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Division of Allergy, Immunology and Pediatric Rheumatology, Women & Children’s Hospital of Buffalo, State University of New York at Buffalo School of Medicine and Biomedical Sciences, NY, USA
Division of Allergy, Immunology and Pediatric Rheumatology, Women & Children’s Hospital of Buffalo, State University of New York at Buffalo School of Medicine and Biomedical Sciences, NY, USA
Antibodies have been used for more than a century to prevent and treat illness, neutralize drugs and poisons, and accentuate or depress the immune system. Their specificity and diversity and their relative safety make them potent therapy in antibody deficiencies, certain infections and several autoimmune/inflammatory disorders.
This article discusses 3 principal uses of immunoglobulins: for infectious diseases, for immunodeficiency, and for immunomodulation. These subjects are discussed in that order, because antibody was first used for infections (since the 1890s), next used for immunodeficiency (since the 1950s), and then used for immunomodulation (since the 1970s, after the introduction of intravenous immunoglobulin [IVIG]). The last use, for a great variety of disorders, is now the largest consumer for immunoglobulin products.
This article does not discuss the use of therapeutic monoclonal antibodies, of which 18 are now licensed in the United States, and more are in the pipeline. The therapeutic use of monoclonals for infections and for immunomodulation is in its neonatal period, and, like infants, great expectations have been bestowed upon them.
Immunoglobulins for prevention and treatment of infectious diseases
Emil von Behring was awarded the first Nobel Prize in Medicine in 1901 for development of equine antiserum for the treatment of diphtheria and tetanus. His citation stated “For his work on serum therapy, especially its application against diphtheria, by which he has opened a new road in the domain of medical science and thereby placed in the hands of the physician a victorious weapon against illness and death.”
Since then antibodies in multiple forms (animal and human serums, immune globulins and monoclonal antibodies) have been developed, primarily for prevention of infectious diseases, and less commonly for their treatment. These antibodies are presented in Table 1. This section reviews their uses, with an emphasis on their value in the treatment of human infections, as summarized in Table 2.
Table 1Antibody preparations available for passive immunity in the United States
Product
Abbreviation(s)/brand name(s)
Principal use
Standard Human Immune Serum Globulins (HISG, γ-Globulin)
Immune globulin, intravenous
IVIG, IGIV
Treatment of antibody deficiency, immune thrombocytopenic purpura, Kawasaki disease, other immunoregulatory and inflammatory diseases
Immune globulin, intramuscular
Immunoglobulin, IGIM
Treatment of antibody deficiency; prevention of measles, hepatitis A
Immune globulin, subcutaneous
SCIG
Treatment of antibody deficiency
Special Human Immune Serum Globulins for Intramuscular or Subcutaneous Use
Hepatitis B immune globulin
HBIG
Prevention of hepatitis B
Varicella-zoster immune globulin
VZIG
Prevention or modification of chickenpox
Rabies immune globulin
RIG
Prevention of rabies
Tetanus immune globulin
TIG
Prevention or treatment of tetanus
Vaccinia immune globulin
VIG
Prevention or treatment of vaccinia, prevention of smallpox
Rho(D) immune globulin
RhoGAM
Prevention of Rh hemolytic disease
Special Human Intravenous Immune Globulins
Cytomegalovirus immune globulin
CMV-IVIG, CMVIG, CytoGam
Prevention or treatment of cytomegalovirus infection
Hepatitis B immune globulin, intravenous
HepaGam B
Prevention of hepatitis B (including liver transplantation)
Vaccinia immune globulin, intravenous
VIG-IVIG
Prevention or treatment of vaccinia, prevention of smallpox
Rho(D) immune globulin intravenous
WinRho SDF
Treatment of immune thrombocytopenic purpura
Botulinum immune globulin
BIG, Baby BIG
Treatment of newborn botulism
Animal Serums and Globulins
Tetanus antitoxin (equine)
TAT
Prevention or treatment of tetanus (when TIG unavailable)
Antibody works by several mechanisms. It can neutralize viruses and bacterial toxins, lyse bacteria with the aid of complement, prevent the spread of microbes to adjacent cells or along nerve roots, coat bacteria for opsonization by phagocytes, block microbial attachment by saturating microbial receptors, and facilitate lysis of infected cells by binding them to cytotoxic cells with an Fc receptor.
Bacterial Infections
Antibody is particularly valuable in bacterial diseases associated with toxin production because much of the tissue damage results from action of the toxin; these can be neutralized rapidly by antibody before antibiotics kill the bacterium.
Anthrax (Bacillus anthracis)
Anthrax is a rare but serious infection, predominantly of ruminant animals, caused by an aerobic gram-positive rod [
in: Mandel G. Bennett J.E. Donin R. Principles and practice of infectious diseases. 6th edition. Elsevier/Churchill Livingston,
Philadelphia2005: 3618-3624
]. Humans are infected through the skin (cutaneous anthrax), by ingestion (gastrointestinal anthrax), or by inhalation of anthrax spores (inhalational anthrax) [
in: Mandel G. Bennett J.E. Donin R. Principles and practice of infectious diseases. 6th edition. Elsevier/Churchill Livingston,
Philadelphia2005: 3618-3624
]. The last often results from prolonged exposure to animal hides or carcasses or infected soil, and rarely by deliberate spore exposure in the bioterrorism setting. After inhalation the spores are ingested by alveolar macrophages and transported to regional nodes, where the spores germinate and release potent exotoxins. These toxins damage cell membranes, increase capillary permeability, cause pulmonary damage, and lead to shock and cardiovascular collapse.
A vaccine is available for individuals at high risk for exposure and for the military.
Before the antibiotic era and as early as 1903, anthrax antitoxin (usually equine) was used in therapy [
]. An antitoxin is of value in a bioterrorism attack, both before and after exposure. The US Government is collecting plasma from immunized donors to develop a human high-titer IGIV [
in: Pickering L.K. Baker C.J. Kimberlin D.W. Red Book: 2009 Report of the Committee on infectious diseases. 28th edition. American Academy of Pediatrics,
Elk Grove Village (IL)2009: 280-283
]. The dose used depends on the localization and severity of infection, ranging from 20,000 units for mild infection of short duration to 120,000 units for severe illness with neck edema. The equine antitoxin is given intravenously, so must be preceded by skin testing for hypersensitivity and possible desensitization. The antitoxin is available through the US Centers for Disease Control (CDC).
