perhaps not tolerability. trough serum IgG level of >500 mg/dL was effective in preventing
The newer Ig formulations are isoosmolar, low-sodium, and severe acute bacterial infections, these levels did not prevent
low-IgA liquid products. The characteristics of IVIG preparations pulmonary disease, sinusitis, or meningoencephalitis. The authors
available in the United States are reviewed in Table 84.2. suggested that more intensive therapy to maintain a higher serum
In this chapter, the application of IVIG as replacement therapy IgG trough level (e.g., >800 mg/dL) may improve the pulmonary
in patients with primary immune deficiency (PID) and the outcome.
potential mechanisms of action of Ig therapy in the treatment Several studies have shown that pulmonary abnormalities
of autoimmune and inflammatory diseases are reviewed. For are the most important factors associated with morbidity and
more information on the use of Ig therapy in specific diseases, mortality in patients with PIDs. The number of infections, days
the reader is referred to an evidence-based review of the topic on antibiotic therapy, days missed from school or at work, and
elsewhere. 1,2 hospitalized days may not be sufficient indicators of adequate
treatment. Therefore the improvement or maintenance of
REPLACEMENT THERAPY WITH IVIG pulmonary function is an important measure of the success of
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therapy. Orange et al. examined the impact of serum IgG trough
Several early trials in the 1980s have been conducted to examine levels on pneumonia incidence in patients with PIDDs receiving
the efficacy of IVIG with intramuscular (IM) gammaglobulin, replacement IVIG therapy in a meta-analysis of published clinical

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