A smaller dose of antitoxin can be used in asymptomatic, exposed, susceptible individuals. Before the availability of diphtheria vaccine, antitoxins were given to health care workers caring for patients with diphtheria [
Equine antitoxin for the treatment of tetanus was initiated by von Behring in the 1890s for toxin neutralization. Extensive studies have been carried out to determine the optimal dose of antitoxin and the possible benefit of intrathecal antitoxin, particularly in tetanus neonatorum, a common problem in developing countries [
in: Pickering L.K. Baker C.J. Kimberlin D.W. Red Book: 2009 Report of the Committee on infectious diseases. 28th edition. American Academy of Pediatrics,
Elk Grove Village (IL)2009: 655-660
in: Pickering L.K. Baker C.J. Kimberlin D.W. Red Book: 2009 Report of the Committee on infectious diseases. 28th edition. American Academy of Pediatrics,
Elk Grove Village (IL)2009: 655-660
]. The recommended dose of TIG is 250 IU, along with initiation of active immunization. If TIG is unavailable, human IVIG can also be used; it contains variable titers of tetanus antitoxin but a minimal dose of 200–400 mg/kg is suggested for tetanus prophylaxis [
in: Pickering L.K. Baker C.J. Kimberlin D.W. Red Book: 2009 Report of the Committee on infectious diseases. 28th edition. American Academy of Pediatrics,
Elk Grove Village (IL)2009: 655-660
Clostridium difficile infection of the gastrointestinal tract is usually associated with antibiotic-associated diarrhea, often with pseudomembranous colitis and sometimes toxic megacolon [
]. Infection generally leads to an antibody response to the toxin, and most individuals older than 2 years have such antibodies. High levels of these antibodies acquired after colonization may result in the asymptomatic carrier state [
Some patients with symptomatic infection, many of whom are immunodeficient or immunosuppressed, develop antibiotic-resistant diarrhea; many have low or absent IgG antibodies to toxin A. Such patients may respond to IVIG given 300 to 500 mg/kg every 1 to 3 weeks [
Botulism is a severe paralytic poisoning resulting for the ingestion or absorption of neurotoxin or spores of Clostridium botulinum. Several variants are recognized: food poisoning from ingestion of contaminated canned food, wound botulism from a contaminated soft-tissue infection, inhalational botulism among individuals working with the toxin or in a bioterrorist event, infantile botulism (see next section), and adult-type infant botulism in adults with preexisting gastrointestinal disease [
American Academy of Pediatrics Botulism and infant botulism.
in: Pickering L.K. Baker C.J. Kimberlin D.W. Red Book: 2009 Report of the Committee on infectious diseases. 28th edition. American Academy of Pediatrics,
Elk Grove Village (IL)2009: 259-262
]. Sensitivity testing must be conducted before their use. Antitoxin to all 3 types is given unless the toxin type is known. Additional doses may be needed in severe wound botulism. Antitoxin can also by used prophylactically in individuals known to have ingested contaminated food. It is not used for infantile botulism.
Infantile botulism (Clostridium botulinum)
This severe paralytic disorder of infants results from the ingestion of Clostridium botulinum spores in baby formulae or food, resulting in slow onset of constipation, abdominal bloating, poor feeding, and respiratory paralysis [
American Academy of Pediatrics Botulism and infant botulism.
in: Pickering L.K. Baker C.J. Kimberlin D.W. Red Book: 2009 Report of the Committee on infectious diseases. 28th edition. American Academy of Pediatrics,
Elk Grove Village (IL)2009: 259-262
]. Such infants must be hospitalized for prolonged periods for tube feeding and respiratory support, often for as long as 6 to 9 months. Human IV botulism immune globulin is available for treatment of infantile botulism [
]. Despite its high cost ($50,000 per vial) it is cost-effective because of the shortened hospital stay needed.
Gas gangrene (Clostridium perfringens)
There is no antitoxin for gas gangrene.
Bacterial respiratory infections
Respiratory infections with Streptoccocci, Streptococcus pneumonia, Haemophilus influenzae, and Neisseria meningitides are reduced in immunodeficient patients receiving immunoglobulin therapy. These patients include young infants with poor antibody responses to polysaccharide antigens, patients infected with the human immunodeficiency virus (HIV), and patients with primary antibody immunodeficiencies. Before antibiotics, immune serum or animal serum was used as therapy for severe bacterial infection [
Thus regular use of IVIG in antibody-deficient patients in doses of 400 to 600 mg/kg every 3 to 4 weeks or an equivalent amount given subcutaneously decreases the frequency and severity of otitis and other respiratory tract infections [
Prophylactic intravenous immunoglobulin in HIV-infected children with CD4+ counts of 0.20 × 109/L or more: effect on viral, opportunistic, and bacterial infections.
National Institute of Child Health and Human Development (NICHHD) Intravenous Immunoglobulin Study Group Intravenous immune globulin for the prevention of bacterial infections in children with symptomatic human immunodeficiency virus infection.
]. Newborns with transplacental antibody and patients on IVIG rarely develop streptococcal illnesses. Equine antitoxin was used with some success in the treatment of erysipelas and scarlet fever in the 1920s and 1930s [
]. Streptococcal pyrogenic exotoxins types A, B, and C and mitogenic factor elaborated by certain strains of streptococci may be responsible for these complications. These exotoxins are potent superantigens that activate certain T lymphocytes directly, leading to synthesis and/or release of multiple cytokines with resultant shock, fever, and organ failure.
IVIG contains neutralizing antibodies to these antigens of varying titers from batch to batch [
Different preparations of intravenous immunoglobulin vary in their efficacy to neutralize streptococcal superantigens: implications for treatment of streptococcal toxic shock syndrome.
]. Despite this variability IVIG is recommended, in addition to antibiotics, in the management of these infections, not only to neutralize pyrogenic toxins but to dampen cytokine storm and release [
]. Large doses of IVIG are recommended (eg, 1–2 g/kg over several days).
Staphylococcal infections
Staphylococcal infections are ubiquitous and of varying severity, ranging from superficial skin infections to deep-seated cellulitis, osteomyelitis, and overwhelming shock [
American Academy of Pediatrics Staphylococcal infections.
in: Pickering L.K. Baker C.J. Kimberlin D.W. Red Book: 2009 Report of the Committee on infectious diseases. 28th edition. American Academy of Pediatrics,
Elk Grove Village (IL)2009: 601-615
]. This syndrome results from release of the toxic shock syndrome toxin-1, a potent superantigen that initiates the release of multiple cytokines and a clinical picture of rapidly progressive fever, shock, and organ failure. Most authorities recommend a high dose of IVIG to neutralize the toxin and dampen cytokine storm [
American Academy of Pediatrics Staphylococcal infections.
in: Pickering L.K. Baker C.J. Kimberlin D.W. Red Book: 2009 Report of the Committee on infectious diseases. 28th edition. American Academy of Pediatrics,
Elk Grove Village (IL)2009: 601-615
A second situation in which IVIG may be of value is in neonatal staphylococcal infection, usually coagulase-negative Staphylococcus epidermidis. This is the most common cause of sepsis in premature infants and is aggravated in part by the use of catheters and central lines [
Newborns, particularly premature newborns with birth weight less than 2000 g are potential candidates for immunoglobulin therapy in view of the frequency and severity of infections. All newborns have low levels of IgM and IgA, and, if premature, a deficiency of transplacental maternal IgG, the deficiency of which is proportional to the degree of immaturity [
]. Premature infants also have defects in antibody synthesis, complement levels, opsonic activity, neutrophil mobilization and killing, and cellular immune responses [
Accordingly several studies sought to determine the value of IGIV in the prevention or early treatment of infection in premature infants. These studies differ in terms of entry criteria, immunoglobulin dose and duration, and end points (eg, type and severity of infection, survival). Meta-analyses of prospective, randomized, placebo-controlled prevention studies suggest a slight reduction (3%) in the frequency of sepsis but no difference in mortality, length of nursery stay, or other complications of prematurity [
By contrast meta-analysis of 6 controlled studies for the treatment of proven sepsis, involving 262 premature infants, showed that IGIV therapy reduced mortality from 20% to 11%, a significant difference [
]. There was a suggestive benefit for infants with suspected sepsis also. Infants with neutropenia may particularly benefit.
Because a common cause of neonatal sepsis is Staphylococcus epidermidis, a hyperimmune staphylococcal IVIG may be of particular benefit in the prevention of neonatal sepsis. Two recent studies of IGIV from either immunized donors (Altastaph) [
Multicenter study to assess safety and efficacy of INH-A21, a donor-selected human staphylococcal immunoglobulin, for prevention of nosocomial infections in very low birth weight infants.
] did not show a significantly decreased incidence of infection. Studies of monoclonal antibodies to staphylococcal antigens are in progress.
Thus the 1990 National Institutes of Health consensus statement that IGIV should not be given routinely to infants of low birth weight but that it may be of value in selected premature newborns with proven or suspected infection remains valid [
Patients undergoing severe stress associated with trauma, extensive surgery, or intensive care have profound exposure to and susceptibility to infection, usually as a result of enteric gram-negative infections [
Polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: a systematic review and meta-analysis.
] reviewed 14 randomized trials of IGIV and found suggestive benefit in terms of length of stay in the intensive care unit (ICU) and mortality. Similar studies in pediatric patients in the ICU have not been performed.
Despite the lack of controlled trials, IGIV is often used in critically ill patients, particularly neutropenic patients, because of possible benefit and rare side effects.
Viral Diseases
Although many viral diseases are prevented by immunoglobulin, just a few are amenable to antibody therapy, as presented in Table 2. This section focuses on some viral diseases in which antibodies can be used in therapy.
Vaccinia and smallpox (variola)
Although smallpox (variola) has been eradicated from the world since 1977, immunization with live vaccinia virus (cowpox virus) is still used by the military and by certain laboratory personnel working with vaccinia [
]. Further, smallpox is a potential bioterrorism weapon so a supply of vaccinia immune globulin (VIG) is being stockpiled by the US Government for complications of smallpox vaccine and for a response to biological warfare.
] used immune globulin from vaccinated individuals (VIG) to prevent the spread in a 1953 outbreak of smallpox in Madras, India. He also showed that VIG could be used to treat the not infrequent complications of smallpox vaccine including vaccinia eczematum, generalized vaccinia, autoinoculation, and prevention of spread to high-risk individuals exposed to a recently vaccinated individual.
VIG, both for IV and intramuscular (IM) use, is prepared from vaccinated donors and is commercially available. The usual dose is 100 mg/kg [
American Academy of Pediatrics Smallpox (variola).
in: Pickering L.K. Baker C.J. Kimberlin D.W. Red Book: 2009 Report of the Committee on infectious diseases. 28th edition. American Academy of Pediatrics,
Elk Grove Village (IL)2009: 596-598
Parvovirus is a DNA virus that causes fifth disease (slapped cheek syndrome, a common exanthem of childhood that usually provides lifelong immunity to subsequent exposure [
in: Mandell G.L. Bennett J.E. Doling R. Mandell, Douglas and Bennett’s principles and practice of infectious diseases. 5th edition. Churchill Livingstone,
Philadelphia2000: 1685-1693
]). Parvovirus infects erythroid progenitors (its receptor is the common red cell P antigen) to cause red cell aplasia in patients with congenital or acquired immunodeficiencies including HIV, immunosuppressed organ transplant recipients, and patients with sickle cell disease [
in: Mandell G.L. Bennett J.E. Doling R. Mandell, Douglas and Bennett’s principles and practice of infectious diseases. 5th edition. Churchill Livingstone,
Philadelphia2000: 1685-1693
IGIV contains neutralizing antibody to parvovirus such that prolonged high-dose therapy can eradicate the infection. Parvovirus infection during pregnancy can also cause fetal hydrops [
in: Pickering L.K. Baker C.J. Kimberlin D.W. Red Book: 2009 Report of the Committee on infectious diseases. 28th edition. American Academy of Pediatrics,
Elk Grove Village (IL)2009: 491-494
in: Pickering L.K. Baker C.J. Kimberlin D.W. Red Book: 2009 Report of the Committee on infectious diseases. 28th edition. American Academy of Pediatrics,
Elk Grove Village (IL)2009: 491-494
The IVIG dose needed to eradicate parvovirus in not established but is large (1–2 g/kg) and should be repeated until the virus is eradicated as indicated by serum polymerase chain reaction analysis [
Antibodies to cytomegalovirus (CMV) either in the form of hyperimmune IV CMV immune globulin (CMVIG-Cytogam) or regular IGIV have been used for more than a decade to prevent CMV infection in recipients of bone marrow and solid organ transplant [
]. CMVIG is prepared from donors with high anti-CMV titers but regular IGIV also contains CMV antibodies at lower titers. Testing of donor and recipient for CMV infection, the use of CMV antibody-negative blood donors, and the use of antiviral drugs have greatly reduced the indications for CMV antibody [
Comparison of combined prophylaxis of cytomegalovirus hyperimmune globulin plus ganciclovir versus cytomegalovirus hyperimmune globulin alone in high-risk heart transplant recipients.
CMVIG may also be of value for in utero CMV infection; infusions of CMVIG were given intraperitoneally at 28 and 29 weeks to a CMV-infected fetus, with possible benefit [
] gave 31 pregnant women with primary CMV infection CMVIG during pregnancy; some women received additional CMVIG into the amniotic sac or umbilical cord. Only one woman gave birth to an infant with CMV infection compared with CMV infection in 7 of 14 infants of control women who did not receive antibody therapy. These data are encouraging but are not from well-controlled studies.
Thus the use of CMVIG in recipients of organ transplant, severe CMV infections, or in utero CMV infections is unproved but of suggestive therapeutic benefit.
Herpes simplex
Transplacental maternal antibody has a proven preventive effect in herpes simplex virus (HSV) infection in the newborn period: mothers with a reactivated herpex infection (ie, preexisting infection) during delivery are 10-fold less likely to transmit HSV to their newborn infants during vaginal delivery than are mothers with primary HSV infection acquired during late pregnancy [
in: Pickering L.K. Baker C.J. Kimberlin D.W. Red Book: 2009 Report of the Committee on infectious diseases. 28th edition. American Academy of Pediatrics,
Elk Grove Village (IL)2009: 363-373
] used IVIG to prevent recurrent genital HSV infection with suggestive benefit. The value of HSV monoclonal antibody or IVIG is being evaluated for treatment of disseminated neonatal disease.
Epstein-Barr virus infection
Epstein-Barr virus (EBV) antibodies are present in variable titers in IVIG, particularly in CMVIG, because donors with high titers of CMV often have high titers of EBV. A few patients with posttransplant EBV-induced lymphoproliferative syndrome or hepatitis have been treated successfully with a combination of IGIV or CMVIG, antiviral therapy and interferon-α [
The effect of intravenous immunoglobulin and interferon-alpha on Epstein-Barr virus-induced lymphoproliferative disorder in a liver transplant recipient.
]. Similar results have been achieved in EBV infection in X-linked lymphoproliferative syndrome: such patients have a hereditary predisposition to overwhelming EBV infection [
]. The commercial product VariZIG is used for the prevention or modification of susceptible high-risk immunodeficient or immunosuppressed children exposed to chickenpox or shingles. It is also used in susceptible women during late pregnancy, newborn infants whose mother develops chickenpox perinatally, and exposed premature infants of less than 28 weeks’ gestation. It is not of benefit in established chickenpox or zoster infection [
American Academy of Pediatrics Varicella-zoster infections.
in: Pickering L.K. Baker C.J. Kimberlin D.W. Red Book: 2009 Report of the Committee on infectious diseases. 28th edition. American Academy of Pediatrics,
Elk Grove Village (IL)2009: 714-727
Experimental studies on passive immunization against poliomyelitis: I. Protection with human gamma globulin against intramuscular inoculation and combined passive and active immunization.
]. Immunodeficient individuals are susceptible to chronic enteroviral encephalitis, usually echovirus or coxsackievirus or less commonly, attenuated poliovirus vaccine strains [
Successful treatment of echovirus meningoencephalitis in sex-linked agammaglobulinaemia by intrathecal and intravenous injection of high titer gammaglobulin.
]. Regular doses of IGIV given to antibody-deficient patients have markedly reduced the frequency of enterovirus encephalitis in these patients. Attenuated poliovirus has been replaced in many countries by inactivated (Salk) vaccine.
High-dose IVIG (sufficient to increase the serum IgG levels to 1000 mg/mL) has been used successfully in immunodeficient patients with enteroviral encephalomyelitis [
Successful treatment of echovirus meningoencephalitis in sex-linked agammaglobulinaemia by intrathecal and intravenous injection of high titer gammaglobulin.
Successful treatment of echovirus meningoencephalitis in sex-linked agammaglobulinaemia by intrathecal and intravenous injection of high titer gammaglobulin.
]. Not all IVIG-treated patients are cured: some may have viral strains for which the IVIG has no neutralizing antibody. For these instances typing of the cerebrospinal fluid and treatment with selective IVIG units with antibodies to the infecting serotype may be necessary. Antiviral therapy with pleconoril has also been used [
]. Unless the titer in the IVIG is known, large doses are recommended.
Hepatitis B immune globulin in recipients of liver transplant
An increasingly important use of hyperimmune hepatitis B immune globulin (HBIG) is to prevent hepatitis B recurrence in hepatitis B-seropositive recipients of liver transplant, many of whom are transplanted because of complications of hepatitis B [
Such recurrences can be reduced significantly by giving large doses of HBIG for a prolonged period beginning at the time of transplantation and continuing indefinitely after transplantation [
]. Antiviral agents such as lamivudine are also given simultaneously. The dose of HBIG after transplantation is varied so as to maintain a continuous serum anti-HbS titer. Hepatitis B vaccine can also be given to induce active immunity.
The 2 types of HBIG available include the 16% IGIM used for prophylaxis in newborns of hepatic B-positive mothers and for unimmunized exposed susceptibles and a 5% HBIG for IV use in liver transplantation. The use of the latter adds a considerable cost to liver transplantation. The University of California at Los Angeles Medical Center spends $500,000 per year on HBIG, nearly all for the liver transplant program.
A hyperimmune hepatitis C immune globulin for hepatitis C liver transplantation is also under study. Monoclonal antibodies to hepatitis B and C are under development.
Regional viral infections
West Nile fever
West Nile fever, caused by the West Nile virus, is common in many tropical regions where Culex mosquitoes are endemic. It has spread to Europe and the United States, and can also be transmitted by infected blood and organ transplantation. Several case reports and animal studies suggest that IVIG prepared from seropositive donors modifies the severity and mortality [
Ebola virus, a filivirus, causes severe and often fatal hemorrhagic fever in tropical Africa. There is no effective antiviral agent. Goat hyperimmune serum protected guinea pigs from experimental infection if given within 72 hours of exposure. This product was used for emergency prophylaxis in 4 patients exposed by a laboratory accident. Only one developed mild infection [
]. Other animal antisera have been developed, as have monoclonal antibodies.
Tick-borne encephalitis
Tick-borne encephalitis caused by a flavivirus is endemic in central Europe. A vaccine is available as is a hyperimmune immune globulin. A combination has been also used [
Vaccination against tick-borne encephalitis (TBE): influence of simultaneous application of TBE immunoglobulin on seroconversion and rate of adverse events.
] found that immune plasma given before the ninth day of illness reduced mortality to 1% among 91 patients given immune plasma compared with 16.5% mortality among 97 patient given normal plasma.
Severe acute respiratory distress syndrome
Convalescent plasma and IVIG have been used in the treatment of severe acute respiratory distress syndrome caused by a corona virus. Studies were inconclusive [
Antibody is a time-honored way to prevent viral infection after exposure, and has a crucial role in the treatment of bacterial diseases associated with toxin production. It is also of value in prevention of certain viral infections as well as in the treatment of parvovius, enterovirus infection, and certain regional viral infections.
Immunoglobulins in primary immunodeficiencies
Polyclonal immunoglobulin, now used in scores of diverse disorders [
Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology.
Intravenous immunoglobulin utilization in the Canadian Atlantic provinces: a report of the Atlantic Collaborative Intravenous Immune Globulin Utilization Working Group.
] reported a child with agammaglobulinemia and initiated the first use of repeat injections of immunoglobulin as replacement therapy. In his report γ-globulin fractionated from human plasma was administered subcutaneously to an 8-year-old boy who had no known γ-globulin in a serum protein electorophoresis. This child had multiple infections, including 19 episodes of septicemia, which were ameliorated by chronic treatment with the immunoglobulin. This experience represented the dawn of immunoglobulin therapy for primary immunodeficiency and defined its use in a disease for which no therapeutic alterative was available.
Since then, the study of primary immunodeficiency has expanded markedly. There are now more than 140 distinct diagnoses, most of which have defects of humoral immunity [
Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee.
]. Approximately 1 in 2000 people are living with a primary immunodeficiency in the United States, of whom greater than 50% have an antibody deficiency potentially requiring immunoglobulin replacement therapy [
]. Treatment with immunoglobulin remains the best therapeutic option for most of these patients.
Primary Antibody Deficiencies
Characteristics of antibody immunodeficiencies appropriate for replacement therapy are presented in Table 3. The clearest indications for immunoglobulin therapy are those associated with an absence of B cells (category I). These patients are unable to make antibodies or immunoglobulin I. Examples include agammaglobulinemia and certain types of severe combined immunodeficiency. Several gene defects may be responsible for these illnesses [
The next category (II) of patients needing immunoglobulin are those who have B cells but cannot make IgG and generate specific IgG antibodies. Because IgG represents the major defense of humoral immunity against infection, these patients also require immunoglobulin replacement therapy. This diagnostic category includes the hyper IgM syndrome (HIGM) and common variable immunodeficiency (CVID). HIGM is caused by several specific gene mutations [
]. As in patients in category I, continuous and uninterrupted replacement therapy with immunoglobulin is warranted. If the diagnosis is confirmed molecularly, immunoglobulin therapy must be continued. In a few cases, it may be clinically appropriate to stop immunoglobulin therapy once during a lifetime to determine if the defect is fixed [
in: Mandel G. Bennett J.E. Donin R. Principles and practice of infectious diseases. 6th edition. Elsevier/Churchill Livingston,
Philadelphia2005: 3618-3624
]. This strategy should not be repeated if the single trial indicates a persistent deficit. If a trial off immunoglobulin therapy is considered, this should be performed in late spring or summer, when respiratory infections are less prevalent.
A third diagnostic category (III) of antibody deficiencies is those associated with qualitative defects in humoral immunity [
]. These patients have B cells and produce normal quantities of IgG but the quality of IgG is diminished. These individuals are unable to respond appropriately to specific antigenic challenges such as vaccinations or infections. This category includes those with specific antibody deficiency with normal immunoglobulins [
]. Diagnosis is made after documentation of an ineffective vaccination response, a failed humoral response to an infection, or a specific molecular/genetic diagnosis linked to this category [
A fourth category (IV) includes patients with lower than expected levels of IgG but who are able to mount effective antibody responses. This category forms a subset of individuals referred to as having “isolated hypogammaglobulinemia” when only the IgG level is low. Although hypogammaglobulinemia can be a component of many immunologic defects, in isolated hypogammaglobulinemia antibody quality is adequate, with normal responses to vaccination or infection.
Because the normal age-specific ranges of IgG define the lower limit at the 2.5th percentile, one of 40 individuals has low levels of IgG. The question becomes, when there is no deficit of antibody quality, is isolated hypogammaglobulinemia clinically a problem? It is also important to discern when hypogammaglobulinemia represents a primary versus a secondary problem with increased loss of IgG. Examples of the latter include draining chylothorax [
]. In these individuals, the hypogammaglobulinemia is less likely to cause a problem because antibody synthesis is intact and often accelerated.
In patients with primary hypogammaglobulinemia, the level of IgG that is associated with a definitive risk for infection is not defined, especially when antibody quality is intact [
]. Some insurance companies recommend replacement therapy for patients who have an IgG level less than 400 mg/dL and a history of recurrent infection. Although that situation may be reasonable, questions still exist about how to manage the patient recognized as having primary hypogammaglobulinemia with low IgG levels (ie, <150) but no history of infection.
Diagnostic examples include transient hypogammaglobulinemia of infancy (THI) [
]. The former diagnosis is established in retrospect, as the IgG level normalizes with age. Thus, in select cases of THI immunoglobulin replacement may be considered as a temporizing measure. However, primary hypogammaglobulinemia remains a difficult diagnostic and therapeutic dilemma.
Other patients (a fifth diagnostic category [V]) have a deficiency of one of the 3 major IgG subclasses, IgG1, IgG2, or IgG3. IgG4 deficiency is common and should not be considered an abnormality [
Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology.
]. Although a deficiency of one of the major IgG subclasses indicates some immunologic deviation, most of these patients have a normal total IgG level, intact responses to specific antigens, and are not candidates for immunoglobulin replacement therapy. Those with impaired antibody specificity do not fall in to this category, but into the third category. However, even without impairment in antibody quality, immunoglobulin replacement in some patients in a deficiency subclass does reduce the incidence of infections [
]. Nevertheless, most insurers in the United States have additional criteria for justifying therapy in patients with IgG in deficiency subclasses.
A final diagnostic category is patients with recurrent infection who do not have hypogammaglobulinemia subclass deficiency or deficits of antibody quality. Thus, they have infectious susceptibility without evidence of identifiable immune abnormality. The infectious burden in these individuals can be high and most certainly has an explanation, so nonhumoral diagnoses should be aggressively sought. There are also patients an explanation of whose infectious susceptibility presently evades clinical science. immunoglobulin replacement therapy has been considered in these individuals under certain circumstances.
Immunoglobulin Preparations for Antibody Immunodeficiencies
]. This strategy was necessary because the immunoglobulin preparations were not purified to the degree required for IV administration. In the early 1970s, immunoglobulin preparations with low quantities of immunoglobulin aggregates were developed for IV administration. IVIG and IGIV have numerous advantages, including achieving high peak and trough IgG levels and convenient monthly dosing regimens. Although limited studies have compared IVIG with IMIG, the IV route has become the preferred route of immunoglobulin administration worldwide [
Seven IVIG preparations are currently approved by the US Food and Drug Administration (FDA) for replacement therapy in primary immunodeficiency (Table 4). Each has been studied in a licensing trial in patients with primary immunodeficiency and found to be safe and effective. The primary end point in most of these clinical trials has been the prevention of serious bacterial infection compared with the expected frequency of such infections before diagnosis [
] first patient mentioned earlier. The early diagnosis and treatment of primary immunodeficiency with immunoglobulin products has reduced morbidity and mortality and considerable savings of health care expenditures [
All IVIG products are purified from human plasma pools under strict manufacturing guidelines. Although each manufacturer has its own process there are more similarities than differences in the various methods. All processes remove non-IgG impurities and IgG aggregates and add stabilizers to prevent in vitro aggregate formation. Despite these efforts, adverse reactions during IVIG administration are not uncommon [
]. All immunoglobulin manufacturers have robust measures to screen donors and to inactivate blood-borne pathogens; the safety of immunoglobulin preparations in the last decade has been superb [
]. This situation can lead to confusion about which IVIG to administer to which patient.
In general, most IVIG products are tolerated by most patients. The characteristics of the individual IVIG preparations, as outlined in Table 2, may help in selecting the best product for each patient. They differ as to concentration, stabilizers, sugar content, IgA content, sodium content, and osmality. The volume of individual vials, storage requirements, need to reconstitute a lyophilized product before use, local availability, and price are also variable. Many patients may tolerate one product more effectively than another. Thus, when a patient tolerates a particular immunoglobulin product it is advisable to continue with that product whenever possible [
Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology.
Three other preparations of immunoglobulin are approved by the US FDA (Table 5). One is approved for IM administration and two for SC administration. Few patients receive their immunoglobulin by the IM route.
Table 5Other immunoglobulin products for replacement therapy in primary immunodeficiency available in the United States in 2010
]. Subcutaneous immunoglobulin (SCIG) is usually given in the abdominal wall or thigh with a thin bored needle and an infusion pump, delivered over several hours. Although its initial use in the United States was limited, the SC route gained popularity in Europe; extensive clinical experience indicated that it was equivalent to IVIG therapy [
]. A crossover trial with IVIG and a US FDA licensing trial showed that SCIG was equivalent to IVIG in preventing infection in primary immunodeficiency [
]. Another is eliminating the need for IV access or indwelling IV access devices. The most serious disadvantage is the need for more frequent administration (at least weekly) to administer sufficient immunoglobulin [
]. Another disadvantage is less frequent physician encounters because most SCIG infusions are given at home by caretakers or home infusion companies.
Dose and Administration of IVIG and SCIG
The dose and frequency of immunoglobulin therapy is a complex topic and draws on both evidence- and experience-based sources. These recommendations are presented in a several reviews and consensus statements [
Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology.
]. The recommendations include starting doses of 400 to 600 mg/kg/mo. After several months this dose can be altered depending on the trough level and the clinical response. Patients vary as to their requirement to maintain reasonable resistance to infection [
SCIG is typically used after the patient has been on IVIG for several months. The weekly SCIG dose is usually one-fourth of the previous monthly IVIG dose. Some immunoglobulin-naive patients are started on immunoglobulin therapy with SCIG so the number of initial doses may need to be increased.
The amount of SCIG given at a single site for an adult is usually 20 mL of the 16% solution (ie, 3.2 g). More than one site can be used simultaneously to deliver the target dose. This procedure has been facilitated by the availability of special tubing, needle sets, catheters, and pumps. Infusion site reactions are not uncommon but are rarely severe [
IVIG is usually administered monthly and SCIG is usually administered weekly, but other schedules are often used. These schedules include shorter or longer intervals between infusions of IVIG to achieve a satisfactory clinical response. SCIG can be given biweekly, or divided into more frequent injections, even small daily doses. The latter is generally self-administered at home, well tolerated, and preferred by some patients because of the small daily dose needed [
Quality of life and health-care resource utilization among children with primary immunodeficiency receiving home treatment with subcutaneous human immunoglobulin.
Trough levels of immunoglobulin achieved must be considered. Several studies have correlated resistance to infection with specific IgG trough levels. Targeting a specific trough level may be feasible for patients with agammaglobulinemia who have a profound deficiency of IgG [
The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia. A randomized, double-blind, multicenter crossover trial.
Comparison of the efficacy of IGIV-C, 10% (caprylate/chromatography) and IGIV-SD, 10% as replacement therapy in primary immune deficiency. A randomized double-blind trial.
Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology.
]. These recommendations may not be appropriate in other disorders in which baseline IgG levels and antibody titers are variable; in these cases the clinical response must be considered.
Summary of Immunoglobulin Use in Primary Immunodeficiency
Polyclonal immunoglobulin is essential therapy for the primary antibody immunodeficiency diseases. The different disorders in which immunoglobulin therapy are used are reviewed. Several immunoglobulin products are available for their treatment; they have similar therapeutic properties but there are individual differences among the available products. immunoglobulin can be given either intravenously (IVIG) or subcutaneously (SCIG). Dosage, frequency of infusions, achieved trough levels, and advantages and disadvantages of IVIG and SCIG are discussed.
IVIG in autoimmune and inflammatory diseases
The early 1980s witnessed an increase in the use of IVIG as an immunomodulator for inflammatory and autoimmune disorders. More than 70% of the IVIG prescribed is for patients with autoimmune and inflammatory diseases, despite the fact that IVIG is approved for just a handful of indications (Box 1). In the late 1990s, this situation led to an IVIG shortage, compromising those patients who depend on IgG replacement therapy to correct their underlying antibody deficiency.
In 2006, the American Academy of Allergy, Asthma and Immunology’s Committee on Primary Immunodeficiency evaluated the use of IVIG for multiple disorders. The strength of the evidence for a beneficial effect and the basis for this recommendation were classified (Box 2). This section reviews the use of IVIG for the autoimmune and inflammatory conditions in this report (Box 3), in the context of a review of the mechanisms of action of IVIG in these conditions.
Prevention of acute humoral rejection in renal transplants (Ib-A)
Treatment of acute humoral rejection in renal transplants (III-C)
Pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS) (IIb-B)
Delayed pressure urticaria (IIb-B)
Chronic urticaria (III-C)
Acute myocarditis (III-C)
Autoimmune blistering diseases (III-C)
Autoimmune liver disease (III-D)
Prevention of pregnancy loss in a subset of women (repeat second-trimester loss) with spontaneous recurrent abortions (Ia-A)
•
Unlikely to be beneficial:
Nonsteroid-dependent asthma (Ib-A)
Prevention of chronic GVHD after bone marrow transplantation (Ib-A)
Chronic fatigue syndrome (Ib-A)
Atopic dermatitis (IIa-B)
Autism (III-C)
The multiple effects of IVIG on the innate and adaptive immune system are illustrated in Fig. 1.
Fig. 1Multiple effects of IVIG on the innate and adaptive immune system.
(Adapted from Tha-In T, Bayry J, Metselaar HJ, et al. Modulation of the cellular immune system by intravenous immunoglobulin. Trends Immunol 2008;29:613; with permission.)
] observed that antibody-deficient patients receiving IVIG who also had ITP had a marked increase in platelet count after IVIG infusions. Subsequently, these investigators examined the therapeutic effects of IVIG in children with a primary diagnosis of ITP; they used high-dose IVIG (400 mg/kg) for 4 consecutive days. The investigators reported a dramatic increase in platelet count within hours of the administration of IVIG. In some patients, the increase in platelet count was sustained; in others, repeat IVIG treatments were necessary.
Fc Receptor Blockade
Box 3 presents the indications for IVIG in autoimmune cytopenias as well its likely benefit. Several hypotheses have been proposed to explain the rapid increase in platelet count (or other antibody-coated cells) after IVIG administration. The most accepted hypothesis is that high-dose IVIG induces an Fc receptor blockade of reticuloendothelial cells in the liver and spleen, preventing them from removing antibody-sensitized cells.
] provided evidence for this hypothesis when they infused Fcγ fragments in children with ITP, and showed an increase in platelet count after the infusion. The Fc receptor blockade theory may account for the rapid increase in platelet count after the IVIG infusion, but not for the long-term benefits of IVIG. Thus additional mechanisms have been sought.
Fc Receptor Modulation
One such mechanism, supported by animal studies, is that IVIG stimulates inhibitory FcγRIIB receptors found on a variety of cell types including B cells that in turn inhibit antibody and immune function [
] identified distinct motifs in the IVIG that have a propensity to engage and activate the FcγRIIB inhibitor receptor that inhibits antibody synthesis. These distinct properties were attributed to the carbohydrate moiety in the IVIG molecule, representing about 5% of the total IgG molecule. More than 30 different covalently attached carbohydrate glycans in the IgG molecule have been identified. Glycosylation of the IgG is essential for binding to all Fcγ receptors. The important glycan moiety in the IgG molecule is attached to the asparagine (Asn297) in the second domain of the constant region of the IgG molecule.
Using a K/BxN serum-induced arthritis model in mice, Kaneko [
] showed that IgG at 1 g/kg inhibited the inflammatory arthritic process. Deglycosylated or neuraminidase-treated IVIGs were unable to inhibit this inflammation. Kaneko then showed that IVIG enriched for the sialylated glycan moiety had comparable inhibitory effects on the inflammatory process at one-tenth of the dosage used with intact IVIG. This investigator showed that this inhibitory activity resided in the IgG Fc fragment, and was dependent on FcγRIIB expression on effector macrophages.
] have engineered a recombinant/sialylated human IgG1 Fc protein that had the same immune modulating activity as native IVIG. These investigators showed that the action of sialylated Fc in the rheumatoid arthritis mouse model is mediated through the interaction of sialylated Fc with the SIGN-R1 receptor on macrophages [
]. The investigators propose that the interaction between sialylated Fc and SIGN-R1 produces an antiinflammatory state that upregulates inhibitory FcγRIIB receptors on effector cells, making these cells more resistant to triggering by immune complexes. They suggest that DC-SIGN, the human homolog of SIGN-R1, has a comparable role for the antiinflammatory effects of IgG Fc fragments.
] suggested that the administration of high-dose IVIG augments the catabolism of endogenous serum IgG. IgG catabolism occurs through a process by which the IgG molecule binds to a specialized Fc receptor found on endothelial cells (eg, FcRn), which protects the IgG molecule from normal catabolism and its removal from the plasma. This process accounts for the long serum IgG half-life (21 days). High-dose IVIG saturates the FcRn receptor, resulting in the accelerated catabolism of autoantibodies [
Accelerated autoantibody clearance by intravenous immunoglobulin therapy: studies in experimental models to determine the magnitude and time course of the effect.
] have supporting data in a rat model of immune thrombocytopenia using monoclonal antibodies.
Presence of Antiidiotypic Antibodies
The uses of IVIG in several autoimmune inflammatory neuropathies are presented in Box 3. The FDA has recently approved the use of IVIG in chronic inflammatory demyelinating polyneuropathy. This table also shows the evidence-based efficacy of IVIG in rheumatic disorders. Aside from the mechanisms involving the FcγRIIB inhibitory receptor and the accelerated catabolism of autoimmune antibodies through the FcRn receptor, it has also been proposed that the administration of IVIG can regulate autoreactive B cells by restoring the idiotypic-antiidiotypic network.
Other autoimmune diseases may be associated with a deficiency of these antiidiotypic antibodies, which are believed to regulate the production and activity of these autoantibodies (Box 4). Kazatchkine and colleagues [
] showed that F(ab′)2 fragments prepared from IVIG could bind to several autoantibodies (eg, antifactor VIII, antithyroglobulin, anti-DNA, antiintrinsic factor, neutrophil cytoplasmic antigens), and thus lead to increased catabolism of these autoimmune antibodies and prevent them from inducing tissue injury [
]. These investigators postulated that IVIG may work, at least in part, in certain autoimmune diseases by neutralizing the functional activity of various autoantibodies or inhibiting their binding to their respective autoantigens [
Intravenous and standard immune serum globulin preparations interfere with uptake of 125I-C3 onto sensitized erythrocytes and inhibit hemolytic complement activity.
] showed that high concentrations of IgG inhibit the uptake of C3 on antibody-sensitized erythrocytes. Thus, any inflammatory or autoimmune process that involves a C3b-or C4b-dependent process could be modulated by IVIG therapy. This situation is best exemplified in patients with dermatomyositis in whom the disease is mediated by activation of C3 and deposition of the membrane attack complex on the endomysial capillaries [
As shown in Box 3, IVIG is used in many other inflammatory diseases. However, the evidence-based data for several of these diseases are not so strong as some of the autoimmune disorders discussed earlier. Nevertheless, one inflammatory disease in which IVIG may be beneficial is toxic epidermal necrolysis or Stevens-Johnson syndrome. Patients with toxic epidermal necrolysis have high levels of serum-soluble Fas ligand that bind to Fas receptors on keratinocytes to induce apoptosis (cell death). Viard and colleagues [
] showed that the anti-Fas antibodies in IVIG block the interaction of Fas ligand with Fas receptors on the keratinocytes, preventing destruction of the epithelium.
Inhibition of Neutrophil Adhesion
IVIG contains antibodies to several cell-surface molecules [
] including antibodies to a 10-peptide sequence containing the (Arg-Gly-Asp) motif that is expressed on cell surfaces and matrix proteins that are part of the integrin adhesion system. IVIG inhibits the adhesion of B cells to fibronectin and inhibits platelet aggregation [
Intravenous immune globulin prevents venular vaso-occlusion in sickle cell mice by inhibiting leukocyte adhesion and the interactions between sickle erythrocytes and adherent leukocytes.
] investigated the effect of IVIG on a mouse model of sickle cell acute vasoocclusive crisis, in which the adhesion of sickled red blood cells to leukocytes causes the vasoocclusive disease. In this model, high-dose IVIG given after the onset of a crisis resulted in improved blood flow and prolonged survival. These investigators showed that IVIG reverses acute vasoocclusive crisis in sickle cell mice by inhibiting neutrophil adhesion to the capillary endothelial cells.
Summary of IVIG Use in Inflammatory/Autoimmune Disorders
The various mechanisms of the antiinflammatory and immunomodulatory properties of IVIG are reviewed. The first use of IVIG was in the treatment of immune thrombocytopenia, presumably because of Fc receptor blockade. Other mechanisms are reviewed as well as the evidence for the value of IVIG in multiple disorders. IVIG may have yet undiscovered immunomodulating properties on both the innate and adaptive immune systems. Future advances will include a better understanding of its mechanisms of action and modification of the IgG molecule to enhance its immunomodulating properties.
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